CA3174816A1 - Compositions for promoting cellular hydration - Google Patents
Compositions for promoting cellular hydration Download PDFInfo
- Publication number
- CA3174816A1 CA3174816A1 CA3174816A CA3174816A CA3174816A1 CA 3174816 A1 CA3174816 A1 CA 3174816A1 CA 3174816 A CA3174816 A CA 3174816A CA 3174816 A CA3174816 A CA 3174816A CA 3174816 A1 CA3174816 A1 CA 3174816A1
- Authority
- CA
- Canada
- Prior art keywords
- complex
- cyclodextrin
- water
- multicellular organism
- composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 138
- 230000036571 hydration Effects 0.000 title claims abstract description 101
- 238000006703 hydration reaction Methods 0.000 title claims abstract description 101
- 230000001413 cellular effect Effects 0.000 title claims abstract description 93
- 230000001737 promoting effect Effects 0.000 title abstract description 9
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 231
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 99
- 150000001875 compounds Chemical class 0.000 claims abstract description 96
- 235000013361 beverage Nutrition 0.000 claims abstract description 66
- 150000001720 carbohydrates Chemical class 0.000 claims abstract description 52
- 230000001965 increasing effect Effects 0.000 claims abstract description 51
- 239000007788 liquid Substances 0.000 claims abstract description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 256
- 210000004027 cell Anatomy 0.000 claims description 45
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 40
- 235000014852 L-arginine Nutrition 0.000 claims description 39
- 229930064664 L-arginine Natural products 0.000 claims description 39
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 34
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims description 32
- 102000010637 Aquaporins Human genes 0.000 claims description 29
- 238000012360 testing method Methods 0.000 claims description 29
- 230000003993 interaction Effects 0.000 claims description 28
- 210000000287 oocyte Anatomy 0.000 claims description 28
- 229960003512 nicotinic acid Drugs 0.000 claims description 26
- 239000011664 nicotinic acid Substances 0.000 claims description 26
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 claims description 22
- 235000001968 nicotinic acid Nutrition 0.000 claims description 21
- 108010063290 Aquaporins Proteins 0.000 claims description 19
- -1 coenzymeQ10 Chemical compound 0.000 claims description 19
- 241000244206 Nematoda Species 0.000 claims description 18
- 230000003834 intracellular effect Effects 0.000 claims description 18
- 235000001014 amino acid Nutrition 0.000 claims description 15
- 150000001413 amino acids Chemical class 0.000 claims description 15
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 claims description 12
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 11
- 235000012754 curcumin Nutrition 0.000 claims description 11
- 229940109262 curcumin Drugs 0.000 claims description 11
- 239000004148 curcumin Substances 0.000 claims description 11
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 claims description 11
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 claims description 10
- CVSVTCORWBXHQV-UHFFFAOYSA-N creatine Chemical compound NC(=[NH2+])N(C)CC([O-])=O CVSVTCORWBXHQV-UHFFFAOYSA-N 0.000 claims description 10
- ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 claims description 10
- GZIFEOYASATJEH-VHFRWLAGSA-N δ-tocopherol Chemical compound OC1=CC(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 GZIFEOYASATJEH-VHFRWLAGSA-N 0.000 claims description 10
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 claims description 8
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 7
- 239000011575 calcium Substances 0.000 claims description 7
- 229910052791 calcium Inorganic materials 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- 229910019142 PO4 Inorganic materials 0.000 claims description 6
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 claims description 6
- 241000269368 Xenopus laevis Species 0.000 claims description 6
- 239000003792 electrolyte Substances 0.000 claims description 6
- 230000037406 food intake Effects 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
- 239000010452 phosphate Substances 0.000 claims description 6
- 235000013824 polyphenols Nutrition 0.000 claims description 6
- 229960003080 taurine Drugs 0.000 claims description 6
- 235000019157 thiamine Nutrition 0.000 claims description 6
- 229960003495 thiamine Drugs 0.000 claims description 6
- 239000011721 thiamine Substances 0.000 claims description 6
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 claims description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 5
- GZIFEOYASATJEH-UHFFFAOYSA-N D-delta tocopherol Natural products OC1=CC(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 GZIFEOYASATJEH-UHFFFAOYSA-N 0.000 claims description 5
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 claims description 5
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 claims description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 5
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 5
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 claims description 5
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 claims description 5
- MUYJSOCNDLUHPJ-UHFFFAOYSA-N bishydrocurcumin Natural products C1=C(O)C(OC)=CC(CCC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 MUYJSOCNDLUHPJ-UHFFFAOYSA-N 0.000 claims description 5
- 229960001948 caffeine Drugs 0.000 claims description 5
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 claims description 5
- 229960002173 citrulline Drugs 0.000 claims description 5
- 235000013477 citrulline Nutrition 0.000 claims description 5
- 229960003624 creatine Drugs 0.000 claims description 5
- 239000006046 creatine Substances 0.000 claims description 5
- 235000010389 delta-tocopherol Nutrition 0.000 claims description 5
- MUYJSOCNDLUHPJ-XVNBXDOJSA-N dihydrocurcumin Chemical compound C1=C(O)C(OC)=CC(CCC(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 MUYJSOCNDLUHPJ-XVNBXDOJSA-N 0.000 claims description 5
- BWHPKBOLJFNCPW-UHFFFAOYSA-N dihydrocurcumin Natural products C1=C(O)C(OC)=CC(CCC(=O)C=C(O)C=CC=2C=C(OC)C(O)=CC=2)=C1 BWHPKBOLJFNCPW-UHFFFAOYSA-N 0.000 claims description 5
- 239000011777 magnesium Substances 0.000 claims description 5
- 229910052749 magnesium Inorganic materials 0.000 claims description 5
- 150000008442 polyphenolic compounds Chemical class 0.000 claims description 5
- 239000011591 potassium Substances 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- 235000021283 resveratrol Nutrition 0.000 claims description 5
- 229940016667 resveratrol Drugs 0.000 claims description 5
- 239000002446 δ-tocopherol Substances 0.000 claims description 5
- 235000011752 Inga laurina Nutrition 0.000 claims description 4
- 244000048298 Inga vera Species 0.000 claims description 4
- 238000000034 method Methods 0.000 abstract description 54
- 230000010534 mechanism of action Effects 0.000 abstract description 7
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 87
- 229940097362 cyclodextrins Drugs 0.000 description 68
- 230000000694 effects Effects 0.000 description 52
- 235000014633 carbohydrates Nutrition 0.000 description 48
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 43
- 239000012528 membrane Substances 0.000 description 42
- 150000002632 lipids Chemical class 0.000 description 41
- 239000000654 additive Substances 0.000 description 38
- 102000004169 proteins and genes Human genes 0.000 description 31
- 108090000623 proteins and genes Proteins 0.000 description 31
- 241001465754 Metazoa Species 0.000 description 29
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 28
- 229960003966 nicotinamide Drugs 0.000 description 27
- 239000011570 nicotinamide Substances 0.000 description 27
- 239000000126 substance Substances 0.000 description 27
- 230000000996 additive effect Effects 0.000 description 26
- 235000005152 nicotinamide Nutrition 0.000 description 25
- 239000000243 solution Substances 0.000 description 25
- 229920000856 Amylose Polymers 0.000 description 21
- 230000007423 decrease Effects 0.000 description 18
- 108010052285 Membrane Proteins Proteins 0.000 description 17
- 239000007864 aqueous solution Substances 0.000 description 17
- 238000012856 packing Methods 0.000 description 16
- 235000018102 proteins Nutrition 0.000 description 16
- 230000007226 seed germination Effects 0.000 description 16
- 239000008213 purified water Substances 0.000 description 15
- 230000004853 protein function Effects 0.000 description 14
- 230000004083 survival effect Effects 0.000 description 14
- 229940024606 amino acid Drugs 0.000 description 13
- 150000003904 phospholipids Chemical class 0.000 description 13
- 239000004475 Arginine Substances 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 12
- 235000015097 nutrients Nutrition 0.000 description 12
- 239000000232 Lipid Bilayer Substances 0.000 description 11
- 241000209140 Triticum Species 0.000 description 11
- 235000021307 Triticum Nutrition 0.000 description 11
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 11
- 239000000796 flavoring agent Substances 0.000 description 11
- 235000019634 flavors Nutrition 0.000 description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 11
- 235000002639 sodium chloride Nutrition 0.000 description 11
- 239000008399 tap water Substances 0.000 description 11
- 235000020679 tap water Nutrition 0.000 description 11
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 10
- 235000009697 arginine Nutrition 0.000 description 10
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000001228 spectrum Methods 0.000 description 10
- 239000001116 FEMA 4028 Substances 0.000 description 9
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 9
- 229960004853 betadex Drugs 0.000 description 9
- 235000012000 cholesterol Nutrition 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 9
- 229940088594 vitamin Drugs 0.000 description 9
- 229930003231 vitamin Natural products 0.000 description 9
- 235000013343 vitamin Nutrition 0.000 description 9
- 239000011782 vitamin Substances 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000012867 bioactive agent Substances 0.000 description 8
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 8
- 238000009826 distribution Methods 0.000 description 8
- 230000035784 germination Effects 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000011324 bead Substances 0.000 description 7
- 210000000170 cell membrane Anatomy 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 239000000470 constituent Substances 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 7
- 230000000670 limiting effect Effects 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000000975 bioactive effect Effects 0.000 description 6
- 239000003086 colorant Substances 0.000 description 6
- 238000009792 diffusion process Methods 0.000 description 6
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 6
- 230000002209 hydrophobic effect Effects 0.000 description 6
- 235000016709 nutrition Nutrition 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 230000032258 transport Effects 0.000 description 6
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 5
- 150000001841 cholesterols Chemical class 0.000 description 5
- 239000008139 complexing agent Substances 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 238000000329 molecular dynamics simulation Methods 0.000 description 5
- 230000003204 osmotic effect Effects 0.000 description 5
- 230000035699 permeability Effects 0.000 description 5
- 238000004088 simulation Methods 0.000 description 5
- 229940083542 sodium Drugs 0.000 description 5
- 241000894007 species Species 0.000 description 5
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 5
- 239000003643 water by type Substances 0.000 description 5
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 241000269370 Xenopus <genus> Species 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000003915 cell function Effects 0.000 description 4
- 238000001739 density measurement Methods 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- 235000001727 glucose Nutrition 0.000 description 4
- 150000002339 glycosphingolipids Chemical class 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 230000000050 nutritive effect Effects 0.000 description 4
- 229920001542 oligosaccharide Polymers 0.000 description 4
- 235000021317 phosphate Nutrition 0.000 description 4
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 4
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 108090001004 Aquaporin 1 Proteins 0.000 description 3
- 229920001353 Dextrin Polymers 0.000 description 3
- 239000004375 Dextrin Substances 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 238000004566 IR spectroscopy Methods 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 108091006629 SLC13A2 Proteins 0.000 description 3
- 229920004482 WACKER® Polymers 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 239000012736 aqueous medium Substances 0.000 description 3
- 235000010323 ascorbic acid Nutrition 0.000 description 3
- 239000011668 ascorbic acid Substances 0.000 description 3
- 229960005070 ascorbic acid Drugs 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 235000016614 betalains Nutrition 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000008827 biological function Effects 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- 230000009918 complex formation Effects 0.000 description 3
- 230000001186 cumulative effect Effects 0.000 description 3
- 235000019425 dextrin Nutrition 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 235000019152 folic acid Nutrition 0.000 description 3
- 239000011724 folic acid Substances 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- HPIGCVXMBGOWTF-UHFFFAOYSA-N isomaltol Chemical compound CC(=O)C=1OC=CC=1O HPIGCVXMBGOWTF-UHFFFAOYSA-N 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 229940091250 magnesium supplement Drugs 0.000 description 3
- 150000002482 oligosaccharides Chemical class 0.000 description 3
- 210000003463 organelle Anatomy 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 229960003975 potassium Drugs 0.000 description 3
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 238000007614 solvation Methods 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- 238000011179 visual inspection Methods 0.000 description 3
- 150000003722 vitamin derivatives Chemical class 0.000 description 3
- XPCTZQVDEJYUGT-UHFFFAOYSA-N 3-hydroxy-2-methyl-4-pyrone Chemical compound CC=1OC=CC(=O)C=1O XPCTZQVDEJYUGT-UHFFFAOYSA-N 0.000 description 2
- 102000004888 Aquaporin 1 Human genes 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 235000021537 Beetroot Nutrition 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 125000002353 D-glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 101000684063 Homo sapiens Aquaporin-1 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 102000004310 Ion Channels Human genes 0.000 description 2
- 108090000862 Ion Channels Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 229920002774 Maltodextrin Polymers 0.000 description 2
- 239000005913 Maltodextrin Substances 0.000 description 2
- DATAGRPVKZEWHA-YFKPBYRVSA-N N(5)-ethyl-L-glutamine Chemical compound CCNC(=O)CC[C@H]([NH3+])C([O-])=O DATAGRPVKZEWHA-YFKPBYRVSA-N 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- HLCFGWHYROZGBI-JJKGCWMISA-M Potassium gluconate Chemical compound [K+].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O HLCFGWHYROZGBI-JJKGCWMISA-M 0.000 description 2
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 2
- 229960004373 acetylcholine Drugs 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229930014669 anthocyanidin Natural products 0.000 description 2
- 235000008758 anthocyanidins Nutrition 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000004900 autophagic degradation Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 235000011148 calcium chloride Nutrition 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Chemical compound [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 125000003636 chemical group Chemical group 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000007705 chemical test Methods 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- VEVZSMAEJFVWIL-UHFFFAOYSA-O cyanidin cation Chemical compound [O+]=1C2=CC(O)=CC(O)=C2C=C(O)C=1C1=CC=C(O)C(O)=C1 VEVZSMAEJFVWIL-UHFFFAOYSA-O 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 235000013601 eggs Nutrition 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- NWKFECICNXDNOQ-UHFFFAOYSA-N flavylium Chemical compound C1=CC=CC=C1C1=CC=C(C=CC=C2)C2=[O+]1 NWKFECICNXDNOQ-UHFFFAOYSA-N 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 2
- MLFHJEHSLIIPHL-UHFFFAOYSA-N isoamyl acetate Chemical compound CC(C)CCOC(C)=O MLFHJEHSLIIPHL-UHFFFAOYSA-N 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 229940035034 maltodextrin Drugs 0.000 description 2
- KZMACGJDUUWFCH-UHFFFAOYSA-O malvidin Chemical compound COC1=C(O)C(OC)=CC(C=2C(=CC=3C(O)=CC(O)=CC=3[O+]=2)O)=C1 KZMACGJDUUWFCH-UHFFFAOYSA-O 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- VAMXMNNIEUEQDV-UHFFFAOYSA-N methyl anthranilate Chemical compound COC(=O)C1=CC=CC=C1N VAMXMNNIEUEQDV-UHFFFAOYSA-N 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 230000035764 nutrition Effects 0.000 description 2
- FGPPDYNPZTUNIU-UHFFFAOYSA-N pentyl pentanoate Chemical compound CCCCCOC(=O)CCCC FGPPDYNPZTUNIU-UHFFFAOYSA-N 0.000 description 2
- 239000002831 pharmacologic agent Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 230000008092 positive effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 230000003068 static effect Effects 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 210000000225 synapse Anatomy 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- GZXOHHPYODFEGO-UHFFFAOYSA-N triglycine sulfate Chemical compound NCC(O)=O.NCC(O)=O.NCC(O)=O.OS(O)(=O)=O GZXOHHPYODFEGO-UHFFFAOYSA-N 0.000 description 2
- 238000010865 video microscopy Methods 0.000 description 2
- 229940011671 vitamin b6 Drugs 0.000 description 2
- UEPVWRDHSPMIAZ-IZTHOABVSA-N (1e,4z,6e)-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1-(4-hydroxyphenyl)hepta-1,4,6-trien-3-one Chemical compound C1=C(O)C(OC)=CC(\C=C\C(\O)=C\C(=O)\C=C\C=2C=CC(O)=CC=2)=C1 UEPVWRDHSPMIAZ-IZTHOABVSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- SERLAGPUMNYUCK-DCUALPFSSA-N 1-O-alpha-D-glucopyranosyl-D-mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SERLAGPUMNYUCK-DCUALPFSSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- AEQDJSLRWYMAQI-UHFFFAOYSA-N 2,3,9,10-tetramethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline Chemical compound C1CN2CC(C(=C(OC)C=C3)OC)=C3CC2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 description 1
- PVXPPJIGRGXGCY-DJHAAKORSA-N 6-O-alpha-D-glucopyranosyl-alpha-D-fructofuranose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@](O)(CO)O1 PVXPPJIGRGXGCY-DJHAAKORSA-N 0.000 description 1
- RMZIOVJHUJAAEY-UHFFFAOYSA-N Allyl butyrate Chemical compound CCCC(=O)OCC=C RMZIOVJHUJAAEY-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 244000144730 Amygdalus persica Species 0.000 description 1
- 244000099147 Ananas comosus Species 0.000 description 1
- 235000007119 Ananas comosus Nutrition 0.000 description 1
- 241000269350 Anura Species 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- VGONRPRFJVEJKB-UHFFFAOYSA-O Aurantinidin Chemical compound C1=CC(O)=CC=C1C(C(=C1)O)=[O+]C2=C1C(O)=C(O)C(O)=C2 VGONRPRFJVEJKB-UHFFFAOYSA-O 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 239000004135 Bone phosphate Substances 0.000 description 1
- AYWJSCLAAPJZEF-UHFFFAOYSA-N Butyl 3-methylbutanoate Chemical compound CCCCOC(=O)CC(C)C AYWJSCLAAPJZEF-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- 241000244203 Caenorhabditis elegans Species 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 235000019743 Choline chloride Nutrition 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 244000163122 Curcuma domestica Species 0.000 description 1
- 235000003392 Curcuma domestica Nutrition 0.000 description 1
- HJTVQHVGMGKONQ-LUZURFALSA-N Curcumin II Natural products C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=CC(O)=CC=2)=C1 HJTVQHVGMGKONQ-LUZURFALSA-N 0.000 description 1
- WHGYBXFWUBPSRW-UHFFFAOYSA-N Cycloheptaamylose Natural products O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO WHGYBXFWUBPSRW-UHFFFAOYSA-N 0.000 description 1
- 108010025880 Cyclomaltodextrin glucanotransferase Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 150000000779 D-glucopyranoses Chemical class 0.000 description 1
- UNXHWFMMPAWVPI-QWWZWVQMSA-N D-threitol Chemical compound OC[C@@H](O)[C@H](O)CO UNXHWFMMPAWVPI-QWWZWVQMSA-N 0.000 description 1
- ODBLHEXUDAPZAU-ZAFYKAAXSA-N D-threo-isocitric acid Chemical compound OC(=O)[C@H](O)[C@@H](C(O)=O)CC(O)=O ODBLHEXUDAPZAU-ZAFYKAAXSA-N 0.000 description 1
- JPIJQSOTBSSVTP-GBXIJSLDSA-N D-threonic acid Chemical compound OC[C@@H](O)[C@H](O)C(O)=O JPIJQSOTBSSVTP-GBXIJSLDSA-N 0.000 description 1
- GCPYCNBGGPHOBD-UHFFFAOYSA-N Delphinidin Natural products OC1=Cc2c(O)cc(O)cc2OC1=C3C=C(O)C(=O)C(=C3)O GCPYCNBGGPHOBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical group CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- YIKYNHJUKRTCJL-UHFFFAOYSA-N Ethyl maltol Chemical compound CCC=1OC=CC(=O)C=1O YIKYNHJUKRTCJL-UHFFFAOYSA-N 0.000 description 1
- ICMAFTSLXCXHRK-UHFFFAOYSA-N Ethyl pentanoate Chemical compound CCCCC(=O)OCC ICMAFTSLXCXHRK-UHFFFAOYSA-N 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000713585 Homo sapiens Tubulin beta-4A chain Proteins 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- RJIIQBYZGJSODH-QWRGUYRKSA-N Indicaxanthin Chemical compound C1=C(C(O)=O)N[C@H](C(=O)O)C\C1=C/C=[N+]/1[C@H](C([O-])=O)CCC\1 RJIIQBYZGJSODH-QWRGUYRKSA-N 0.000 description 1
- SOKRTWSMFOUWEI-UHFFFAOYSA-N Indicaxanthin Natural products OC(=O)C1CC(=C/CN2CCCC2C(=O)O)C=C(N1)C(=O)O SOKRTWSMFOUWEI-UHFFFAOYSA-N 0.000 description 1
- ODBLHEXUDAPZAU-FONMRSAGSA-N Isocitric acid Natural products OC(=O)[C@@H](O)[C@H](C(O)=O)CC(O)=O ODBLHEXUDAPZAU-FONMRSAGSA-N 0.000 description 1
- JGFBQFKZKSSODQ-UHFFFAOYSA-N Isothiocyanatocyclopropane Chemical compound S=C=NC1CC1 JGFBQFKZKSSODQ-UHFFFAOYSA-N 0.000 description 1
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- HYMLWHLQFGRFIY-UHFFFAOYSA-N Maltol Natural products CC1OC=CC(=O)C1=O HYMLWHLQFGRFIY-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 241000220225 Malus Species 0.000 description 1
- 235000011430 Malus pumila Nutrition 0.000 description 1
- 235000015103 Malus silvestris Nutrition 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 102000003939 Membrane transport proteins Human genes 0.000 description 1
- 108090000301 Membrane transport proteins Proteins 0.000 description 1
- 229930189464 Miraxanthin Natural products 0.000 description 1
- 240000008790 Musa x paradisiaca Species 0.000 description 1
- 235000018290 Musa x paradisiaca Nutrition 0.000 description 1
- PQNASZJZHFPQLE-UHFFFAOYSA-N N(6)-methyllysine Chemical compound CNCCCCC(N)C(O)=O PQNASZJZHFPQLE-UHFFFAOYSA-N 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 238000004497 NIR spectroscopy Methods 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 238000002940 Newton-Raphson method Methods 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 244000018633 Prunus armeniaca Species 0.000 description 1
- 235000009827 Prunus armeniaca Nutrition 0.000 description 1
- 235000006040 Prunus persica var persica Nutrition 0.000 description 1
- 235000014443 Pyrus communis Nutrition 0.000 description 1
- 240000001987 Pyrus communis Species 0.000 description 1
- 240000001890 Ribes hudsonianum Species 0.000 description 1
- 235000016954 Ribes hudsonianum Nutrition 0.000 description 1
- 235000001466 Ribes nigrum Nutrition 0.000 description 1
- 235000011034 Rubus glaucus Nutrition 0.000 description 1
- 244000235659 Rubus idaeus Species 0.000 description 1
- 235000009122 Rubus idaeus Nutrition 0.000 description 1
- 108010077895 Sarcosine Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- 208000002463 Sveinsson chorioretinal atrophy Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 102100036788 Tubulin beta-4A chain Human genes 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 244000290333 Vanilla fragrans Species 0.000 description 1
- 235000009499 Vanilla fragrans Nutrition 0.000 description 1
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 229930003761 Vitamin B9 Natural products 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical class C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229940037003 alum Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 1
- 229960002576 amiloride Drugs 0.000 description 1
- 229940124277 aminobutyric acid Drugs 0.000 description 1
- 229940072049 amyl acetate Drugs 0.000 description 1
- PGMYKACGEOXYJE-UHFFFAOYSA-N anhydrous amyl acetate Natural products CCCCCOC(C)=O PGMYKACGEOXYJE-UHFFFAOYSA-N 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 235000010208 anthocyanin Nutrition 0.000 description 1
- 239000004410 anthocyanin Substances 0.000 description 1
- 229930002877 anthocyanin Natural products 0.000 description 1
- 150000004636 anthocyanins Chemical class 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 125000003289 ascorbyl group Chemical group [H]O[C@@]([H])(C([H])([H])O*)[C@@]1([H])OC(=O)C(O*)=C1O* 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 238000005102 attenuated total reflection Methods 0.000 description 1
- 229930015058 aurantinidin Natural products 0.000 description 1
- 230000005033 autophagosome formation Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 235000000842 betacyanins Nutrition 0.000 description 1
- 235000016411 betaxanthins Nutrition 0.000 description 1
- 230000007321 biological mechanism Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- JYTVKRNTTALBBZ-UHFFFAOYSA-N bis demethoxycurcumin Natural products C1=CC(O)=CC=C1C=CC(=O)CC(=O)C=CC1=CC=CC(O)=C1 JYTVKRNTTALBBZ-UHFFFAOYSA-N 0.000 description 1
- PREBVFJICNPEKM-YDWXAUTNSA-N bisdemethoxycurcumin Chemical compound C1=CC(O)=CC=C1\C=C\C(=O)CC(=O)\C=C\C1=CC=C(O)C=C1 PREBVFJICNPEKM-YDWXAUTNSA-N 0.000 description 1
- 235000012206 bottled water Nutrition 0.000 description 1
- PWLNAUNEAKQYLH-UHFFFAOYSA-N butyric acid octyl ester Natural products CCCCCCCCOC(=O)CCC PWLNAUNEAKQYLH-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000005251 capillar electrophoresis Methods 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 229960004203 carnitine Drugs 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 241000902900 cellular organisms Species 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical compound [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 description 1
- 229960003178 choline chloride Drugs 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000000882 contact lens solution Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 235000003373 curcuma longa Nutrition 0.000 description 1
- 235000007336 cyanidin Nutrition 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 229960003067 cystine Drugs 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 235000007242 delphinidin Nutrition 0.000 description 1
- FFNDMZIBVDSQFI-UHFFFAOYSA-N delphinidin chloride Chemical compound [Cl-].[O+]=1C2=CC(O)=CC(O)=C2C=C(O)C=1C1=CC(O)=C(O)C(O)=C1 FFNDMZIBVDSQFI-UHFFFAOYSA-N 0.000 description 1
- NMRUIRRIQNAQEB-UHFFFAOYSA-N demethoxycurcumin Natural products OC(=CC(C=CC1=CC(=C(C=C1)O)OC)=O)C=CC1=CC=C(C=C1)O NMRUIRRIQNAQEB-UHFFFAOYSA-N 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- YXAKCQIIROBKOP-UHFFFAOYSA-N di-p-hydroxycinnamoylmethane Natural products C=1C=C(O)C=CC=1C=CC(=O)C=C(O)C=CC1=CC=C(O)C=C1 YXAKCQIIROBKOP-UHFFFAOYSA-N 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 239000007911 effervescent powder Substances 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 229940093503 ethyl maltol Drugs 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 229930003487 europinidin Natural products 0.000 description 1
- XJXMPIWHBIOJSH-UHFFFAOYSA-O europinidin Chemical compound OC1=C(O)C(OC)=CC(C=2C(=CC=3C(OC)=CC(O)=CC=3[O+]=2)O)=C1 XJXMPIWHBIOJSH-UHFFFAOYSA-O 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 150000004665 fatty acids Chemical group 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000012041 food component Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- FBPFZTCFMRRESA-GUCUJZIJSA-N galactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-GUCUJZIJSA-N 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 150000002304 glucoses Chemical class 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229960002743 glutamine Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 102000052557 human AQP1 Human genes 0.000 description 1
- 230000005660 hydrophilic surface Effects 0.000 description 1
- 230000005661 hydrophobic surface Effects 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 230000000055 hyoplipidemic effect Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 235000016241 indicaxanthin Nutrition 0.000 description 1
- CCXPAUKIWRMEET-QWRGUYRKSA-N indicaxanthin Natural products OC(=O)[C@@H]1CCCN1C=CC1=CC(=N[C@@H](C1)C(O)=O)C(O)=O CCXPAUKIWRMEET-QWRGUYRKSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910001504 inorganic chloride Inorganic materials 0.000 description 1
- 229910052816 inorganic phosphate Inorganic materials 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 230000035990 intercellular signaling Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 210000002977 intracellular fluid Anatomy 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 229940117955 isoamyl acetate Drugs 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 239000000905 isomalt Substances 0.000 description 1
- 235000010439 isomalt Nutrition 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- XCAUINMIESBTBL-UHFFFAOYSA-N lead(ii) sulfide Chemical compound [Pb]=S XCAUINMIESBTBL-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229930013978 luteolinidin Natural products 0.000 description 1
- GDNIGMNXEKGFIP-UHFFFAOYSA-O luteolinidin Chemical compound [O+]=1C2=CC(O)=CC(O)=C2C=CC=1C1=CC=C(O)C(O)=C1 GDNIGMNXEKGFIP-UHFFFAOYSA-O 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 239000001755 magnesium gluconate Substances 0.000 description 1
- 235000015778 magnesium gluconate Nutrition 0.000 description 1
- 229960003035 magnesium gluconate Drugs 0.000 description 1
- IAKLPCRFBAZVRW-XRDLMGPZSA-L magnesium;(2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanoate;hydrate Chemical compound O.[Mg+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O IAKLPCRFBAZVRW-XRDLMGPZSA-L 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 229940043353 maltol Drugs 0.000 description 1
- 235000009584 malvidin Nutrition 0.000 description 1
- 210000005171 mammalian brain Anatomy 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 230000009061 membrane transport Effects 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- 229940102398 methyl anthranilate Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004001 molecular interaction Effects 0.000 description 1
- 238000000324 molecular mechanic Methods 0.000 description 1
- 238000012900 molecular simulation Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 235000013923 monosodium glutamate Nutrition 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000002232 neuromuscular Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000006365 organism survival Effects 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000001706 oxygenating effect Effects 0.000 description 1
- 238000006385 ozonation reaction Methods 0.000 description 1
- UEPVWRDHSPMIAZ-UHFFFAOYSA-N p-hydroxycinnamoyl feruloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(O)=CC(=O)C=CC=2C=CC(O)=CC=2)=C1 UEPVWRDHSPMIAZ-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- HKUHOPQRJKPJCJ-UHFFFAOYSA-N pelargonidin Natural products OC1=Cc2c(O)cc(O)cc2OC1c1ccc(O)cc1 HKUHOPQRJKPJCJ-UHFFFAOYSA-N 0.000 description 1
- 235000006251 pelargonidin Nutrition 0.000 description 1
- YPVZJXMTXCOTJN-UHFFFAOYSA-N pelargonidin chloride Chemical compound [Cl-].C1=CC(O)=CC=C1C(C(=C1)O)=[O+]C2=C1C(O)=CC(O)=C2 YPVZJXMTXCOTJN-UHFFFAOYSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- CFNJLPHOBMVMNS-UHFFFAOYSA-N pentyl butyrate Chemical compound CCCCCOC(=O)CCC CFNJLPHOBMVMNS-UHFFFAOYSA-N 0.000 description 1
- 229930015721 peonidin Natural products 0.000 description 1
- 235000006404 peonidin Nutrition 0.000 description 1
- OGBSHLKSHNAPEW-UHFFFAOYSA-N peonidin chloride Chemical compound [Cl-].C1=C(O)C(OC)=CC(C=2C(=CC=3C(O)=CC(O)=CC=3[O+]=2)O)=C1 OGBSHLKSHNAPEW-UHFFFAOYSA-N 0.000 description 1
- 238000003359 percent control normalization Methods 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 229930015717 petunidin Natural products 0.000 description 1
- 235000006384 petunidin Nutrition 0.000 description 1
- QULMBDNPZCFSPR-UHFFFAOYSA-N petunidin chloride Chemical compound [Cl-].OC1=C(O)C(OC)=CC(C=2C(=CC=3C(O)=CC(O)=CC=3[O+]=2)O)=C1 QULMBDNPZCFSPR-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- AVTYONGGKAJVTE-OLXYHTOASA-L potassium L-tartrate Chemical compound [K+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O AVTYONGGKAJVTE-OLXYHTOASA-L 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- 239000004224 potassium gluconate Substances 0.000 description 1
- 235000013926 potassium gluconate Nutrition 0.000 description 1
- 229960003189 potassium gluconate Drugs 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000001472 potassium tartrate Substances 0.000 description 1
- 229940111695 potassium tartrate Drugs 0.000 description 1
- 235000011005 potassium tartrates Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- FCHXJFJNDJXENQ-UHFFFAOYSA-N pyridoxal hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(C=O)=C1O FCHXJFJNDJXENQ-UHFFFAOYSA-N 0.000 description 1
- 235000008160 pyridoxine Nutrition 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000001223 reverse osmosis Methods 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 229920002477 rna polymer Polymers 0.000 description 1
- 229930002286 rosinidin Natural products 0.000 description 1
- GNONHFYAESLOCB-UHFFFAOYSA-O rosinidin Chemical compound [O+]=1C2=CC(OC)=CC(O)=C2C=C(O)C=1C1=CC=C(O)C(OC)=C1 GNONHFYAESLOCB-UHFFFAOYSA-O 0.000 description 1
- 229940043230 sarcosine Drugs 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical class [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000000176 sodium gluconate Substances 0.000 description 1
- 235000012207 sodium gluconate Nutrition 0.000 description 1
- 229940005574 sodium gluconate Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- MSXHSNHNTORCAW-GGLLEASOSA-M sodium;(2s,3s,4s,5r,6s)-3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].O[C@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O MSXHSNHNTORCAW-GGLLEASOSA-M 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 229920000247 superabsorbent polymer Polymers 0.000 description 1
- 239000004583 superabsorbent polymers (SAPs) Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 230000003319 supportive effect Effects 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940026510 theanine Drugs 0.000 description 1
- ODBLHEXUDAPZAU-UHFFFAOYSA-N threo-D-isocitric acid Natural products OC(=O)C(O)C(C(O)=O)CC(O)=O ODBLHEXUDAPZAU-UHFFFAOYSA-N 0.000 description 1
- 210000001578 tight junction Anatomy 0.000 description 1
- 230000000287 tissue oxygenation Effects 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000000411 transmission spectrum Methods 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 235000013976 turmeric Nutrition 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 235000019158 vitamin B6 Nutrition 0.000 description 1
- 239000011726 vitamin B6 Substances 0.000 description 1
- 235000019159 vitamin B9 Nutrition 0.000 description 1
- 239000011727 vitamin B9 Substances 0.000 description 1
- 235000008964 vulgaxanthin Nutrition 0.000 description 1
- 229930185155 vulgaxanthin Natural products 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/52—Adding ingredients
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/20—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
- A23L29/206—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of vegetable origin
- A23L29/212—Starch; Modified starch; Starch derivatives, e.g. esters or ethers
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/175—Amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/724—Cyclodextrins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
A beverage composition promotes cellular hydration when ingested by a multicellular organism, and includes a carbohydrate clathrate component that includes cyclodextrin, in a concentration of 0.01-5% w/w. A complex-forming compound is also included in a concentration that is less than the clathrate component, and there is an aqueous liquid component, such as still and carbonated aqueous liquids. An inclusion complex is formed with at least some of the clathrate component and at least some of the complex-forming compound and the composition promotes cellular hydration of the multicellular organism when the multicellular organism ingests it. There is also a beverage composition that increases lifespan in the multicellular organism, and methods of promoting cellular hydration and increasing lifespan of the multicellular organism according to a mechanism of action.
