WO2022094916A1 - 一种提高烟酰胺磷酸核糖转移酶活性的方法及其组合物 - Google Patents
一种提高烟酰胺磷酸核糖转移酶活性的方法及其组合物 Download PDFInfo
- Publication number
- WO2022094916A1 WO2022094916A1 PCT/CN2020/127059 CN2020127059W WO2022094916A1 WO 2022094916 A1 WO2022094916 A1 WO 2022094916A1 CN 2020127059 W CN2020127059 W CN 2020127059W WO 2022094916 A1 WO2022094916 A1 WO 2022094916A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- nicotine
- aging
- activity
- disease
- Prior art date
Links
- 108010064862 Nicotinamide phosphoribosyltransferase Proteins 0.000 title claims abstract description 89
- 102000015532 Nicotinamide phosphoribosyltransferase Human genes 0.000 title claims abstract description 89
- 230000000694 effects Effects 0.000 title claims abstract description 61
- 239000000203 mixture Substances 0.000 title claims abstract description 48
- 238000000034 method Methods 0.000 title claims abstract description 25
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims abstract description 124
- 229960002715 nicotine Drugs 0.000 claims abstract description 124
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims abstract description 124
- 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 abstract description 23
- 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 abstract description 22
- 235000021283 resveratrol Nutrition 0.000 claims abstract description 22
- 229940016667 resveratrol Drugs 0.000 claims abstract description 22
- 102000004190 Enzymes Human genes 0.000 claims abstract description 17
- 108090000790 Enzymes Proteins 0.000 claims abstract description 17
- 230000006196 deacetylation Effects 0.000 claims abstract description 15
- 238000003381 deacetylation reaction Methods 0.000 claims abstract description 15
- 230000001965 increasing effect Effects 0.000 claims abstract description 15
- IASPBORHOMBZMY-UHFFFAOYSA-N srt1720 Chemical compound C=1N=C2C=CC=CC2=NC=1C(=O)NC1=CC=CC=C1C(N=C1SC=2)=CN1C=2CN1CCNCC1 IASPBORHOMBZMY-UHFFFAOYSA-N 0.000 claims abstract description 12
- 230000032683 aging Effects 0.000 claims description 43
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 27
- 201000010099 disease Diseases 0.000 claims description 25
- 208000019901 Anxiety disease Diseases 0.000 claims description 21
- 230000036506 anxiety Effects 0.000 claims description 21
- 239000007788 liquid Substances 0.000 claims description 15
- 239000000463 material Substances 0.000 claims description 14
- 239000008187 granular material Substances 0.000 claims description 11
- 239000000843 powder Substances 0.000 claims description 10
- 239000003826 tablet Substances 0.000 claims description 10
- 230000007850 degeneration Effects 0.000 claims description 9
- 108010041216 Sirtuin 2 Proteins 0.000 claims description 8
- 102000000477 Sirtuin 2 Human genes 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 235000013361 beverage Nutrition 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 6
- 239000004615 ingredient Substances 0.000 claims description 6
- 208000024827 Alzheimer disease Diseases 0.000 claims description 5
- 208000018737 Parkinson disease Diseases 0.000 claims description 5
- 230000004770 neurodegeneration Effects 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 206010003591 Ataxia Diseases 0.000 claims description 4
- 208000002381 Brain Hypoxia Diseases 0.000 claims description 4
- 208000009810 Catatonic Schizophrenia Diseases 0.000 claims description 4
- 206010008748 Chorea Diseases 0.000 claims description 4
- 208000014094 Dystonic disease Diseases 0.000 claims description 4
- 208000023105 Huntington disease Diseases 0.000 claims description 4
- 208000032382 Ischaemic stroke Diseases 0.000 claims description 4
- 208000036626 Mental retardation Diseases 0.000 claims description 4
- 206010028570 Myelopathy Diseases 0.000 claims description 4
- 206010056677 Nerve degeneration Diseases 0.000 claims description 4
- 201000005625 Neuroleptic malignant syndrome Diseases 0.000 claims description 4
- 208000036754 Schizophrenia, catatonic type Diseases 0.000 claims description 4
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 4
- 230000003376 axonal effect Effects 0.000 claims description 4
- 208000012601 choreatic disease Diseases 0.000 claims description 4
- 208000010118 dystonia Diseases 0.000 claims description 4
- 201000006517 essential tremor Diseases 0.000 claims description 4
- 210000000609 ganglia Anatomy 0.000 claims description 4
- 230000007954 hypoxia Effects 0.000 claims description 4
- 208000007431 neuroacanthocytosis Diseases 0.000 claims description 4
- 201000002212 progressive supranuclear palsy Diseases 0.000 claims description 4
- 210000001116 retinal neuron Anatomy 0.000 claims description 4
- 208000003755 striatonigral degeneration Diseases 0.000 claims description 4
- 230000009529 traumatic brain injury Effects 0.000 claims description 4
- 108010039224 Amidophosphoribosyltransferase Proteins 0.000 claims description 2
- 102100039239 Amidophosphoribosyltransferase Human genes 0.000 claims 1
- 239000000779 smoke Substances 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 52
- 101710112216 NAD-dependent histone deacetylase SIR2 Proteins 0.000 abstract description 39
- DAYLJWODMCOQEW-TURQNECASA-N NMN zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)([O-])=O)O2)O)=C1 DAYLJWODMCOQEW-TURQNECASA-N 0.000 abstract description 29
- 108090000623 proteins and genes Proteins 0.000 abstract description 14
- 102000004169 proteins and genes Human genes 0.000 abstract description 13
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 230000001766 physiological effect Effects 0.000 abstract description 8
- 230000019491 signal transduction Effects 0.000 abstract description 7
- 230000006044 T cell activation Effects 0.000 abstract description 6
- 238000006731 degradation reaction Methods 0.000 abstract description 6
- 230000003914 insulin secretion Effects 0.000 abstract description 6
- 230000037356 lipid metabolism Effects 0.000 abstract description 6
- 230000005971 DNA damage repair Effects 0.000 abstract description 3
- BAWFJGJZGIEFAR-NNYOXOHSSA-O NAD(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-O 0.000 abstract description 3
- FZAQROFXYZPAKI-UHFFFAOYSA-N anthracene-2-sulfonyl chloride Chemical compound C1=CC=CC2=CC3=CC(S(=O)(=O)Cl)=CC=C3C=C21 FZAQROFXYZPAKI-UHFFFAOYSA-N 0.000 abstract description 3
- 230000015556 catabolic process Effects 0.000 abstract description 2
- 230000010094 cellular senescence Effects 0.000 abstract description 2
- 230000023852 carbohydrate metabolic process Effects 0.000 abstract 1
- 235000021256 carbohydrate metabolism Nutrition 0.000 abstract 1
- 230000001502 supplementing effect Effects 0.000 abstract 1
- 241000699670 Mus sp. Species 0.000 description 52
- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 description 49
- 229950006238 nadide Drugs 0.000 description 49
- 241000699666 Mus <mouse, genus> Species 0.000 description 24
- 210000004556 brain Anatomy 0.000 description 17
- 210000001519 tissue Anatomy 0.000 description 15
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 14
- 210000001320 hippocampus Anatomy 0.000 description 13
- 230000037361 pathway Effects 0.000 description 12
- 108091035539 telomere Proteins 0.000 description 12
- 102000055501 telomere Human genes 0.000 description 12
- 210000003411 telomere Anatomy 0.000 description 12
- 210000002569 neuron Anatomy 0.000 description 11
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 210000004295 hippocampal neuron Anatomy 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 9
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- WQZGKKKJIJFFOK-SVZMEOIVSA-N (+)-Galactose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 description 8
- JLEBZPBDRKPWTD-TURQNECASA-O N-ribosylnicotinamide Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=C1 JLEBZPBDRKPWTD-TURQNECASA-O 0.000 description 8
- 239000003651 drinking water Substances 0.000 description 8
- 235000020188 drinking water Nutrition 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000000749 co-immunoprecipitation Methods 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 239000003755 preservative agent Substances 0.000 description 7
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 6
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000021736 acetylation Effects 0.000 description 6
- 238000006640 acetylation reaction Methods 0.000 description 6
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 6
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 5
- -1 aromatics Substances 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 5
- 210000001947 dentate gyrus Anatomy 0.000 description 5
- 239000007884 disintegrant Substances 0.000 description 5
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 5
- 230000004153 glucose metabolism Effects 0.000 description 5
- 230000009758 senescence Effects 0.000 description 5
- 235000010199 sorbic acid Nutrition 0.000 description 5
- 229940075582 sorbic acid Drugs 0.000 description 5
- 239000004334 sorbic acid Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 4
- 238000000692 Student's t-test Methods 0.000 description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 210000003710 cerebral cortex Anatomy 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000008395 clarifying agent Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 235000003599 food sweetener Nutrition 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 210000002216 heart Anatomy 0.000 description 4
- 230000000971 hippocampal effect Effects 0.000 description 4
- 230000002757 inflammatory effect Effects 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000006366 phosphorylation reaction Methods 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 230000009822 protein phosphorylation Effects 0.000 description 4
- 238000001243 protein synthesis Methods 0.000 description 4
- 230000017854 proteolysis Effects 0.000 description 4
- 210000002027 skeletal muscle Anatomy 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 230000035882 stress Effects 0.000 description 4
- 239000013589 supplement Substances 0.000 description 4
- 239000003765 sweetening agent Substances 0.000 description 4
- 238000012353 t test Methods 0.000 description 4
- 230000014616 translation Effects 0.000 description 4
- 238000001262 western blot Methods 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 102000004495 STAT3 Transcription Factor Human genes 0.000 description 3
- 108010017324 STAT3 Transcription Factor Proteins 0.000 description 3
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 210000005013 brain tissue Anatomy 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 238000001543 one-way ANOVA Methods 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- 230000008439 repair process Effects 0.000 description 3
- 230000009469 supplementation Effects 0.000 description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- 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 2
- 206010012335 Dependence Diseases 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- 101000720704 Homo sapiens Neuronal migration protein doublecortin Proteins 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 102100025929 Neuronal migration protein doublecortin Human genes 0.000 description 2
- 238000011529 RT qPCR Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- GZCGUPFRVQAUEE-KCDKBNATSA-N aldehydo-D-galactose Chemical group OC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-KCDKBNATSA-N 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- 230000003712 anti-aging effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000008049 biological aging Effects 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 2
- 235000011132 calcium sulphate Nutrition 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000032677 cell aging Effects 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 238000010812 external standard method Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 238000003119 immunoblot Methods 0.000 description 2
- 238000003125 immunofluorescent labeling Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000013336 milk Nutrition 0.000 description 2
- 239000008267 milk Substances 0.000 description 2
- 210000004080 milk Anatomy 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229960003966 nicotinamide Drugs 0.000 description 2
- 235000005152 nicotinamide Nutrition 0.000 description 2
- 239000011570 nicotinamide Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 108010011485 Aspartame Proteins 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 230000007035 DNA breakage Effects 0.000 description 1
- 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 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010057852 Nicotine dependence Diseases 0.000 description 1
- 108050002485 Sirtuin Proteins 0.000 description 1
- 102000011990 Sirtuin Human genes 0.000 description 1
- 239000004376 Sucralose Substances 0.000 description 1
- 208000025569 Tobacco Use disease Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000003851 biochemical process Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000779 depleting effect Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 235000013861 fat-free Nutrition 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000020604 functional milk Nutrition 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000001404 mediated effect 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
- 229910002055 micronized silica Inorganic materials 0.000 description 1
- 230000006540 mitochondrial respiration Effects 0.000 description 1
- 230000031990 negative regulation of inflammatory response Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000007511 neuronal proliferation Effects 0.000 description 1
- 108010021066 nicotinamide riboside kinase Proteins 0.000 description 1
- 231100000065 noncytotoxic Toxicity 0.000 description 1
- 230000002020 noncytotoxic effect Effects 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 201000008129 pancreatic ductal adenocarcinoma Diseases 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000002331 protein detection Methods 0.000 description 1
- 230000008943 replicative senescence Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical class OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 238000007492 two-way ANOVA Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 229920002554 vinyl polymer Polymers 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
Images
Classifications
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- 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
-
- 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
- A61K31/465—Nicotine; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- the present invention relates to the field of general health, in particular to the fields of food, health care products and medicines in the field of general health, in particular to a method for improving the activity of nicotinamide phosphoribosyltransferase and a composition thereof.
