JP6502335B2 - 脂質異常症の予防または治療のための化合物および該化合物を含む組成物 - Google Patents
脂質異常症の予防または治療のための化合物および該化合物を含む組成物 Download PDFInfo
- Publication number
- JP6502335B2 JP6502335B2 JP2016521712A JP2016521712A JP6502335B2 JP 6502335 B2 JP6502335 B2 JP 6502335B2 JP 2016521712 A JP2016521712 A JP 2016521712A JP 2016521712 A JP2016521712 A JP 2016521712A JP 6502335 B2 JP6502335 B2 JP 6502335B2
- Authority
- JP
- Japan
- Prior art keywords
- cells
- compound
- fat
- typically
- membrane
- 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.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 title claims description 101
- 238000011282 treatment Methods 0.000 title claims description 22
- 230000002265 prevention Effects 0.000 title claims description 14
- 208000032928 Dyslipidaemia Diseases 0.000 title description 41
- 208000017170 Lipid metabolism disease Diseases 0.000 title description 38
- 239000000203 mixture Substances 0.000 title description 35
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 34
- LPMBTLLQQJBUOO-KTKRTIGZSA-N (z)-n,n-bis(2-hydroxyethyl)octadec-9-enamide Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)N(CCO)CCO LPMBTLLQQJBUOO-KTKRTIGZSA-N 0.000 claims description 13
- LUXUAZKGQZPOBZ-SAXJAHGMSA-N [(3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] (Z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O LUXUAZKGQZPOBZ-SAXJAHGMSA-N 0.000 claims description 13
- QQVGEJLUEOSDBB-KTKRTIGZSA-N [3-hydroxy-2,2-bis(hydroxymethyl)propyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(CO)(CO)CO QQVGEJLUEOSDBB-KTKRTIGZSA-N 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 5
- 235000015872 dietary supplement Nutrition 0.000 claims description 4
- 235000013376 functional food Nutrition 0.000 claims description 4
- -1 glitazones Chemical class 0.000 claims description 4
- 229940123208 Biguanide Drugs 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 3
- 239000003472 antidiabetic agent Substances 0.000 claims description 3
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 claims description 3
- 229940126904 hypoglycaemic agent Drugs 0.000 claims description 3
- 239000000859 incretin Substances 0.000 claims description 3
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- 229940124530 sulfonamide Drugs 0.000 claims description 3
- 150000003456 sulfonamides Chemical class 0.000 claims description 3
- 150000004283 biguanides Chemical class 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 210000004027 cell Anatomy 0.000 description 81
- 239000003925 fat Substances 0.000 description 61
- 235000019197 fats Nutrition 0.000 description 61
- 239000012528 membrane Substances 0.000 description 55
- 150000004671 saturated fatty acids Chemical class 0.000 description 47
- 150000003904 phospholipids Chemical class 0.000 description 46
- 235000003441 saturated fatty acids Nutrition 0.000 description 45
- 231100000572 poisoning Toxicity 0.000 description 42
- 230000000607 poisoning effect Effects 0.000 description 42
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 36
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 33
- 150000002632 lipids Chemical class 0.000 description 33
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 30
- 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 28
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 28
- 230000004906 unfolded protein response Effects 0.000 description 27
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 27
- 208000001145 Metabolic Syndrome Diseases 0.000 description 26
- 235000014113 dietary fatty acids Nutrition 0.000 description 26
- 239000000194 fatty acid Substances 0.000 description 26
- 229930195729 fatty acid Natural products 0.000 description 26
- 150000004665 fatty acids Chemical class 0.000 description 26
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 26
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 25
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 25
- 108090000623 proteins and genes Proteins 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 22
- PWTCCMJTPHCGMS-YRBAHSOBSA-N 1-Oleoyl-2-acetyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](CO)OC(C)=O PWTCCMJTPHCGMS-YRBAHSOBSA-N 0.000 description 22
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 22
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 22
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 22
- 239000005642 Oleic acid Substances 0.000 description 22
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 22
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 22
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 22
- 235000021313 oleic acid Nutrition 0.000 description 22
- 229930182558 Sterol Natural products 0.000 description 21
- 102000004169 proteins and genes Human genes 0.000 description 21
- 235000003702 sterols Nutrition 0.000 description 21
- 208000024891 symptom Diseases 0.000 description 21
- 150000003432 sterols Chemical class 0.000 description 20
- 239000002609 medium Substances 0.000 description 19
- 150000003626 triacylglycerols Chemical class 0.000 description 19
- 230000000694 effects Effects 0.000 description 18
- 230000006907 apoptotic process Effects 0.000 description 17
- 229940125396 insulin Drugs 0.000 description 17
- 229920006395 saturated elastomer Polymers 0.000 description 17
- 102000004877 Insulin Human genes 0.000 description 16
- 108090001061 Insulin Proteins 0.000 description 16
- 230000001413 cellular effect Effects 0.000 description 15
- 230000035508 accumulation Effects 0.000 description 14
- 238000009825 accumulation Methods 0.000 description 14
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 14