Description
COMPOSITIONS FOR PROMOTING CELLULAR HYDRATION
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Patent Application Serial No.
16/841,631, filed April 6, 2020, which application is a continuation-in-part of U.S. Patent Application Serial No. 14/932,929, filed November 4, 2015, now U.S. Patent No. 10,610,524, which application is a continuation of U.S. Patent Application Serial NO. 12/983,234, filed December 31, 2020, now abandoned, the disclosures of which are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention generally relates to regulation of biological cell activity, particularly cell activity dependent on hydration state. A biologically active component is constructed to increase an activity of a biological cell system by increasing the hydration of one or more components of that cell system. That biologically active component may include a primary carbohydrate clathrate subcomponent that increases the H-bonded structure of water. More particularly, the present invention relates to a beverage composition comprising the biologically active component for increasing the cell hydration and consequently modifying physiological activity of multicellular organisms, including mammals. Furthermore, the present invention relates to a mechanism of action for increasing cellular hydration in multicellular organisms, including mammals.
BACKGROUND OF THE INVENTION
Water molecules interact principally through hydrogen (H)-bonding and through alignment of dipole moments. For example, bonds between neighboring water molecules are reinforced, or stabilized, by alignment of bond axes with next-adjacent water molecules. In liquid state water,
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Patent Application Serial No.
16/841,631, filed April 6, 2020, which application is a continuation-in-part of U.S. Patent Application Serial No. 14/932,929, filed November 4, 2015, now U.S. Patent No. 10,610,524, which application is a continuation of U.S. Patent Application Serial NO. 12/983,234, filed December 31, 2020, now abandoned, the disclosures of which are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention generally relates to regulation of biological cell activity, particularly cell activity dependent on hydration state. A biologically active component is constructed to increase an activity of a biological cell system by increasing the hydration of one or more components of that cell system. That biologically active component may include a primary carbohydrate clathrate subcomponent that increases the H-bonded structure of water. More particularly, the present invention relates to a beverage composition comprising the biologically active component for increasing the cell hydration and consequently modifying physiological activity of multicellular organisms, including mammals. Furthermore, the present invention relates to a mechanism of action for increasing cellular hydration in multicellular organisms, including mammals.
BACKGROUND OF THE INVENTION
Water molecules interact principally through hydrogen (H)-bonding and through alignment of dipole moments. For example, bonds between neighboring water molecules are reinforced, or stabilized, by alignment of bond axes with next-adjacent water molecules. In liquid state water,
2 such alignments propagate into the surrounding aqueous medium and establish sub-micrometer scale molecular structure.
Examples of products and methods of using cyclodextrins as clathrates to form inclusions with bioactive guest molecules to improve solubility and/or bioavailability of' pharmaceutical compounds are described in: U.S. Patent Nos. 7,115,586 and 7,202,233, and U.S.
Patent Application Publication Nos. 2004/0137625, and 2009/0227690, the complete disclosures of which are hereby incorporated by reference for all purposes.
Examples of products and methods of using products containing clathrates that bind hydrophobic biomolecules are described in U.S. Patent Nos. 6,890,549, 7,105,195, 7,166,575, 7,423,027, and 7,547,459; U.S. Patent Application Publication Nos.
2004/0161526, 2007/0116837, 2008/0299166, and 2009/0023682; Japanese Patent Application JP
60-094912;
Suzuki and Sato, "Nutritional significance of cyclodextrins: indigestibility and hypolipemic effect of a-cyclodextrin" J. Nutr. Sci. Vitaminol. (Tokyo 1985; 31:209-223); and Szejtli et al., StaerkeiStarch, 27(11), 1975, pp. 368-376, the complete disclosures of which are hereby incorporated by reference for all purposes.
U.S. Patent Application Publication No. 2009/0110746 describes chemical agents which have the property of increasing aqueous diffusivity of dissolved molecular oxygen (a) in the human body, wherein cyclodextrins may be included as secondary "carrier"
components to improve the solubility of primary pro-oxygenating agents, and wherein cyclodextrins are not contemplated as agents to directly alter aqueous diffusivity, tissue oxygenation, water structure, or cellular hydration.
Also, Park et al. (2013) describes effect of type of water on the life span extension of C.
elegans. Similarly, Gelino etal. (2016) describes longevity in C. elegans with respect to functions
Examples of products and methods of using cyclodextrins as clathrates to form inclusions with bioactive guest molecules to improve solubility and/or bioavailability of' pharmaceutical compounds are described in: U.S. Patent Nos. 7,115,586 and 7,202,233, and U.S.
Patent Application Publication Nos. 2004/0137625, and 2009/0227690, the complete disclosures of which are hereby incorporated by reference for all purposes.
Examples of products and methods of using products containing clathrates that bind hydrophobic biomolecules are described in U.S. Patent Nos. 6,890,549, 7,105,195, 7,166,575, 7,423,027, and 7,547,459; U.S. Patent Application Publication Nos.
2004/0161526, 2007/0116837, 2008/0299166, and 2009/0023682; Japanese Patent Application JP
60-094912;
Suzuki and Sato, "Nutritional significance of cyclodextrins: indigestibility and hypolipemic effect of a-cyclodextrin" J. Nutr. Sci. Vitaminol. (Tokyo 1985; 31:209-223); and Szejtli et al., StaerkeiStarch, 27(11), 1975, pp. 368-376, the complete disclosures of which are hereby incorporated by reference for all purposes.
U.S. Patent Application Publication No. 2009/0110746 describes chemical agents which have the property of increasing aqueous diffusivity of dissolved molecular oxygen (a) in the human body, wherein cyclodextrins may be included as secondary "carrier"
components to improve the solubility of primary pro-oxygenating agents, and wherein cyclodextrins are not contemplated as agents to directly alter aqueous diffusivity, tissue oxygenation, water structure, or cellular hydration.
Also, Park et al. (2013) describes effect of type of water on the life span extension of C.
elegans. Similarly, Gelino etal. (2016) describes longevity in C. elegans with respect to functions
3 for autophagy in the intestine of dietary-restricted C. elegans (also known as Caenorhabditis elegans) and water absorption.
The present invention overcomes the drawback of conventional compositions, systems and methods.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a chemical bond model of f3-cyclodextrin, a cyclic oligosacchari de having seven a[1 -4] linked glucose units.
FIG. 2 shows a structural model of cyclodextrins having an overall toroid topology.
FIG. 3 shows a cyclodextrin structural model including the disposition of glucosyl hydroxyl groups along the toroid rims FIG. 4 depicts a calculated molecular dynamic distribution of water molecules surrounding a f3-cyclodextrin molecule at 1 picosecond after initial contact.
FIG. 5 depicts the calculated molecular dynamic distribution of water molecules of FIG. 4 at 1000 picoseconds after initial contact, including a more organized open water structure.
FIG. 6 shows threshold images of the water molecule distributions shown in FIGS. 4 and 5.
FIGS. 7-10 show a comparison of NIR spectra derivatives, including particular wavelength regions, for water samples with and without dissolved cyclodextrins.
FIG. 11 shows a comparison of seed germination kinetics in water variably including a cyclodextrin, an amino acid, and a cyclodextrin/amino acid inclusion complex.
FIG. 12 shows a comparison of seed germination kinetics in water variably including a cyclodextrin, a vitamin, and a cyclodextrin/vitamin inclusion complex.
The present invention overcomes the drawback of conventional compositions, systems and methods.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a chemical bond model of f3-cyclodextrin, a cyclic oligosacchari de having seven a[1 -4] linked glucose units.
FIG. 2 shows a structural model of cyclodextrins having an overall toroid topology.
FIG. 3 shows a cyclodextrin structural model including the disposition of glucosyl hydroxyl groups along the toroid rims FIG. 4 depicts a calculated molecular dynamic distribution of water molecules surrounding a f3-cyclodextrin molecule at 1 picosecond after initial contact.
FIG. 5 depicts the calculated molecular dynamic distribution of water molecules of FIG. 4 at 1000 picoseconds after initial contact, including a more organized open water structure.
FIG. 6 shows threshold images of the water molecule distributions shown in FIGS. 4 and 5.
FIGS. 7-10 show a comparison of NIR spectra derivatives, including particular wavelength regions, for water samples with and without dissolved cyclodextrins.
FIG. 11 shows a comparison of seed germination kinetics in water variably including a cyclodextrin, an amino acid, and a cyclodextrin/amino acid inclusion complex.
FIG. 12 shows a comparison of seed germination kinetics in water variably including a cyclodextrin, a vitamin, and a cyclodextrin/vitamin inclusion complex.
4 FIG. 13 shows a comparison of seed germination rate in water variably including active components of hydration according to the present disclosure.
FIG. 14 shows a comparison of nematode longevity in media variably including cyclodextrins as an active component of hydration according to the present disclosure.
FIG. 15 shows a comparison of nematode longevity in media variably including derivatized cyclodextrins as an active component of hydration according to the present disclosure.
FIG. 16 shows a comparison of nematode longevity in media variably including cyclodextrin inclusion complexes as an active component of hydration according to the present disclosure.
FTG. 17 shows nematode mortality frequency in media with and without a cyclodextrin inclusion complex included as an active component of hydration according to the present disclosure.
FIG. 18 shows population survival curves for nematodes living in media with and without a cyclodextrin inclusion complex as an active component of hydration according to the present disclosure.
FIG. 19 shows lipid bilayer representing arrangement of phospholipids, membrane proteins, cholesterol, functional proteins etc. within the lipid bilayer.
FIG. 20 shows water paracellular transport.
FIG. 21 shows the effect of 0.1% alpha-cyclodextrin containing water versus a control (plain water with no additive).
FIG. 22a shows the effect of 0.1 % Alpha-CD, 0.1 % alpha-CD¨nicotinic acid complex, and 0.1 % alpha-CD-arginine complex on the lifespan of C. elegans.
FIG. 22b shows the effect of 0.5% of alpha-cyclodextrin and 0.05% alpha-cyclodextrin containing water versus control (plain water with no additives) on the lifespan of C. elegans.
FIG. 22c shows the effect of 0.05% of alpha-cyclodextrin-nicotinic acid complex and 0.05% of alpha-cyclodextrin-L-arginine complex, versus control (no additives in water) on the
FIG. 14 shows a comparison of nematode longevity in media variably including cyclodextrins as an active component of hydration according to the present disclosure.
FIG. 15 shows a comparison of nematode longevity in media variably including derivatized cyclodextrins as an active component of hydration according to the present disclosure.
FIG. 16 shows a comparison of nematode longevity in media variably including cyclodextrin inclusion complexes as an active component of hydration according to the present disclosure.
FTG. 17 shows nematode mortality frequency in media with and without a cyclodextrin inclusion complex included as an active component of hydration according to the present disclosure.
FIG. 18 shows population survival curves for nematodes living in media with and without a cyclodextrin inclusion complex as an active component of hydration according to the present disclosure.
FIG. 19 shows lipid bilayer representing arrangement of phospholipids, membrane proteins, cholesterol, functional proteins etc. within the lipid bilayer.
FIG. 20 shows water paracellular transport.
FIG. 21 shows the effect of 0.1% alpha-cyclodextrin containing water versus a control (plain water with no additive).
FIG. 22a shows the effect of 0.1 % Alpha-CD, 0.1 % alpha-CD¨nicotinic acid complex, and 0.1 % alpha-CD-arginine complex on the lifespan of C. elegans.
FIG. 22b shows the effect of 0.5% of alpha-cyclodextrin and 0.05% alpha-cyclodextrin containing water versus control (plain water with no additives) on the lifespan of C. elegans.
FIG. 22c shows the effect of 0.05% of alpha-cyclodextrin-nicotinic acid complex and 0.05% of alpha-cyclodextrin-L-arginine complex, versus control (no additives in water) on the
5 lifespan of C. elegans.
FIG. 23 shows human-aquaporin-expressed frog oocyte osmotic water permeability according to the present disclosure. A calibration oocyte on the right of the photo FIG. 24 shows human-aquaporin-expressed frog oocyte osmotic water permeability according to the present disclosure. The control un-swollen small oocyte is on the right of each photo FIGS. 25A and 25B show the osmotic water permeability (Pf values) of human-aquaporin-expressed frog oocytes in two-time scales according to the present disclosure;
wherein Cl: control (purified water), C2-C4: ACD 0.05%, 0.1%, 0.5%; C5-C7: ACD-nicotinic acid complex, 0.05%, 0.1%, 0.5%, C8-C10: ACD-L-arginine complex, 0.05%, 0.1%, 0.5%.
SUMMARY OF INVENTION
The present invention provides a beverage composition comprising cyclodextrin and complex-forming compound (also referred to as an agent). The cyclodextrin and the complex forming agent, generally, are present in a molar ratio of about 1:1. However, the invention includes mixtures of cyclodextrin and complex-forming agents in a range of molar ratios from 1:10 to 10:1 and, more narrowly, in a range of molar ratios of 1:1 to 10:1. There are two types of complex-forming compounds for purposes of this invention. The first type is simply referred to as complex-forming compunds are several non-limiting examples are given below in the Detailed Description section. A second type if "outer sphere" complexing agents, and non-limiting examples of these
FIG. 23 shows human-aquaporin-expressed frog oocyte osmotic water permeability according to the present disclosure. A calibration oocyte on the right of the photo FIG. 24 shows human-aquaporin-expressed frog oocyte osmotic water permeability according to the present disclosure. The control un-swollen small oocyte is on the right of each photo FIGS. 25A and 25B show the osmotic water permeability (Pf values) of human-aquaporin-expressed frog oocytes in two-time scales according to the present disclosure;
wherein Cl: control (purified water), C2-C4: ACD 0.05%, 0.1%, 0.5%; C5-C7: ACD-nicotinic acid complex, 0.05%, 0.1%, 0.5%, C8-C10: ACD-L-arginine complex, 0.05%, 0.1%, 0.5%.
SUMMARY OF INVENTION
The present invention provides a beverage composition comprising cyclodextrin and complex-forming compound (also referred to as an agent). The cyclodextrin and the complex forming agent, generally, are present in a molar ratio of about 1:1. However, the invention includes mixtures of cyclodextrin and complex-forming agents in a range of molar ratios from 1:10 to 10:1 and, more narrowly, in a range of molar ratios of 1:1 to 10:1. There are two types of complex-forming compounds for purposes of this invention. The first type is simply referred to as complex-forming compunds are several non-limiting examples are given below in the Detailed Description section. A second type if "outer sphere" complexing agents, and non-limiting examples of these
6 are also given below in the discussion of electrolytes, including both the cations and anions described in that section below. For certain complex-forming agents like arginine and niacin, the ratio could also be stated as a mass ratio, and in these cases, the mass ratio for cyclodextrin and arginine or niacin is about 10:1.
The cyclodextrin of the beverage composition is an alpha-cyclodextrin, a beta-cyclodextrin, or a gamma-cyclodextrin or combinations thereof. The complex-forming compound is selected from L-arginine, citrulline, creatine, taurine, nicotinic acid, nicotinamide, resveratrol, curcumin, thiamine, natural colorants like betalains from beetroot, flavonoids, and other compounds described below.
In an embodiment, the beverage composition comprising cyclodextrin and complex forming compound comprises: 0.05 % alpha-cyclodextrin in water, 0.05 % alpha-cyclodextrin-L-Arginine inclusion complex in water, 0.05 % alpha-cyclodextrin-nicotinamide inclusion complex in water, 0.05 % alpha-cyclodextrin-nicotinic acid (niacin) complex in water.
hi another embodiment, the cyclodextrin is present in a concentration range from 0.025 %
to 0.1%
In another embodiment, the present invention comprises gamma cyclodextrins based beverage compositions along with complex-forming compound.
In a still further embodiment, the present invention comprises beta-cyclodextrin-based compositions along with complex-forming compound. The composition comprises 0.01-0.05 % of b eta-cyclo dextrin.
As to compositions and systems, the present invention also provides a beverage composition for promoting cellular hydration on ingestion by a multi-cellular organism. The present invention also provides a beverage composition that promotes increased lifespan when
The cyclodextrin of the beverage composition is an alpha-cyclodextrin, a beta-cyclodextrin, or a gamma-cyclodextrin or combinations thereof. The complex-forming compound is selected from L-arginine, citrulline, creatine, taurine, nicotinic acid, nicotinamide, resveratrol, curcumin, thiamine, natural colorants like betalains from beetroot, flavonoids, and other compounds described below.
In an embodiment, the beverage composition comprising cyclodextrin and complex forming compound comprises: 0.05 % alpha-cyclodextrin in water, 0.05 % alpha-cyclodextrin-L-Arginine inclusion complex in water, 0.05 % alpha-cyclodextrin-nicotinamide inclusion complex in water, 0.05 % alpha-cyclodextrin-nicotinic acid (niacin) complex in water.
hi another embodiment, the cyclodextrin is present in a concentration range from 0.025 %
to 0.1%
In another embodiment, the present invention comprises gamma cyclodextrins based beverage compositions along with complex-forming compound.
In a still further embodiment, the present invention comprises beta-cyclodextrin-based compositions along with complex-forming compound. The composition comprises 0.01-0.05 % of b eta-cyclo dextrin.
As to compositions and systems, the present invention also provides a beverage composition for promoting cellular hydration on ingestion by a multi-cellular organism. The present invention also provides a beverage composition that promotes increased lifespan when
7 ingested by a multicellular organism. The present invention also provides a system that promotes cellular hydration when ingested by a multicellular organism.
As to methods, the present invention provides a method of promoting increased cellular hydration in a multicellular organism that is capable of intracellular water permeation. Another method of the invention is to promote increased cellular hydration in a multicellular organism that includes water by decreasing the density of at least some of the water in the aqueous solution.
In accord with these and other objects, the present invention provides a beverage composition comprising a carbohydrate clathrate component that includes cyclodextrins, in a concentration of 0.01-5% w/w; a complex-forming compound, in a concentration that is less than the clathrate component; an aqueous liquid component, chosen from the group consisting of still and carbonated aqueous liquids; wherein an inclusion complex is formed with at least some of the clathrate component and at least some of the complex-forming compound.
In one of the embodiments, the ratio of clathrate component to complex-forming compound is in a range from about 5:1 to about 15:1.
In a another embodiment, the present invention provides a method for increasing hydration of cell system to promote cellular hydration in a multicellular organism when the mixture is ingested, the multicellular organism containing membrane lipids, lipid packing and membrane proteins, protein structure and protein function, and membrane permeation of nutrients and water, the method comprising the step of: causing the multicellular organism to ingest an aqueous solution that contains an amount of a carbohydrate clathrate component; and changing the multicellular organism by (i) temporary disintegration of the membrane lipids, (ii) loosening of the lipid packing and membrane proteins, and (iii) altering the protein structure and protein function, collectively to enhance membrane permeation of nutrients and water.
DETAILED DESCRIPTION
Water structure is purposefully increased, or organized, by addition of one or more solutes or suitable molecular aggregates whose surfaces are capable of strongly competing with water molecules for H-bonding and/or dipole orientation. In particular, factors and agents that strengthen water molecule interactions and increase water structure thereby alter the hydration, or solvation, of a further molecular surface. Thus, a primary solution additive that increases water structure may increase hydration interactions (e.g., bonding strength and kinetics) with a molecular surface of a secondary solution component, or alternatively decrease such interactions, depending on the H-bonding surface characteristics of the secondary component.
In addition, factors that modify water structure typically change the average distance between water molecules, and may thereby increase or decrease water density.
For example, as water temperature decreases below its freezing point, H-bonding between the water molecules overcomes the kinetic energy of the water molecules, resulting in an increase in water structure that decreases the density of frozen water by approximately 9%. Similarly, in liquid state water, an increase in the strength of water H-bonding increases the average distance between water molecules, which is observed as an increase in specific volume (i.e., decrease in density). A
decrease in density of liquid water may increase the diffusivity of a dissolved solute. Thus, an aqueous additive component which decreases water density may increase the diffusivity of a co-dissolved solute.
Chaotropes, as used herein, are aqueous solute additives that disrupt hydrogen bonded networks in aqueous solutions, and thereby act to decrease water structure.
Chaotropes typically are less polar and have weaker H-bonding potentials than water molecules.
Chaotropes may preferentially bind to non-polar solutes and particles, and thereby increase solubility of a non-polar solute.
Kosmotropes, as used herein, are solutes that promote strong and extended H-bonded networks in aqueous solutions, and which thereby increase and/or stabilize the sub-micrometer scale structure of water molecule interactions. A kosmotrope having an H-bonding chemical potential greater than that of water, and/or having a dipole moment greater than that of water, may increase H-bonded networks between water molecules. Further, by strengthening hydration structure, a kosmotrope may increase hydration interactions at a molecular surface, which may include a binding site between molecules. A kosmotrope may thus be used as an aqueous solution additive to stabilize molecular interactions Further, a kosmotrope may increase the effective chemical activity of a dissolved co-solute.
An increase in the strength of H-bonding interactions between water molecules causes water to adopt a more open architecture having a lower specific density and higher specific volume. Thus, by causing a decrease in density, addition of a kosmotrope to an aqueous solution may increase a diffusivity of one or more of a dissolved co-solute species or compounds.
Increasing the diffusivity of a solute species or compound may increase its reactivity, chemical potential, effective concentration, and availability.
As discussed herein, clathrate components are amphipathic carbohydrate compounds which have external surfaces that are hydrophilic and H-bond strongly with water, and also internal surfaces that are less hydrophilic. A clathrate's internal surface may selectively bind a molecular structure which is relatively non-polar or less hydrophilic than water.
An inclusion complex, as used herein, is a chemical complex formed between two or more compounds, where a first compound (also referred to as a host) has a structure that defines a partially enclosed space into which a molecule of a second compound (also referred to as a guest) fits and binds to the first compound. The host molecule may be referred to as a clathrate and may bind the guest molecule reversibly or irreversibly.
A biological cell, as used herein, is the self-replicating functional metabolic unit of a living organism, which may live as a unicellular organism or as a sub-unit in a multicellular organism, and which comprises a lipid membrane structure containing a functional network of interacting biomolecules, such as proteins, nucleic acids, and saccharides. Biological cells include prokaryote cells, eukaryotic cells, and cells dissociated from a multi cellular organism, which may include cultured cells previously derived from a multi cellul ar organism.
A biological cell system, as used herein, is a functionally interconnected network of biological cells and/or sub-cellular elements, which may include living cells, non-living cells, cellular organelles, and/or biomolecules.
A bioactive molecule, as used herein, is a molecular compound having a functional activity in a biological cell system.
A biomolecule, as used herein, is a molecular compound that is synthesized by a biological cell. Biomolecules include compounds normally synthesized by cells, and compounds synthesized by genetically engineered cells, and chemically synthesized copies of cell-derived compounds.
A biomolecular surface, as used herein, is an outer atomic boundary of a biomolecule, which may include a biochemical interaction surface, such as a binding site.
Cellular components, as used herein, are functional elements of a biological cell, which include biomolecules, biomolecule complexes, organelles, polymeric structures, membranes and membrane-bound structures, and may further include functional pathways and/or networks, such as a sequence of molecular events.
The density of a substance is the mass per unit volume of that substance under specified conditions of temperature and pressure.
The specific volume of a substance is the volume per unit mass of the substance, which may be expressed, for example, as m3/kg. The specific volume of a substance is equivalent to the reciprocal of the density of that substance.
A biologically active component, as used herein, is a molecular substance that modifies (increases or decreases) an activity of a biological cell system.
A bioactive agent, as used herein, is a substance that when added to a biological cell system, or to a cellular component, causes a change in the biological activity of that system, or that component The bonded structure of water, as used herein, refers to the network of H-bonds that hold and organize the orientation of water molecules in liquid and solid states.