- NAD + is an important coenzyme in the body and is involved in hundreds of physiological activities. Changes in NAD + levels can regulate DNA damage repair, glucose metabolism and lipid metabolism, T cell activation, insulin release, protein synthesis and degradation, cell transmembrane signal transduction, cellular senescence and other physiological activities. Scientific research has shown that during aging, the level of NAD + in the body gradually declines. There are three pathways for mammalian NAD + synthesis: (1) Preiss-handler pathway; (2) de novo synthesis pathway; (3) salvage synthesis pathway.
- the salvage pathway is the synthesis of ⁇ -nicotinamide mononucleotide ( ⁇ -NMN) from nicotinamide ribose via nicotinamide riboside kinase or nicotinamide phosphoribosyltransferase (NAMPT), and then ⁇ -NMN via nicotinamide mononuclear
- ⁇ -NMN ⁇ -nicotinamide mononucleotide
- SIRT1 Silent information regulator 2
- NAMPT extracellular NAMPT
- eNAMPT extracellular NAMPT
- NAD + biosynthesis Yoshida et al., 2019; Cell Metabolism 30, 1-14 .
- various forms of supplements mainly include nicotinamide ribose, nicotinamide adenine dinucleotide, and nicotinamide mononucleotide.
- nicotinamide ribose is the precursor of NAD + , but it can only be chemically synthesized because chlorine gas needs to be added during the production process to ensure stability. Chlorine itself is toxic and volatile, which makes nicotinamide ribose a safety hazard.
- NR needs the help of enzymes and needs to go through multiple steps to be converted into NAD + , resulting in a low conversion rate. Therefore, the conversion rate and safety factor of nicotinamide ribose are relatively low.
- Nicotinamide adenine dinucleotide (Reduced form of nicotinamide-adenine dinucleotid, NADH) is the reduced state of NAD + , which can be quickly decomposed into NAD + and hydrogen after entering the human body, because the body ingests nicotinamide ribose and nicotinamide mononuclear
- the nucleotides are followed by a synthesis reaction, while the NADH enters the body for a decomposition reaction, and is less restricted by enzymes, so the conversion efficiency is the highest in the NAD + family.
- NADH also has obvious shortcomings. It is easy to degrade and is extremely unstable.
- ⁇ -Nicotinamide mononucleotide is a key NAD + intermediate with relatively simple production process and easy commercialization.
- the quality of commercialized nicotinamide mononucleotide on the market Differently, nicotinamide mononucleotide supplementation increases the NAD + /NADH ratio in replicative senescence and significantly enhances the pro-inflammatory senescence-associated secretory phenotype, which is tumorigenic. Supplementation with nicotinamide mononucleotide also promotes the progression of pancreatic ductal adenocarcinoma.
- the above supplements are all directly related to NAD + , either the precursor of NAD + or its reduced or intermediate state.
- the supplement can be converted into NAD + in the body to increase the content of NAD + in the body, but the supplement There are a series of disadvantages such as poor stability, complex production process, high cost, low safety, low conversion rate, and increased cancer risk.
- the present invention proposes a method for improving the activity of nicotinamide phosphoribosyltransferase and a composition thereof.
- the composition is treated, and a certain amount of nicotine, resveratrol or SRT1720 Increase the level of deacetylation of NAMPT by SIRT1 and increase the level of NAD + , thereby regulating DNA damage repair, glucose metabolism and lipid metabolism, T cell activation, insulin release, protein synthesis and degradation, cell transmembrane signal transduction, cellular Aging and other physiological activities.
- the present invention provides a method of increasing nicotinamide phosphoribosyltransferase activity, the method comprising administering to a subject an effective amount of a composition that increases nicotinamide phosphoribosyltransferase by sirtuin 2-related enzyme 1
- the deacetylation level of the enzyme increases the activity of nicotinamide phosphoribosyltransferase in the subject.
- the method for increasing nicotinamide phosphoribosyltransferase activity comprises continuously administering the composition to the subject for 2-6 months. It started to take effect after 2 months of continuous application, and the effect was obvious after 6 months.
- the present invention also provides a composition for improving the activity of nicotinamide phosphoribosyltransferase, the composition increases the level of deacetylation of nicotinamide phosphoribosyltransferase by sirtuin 2-related enzyme 1, and improves the transfer of nicotinamide phosphoribosyltransferase.
- Enzyme activity wherein the composition includes any one of nicotine, resveratrol and SRT1720.
- the nicotine concentration is 1 ng/mL-25 ⁇ g/mL. This concentration is very low, non-addictive, and non-cytotoxic.
- Both resveratrol and SRT1720 are specific activators of SIRT1, and both can promote the binding of SIRT1 and NAMPT.
- the concentration of the resveratrol is 8-12 ⁇ mol/L, and the concentration of the SRT1720 is 3-8 ⁇ mol/L.
- composition also includes preparation auxiliary materials.
- composition is an oral liquid, tablet, granule or capsule.
- composition is a powder or a beverage.
- the present invention also provides a method for preventing aging, preventing aging-related diseases, and preventing anxiety-related diseases, the method comprising administering to a subject an effective amount of a composition that increases a sirtuin 2-related enzyme 1 Deacetylation levels of nicotinamide phosphoribosyltransferase.
- the present invention also provides a composition for preventing aging, preventing aging-related diseases and preventing anxiety-related diseases, the composition comprising the ability to increase the deacetylation of sirtuin 2-related enzyme 1 to nicotinamide phosphoribosyltransferase horizontal ingredients.
- the aging and aging-related diseases and anxiety-related diseases include retinal neuron degeneration, axonal degeneration, essential tremor, Parkinson's disease, Alzheimer's disease, Huntington's disease, Ataxia Disorders, catatonic schizophrenia, neuroleptic malignant syndrome, chorea, corticobasal ganglia degeneration, dystonia, mental retardation, neuroacanthocytosis, Pelizois-Metzbach disease, progressive Supranuclear palsy, striatonigral degeneration, ischemic stroke, myelopathy, traumatic brain injury, and hypoxia.
- the aging and aging-related diseases and anxiety-related diseases include retinal neuron degeneration, axonal degeneration, essential tremor, Parkinson's disease, Alzheimer's disease, Huntington's disease, co-morbidity Ataxia, catatonic schizophrenia, neuroleptic malignant syndrome, chorea, corticobasal ganglia degeneration, dystonia, mental retardation, neuroacanthocytosis, Pelizois-Metzbach disease, Progressive supranuclear palsy, striatonigral degeneration, ischemic stroke, myelopathy, traumatic brain injury, and hypoxia.
- the present invention also provides the application of the composition in the preparation of medicines for treating aging, aging-related diseases and anxiety-related diseases.
- the present invention achieves the following technical effects:
- the method of the present invention increases the deacetylation level of NAMPT by SIRT1 under the situation of applying low-concentration nicotine, resveratrol or SRT1720, causing the NAMPT activity to rise, and then promoting the level of ⁇ -NMN and NAD + , thereby regulating DNA breakage. It has a variety of physiological activities such as repair, glucose metabolism and lipid metabolism, T cell activation, insulin release, protein synthesis and degradation, and cell transmembrane signal transduction.
- the dose of nicotine addiction is generally above 100 mg/mL, and the concentration in the present invention is low, ranging from 1 ng/mL to 25 ⁇ g/mL.
- Figure 1 shows the co-immunoprecipitation results of the binding levels of SIRT1 and NAMPT in the cerebral cortex and hippocampus of 6-month-old mice after ingesting nicotine for 6 months.