- 208000035150 Hypercholesterolemia Diseases 0.000 description 13
- WRGQSWVCFNIUNZ-HXUWFJFHSA-N [(2r)-2-hydroxy-3-phosphonooxypropyl] octadec-9-enoate Chemical compound CCCCCCCCC=CCCCCCCCC(=O)OC[C@@H](O)COP(O)(O)=O WRGQSWVCFNIUNZ-HXUWFJFHSA-N 0.000 description 13
- 210000004369 blood Anatomy 0.000 description 13
- 239000008280 blood Substances 0.000 description 13
- 230000036772 blood pressure Effects 0.000 description 13
- 235000021588 free fatty acids Nutrition 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 230000005856 abnormality Effects 0.000 description 12
- 235000021314 Palmitic acid Nutrition 0.000 description 11
- 210000001789 adipocyte Anatomy 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 235000012000 cholesterol Nutrition 0.000 description 11
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 11
- 230000035882 stress Effects 0.000 description 11
- 230000001988 toxicity Effects 0.000 description 11
- 231100000419 toxicity Toxicity 0.000 description 11
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 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 10
- 206010020772 Hypertension Diseases 0.000 description 10
- 210000000170 cell membrane Anatomy 0.000 description 10
- 239000008103 glucose Substances 0.000 description 10
- 230000007935 neutral effect Effects 0.000 description 10
- 230000027425 release of sequestered calcium ion into cytosol Effects 0.000 description 10
- 239000000523 sample Substances 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 206010022489 Insulin Resistance Diseases 0.000 description 9
- 239000012894 fetal calf serum Substances 0.000 description 9
- 230000006698 induction Effects 0.000 description 9
- 230000003834 intracellular effect Effects 0.000 description 9
- 230000001575 pathological effect Effects 0.000 description 9
- 230000037361 pathway Effects 0.000 description 9
- 230000003938 response to stress Effects 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 239000011575 calcium Substances 0.000 description 8
- 210000002288 golgi apparatus Anatomy 0.000 description 8
- 230000012010 growth Effects 0.000 description 8
- 208000006575 hypertriglyceridemia Diseases 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- WRGQSWVCFNIUNZ-GDCKJWNLSA-N 1-oleoyl-sn-glycerol 3-phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)COP(O)(O)=O WRGQSWVCFNIUNZ-GDCKJWNLSA-N 0.000 description 7
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 7
- 101100072149 Drosophila melanogaster eIF2alpha gene Proteins 0.000 description 7
- 206010019280 Heart failures Diseases 0.000 description 7
- 206010019708 Hepatic steatosis Diseases 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 229910052791 calcium Inorganic materials 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 239000011521 glass Substances 0.000 description 7
- 201000001421 hyperglycemia Diseases 0.000 description 7
- 230000001965 increasing effect Effects 0.000 description 7
- 238000011534 incubation Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 230000035800 maturation Effects 0.000 description 7
- 125000004430 oxygen atom Chemical group O* 0.000 description 7
- 230000003248 secreting effect Effects 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 206010012335 Dependence Diseases 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 150000004668 long chain fatty acids Chemical class 0.000 description 6
- 210000004962 mammalian cell Anatomy 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 6
- 229920001817 Agar Polymers 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- 102000004882 Lipase Human genes 0.000 description 5
- 108090001060 Lipase Proteins 0.000 description 5
- 239000004367 Lipase Substances 0.000 description 5
- 239000008272 agar Substances 0.000 description 5
- 108010005774 beta-Galactosidase Proteins 0.000 description 5
- 230000007812 deficiency Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 230000008482 dysregulation Effects 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 101150066555 lacZ gene Proteins 0.000 description 5
- 235000019421 lipase Nutrition 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 210000000056 organ Anatomy 0.000 description 5
- 238000012856 packing Methods 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 241000894007 species Species 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 231100000331 toxic Toxicity 0.000 description 5
- 230000002588 toxic effect Effects 0.000 description 5
- 230000032258 transport Effects 0.000 description 5
- 238000001262 western blot Methods 0.000 description 5
- 206010018910 Haemolysis Diseases 0.000 description 4
- 206010021143 Hypoxia Diseases 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 108010076181 Proinsulin Proteins 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 4
- 230000030833 cell death Effects 0.000 description 4
- 230000003915 cell function Effects 0.000 description 4
- 125000001475 halogen functional group Chemical group 0.000 description 4
- 230000008588 hemolysis Effects 0.000 description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 4
- 230000000512 lipotoxic effect Effects 0.000 description 4
- 150000005830 nonesterified fatty acids Chemical class 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
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 4
- 235000010692 trans-unsaturated fatty acids Nutrition 0.000 description 4
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 4
- 230000007332 vesicle formation Effects 0.000 description 4
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 3
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 description 3