Water structure, as used herein, increases when H-bonds between water molecules at a given temperature are strengthened, and decreases when H-bonds between water molecules at a given temperature are weakened.
An interaction between cellular components, as used herein, refers to a chemical binding between biomolecular surfaces. Such interaction may include binding between two biomolecul es, such as a ligand and its specific receptor. Alternatively, such interaction may include binding between a biomolecule and an organelle, such as a cell membrane.
Extracellular signals, as used herein, are biomolecules that can modify (increase or decrease) an activity of a cell when applied to the outside of the cell. An extracellular signal may bind to a component of the cell's plasma (outer) membrane, or alternatively may pass through the plasma membrane to regulate an intracellular activity. Extracellular signals may include, but are not limited to, extracellular matrix components; cell membrane components such as glycoproteins and glyocolipids; antigens; and diffusible biomolecules such as nitric oxide.
An intracellular messenger, as used herein, is an internal component of a biological cell that has an active state, and which serves in an active state as an intermediate signal to transmit an extracell ul ar sign al to an intracellular target.
A mechanism of action, as used herein, refers to a process, which may be a step-by-step one, that takes place to achieve a certain or desired outcome.
A multi-cellular organism, as used herein, refers to an organism that consists of more than one cell, and includes organisms as complex as mammals, including animals and humans, to less complex ones such as C. elegans and other nematodes, and to as plants and other vegetation..
A pharmacological agent, as used herein, is a synthetic chemical substance that binds to and thereby alters the activity of a biomolecule or a biomolecule complex.
The present invention includes active compositions that increase an activity of a biological cell system by increasing the hydration of one or more components of that cell system.
Preferably, an active composition for modifying cellular hydration includes a primary carbohydrate clathrate component that increases the H-bonded structure of water. In some examples, the active composition preferably includes a primary carbohydrate clathrate component that increases the FT-bonded structure of water and a secondary solute compound, which may be a bioactive agent. In some examples, the active composition preferably includes an inclusion complex formed between a clathrate component and a complex-forming compound, which may be a bioactive agent.
Biological cells are multi-compartment structures, comprising chemically active water-based chambers and lipid-based membranes. The structure and activity of cells derives from highly selective chemical bonding associations between their biomolecular components, such as lipids, structural proteins, enzymatic proteins, carbohydrates, salts, nucleotides, and other metabolic and signaling biomolecules. The strength and specificity of biomolecule bonding reflects complementary chemical topologies at the bonding interface.
Hydrophilic and/or hydrophobic surfaces commonly dominate the chemical topology of biomolecular bond interfaces.
In aqueous systems, hydrophobic and hydrophilic interactions are substantially driven by competing hydration interactions with molecules of water, whose concentration exceeds 50 M.
Cellular hydration, as used herein, refers to interaction between water molecules and biomolecular components of a cellular system. Cellular hydration may be modified by changing the strength and/or kinetics of H-bon ding between water molecules and biomolecular surfaces.
An aqueous solution additive that modifies water structure may, by modifying the hydration of biomolecular binding surfaces, alter the strength, kinetics, and/or specificity of binding between cellular components. For example, a kosmotrope aqueous additive that increases water structure may alter the strength, kinetics, and/or specificity of binding between a secreted intercellular signaling factor and a cognate receptor located in the plasma membrane of a potential target cell for that factor, and hence bias the outcome of a cellular signaling network.
Clathrates that are suitable as active components of cellular hydration according to the present invention include amyloses and cyclodextrins. Amyloses are linear polysaccharides of D-glucose units. As shown in FIG. 1, cyclodextrins are macrocyclic oligosaccharides of D-glucose units linked by a(1-4) interglucose bonds. Amylose and cyclodextrin are readily prepared in large quantities from hydrolyzed starch. Cyclodextrin preparation includes enzymatic conversion, most commonly using the enzyme cyclodextrin-glycosyl transferase produced by Bacillus strains.
As shown in FIG. 2, cyclodextrins may differ by the number of glucose units included in the ring. Cyclodextrin species include a-cyclodextrin (6 units), P-cyclodextrin (7 units), 7-cyclodextrin (8 units), and 8-cyclodextrin (9 units). Parent cyclodextrins, as used herein, are natural, chemically underivatized a- [3- and 'y-cyclodextrins, having 18 (a-), 21 (1:1-) and 24 (y) free, unmodified hydroxyl groups, respectively.
As schematically shown in FIG. 3, cyclodextrins have a toroid topology, a shape which generally resembles a truncated cone, or half of an open-ended barrel.
Accordingly, a cyclodextrin may be described as including an exterior chemical surface, which includes the outer surface and the rims of the barrel, and an interior chemical surface surrounding an internal cavity (the inside of the barrel).
Cyclodextrin exterior surfaces include a high density of hydrophilic chemical groups that H-bond with water. In particular, the hydroxyl groups of the parent a-cyclodextrin, p-cyclodextrin, and 'y-cyclodextrin structures are all concentrated at the ends of the cyclodextrin barrel. More particularly, cyclodextrin hydroxyl (-OH) chemical groups are located along the barrel rims, and their orientation is sterically restricted. Hydroxyl groups at glucose position C(6), which may be called primary OH groups, point in a counter-clockwise direction with respect to the narrower open end of the cyclodextrin barrel. Hydroxyl groups at glucose position C(2), which may be called secondary hydroxyl groups, angle in a clockwise direction with respect to the wider open end of the cyclodextrin barrel.
The high density and constrained orientation of cyclodextrin hydroxyl groups creates particularly strong H-bonding surfaces at both ends of the cyclodextrin barrel. Physicochemical analysis and solvation modeling of cyclodextrins show water molecules adjacent the cyclodextrin have fixed positions and low angular (rotational) mobility. Usefully, species of cyclodextrin, which differ in barrel diameter as well as number of hydroxyl groups, also differ in the number and mobility of strongly bound water molecules.
The H-bonding activity of a cyclodextrin compound may propagate into a surrounding aqueous medium. As shown in FIGS. 4 and 5, dynamic modeling of a cyclodextrin molecule 5 introduced into a defined population of water molecules at standard temperature and pressure causes a nanosecond reorganization of water throughout the volume. FIG. 4 depicts a population distribution at one picosecond (ps) after initiating the mixing simulation;
FIG. 5 depicts a redistribution of the same population at 1000 Ps (1 nanosecond), wherein water molecules have adopted a more open structure.
10 In some examples, a cyclodextrin may function as an active component of cellular hydration through a kosmotrope activity that increases the bonded structure of water, wherein an increase in H-bonding between water molecules modifies the hydration of biomolecular surfaces, and thereby alters the strength, kinetics, and/or specificity of binding between cellular components.
In some examples, a cyclodextrin may function as an active component of cellular hydration 15 through a kosmotrope activity that increases the bonded structure of water, wherein stronger H-bonding between water molecules causes an open water structure having a lower specific density (i.e., a higher specific volume), and wherein a rate of diffusion of bioactive molecules is increased.
Such examples may include a soluble bioactive molecule such as an enzyme, enzyme substrate, nutrient, metabolite, cytokine, neurotransmitter, hormone, extracellular signal, intracellular messenger, or pharmacological agent.
An active component of cellular hydration that increases a rate of diffusion in water may regulate one of the many biological processes that are limited by the rate of change in the concentration of a bioactive component. For example, clearance of a neurotransmitter from synaptic clefts is commonly diffusion limited, including the passive dispersal of glutamate from excitatory synapses in the mammalian brain, and the active catabolism of acetylcholine at vertebrate neuromuscular synapses by the diffusion-limited enzyme acetylcholine esterase.
Similarly, the activity of electrically excitable cells, such as muscle cells, is commonly coordinated by the diffusion-limited changes in the concentration of the intracellular second messenger signal calcium.
The cellular hydration activity of a cyclodextrin may be modified, either increased or decreased, by forming an inclusion complex with a complex-forming compound.
Internal surfaces of cyclodextrins lack hydroxyl groups, are less hydrophilic than the surrounding aqueous environment, and thereby preferentially bind co-solute molecules having low hydrophilic and H-bonding potential.
Upon ingestion by an animal, carbohydrate clathrate compositions that increase the hydrogen bonding structure of interstitial and intracellular fluids may improve cellular hydration, including hydration structure at cell membrane surfaces as well as solvation of biomolecules that sub-serve healthy cell function. Improved cellular hydration may support healthy cell function by, for example, increasing the import, export, and/or diffusivity of solutes, nutrients, waste products, cytokines, metabolites, and other molecular agents supportive of cell function, differentiation, repair, growth, and survival, and by stabilizing cellular membranes in vulnerable tissues, such as muscle and nerve.
In some examples, a carbohydrate inclusion complex ingested by an animal may increase water H-bonding structure and thereby improve cellular hydration and/or diffusivity of cellular components. In some examples, a carbohydrate inclusion complex ingested by an animal may dissociate to release a free (i.e., non-complexed) cyclodextrin clathrate component that increases water hydrogen-bonding structure and thereby improves cellular hydration and/or diffusivity of cellular components. In some examples, a carbohydrate inclusion complex may increase water structure and improve cellular hydration without dissociating. In some examples, a carbohydrate inclusion complex may dissociate into a clathrate component for increasing water structure and cellular hydration, and a complex-forming compound which may further increase water-structure and/or provide other beneficial properties, such as nutrition or flavor.
The carbohydrate clathrate compositions of the present invention may be provided in various forms, including being formed into a solid powder, tablet, capsule, caplet, granule, pellet, wafer, powder, instant drink powder, effervescent powder, or effervescent tablet. Some carbohydrate clathrate compositions may also be formed as, or incorporated into, aqueous beverages or other food products. Such carbohydrate clathrate compositions may be inclusion complexes that remain reasonably stable during storage, so that the clathrate component does not dissociate from the complex-forming compound and form a stronger complex with another compound that reduces the kosmotropic activity of the complex and thereby decrease its ability to improve cellular hydration.
The present disclosure also provides methods for improving cellular hydration in an animal, such as a human. For example, some methods may include (a) preparing a beverage with a carbohydrate clathrate component and water, or by dissolving an inclusion complex formed by a carbohydrate clathrate component and a complex-forming compound capable of dissociating from carbohydrate clathrate component under physiological conditions, and (b) having the animal orally ingest the beverage, whereupon the carbohydrate clathrate component modifies the strength, extent, and kinetics of the hydrogen bonded water structure at cellular biomolecular surfaces, and 1g does so whether in an aqueous solution, or if it is in an inclusion complex, dissociates from the complex-forming compound.
Carbohydrate Clathrate Composition The carbohydrate clathrate component may include any suitable carbohydrate including, but not limited to, a-cyclodextrin, p-cyclodextrin, y-cyclodextrin, methylated ri-cyclodextrins, 2-hydroxypropylated f3-cyclodextrins, water soluble 3-cyclodextrin polymers, partially acetylated a-3-, and y- cyclodextrins, ethylated a-, (3-, and f3-cyclodextrins, carboxy-alkylated P-cyclodextrins, quaternary-ammonium salts of a-, p-, and y-cyclodextrins, an amylose (e.g., an acetylated amylose), and mixtures thereof.
In preferred embodiments, the carbohydrate clathrate may be selected based upon a kosmotrope activity that increases water structure alone or in combination with other solutes.
Preferred cyclodextrin kosmotrop es may include a¨cyclodextrin, 13¨cyclodextrin, 7¨cyclodextrin, 2-hydroxypropyl-cycl odextrins, carboxymethyl ate d- cycl odextrin s, and quatern ary-amm on i urn-cyclodextrins.
Cyclodextrin derivatives may include alkylated, hydroxyalkylated, alkoxyalkylated, acetylated, quaternary ammonium salts, carboxyalkylated, maltosylated, and glucosylated derivatives. Alkyl groups of cyclodextrin derivatives may be straight chain or branched, may have main chain lengths of one to three carbons, and may have a total of one to six, and preferably one to three carbon atoms. Some non-limiting examples of cyclodextrin derivatives may include methylated beta-cyclodextrins, 2-hydroxypropylated il-cyclodextrins, water soluble beta-cyclodextrin polymers, partially acetylated a-, 13, and/or y-cyclodextrins, ethylated a-, p-, and/or y-cyclodextrins, carboxyalkylated 13-cyclodextrins, quaternary ammonium salts of a-, 13, and/or 7-cyclodextrins, as well as mixtures of any combination of these derivatives, together or in combination with one or more cyclodextrins. An exemplary mixture of cyclodextrins may include a combination of a-, 13, and/or y-cyclodextrin in a weight ratio range of about 1:1:1 to 2:2:1, respectively. The cyclodextrin may be in a hydrate crystalline and/or amorphous form, including but not limited to the hydrate and/or amorphous forms of a-, (3, and/or 'y-cyclodextrin, and mixtures thereof.
If the carbohydrate clathrate composition is in solid form, the cyclodextrin component may be present in a concentration range of about 10-90% w/w, or about 15-70% w/w, or about 15-60%
w/w. Preferably, the cyclodextrin component may be present in a concentration range of about 10-50% w/w, or about 15-40% w/w. More preferably, the cyclodextrin component may be present in a concentration range of about 20-25% w/w.
If the carbohydrate clathrate composition is in the form of an aqueous beverage, the cyclodextrin component may be present in a concentration range of about 0.01-75% w/w, or about 0.05-50% w/w, or about 0.1-25% w/w. Preferably, the cyclodextrin component may be present in a concentration range of about 0.1-10% w/w. More preferably, the cyclodextrin component may be present in a concentration range of 0.1-5% w/w.
The carbohydrate clathrate composition may preferably include a clathrate capable of forming an inclusion complex with a variety of complex-forming compounds, such as amino acids, vitamins, flavorants, odorants, colorants, and the like. Non-exclusive examples of carbohydrate clathrate components capable of binding a complex-forming compound to form an inclusion may include a¨cyclodextrin, 13¨cyc1odextrin, 'y¨cyclodextrin, 2-hydroxypropyl-cyclodextrins, caboxymethylated-cyclo dextrins, quaternary-ammonium- cycl o dextrins, amyl o s e s, amyl o s e derivatives, or any desired mixture of these.
A cyclodextrin clathrate component may be further selected based upon its desired binding properties with selected complex-forming compounds. Non-limiting examples of acceptable cyclodextrins may include commercially available and government regulatory approved forms of a-, 13- and y-cyclodextrins. The number of glucose units determines the internal dimensions of the 5 cavity and its volume, and may determine a selectivity in forming inclusion complexes with a guest molecule.Selected complex-forming compounds, when bound to a host cyclodextrin or other host carbohydrate clathrate, may modify the physico-chemical properties of the complexed host to increase its kosmotropic activity.
If the clathrate component is in the form of an amylose component, the amylose component 10 may contain glucose units expressed as degree of polymerization (DP) in the range of DP = 10-900, and more preferably DP = 20-200, and most preferably DP = 30-80. Amylose derivatives may include, but are not limited to, acetylated amyloses. The amylose component preferably may have a structure that includes a1,4-linked D-glucopyranoses in a helical arrangement that defines a central cavity for binding hydrophobic molecules. For example, the A- and B-starch helix of V-15 amylose may include a parallel, left-handed double helix defining a central cavity. The helices of amylose inclusion complexes may be stabilized by the hydrophobic forces created by the host-guest interactions, intermolecular H-bonds between glucoses in adjacent amyloses, and intramolecular H-bonds formed by adjacent turns of the helix. See Hinrichs, W., et al., "An Amylose Antiparallel Double Helix at Atomic Resolution," Science, (1987), 238(4824): 205-208, 20 the complete disclosure of which is hereby incorporated by reference for all purposes. An amylose clathrate component maybe used to form an inclusion complex with a complex-forming compound having a low molecular weight, such as the non-limiting examples of flavorants, colorants, vitamins, amino acids, and/or amines.
If the composition containing an amylose clathrate component is in solid form, the amylose component preferably may be present in a concentration range of about 10-90%
w/w, or about 15-70% w/w, or about 15-60% w/w. More preferably, the amylose component may be present in a concentration range of about 10-50% w/w, or about 15-40% w/w. Most preferably, the amylose component may be present in a concentration range of about 20-25% w/w. If the composition containing the amylose clathrate component is in the form of an aqueous beverage, the amylose component preferably may be present in a concentration range of about 0.1-75%
w/w, or about 1-50% w/w, or about 1-25 % w/w.
Complex-forming Compound In some examples, the clathrate compositions disclosed herein may optionally contain a complex-forming compound (also referred to as an agent), which may include one or more amino acids, vitamins, flavorants, odorants, and/or other nutritional components, as well as combinations or mixtures of these agents. The carbohydrate clathrate compositions may further include one or more carbonation forming components for use in forming beverage products.
The complex-forming compound may strongly complex with the clathrate component so as to increase a kosmotropic activity and thereby influence cellular hydration. Alternatively, these agents may weakly complex with the clathrate component so as to have the capability of dissociating therefrom in order to allow a free clathrate component to increase water structure.
As used herein, it is intended that a complex-forming compound is any compound that has utility in the beverage compositions described below, regardless of how strong or weakly it complexes with the clathrate component, and even if it does not complex at all with the clathrate component. As noted above, there are two types of complex-forming compounds, a first type being simply referred to as complex-forming compounds, and a second type of "outer sphere"
complexing agents.
Non-limiting examples of amino acids suitable for forming inclusion complexes with the carbohydrate cl athrate compositions of the present disclosure may include aspartic acid, arginine, glycine, glutamic acid, proline, threonine, theanine, cysteine, cystine, alanine, valine, tyrosine, leucine, isoleucine, asparagine, serine, lysine, histidine, omithine, methionine, carnitine, aminobutyric acid (alpha-, beta-, and gamma-isomers), glutamine, hydroxyproline, taurine, norvaline, sarcosine, salts thereof, and mixtures thereof. Also included are N-alkyl Ci-C3 and N-acylated Ci-C3 derivatives of these amino acids, and mixtures of any of the amino acids or derivatives thereof. Preferred complex forming amino-acids that may he included with cyclodextrins to increase water structure and cellular hydration include L-arginine, L-lysine, N-methyl-lysine, and L-carnitine.
Non-limiting examples of vitamins may include nicotinamide (vitamin B3), niacinamide, niacin, pyridoxal hydrochloride (vitamin B6), ascorbic acid, edible ascorbyl esters, riboflavin, pyridoxine, thiamine, vitamin B9, folic acid, folate, pteroyl-L-glutamic acid, pteroyl-L-glutamate, salts thereof, and mixtures thereof. Preferred vitamins included with cyclodextrins to increase water structure and cellular hydration may include nicotinamide and niacinamide.
Non-limiting examples of flavorants may include apple, apricot, banana, grape, blackcurrant, raspberry, peach, pear, pineapple, plum, orange, and vanilla flavorants. Examples of flavorant related compounds include butyl acetate, butyl isovalerate, allyl butyrate, amyl valerate, ethyl acetate, ethyl valerate, amyl acetate, maltol, isoamyl acetate, ethyl maltol, isomaltol, diacetyl, ethyl propionate, methyl anthranilate, methyl butyrate, pentyl butyrate, and pentyl pentanoate. A
flavorant may be selected so that it weakly binds to a selected cyclodextrin component with a binding constant in the range of about 10 to 800 M-1, preferably 30 tol 50 M-1, and more preferably 40 to 100M'.
Non-limiting examples of other taste improving components may include polyol additives such as erythritol, maltitol, mannitol, sorbitol, lactitol, xylitol, inositol, isomalt, propylene glycol, glycerol (glycerine), threitol, galactitol, palatinose, reduced isomalto-oligosaccharides, reduced xylo-oligosacchari des, reduced gentio-oligosacchari des, reduced maltose syrup, and reduced glucose syrup.
Non-limiting examples of colorants may include those that are known to be more water soluble and less lipophilic. Examples of colorants with those properties are betalains, which may be from beetroot Examples of betalains include betacyanins and betaxanthins, including vulgaxanthin, miraxanthin, portulaxanthin and indicaxanthin; anthocyanidins, such as aurantinidin, cyanidin, delphinidin, europinidin, luteolinidin, pelargonidin, malvidin, peonidin, petunidin and rosinidin, as well as all corresponding anthocyanins (or glucosides) of these anthocyanidins; and turmeric type colorants including phenolic curcuminoids, such as curcumin, demethoxycurcumin and bisdemethoxycurcumin.
In addition to those described above, non-limiting examples of other complex-forming compounds may include curcumin, polyphenols, dihydrocurcumin, spermidin, L-lysin, reservatrol, coenzymeQ10, delta-tocopherol, delphindin, caffeine, and guama.
Another group of non-limiting examples of complex-forming compounds, of the outer-sphere type, are electrolytes, and specifically, magnesium, sodium, potassium, chloride, calcium, phosphate, and bicarbonate.
All of the above examples of amino acids, vitamins, flavorants and related compounds may be in appropriate salt or hydrate forms.
The complex-forming compound may be selected to form an inclusion complex with a selected clathrate component. The complex-forming compound may bind to the clathrate component as a guest molecule in the cavity of the clathrate molecule, and/or may form a so-called outer sphere complex, where the selected weak complex-forming compound binds to the clathrate molecule at a position at or around the rim(s) of the clathrate. For example, the selected weak complex-forming compound may be bound to a cyclodextrin molecule at or around the primary and/or secondary hydroxyl groups at the rims of the cyclodextrin torus. Some complex-forming compound that form an outer sphere complex with the selected cyclodextrin may reduce or prevent self-aggregation of dissolved, hydrated cyclodextrin molecules by masking intermolecular hydrogen bonds that form between two neighboring cyclodextrin molecules in water.
If the carbohydrate clathrate composition is in solid form, the complex-forming compound may be present in a concentration range of about 1-50% w/w. Preferably, the complex-forming compound may be present in a concentration range of about 1-40% w/w or about 1-25% w/w.
More preferably, the complex-forming compound may be present in a concentration range of about 5-15%w/w.
If the carbohydrate clathrate composition is in the form of an aqueous beverage, the complex-forming compound may be present in a concentration range of about 0.1-25% w/w or about 1-20% w/w. Preferably, the complex-forming compound may be present in a concentration range of about 1-15% w/w or about 1-10% w/w or about 3-8% w/w. More preferably, the complex-forming compound may be present in a concentration range of about 5-8% w/w.
The Inclusion Complex As noted above, the inclusion complex may include a clathrate host molecule complexed with one or more complex-forming compound. In the form of a solid product, such as a solid powder or tablet, the inclusion complex may exhibit some unique properties as compared to a solid composition containing essentially the same components, but without the preliminary formation of the inclusion complex. The inclusion complex is essentially a chemical entity having non-covalent hydrogen bonds formed between the clathrate molecule and the weak complex-forming 5 compound molecule. The inclusion complex, in its solid form, has the potential of dissociating into the clathrate component for increasing water structure and the complex-forming compound, which may further increase water structure or provide other beneficial properties, such as nutrition or flavor, when the inclusion complex is introduced to an aqueous environment, such as upon dissolution in an aqueous beverage, or upon ingestion.
10 When in the form of a solid product, the clathrate component and one or more types of a complex-forming compound may be substantially in the form of an inclusion complex, as described above. Preferably, over about 25% of the clathrate component is complexed with one or more types of a complex-forming compound in the form of an inclusion complex.
It is progressively more preferable to have over 35%, 45%, 50%, 60%, 70%, 80%, 90%, and 95% of 15 the clathrate component complexed.
IV Carbonation-Forming Components Some clathrate compositions may include carbonation-forming components that produce carbonation, or effervescence, upon dissolution into an aqueous environment.
Carbonation-forming components advantageously may inhibit self-aggregation of clathrate molecules, thereby 20 increasing clathrate surface area for structuring water and increasing cellular hydration.
Non-limiting examples of carbonation-forming components may include sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate. Preferred carbonation-forming components may include sodium carbonate, and sodium bicarbonate.
If the carbohydrate clathrate composition is in solid form, the carbonation-forming component may be present in a concentration range of about 1-60% w/w or about 5-60% w/w.
Preferably, the carbonation-forming component may be present in a concentration range of about 5-45% w/w or 10-45% w/w. More preferably, the carbonation-forming component may be present in a concentration range of about 10-15% w/w.
If the carbohydrate clathrate composition is in the form of an aqueous beverage, the carbonation-forming component may be present in a concentration range of about 1-30% w/w or about 1-25% w/w. Preferably, the carbonation-forming component may be present in a concentration range of about 2-15% w/w or 2-10% w/w. More preferably, the carbonation-forming component may be present in a concentration range of about 2-5% w/w V Other Components Some compositions may include yet other components that affect the taste and/or nutritional value of the composition. These additional components may include, but are not limited to, one or more of the following: flavor additives, nutritional ingredients and/or various hydroxyl-acids that act as clathrate aggregation-preventing additives in the formulations. Non-limiting examples of such other components may include citric acid, ascorbic acid, sodium chloride, potassium chloride, sodium sulfate, potassium citrate, magnesium sulfate, alum, magnesium chloride, maltodextrin, mono-, di-, tri-basic sodium or potassium salts of phosphoric acid (e.g., inorganic phosphates), salts of hydrochloric acid (e.g., inorganic chlorides), sodium bisulfate. Non-limiting examples of hydroxyl-acids that prevent cyclodextrin aggregation may include isocitric acid, citric acid, tartaric acid, malic acid, threonic acid, salts thereof and mixtures thereof. These hydroxyl-acids also may exhibit some nutritional benefits Other non-limiting examples of additional optional components, such as taste additives, that may be used include suitable organic salts, such as choline chloride, alginic acid sodium salt (sodium alginate), glucoheptonic acid sodium salt, gluconic acid sodium salt (sodium gluconate), gluconic acid potassium salt (potassium gluconate), guanidine HC1, glucosamine HC1, amiloride 11C1, monosodium glutamate (MSG), adenosine monophosphate salt, magnesium gluconate, potassium tartrate (monohydrate), and sodium tartrate (dihydrate).
Preferred other components may include, for example, citric acid, ascorbic acid, and maltodextrin.
If the carbohydrate clathrate composition is in solid form, the one or more other components each may be present in a concentration range of about 1-30% w/w or about 1-25%
w/w Preferably, the one or more other components each may be present in a concentration range of about 1-20% w/w or 1-15% w/w. More preferably, the one or more other components each may be present in a concentration range of about 2-5% w/w.
If the carbohydrate clathrate composition is in the form of an aqueous beverage, the one or more other components may be present in a concentration range of about 1-20%
w/w or about 1-15% w/w. Preferably, the one or more other components may be present in a concentration range of about 1-10% w/w or 1-5% w/w. More preferably, the one or more other components may be present in a concentration range of about 1-3% w/w.
VI. Component Ratios In addition to the above descriptions regarding the types and amounts of the various components that may be employed in the carbohydrate clathrate compositions disclosed herein, it is additionally noted that the relative amounts of these components can be described as well.
Preferably, the weight ratio of the clathrate component to the complex-forming compound may be in the range of about 5:1 to 1:10, more preferably may be in the range of about 2:1 to 1:5, still 2g more preferably may be in the range of about 2:1 to 1:2, and yet more preferably may be in the range of about 1:1 to 1:2.
Regarding the other possible components, such as flavor components, carbonation-forming components, and other components described above, the weight ratio of the clathrate component to each of the other components separately may be in the range of about 25:1 to 1:25, or about 10:1 to 1:10, or about 5:1 to 1:5, or optionally about 2:1 to 1:2, as well as 1:1.
The present invention provides a beverage composition, system and method of use, and a mechanism of action of the beverage composition for increasing cellular hydration and for increasing lifespan.
In an embodiment, the present invention provides a beverage composition comprising a carbohydrate clathrate component that includes cyclodextrin, in a concentration of 0.01-5% w/w;
a complex-forming compound; an aqueous liquid component, chosen from the group consisting of still and carbonated aqueous liquids; wherein an inclusion complex is formed with at least some of the clathrate component and at least some of the complex-forming compound.
Further, the ratio of clathrate component to complex-forming compound is preferred in the range from about 5:1 to about 15:1.
In another embodiment, the beverage composition of the present invention comprises a cyclodextrin, or mixture of cyclodextrins, and complex forming compound. One embodiment may include 0.05 % alpha-cyclodextrin in water, 0.05 % alpha-cyclodextrin-L-Arginine inclusion complex in water, 0.05 % alpha-cyclodextrin-nicotinamide inclusion complex in water, 0.05 %
alpha-cyclodextrin-nicotinic acid (niacin) complex in water; or mixtures of one or more of the aforementioned substances.
In another embodiment, the present invention includes gamma cyclodextrins-based beverage compositions and a the complex-forming compound.
To describe the mechanism of action of the invention, certain tissue present in multicellular organisms must first be described to provide perspective of how that mechanism of action functions. A lipid bilayer or phospholipid bilayer is a thin polar membrane made of two layers of lipid molecules. The lipid bilayer is the barrier that keeps ions, proteins and other molecules where they are needed and prevents them from diffusing into areas where they should not be. Biological bilayers are usually composed of amphiphilic phospholipids that have a hydrophilic phosphate head and a hydrophobic tail consisting of two fatty acid chains. Apart from phospholipids, the bilayer comprises cholesterol which helps strengthen the bilayer and decreasing its permeability.
It also comprises integral membrane proteins and other functional proteins like ion-channels, aquaporins etc. (as shown in FIG. 19).