- N 3, *p ⁇ 0.05, the control group was significant relative to the nicotine group, 2way ANOVA, multiple comparisons.
- Figure 5 shows the effect of nicotine on telomere length in various tissues of aging mice.
- Real-time quantitative PCR was used to detect the changes of T/S ratio of each tissue in 6-month-old mice with and without nicotine intake.
- N 3, *p ⁇ 0.05 vs control group, two way ANOVA for multiple comparisons.
- Figure 9 shows the co-immunoprecipitation results of changes in the acetylation level of NAMPT with or without nicotine added to HT22 cells.
- Figure 10 shows the effect of nicotine on the NAMPT enzyme activity of HT22 cells.
- Figure 11 is the detection of the binding level of SIRT1 and NAMPT by co-immunoprecipitation and western blot.
- HT22 cells were treated with D-galactose (50 mM) for 1 week after adding 10 ng of nicotine.
- N 3, *p ⁇ 0.05, one-way ANOVA.
- Figure 12 shows the effect of nicotine on the ratio of NAD + /NADH in senescent cells. Changes of intracellular NAD + and NADH contents in HT22 cells treated with D-galactose for 1 week with or without nicotine. ***p ⁇ 0.001, control group vs D-galactose group; ⁇ p ⁇ 0.001 control group vs D-galactose+nicotine group. ANOVA.
- Figure 13 shows the effect of nicotine on the content of ⁇ -NMN in HT22 cells. 48 hours after HT22 cells were added with or without nicotine, the changes of intracellular ⁇ -NMN content were quantitatively detected by LC-MS. *p ⁇ 0.05 control vs nicotine.
- Figure 15 shows the binding of SIRT1 to NAMPT in the mouse hippocampal neuron cell line HT22 after adding resveratrol and STR1720.
- Nicotinamide phosphoribosyltransferase is a key rate-limiting enzyme in the synthesis and rescue pathway of nicotinamide adenine dinucleotide (NAD + ), and its activity is affected by Silent information regulator 2-related enzyme 1 (Silent information regulator 2, SIRT1) regulation.
- the present invention increases the deacetylation level of SIRT1 to NAMPT by applying nicotine, causes the activity of NAMPT to increase, promotes the combination of SIRT1 and NAMPT, and then increases the level of ⁇ -NMN and NAD + , thereby regulating DNA loss repair, glucose metabolism and lipid metabolism, T cell activation, insulin release, protein synthesis and degradation, cell transmembrane signal transduction, cell senescence and other physiological activities.
- both resveratrol and SRT1720 are specific activators of SIRT1, and both can promote the binding of SIRT1 and NAMPT, thereby increasing the levels of ⁇ -NMN and NAD + , thereby regulating a series of cellular physiological activities.
- the CAS number of SRT1720 is 925434-55-5, and its structural formula is as follows:
- the 6-month-old C57BL/6J male mice were used as experimental materials.
- the 6-month-old mice were considered to be senescent mice.
- the control group was the 6-month-old C57BL/6J male mice without nicotine added in the drinking water.
- the nicotine group Add nicotine to the drinking water of 6-month-old C57BL/6J male mice.
- the concentration of nicotine in the drinking water is 1ng/mL-25 ⁇ g/mL.
- the standard curve is used to detect the nicotine concentration in the mouse brain tissue.
- the test results show that the nicotine concentration in the mouse brain tissue is 10-20ng/g, and most of the nicotine fed by drinking water will not be absorbed by the mice. ,
- the nicotine content in the mouse brain is very low, and there is no hidden danger of addiction.
- the hippocampus of the mice in the control group and the nicotine group were taken to detect the NAMPT activity using a colorimetric NAMPT activity detection kit (the kit product number is MBL CY1251V2). As shown in Figure 2, the NAMPT enzyme activity of the nicotine group was significantly higher than that of the control group, indicating that nicotine could significantly increase the NAMPT enzyme activity.
- telomere theory of aging is well known. Each time a cell divides to produce a new cell, the telomere shortens until the telomere reaches a critical length, at which point the cell also becomes inactive and dies. So telomeres shorten as individual cells age. But each cell's telomere length is innate, not the same at first, and shortens at different rates thereafter. The rate of telomere loss is one measure of "biological aging". Therefore, the present invention tests the effect of adding nicotine on the telomere length of senescent cells, and verifies that the intake of nicotine is effective for delaying senescence from another perspective.
- the brain, heart, liver, and skeletal muscle tissues of the mice in the control group and the nicotine group were taken, and the genomic DNA of the above tissues was extracted, and the telomere length of each tissue was detected by real-time quantitative PCR to calculate the T/S ratio (telomere/single).
- the results As shown in Figure 5, the relative T/S ratios in the heart, liver, and skeletal muscle of the mice in the nicotine group were higher than those in the control group. The above results indicate that nicotine can protect the telomere length of senescent cells. Anti-aging is effective.
- the present invention detects the carbonyl protein level of each tissue of the mice after adding nicotine, and verifies that the intake of nicotine is effective for delaying aging from another perspective.
- the brain, heart, liver, and skeletal muscle tissues of the mice in the control group and the nicotine group were respectively taken using a colorimetric carbonyl protein detection kit (kit product number: caymanchem NO.10005020) to detect the level of carbonyl protein in the aging tissues of mice.
- kit product number: caymanchem NO.10005020 caymanchem NO.10005020
- the decreased level of protein phosphorylation can inhibit the target genes downstream of the pathway, inhibit the activation of the inflammatory pathway, and thus resist the inflammatory response. Therefore, the present invention also verifies the phosphorylation level of the inflammatory pathway protein.
- the cerebral cortex and hippocampus of mice in the control group and the nicotine group were taken, and the protein phosphorylation levels of the inflammatory pathway JAK2-STAT3 were detected by western blotting. The results are shown in Figure 7.
- the ordinate represents the phosphorylation levels of JAK2 and STAT3, respectively.
- the phosphorylation levels of JAK2 and STAT3 proteins in the nicotine group were significantly decreased in the cortex and hippocampus, indicating that nicotine induces the phosphorylation of JAK2 and STAT3 proteins in the inflammatory pathway. Levels decrease, thereby anti-inflammatory response.
- this example uses 6-month-old aged C57BL/6J male mice as experimental materials to verify that nicotine can promote the binding of SIRT1 to NAMPT, increase NAMPT enzyme activity, increase NAD + level, and increase NAMPT in aging mice.
- ⁇ -NMN level protect the telomere length of senescent cells, reduce carbonyl protein levels in various tissues of senescent mice, reduce the protein phosphorylation level of JAK2-STAT3, and relieve anxiety.
- Example 1 The effect of nicotine was verified by using 6-month-old aged C57BL/6J male mice as experimental materials. This example further verifies whether nicotine can reduce the acetylation level of NAMPT and increase the activity of NAMPT enzyme at the cellular level.
- the control group was mouse hippocampal neuron cell line HT22 without nicotine
- the nicotine group was mouse hippocampal neuron cell line HT22 with 10ng/mL nicotine added for 48 hours.
- NAMPT acetylation levels were detected by co-immunoprecipitation and immunoblotting. As shown in Figure 9, the NAMPT acetylation level of the nicotine group is much lower than that of the control group, indicating that nicotine can significantly reduce the NAMPT acetylation level. Therefore, the present invention increases the NAMPT activity by increasing the deacetylation level of SIRT1 to NAMPT. This in turn increases ⁇ -NMN and NAD + levels, thereby delaying aging and relieving anxiety.
- the NAMPT activity was detected by a colorimetric NAMPT activity detection kit (the kit product number is MBL CY1251V2).
- kit product number is MBL CY1251V2
- Figure 10 the NAMPT enzyme activity of the nicotine group was significantly higher than that of the control group, indicating that nicotine can significantly increase the NAMPT enzyme activity.
- Example 2 nicotine has been shown to reduce the acetylation level of NAMPT, increase the activity of NAMPT enzyme, and then increase the level of ⁇ -NMN and NAD + at both the individual level and the cellular level of mice. anxiety.
- D-galactoside is used to construct a senescent cell model in this example to simulate the experimental results in senescent cells.
- D-galactoside can promote cell aging. The mechanism is to generate a large amount of reactive oxygen species by enhancing mitochondrial respiration. The increase of reactive oxygen species content will accelerate the aging of cells.
- the mouse hippocampal neuron cell line HT22 was added to the high-glucose DMEM medium at a density of 5x 10 6 cells/plate.
- control group was not supplemented with nicotine
- D-galactoside group was supplemented with 50 mM D- Galactoside
- HT22 cells can be senescent after 7 days of culture.
- the D-galactoside + nicotine group was treated with 10ng/mL nicotine on the basis of the D-galactoside group for one week.
- the ratio of NAD + /NADH in the control group, D-galactoside group and D-galactoside + nicotine group was detected by colorimetric method (the kit product No. For ab65348), the ratio of NAD + /NADH can reflect the level of NAD + .
- D-galactose can cause the level of NAD + in cells to decrease, indicating that adding nicotine to cells can protect the level of NAD + in senescent cells.
- this example proves that nicotine can protect the binding of SIRT1 and NAMPT in senescent cells, and protect the NAD + level in senescent cells, indicating that for senescent animals and tissues, intake of nicotine can delay the treatment. senescence.
- the control group was the mouse hippocampal neuron cell line HT22 without nicotine
- the nicotine group was the mouse hippocampal neuron cell line HT22 added with 1 ng/mL and 10 ng/mL nicotine, respectively.
- the control group was 6-month-old C57BL/6J male mice without nicotine added to the drinking water
- the nicotine group was 6-month-old C57BL/6J male mice with nicotine added to the drinking water.
- the concentration of nicotine in the drinking water was 1ng/mL-25 ⁇ g/mL, regularly The drinking water was changed, and after 2 months of continuous feeding, the mice were perfused to take the brains, and the brain sections were frozen, and the newborn neurons were labeled with doublecortin by immunofluorescence staining.