Aquaporins are the only known water channel, however, water also diffuses via passive diffusion in response to osmotic gradient established by sodium in the intestinum. The bulk of the water absorption is a transcellular process, i.e., it goes through membrane bilayers by passive diffusion via the water channels (aquaporins), but some also diffuses through the tight junctions (called paracellular pathway, and shown in FIG. 20).
According to the present invention, the cyclodextrin-based beverages influence the cellular hydration with a mechanism of temporary and reversibly changing the cell membrane lipid packing and the membrane fluidity, due to the non-covalent inclusion complex formation. This feature of the mechanism of action is also referred to as reversibly and temporarily disintegrating the membrane lipids, but disintegrating is not used in its usual sense to mean destruction. Rather, the lipids are changed or moved but the process is reversible so they can return to the location they were and can again pack together. The cyclodextrin-based beverages of the invention may comprise alpha cyclodextrin or its derivatives, or beta cyclodextrin or its derivatives.
The alpha cyclodextrin and its derivatives primarily affect the phospholipid constituents, and the membrane anchored-proteins in the vicinity of these consituents. On the other hand, beta-5 cyclodextrins and derivatives target mainly cholesterol and cholesterol-phospholipid complexes in the membrane.
Further, the alpha-cyclodextrin and its derivatives preferably interact with slim membrane lipid components such as glycosphingolipids, sphingomyelin, phosphatidylcholine, phosphatidyl ethanolamine etc., wherein, all these phospholipids are integral constituents of lipid rafts, where 10 most of the membrane-bound functional proteins are located, such as ion channels, or water channels/aquaporins.
The interaction between cyclodextrins and phospholipids is a reversible non-covalent complex formation, a molecular event, during which the lipid environment of membrane-anchored proteins will alter and the cell-physiological functions of these transporter proteins (e.g. ion 15 transport) will change leading to enhanced water transport The lipid-cyclodextrin interaction is completely reversible that leads to change in lipid packing in a cyclodextrin concentration dependent manner. The low concentration of hydration-enhancing cyclodextrins exerts no irreversible cellular damage.
The highly hydrated form is a dissolved alpha-cyclodextrin; and in an alpha-CD
water 20 solution, water structure (monomers-and clusters) will be changed. In carbonated water, more importantly dissolved alpha-CD will contain less aggregates of the cyclodextrins and more hydrated monomers. The lower the number of aggregated alpha-CDs in water solution, the higher the number of accessible cyclodextrin cavities, ready for complex formation.
Similarly, the beta-cyclodextrin and its derivatives affect the membrane cholesterol-rich domains around the membrane-bound proteins. Both alpha- and beta-cyclodextrins cause change in membrane transport processes, initiate cell signaling, and affect water transport across aquaporins.
The cellular hydration plays a role in different cell functions and enhancement of cell hydration has an effect on cellular autophagosome formation or on autophagy.
(References: S.
Vom Dahl, et al. Biochem. J. 2001. 354. (1) 31-36. and Schliess, F. et al Acta Physiologic 187. 1-2. 2006., and Haussinger, D.). Further, cellular hydration state is an important determinant of protein catabolism in health and disease (Lancet 341. 8856. 1330-1332. 1993).
In another embodiment, the present invention includes a beverage composition that causes cellular hydration in a multicellular organism when a multicellular organism ingests it. The multicellular organism is capable of intracellular water permeation, and the ingestion of the composition by the multicellular organism enhances the intracellular permeation. The organism contains aquaporins, and the cellular hydration is caused by interaction of the composition with the aquaporins.
The present invention also provides a method of promoting increased cellular hydration in a multicellular organism that is capable of intracellular water permeation, comprising; causing the multicellular organism to ingest an aqueous solution that contains an amount of a carbohydrate clathrate component; and enhancing the intracellular permeation. The multicellular organism contains aquaporins and causes interaction of the composition with the aquaporins. The cyclodextrin-assisted enhancement of intracellular water permeation was assessed and corroborated by single cell Xenopus laevis frog oocytes having expressed human aquaporin AQP-1 water channels. The results of the biological tests are illustrated Example 7.
In another embodiment, the present invention provides a method of promoting increased cellular hydration in a multicellular organism that includes water and a carbohydrate clathrate component, and functions to decrease the density of at least some of the water in the aqueous solution. The physico-chemical properties for this embodiment of the invention that lowers the density of water in the aqueous solution is shown in Example 2.
Further, as described in (M.F. Chaplin Biophysical Chemistry 83 (1999) 211 ¨
221), dodecahedral water clusters have been reported at hydrophobic and protein surfaces, where low-density water with stronger hydrogen bonds and lower entropy has been found.
Similar cavities have been found in low density amorphous ice (LDA) and shown to be formed relatively easily in water during molecular simulations. The basis of the model described herein is a network that can convert between lower and higher density forms without breaking hydrogen bonds. It contains a mixture of hexamer and pentamer substructures and contains cavities capable of enclosing small solutes.
The above embodiment of the invention applies this theory and results in a novel mechanism that changes the structure of water by reducing its density.
The present invention provides another method for increasing hydration of cell system to promote cellular hydration in a multicellular organism when the mixture is ingested. The multicellular organism contains membrane lipids, lipid packing and membrane proteins, protein structure and protein function, and membrane permeation of nutrients and water. The method further includes the steps of causing the multicellular organism to ingest an aqueous solution that contains an amount of a carbohydrate clathrate component; and changing the lipid bilayer structure of multicellular organism by (i) temporary disintegration of the membrane lipids, (ii) loosening of the lipid packing and membrane proteins, and (iii) altering the protein structure and protein function, collectively to enhance membrane permeation of nutrients and water.
VII. Preferred Embodiments Preferred embodiments of the carbohydrate clathrate composition disclosed herein are provided as illustrations, and are not intended to limit the scope of this disclosure in any way.
Effect of cyclodextrin on molecular dynamics of water structure.
A simulated water solvated cyclodextrin molecular system was created using HyperChem0 5.11 software (from HyperCube Inc, Gainesville, FL), with input parameters derived from single ciystal analysis of cyclohepta-amylose dodecahydrate clathrate (or, fi-cyclodextrin) reported by Lindner and Saenger (see: Carbohydr.Res., 99:103, 1982), and using a water periodic solvent box (3.1x3.1x3.1 nm3) containing altogether 984 water molecules. Molecule conversion and atom type were adjusted to the proper format using TinkerFFE
4.2 (TINKER
Software Tools for Molecular Design, Version 5.0, Jay William Ponder, Washington University, St. Louis, MO). Molecular mechanics and dynamics calculations were performed with Tinker 5.0 software after preliminary optimization of the truncated Newton-Raphson method using a Linux x86-64 operating system (Slamd 64 v12.2).
Molecular dynamics simulations were run using MM3 Force Field molecular mechanics software, at constant temperature (298 K) for 120 picosecond (psec), with 0.1 femtosecond (fsec) steps. Recordings were generated by dumping intermediate structures every 100,000 steps (equivalent to 10 psec elapsed time).
Observations:
At time zero of each simulation, the standard water solvent box contained one fi-cy clod extrin clathrate molecule and a uniformly distributed population of 984 water molecules.
FIGS. 4 and 5 show a representation of the central portion of the solvent box at particular elapsed times during one representative simulation. It will be appreciated that water molecule positions and orientations are represented as (bent) rods, while P-cyclodextrin is represented as a van der Waals surface. It will be further appreciated that FIGS. 4 and 5 depict a volume of the solvent box, and therefore compress a three dimensional molecular distribution into two dimensions.
FIG. 4 shows a central portion of the solvent box at 1 psec of elapsed time of a simulation. In particular, at 1 psec of elapsed time, water molecules immediately adjacent to ii-cycl dextrin have acquired relatively static (stable) positions through H-bonding to cyclodextrin. Such water molecules may be referred to as a first hydration layer. However, the distribution of most water molecules in the solvent box remains generally similar to the starting distribution (1 psec previous), which is unstructured.
FIG. 5 shows the simulation of after 1000 psec (i.e., 1 nsec) of elapsed time.
At 1000 psec, water molecules immediately adjacent to f3-cyclodextrin continue to occupy relatively static (stable) positions. However, compared to 1 psec (FIG. 4), water molecules beyond the first hydration layer have acquired a more open microstructure.
Differences in water structure may be more readily observed in the absence of the perspective shadowing detail included in FIGS. 4 and 5. FIG. 6 shows alternative views of the water molecule distributions shown in FIG. 4 (left side, labeled 1 psec) and FIG. 5 (right side, labeled 1000 psec), which were produced by the following methods: image files for FIG. 4 and 5, having 256 grey levels (8 bits), were opened in Photoshop 9.0 (Adobe, Inc), adjusted to 300 dpi, thresholded at grey level 207; images were cropped to an identical outer annulus diameter using the circle select tool, and the outer square corners filled with black (grey level 0), and then further cropped to blacken an inner annulus that barely includes the cyclodextrin molecule. The dimensions of the outer and inner annuli are identically applied to the compared images. The 5 resulting thresholded representations qualitatively show water molecules surrounding the central (occluded) cyclodextrin molecule have a more open and coordinated structure at 1000 psec (e.g., right side panel of FIG. 6).
To quantitatively assess the change in microstructure of water represented in FIGS. 4-6, molecular density was approximated by measuring open paths through the depicted volume, a 10 method similar to a mean free path analysis, where a mean free path in a defined volume of a molecular substance is inversely related to the density of the molecules. In particular, an open path between water molecules is shown by a white pixel element, and the number of open paths in the volume is readily quantitated using the histogram tool of Photoshop 9.0 to count the number of white pixel elements. Applied to the panels of FIG. 6, a measured increase of 2% was calculated 15 for open paths at 1000 psec of elapsed time compared to open paths at 1 psec of elapsed time. For comparison, freezing of pure water results in a 9 % decrease in density. As path length is inversely proportional to molecule density, the analysis indicates that dissolved cyclodextrins decrease the density of an aqueous solution by increasing the organization of water molecules.
In summary, the results indicate a rapid (psec) H-bonding adhesion between the outer 20 surface hydroxyls of 3-cyclodextrin and water molecules is followed by a slower (nanosecond) propagation of water molecule reorientation throughout the solvent box, resulting in a more open water structure. The measured results further indicate that a cyclodextrin may sufficiently increase H-bonding between water molecules in the surrounding aqueous volume to result in a decrease in the density of water.
Physicochemical Properties (Density measurements) The current study further manifests the density measurements in a cyclodextrin concentration dependent manner. The materials used were specified as: a-cyclodextrin (Wacker -food grade, internal ID: B002/18); three weak complex forming additives (in a-cyclodextrin complex, 1:1 mol/mol) are L-arginine (Sigma-Aldrich Cat. No A5006), Nicotinic acid (Sigma-Aldrich Cat. No 72309), Nicotinamide (Sigma-Aldrich Cat. No 72340) y-cyclodextrin (Wacker -food grade, internal ID: B064/18).
Water samples used were bottled water and tap water; wherein the tap water comprises the following impurities and properties: Free active chlorine (0.18 mg/1), Chloride (24 mg/1), Iron (6 pig/1), Manganese (2 fig/1), Nitrate (9 mg/1), Nitrite (<0.03 mg/1), Ammonium (<0.04 mg/1), Hardness of water (122 mg/1 CaO), Conductivity (442 1AS/cm) and pH 8. Purified water was produced by removal of dissolved ions by Merck/Millipore Synergy Water Purification System at Cyclolab. The water quality produced Type 1 water (18.2 M12-cm at 25 C
ultrapure water) from pretreated water.
1:1 mol/mol stoichiometry complexes were prepared for the experiment.
Nicotinic acid /
alpha-CD complex was prepared by dissolving 11.22 g nicotinic acid and 98.63 g alpha-CD (89.66 g on dry basis) in 700 ml purified water. Nicotinamide / alpha-CD complex was prepared by dissolving 5.57 g nicotinamide and 49.3 g alpha-CD (44.4 g on dry basis) in 350 ml purified water and L-arginine / alpha-CD complex was prepared by dissolving 15.18 g L-arginine and 94.26 g alpha-CD (85.69 g on dry basis) in 700 ml purified water. Further, for all the three complexes, the liquid was frozen in dry ice bath and lyophilized. The dry lyophilizate was ground and sieved.
Clarity, phi, conductivity, density, viscosity, turbidity, surface tension and osmolality were determined in solutions prepared with purified water. The concentration noted for the complex solutions are indicating the actual alpha cyclodextrin content. Alpha & gamma cyclodextrin mix is a 50-50 weight% mixture of the two constituents and the percentage indicates the total cyclodextrin content. Tables 1-3 summarize the results of the physico-chemical tests.
Physico-Chemical properties of test solutions containing alpha- and gamma cyclodextrin vs.
control purified water Purified Water No Additive Alpha Cyclodextrin Gamma cyclodextrin 0.00% 0.05% 010% 1.00% 2.00% 0.05% 0.10% 1.00%
2.00%
6.28 6.20 6.38 8.55 6.70 6.82 6.79 6.87 6.77 PH
Conductivity 34.3 35.3 39.0 39.6 38.7 25.0 25.0 27.0 27.0 (pS-cm') Density (at 22 C) 0.9980 0.00 0.990 0.0 0.989 0.993 1.048 0.995 0.0 0.997 0.999 1.003 (g. ail') 05 02 01 0.91 0.91 0.92 0.97 1.01 .92 .92 .94 0.97 Viscosity (25 C) (cP) Titibidity (Abs, (reference) 0.003 0.000 0.017 0.015 0.005 0.008 0.065 0.108 2=410nm) clear clear clear clear clear clear clear hazy hazy Visual Inspection Surface Tension 72 72 72 72 73 72 72 73 (mN-m') Osmolality o o 2 8 18 0 0 4 (mOstn/kg) 3g Physico-Chemical properties of test solutions prepared of alpha-cyclo dextrin complexes vs.
control purified water Purified Water No Additive Alpha Cyclodextrin Gamma Cyclodextrin 0.00%
0.05% 0.10% 1.00% 2.00 A; 0.05% 0.10% 1.00% 2.00%
6.28 8.88 9.18 9.87 10.12 6.48 6.42 6.55 6.59 pH
Conductivity 34.3 46.6 52.6 97.3 130.0 40.7 43.6 44.0 45.8 (tiS-cm') Density (at 22 C) 0.99800.000 0.995 0.00 0.981 0.990 1.010 0.995 0.00 0.996 1.003 1.005 (g- c911) 5 1 1 0.91 0.94 0.91 1.02 1.06 0.93 0.95 1.00 1.06 Viscosity (25 C) (cP) Turbidity (Abs, (reference) 0.006 0.010 0.095 0.165 0.0152 0.0296 0.0463 0.0981 2=410nm) Visual Inspection clear clear clear hazy hazy clear clear hazy hazy Surface Tension 72 72 72 72 73 72 72 72 73 (tnN -tri-l) Osmolality 0 0 1 17 34 / / 21 (mOstn/kg) In Table 2, the second-fifth columns correspond to mixtures of alpha cyclodextrin with an L-arginine complex and ACD/Nicatinamide, and the sixth-ninth columns correspond to gamma cyclo dextrin mixtures.
Physico-Chemical properties of test solutions prepared of alpha-cyclodextrin/nicotinic acid complex, alpha & gamma cyclodextrin mix vs. control purified water Purified Water No Additive Alpha Cycludextrin / Nicotinic acid Alpha & Gamma Cyclodextrin Mix 0.00% 0.05% 0.10% 1.00% 2.00% 0.05% 0.10% 1.00%
2.00%
pH 6.28 4.26 3.79 3.60 3.45 6.64 6.72 6.67 6.93 Conductivity 34.3 46.1 56.1 123.7 154.5 33.0 25.0 27.0 28.0 (1.1.S=cm-1) Density (at 22 C) 0.9980+0.00 0.994+0.00 0.994+0.00 0.994 0.995 0.994 0.997 0.998 1.002 (g. cm-1) 05 1 1 Viscosity (25 C) 0.91 0.92 0.91 1.01 1.07 0.91 0.91 0.94 1.04 (cP) Turbidity (Abs, (Reference) 0.000 0.001 0.103 0.28 0.005 0.007 0.003 0.055 I:1=410nm) Visual Inspection Clear Clear Clear Hazy Turbid Clear Clear Clear Hazy Surface Tension (mN=m-l) Osmolality o o o 15 28 o o 6 (mOsm/kg) Tables 1-3 report the results of the physico-chemical test, wherein a notable effect is manifested in the density measurements, that presence of dissolved cyclodextrins at low concentration (0.05%) has a density-decreasing effect of purified water, and this phenomenon occurs also in the case of both L-Arginine and nicotinic acid complexes in low (0.05 %) concentration. At higher concentration (0.5 and 1.0% solutions), however, this effect does not show up due to the higher solid content which evidently increase the density of the liquids.
The density measurements were repeated using tap water and it was found that the above-mentioned phenomenon does not occur probably due to the perturbating presence of ions in tap water. However, it may not be established exactly which ionic species (Mg2+, Ca2+, Na+) causes this perturbation. The results are shown in Table 4.
Density of alpha- and gamma-CD solutions prepared with Tap water Tap water No Additive Alpha Cyclodexrin Concentration 0.05% 0.10% 1.00%
2.00%
Density (at 22 0.9987+0.005 0.9992+0.007 0.9994+0.004 1.0021+0.007 1.0088+0.005 C) (g.cint) Gamma cyclodextrin Concentration 0.05% 0.10% 1.00%
2.00%
Density (at 22 0.9997+0.0007 1.0002+0.0004 1.0035+0.0007 1.0094+0.0006 C) ( 5 Effect of cycodextrin additives on water bonding detected by IR
spectroscopy Physical micro-structure studies of water, water-sugar interactions, and detection of sugar effects on increasing and decreasing water structure have preferentially employed infrared (IR) spectroscopy, and particularly near infrared (NIR) spectroscopy, as for example reported by Segtan et al. (see: Anal. Chem. 2001; 73, 3153-3161), and R. Giangiacomo (see: Food Chemistry, 2006, 10 96.3. 371-379.) Hydration bond energies in pure waters and solutions of the same waters containing cyclodextrin compounds were assayed using IR spectroscopy in the near and middle infrared ranges. To record linear signals throughout an entire wavelength range, attenuation from water absorbance was minimized with a short optical length cuvette.
NIR range spectra were registered on a FOSS MR Systems, Inc. 6500 spectrometer and Sample Transport Module (STM) using a lmm-sized cuvette. Transmission spectra were collected from 1100-2498 nm using a lead sulfide (PbS) detector and Vision 2.51 software (2001; FOSS
NIRSystems, Inc.) A Perkin-Elmer Spectrum 400 FT-MR/FT-IR spectrometer and UATR (Universal Attenuated Total Reflectance; ZnSe-diamond crystal, 1 x flat top plate) sample handling unit were used to obtain spectra across 2500-15385 nm (reported as 4000 ¨ 650 cm-').
Measurements were performed at 24C using a triglycine-sulfate (TGS) detector and Spectrum ES
6.3.2 software (PerkinElmer, 2008).
Three samples of water were used in the present study. A first water sample was purified by reverse osmosis, carbon filtration, ultraviolet light exposure, membrane filtration to 0.2 micron absolute, and ozonation. Second and third water samples were not purified.
Capillary electrophoresis revealed similar ionic components but at different concentrations between the three waters.
The following cyclodextrins were added to the above described water samples at a concentration range of 0.1% - 5% w/w:
a-cyclodextrin (aCD also denoted as ACD), Lot. No. CYL-2322.
13-cyclodextrin (f3CD also denoted as BCD). Lot. No. CYL-2518/2.
7-cyclodextrin (7CD also denoted as GCD), Lot. No. CYL-2323.
2-hydroxypropyl-f3-cyclodextrin (HP0CD, HPBCD), DS* = 3.5, Lot. No. CYL-2232.
2-hydroxypropylmcyclodextrin (HPCD, HPGCD), DS* = 4.8, Lot. No. CYL-2258.
carboxymethyl-fl-cyclodextrin (CMBCD), Lot. No. CYL-2576.
quaternary-ammonium-P-cyclodextrin (QABCD).
For some examples, various inclusion complexes were formed between cyclodextrins and complex-forming bioactive agents, including the amino acids L-arginine and L-carnitine and the vitamin niacinamide (also known as nicotinamide). All reagents were of analytical purity. For some examples, L-arginine and nicotinamide were added in free form and alternatively in a cyclodextrin-complexed (molecularly entrapped) form to assess independent and co-dependent activities of a cyclodexrin and a bioactive agent. Concentrations of above additives in free form, and as cyclodextrin inclusion complex forms, were in the range of 0.1% to 5.0%
w/w.
Observations:
FIG. 7 shows second-derivative NIR spectra for the wavelength region 900-1200 nm. The results show water-bond interactions are significantly modified by addition of QABCD, and further significantly modified by addition of CMBCD and HPBCD.
FIG. 8 shows second-derivative NIR spectra shown for 1200-1500 nm. The results show water-bond interactions are significantly modified by addition of QABCD and HF'BCD, and further significantly modified by addition of CMBCD
FIG. 9 shows second-derivative NIR spectra shown for 1620-1710 nm. The results show water-bond interactions are significantly modified by addition of CMBCD, QABCD, and HPBCD.
FIG. 10 shows second-derivative NIR spectra shown for 2170-2370 nm. The results show water-bond interactions are significantly modified by addition of CMBCD and HPBCD, and further significantly modified by addition of QABCD.
As shown in FIGS. 7-10, addition of cyclodextrins alters molecular bonding interactions of the aqueous medium. Referring particularly to FIG. 9, refined MR spectra derivatives in the wavelength range of 1 620-1 770 nm show the carbon hydrogen bond related alterations involve CH3- CH2- and CH- groups of cyclodextrin additives. The significant spectral changes occurring in each cyclodextrin-treated water sample indicate the modified micro-structure of hydrogen bonds governed cluster systems in bulk water. This effect was largest in the water samples treated with charged quaternary-ammonium-fl-cyclodextrins (QABCD), as shown for example in FIGS. 9 and 10.
Acceleration of plant embryo germination.
Wheat seeds (Triticum aestivtan) were germinated using USA I, USA II, and BP I
waters described for Example 2. Germination rate using un-supplemented (control) water was compared to that with the same water variously supplemented with a cyclodextrin component, and/or a bioactive agent, as an active component of cellular hydration. For each condition, ten seeds were placed in continuous water contact in a Petri-type dish kept at 25C in 12 hr light/dark cycles.
Photometric images were recorded on days 1 to 6 after seeding. The percentage of seeds germinated was calculated and compared as a function of time and of the applied additive concentrations Water samples for seed germination were used alone with no additive, or containing cyclodextrins, or containing clathrate inclusion complexes of cyclodextrin with L-arginine or with nicotinamide (both obtained from Sigma Chemical Co.; St. Louis, MO), or with L-carnitine (from Lonza AG; Switzerland). Additives were included at 0.1 and 5. % (w/w).
Additive solutions were prepared fresh on the day of germination start_ Parent cyclodextrins a-cyclo dextrin (A CD), 0-cyclodextrin (BCD), and y-cyclodextrin (GCD), were obtained from Wacker Chemie (Munich, Germany). The following derivatized cyclodextrins were obtained from Cyclolab Ltd. (Budapest, Hungary):
hydroxypropyl ated-beta-cyclodextrin (DS-3)(HPBCD), carboxymethylated-O-cyclodextrin (DS-3.5)(CMBCD), hydroxy-3-N,N,N-trimethylamino)propyl-P-cyclodextrin chloride (DS-3.6)(QABCD).
Observations:
Germination kinetics in control and additive-modified water under identical conditions were quantified as the percentage of the seeds having a sprout. Each determination consisted of 100 seeds for each parameter. Results are reported in Table 5, below, and in FIGS. 1 7 -1 3.
A) Cyclodextrin/L-Arg Inclusion Complex Increases Seed Germination.
Effect of a-cyclodextrin and L-arginine on wheat seed germination rate (values = percentage of total seeds) Days control (water) a-Cyclodextrin, 0.5%
L-Arg, 0.5% a-CD/L-Arg inc. complex Table 5 shows comparative effects on the germination of wheat seeds of 0.5%
w/w a-CD, 0.5% w/w L-arginine (L-Arg), and 0.5% w/w of an a-CD/L-arginine inclusion complex, each dissolved in USA I water. The above-tabulated results indicate that, compared to pure water lacking any additive (control), wheat seed germination rate is much higher in water including 0.5%
(w/w) inclusion complex between a-cyclodextrin and L-arginine (aCD/L-Arg inc.
complex). In addition, the results in Table 5 indicate that wheat seed germination rate is much higher in water including inclusion complex between a-cyclodextrin and L-arginine (aCD/L-Arg inc. complex) compared to water including 0.5% (w/w) a-cyclodextrin (aCD) as an additive alone, and also compared to water including 0.5% (w/w) L-arginine (L-Arg) as an additive alone. Thus, the results indicate a complex of a-cyclodextrin and L-arginine has a synergistic effect on increasing seed germination rate, which is not shown by either individual component of the complex used as a solitary additive. Results of Table 5 are also shown in FIGS. 11 and 13.
B) Cyclodextrin/nicotinami de Inclusion Complex Increases Seed Germination.
Effect of a-cyclodextrin and nicotinamide on wheat seed germination rate Days Control (water) a-Cyclodextrin, 0.5%
nicotinamide, a-CD/nicot.
0.5% inc.
complex 10 Table 6 shows comparative effects on the germination of wheat seeds of 0.5% w/w a-cyclodextrin, 0.5% w/w nicotinamide, and 0.5% w/w of an a-cyclodextrin/nicotinamide inclusion complex (aCD/nicot. inc. Complex), each dissolved in USA I water. The above-tabulated results indicate that, compared to pure water lacking any additive (control), wheat seed germination rate is much higher in water including inclusion complex between a-cyclodextrin and nicotinamide.
15 In addition, the results in Table 6 indicate that wheat seed germination rate is much higher in water including inclusion complex between a-cyclodextrin and nicotinamide (aCD/nicot. inc. complex) compared to water including a-cyclodextrin (aCD) as an additive alone, and also compared to water including nicotinamide as an additive alone. Thus, the results indicate that when used as an inclusion complex, a-cyclodextrin and nicotinamide have a synergistic biological activity that 20 signficantly increases seed germination rate. Such biological activity was not demonstrated by either individual component of the complex used as a solitary additive.
Results of Table 6 are also shown in FIGS. 12 and 13.
C) Qualitatively similar results as those reported in Tables 5 and 6, and FIGS. 11-13, were obtained using USA II and BP I water for germination. Thus, in particular, cyclodextrin inclusion complexes containing L-arginine, or alternatively containing nicotinamide, when dissolved in USA II or alternatively in BP I water, each significantly increased wheat seed germination rate, as shown above using USA I water.
D) Lengths of sprouts (rate of sprout growth during germination) did not differ between conditions within a statistically significant confidence interval (P<0.05).
This result indicates that cyclodextrins, and particularly cyclodextrin inclusion complexes, may be used selectively as active components of cellular hydration to promote a rate of seed germination without necessarily also affecting a sprout growth rate.
Lifespan extension of C. elegans in hydration modified water C. elegans nematodes were grown in petri-type dishes containing normal nutrient liquid media prepared alternatively with USA I water (described in Example 2) lacking any further additive component (control) or the same water supplemented with a parent a-, 0-, or y-cyclodextrin, and/or a bioactive agent, as an active component of cellular hydration. Fifty 3 worms were transferred to each dish. Each condition was repeated in triplicate. Experiments were repeated for USA II and BP I waters described in Example 2.
Water additives:
A. Addition of parent a-, 13- and 'y-cyclodextrins.
B. Addition of L-arginine and nicotinamide.
C. Addition of inclusion complexes of cyclodextrins with L-arginine and nicotinamide.
Observations:
The results recorded are displayed below in Tables 7-9 and further presented in FIGS. 14-18.
Effect of cyclodextrins on C. elegans longevity Animals alive, % of initial (N=50) Life Span Control (water) a-Cyclodextrin , p-Cyclodextrin, y-Cyclodextrin, (days) 0.1% 0.1%
0.1%
Table 7 reports the percentage of animals surviving to midlife (10 days), advanced age (15 days) and old age (18 days), in media variably containing a parent a-, P-, and y-cyclodextrin as an active component of cellular hydration. In this example, parent cyclodextrins were added at a concentration of 0.1% w/w to nutritive media dissolved in USA I water.
Consistent with all previous studies, normal C. elegans animals in the present example survived two weeks in normal media. Each of the parent cyclodextrins markedly increased C.
elegans survival (percentage alive) at advanced li fesp an ages (days 10-15).
Further, a-cy cl o dextrin and 'y-cyclodextrins significantly increased the number of animals surviving to old ages, i.e., after day 15. The results are also represented graphically in FIG. 14, which compares the cumulative percentages of animals surviving to 15 and 18 days in media containing each additive parent cyclodextrin. The results show parent cyclodextrins, particularly a- and P-cyclodextrin, may be used as an active component of cellular hydration to improve biological function in a live animal.
Biological mechanisms supporting advanced aging may include improvement of broad spectrum cellular activity during aging, or alternatively by selectively activating slow-aging cellular activity pathways. Clathrate-induced increases in water structure, hydration of cellular components, and diffusivity of bioactive cellular components, including inter- and intra-cellular signals, may all contribute to the overall effects of cyclodextrins on organism survival.