- the results are shown in Figure 14.
- the ordinate represents the number of dentate gyrus neurons in the hippocampus.
- the number of hippocampal dentate gyrus neurons in the brains of mice in the nicotine group increased significantly, indicating that nicotine can make the hippocampal dentate gyrus neurons in the brains of aging mice.
- the number of yuan increases.
- neuronal cells will die, and replenishing the aging and dead neuron cells can reduce the degeneration of neurons, thereby slowing down aging to a certain extent.
- the mouse hippocampal neuronal cell line HT22 was added to high glucose DMEM medium at a density of 1 x 10 6 cells/plate.
- the control group was the mouse hippocampal neuron cell line HT22 without adding resveratrol and STR1720
- the resveratrol group was the mouse hippocampal neuron cell line HT22 with 8-12 ⁇ mol/L resveratrol added.
- STR1720 group was added 3-8 ⁇ mol/L of STR1720 to the mouse hippocampal neuron cell line HT22, and treated for 48h respectively. Co-immunoprecipitation and immunoblotting were used to detect the binding of SIRT1 to NAMPT in the cells of the control and experimental groups, respectively. The results are shown in Figure 15, resveratrol (10 ⁇ mol/L) and SRT1720 (5 ⁇ mol/L) can enhance the binding of SIRT1 to NAMPT.
- nicotine, resveratrol and STR1720 can strongly bind SIRT1 to NAMPT, thereby increasing the levels of ⁇ -NMN and NAD + , thereby regulating DNA loss repair, glucose metabolism and lipid metabolism, T cell activation, insulin release, protein The synthesis and degradation of cells, transmembrane signal transduction of cells, cell senescence and other physiological activities.
- the present invention can produce multiple embodiments according to ingredient types, ingredient contents, dosage forms, and the like.
- Embodiment 1 Oral liquid with nicotine, resveratrol or STR1720 as medicinal components
- oral liquid is a new dosage form developed on the basis of decoction and injection. It has the advantages of small dose, fast absorption, stable quality, convenient carrying and taking, and easy storage. It contains a variety of active ingredients. Great impact on quality and taste. On the premise of not changing the structure and function of the main active ingredients, how to retain the active ingredients to the maximum extent and improve the taste is a difficulty in the selection of excipients. Adding excipients to oral liquid can improve taste, improve clarity, enhance stability and improve product quality.
- excipients for oral liquid are: solvent, fragrance, flavoring agent, clarifying agent, preservative, etc. These excipients can be added at the same time, or one of them can be added. Among them, the solvent must be added, and water can be used. Different adjuvants are combined with sweeteners, aromatics, clarifying agents or preservatives, or a combination of sweeteners and preservatives, preferably a combination of sweeteners and preservatives. Some excipients have the functions of sweetening and flavoring, and only one kind of excipient can be added at this time.
- the sweetener is selected from one or more of protein sugar, xylitol, aspartame and sucralose.
- the preservative is selected from one or more of parabens, butylated hydroxyanisole, butylated hydroxytoluene and sorbic acid.
- Preservatives can be selected from parabens, butylated hydroxytoluene or sorbic acid, preferably butylated hydroxytoluene. Combinations of hydroxybenzoates and butylated hydroxytoluene are also possible, or butylated hydroxytoluene and sorbic acid, or parabens and sorbic acid, or parabens , a combination of butylated hydroxytoluene and sorbic acid.
- the fragrance is fruit essence.
- the clarifying agent is one or both of chitosan and gelatin.
- Embodiment 2 Tablets with nicotine, resveratrol or STR1720 as active ingredients
- the tablet has the advantages of accurate dosage, stable quality, convenient taking, carrying and transportation.
- the formulation auxiliary materials include one or more of diluents, binders, lubricants and disintegrants, preferably a combination of diluents, binders, lubricants and disintegrants.
- the diluent is one or more of cellulose and inorganic salts.
- cellulose and inorganic salts Such as microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate and medicinal calcium carbonate, mannitol, etc., to increase the volume of raw materials to help them shape.
- the binder is one of water, ethanol, sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, gelatin, polyvinylpyrrolidone, etc. or more.
- the lubricant is one or more of magnesium stearate, micropowder silica gel, talc, hydrogenated vegetable oil, polyethylene glycol and magnesium lauryl sulfate.
- the disintegrant is one or more of low-substituted hydroxypropyl, cross-linked polyvinyl pyrrolidone, and cross-linked sodium carboxymethyl cellulose.
- Embodiment 3 Capsules with nicotine, resveratrol or STR1720 as active ingredients
- the capsule mainly improves the stability and bioavailability of the drug.
- the preparation auxiliary material is a capsule shell, and the capsule shell is a hard capsule shell or a soft capsule shell.
- Embodiment 4 Granules with nicotine, resveratrol or STR1720 as medicinal ingredients
- Granules can be swallowed directly, or can be washed into water with warm water to drink, it is more convenient to apply and carry, and the dissolution and absorption speed are faster.
- the formulation auxiliary materials used in granules are similar to those of tablets, involving one or more of fillers, binders, wetting agents, disintegrants, lubricants and film coating materials.
- the filler is one or more of cellulose and inorganic salts.
- cellulose and inorganic salts Such as microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate and medicinal calcium carbonate, mannitol, etc., to increase the volume of raw materials to help them shape.
- the binder is one of water, ethanol, sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, gelatin, polyvinylpyrrolidone, etc. or more.
- the wetting agent is water or ethanol or a mixture of both.
- the wetting agent is water or ethanol or a mixture of both.
- the disintegrant is one or more of low-substituted hydroxypropyl, cross-linked polyvinyl pyrrolidone, and cross-linked sodium carboxymethyl cellulose.
- the film coating material is one or more of hydroxypropyl methylcellulose, polyethylene glycol, cellulose acetate phthalate and polyvinyl acetal diethylamine acetate .
- Embodiment 5 Powder with nicotine, resveratrol or STR1720 as medicinal ingredients
- the present invention can also be made into powder, and the powder is convenient to be divided into doses and taken.
- composition of the present invention can be made into beverages with different flavors, which will be very popular as daily beverages.
- the preparation auxiliary materials used in the beverage are at least one of clarifying agent, preservative and flavoring agent.
- composition of the present invention can also be made into other powders, such as functional milk powder, and the added auxiliary materials are mainly milk powder, such as skimmed milk powder, non-fat sugar-free milk powder.
- the above multiple embodiments can adjust the amount of medicine in a unit product to suit different uses, such as medicine, health care product, food and so on.
- nicotine, resveratrol or STR1720 can promote the binding of SIRT1 to NAMPT at the tissue, individual and cellular levels, cause the increase of NAMPT enzyme activity, increase the level of NAD + , increase the level of ⁇ -NMN, and inhibit the senescent cell end.
- Increase in granule length reduce carbonyl protein levels in various tissues of aging mice, reduce protein phosphorylation levels of JAK2-STAT3, increase neuronal proliferation, relieve anxiety, protect the combination of SIRT1 and NAMPT in senescent cells, and protect NAD in senescent cells. + level.
Abstract
一种提高烟酰胺磷酸核糖转移酶活性的方法及其组合物，所述方法和组合物能够增加沉默信息调节因子2相关酶1(SIRT1)对烟酰胺磷酸核糖转移酶(NAMPT)的去乙酰化水平，引起NAMPT活性升高，进而提高β-烟酰胺单核苷酸(β-NMN)与NAD +水平。将所述组合物经过处理，通过补充一定量的尼古丁、白藜芦醇或SRT1720提高烟酰胺磷酸核糖转移酶活性。NAD +水平的改变能够调控DNA损伤修复、糖代谢和脂代谢、T细胞激活、胰岛素释放、蛋白质的合成和降解、细胞的跨膜信号转导、细胞衰老等多种生理活动。
Description
本发明涉及大健康领域，特别涉及大健康领域下的食品、保健品和药物领域，具体涉及一种提高烟酰胺磷酸核糖转移酶活性的方法及其组合物。
NAD
+是体内重要的辅酶，参与上百种生理活动。NAD
+水平的改变能够调控DNA损伤修复、糖代谢和脂代谢、T细胞激活、胰岛素释放、蛋白质的合成和降解、细胞的跨膜信号转导、细胞衰老等多种生理活动。科学研究表明，衰老过程中，机体内NAD
+的水平逐渐下降。哺乳动物NAD
+合成有三条通路：(1)Preiss-handler途径；(2)从头合成途径；(3)补救合成途径。其中补救途径为烟酰胺核糖经烟酰胺核苷激酶或烟酰胺经烟酰胺磷酸核糖转移酶(NAMPT)合成β-烟酰胺单核苷酸(β-NMN)，然后β-NMN经烟酰胺单核苷酸腺苷酰转移酶合成NAD
+的途径。NAMPT的活性受沉默信息调节因子2相关酶1(Silent information regulator 2，SIRT1)调节。SIRT1是一种NAD
+消耗酶，具有很强的去乙酰化酶活性。SIRT1介导的NAMPT去乙酰化可以促进脂肪细胞的胞外NAMPT(eNAMPT)分泌，引起β-NMN水平升高，增强NAD
+的生物合成(Yoshida et al.,2019；Cell Metabolism 30,1-14)。但是直接补充NAD
+不能被细胞吸收利用，于是各种形式的补充剂主要有烟酰胺核糖、烟酰胺腺嘌呤二核苷酸、烟酰胺单核苷酸。
其中，烟酰胺核糖(Nicotinamide ribose，NR)是NAD
+的前体，但是因为生产过程中需要添加氯气来保证稳定性，所以只能化学合成。氯气本身有毒，容易挥发，这使得烟酰胺核糖存在安全隐患。另外NR需要酶的帮助，要经过多个步骤才能转化成NAD
+，导致转化率低。所以烟酰胺核糖的转化率、安全系数都相对较低。
烟酰胺腺嘌呤二核苷酸(Reduced form of nicotinamide-adenine dinucleotid，NADH)是NAD
+的还原态，进入人体后可迅速分解为NAD
+和氢，因为机体摄入烟酰胺核糖和烟酰胺单核苷酸都是随后进行合成反应，而NADH进入机体是进行分解反应，且受酶的限制较小，因此转化效率是NAD
+家族中最高的。但是NADH也存在明显的缺点，易降解，极不稳定，只能现配现用，难生产应用，难以推广。
β-烟酰胺单核苷酸(β-Nicotinamide mononucleotide，β-NMN)是一种关键的NAD
+中间体，生产工艺相对简单，容易商业化，然而市场上商品化的烟酰胺单核苷酸品质不一，补充烟酰胺单核苷酸会增加复制性衰老中的NAD
+/NADH比值，显著增强促炎衰老相关分泌表型，促炎衰老相关分泌表型具有致瘤性。补充烟酰胺单核苷酸还会促进胰腺导管腺癌的进展。
以上补充剂都与NAD
+直接相关，不是NAD
+的前体就是其还原态或中间态，在原理上就是补充剂进入体内能够转化为NAD
+从而提高体内NAD
+的含量，但是所述补充剂存在稳定性差、生产工艺复杂、成本高、安全性低、转化率低、增加癌症风险等一系列缺点。
发明内容
针对现有技术中的缺陷，本发明提出了一种提高烟酰胺磷酸核糖转移酶活性的方法及其组合物，将所述组合物经过处理，通过补充一定量的尼古丁、白藜芦醇或SRT1720增加SIRT1对NAMPT的去乙酰化水平，提高NAD
+的水平，进而调控DNA损伤修复、糖代谢和脂代谢、T细胞激活、胰岛素释放、蛋白质的合成和降解、细胞的跨膜信号转导、细胞衰老等多种生理活动。
本发明提供一种提高烟酰胺磷酸核糖转移酶活性的方法，所述方法包括施用有效量的组合物至受试者,所述组合物增加沉默信息调节因子2相关酶1对烟酰胺磷酸核糖转移酶的去乙酰化水平，提高所述受试者中烟酰胺 磷酸核糖转移酶的活性。
进一步的，所述提高烟酰胺磷酸核糖转移酶活性的方法中包括连续施用2-6个月所述组合物至所述受试者。持续施用2个月开始起效，6个月时有明显效果。
本发明还提供一种提高烟酰胺磷酸核糖转移酶活性的组合物，所述组合物增加沉默信息调节因子2相关酶1对烟酰胺磷酸核糖转移酶的去乙酰化水平，提高烟酰胺磷酸核糖转移酶的活性；其中，所述组合物包括尼古丁、白藜芦醇、SRT1720中的任意一种。所述尼古丁的浓度为1ng/mL-25μg/mL。这个浓度非常低，不会成瘾，无细胞毒性。白藜芦醇和SRT1720均是SIRT1的特异性激活剂，都能促进SIRT1和NAMPT的结合。所述白藜芦醇的浓度为8-12μmol/L，所述SRT1720的浓度为3-8μmol/L。
进一步的，所述组合物还包括制剂辅料。
进一步的，所述组合物为口服液、片剂、颗粒剂或者胶囊剂。
进一步的，所述组合物为散剂或者饮料。
本发明还提供一种用于防止衰老、防止衰老相关疾病以及防止焦虑相关疾病的方法，所述方法包括施用有效量的组合物至受试者,所述组合物增加沉默信息调节因子2相关酶1对烟酰胺磷酸核糖转移酶的去乙酰化水平。
本发明还提供一种用于防止衰老、防止衰老相关疾病以及防止焦虑相关疾病的组合物，所述组合物包括能够增加沉默信息调节因子2相关酶1对烟酰胺磷酸核糖转移酶的去乙酰化水平的成分。
进一步的，根据所述的方法，所述衰老及衰老相关疾病和焦虑相关疾病包括视网膜神经元变性、轴突变性、特发性震颤、帕金森病、阿尔茨海默病、亨廷顿病、共济失调、紧张性精神分裂症、神经阻滞剂恶性综合征、舞蹈病、皮质基底神经节变性、肌张力障碍、智力迟钝、神经棘红细胞增 多症、佩利措伊斯-梅茨巴赫病、进行性核上性麻痹、纹状体黑质变性、缺血性中风、脊髓病变、外伤性脑损伤和缺氧症。
进一步的，根据所述的组合物，所述衰老及衰老相关疾病和焦虑相关疾病包括视网膜神经元变性、轴突变性、特发性震颤、帕金森病、阿尔茨海默病、亨廷顿病、共济失调、紧张性精神分裂症、神经阻滞剂恶性综合征、舞蹈病、皮质基底神经节变性、肌张力障碍、智力迟钝、神经棘红细胞增多症、佩利措伊斯-梅茨巴赫病、进行性核上性麻痹、纹状体黑质变性、缺血性中风、脊髓病变、外伤性脑损伤和缺氧症。
本发明还提供所述的组合物在制备治疗衰老及衰老相关疾病和焦虑相关疾病的药物中的应用。
综上，与现有技术相比，本发明达到了以下技术效果：
1.本发明的方法在施加低浓度尼古丁、白藜芦醇或SRT1720情况下，增加SIRT1对NAMPT去乙酰化水平，引起NAMPT活性升高，进而促进β-NMN与NAD
+水平，从而调控DNA断裂的修复、糖代谢和脂代谢、T细胞激活、胰岛素释放、蛋白质的合成和降解、细胞的跨膜信号转导等多种生理活动。
2.本发明的方法长期使用尼古丁不会引起成瘾以及增加癌症风险。尼古丁成瘾的剂量一般在100mg/mL以上，本发明中浓度低，为1ng/mL-25μg/mL。
为了更清楚地说明本发明实施例的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，应当理解，以下附图仅示出了本发明的某些实施例，因此不应被看作是对范围的限定，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他相关的附图。
图1为6月龄小鼠摄入尼古丁6个月后，小鼠大脑皮层与海马区SIRT1与 NAMPT结合水平的免疫共沉淀结果。N＝3，*p<0.05，对照组相对尼古丁组具有显著性，2way ANOVA，多重比较。
图2为尼古丁对小鼠海马区NAMPT酶活的影响。显示6月龄小鼠摄入或不摄入尼古丁(25ng)，6个月后，检测NAMPT急性酶活水平。N＝3，t检验。
图3为尼古丁对小鼠大脑内总NAD
+浓度的影响。显示6月龄小鼠摄入或不摄入尼古丁，6个月后，检测脑组织总NAD
+水平。N＝3，t检验。
图4为尼古丁对小鼠大脑内β-NMN含量的影响。显示6月龄小鼠摄入或不摄入尼古丁，6个月后，利用LC-MS定量检测β-NMN水平。N＝3，t检验。
图5为尼古丁对衰老小鼠各组织端粒长度的影响。实时定量PCR检测6月龄小鼠摄入与不摄入尼古丁，各组织T/S比值的变化。N＝3，*p<0.05vs对照组，two way ANOVA多重比较。
图6为尼古丁对衰老小鼠各组织羰基蛋白水平的影响。检测6月龄小鼠摄入与不摄入尼古丁，各组织羰基蛋白含量的变化。N＝3，*p<0.05vs对照组，单因素方差分析。
图7为尼古丁对衰老的小鼠脑内炎症水平的影响。检测小鼠摄入与不摄入尼古丁，炎症相关信号通路JAK2-STAT3的变化。N＝3，*p，^p<0.05vs对照组，单因素方差分析。
图8为尼古丁对衰老小鼠焦虑情绪的影响。显示6月龄小鼠摄入或不摄入尼古丁6个月后，对小鼠进行旷场实验，检测小鼠焦虑情绪。对统计小鼠进入中心区的次数及在中心区停留时间。N＝12，*p<0.05vs对照组。
图9为HT22细胞加入或不加入尼古丁，NAMPT乙酰化水平的变化的免疫共沉淀结果。
图10为尼古丁对HT22细胞NAMPT酶活的影响。显示HT22细胞加入或不加入尼古丁48小时后NAMPT急性酶活水平。**p<0.05，N＝3，t检验。
图11为利用免疫共沉淀及免疫印迹检测SIRT1与NAMPT结合水平。HT22细胞加入10ng尼古丁后经D-半乳糖(50mM)处理1周。N＝3，*p<0.05，单因素方差分析。
图12为尼古丁对衰老细胞NAD
+/NADH比值的影响。显示HT22细胞加入或不加尼古丁后经D-半乳糖处理1周，细胞内NAD
+与NADH含量的变化。***p<0.001，对照组vs D-半乳糖组；^^^p<0.001对照组vs D-半乳糖+尼古丁组。单因素方差分析。
图13为尼古丁对HT22细胞β-NMN含量的影响。显示HT22细胞加入或不加尼古丁48小时后，利用LC-MS定量检测细胞内β-NMN含量的变化。*p<0.05对照组vs尼古丁。
图14为尼古丁对小鼠海马齿状回区新生神经元数目的影响。对小鼠海马区进行免疫荧光染色，统计海马齿状回表达DCX蛋白的神经元数目。N＝3*p<0.05vs对照组。