Effect of chemically-modified cyclodextrins C. eleg-ans longevity Animals alive, % of initial (N=50) Life Span Control HP-I3-Cyc1odextrin Carboxymethyl-Quaternaryammonium-(days) (water) P-Cyclodextrin f3-Cyclodextrin
As to methods, the present invention provides a method of promoting increased cellular hydration in a multicellular organism that is capable of intracellular water permeation. Another method of the invention is to promote increased cellular hydration in a multicellular organism that includes water by decreasing the density of at least some of the water in the aqueous solution.
In accord with these and other objects, the present invention provides a beverage composition comprising a carbohydrate clathrate component that includes cyclodextrins, in a concentration of 0.01-5% w/w; a complex-forming compound, in a concentration that is less than the clathrate component; an aqueous liquid component, chosen from the group consisting of still and carbonated aqueous liquids; wherein an inclusion complex is formed with at least some of the clathrate component and at least some of the complex-forming compound.
In one of the embodiments, the ratio of clathrate component to complex-forming compound is in a range from about 5:1 to about 15:1.
In a another embodiment, the present invention provides a method for increasing hydration of cell system to promote cellular hydration in a multicellular organism when the mixture is ingested, the multicellular organism containing membrane lipids, lipid packing and membrane proteins, protein structure and protein function, and membrane permeation of nutrients and water, the method comprising the step of: causing the multicellular organism to ingest an aqueous solution that contains an amount of a carbohydrate clathrate component; and changing the multicellular organism by (i) temporary disintegration of the membrane lipids, (ii) loosening of the lipid packing and membrane proteins, and (iii) altering the protein structure and protein function, collectively to enhance membrane permeation of nutrients and water.
DETAILED DESCRIPTION
Water structure is purposefully increased, or organized, by addition of one or more solutes or suitable molecular aggregates whose surfaces are capable of strongly competing with water molecules for H-bonding and/or dipole orientation. In particular, factors and agents that strengthen water molecule interactions and increase water structure thereby alter the hydration, or solvation, of a further molecular surface. Thus, a primary solution additive that increases water structure may increase hydration interactions (e.g., bonding strength and kinetics) with a molecular surface of a secondary solution component, or alternatively decrease such interactions, depending on the H-bonding surface characteristics of the secondary component.
In addition, factors that modify water structure typically change the average distance between water molecules, and may thereby increase or decrease water density.
For example, as water temperature decreases below its freezing point, H-bonding between the water molecules overcomes the kinetic energy of the water molecules, resulting in an increase in water structure that decreases the density of frozen water by approximately 9%. Similarly, in liquid state water, an increase in the strength of water H-bonding increases the average distance between water molecules, which is observed as an increase in specific volume (i.e., decrease in density). A
decrease in density of liquid water may increase the diffusivity of a dissolved solute. Thus, an aqueous additive component which decreases water density may increase the diffusivity of a co-dissolved solute.
Chaotropes, as used herein, are aqueous solute additives that disrupt hydrogen bonded networks in aqueous solutions, and thereby act to decrease water structure.
Chaotropes typically are less polar and have weaker H-bonding potentials than water molecules.
Chaotropes may preferentially bind to non-polar solutes and particles, and thereby increase solubility of a non-polar solute.
Kosmotropes, as used herein, are solutes that promote strong and extended H-bonded networks in aqueous solutions, and which thereby increase and/or stabilize the sub-micrometer scale structure of water molecule interactions. A kosmotrope having an H-bonding chemical potential greater than that of water, and/or having a dipole moment greater than that of water, may increase H-bonded networks between water molecules. Further, by strengthening hydration structure, a kosmotrope may increase hydration interactions at a molecular surface, which may include a binding site between molecules. A kosmotrope may thus be used as an aqueous solution additive to stabilize molecular interactions Further, a kosmotrope may increase the effective chemical activity of a dissolved co-solute.
An increase in the strength of H-bonding interactions between water molecules causes water to adopt a more open architecture having a lower specific density and higher specific volume. Thus, by causing a decrease in density, addition of a kosmotrope to an aqueous solution may increase a diffusivity of one or more of a dissolved co-solute species or compounds.
Increasing the diffusivity of a solute species or compound may increase its reactivity, chemical potential, effective concentration, and availability.
As discussed herein, clathrate components are amphipathic carbohydrate compounds which have external surfaces that are hydrophilic and H-bond strongly with water, and also internal surfaces that are less hydrophilic. A clathrate's internal surface may selectively bind a molecular structure which is relatively non-polar or less hydrophilic than water.
An inclusion complex, as used herein, is a chemical complex formed between two or more compounds, where a first compound (also referred to as a host) has a structure that defines a partially enclosed space into which a molecule of a second compound (also referred to as a guest) fits and binds to the first compound. The host molecule may be referred to as a clathrate and may bind the guest molecule reversibly or irreversibly.
A biological cell, as used herein, is the self-replicating functional metabolic unit of a living organism, which may live as a unicellular organism or as a sub-unit in a multicellular organism, and which comprises a lipid membrane structure containing a functional network of interacting biomolecules, such as proteins, nucleic acids, and saccharides. Biological cells include prokaryote cells, eukaryotic cells, and cells dissociated from a multi cellular organism, which may include cultured cells previously derived from a multi cellul ar organism.
A biological cell system, as used herein, is a functionally interconnected network of biological cells and/or sub-cellular elements, which may include living cells, non-living cells, cellular organelles, and/or biomolecules.
A bioactive molecule, as used herein, is a molecular compound having a functional activity in a biological cell system.
A biomolecule, as used herein, is a molecular compound that is synthesized by a biological cell. Biomolecules include compounds normally synthesized by cells, and compounds synthesized by genetically engineered cells, and chemically synthesized copies of cell-derived compounds.
A biomolecular surface, as used herein, is an outer atomic boundary of a biomolecule, which may include a biochemical interaction surface, such as a binding site.
Cellular components, as used herein, are functional elements of a biological cell, which include biomolecules, biomolecule complexes, organelles, polymeric structures, membranes and membrane-bound structures, and may further include functional pathways and/or networks, such as a sequence of molecular events.
The density of a substance is the mass per unit volume of that substance under specified conditions of temperature and pressure.
The specific volume of a substance is the volume per unit mass of the substance, which may be expressed, for example, as m3/kg. The specific volume of a substance is equivalent to the reciprocal of the density of that substance.
A biologically active component, as used herein, is a molecular substance that modifies (increases or decreases) an activity of a biological cell system.
A bioactive agent, as used herein, is a substance that when added to a biological cell system, or to a cellular component, causes a change in the biological activity of that system, or that component The bonded structure of water, as used herein, refers to the network of H-bonds that hold and organize the orientation of water molecules in liquid and solid states.
Water structure, as used herein, increases when H-bonds between water molecules at a given temperature are strengthened, and decreases when H-bonds between water molecules at a given temperature are weakened.
An interaction between cellular components, as used herein, refers to a chemical binding between biomolecular surfaces. Such interaction may include binding between two biomolecul es, such as a ligand and its specific receptor. Alternatively, such interaction may include binding between a biomolecule and an organelle, such as a cell membrane.
Extracellular signals, as used herein, are biomolecules that can modify (increase or decrease) an activity of a cell when applied to the outside of the cell. An extracellular signal may bind to a component of the cell's plasma (outer) membrane, or alternatively may pass through the plasma membrane to regulate an intracellular activity. Extracellular signals may include, but are not limited to, extracellular matrix components; cell membrane components such as glycoproteins and glyocolipids; antigens; and diffusible biomolecules such as nitric oxide.
An intracellular messenger, as used herein, is an internal component of a biological cell that has an active state, and which serves in an active state as an intermediate signal to transmit an extracell ul ar sign al to an intracellular target.
A mechanism of action, as used herein, refers to a process, which may be a step-by-step one, that takes place to achieve a certain or desired outcome.
A multi-cellular organism, as used herein, refers to an organism that consists of more than one cell, and includes organisms as complex as mammals, including animals and humans, to less complex ones such as C. elegans and other nematodes, and to as plants and other vegetation..
A pharmacological agent, as used herein, is a synthetic chemical substance that binds to and thereby alters the activity of a biomolecule or a biomolecule complex.
The present invention includes active compositions that increase an activity of a biological cell system by increasing the hydration of one or more components of that cell system.
Preferably, an active composition for modifying cellular hydration includes a primary carbohydrate clathrate component that increases the H-bonded structure of water. In some examples, the active composition preferably includes a primary carbohydrate clathrate component that increases the FT-bonded structure of water and a secondary solute compound, which may be a bioactive agent. In some examples, the active composition preferably includes an inclusion complex formed between a clathrate component and a complex-forming compound, which may be a bioactive agent.
Biological cells are multi-compartment structures, comprising chemically active water-based chambers and lipid-based membranes. The structure and activity of cells derives from highly selective chemical bonding associations between their biomolecular components, such as lipids, structural proteins, enzymatic proteins, carbohydrates, salts, nucleotides, and other metabolic and signaling biomolecules. The strength and specificity of biomolecule bonding reflects complementary chemical topologies at the bonding interface.
Hydrophilic and/or hydrophobic surfaces commonly dominate the chemical topology of biomolecular bond interfaces.
In aqueous systems, hydrophobic and hydrophilic interactions are substantially driven by competing hydration interactions with molecules of water, whose concentration exceeds 50 M.
Cellular hydration, as used herein, refers to interaction between water molecules and biomolecular components of a cellular system. Cellular hydration may be modified by changing the strength and/or kinetics of H-bon ding between water molecules and biomolecular surfaces.
An aqueous solution additive that modifies water structure may, by modifying the hydration of biomolecular binding surfaces, alter the strength, kinetics, and/or specificity of binding between cellular components. For example, a kosmotrope aqueous additive that increases water structure may alter the strength, kinetics, and/or specificity of binding between a secreted intercellular signaling factor and a cognate receptor located in the plasma membrane of a potential target cell for that factor, and hence bias the outcome of a cellular signaling network.
Clathrates that are suitable as active components of cellular hydration according to the present invention include amyloses and cyclodextrins. Amyloses are linear polysaccharides of D-glucose units. As shown in FIG. 1, cyclodextrins are macrocyclic oligosaccharides of D-glucose units linked by a(1-4) interglucose bonds. Amylose and cyclodextrin are readily prepared in large quantities from hydrolyzed starch. Cyclodextrin preparation includes enzymatic conversion, most commonly using the enzyme cyclodextrin-glycosyl transferase produced by Bacillus strains.
As shown in FIG. 2, cyclodextrins may differ by the number of glucose units included in the ring. Cyclodextrin species include a-cyclodextrin (6 units), P-cyclodextrin (7 units), 7-cyclodextrin (8 units), and 8-cyclodextrin (9 units). Parent cyclodextrins, as used herein, are natural, chemically underivatized a- [3- and 'y-cyclodextrins, having 18 (a-), 21 (1:1-) and 24 (y) free, unmodified hydroxyl groups, respectively.
As schematically shown in FIG. 3, cyclodextrins have a toroid topology, a shape which generally resembles a truncated cone, or half of an open-ended barrel.
Accordingly, a cyclodextrin may be described as including an exterior chemical surface, which includes the outer surface and the rims of the barrel, and an interior chemical surface surrounding an internal cavity (the inside of the barrel).
Cyclodextrin exterior surfaces include a high density of hydrophilic chemical groups that H-bond with water. In particular, the hydroxyl groups of the parent a-cyclodextrin, p-cyclodextrin, and 'y-cyclodextrin structures are all concentrated at the ends of the cyclodextrin barrel. More particularly, cyclodextrin hydroxyl (-OH) chemical groups are located along the barrel rims, and their orientation is sterically restricted. Hydroxyl groups at glucose position C(6), which may be called primary OH groups, point in a counter-clockwise direction with respect to the narrower open end of the cyclodextrin barrel. Hydroxyl groups at glucose position C(2), which may be called secondary hydroxyl groups, angle in a clockwise direction with respect to the wider open end of the cyclodextrin barrel.
The high density and constrained orientation of cyclodextrin hydroxyl groups creates particularly strong H-bonding surfaces at both ends of the cyclodextrin barrel. Physicochemical analysis and solvation modeling of cyclodextrins show water molecules adjacent the cyclodextrin have fixed positions and low angular (rotational) mobility. Usefully, species of cyclodextrin, which differ in barrel diameter as well as number of hydroxyl groups, also differ in the number and mobility of strongly bound water molecules.
The H-bonding activity of a cyclodextrin compound may propagate into a surrounding aqueous medium. As shown in FIGS. 4 and 5, dynamic modeling of a cyclodextrin molecule 5 introduced into a defined population of water molecules at standard temperature and pressure causes a nanosecond reorganization of water throughout the volume. FIG. 4 depicts a population distribution at one picosecond (ps) after initiating the mixing simulation;
FIG. 5 depicts a redistribution of the same population at 1000 Ps (1 nanosecond), wherein water molecules have adopted a more open structure.
10 In some examples, a cyclodextrin may function as an active component of cellular hydration through a kosmotrope activity that increases the bonded structure of water, wherein an increase in H-bonding between water molecules modifies the hydration of biomolecular surfaces, and thereby alters the strength, kinetics, and/or specificity of binding between cellular components.
In some examples, a cyclodextrin may function as an active component of cellular hydration 15 through a kosmotrope activity that increases the bonded structure of water, wherein stronger H-bonding between water molecules causes an open water structure having a lower specific density (i.e., a higher specific volume), and wherein a rate of diffusion of bioactive molecules is increased.
Such examples may include a soluble bioactive molecule such as an enzyme, enzyme substrate, nutrient, metabolite, cytokine, neurotransmitter, hormone, extracellular signal, intracellular messenger, or pharmacological agent.
An active component of cellular hydration that increases a rate of diffusion in water may regulate one of the many biological processes that are limited by the rate of change in the concentration of a bioactive component. For example, clearance of a neurotransmitter from synaptic clefts is commonly diffusion limited, including the passive dispersal of glutamate from excitatory synapses in the mammalian brain, and the active catabolism of acetylcholine at vertebrate neuromuscular synapses by the diffusion-limited enzyme acetylcholine esterase.
Similarly, the activity of electrically excitable cells, such as muscle cells, is commonly coordinated by the diffusion-limited changes in the concentration of the intracellular second messenger signal calcium.
The cellular hydration activity of a cyclodextrin may be modified, either increased or decreased, by forming an inclusion complex with a complex-forming compound.
Internal surfaces of cyclodextrins lack hydroxyl groups, are less hydrophilic than the surrounding aqueous environment, and thereby preferentially bind co-solute molecules having low hydrophilic and H-bonding potential.
Upon ingestion by an animal, carbohydrate clathrate compositions that increase the hydrogen bonding structure of interstitial and intracellular fluids may improve cellular hydration, including hydration structure at cell membrane surfaces as well as solvation of biomolecules that sub-serve healthy cell function. Improved cellular hydration may support healthy cell function by, for example, increasing the import, export, and/or diffusivity of solutes, nutrients, waste products, cytokines, metabolites, and other molecular agents supportive of cell function, differentiation, repair, growth, and survival, and by stabilizing cellular membranes in vulnerable tissues, such as muscle and nerve.
In some examples, a carbohydrate inclusion complex ingested by an animal may increase water H-bonding structure and thereby improve cellular hydration and/or diffusivity of cellular components. In some examples, a carbohydrate inclusion complex ingested by an animal may dissociate to release a free (i.e., non-complexed) cyclodextrin clathrate component that increases water hydrogen-bonding structure and thereby improves cellular hydration and/or diffusivity of cellular components. In some examples, a carbohydrate inclusion complex may increase water structure and improve cellular hydration without dissociating. In some examples, a carbohydrate inclusion complex may dissociate into a clathrate component for increasing water structure and cellular hydration, and a complex-forming compound which may further increase water-structure and/or provide other beneficial properties, such as nutrition or flavor.
The carbohydrate clathrate compositions of the present invention may be provided in various forms, including being formed into a solid powder, tablet, capsule, caplet, granule, pellet, wafer, powder, instant drink powder, effervescent powder, or effervescent tablet. Some carbohydrate clathrate compositions may also be formed as, or incorporated into, aqueous beverages or other food products. Such carbohydrate clathrate compositions may be inclusion complexes that remain reasonably stable during storage, so that the clathrate component does not dissociate from the complex-forming compound and form a stronger complex with another compound that reduces the kosmotropic activity of the complex and thereby decrease its ability to improve cellular hydration.
The present disclosure also provides methods for improving cellular hydration in an animal, such as a human. For example, some methods may include (a) preparing a beverage with a carbohydrate clathrate component and water, or by dissolving an inclusion complex formed by a carbohydrate clathrate component and a complex-forming compound capable of dissociating from carbohydrate clathrate component under physiological conditions, and (b) having the animal orally ingest the beverage, whereupon the carbohydrate clathrate component modifies the strength, extent, and kinetics of the hydrogen bonded water structure at cellular biomolecular surfaces, and 1g does so whether in an aqueous solution, or if it is in an inclusion complex, dissociates from the complex-forming compound.
Carbohydrate Clathrate Composition The carbohydrate clathrate component may include any suitable carbohydrate including, but not limited to, a-cyclodextrin, p-cyclodextrin, y-cyclodextrin, methylated ri-cyclodextrins, 2-hydroxypropylated f3-cyclodextrins, water soluble 3-cyclodextrin polymers, partially acetylated a-3-, and y- cyclodextrins, ethylated a-, (3-, and f3-cyclodextrins, carboxy-alkylated P-cyclodextrins, quaternary-ammonium salts of a-, p-, and y-cyclodextrins, an amylose (e.g., an acetylated amylose), and mixtures thereof.
In preferred embodiments, the carbohydrate clathrate may be selected based upon a kosmotrope activity that increases water structure alone or in combination with other solutes.
Preferred cyclodextrin kosmotrop es may include a¨cyclodextrin, 13¨cyclodextrin, 7¨cyclodextrin, 2-hydroxypropyl-cycl odextrins, carboxymethyl ate d- cycl odextrin s, and quatern ary-amm on i urn-cyclodextrins.
Cyclodextrin derivatives may include alkylated, hydroxyalkylated, alkoxyalkylated, acetylated, quaternary ammonium salts, carboxyalkylated, maltosylated, and glucosylated derivatives. Alkyl groups of cyclodextrin derivatives may be straight chain or branched, may have main chain lengths of one to three carbons, and may have a total of one to six, and preferably one to three carbon atoms. Some non-limiting examples of cyclodextrin derivatives may include methylated beta-cyclodextrins, 2-hydroxypropylated il-cyclodextrins, water soluble beta-cyclodextrin polymers, partially acetylated a-, 13, and/or y-cyclodextrins, ethylated a-, p-, and/or y-cyclodextrins, carboxyalkylated 13-cyclodextrins, quaternary ammonium salts of a-, 13, and/or 7-cyclodextrins, as well as mixtures of any combination of these derivatives, together or in combination with one or more cyclodextrins. An exemplary mixture of cyclodextrins may include a combination of a-, 13, and/or y-cyclodextrin in a weight ratio range of about 1:1:1 to 2:2:1, respectively. The cyclodextrin may be in a hydrate crystalline and/or amorphous form, including but not limited to the hydrate and/or amorphous forms of a-, (3, and/or 'y-cyclodextrin, and mixtures thereof.
If the carbohydrate clathrate composition is in solid form, the cyclodextrin component may be present in a concentration range of about 10-90% w/w, or about 15-70% w/w, or about 15-60%
w/w. Preferably, the cyclodextrin component may be present in a concentration range of about 10-50% w/w, or about 15-40% w/w. More preferably, the cyclodextrin component may be present in a concentration range of about 20-25% w/w.
If the carbohydrate clathrate composition is in the form of an aqueous beverage, the cyclodextrin component may be present in a concentration range of about 0.01-75% w/w, or about 0.05-50% w/w, or about 0.1-25% w/w. Preferably, the cyclodextrin component may be present in a concentration range of about 0.1-10% w/w. More preferably, the cyclodextrin component may be present in a concentration range of 0.1-5% w/w.
The carbohydrate clathrate composition may preferably include a clathrate capable of forming an inclusion complex with a variety of complex-forming compounds, such as amino acids, vitamins, flavorants, odorants, colorants, and the like. Non-exclusive examples of carbohydrate clathrate components capable of binding a complex-forming compound to form an inclusion may include a¨cyclodextrin, 13¨cyc1odextrin, 'y¨cyclodextrin, 2-hydroxypropyl-cyclodextrins, caboxymethylated-cyclo dextrins, quaternary-ammonium- cycl o dextrins, amyl o s e s, amyl o s e derivatives, or any desired mixture of these.
A cyclodextrin clathrate component may be further selected based upon its desired binding properties with selected complex-forming compounds. Non-limiting examples of acceptable cyclodextrins may include commercially available and government regulatory approved forms of a-, 13- and y-cyclodextrins. The number of glucose units determines the internal dimensions of the 5 cavity and its volume, and may determine a selectivity in forming inclusion complexes with a guest molecule.Selected complex-forming compounds, when bound to a host cyclodextrin or other host carbohydrate clathrate, may modify the physico-chemical properties of the complexed host to increase its kosmotropic activity.
If the clathrate component is in the form of an amylose component, the amylose component 10 may contain glucose units expressed as degree of polymerization (DP) in the range of DP = 10-900, and more preferably DP = 20-200, and most preferably DP = 30-80. Amylose derivatives may include, but are not limited to, acetylated amyloses. The amylose component preferably may have a structure that includes a1,4-linked D-glucopyranoses in a helical arrangement that defines a central cavity for binding hydrophobic molecules. For example, the A- and B-starch helix of V-15 amylose may include a parallel, left-handed double helix defining a central cavity. The helices of amylose inclusion complexes may be stabilized by the hydrophobic forces created by the host-guest interactions, intermolecular H-bonds between glucoses in adjacent amyloses, and intramolecular H-bonds formed by adjacent turns of the helix. See Hinrichs, W., et al., "An Amylose Antiparallel Double Helix at Atomic Resolution," Science, (1987), 238(4824): 205-208, 20 the complete disclosure of which is hereby incorporated by reference for all purposes. An amylose clathrate component maybe used to form an inclusion complex with a complex-forming compound having a low molecular weight, such as the non-limiting examples of flavorants, colorants, vitamins, amino acids, and/or amines.
If the composition containing an amylose clathrate component is in solid form, the amylose component preferably may be present in a concentration range of about 10-90%
w/w, or about 15-70% w/w, or about 15-60% w/w. More preferably, the amylose component may be present in a concentration range of about 10-50% w/w, or about 15-40% w/w. Most preferably, the amylose component may be present in a concentration range of about 20-25% w/w. If the composition containing the amylose clathrate component is in the form of an aqueous beverage, the amylose component preferably may be present in a concentration range of about 0.1-75%
w/w, or about 1-50% w/w, or about 1-25 % w/w.
Complex-forming Compound In some examples, the clathrate compositions disclosed herein may optionally contain a complex-forming compound (also referred to as an agent), which may include one or more amino acids, vitamins, flavorants, odorants, and/or other nutritional components, as well as combinations or mixtures of these agents. The carbohydrate clathrate compositions may further include one or more carbonation forming components for use in forming beverage products.
The complex-forming compound may strongly complex with the clathrate component so as to increase a kosmotropic activity and thereby influence cellular hydration. Alternatively, these agents may weakly complex with the clathrate component so as to have the capability of dissociating therefrom in order to allow a free clathrate component to increase water structure.
As used herein, it is intended that a complex-forming compound is any compound that has utility in the beverage compositions described below, regardless of how strong or weakly it complexes with the clathrate component, and even if it does not complex at all with the clathrate component. As noted above, there are two types of complex-forming compounds, a first type being simply referred to as complex-forming compounds, and a second type of "outer sphere"
complexing agents.
Non-limiting examples of amino acids suitable for forming inclusion complexes with the carbohydrate cl athrate compositions of the present disclosure may include aspartic acid, arginine, glycine, glutamic acid, proline, threonine, theanine, cysteine, cystine, alanine, valine, tyrosine, leucine, isoleucine, asparagine, serine, lysine, histidine, omithine, methionine, carnitine, aminobutyric acid (alpha-, beta-, and gamma-isomers), glutamine, hydroxyproline, taurine, norvaline, sarcosine, salts thereof, and mixtures thereof. Also included are N-alkyl Ci-C3 and N-acylated Ci-C3 derivatives of these amino acids, and mixtures of any of the amino acids or derivatives thereof. Preferred complex forming amino-acids that may he included with cyclodextrins to increase water structure and cellular hydration include L-arginine, L-lysine, N-methyl-lysine, and L-carnitine.
Non-limiting examples of vitamins may include nicotinamide (vitamin B3), niacinamide, niacin, pyridoxal hydrochloride (vitamin B6), ascorbic acid, edible ascorbyl esters, riboflavin, pyridoxine, thiamine, vitamin B9, folic acid, folate, pteroyl-L-glutamic acid, pteroyl-L-glutamate, salts thereof, and mixtures thereof. Preferred vitamins included with cyclodextrins to increase water structure and cellular hydration may include nicotinamide and niacinamide.
Non-limiting examples of flavorants may include apple, apricot, banana, grape, blackcurrant, raspberry, peach, pear, pineapple, plum, orange, and vanilla flavorants. Examples of flavorant related compounds include butyl acetate, butyl isovalerate, allyl butyrate, amyl valerate, ethyl acetate, ethyl valerate, amyl acetate, maltol, isoamyl acetate, ethyl maltol, isomaltol, diacetyl, ethyl propionate, methyl anthranilate, methyl butyrate, pentyl butyrate, and pentyl pentanoate. A
flavorant may be selected so that it weakly binds to a selected cyclodextrin component with a binding constant in the range of about 10 to 800 M-1, preferably 30 tol 50 M-1, and more preferably 40 to 100M'.
Non-limiting examples of other taste improving components may include polyol additives such as erythritol, maltitol, mannitol, sorbitol, lactitol, xylitol, inositol, isomalt, propylene glycol, glycerol (glycerine), threitol, galactitol, palatinose, reduced isomalto-oligosaccharides, reduced xylo-oligosacchari des, reduced gentio-oligosacchari des, reduced maltose syrup, and reduced glucose syrup.
Non-limiting examples of colorants may include those that are known to be more water soluble and less lipophilic. Examples of colorants with those properties are betalains, which may be from beetroot Examples of betalains include betacyanins and betaxanthins, including vulgaxanthin, miraxanthin, portulaxanthin and indicaxanthin; anthocyanidins, such as aurantinidin, cyanidin, delphinidin, europinidin, luteolinidin, pelargonidin, malvidin, peonidin, petunidin and rosinidin, as well as all corresponding anthocyanins (or glucosides) of these anthocyanidins; and turmeric type colorants including phenolic curcuminoids, such as curcumin, demethoxycurcumin and bisdemethoxycurcumin.
In addition to those described above, non-limiting examples of other complex-forming compounds may include curcumin, polyphenols, dihydrocurcumin, spermidin, L-lysin, reservatrol, coenzymeQ10, delta-tocopherol, delphindin, caffeine, and guama.
Another group of non-limiting examples of complex-forming compounds, of the outer-sphere type, are electrolytes, and specifically, magnesium, sodium, potassium, chloride, calcium, phosphate, and bicarbonate.
All of the above examples of amino acids, vitamins, flavorants and related compounds may be in appropriate salt or hydrate forms.
The complex-forming compound may be selected to form an inclusion complex with a selected clathrate component. The complex-forming compound may bind to the clathrate component as a guest molecule in the cavity of the clathrate molecule, and/or may form a so-called outer sphere complex, where the selected weak complex-forming compound binds to the clathrate molecule at a position at or around the rim(s) of the clathrate. For example, the selected weak complex-forming compound may be bound to a cyclodextrin molecule at or around the primary and/or secondary hydroxyl groups at the rims of the cyclodextrin torus. Some complex-forming compound that form an outer sphere complex with the selected cyclodextrin may reduce or prevent self-aggregation of dissolved, hydrated cyclodextrin molecules by masking intermolecular hydrogen bonds that form between two neighboring cyclodextrin molecules in water.
If the carbohydrate clathrate composition is in solid form, the complex-forming compound may be present in a concentration range of about 1-50% w/w. Preferably, the complex-forming compound may be present in a concentration range of about 1-40% w/w or about 1-25% w/w.
More preferably, the complex-forming compound may be present in a concentration range of about 5-15%w/w.
If the carbohydrate clathrate composition is in the form of an aqueous beverage, the complex-forming compound may be present in a concentration range of about 0.1-25% w/w or about 1-20% w/w. Preferably, the complex-forming compound may be present in a concentration range of about 1-15% w/w or about 1-10% w/w or about 3-8% w/w. More preferably, the complex-forming compound may be present in a concentration range of about 5-8% w/w.
The Inclusion Complex As noted above, the inclusion complex may include a clathrate host molecule complexed with one or more complex-forming compound. In the form of a solid product, such as a solid powder or tablet, the inclusion complex may exhibit some unique properties as compared to a solid composition containing essentially the same components, but without the preliminary formation of the inclusion complex. The inclusion complex is essentially a chemical entity having non-covalent hydrogen bonds formed between the clathrate molecule and the weak complex-forming 5 compound molecule. The inclusion complex, in its solid form, has the potential of dissociating into the clathrate component for increasing water structure and the complex-forming compound, which may further increase water structure or provide other beneficial properties, such as nutrition or flavor, when the inclusion complex is introduced to an aqueous environment, such as upon dissolution in an aqueous beverage, or upon ingestion.