图15为添加白藜芦醇与STR1720后小鼠海马神经元细胞系HT22中SIRT1与NAMPT的结合情况。
为了使本技术领域的人员更好地理解本发明方案，下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分的实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例，都应当属于本发明保护的范围。
本发明的方法提高机体内NAD
+水平的机理是全新的，烟酰胺磷酸核糖转移酶(NAMPT)是烟酰胺腺嘌呤二核苷酸(NAD
+)合成补救途径中关键限速酶，其活性受沉默信息调节因子2相关酶1(Silent information regulator 2，SIRT1)调节。本发明通过施加尼古丁增加SIRT1对NAMPT 的去乙酰化水平，引起NAMPT活性升高，促进SIRT1和NAMPT的结合，进而提高β-NMN与NAD
+水平，从而调控DNA损失修复、糖代谢和脂代谢、T细胞激活、胰岛素释放、蛋白质的合成和降解、细胞的跨膜信号转导、细胞衰老等多种生理活动。此外，白藜芦醇和SRT1720均是SIRT1的特异性激活剂，都能促进SIRT1和NAMPT的结合，进而提高β-NMN与NAD
+水平，从而调控一系列细胞生理活动。SRT1720的CAS号为925434-55-5，其结构式如下：
为了验证本发明的方法的确增加了SIRT1对NAMPT的去乙酰化水平、引起NAMPT活性升高、提高β-NMN与NAD
+水平，从而达到延缓衰老和缓解焦虑的效果，以衰老C57BL/6J雄性小鼠和小鼠海马神经元细胞系HT22为实验材料进行了下述的实验验证。下述实施例中所用的材料、试剂、药品、细胞系和衰老C57BL/6J小鼠等，如无特殊说明，均可从公司通过商业途径购买。
实施例1
取6月龄C57BL/6J雄性小鼠为实验材料，6月龄的小鼠被认为是已经发生衰老的小鼠，对照组为6月龄C57BL/6J雄性小鼠饮水中不添加尼古丁，尼古丁组为6月龄C57BL/6J雄性小鼠饮水中加入尼古丁，饮水中尼古丁的浓度为1ng/mL-25μg/mL，连续喂养6个月后，通过液相和气相联用色谱IC-MS 利用外标法做标准曲线，对小鼠脑组织内的尼古丁浓度做检测，检测结果说明小鼠脑组织内的尼古丁浓度为10-20ng/g，通过饮水喂养的尼古丁的绝大部分不会被小鼠吸收，在小鼠脑内的尼古丁含量非常低，不会有成瘾的隐患。
为了验证尼古丁是否会促进SIRT1与NAMPT的结合，分别取对照组和尼古丁组小鼠的大脑皮层和海马区，因为大脑皮层和海马区是因衰老导致焦虑情绪的发病区域，该区域病变会影响小鼠认知功能。采用免疫共沉淀和免疫印迹检测小鼠皮层和海马区中SIRT1与NAMPT结合情况。结果如图1所示，尼古丁组小鼠皮层和海马区SIRT1与NAMPT结合水平显著高于对照组。说明对照组相对尼古丁组具有显著性差异，以上结果说明尼古丁可以促进SIRT1与NAMPT的结合。
为了验证尼古丁能够引起NAMPT酶活升高，分别取对照组和尼古丁组的小鼠大脑海马区利用比色法NAMPT活性检测试剂盒检测NAMPT活性(试剂盒商品号为MBL CY1251V2)。结果如图2所示，尼古丁组的NAMPT酶活显著高于对照组，说明尼古丁能够显著引起NAMPT酶活升高。
为了验证尼古丁是否引起小鼠脑内NAD
+水平升高，分别取对照组和尼古丁组的小鼠大脑海马区利用比色法NAD
+/NADH检测试剂盒检测NAMPT活性(试剂盒商品号ab65348)。结果如图3所示，尼古丁组NAD
+的比值明显高于对照组，说明尼古丁能够显著引起小鼠脑内NAD
+水平升高。
为了验证尼古丁是否会提高β-NMN水平，分别取对照组和尼古丁组的小鼠大脑，液氮淬灭30min后研磨加入甲醇：水＝1:1溶解沉淀，10000g离心后，取上清过滤，通过液相和气相联用色谱LC-MS，利用外标法制作标准曲线的方法，定量检测小鼠脑内β-NMN含量。结果如图4所示，尼古丁组的β-NMN含量明显高于对照组，说明尼古丁能够引起小鼠脑内β-NMN水平升高。
衰老的“端粒学说”众所周知，每当细胞分裂产生新细胞时，端粒就会 变短，直到端粒达到一个临界长度，这时细胞也失去活性而死亡。所以端粒随着细胞个体的衰老而变短。但每个细胞的端粒长度是天生的，并非一开始就相同，并且之后的缩短速度也各不相同。端粒损耗的速度是衡量“生物衰老”的一个方法。因此本发明检测了添加尼古丁对于衰老细胞端粒长度的效果，从另一个角度验证尼古丁的摄入对于延缓衰老有效。分别取对照组和尼古丁组的小鼠大脑、心脏、肝脏、骨骼肌组织，提取上述组织的基因组DNA，利用实时定量PCR检测各组织细胞端粒长度计算T/S比值(telomere/single)，结果如图5所示，尼古丁组的小鼠心脏、肝脏、骨骼肌中的相对T/S比值均高于对照组，以上结果表明尼古丁可以保护衰老细胞的端粒长度，故说明尼古丁的摄入对于延缓衰老有效。
现有的研究表明，活性羰基类物质参与了心血管疾病(如动脉粥样硬化)、神经退行性疾病(如阿尔兹海莫病、帕金森病)、脑缺血、类风湿性关节炎、局部缺血再灌注等许多疾病和应激的启动和发展过程。正是如此，羰基应激衰老理论认为羰基应激是生物衰老的核心生化过程之一。羰基应激是指生物体系中活性羰基类物质的产生超过了机体的清除能力，从而导致蛋白质等生物大分子的羰基化修饰。因此本发明检测了添加尼古丁后小鼠各组织的羰基蛋白水平，从另一个角度验证尼古丁的摄入对于延缓衰老有效。分别取对照组和尼古丁组的小鼠大脑、心脏、肝脏、骨骼肌组织利用比色法羰基蛋白检测试剂盒(试剂盒商品号为caymanchem NO.10005020)，检测小鼠衰老组织羰基蛋白水平。结果如图6所示，尼古丁组的小鼠大脑、心脏、肝脏、骨骼肌中的羰基蛋白含量均低于对照组，说明尼古丁能够降低衰老小鼠各组织羰基蛋白水平，故说明尼古丁的摄入对于延缓衰老有效。
蛋白磷酸化水平下降能够抑制通路下游的靶基因，抑制炎症通路的激活，从而抗炎症反应。所以本发明还验证了炎症通路蛋白的磷酸化水平。分别取对照组和尼古丁组的小鼠大脑皮层和海马区，通过免疫印迹检测炎 症通路JAK2-STAT3的蛋白磷酸化水平。结果如图7所示，纵坐标分别代表JAK2和STAT3的磷酸化水平，尼古丁组的JAK2蛋白和STAT3蛋白在皮层和海马的磷酸化水平均明显下降，说明尼古丁引起炎症通路JAK2和STAT3蛋白磷酸化水平下降，从而抗炎症反应。
为了验证尼古丁是否对缓解焦虑有效，分别对上述对照组和尼古丁组的小鼠进行行为学实验：旷场实验，记录小鼠在中心区域经过次数和停留时间评估反映小鼠焦虑情绪。结果如图8所示，摄入尼古丁小鼠在旷场中心区经过次数和停留时间显著高于对照组小鼠，说明摄入尼古丁小鼠焦虑情绪得到显著缓解。
综上，本实施例以6月龄衰老C57BL/6J雄性小鼠为实验材料，验证了尼古丁在衰老小鼠中能够促进SIRT1与NAMPT的结合、引起NAMPT酶活升高、提高NAD
+水平、提高β-NMN水平、保护衰老细胞的端粒长度、降低衰老小鼠各组织羰基蛋白水平、降低JAK2-STAT3的蛋白磷酸化水平、缓解焦虑。
实施例2
实施例1以6月龄衰老C57BL/6J雄性小鼠为实验材料，验证了尼古丁的效果。本实施例在细胞层面进一步验证尼古丁是否会降低NAMPT的乙酰化水平、升高NAMPT酶的活性。实验中对照组为小鼠海马神经元细胞系HT22中不添加尼古丁，尼古丁组为小鼠海马神经元细胞系HT22中加入10ng/mL尼古丁，处理48h。
通过免疫共沉淀和免疫印迹检测NAMPT乙酰化水平。结果如图9所示，尼古丁组的NAMPT乙酰化水平远低于对照组，说明尼古丁能够显著降低NAMPT乙酰化水平，故本发明通过增加SIRT1对NAMPT的去乙酰化水平，引起NAMPT活性升高，继而提高β-NMN与NAD
+水平，从而延缓衰老和缓解焦虑。
为了验证尼古丁是否能升高NAMPT酶的活性，利用比色法NAMPT活性 检测试剂盒检测NAMPT活性(试剂盒商品号为MBL CY1251V2)。结果如图10所示，尼古丁组的NAMPT酶活显著高于对照组，说明尼古丁能够显著引起NAMPT酶活升高。
结合实施例1和实施例2，在小鼠个体水平和细胞水平，尼古丁均显示能降低NAMPT的乙酰化水平、升高NAMPT酶的活性，进而提高β-NMN和NAD
+水平，延缓衰老和缓解焦虑。
实施例3
为了验证本发明的方法在已经发生衰老的细胞上的效果，本实施例利用D-半乳糖苷构建衰老细胞模型，以模拟在衰老细胞中的实验结果。D-半乳糖苷能够促使细胞衰老，其机理是通过增强线粒体的呼吸作用产生大量的活性氧，活性氧的含量提高就会加速细胞的衰老。在高糖DMEM培养基中添加小鼠海马神经元细胞系HT22，密度为5x 10
6细胞/板，培养48小时后，对照组不添加尼古丁，D-半乳糖苷组添加浓度为50mM的D-半乳糖苷，培养7天即可使HT22细胞发生衰老。D-半乳糖苷+尼古丁组在D-半乳糖苷组基础上加入10ng/mL尼古丁，处理一周。
为了验证尼古丁是否能够保护衰老细胞中SIRT1与NAMPT的结合，采用免疫共沉淀和免疫印迹检测细胞中SIRT1与NAMPT结合情况。结果如图11所示，说明对照组相对D-半乳糖苷组以及对照组相对D-半乳糖苷+尼古丁组均具有显著性差异。实验结果表明D-半乳糖会引起SIRT1与NAMPT结合水平下降，细胞加入尼古丁能够保护SIRT1和NAMPT结合水平。以上结果说明尼古丁能够保护衰老细胞中SIRT1与NAMPT的结合。
为了验证尼古丁能够保护衰老细胞中的NAD
+水平，利用比色法分别检测对照组、D-半乳糖苷组和D-半乳糖苷+尼古丁组的NAD
+/NADH的比值(所用试剂盒商品号为ab65348)，NAD
+/NADH的比值可以反映出NAD
+的水平，结果如图12所示，D-半乳糖会引起细胞NAD
+水平下降，说明细胞加入尼古丁能够保护衰老细胞的NAD
+水平。
综上，以衰老细胞为模型，本实施例证明了尼古丁能够保护衰老细胞中SIRT1与NAMPT的结合、保护衰老细胞中的NAD
+水平，说明对于已经发生衰老的动物和组织，摄入尼古丁可延缓衰老。
实施例4