10 When in the form of a solid product, the clathrate component and one or more types of a complex-forming compound may be substantially in the form of an inclusion complex, as described above. Preferably, over about 25% of the clathrate component is complexed with one or more types of a complex-forming compound in the form of an inclusion complex.
It is progressively more preferable to have over 35%, 45%, 50%, 60%, 70%, 80%, 90%, and 95% of 15 the clathrate component complexed.
IV Carbonation-Forming Components Some clathrate compositions may include carbonation-forming components that produce carbonation, or effervescence, upon dissolution into an aqueous environment.
Carbonation-forming components advantageously may inhibit self-aggregation of clathrate molecules, thereby 20 increasing clathrate surface area for structuring water and increasing cellular hydration.
Non-limiting examples of carbonation-forming components may include sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate. Preferred carbonation-forming components may include sodium carbonate, and sodium bicarbonate.
If the carbohydrate clathrate composition is in solid form, the carbonation-forming component may be present in a concentration range of about 1-60% w/w or about 5-60% w/w.
Preferably, the carbonation-forming component may be present in a concentration range of about 5-45% w/w or 10-45% w/w. More preferably, the carbonation-forming component may be present in a concentration range of about 10-15% w/w.
If the carbohydrate clathrate composition is in the form of an aqueous beverage, the carbonation-forming component may be present in a concentration range of about 1-30% w/w or about 1-25% w/w. Preferably, the carbonation-forming component may be present in a concentration range of about 2-15% w/w or 2-10% w/w. More preferably, the carbonation-forming component may be present in a concentration range of about 2-5% w/w V Other Components Some compositions may include yet other components that affect the taste and/or nutritional value of the composition. These additional components may include, but are not limited to, one or more of the following: flavor additives, nutritional ingredients and/or various hydroxyl-acids that act as clathrate aggregation-preventing additives in the formulations. Non-limiting examples of such other components may include citric acid, ascorbic acid, sodium chloride, potassium chloride, sodium sulfate, potassium citrate, magnesium sulfate, alum, magnesium chloride, maltodextrin, mono-, di-, tri-basic sodium or potassium salts of phosphoric acid (e.g., inorganic phosphates), salts of hydrochloric acid (e.g., inorganic chlorides), sodium bisulfate. Non-limiting examples of hydroxyl-acids that prevent cyclodextrin aggregation may include isocitric acid, citric acid, tartaric acid, malic acid, threonic acid, salts thereof and mixtures thereof. These hydroxyl-acids also may exhibit some nutritional benefits Other non-limiting examples of additional optional components, such as taste additives, that may be used include suitable organic salts, such as choline chloride, alginic acid sodium salt (sodium alginate), glucoheptonic acid sodium salt, gluconic acid sodium salt (sodium gluconate), gluconic acid potassium salt (potassium gluconate), guanidine HC1, glucosamine HC1, amiloride 11C1, monosodium glutamate (MSG), adenosine monophosphate salt, magnesium gluconate, potassium tartrate (monohydrate), and sodium tartrate (dihydrate).
Preferred other components may include, for example, citric acid, ascorbic acid, and maltodextrin.
If the carbohydrate clathrate composition is in solid form, the one or more other components each may be present in a concentration range of about 1-30% w/w or about 1-25%
w/w Preferably, the one or more other components each may be present in a concentration range of about 1-20% w/w or 1-15% w/w. More preferably, the one or more other components each may be present in a concentration range of about 2-5% w/w.
If the carbohydrate clathrate composition is in the form of an aqueous beverage, the one or more other components may be present in a concentration range of about 1-20%
w/w or about 1-15% w/w. Preferably, the one or more other components may be present in a concentration range of about 1-10% w/w or 1-5% w/w. More preferably, the one or more other components may be present in a concentration range of about 1-3% w/w.
VI. Component Ratios In addition to the above descriptions regarding the types and amounts of the various components that may be employed in the carbohydrate clathrate compositions disclosed herein, it is additionally noted that the relative amounts of these components can be described as well.
Preferably, the weight ratio of the clathrate component to the complex-forming compound may be in the range of about 5:1 to 1:10, more preferably may be in the range of about 2:1 to 1:5, still 2g more preferably may be in the range of about 2:1 to 1:2, and yet more preferably may be in the range of about 1:1 to 1:2.
Regarding the other possible components, such as flavor components, carbonation-forming components, and other components described above, the weight ratio of the clathrate component to each of the other components separately may be in the range of about 25:1 to 1:25, or about 10:1 to 1:10, or about 5:1 to 1:5, or optionally about 2:1 to 1:2, as well as 1:1.
The present invention provides a beverage composition, system and method of use, and a mechanism of action of the beverage composition for increasing cellular hydration and for increasing lifespan.
In an embodiment, the present invention provides a beverage composition comprising a carbohydrate clathrate component that includes cyclodextrin, in a concentration of 0.01-5% w/w;
a complex-forming compound; an aqueous liquid component, chosen from the group consisting of still and carbonated aqueous liquids; wherein an inclusion complex is formed with at least some of the clathrate component and at least some of the complex-forming compound.
Further, the ratio of clathrate component to complex-forming compound is preferred in the range from about 5:1 to about 15:1.
In another embodiment, the beverage composition of the present invention comprises a cyclodextrin, or mixture of cyclodextrins, and complex forming compound. One embodiment may include 0.05 % alpha-cyclodextrin in water, 0.05 % alpha-cyclodextrin-L-Arginine inclusion complex in water, 0.05 % alpha-cyclodextrin-nicotinamide inclusion complex in water, 0.05 %
alpha-cyclodextrin-nicotinic acid (niacin) complex in water; or mixtures of one or more of the aforementioned substances.
In another embodiment, the present invention includes gamma cyclodextrins-based beverage compositions and a the complex-forming compound.
To describe the mechanism of action of the invention, certain tissue present in multicellular organisms must first be described to provide perspective of how that mechanism of action functions. A lipid bilayer or phospholipid bilayer is a thin polar membrane made of two layers of lipid molecules. The lipid bilayer is the barrier that keeps ions, proteins and other molecules where they are needed and prevents them from diffusing into areas where they should not be. Biological bilayers are usually composed of amphiphilic phospholipids that have a hydrophilic phosphate head and a hydrophobic tail consisting of two fatty acid chains. Apart from phospholipids, the bilayer comprises cholesterol which helps strengthen the bilayer and decreasing its permeability.
It also comprises integral membrane proteins and other functional proteins like ion-channels, aquaporins etc. (as shown in FIG. 19).
Aquaporins are the only known water channel, however, water also diffuses via passive diffusion in response to osmotic gradient established by sodium in the intestinum. The bulk of the water absorption is a transcellular process, i.e., it goes through membrane bilayers by passive diffusion via the water channels (aquaporins), but some also diffuses through the tight junctions (called paracellular pathway, and shown in FIG. 20).
According to the present invention, the cyclodextrin-based beverages influence the cellular hydration with a mechanism of temporary and reversibly changing the cell membrane lipid packing and the membrane fluidity, due to the non-covalent inclusion complex formation. This feature of the mechanism of action is also referred to as reversibly and temporarily disintegrating the membrane lipids, but disintegrating is not used in its usual sense to mean destruction. Rather, the lipids are changed or moved but the process is reversible so they can return to the location they were and can again pack together. The cyclodextrin-based beverages of the invention may comprise alpha cyclodextrin or its derivatives, or beta cyclodextrin or its derivatives.
The alpha cyclodextrin and its derivatives primarily affect the phospholipid constituents, and the membrane anchored-proteins in the vicinity of these consituents. On the other hand, beta-5 cyclodextrins and derivatives target mainly cholesterol and cholesterol-phospholipid complexes in the membrane.
Further, the alpha-cyclodextrin and its derivatives preferably interact with slim membrane lipid components such as glycosphingolipids, sphingomyelin, phosphatidylcholine, phosphatidyl ethanolamine etc., wherein, all these phospholipids are integral constituents of lipid rafts, where 10 most of the membrane-bound functional proteins are located, such as ion channels, or water channels/aquaporins.
The interaction between cyclodextrins and phospholipids is a reversible non-covalent complex formation, a molecular event, during which the lipid environment of membrane-anchored proteins will alter and the cell-physiological functions of these transporter proteins (e.g. ion 15 transport) will change leading to enhanced water transport The lipid-cyclodextrin interaction is completely reversible that leads to change in lipid packing in a cyclodextrin concentration dependent manner. The low concentration of hydration-enhancing cyclodextrins exerts no irreversible cellular damage.
The highly hydrated form is a dissolved alpha-cyclodextrin; and in an alpha-CD
water 20 solution, water structure (monomers-and clusters) will be changed. In carbonated water, more importantly dissolved alpha-CD will contain less aggregates of the cyclodextrins and more hydrated monomers. The lower the number of aggregated alpha-CDs in water solution, the higher the number of accessible cyclodextrin cavities, ready for complex formation.
Similarly, the beta-cyclodextrin and its derivatives affect the membrane cholesterol-rich domains around the membrane-bound proteins. Both alpha- and beta-cyclodextrins cause change in membrane transport processes, initiate cell signaling, and affect water transport across aquaporins.
The cellular hydration plays a role in different cell functions and enhancement of cell hydration has an effect on cellular autophagosome formation or on autophagy.
(References: S.
Vom Dahl, et al. Biochem. J. 2001. 354. (1) 31-36. and Schliess, F. et al Acta Physiologic 187. 1-2. 2006., and Haussinger, D.). Further, cellular hydration state is an important determinant of protein catabolism in health and disease (Lancet 341. 8856. 1330-1332. 1993).
In another embodiment, the present invention includes a beverage composition that causes cellular hydration in a multicellular organism when a multicellular organism ingests it. The multicellular organism is capable of intracellular water permeation, and the ingestion of the composition by the multicellular organism enhances the intracellular permeation. The organism contains aquaporins, and the cellular hydration is caused by interaction of the composition with the aquaporins.
The present invention also provides a method of promoting increased cellular hydration in a multicellular organism that is capable of intracellular water permeation, comprising; causing the multicellular organism to ingest an aqueous solution that contains an amount of a carbohydrate clathrate component; and enhancing the intracellular permeation. The multicellular organism contains aquaporins and causes interaction of the composition with the aquaporins. The cyclodextrin-assisted enhancement of intracellular water permeation was assessed and corroborated by single cell Xenopus laevis frog oocytes having expressed human aquaporin AQP-1 water channels. The results of the biological tests are illustrated Example 7.
In another embodiment, the present invention provides a method of promoting increased cellular hydration in a multicellular organism that includes water and a carbohydrate clathrate component, and functions to decrease the density of at least some of the water in the aqueous solution. The physico-chemical properties for this embodiment of the invention that lowers the density of water in the aqueous solution is shown in Example 2.
Further, as described in (M.F. Chaplin Biophysical Chemistry 83 (1999) 211 ¨
221), dodecahedral water clusters have been reported at hydrophobic and protein surfaces, where low-density water with stronger hydrogen bonds and lower entropy has been found.
Similar cavities have been found in low density amorphous ice (LDA) and shown to be formed relatively easily in water during molecular simulations. The basis of the model described herein is a network that can convert between lower and higher density forms without breaking hydrogen bonds. It contains a mixture of hexamer and pentamer substructures and contains cavities capable of enclosing small solutes.
The above embodiment of the invention applies this theory and results in a novel mechanism that changes the structure of water by reducing its density.
The present invention provides another method for increasing hydration of cell system to promote cellular hydration in a multicellular organism when the mixture is ingested. The multicellular organism contains membrane lipids, lipid packing and membrane proteins, protein structure and protein function, and membrane permeation of nutrients and water. The method further includes the steps of causing the multicellular organism to ingest an aqueous solution that contains an amount of a carbohydrate clathrate component; and changing the lipid bilayer structure of multicellular organism by (i) temporary disintegration of the membrane lipids, (ii) loosening of the lipid packing and membrane proteins, and (iii) altering the protein structure and protein function, collectively to enhance membrane permeation of nutrients and water.
VII. Preferred Embodiments Preferred embodiments of the carbohydrate clathrate composition disclosed herein are provided as illustrations, and are not intended to limit the scope of this disclosure in any way.
Effect of cyclodextrin on molecular dynamics of water structure.
A simulated water solvated cyclodextrin molecular system was created using HyperChem0 5.11 software (from HyperCube Inc, Gainesville, FL), with input parameters derived from single ciystal analysis of cyclohepta-amylose dodecahydrate clathrate (or, fi-cyclodextrin) reported by Lindner and Saenger (see: Carbohydr.Res., 99:103, 1982), and using a water periodic solvent box (3.1x3.1x3.1 nm3) containing altogether 984 water molecules. Molecule conversion and atom type were adjusted to the proper format using TinkerFFE
4.2 (TINKER
Software Tools for Molecular Design, Version 5.0, Jay William Ponder, Washington University, St. Louis, MO). Molecular mechanics and dynamics calculations were performed with Tinker 5.0 software after preliminary optimization of the truncated Newton-Raphson method using a Linux x86-64 operating system (Slamd 64 v12.2).
Molecular dynamics simulations were run using MM3 Force Field molecular mechanics software, at constant temperature (298 K) for 120 picosecond (psec), with 0.1 femtosecond (fsec) steps. Recordings were generated by dumping intermediate structures every 100,000 steps (equivalent to 10 psec elapsed time).
Observations:
At time zero of each simulation, the standard water solvent box contained one fi-cy clod extrin clathrate molecule and a uniformly distributed population of 984 water molecules.
FIGS. 4 and 5 show a representation of the central portion of the solvent box at particular elapsed times during one representative simulation. It will be appreciated that water molecule positions and orientations are represented as (bent) rods, while P-cyclodextrin is represented as a van der Waals surface. It will be further appreciated that FIGS. 4 and 5 depict a volume of the solvent box, and therefore compress a three dimensional molecular distribution into two dimensions.
FIG. 4 shows a central portion of the solvent box at 1 psec of elapsed time of a simulation. In particular, at 1 psec of elapsed time, water molecules immediately adjacent to ii-cycl dextrin have acquired relatively static (stable) positions through H-bonding to cyclodextrin. Such water molecules may be referred to as a first hydration layer. However, the distribution of most water molecules in the solvent box remains generally similar to the starting distribution (1 psec previous), which is unstructured.
FIG. 5 shows the simulation of after 1000 psec (i.e., 1 nsec) of elapsed time.
At 1000 psec, water molecules immediately adjacent to f3-cyclodextrin continue to occupy relatively static (stable) positions. However, compared to 1 psec (FIG. 4), water molecules beyond the first hydration layer have acquired a more open microstructure.
Differences in water structure may be more readily observed in the absence of the perspective shadowing detail included in FIGS. 4 and 5. FIG. 6 shows alternative views of the water molecule distributions shown in FIG. 4 (left side, labeled 1 psec) and FIG. 5 (right side, labeled 1000 psec), which were produced by the following methods: image files for FIG. 4 and 5, having 256 grey levels (8 bits), were opened in Photoshop 9.0 (Adobe, Inc), adjusted to 300 dpi, thresholded at grey level 207; images were cropped to an identical outer annulus diameter using the circle select tool, and the outer square corners filled with black (grey level 0), and then further cropped to blacken an inner annulus that barely includes the cyclodextrin molecule. The dimensions of the outer and inner annuli are identically applied to the compared images. The 5 resulting thresholded representations qualitatively show water molecules surrounding the central (occluded) cyclodextrin molecule have a more open and coordinated structure at 1000 psec (e.g., right side panel of FIG. 6).
To quantitatively assess the change in microstructure of water represented in FIGS. 4-6, molecular density was approximated by measuring open paths through the depicted volume, a 10 method similar to a mean free path analysis, where a mean free path in a defined volume of a molecular substance is inversely related to the density of the molecules. In particular, an open path between water molecules is shown by a white pixel element, and the number of open paths in the volume is readily quantitated using the histogram tool of Photoshop 9.0 to count the number of white pixel elements. Applied to the panels of FIG. 6, a measured increase of 2% was calculated 15 for open paths at 1000 psec of elapsed time compared to open paths at 1 psec of elapsed time. For comparison, freezing of pure water results in a 9 % decrease in density. As path length is inversely proportional to molecule density, the analysis indicates that dissolved cyclodextrins decrease the density of an aqueous solution by increasing the organization of water molecules.
In summary, the results indicate a rapid (psec) H-bonding adhesion between the outer 20 surface hydroxyls of 3-cyclodextrin and water molecules is followed by a slower (nanosecond) propagation of water molecule reorientation throughout the solvent box, resulting in a more open water structure. The measured results further indicate that a cyclodextrin may sufficiently increase H-bonding between water molecules in the surrounding aqueous volume to result in a decrease in the density of water.
Physicochemical Properties (Density measurements) The current study further manifests the density measurements in a cyclodextrin concentration dependent manner. The materials used were specified as: a-cyclodextrin (Wacker -food grade, internal ID: B002/18); three weak complex forming additives (in a-cyclodextrin complex, 1:1 mol/mol) are L-arginine (Sigma-Aldrich Cat. No A5006), Nicotinic acid (Sigma-Aldrich Cat. No 72309), Nicotinamide (Sigma-Aldrich Cat. No 72340) y-cyclodextrin (Wacker -food grade, internal ID: B064/18).
Water samples used were bottled water and tap water; wherein the tap water comprises the following impurities and properties: Free active chlorine (0.18 mg/1), Chloride (24 mg/1), Iron (6 pig/1), Manganese (2 fig/1), Nitrate (9 mg/1), Nitrite (<0.03 mg/1), Ammonium (<0.04 mg/1), Hardness of water (122 mg/1 CaO), Conductivity (442 1AS/cm) and pH 8. Purified water was produced by removal of dissolved ions by Merck/Millipore Synergy Water Purification System at Cyclolab. The water quality produced Type 1 water (18.2 M12-cm at 25 C
ultrapure water) from pretreated water.
1:1 mol/mol stoichiometry complexes were prepared for the experiment.
Nicotinic acid /
alpha-CD complex was prepared by dissolving 11.22 g nicotinic acid and 98.63 g alpha-CD (89.66 g on dry basis) in 700 ml purified water. Nicotinamide / alpha-CD complex was prepared by dissolving 5.57 g nicotinamide and 49.3 g alpha-CD (44.4 g on dry basis) in 350 ml purified water and L-arginine / alpha-CD complex was prepared by dissolving 15.18 g L-arginine and 94.26 g alpha-CD (85.69 g on dry basis) in 700 ml purified water. Further, for all the three complexes, the liquid was frozen in dry ice bath and lyophilized. The dry lyophilizate was ground and sieved.
Clarity, phi, conductivity, density, viscosity, turbidity, surface tension and osmolality were determined in solutions prepared with purified water. The concentration noted for the complex solutions are indicating the actual alpha cyclodextrin content. Alpha & gamma cyclodextrin mix is a 50-50 weight% mixture of the two constituents and the percentage indicates the total cyclodextrin content. Tables 1-3 summarize the results of the physico-chemical tests.
Physico-Chemical properties of test solutions containing alpha- and gamma cyclodextrin vs.
control purified water Purified Water No Additive Alpha Cyclodextrin Gamma cyclodextrin 0.00% 0.05% 010% 1.00% 2.00% 0.05% 0.10% 1.00%
2.00%
6.28 6.20 6.38 8.55 6.70 6.82 6.79 6.87 6.77 PH
Conductivity 34.3 35.3 39.0 39.6 38.7 25.0 25.0 27.0 27.0 (pS-cm') Density (at 22 C) 0.9980 0.00 0.990 0.0 0.989 0.993 1.048 0.995 0.0 0.997 0.999 1.003 (g. ail') 05 02 01 0.91 0.91 0.92 0.97 1.01 .92 .92 .94 0.97 Viscosity (25 C) (cP) Titibidity (Abs, (reference) 0.003 0.000 0.017 0.015 0.005 0.008 0.065 0.108 2=410nm) clear clear clear clear clear clear clear hazy hazy Visual Inspection Surface Tension 72 72 72 72 73 72 72 73 (mN-m') Osmolality o o 2 8 18 0 0 4 (mOstn/kg) 3g Physico-Chemical properties of test solutions prepared of alpha-cyclo dextrin complexes vs.
control purified water Purified Water No Additive Alpha Cyclodextrin Gamma Cyclodextrin 0.00%
0.05% 0.10% 1.00% 2.00 A; 0.05% 0.10% 1.00% 2.00%
6.28 8.88 9.18 9.87 10.12 6.48 6.42 6.55 6.59 pH
Conductivity 34.3 46.6 52.6 97.3 130.0 40.7 43.6 44.0 45.8 (tiS-cm') Density (at 22 C) 0.99800.000 0.995 0.00 0.981 0.990 1.010 0.995 0.00 0.996 1.003 1.005 (g- c911) 5 1 1 0.91 0.94 0.91 1.02 1.06 0.93 0.95 1.00 1.06 Viscosity (25 C) (cP) Turbidity (Abs, (reference) 0.006 0.010 0.095 0.165 0.0152 0.0296 0.0463 0.0981 2=410nm) Visual Inspection clear clear clear hazy hazy clear clear hazy hazy Surface Tension 72 72 72 72 73 72 72 72 73 (tnN -tri-l) Osmolality 0 0 1 17 34 / / 21 (mOstn/kg) In Table 2, the second-fifth columns correspond to mixtures of alpha cyclodextrin with an L-arginine complex and ACD/Nicatinamide, and the sixth-ninth columns correspond to gamma cyclo dextrin mixtures.
Physico-Chemical properties of test solutions prepared of alpha-cyclodextrin/nicotinic acid complex, alpha & gamma cyclodextrin mix vs. control purified water Purified Water No Additive Alpha Cycludextrin / Nicotinic acid Alpha & Gamma Cyclodextrin Mix 0.00% 0.05% 0.10% 1.00% 2.00% 0.05% 0.10% 1.00%
2.00%
pH 6.28 4.26 3.79 3.60 3.45 6.64 6.72 6.67 6.93 Conductivity 34.3 46.1 56.1 123.7 154.5 33.0 25.0 27.0 28.0 (1.1.S=cm-1) Density (at 22 C) 0.9980+0.00 0.994+0.00 0.994+0.00 0.994 0.995 0.994 0.997 0.998 1.002 (g. cm-1) 05 1 1 Viscosity (25 C) 0.91 0.92 0.91 1.01 1.07 0.91 0.91 0.94 1.04 (cP) Turbidity (Abs, (Reference) 0.000 0.001 0.103 0.28 0.005 0.007 0.003 0.055 I:1=410nm) Visual Inspection Clear Clear Clear Hazy Turbid Clear Clear Clear Hazy Surface Tension (mN=m-l) Osmolality o o o 15 28 o o 6 (mOsm/kg) Tables 1-3 report the results of the physico-chemical test, wherein a notable effect is manifested in the density measurements, that presence of dissolved cyclodextrins at low concentration (0.05%) has a density-decreasing effect of purified water, and this phenomenon occurs also in the case of both L-Arginine and nicotinic acid complexes in low (0.05 %) concentration. At higher concentration (0.5 and 1.0% solutions), however, this effect does not show up due to the higher solid content which evidently increase the density of the liquids.
The density measurements were repeated using tap water and it was found that the above-mentioned phenomenon does not occur probably due to the perturbating presence of ions in tap water. However, it may not be established exactly which ionic species (Mg2+, Ca2+, Na+) causes this perturbation. The results are shown in Table 4.
Density of alpha- and gamma-CD solutions prepared with Tap water Tap water No Additive Alpha Cyclodexrin Concentration 0.05% 0.10% 1.00%
2.00%
Density (at 22 0.9987+0.005 0.9992+0.007 0.9994+0.004 1.0021+0.007 1.0088+0.005 C) (g.cint) Gamma cyclodextrin Concentration 0.05% 0.10% 1.00%
2.00%
Density (at 22 0.9997+0.0007 1.0002+0.0004 1.0035+0.0007 1.0094+0.0006 C) ( 5 Effect of cycodextrin additives on water bonding detected by IR
spectroscopy Physical micro-structure studies of water, water-sugar interactions, and detection of sugar effects on increasing and decreasing water structure have preferentially employed infrared (IR) spectroscopy, and particularly near infrared (NIR) spectroscopy, as for example reported by Segtan et al. (see: Anal. Chem. 2001; 73, 3153-3161), and R. Giangiacomo (see: Food Chemistry, 2006, 10 96.3. 371-379.) Hydration bond energies in pure waters and solutions of the same waters containing cyclodextrin compounds were assayed using IR spectroscopy in the near and middle infrared ranges. To record linear signals throughout an entire wavelength range, attenuation from water absorbance was minimized with a short optical length cuvette.
NIR range spectra were registered on a FOSS MR Systems, Inc. 6500 spectrometer and Sample Transport Module (STM) using a lmm-sized cuvette. Transmission spectra were collected from 1100-2498 nm using a lead sulfide (PbS) detector and Vision 2.51 software (2001; FOSS
NIRSystems, Inc.) A Perkin-Elmer Spectrum 400 FT-MR/FT-IR spectrometer and UATR (Universal Attenuated Total Reflectance; ZnSe-diamond crystal, 1 x flat top plate) sample handling unit were used to obtain spectra across 2500-15385 nm (reported as 4000 ¨ 650 cm-').
Measurements were performed at 24C using a triglycine-sulfate (TGS) detector and Spectrum ES
6.3.2 software (PerkinElmer, 2008).
Three samples of water were used in the present study. A first water sample was purified by reverse osmosis, carbon filtration, ultraviolet light exposure, membrane filtration to 0.2 micron absolute, and ozonation. Second and third water samples were not purified.
Capillary electrophoresis revealed similar ionic components but at different concentrations between the three waters.
The following cyclodextrins were added to the above described water samples at a concentration range of 0.1% - 5% w/w:
a-cyclodextrin (aCD also denoted as ACD), Lot. No. CYL-2322.
13-cyclodextrin (f3CD also denoted as BCD). Lot. No. CYL-2518/2.
7-cyclodextrin (7CD also denoted as GCD), Lot. No. CYL-2323.
2-hydroxypropyl-f3-cyclodextrin (HP0CD, HPBCD), DS* = 3.5, Lot. No. CYL-2232.
2-hydroxypropylmcyclodextrin (HPCD, HPGCD), DS* = 4.8, Lot. No. CYL-2258.
carboxymethyl-fl-cyclodextrin (CMBCD), Lot. No. CYL-2576.
quaternary-ammonium-P-cyclodextrin (QABCD).
For some examples, various inclusion complexes were formed between cyclodextrins and complex-forming bioactive agents, including the amino acids L-arginine and L-carnitine and the vitamin niacinamide (also known as nicotinamide). All reagents were of analytical purity. For some examples, L-arginine and nicotinamide were added in free form and alternatively in a cyclodextrin-complexed (molecularly entrapped) form to assess independent and co-dependent activities of a cyclodexrin and a bioactive agent. Concentrations of above additives in free form, and as cyclodextrin inclusion complex forms, were in the range of 0.1% to 5.0%
w/w.
Observations:
FIG. 7 shows second-derivative NIR spectra for the wavelength region 900-1200 nm. The results show water-bond interactions are significantly modified by addition of QABCD, and further significantly modified by addition of CMBCD and HPBCD.
FIG. 8 shows second-derivative NIR spectra shown for 1200-1500 nm. The results show water-bond interactions are significantly modified by addition of QABCD and HF'BCD, and further significantly modified by addition of CMBCD
FIG. 9 shows second-derivative NIR spectra shown for 1620-1710 nm. The results show water-bond interactions are significantly modified by addition of CMBCD, QABCD, and HPBCD.
FIG. 10 shows second-derivative NIR spectra shown for 2170-2370 nm. The results show water-bond interactions are significantly modified by addition of CMBCD and HPBCD, and further significantly modified by addition of QABCD.
As shown in FIGS. 7-10, addition of cyclodextrins alters molecular bonding interactions of the aqueous medium. Referring particularly to FIG. 9, refined MR spectra derivatives in the wavelength range of 1 620-1 770 nm show the carbon hydrogen bond related alterations involve CH3- CH2- and CH- groups of cyclodextrin additives. The significant spectral changes occurring in each cyclodextrin-treated water sample indicate the modified micro-structure of hydrogen bonds governed cluster systems in bulk water. This effect was largest in the water samples treated with charged quaternary-ammonium-fl-cyclodextrins (QABCD), as shown for example in FIGS. 9 and 10.
Acceleration of plant embryo germination.
Wheat seeds (Triticum aestivtan) were germinated using USA I, USA II, and BP I
waters described for Example 2. Germination rate using un-supplemented (control) water was compared to that with the same water variously supplemented with a cyclodextrin component, and/or a bioactive agent, as an active component of cellular hydration. For each condition, ten seeds were placed in continuous water contact in a Petri-type dish kept at 25C in 12 hr light/dark cycles.
Photometric images were recorded on days 1 to 6 after seeding. The percentage of seeds germinated was calculated and compared as a function of time and of the applied additive concentrations Water samples for seed germination were used alone with no additive, or containing cyclodextrins, or containing clathrate inclusion complexes of cyclodextrin with L-arginine or with nicotinamide (both obtained from Sigma Chemical Co.; St. Louis, MO), or with L-carnitine (from Lonza AG; Switzerland). Additives were included at 0.1 and 5. % (w/w).
Additive solutions were prepared fresh on the day of germination start_ Parent cyclodextrins a-cyclo dextrin (A CD), 0-cyclodextrin (BCD), and y-cyclodextrin (GCD), were obtained from Wacker Chemie (Munich, Germany). The following derivatized cyclodextrins were obtained from Cyclolab Ltd. (Budapest, Hungary):
hydroxypropyl ated-beta-cyclodextrin (DS-3)(HPBCD), carboxymethylated-O-cyclodextrin (DS-3.5)(CMBCD), hydroxy-3-N,N,N-trimethylamino)propyl-P-cyclodextrin chloride (DS-3.6)(QABCD).
Observations:
Germination kinetics in control and additive-modified water under identical conditions were quantified as the percentage of the seeds having a sprout. Each determination consisted of 100 seeds for each parameter. Results are reported in Table 5, below, and in FIGS. 1 7 -1 3.
A) Cyclodextrin/L-Arg Inclusion Complex Increases Seed Germination.
Effect of a-cyclodextrin and L-arginine on wheat seed germination rate (values = percentage of total seeds) Days control (water) a-Cyclodextrin, 0.5%
L-Arg, 0.5% a-CD/L-Arg inc. complex Table 5 shows comparative effects on the germination of wheat seeds of 0.5%
w/w a-CD, 0.5% w/w L-arginine (L-Arg), and 0.5% w/w of an a-CD/L-arginine inclusion complex, each dissolved in USA I water. The above-tabulated results indicate that, compared to pure water lacking any additive (control), wheat seed germination rate is much higher in water including 0.5%
(w/w) inclusion complex between a-cyclodextrin and L-arginine (aCD/L-Arg inc.
complex). In addition, the results in Table 5 indicate that wheat seed germination rate is much higher in water including inclusion complex between a-cyclodextrin and L-arginine (aCD/L-Arg inc. complex) compared to water including 0.5% (w/w) a-cyclodextrin (aCD) as an additive alone, and also compared to water including 0.5% (w/w) L-arginine (L-Arg) as an additive alone. Thus, the results indicate a complex of a-cyclodextrin and L-arginine has a synergistic effect on increasing seed germination rate, which is not shown by either individual component of the complex used as a solitary additive. Results of Table 5 are also shown in FIGS. 11 and 13.
B) Cyclodextrin/nicotinami de Inclusion Complex Increases Seed Germination.
Effect of a-cyclodextrin and nicotinamide on wheat seed germination rate Days Control (water) a-Cyclodextrin, 0.5%
nicotinamide, a-CD/nicot.
0.5% inc.
complex 10 Table 6 shows comparative effects on the germination of wheat seeds of 0.5% w/w a-cyclodextrin, 0.5% w/w nicotinamide, and 0.5% w/w of an a-cyclodextrin/nicotinamide inclusion complex (aCD/nicot. inc. Complex), each dissolved in USA I water. The above-tabulated results indicate that, compared to pure water lacking any additive (control), wheat seed germination rate is much higher in water including inclusion complex between a-cyclodextrin and nicotinamide.
15 In addition, the results in Table 6 indicate that wheat seed germination rate is much higher in water including inclusion complex between a-cyclodextrin and nicotinamide (aCD/nicot. inc. complex) compared to water including a-cyclodextrin (aCD) as an additive alone, and also compared to water including nicotinamide as an additive alone. Thus, the results indicate that when used as an inclusion complex, a-cyclodextrin and nicotinamide have a synergistic biological activity that 20 signficantly increases seed germination rate. Such biological activity was not demonstrated by either individual component of the complex used as a solitary additive.
Results of Table 6 are also shown in FIGS. 12 and 13.
C) Qualitatively similar results as those reported in Tables 5 and 6, and FIGS. 11-13, were obtained using USA II and BP I water for germination. Thus, in particular, cyclodextrin inclusion complexes containing L-arginine, or alternatively containing nicotinamide, when dissolved in USA II or alternatively in BP I water, each significantly increased wheat seed germination rate, as shown above using USA I water.
D) Lengths of sprouts (rate of sprout growth during germination) did not differ between conditions within a statistically significant confidence interval (P<0.05).
This result indicates that cyclodextrins, and particularly cyclodextrin inclusion complexes, may be used selectively as active components of cellular hydration to promote a rate of seed germination without necessarily also affecting a sprout growth rate.
Lifespan extension of C. elegans in hydration modified water C. elegans nematodes were grown in petri-type dishes containing normal nutrient liquid media prepared alternatively with USA I water (described in Example 2) lacking any further additive component (control) or the same water supplemented with a parent a-, 0-, or y-cyclodextrin, and/or a bioactive agent, as an active component of cellular hydration. Fifty 3 worms were transferred to each dish. Each condition was repeated in triplicate. Experiments were repeated for USA II and BP I waters described in Example 2.
Water additives:
A. Addition of parent a-, 13- and 'y-cyclodextrins.
B. Addition of L-arginine and nicotinamide.
C. Addition of inclusion complexes of cyclodextrins with L-arginine and nicotinamide.
Observations:
The results recorded are displayed below in Tables 7-9 and further presented in FIGS. 14-18.
Effect of cyclodextrins on C. elegans longevity Animals alive, % of initial (N=50) Life Span Control (water) a-Cyclodextrin , p-Cyclodextrin, y-Cyclodextrin, (days) 0.1% 0.1%
0.1%
Table 7 reports the percentage of animals surviving to midlife (10 days), advanced age (15 days) and old age (18 days), in media variably containing a parent a-, P-, and y-cyclodextrin as an active component of cellular hydration. In this example, parent cyclodextrins were added at a concentration of 0.1% w/w to nutritive media dissolved in USA I water.
Consistent with all previous studies, normal C. elegans animals in the present example survived two weeks in normal media. Each of the parent cyclodextrins markedly increased C.
elegans survival (percentage alive) at advanced li fesp an ages (days 10-15).
Further, a-cy cl o dextrin and 'y-cyclodextrins significantly increased the number of animals surviving to old ages, i.e., after day 15. The results are also represented graphically in FIG. 14, which compares the cumulative percentages of animals surviving to 15 and 18 days in media containing each additive parent cyclodextrin. The results show parent cyclodextrins, particularly a- and P-cyclodextrin, may be used as an active component of cellular hydration to improve biological function in a live animal.
Biological mechanisms supporting advanced aging may include improvement of broad spectrum cellular activity during aging, or alternatively by selectively activating slow-aging cellular activity pathways. Clathrate-induced increases in water structure, hydration of cellular components, and diffusivity of bioactive cellular components, including inter- and intra-cellular signals, may all contribute to the overall effects of cyclodextrins on organism survival.
Effect of chemically-modified cyclodextrins C. eleg-ans longevity Animals alive, % of initial (N=50) Life Span Control HP-I3-Cyc1odextrin Carboxymethyl-Quaternaryammonium-(days) (water) P-Cyclodextrin f3-Cyclodextrin
8 17 11 13 Table 8 reports the percentage of animals surviving to midlife (10 days), advanced age (15 days) and old age (18 days), in media variably containing a derivatized a-, and 7-cyclodextrin as an active component of cellular hydration. In this example, derivatized cyclodextrins were added at 0.1% w/w to nutritive media dissolved in USA I water.
10 HP-, carboxymethyl-, and quaternary ammonium- derivatives of P-cyclodextrin had only slight effect on the initial survival of C. elegans to 10 days, as listed in Table 8. In contrast, significant increases in survival were observed at advanced ages (15 days), but not at old ages (18 days). The results are also shown graphically in FIG. 15, which compares the cumulative percentages of animals surviving to 15 and 18 days in media containing each additive derivatized 15 cyclodextrin. The results indicate derivatized cyclodextrins may be used as an active component of cellular hydration to improve biological function in a live animal.
Effect of cyclodextrin complexes on C. elegans longevity Animals alive, % of initial (N=50) Life Span Control a-CD/L-Arg a-CD/L-carnitine a-CD/nicotinamide (days) (water) Table 9 reports the percentage of animals surviving to midlife (10 days), advanced age (14 days), and old age (18 days), in nutritive media dissolved in USA I water variably supplemented 5 with a cyclodextrin inclusion complex at 0.1 % w/w, as an active component of cellular hydration.
In this example, inclusion complexes contained a-cyclodextrin and a bioactive agent, particularly L-arginine, L-camitine, or niacinamide.
As in previous examples, C. elegans animals in un-supplemented media survived two weeks. a-Cyclodextrin complexes with L-arginine and niacinamide more than doubled C. elegans 10 survival at advanced ages (day 14), and further permitted a small but significant number of animals to survive to an old age, to which no animal survived in nutritive media alone. In contrast, a-cyclodextrin complexes with L-camitine had little or no significant effect on C. elegans survival.
Similarly, L-arginine and nicotinamide added alone to the culture media without a-cyclodextrin had little effect on C. elegans survival. Results are also shown graphically in FIG. 16, which compares the cumulative percentages of animals surviving to 14 and 18 days in media containing each cyclodextrin inclusion complex as an additive. The results indicate a-cyclodextrin inclusion complexes, particularly complexes with L-arginine and niacinamide, may be used as an active component of cellular hydration to improve biological function in a live animal.
As further shown in FIG. 17, an inclusion complex of a-cyclodextrin and L-arginine (data series A; 1:1 complex, dissolved at 0.1% w/w in media made with USA I water), and an inclusion complex of a-cyclodextrin and niacinamide (data series B; 1:1 complex, dissolved at 0.1% w/w in media made with USA I water) can decrease the mortality rate of (7. elegans worms. FIG. 17 5 shows the number of animals dying on each day for each media condition, wherein the control data series is media made with USA I water and lacking a further additive or supplement. The results show complexed forms of a-cyclodextrin may be used as an active component of cellular hydration to retard mortality of a live animal.
FIG. 18 alternatively represents the data of FIG. 17 as a survival curve for animals growing 10 in normal media using USA T water (Control), or alternatively in media supplemented with a 11 inclusion complex of a-cyclodextrin and L-arginine (Sample 1); or in media supplemented with a 1:1 inclusion complex of cyclodextrin and niacinamide (Sample 2). Thus, the delay in mortality shown in FIG 17 results in an older age of survival, the average age of survival (50% survival) increasing from nearly 13 days in normal media to nearly 14 days in media including a cyclodextrin 15 inclusion complex as an active component of cellular hydration, which represents an 8% increase in lifespan.
Lifespan extension of C. elegans in hydration modified water C. elegans study performed for the present invention is a follow-up and repetition of the observations carried out earlier (referred as Test A here). The results of the current C. elegans study (Test B) were recorded with higher number of animals compared to the Test A (50 worms per treated groups versus 130 worms per groups). Nematodes were maintained and propagated on Nematode Growth Medium - (NGM) containing plates and fed with Eseheriehia.
coil 0P50 bacteria. The C. elegans strain used in this study is Bristol (N2) as wild-type.
Observations:
The results recorded are displayed below in Table 10 and further presented in FIGS. 21 &
22.
Effect of alpha-cyclodextrin and its complexes on C. elegans lifespan C. elegans in Test A C. elegans in Test B
Fraction of worms alive Fraction of worms alive Control 0.1% 0.1% 0.1% Control 0.1% 0.1%
0.1%
Alpha CD ACD- ACD- Alpha CD ACD-ACD-nicotinic Arginine nicotinic Arginine acid acid 7-9 % 25 % 20-25 % 20-25 % 10 % 20 % 22-23 % 21-23 %
The present study (Test B) showed that the survival rate of control and 'only water-treated' animals on day 15 was 10%; hence, the two studies show results which are consistent with each other. Further, fair reproducibility of the 0.1% alpha-cyclodextrin-treated C.
elegans lifespan was found. On the day 15 of experiments (which is equivalent in human 60 years of age) in 2009, about 20-25 % of alpha-CD and alpha-CD complexes treated worms were found alive, while the same treatments resulted in about 20% - 23% live fraction of C. elegans in the current study.
The C. elegans multi-cell testing (performed at the Institute of Genetics at University E6tvOs Lorand, Vellai lab.) demonstrated a statistically significant enhancement in entire life span for the C. elegans treated with CD-enabled tap water compared to that of the control group.
Moreover, it is noteworthy that the alpha-cyclodextrin treated C. elegans appeared more active and vibrant during early to mid-cycle (between 8-13 days) of their lives.
Results are also shown graphically in Figures 21-22.
FIG. 21, illustrates the lifespan of control and alpha-cyclodextrin-treated worms. The control C. elegans lived on a medium made with tap water. The treated worms were maintained on culture media made with 0.1% alpha-cyclodextrin, 0.1% alpha-CD/nicotinic acid and 0.1%
alpha-CD/arginine complex containing tap water. The lifespan curves are shown in FIGs 21 and 22a.
Water samples containing alpha-CD and its complexes had a highly positive effect on C.
elegans during the early- and mid-cycle of their lives (during 8-13 days of their lives). The average lifespan of control animals was 12.33 days while for the alpha-CD treated ones was 13.25 days.
Approximately lday survival of the nematodes is equivalent to 4 or 5 years in a human life.
The tests were repeated with lower and higher alpha-CD concentrations (0.05 and 0.5%) as well as complex solutions of 0.05% concentration. The lifespan curves are shown in FIG 22b and 22c, respectively. It is notable that the dose dependence of the lifespan elongation effect of cyclodextrin and its complexes is non-linear: the efficacy of 0.05%
concentration surpasses that of the tested higher concentration samples. Nevertheless, the effect of alpha cyclodextrin was significant in all the three studied concentrations.
The Caenorhabdilis elegans life span testing demonstrated a statistically significant enhancement in entire life span when treated with CD-enabled water, compared to the control group. It was observed that the alpha-cyclodextrin treated C. elegans appeared more active and vibrant during early to mid-cycle (between 8-13 days) of their lives. The effect was similarly beneficial when alpha cyclodextrin complexes (prepared of L-arginine or nicotinic acid) were applied.
Effect of cyclodextrins on cell hydration using Xenopus frog oocytes For Xenopus oocyte test, oocyte was harvested by anaesthetizing Xenopus laevis with 0.15% MS-222 in water for 15 min. They were then kept on ice for another 15 min before ovarectomy was performed. Ovaries were incubated in collagenase (Worthington Type II, 10 mg/ml) in calcium free Barth's solution (CFBS, NaC1 88 mM, KC11 mM, MgSO4 U.S
mM, TRIS-HC1 5 mM, NaHCO3 2.4 mM). Following defolliculation, oocytes were rinsed in normal Barth's solution (MBS, NaC1 88 mM, KC1 1 mM, CaCl2 0.4 mM, Ca(NO3)2 0.33 mM, MgSO4 0.8 mM, TRIS-HC1 5 mM, NaHCO3 2.4 mM ) before they were transferred to 96-well plates.
For nuclear injection of the different DNA's into the oocytes and for cytoplasmic injection of the mRNA
encoding human Aquaporin-1 channels into the oocytes, the Roboocyte automated injection and recording system was used (Human Aquaporine 1 cDNA cloned in expressing vector pGEM-T
were purchased from Sino Biological Inc. Transcription to AQP1 mRNA was performed by an Ecocyte cooperation partner lab.) The mRNA injection volume was in the range 20-50 n1 at a mRNA concentration of 100 ng4t1. After two to three days of incubation in Barth's solution supplemented with Gentamycin, water uptake of the Xenopus Oocytes through AQP1 channels was tested in a swelling assay using video microscopy.
All test compound mixtures (Alpha cyclodextrin (ACD) 0.05%, 0.1%7 0.5%; ACD-nicotinic acid complex, 0.05%, 0.1%7 0.50/7 ACD-arginine complex, 0.05%, 0.1%, 0.5%) were prepared in purified water and were supported by Cyclolab in 500 ml amounts as well as a 500 ml purified water sample. Normal frog ringer (NFR, NaC1 90 mM, KC1 2 mM, CaCl2 2 m_1\4, MgCl2 1 m_M, HEPES 5 mM, osmolarity 200 mOsm/1) was used as control solution and was prepared freshly on the day of the experiments. All solutions were handled in double blind experiments.
Compound mixtures as well as water controls were labelled as Cl-C10. Then the swelling assay/video microscopy and data analysis was performed.
Water is a major component of the cell, it represents 70- 95% of its weight.
Water can cross lipid bilayers of all biological membranes by simple diffusion and the discovery of water channels, by Nobel-laurate Peter Agre in cells called aquaporins, provides a molecular explanation for the rapid and regulated transport of' water across the lipid bilayers of cell membranes.
The study used the same biological system that was used by Peter Agre. Frog oocytes (eggs) are resistant to water permeation, as mother frogs lay their eggs in water. Peter Agre used genetic material by injecting ribonucleic acid into these oocytes, causing expression membrane integrated water channel proteins. So, the oocytes became permeable for water.
Oocyte water channel testing method was used for the description of the effect of cyclodextrins on cellular water uptake through human aquaporin 1 (AQP1). The results of oocyte osmotic water permeability are illustrated on FIG. 24-25.
The results of the Xenopus oocyte test show that the highest water permeation was recorded to water solutions containing 0.05% alpha-cyclodextrin and 0.05% alpha-cyclodextrin /arginine complex. Surprisingly, the tested solutions with higher (0.1- 0.5%) cyclodextrin content showed reduced water permeation compared to control tap water. Further, the single-celled oocyte test also indicates the positive effect of the same low concentration (0.05 %) of cyclodextrins on the cellular water uptake.
Effect of cyclodextrins and complexing agent on water absorption using Orbeez beads A set of observational experiments using different concentrations of the Cyclodextrin formula, complexing agents (arginine and niacin) and a control were performed.
These experiments are visual in nature. Orbeez beads, made of super absorbent polymers and colored contact lenses which also absorb water, were selected for the experiment.
Equal amounts of Orbeez and Contact lenses were taken and placed / weighed using a calibrated scientific scale. 500m1 solutions of Cyclodextrin + Arginine arid Niacin (our complexing agents) in 1% and 2% concentrations were mixed up. The different solutions with the test products were combined in petri dishes and were observed / photographed at standard time intervals: 30 5 mins., 1 hour, 3 hours. Tap water was used as the Control solution for Orbeez heads and the Control for the Contact lens solution was saline. 1% and 2% formulations of CD+Arg+Niacin were solubilized in saline for the contact lens test. The test products were removed from water and weighed after the 3-hour interval. The test products were photographed in a side by side comparison after the 3-hour interval.
10 Observations Orbeez beads Experiment Orbeez beads (experiment Observation time) Prior to Orbeez beads are hard yet absorbent and multi-colored.
Experiment At 1 Hr Measurement clearly shows 1% and 2% solution more defined and larger than the control group At 3 Hours, the Orbeez beads in the 2% solution exhibited the greatest growth compared At 3 Hrs to the control. The 2% solution of cyclodextrin ¨
Arginine and Niacin produced a weight 40% greater than the control. Orbccz beads at 3 hours exhibited significantly greater absorption in the 2% cyclodextrin solution.
The experiment is an illustration of the enhanced water absorbing effect that cyclodextrin complexes offer in comparison to standard water for the Orbeez test and saline for the Contact lens 15 test. Furthermore, we believe that these results can be extrapolated to consumed beverages and their ability to penetrate biological cells, thus improving a human body's hydration and its ability to absorb liquids and nutrients.
The invention may also be described by the following numbered paragraphs:
1. A beverage composition that promotes cellular hydration when ingested by a multicellular organism, comprising:
a carbohydrate clathrate component that includes cyclodextrin, in a concentration of 0.01-5% w/w;
a complex-forming compound, in a concentration that is less than the clathrate component;
an aqueous liquid component, chosen from the group consisting of still and carbonated aqueous liquids;
wherein an inclusion complex is formed with at least some of the clathrate component and at least some of the complex-forming compound; and wherein the composition promotes cellular hydration of the multicellular organism when the multicellular organism ingests it.
2. The beverage composition of paragraph 1, wherein the ratio of clathrate component to complex-forming compound is in a range from about 5:1 to about 15:1.
3. The beverage composition of paragraph 1, wherein the complex-forming compound is selected from the group consisting of amino acids, including L-arginine, citrulline, creatine, taurine, nicotinic acid, nicotinamide, resveratrol, curcumin, thiamine, curcumin, polyphenols, dihydrocurcumin, spermidin, L-lysin, coenzymeQ10, delta-tocopherol, delphindin, caffeine, and guama.
4. The beverage composition of paragraph 1, wherein the complex-forming compound is selected from the group consisting of any electrolyte, and specifically, from the group consisting of magnesium, sodium, potassium, chloride, calcium, phosphate, and bicarbonate.
5. The beverage composition of paragraph 1, wherein the composition causes cellular hydration in a multicellular organism when a multicellular organism ingests it.
6. The beverage composition of paragraph 1, wherein the multicellular organism is capable of intracellular water permeation, and the ingestion of the composition by the multicellular organism enhances the intracellular permeation.
7. The beverage composition of paragraph 6, wherein the multicellular organism contains aquaporins, and the cellular hydration is caused by interaction of the composition with the aquaporins.
8. The beverage composition of paragraph 7, wherein the cellular hydration is corroborated by a test that uses human-aquaporin-expressed frog oocytes.
10 HP-, carboxymethyl-, and quaternary ammonium- derivatives of P-cyclodextrin had only slight effect on the initial survival of C. elegans to 10 days, as listed in Table 8. In contrast, significant increases in survival were observed at advanced ages (15 days), but not at old ages (18 days). The results are also shown graphically in FIG. 15, which compares the cumulative percentages of animals surviving to 15 and 18 days in media containing each additive derivatized 15 cyclodextrin. The results indicate derivatized cyclodextrins may be used as an active component of cellular hydration to improve biological function in a live animal.
Effect of cyclodextrin complexes on C. elegans longevity Animals alive, % of initial (N=50) Life Span Control a-CD/L-Arg a-CD/L-carnitine a-CD/nicotinamide (days) (water) Table 9 reports the percentage of animals surviving to midlife (10 days), advanced age (14 days), and old age (18 days), in nutritive media dissolved in USA I water variably supplemented 5 with a cyclodextrin inclusion complex at 0.1 % w/w, as an active component of cellular hydration.
In this example, inclusion complexes contained a-cyclodextrin and a bioactive agent, particularly L-arginine, L-camitine, or niacinamide.
As in previous examples, C. elegans animals in un-supplemented media survived two weeks. a-Cyclodextrin complexes with L-arginine and niacinamide more than doubled C. elegans 10 survival at advanced ages (day 14), and further permitted a small but significant number of animals to survive to an old age, to which no animal survived in nutritive media alone. In contrast, a-cyclodextrin complexes with L-camitine had little or no significant effect on C. elegans survival.
Similarly, L-arginine and nicotinamide added alone to the culture media without a-cyclodextrin had little effect on C. elegans survival. Results are also shown graphically in FIG. 16, which compares the cumulative percentages of animals surviving to 14 and 18 days in media containing each cyclodextrin inclusion complex as an additive. The results indicate a-cyclodextrin inclusion complexes, particularly complexes with L-arginine and niacinamide, may be used as an active component of cellular hydration to improve biological function in a live animal.
As further shown in FIG. 17, an inclusion complex of a-cyclodextrin and L-arginine (data series A; 1:1 complex, dissolved at 0.1% w/w in media made with USA I water), and an inclusion complex of a-cyclodextrin and niacinamide (data series B; 1:1 complex, dissolved at 0.1% w/w in media made with USA I water) can decrease the mortality rate of (7. elegans worms. FIG. 17 5 shows the number of animals dying on each day for each media condition, wherein the control data series is media made with USA I water and lacking a further additive or supplement. The results show complexed forms of a-cyclodextrin may be used as an active component of cellular hydration to retard mortality of a live animal.
FIG. 18 alternatively represents the data of FIG. 17 as a survival curve for animals growing 10 in normal media using USA T water (Control), or alternatively in media supplemented with a 11 inclusion complex of a-cyclodextrin and L-arginine (Sample 1); or in media supplemented with a 1:1 inclusion complex of cyclodextrin and niacinamide (Sample 2). Thus, the delay in mortality shown in FIG 17 results in an older age of survival, the average age of survival (50% survival) increasing from nearly 13 days in normal media to nearly 14 days in media including a cyclodextrin 15 inclusion complex as an active component of cellular hydration, which represents an 8% increase in lifespan.
Lifespan extension of C. elegans in hydration modified water C. elegans study performed for the present invention is a follow-up and repetition of the observations carried out earlier (referred as Test A here). The results of the current C. elegans study (Test B) were recorded with higher number of animals compared to the Test A (50 worms per treated groups versus 130 worms per groups). Nematodes were maintained and propagated on Nematode Growth Medium - (NGM) containing plates and fed with Eseheriehia.
coil 0P50 bacteria. The C. elegans strain used in this study is Bristol (N2) as wild-type.
Observations:
The results recorded are displayed below in Table 10 and further presented in FIGS. 21 &
22.
Effect of alpha-cyclodextrin and its complexes on C. elegans lifespan C. elegans in Test A C. elegans in Test B
Fraction of worms alive Fraction of worms alive Control 0.1% 0.1% 0.1% Control 0.1% 0.1%
0.1%
Alpha CD ACD- ACD- Alpha CD ACD-ACD-nicotinic Arginine nicotinic Arginine acid acid 7-9 % 25 % 20-25 % 20-25 % 10 % 20 % 22-23 % 21-23 %
The present study (Test B) showed that the survival rate of control and 'only water-treated' animals on day 15 was 10%; hence, the two studies show results which are consistent with each other. Further, fair reproducibility of the 0.1% alpha-cyclodextrin-treated C.
elegans lifespan was found. On the day 15 of experiments (which is equivalent in human 60 years of age) in 2009, about 20-25 % of alpha-CD and alpha-CD complexes treated worms were found alive, while the same treatments resulted in about 20% - 23% live fraction of C. elegans in the current study.
The C. elegans multi-cell testing (performed at the Institute of Genetics at University E6tvOs Lorand, Vellai lab.) demonstrated a statistically significant enhancement in entire life span for the C. elegans treated with CD-enabled tap water compared to that of the control group.
Moreover, it is noteworthy that the alpha-cyclodextrin treated C. elegans appeared more active and vibrant during early to mid-cycle (between 8-13 days) of their lives.
Results are also shown graphically in Figures 21-22.
FIG. 21, illustrates the lifespan of control and alpha-cyclodextrin-treated worms. The control C. elegans lived on a medium made with tap water. The treated worms were maintained on culture media made with 0.1% alpha-cyclodextrin, 0.1% alpha-CD/nicotinic acid and 0.1%
alpha-CD/arginine complex containing tap water. The lifespan curves are shown in FIGs 21 and 22a.
Water samples containing alpha-CD and its complexes had a highly positive effect on C.
elegans during the early- and mid-cycle of their lives (during 8-13 days of their lives). The average lifespan of control animals was 12.33 days while for the alpha-CD treated ones was 13.25 days.
Approximately lday survival of the nematodes is equivalent to 4 or 5 years in a human life.
The tests were repeated with lower and higher alpha-CD concentrations (0.05 and 0.5%) as well as complex solutions of 0.05% concentration. The lifespan curves are shown in FIG 22b and 22c, respectively. It is notable that the dose dependence of the lifespan elongation effect of cyclodextrin and its complexes is non-linear: the efficacy of 0.05%
concentration surpasses that of the tested higher concentration samples. Nevertheless, the effect of alpha cyclodextrin was significant in all the three studied concentrations.
The Caenorhabdilis elegans life span testing demonstrated a statistically significant enhancement in entire life span when treated with CD-enabled water, compared to the control group. It was observed that the alpha-cyclodextrin treated C. elegans appeared more active and vibrant during early to mid-cycle (between 8-13 days) of their lives. The effect was similarly beneficial when alpha cyclodextrin complexes (prepared of L-arginine or nicotinic acid) were applied.
Effect of cyclodextrins on cell hydration using Xenopus frog oocytes For Xenopus oocyte test, oocyte was harvested by anaesthetizing Xenopus laevis with 0.15% MS-222 in water for 15 min. They were then kept on ice for another 15 min before ovarectomy was performed. Ovaries were incubated in collagenase (Worthington Type II, 10 mg/ml) in calcium free Barth's solution (CFBS, NaC1 88 mM, KC11 mM, MgSO4 U.S
mM, TRIS-HC1 5 mM, NaHCO3 2.4 mM). Following defolliculation, oocytes were rinsed in normal Barth's solution (MBS, NaC1 88 mM, KC1 1 mM, CaCl2 0.4 mM, Ca(NO3)2 0.33 mM, MgSO4 0.8 mM, TRIS-HC1 5 mM, NaHCO3 2.4 mM ) before they were transferred to 96-well plates.
For nuclear injection of the different DNA's into the oocytes and for cytoplasmic injection of the mRNA
encoding human Aquaporin-1 channels into the oocytes, the Roboocyte automated injection and recording system was used (Human Aquaporine 1 cDNA cloned in expressing vector pGEM-T
were purchased from Sino Biological Inc. Transcription to AQP1 mRNA was performed by an Ecocyte cooperation partner lab.) The mRNA injection volume was in the range 20-50 n1 at a mRNA concentration of 100 ng4t1. After two to three days of incubation in Barth's solution supplemented with Gentamycin, water uptake of the Xenopus Oocytes through AQP1 channels was tested in a swelling assay using video microscopy.