为了验证添加不同剂量的尼古丁的效果是否不同，进行了下述实验。对照组为小鼠海马神经元细胞系HT22中不添加尼古丁，尼古丁组为小鼠海马神经元细胞系HT22中分别加入1ng/mL和10ng/mL尼古丁，48h后，收集细胞沉淀，液氮淬灭30min，加入甲醇：水＝1:1的溶液溶解细胞沉淀，10000g离心后，取上清过滤，通过液相和气相联用色谱LC-MS，利用外标法制作标准曲线的方法，定量检测细胞内β-NMN含量。结果如图13所示，尼古丁引起细胞内β-NMN水平升高，且10ng尼古丁组比1ng尼古丁组β-NMN水平更高，说明在一定范围内增加尼古丁的浓度对于延缓衰老效果更好。
实施例5
为了验证尼古丁是否能增加神经元的数目，进行以下实验。对照组为6月龄C57BL/6J雄性小鼠饮水中不添加尼古丁，尼古丁组为6月龄C57BL/6J雄性小鼠饮水中加入尼古丁，饮水中尼古丁的浓度为1ng/mL-25μg/mL，定期更换饮水，连续喂养2个月后，小鼠灌流取脑，冰冻脑切片，通过免疫荧光染色，用双肾上腺皮质激素(Doublecortin)标记新生神经元。结果如图14所示，纵坐标代表海马区齿状回神经元数目，尼古丁组的小鼠脑内海马齿状回神经元数目明显增多，说明尼古丁可使衰老小鼠脑内海马齿状回神经元数目增多。衰老过程中，神经元细胞会发生死亡，补充衰老和死亡的神经元细胞可以减少神经元的退化，从而在一定程度上减缓衰老。
实施例6
为了验证SIRT1特异性激活剂白藜芦醇与STR1720是否能增加SIRT1与NAMPT的结合，进行以下实验。在高糖DMEM培养基中添加小鼠海马神经元细胞系HT22，密度为1 x 10
6细胞/板。实验中对照组为小鼠海马神经元细 胞系HT22中不添-加白藜芦醇与STR1720，白藜芦醇组为小鼠海马神经元细胞系HT22中加入8-12μmol/L的白藜芦醇，STR1720组为小鼠海马神经元细胞系HT22中加入3-8μmol/L的STR1720，分别处理48h。采用免疫共沉淀和免疫印迹分别检测对照组和实验组细胞中SIRT1与NAMPT的结合情况。结果如图15所示，白藜芦醇(10μmol/L)和SRT1720(5μmol/L)能够增强SIRT1与NAMPT的结合。
综合以上结果，尼古丁、白藜芦醇和STR1720均能够强SIRT1与NAMPT的结合，进而提高β-NMN与NAD
+水平，从而调控DNA损失修复、糖代谢和脂代谢、T细胞激活、胰岛素释放、蛋白质的合成和降解、细胞的跨膜信号转导、细胞衰老等多种生理活动。
虽然以上实验仅进行了单纯化合物的测试，但其制成的口服剂型均能达到以上药效，尼古丁、白藜芦醇和STR1720适用的剂型及相应辅料如下所述。
本发明可根据成分种类、成分含量、剂型等产生多个实施例方式。例如：
实施方式1：以尼古丁、白藜芦醇或STR1720为药效成分的口服液
以口服液为例，口服液是在汤剂、注射剂基础上发展起来的新剂型，具有剂量小、吸收较快、质量稳定、携带和服用方便、易于保存的优点，其含有多种有效成分，对质量和口感有很大的影响。在不改变主要活性成分结构和功能前提下，如何能最大限度的保留有效成分、改善口感是其选用辅料的一个难点。在口服液中添加辅料可以提高口感，改善澄清度，增强稳定性，提高产品质量。
口服液常用辅料有：溶剂、芳香剂、矫味剂、澄清剂、防腐剂等，这些辅料可同时加入，也可择其一加入，其中溶剂是必加的，可以采用水。不同的辅料组合有甜味剂、芳香剂、澄清剂或防腐剂，或甜味剂和防腐剂的组合，优选甜味剂和防腐剂的组合。部分辅料兼具增甜和增香的作用，此时只需加入一种辅料即可。
针对口服液，优选地，所述甜味剂选自蛋白糖、木糖醇、阿斯巴甜和三氯蔗糖中的一种或多种。
针对口服液，优选地，所述防腐剂选自对羟基苯甲酸酯、丁基羟基茴香醚、丁基羟基甲苯和山梨酸中的一种或多种。
防腐剂可选用对羟基苯甲酸酯、丁基羟基甲苯或山梨酸，优选丁基羟基甲苯。也可以组合使用，例如羟基苯甲酸酯与丁基羟基甲苯的组合，或丁基羟基甲苯与山梨酸的组合，或对羟基苯甲酸酯与山梨酸的组合，或对羟基苯甲酸酯、丁基羟基甲苯和山梨酸的组合。
针对口服液，优选地，所述芳香剂为水果香精。
针对口服液，优选地，所述澄清剂为壳聚糖和明胶中的一种或两种混合。
实施方式2：以尼古丁、白藜芦醇或STR1720为药效成分的片剂
片剂具有剂量准确，质量稳定，服用、携带及运输方便等优点。
针对片剂，所述制剂辅料包括稀释剂、粘合剂、润滑剂和崩解剂中一种或多种，优选稀释剂、粘合剂、润滑剂和崩解剂的组合。
针对片剂，优选地，所述稀释剂为纤维素类和无机盐类中的一种或多种。例如微晶纤维素、硫酸钙、磷酸氢钙及药用碳酸钙、甘露醇等，以增加原料体积助其成型的。
针对片剂，优选地，所述粘合剂为水、乙醇、羧甲基纤维素钠、羟丙基纤维素、甲基纤维素、乙基纤维素、明胶和聚乙烯吡咯烷酮等中的一种或多种。
针对片剂，优选地，所述润滑剂为硬脂酸镁、微粉硅胶、滑石粉、氢化植物油、聚乙二醇和月桂醇硫酸镁中的一种或多种。
针对片剂，优选地，所述崩解剂为低取代羟丙基、交联聚乙烯吡咯烷酮和交联羧甲基纤维素钠等中的一种或多种。
实施方式3：以尼古丁、白藜芦醇或STR1720为药效成分的胶囊
在本发明中，胶囊主要提高药物的稳定性和生物利用度。所述制剂辅料为胶囊壳，所述胶囊壳为硬胶囊壳或软胶囊壳。
实施方式4：以尼古丁、白藜芦醇或STR1720为药效成分的颗粒剂
颗粒剂可以直接吞服，也可以用温水冲入水中饮入，应用和携带比较方便，溶出和吸收速度较快。颗粒剂所用的制剂辅料与片剂相似，涉及填充剂、粘合剂、润湿剂、崩解剂、润滑剂和薄膜包衣材料中的一种或多种。
针对颗粒剂，优选地，所述填充剂为纤维素类和无机盐类中的一种或多种。例如微晶纤维素、硫酸钙、磷酸氢钙及药用碳酸钙、甘露醇等，以增加原料体积助其成型的。
针对颗粒剂，优选地，所述粘合剂为水、乙醇、羧甲基纤维素钠、羟丙基纤维素、甲基纤维素、乙基纤维素、明胶和聚乙烯吡咯烷酮等中的一种或多种。
针对颗粒剂，优选地，所述润湿剂为水或乙醇或两者的混合。例如为硬脂酸镁、微粉硅胶、滑石粉、氢化植物油、聚乙二醇和月桂醇硫酸镁中的一种或多种。
针对颗粒剂，优选地，所述崩解剂为低取代羟丙基、交联聚乙烯吡咯烷酮和交联羧甲基纤维素钠等中的一种或多种。
针对颗粒剂，优选地，所述薄膜包衣材料羟丙基甲基纤维素、聚乙二醇、醋酸纤维素酞酸酯和聚乙烯缩乙醛二乙胺醋酸酯中的一种或多种。
实施方式5：以尼古丁、白藜芦醇或STR1720为药效成分的散剂
本发明也可制成散剂，散剂便于分剂量和服用。
以饮料为例，将本发明的组合物制成不同风味的饮料，作为日常饮品将深受欢迎。
饮料所用的制剂辅料为澄清剂、防腐剂和香味剂中的至少一种。
本发明的组合物也可制成其它散剂，例如制成功能性奶粉，加入的辅料主要为奶粉，例如脱脂奶粉，脱脂无糖奶粉。
以上多个实施方式可调整单位产品中的药剂量大小，以适应不同的用途，如药品、保健品、食品等。
综上所述，尼古丁、白藜芦醇或STR1720在组织、个体和细胞层面可以促进SIRT1与NAMPT的结合、引起NAMPT酶活升高、提高NAD
+水平、提高β-NMN水平、抑制衰老细胞端粒长度下降、降低衰老小鼠各组织羰基蛋白水平、降低JAK2-STAT3的蛋白磷酸化水平、增加神经元的增殖、缓解焦虑，能够保护衰老细胞中SIRT1与NAMPT的结合、保护衰老细胞中的NAD
+水平。
以上所述仅为本发明的较佳实施例，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (15)
- 一种提高烟酰胺磷酸核糖转移酶活性的方法，其特征在于，所述方法包括施用有效量的组合物至受试者,通过增加沉默信息调节因子2相关酶1对烟酰胺磷酸核糖转移酶的去乙酰化水平，提高所述受试者中烟酰胺磷酸核糖转移酶的活性。
- 根据权利要求1所述的方法，其特征在于，所述方法中包括连续施用2-6个月所述组合物至所述受试者。
- 一种提高烟酰胺磷酸核糖转移酶活性的组合物，其特征在于，所述组合物增加沉默信息调节因子2相关酶1对烟酰胺磷酸核糖转移酶的去乙酰化水平，提高烟酰胺磷酸核糖转移酶的活性。
- 根据权利要求3所述的组合物，其特征在于，所述组合物包括尼古丁、白藜芦醇、SRT1720中的任意一种。
- 根据权利要求4所述的组合物，其特征在于，所述组合物中所述尼古丁的浓度为1ng/mL-25μg/mL。
- 根据权利要求4所述的组合物，其特征在于，所述组合物中所述白藜芦醇的浓度为8-12μmol/L。
- 根据权利要求4所述的组合物，其特征在于，所述组合物中所述SRT1720的浓度为3-8μmol/L。
- 根据权利要求3所述的组合物，其特征在于，所述组合物还包括制剂辅料。
- 根据权利要求3所述的组合物，其特征在于，所述组合物为口服液、片剂、颗粒剂或者胶囊剂。
- 根据权利要求3所述的组合物，其特征在于，所述组合物为散剂或 者饮料。
- 一种用于防止衰老、防止衰老相关疾病以及防止焦虑相关疾病的方法，其特征在于，所述方法包括施用有效量的组合物至受试者,通过增加沉默信息调节因子2相关酶1对烟酰胺磷酸核糖转移酶的去乙酰化水平。
- 一种用于防止衰老、防止衰老相关疾病以及防止焦虑相关疾病的组合物，其特征在于，所述组合物包括能够增加沉默信息调节因子2相关酶1对烟酰胺磷酸核糖转移酶的去乙酰化水平的成分。
- 根据权利要求11所述的方法，其特征在于，所述衰老及衰老相关疾病和焦虑相关疾病包括视网膜神经元变性、轴突变性、特发性震颤、帕金森病、阿尔茨海默病、亨廷顿病、共济失调、紧张性精神分裂症、神经阻滞剂恶性综合征、舞蹈病、皮质基底神经节变性、肌张力障碍、智力迟钝、神经棘红细胞增多症、佩利措伊斯-梅茨巴赫病、进行性核上性麻痹、纹状体黑质变性、缺血性中风、脊髓病变、外伤性脑损伤和缺氧症。
- 根据权利要求12所述的组合物，其特征在于，所述衰老及衰老相关疾病和焦虑相关疾病包括视网膜神经元变性、轴突变性、特发性震颤、帕金森病、阿尔茨海默病、亨廷顿病、共济失调、紧张性精神分裂症、神经阻滞剂恶性综合征、舞蹈病、皮质基底神经节变性、肌张力障碍、智力迟钝、神经棘红细胞增多症、佩利措伊斯-梅茨巴赫病、进行性核上性麻痹、纹状体黑质变性、缺血性中风、脊髓病变、外伤性脑损伤和缺氧症。
- 一种权利要求3所述的组合物在制备治疗衰老及衰老相关疾病和焦虑相关疾病的药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2020/127059 WO2022094916A1 (zh) | 2020-11-06 | 2020-11-06 | 一种提高烟酰胺磷酸核糖转移酶活性的方法及其组合物 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2020/127059 WO2022094916A1 (zh) | 2020-11-06 | 2020-11-06 | 一种提高烟酰胺磷酸核糖转移酶活性的方法及其组合物 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2022094916A1 true WO2022094916A1 (zh) | 2022-05-12 |