All test compound mixtures (Alpha cyclodextrin (ACD) 0.05%, 0.1%7 0.5%; ACD-nicotinic acid complex, 0.05%, 0.1%7 0.50/7 ACD-arginine complex, 0.05%, 0.1%, 0.5%) were prepared in purified water and were supported by Cyclolab in 500 ml amounts as well as a 500 ml purified water sample. Normal frog ringer (NFR, NaC1 90 mM, KC1 2 mM, CaCl2 2 m_1\4, MgCl2 1 m_M, HEPES 5 mM, osmolarity 200 mOsm/1) was used as control solution and was prepared freshly on the day of the experiments. All solutions were handled in double blind experiments.
Compound mixtures as well as water controls were labelled as Cl-C10. Then the swelling assay/video microscopy and data analysis was performed.
Water is a major component of the cell, it represents 70- 95% of its weight.
Water can cross lipid bilayers of all biological membranes by simple diffusion and the discovery of water channels, by Nobel-laurate Peter Agre in cells called aquaporins, provides a molecular explanation for the rapid and regulated transport of' water across the lipid bilayers of cell membranes.
The study used the same biological system that was used by Peter Agre. Frog oocytes (eggs) are resistant to water permeation, as mother frogs lay their eggs in water. Peter Agre used genetic material by injecting ribonucleic acid into these oocytes, causing expression membrane integrated water channel proteins. So, the oocytes became permeable for water.
Oocyte water channel testing method was used for the description of the effect of cyclodextrins on cellular water uptake through human aquaporin 1 (AQP1). The results of oocyte osmotic water permeability are illustrated on FIG. 24-25.
The results of the Xenopus oocyte test show that the highest water permeation was recorded to water solutions containing 0.05% alpha-cyclodextrin and 0.05% alpha-cyclodextrin /arginine complex. Surprisingly, the tested solutions with higher (0.1- 0.5%) cyclodextrin content showed reduced water permeation compared to control tap water. Further, the single-celled oocyte test also indicates the positive effect of the same low concentration (0.05 %) of cyclodextrins on the cellular water uptake.
Effect of cyclodextrins and complexing agent on water absorption using Orbeez beads A set of observational experiments using different concentrations of the Cyclodextrin formula, complexing agents (arginine and niacin) and a control were performed.
These experiments are visual in nature. Orbeez beads, made of super absorbent polymers and colored contact lenses which also absorb water, were selected for the experiment.
Equal amounts of Orbeez and Contact lenses were taken and placed / weighed using a calibrated scientific scale. 500m1 solutions of Cyclodextrin + Arginine arid Niacin (our complexing agents) in 1% and 2% concentrations were mixed up. The different solutions with the test products were combined in petri dishes and were observed / photographed at standard time intervals: 30 5 mins., 1 hour, 3 hours. Tap water was used as the Control solution for Orbeez heads and the Control for the Contact lens solution was saline. 1% and 2% formulations of CD+Arg+Niacin were solubilized in saline for the contact lens test. The test products were removed from water and weighed after the 3-hour interval. The test products were photographed in a side by side comparison after the 3-hour interval.
10 Observations Orbeez beads Experiment Orbeez beads (experiment Observation time) Prior to Orbeez beads are hard yet absorbent and multi-colored.
Experiment At 1 Hr Measurement clearly shows 1% and 2% solution more defined and larger than the control group At 3 Hours, the Orbeez beads in the 2% solution exhibited the greatest growth compared At 3 Hrs to the control. The 2% solution of cyclodextrin ¨
Arginine and Niacin produced a weight 40% greater than the control. Orbccz beads at 3 hours exhibited significantly greater absorption in the 2% cyclodextrin solution.
The experiment is an illustration of the enhanced water absorbing effect that cyclodextrin complexes offer in comparison to standard water for the Orbeez test and saline for the Contact lens 15 test. Furthermore, we believe that these results can be extrapolated to consumed beverages and their ability to penetrate biological cells, thus improving a human body's hydration and its ability to absorb liquids and nutrients.
The invention may also be described by the following numbered paragraphs:
1. A beverage composition that promotes cellular hydration when ingested by a multicellular organism, comprising:
a carbohydrate clathrate component that includes cyclodextrin, in a concentration of 0.01-5% w/w;
a complex-forming compound, in a concentration that is less than the clathrate component;
an aqueous liquid component, chosen from the group consisting of still and carbonated aqueous liquids;
wherein an inclusion complex is formed with at least some of the clathrate component and at least some of the complex-forming compound; and wherein the composition promotes cellular hydration of the multicellular organism when the multicellular organism ingests it.
2. The beverage composition of paragraph 1, wherein the ratio of clathrate component to complex-forming compound is in a range from about 5:1 to about 15:1.
3. The beverage composition of paragraph 1, wherein the complex-forming compound is selected from the group consisting of amino acids, including L-arginine, citrulline, creatine, taurine, nicotinic acid, nicotinamide, resveratrol, curcumin, thiamine, curcumin, polyphenols, dihydrocurcumin, spermidin, L-lysin, coenzymeQ10, delta-tocopherol, delphindin, caffeine, and guama.
4. The beverage composition of paragraph 1, wherein the complex-forming compound is selected from the group consisting of any electrolyte, and specifically, from the group consisting of magnesium, sodium, potassium, chloride, calcium, phosphate, and bicarbonate.
5. The beverage composition of paragraph 1, wherein the composition causes cellular hydration in a multicellular organism when a multicellular organism ingests it.
6. The beverage composition of paragraph 1, wherein the multicellular organism is capable of intracellular water permeation, and the ingestion of the composition by the multicellular organism enhances the intracellular permeation.
7. The beverage composition of paragraph 6, wherein the multicellular organism contains aquaporins, and the cellular hydration is caused by interaction of the composition with the aquaporins.
8. The beverage composition of paragraph 7, wherein the cellular hydration is corroborated by a test that uses human-aquaporin-expressed frog oocytes.
9. The beverage composition of paragraph 8, wherein the test uses single cell Xen opus laevis human-aquaporin-expressed frog oocytes having expressed human aquaporin AGP1 water channels.
10. The beverage composition of paragraph 1, wherein the composition also promotes increased lifespan of the multicellular organism.
11. The beverage composition of paragraph 10, wherein the promotion of increased lifespan is corroborated by lifespan studies on C. elegans nematodes.
12. The beverage composition of paragraph 11, wherein the composition causes increased lifespan of the multicellular organism.
13. The beverage composition of paragraph 10, wherein the cause of increased lifespan is corroborated by lifespan studies on C. elegans nematodes.
14. The beverage composition of paragraph 1, wherein the cyclodextrin is chosen from the group consisting of alpha-, beta-, and gamma-cyclodextrins.
15. A beverage composition that promotes increased lifespan when ingested by a multicellular organism, comprising:
a carbohydrate clathrate component that includes cyclodextrin, in a concentration of 0.01-5% w/w;
a complex-forming compound, in a concentration that is less than the clathrate component;
an aqueous liquid component, chosen from the group consisting of still and carbonated aqueous liquids;
wherein an inclusion complex is formed with at least some of the clathrate component and at least some of the complex-forming compound; and wherein the composition promotes increased lifespan of the multicellular organism when the multicellular organism ingests it.
a carbohydrate clathrate component that includes cyclodextrin, in a concentration of 0.01-5% w/w;
a complex-forming compound, in a concentration that is less than the clathrate component;
an aqueous liquid component, chosen from the group consisting of still and carbonated aqueous liquids;
wherein an inclusion complex is formed with at least some of the clathrate component and at least some of the complex-forming compound; and wherein the composition promotes increased lifespan of the multicellular organism when the multicellular organism ingests it.
16. The beverage composition of paragraph 15, wherein the promotion of increased lifespan is corroborated by lifespan studies on C. elegans nematodes.
17. The beverage composition of paragraph 16, wherein the composition causes in creased lifespan of the multicellular organism.
18. The beverage composition of paragraph 17, wherein the cause of increased lifespan is corroborated by lifespan studies on C. elegans nematodes.
19. A system that promotes cellular hydration when ingested by a multicellular organism, comprising:
a carbohydrate clathrate component that includes cyclodextrin, in a concentration of 0.01 -5% w/w;
a complex-forming compound, in a concentration that is less than the clathrate component;
an aqueous liquid component, chosen from the group consisting of still and carbonated aqueous liquids;
wherein an inclusion complex is formed with at least some of the clathrate component and at least some of the complex-forming compound; and wherein the composition promotes cellular hydration when a multicellular organism ingests it.
a carbohydrate clathrate component that includes cyclodextrin, in a concentration of 0.01 -5% w/w;
a complex-forming compound, in a concentration that is less than the clathrate component;
an aqueous liquid component, chosen from the group consisting of still and carbonated aqueous liquids;
wherein an inclusion complex is formed with at least some of the clathrate component and at least some of the complex-forming compound; and wherein the composition promotes cellular hydration when a multicellular organism ingests it.
20. The system of paragraph 19, wherein the ratio of clathrate component to complex-forming compound is in a range from about 5:1 to about 15:1.
21. The system of paragraph 20, wherein the complex-forming compound is selected from the group consisting of amino acids, including L-arginine, citrulline, creatine, taurine, nicotinic acid, nicotinamide, resveratrol, curcumin, thiamine, curcumin, polyphenols, dihydrocurcumin, spermidin, L-lysin, reservatrol, coenzymeQ10, delta-tocopherol, delphindin, caffeine, and guama.
22. The system of paragraph 20, wherein the complex-forming compound is selected from the group consisting of any electrolyte, and specifically, from the group consisting of magnesium, sodium, potassium, chloride, calcium, phosphate, and bicarbonate.
23. A method of promoting increased cellular hydration in a multicellular organism that is capable of intracellular water permeation, comprising:
causing the multicellular organism to ingest an aqueous solution that contains an amount of a carbohydrate clathrate component; and enhancing the intracellular permeation.
causing the multicellular organism to ingest an aqueous solution that contains an amount of a carbohydrate clathrate component; and enhancing the intracellular permeation.
24. The method of paragraph 23, wherein the multicellular organism contains aquaporins, and the causing step involves interaction of the composition with the aquaporins.
25. The method of paragraph 24, wherein the cellular hydration is corroborated by a test that uses human-aquaporin-expressed frog oocytes.
26. The method of paragraph 25, wherein the test uses single cell Xenopus laevis human-aquaporin-expressed frog oocytes having expressed human aquaporin AGP1 water channels.
27. The method of paragraph 23, wherein the multicellular organism has lipid bilayer constituents, and further including forming non-covalent inclusion complexes between the clathrate component and the lipid bilayer constituents.
28. The method of paragraph 23, wherein the multicellular organism also has phospholipids chosen from the group consisting of glycosphingolipids, sphingomyelin, phosphatidylcholine, phosphatidyl ethanolamine.
29. The method of paragraph 23, wherein the phospholipids are linear.
30. The method of paragraph 23, wherein the multicellular organism also includes membrane lipids and proteins, and the causing results in temporary disintegration of membrane lipids and proteins.
31. The method of paragraph 23, wherein the multicellular organism includes lipid packing, and the causing results in loosening of lipid packing.
32. The method of paragraph 23, wherein the multicellular organism includes membrane proteins, and the causing results in untightening of membrane proteins in an area that includes the membrane proteins.
33. The method of paragraph 23, wherein the multicellular organism includes protein structure and protein function, and the causing results in changes in the protein structure and protein function.
34. The method of paragraph 23, wherein the multicellular organism includes membrane lipids, lipid packing, membrane proteins, protein structure and protein function, and the causing results in temporary disintegration of the membrane lipids, loosening of the lipid packing, untightening of the membrane proteins, and changes in the protein structure and the protein function.
35. The method of paragraph 27, wherein multicellular organism includes cellular layers, and the temporary disintegration of membrane lipids and proteins leads to enhanced membrane permeation of nutrients and water into the cellular layers.
36. The method of paragraph 23, wherein the multicellular organism includes cholesterols, the clathrate component includes beta cyclodextrin, and the causing results in binding to the cholesterols.
37. A method of promoting increased cellular hydration in a multicellular organism that includes water, comprising:
causing the multicellular organism to ingest an aqueous solution that contains an amount of a carbohydrate clathrate component; and decreasing the density of at least some of the water in the aqueous solution.
causing the multicellular organism to ingest an aqueous solution that contains an amount of a carbohydrate clathrate component; and decreasing the density of at least some of the water in the aqueous solution.
38. The method of paragraph claim 37, wherein the multicellular organism also contains aquaporins, and the causing step involves interaction of the composition with the aquaporins.
39. The method of paragraph 38, wherein the cellular hydration is corroborated by a test that uses human-aquaporin-expressed frog oocytes.
40. The method of paragraph 39, wherein the test uses single cell Xenopus laevis human-aquaporin-expressed frog oocytes having expressed human aquaporin AGP1 water channels.
41. The method of paragraph 37, wherein the multicellular organism has lipid bilayer constituents, and further including forming non-covalent inclusion complexes between the clathrate component and the lipid bilayer constituents.
42. The method of paragraph 37, wherein the multicellular organism also has phospholipids chosen from the group consisting of glycosphingolipids, sphingomyelin, phosphatidylcholine, phosphatidyl ethanolamine.
43. The method of paragraph 37, wherein the phospholipids are linear.
44. The method of paragraph 37, wherein the multicellular organism also includes membrane lipids and proteins, and the causing results in temporary disintegration of membrane lipids and proteins.
45. The method of paragraph 37, wherein the multicellular organism includes lipid packing, and the causing results in loosening of lipid packing.
46. The method of paragraph 37, wherein the multicellular organism includes membrane proteins, and the causing results in untightening of membrane proteins.
47. The method of paragraph 37, wherein the multicellular organism includes protein structure and protein function, and the causing results in changes in the protein structure and protein function.
48. The method of paragraph 37, wherein the multicellular organism includes membrane lipids, lipid packing, membrane proteins, protein structure and protein function, and the causing results in temporary disintegration of the membrane lipids, loosening of the lipid packing, untightening of the membrane proteins, and changes in the protein structure and the protein function.
49. The method of paragraph 44, wherein multicellular organism includes cellular layers, and the temporary disintegration of membrane lipids and proteins leads to enhanced membrane permeation of nutrients and water into the cellular layers.
50. The method of paragraph 37, wherein the multicellular organism includes cholesterols, the clathrate component includes beta cyclodextrin, and the causing results in binding to the cholesterols.
51. A method for increasing hydration of cell system to promote cellular hydration in a multicellular organism when the mixture is ingested, the multicellular organism containing membrane lipids, lipid packing and membrane proteins, protein structure and protein function, and membrane permeation of nutrients and water, the method comprising the step of:
causing the multicellular organism to ingest an aqueous solution that contains an amount of a carbohydrate clathrate component; and changing the multicellular organism by (i) temporary disintegration of the membrane lipids, (ii) loosening of the lipid packing and membrane proteins, and (iii) altering the protein structure and protein function, collectively to enhance membrane permeation of nutrients and water.
causing the multicellular organism to ingest an aqueous solution that contains an amount of a carbohydrate clathrate component; and changing the multicellular organism by (i) temporary disintegration of the membrane lipids, (ii) loosening of the lipid packing and membrane proteins, and (iii) altering the protein structure and protein function, collectively to enhance membrane permeation of nutrients and water.
52. The method of paragraph 51, wherein the clathrate is alpha cyclodextrin, and further including the step of binding the alpha cyclodextrin to linear phospholipids in the human body, with the phospholipids chosen from the group consisting of glycosphingolipids, sphingomyelin, phosphatidylcholine, phosphatidyl ethanol amine
53.
The method of paragraph 51, wherein the clathrate is beta cyclodextrin, and further including the step of binding to cholesterols.
Although the present invention has been shown and described with reference to the foregoing operational principles and preferred embodiments, it will be apparent to those skilled in the art that various changes in form and detail may be made without departing from the spirit and scope of the invention. The present invention is intended to embrace all such alternatives, modifications and variances that fall within the scope of the appended claims.
The method of paragraph 51, wherein the clathrate is beta cyclodextrin, and further including the step of binding to cholesterols.
Although the present invention has been shown and described with reference to the foregoing operational principles and preferred embodiments, it will be apparent to those skilled in the art that various changes in form and detail may be made without departing from the spirit and scope of the invention. The present invention is intended to embrace all such alternatives, modifications and variances that fall within the scope of the appended claims.
Claims (22)
1. A beverage composition that promotes cellular hydration when ingested by a multicellular organism, comprising:
a carbohydrate clathrate component that includes cyclodextrin, in a concentration of 0.01-5% w/w;
a complex-forming compound, in a concentration that is less than the clathrate component;
an aqueous liquid component, chosen from the group consisting of still and carbonated aqueous liquids;
wherein an inclusion complex is formed with at least some of the clathrate component and at least some of the complex-forming compound; and wherein the composition promotes cellular hydration of the multicellular organism when the multicellular organism ingests it.
a carbohydrate clathrate component that includes cyclodextrin, in a concentration of 0.01-5% w/w;
a complex-forming compound, in a concentration that is less than the clathrate component;
an aqueous liquid component, chosen from the group consisting of still and carbonated aqueous liquids;
wherein an inclusion complex is formed with at least some of the clathrate component and at least some of the complex-forming compound; and wherein the composition promotes cellular hydration of the multicellular organism when the multicellular organism ingests it.
2. The beverage composition of claim 1, wherein the ratio of clathrate component to complex-forming compound is in a range from about 5:1 to about 15:1.
3. The beverage composition of claim 1, wherein the complex-forming compound is selected from the group consisting of amino acids, including L-arginine, citrulline, creatine, taurine, nicotinic acid, nicotinamide, resveratrol, curcumin, thiamine, curcumin, polyphenols, dihydrocurcumin, spermidin, L-lysin, coenzymeQ10, delta-tocopherol, delphindin, caffeine, and guama.
4. The beverage composition of claim 1, wherein the complex-forming compound is selected from the group consisting of any electrolyte, and specifically, from the group consisting of magnesium, sodium, potassium, chloride, calcium, phosphate, and bicarbonate.
5. The beverage composition of claim 1, wherein the composition causes cellular hydration in a multicellular organism when a multicellular organism ingests it.
6. The beverage composition of claim 1, wherein the multicellular organism is capable of intracellular water permeation, and the ingestion of the composition by the multicellular organism enhances the intracellular permeation.
7. The beverage composition of claim 6, wherein the multicellular organism contains aquaporins, and the cellular hydration is caused by interaction of the composition with the aquaporins.
8. The beverage composition of claim 7, wherein the cellular hydration is corroborated by a test that uses human-aquaporin-expressed frog oocytes.
9. The beverage composition of claim 8, wherein the test uses single cell Xenopus laevis human-aquaporin-expressed frog oocytes having expressed human aquaporin AGP1 water channels.
10. The beverage composition of claim 1, wherein the composition also promotes increased lifespan of the multicellular organism.
11. The beverage composition of claim 10, wherein the promotion of increased lifespan is corroborated by lifespan studies on C. elegans nematodes.
12. The beverage composition of claim 11, wherein the composition causes increased lifespan of the multicellular organism.
13. The beverage composition of claim 10, wherein the cause of increased lifespan is corroborated by lifespan studies on C. elegans nematodes.
14. The beverage composition of claim 1, wherein the cyclodextrin is chosen from the group consisting of alpha-, beta-, and gamma-cyclodextrins.
15. A beverage composition that promotes increased lifespan when ingested by a multicellular organism, comprising:
a carbohydrate clathrate component that includes cyclodextrin, in a concentration of 0.01-5% w/w;
a complex-forming compound, in a concentration that is less than the clathrate component;
an aqueous liquid component, chosen from the group consisting of still and carbonated aqueous liquids;
wherein an inclusion complex is formed with at least some of the clathrate component and at least some of the complex-forming compound; and wherein the composition promotes increased lifespan of the multicellular organism when the multicellular organism ingests it.
6g
a carbohydrate clathrate component that includes cyclodextrin, in a concentration of 0.01-5% w/w;
a complex-forming compound, in a concentration that is less than the clathrate component;
an aqueous liquid component, chosen from the group consisting of still and carbonated aqueous liquids;
wherein an inclusion complex is formed with at least some of the clathrate component and at least some of the complex-forming compound; and wherein the composition promotes increased lifespan of the multicellular organism when the multicellular organism ingests it.
6g
16. The beverage composition of claim 15, wherein the promotion of increased lifespan is corroborated by lifespan studies on C. elegans nematodes.
17. The beverage composition of claim 16, wherein the composition causes increased lifespan of the multicellular organism.
18. The beverage composition of claim 17, wherein the cause of increased lifespan is corroborated by lifespan studies on C. elegans nematodes.
19. A system that promotes cellular hydration when ingested by a multicellular organism, comprising:
a carbohydrate clathrate component that includes cyclodextrin, in a concentration of 0.01-5% w/w;
a complex-forming compound, in a concentration that is less than the clathrate component;
an aqueous liquid component, chosen from the group consisting of still and carbonated aqueous liquids;
wherein an inclusion complex is formed with at least some of the clathrate component and at least some of the complex-forming compound; and wherein the composition promotes cellular hydration when a multicellular organism ingests it.
a carbohydrate clathrate component that includes cyclodextrin, in a concentration of 0.01-5% w/w;
a complex-forming compound, in a concentration that is less than the clathrate component;
an aqueous liquid component, chosen from the group consisting of still and carbonated aqueous liquids;
wherein an inclusion complex is formed with at least some of the clathrate component and at least some of the complex-forming compound; and wherein the composition promotes cellular hydration when a multicellular organism ingests it.
20. The system of claim 19, wherein the ratio of clathrate component to complex-forming compound is in a range from about 5:1 to about 15:1.
21. The system of claim 20, wherein the complex-forming compound is selected from the group consisting of amino acids, including L-arginine, citrulline, creatine, taurine, nicotinic acid, nicotinamide, resveratrol, curcumin, thiamine, curcumin, polyphenols, dihydrocurcumin, spermidin, L-lysin, reservatrol, coenzymeQ10, delta-tocopherol, delphindin, caffeine, and guarna.
22. The system of claim 20, wherein the complex-forming compound is selected from the group consisting of any electrolyte, and specifically, from the group consisting of magnesium, sodium, potassium, chloride, calcium, phosphate, and bicarbonate.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16/841,631 US20200230124A1 (en) | 2010-12-31 | 2020-04-06 | Compositions and methods of promoting cellular hydration |
US16/841,631 | 2020-04-06 | ||
PCT/IB2021/000374 WO2021205237A1 (en) | 2020-04-06 | 2021-04-06 | Compositions for promoting cellular hydration |
Publications (1)
Publication Number | Publication Date |
---|---|
CA3174816A1 true CA3174816A1 (en) | 2021-10-14 |
Family
ID=77274810
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA3174816A Pending CA3174816A1 (en) | 2020-04-06 | 2021-04-06 | Compositions for promoting cellular hydration |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP4132294A1 (en) |
JP (1) | JP2023520903A (en) |
CA (1) | CA3174816A1 (en) |
MX (1) | MX2022012532A (en) |
WO (1) | WO2021205237A1 (en) |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6094912A (en) | 1983-10-28 | 1985-05-28 | Masashige Suzuki | Agent for reducing neutral fat in body |
US6740643B2 (en) | 1999-01-21 | 2004-05-25 | Mirus Corporation | Compositions and methods for drug delivery using amphiphile binding molecules |
DE60115217T2 (en) | 2000-03-28 | 2006-07-20 | Farmarc Nederland B.V. | ALPRAZOLAM INCLUSION COMPLEXES AND ITS PHARMACEUTICAL COMPOSITIONS |
WO2003033025A2 (en) | 2001-10-18 | 2003-04-24 | Decode Genetics Ehf | Cyclodextrin complexes |
EP1499361B1 (en) | 2002-04-19 | 2012-08-08 | Novartis AG | Novel biomaterials, their preparation and use |
PT2138190E (en) | 2002-08-19 | 2014-04-14 | Soho Flordis Internat Pty Ltd | Compositions comprising dietary fat complexer and methods for their use |
US7166575B2 (en) | 2002-12-17 | 2007-01-23 | Nastech Pharmaceutical Company Inc. | Compositions and methods for enhanced mucosal delivery of peptide YY and methods for treating and preventing obesity |
EP1447013A1 (en) | 2003-02-14 | 2004-08-18 | Wacker-Chemie GmbH | Method for reducing the glycemic index of food |
US7105195B2 (en) | 2003-07-25 | 2006-09-12 | General Mills, Inc. | Reduced trans fat product |
WO2006004574A2 (en) | 2004-02-19 | 2006-01-12 | Abbott Laboratories | Method for using gamma cyclodextrin to control blood glucose and insulin secretion |
AU2004323721A1 (en) | 2004-09-27 | 2006-04-06 | Cargill, Incorporated | Cyclodextrin inclusion complexes and methods of preparing same |
US8512789B2 (en) | 2005-11-23 | 2013-08-20 | The Coca-Cola Company | High-potency sweetener composition with dietary fiber and compositions sweetened therewith |
US20090023682A1 (en) | 2007-07-19 | 2009-01-22 | Joseph Artiss | Composition Comprising Dietary Fat Complexer and Methods of Using Same |
MX2010004803A (en) | 2007-10-31 | 2010-09-09 | Diffusion Pharmaceuticals Llc | A new class of therapeutics that enhance small molecule diffusion. |
US20120171184A1 (en) * | 2010-12-31 | 2012-07-05 | Lajos Szente | Cellular hydration compositions |
-
2021
- 2021-04-06 EP EP21752587.2A patent/EP4132294A1/en active Pending
- 2021-04-06 CA CA3174816A patent/CA3174816A1/en active Pending
- 2021-04-06 WO PCT/IB2021/000374 patent/WO2021205237A1/en unknown
- 2021-04-06 MX MX2022012532A patent/MX2022012532A/en unknown
- 2021-04-06 JP JP2022560958A patent/JP2023520903A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
MX2022012532A (en) | 2023-03-15 |
WO2021205237A1 (en) | 2021-10-14 |
JP2023520903A (en) | 2023-05-22 |
EP4132294A1 (en) | 2023-02-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2822995C (en) | Cellular hydration compositions containing cyclodextrins | |
US10610524B2 (en) | Cellular hydration compositions | |
KR101829705B1 (en) | Composition for injection having improved stability | |
RU2552927C2 (en) | Fat-biding composition | |
Lumholdt et al. | In vitro investigations of α-amylase mediated hydrolysis of cyclodextrins in the presence of ibuprofen, flurbiprofen, or benzo [a] pyrene | |
Fang et al. | Insights on the potential of natural deep eutectic solvents (NADES) to fine-tune durian seed gum for use as edible food coating | |
Dong et al. | Solubilities of quercetin in three β‐cyclodextrin derivative solutions at different temperatures | |
Yang et al. | Utilization of cyclodextrins and its derivative particles as nucleants for protein crystallization | |
Higashi et al. | Stabilizing effects for antibody formulations and safety profiles of cyclodextrin polypseudorotaxane hydrogels | |
Geng et al. | Preparation and characterization of butachlor/(2-hydroxypropyl)-β-cyclodextrin inclusion complex: improve soil mobility and herbicidal activity and decrease fish toxicity | |
US20220323431A1 (en) | Compositions and methods of promoting cellular hydration | |
US20230020535A1 (en) | Compositions and methods of promoting cellular hydration | |
US20220378774A1 (en) | Method of promoting cellular hydration by enhancing intracellular permeation | |
CA3174816A1 (en) | Compositions for promoting cellular hydration | |
CN105903028B (en) | Cellular hydration compositions containing cyclodextrins | |
JP2022167905A (en) | Cell hydration composition comprising cyclodextrin | |
JP2017155046A (en) | Cell hydration composition comprising cyclodextrin | |
JP2015044850A (en) | Cell hydration composition containing cyclodextrin | |
Kuranov et al. | Complex formation of cyclodextrins with sulfasalazine in buffer solutions | |
Rogel et al. | Formulation and characterization of inclusion complexes using hydroxypropyl-β-cyclodextrin and florfenicol with chitosan microparticles | |
Sakran et al. | Investigation and physicochemical characterization of binary febuxostat-sulfobutyl ether β-cyclodextrin inclusion complexes | |
Nikolic et al. | Cyclodextrins as advanced materials for pharmaceutical applications | |
Kumari et al. | Optimization of drug release from chitosan-starch crosslinked beads by response surface methodology | |
Gündoğdu et al. | Evaluation of cefpodoxime proxetil complex with hydroxypropyl-β-cyclodextrin in the presence of a water soluble polymer: Characterization and permeability studies | |
WO2008007415A1 (en) | Inclusion coenzyme q10 and method of producing inclusion coenzyme q10 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request |
Effective date: 20221221 |
|
EEER | Examination request |
Effective date: 20221221 |
|
EEER | Examination request |
Effective date: 20221221 |
|
EEER | Examination request |
Effective date: 20221221 |
|
EEER | Examination request |
Effective date: 20221221 |
|
EEER | Examination request |
Effective date: 20221221 |
|
EEER | Examination request |
Effective date: 20221221 |