Family
ID=81456936
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2020/127059 WO2022094916A1 (zh) | 2020-11-06 | 2020-11-06 | 一种提高烟酰胺磷酸核糖转移酶活性的方法及其组合物 |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2022094916A1 (zh) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1738621A (zh) * | 2002-12-20 | 2006-02-22 | 尼科诺瓦姆股份公司 | 物理和化学稳定的含尼古丁的颗粒物质 |
| CN101257897A (zh) * | 2005-07-07 | 2008-09-03 | 西特里斯药业公司 | 用于治疗或预防肥胖、胰岛素抵抗障碍和线粒体相关障碍的方法和相关组合物 |
| CN107072278A (zh) * | 2014-06-11 | 2017-08-18 | 波维瓦茶业有限责任公司 | 加入亲脂性活性剂的食品和饮料组合物及其使用方法 |
| CN108025187A (zh) * | 2015-04-28 | 2018-05-11 | 新南创新私人有限公司 | 靶向nad+以治疗化学疗法和放射疗法引发的认知损害、神经病变和不活动 |
| CN108137639A (zh) * | 2015-08-05 | 2018-06-08 | 麦德龙国际生物科技有限责任公司 | 烟酰胺单核苷酸衍生物及其用途 |
| WO2019175587A1 (en) * | 2018-03-13 | 2019-09-19 | Nuchido Limited | Compositions |
-
2020
- 2020-11-06 WO PCT/CN2020/127059 patent/WO2022094916A1/zh active Application Filing
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1738621A (zh) * | 2002-12-20 | 2006-02-22 | 尼科诺瓦姆股份公司 | 物理和化学稳定的含尼古丁的颗粒物质 |
| CN101257897A (zh) * | 2005-07-07 | 2008-09-03 | 西特里斯药业公司 | 用于治疗或预防肥胖、胰岛素抵抗障碍和线粒体相关障碍的方法和相关组合物 |
| CN107072278A (zh) * | 2014-06-11 | 2017-08-18 | 波维瓦茶业有限责任公司 | 加入亲脂性活性剂的食品和饮料组合物及其使用方法 |
| CN108025187A (zh) * | 2015-04-28 | 2018-05-11 | 新南创新私人有限公司 | 靶向nad+以治疗化学疗法和放射疗法引发的认知损害、神经病变和不活动 |
| CN108137639A (zh) * | 2015-08-05 | 2018-06-08 | 麦德龙国际生物科技有限责任公司 | 烟酰胺单核苷酸衍生物及其用途 |
| WO2019175587A1 (en) * | 2018-03-13 | 2019-09-19 | Nuchido Limited | Compositions |
Non-Patent Citations (1)
| Title |
|---|
| YOON, MYEONG JIN ET AL.: "SIRT1-Mediated eNAMPT Secretion from Adipose Tissue Regulates Hypothalamic NAD+ and Function in Mice", CELL METABOLISM, vol. 21, 5 May 2015 (2015-05-05), pages 706 - 717, XP029575851, DOI: 10.1016/j.cmet.2015.04.002 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3682746A1 (en) | Anti-aging agent and anti-aging method | |
| CA2611389C (en) | Composition for moderating alcohol metabolism and for reducing the risk of alcohol induced diseases | |
| EP3513796A1 (en) | Sleep disorder improvement agent and method for improving sleep disorders | |
| EP4011374A1 (en) | Hydroxybutyrate ester and medical use thereof | |
| EP3850954A1 (en) | Anti-aging agent and anti-aging method | |
| JP5989319B2 (ja) | 睡眠の質改善剤 | |
| CN107847513B (zh) | 包含烟酰胺腺嘌呤二核苷酸的用于预防及治疗肥胖或糖耐量减低的组合物 | |
| CN109745359A (zh) | 有利于保持血糖平衡和预防糖尿病及其并发症的组合物及其制备方法 | |
| US20040171624A1 (en) | Pharmaceutical composition for treating mood disorders | |
| US20220362249A1 (en) | Methods for treating hyperphenylalaninemia | |
| ITMI20001093A1 (it) | Composizioni a rilascio controllato contenenti un principio attivo, preferibilmente melatonina, e processo di preparazione delle stesse. | |
| CN112294821B (zh) | 5-甲基四氢叶酸的用途及其组合物 | |
| WO2022094916A1 (zh) | 一种提高烟酰胺磷酸核糖转移酶活性的方法及其组合物 | |
| EP3431090A1 (en) | Proliferative agent for bacteria of genus faecalibacterium | |
| EP3993770A1 (en) | Compositions and methods using trigonelline to produce intracellular nicotinamide adenine dinucleotide (nad+) for treating or preventing physiological disorders or states | |
| US9579337B2 (en) | Use of uridine and deoxyuridine to treat folate-responsive pathologies | |
| CN114432309A (zh) | 一种提高烟酰胺磷酸核糖转移酶活性的方法及其组合物 | |
| Kimura et al. | Comparison of metabolic fates of nicotinamide, NAD+ and NADH administered orally and intraperitoneally; characterization of oral NADH | |
| KR20140119236A (ko) | 패류 추출물을 유효성분으로 포함하는 불안 완화, 경련 개선, 진정 작용, 또는 수면 유도 또는 개선용 조성물 | |
| CA2459240C (en) | Pharmaceutical composition for treating mood disorders | |
| Murray | Pyrroloquinoline quinone (PQQ): The next essential nutrient and supplement superstar | |
| EP4209215A1 (en) | Treatment of gm2 gangliosidosis | |
| JP2003252756A (ja) | ドーパミン遊離抑制組成物 | |
| KR102588274B1 (ko) | D-리모넨을 유효성분으로 포함하는 뇌전증 또는 발작 관련 질환의 예방 또는 치료용 약제학적 조성물 | |
| CN116265019A (zh) | 一种预防和改善老年痴呆症的组合物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 20960377 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 20960377 Country of ref document: EP Kind code of ref document: A1 |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 20960377 Country of ref document: EP Kind code of ref document: A1 |