- ZVTDEEBSWIQAFJ-KHPPLWFESA-N 2-hydroxypropyl (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(C)O ZVTDEEBSWIQAFJ-KHPPLWFESA-N 0.000 description 3
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 102100026189 Beta-galactosidase Human genes 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- PWTCCMJTPHCGMS-NEQMZLFVSA-N [(2s)-2-acetyloxy-3-hydroxypropyl] (e)-octadec-9-enoate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OC[C@H](CO)OC(C)=O PWTCCMJTPHCGMS-NEQMZLFVSA-N 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 230000008021 deposition Effects 0.000 description 3
- 230000004064 dysfunction Effects 0.000 description 3
- 210000002919 epithelial cell Anatomy 0.000 description 3
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 210000003494 hepatocyte Anatomy 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 210000004020 intracellular membrane Anatomy 0.000 description 3
- 210000005061 intracellular organelle Anatomy 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 231100000956 nontoxicity Toxicity 0.000 description 3
- 210000003463 organelle Anatomy 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 229960005322 streptomycin Drugs 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- RCRCTBLIHCHWDZ-DOFZRALJSA-N 2-arachidonoylglycerol Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)OC(CO)CO RCRCTBLIHCHWDZ-DOFZRALJSA-N 0.000 description 2
- AGNTUZCMJBTHOG-UHFFFAOYSA-N 3-[3-(2,3-dihydroxypropoxy)-2-hydroxypropoxy]propane-1,2-diol Chemical compound OCC(O)COCC(O)COCC(O)CO AGNTUZCMJBTHOG-UHFFFAOYSA-N 0.000 description 2
- 208000000659 Autoimmune lymphoproliferative syndrome Diseases 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 102000058061 Glucose Transporter Type 4 Human genes 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- 101150096690 Mogs gene Proteins 0.000 description 2
- 108700008625 Reporter Genes Proteins 0.000 description 2
- 108091006300 SLC2A4 Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 210000000577 adipose tissue Anatomy 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- WQZGKKKJIJFFOK-FPRJBGLDSA-N beta-D-galactose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-FPRJBGLDSA-N 0.000 description 2
- ZOMBKNNSYQHRCA-UHFFFAOYSA-J calcium sulfate hemihydrate Chemical compound O.[Ca+2].[Ca+2].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O ZOMBKNNSYQHRCA-UHFFFAOYSA-J 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 125000003636 chemical group Chemical group 0.000 description 2
- 210000000805 cytoplasm Anatomy 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 230000000779 depleting effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 235000013861 fat-free Nutrition 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 230000009036 growth inhibition Effects 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000007954 hypoxia Effects 0.000 description 2
- 230000001146 hypoxic effect Effects 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 230000003914 insulin secretion Effects 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- PURKAOJPTOLRMP-UHFFFAOYSA-N ivacaftor Chemical compound C1=C(O)C(C(C)(C)C)=CC(C(C)(C)C)=C1NC(=O)C1=CNC2=CC=CC=C2C1=O PURKAOJPTOLRMP-UHFFFAOYSA-N 0.000 description 2
- 229960004508 ivacaftor Drugs 0.000 description 2
- 230000004322 lipid homeostasis Effects 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 230000007115 recruitment Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 150000003408 sphingolipids Chemical class 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 231100000820 toxicity test Toxicity 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 230000028973 vesicle-mediated transport Effects 0.000 description 2
- 239000007221 ypg medium Substances 0.000 description 2
- RZRNAYUHWVFMIP-QJRAZLAKSA-N 1-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)CO RZRNAYUHWVFMIP-QJRAZLAKSA-N 0.000 description 1
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 description 1
- PHDVPEOLXYBNJY-KTKRTIGZSA-N 2-(2-hydroxyethoxy)ethyl (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCCOCCO PHDVPEOLXYBNJY-KTKRTIGZSA-N 0.000 description 1
- NOKZRPRTHPWZDV-KTKRTIGZSA-N 2-[(z)-octadec-9-enoxy]propane-1,3-diol Chemical compound CCCCCCCC\C=C/CCCCCCCCOC(CO)CO NOKZRPRTHPWZDV-KTKRTIGZSA-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
- IQUPABOKLQSFBK-UHFFFAOYSA-N 2-nitrophenol Chemical compound OC1=CC=CC=C1[N+]([O-])=O IQUPABOKLQSFBK-UHFFFAOYSA-N 0.000 description 1
- UPWGQKDVAURUGE-KTKRTIGZSA-N 2-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC(CO)CO UPWGQKDVAURUGE-KTKRTIGZSA-N 0.000 description 1
- MTJGVAJYTOXFJH-UHFFFAOYSA-N 3-aminonaphthalene-1,5-disulfonic acid Chemical compound C1=CC=C(S(O)(=O)=O)C2=CC(N)=CC(S(O)(=O)=O)=C21 MTJGVAJYTOXFJH-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 description 1
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 1
- 208000004611 Abdominal Obesity Diseases 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- 102000057234 Acyl transferases Human genes 0.000 description 1
- 108700016155 Acyl transferases Proteins 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 1
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 206010065941 Central obesity Diseases 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 102100023580 Cyclic AMP-dependent transcription factor ATF-4 Human genes 0.000 description 1
- 206010011732 Cyst Diseases 0.000 description 1
- 102000012605 Cystic Fibrosis Transmembrane Conductance Regulator Human genes 0.000 description 1
- 108010079245 Cystic Fibrosis Transmembrane Conductance Regulator Proteins 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 108700041152 Endoplasmic Reticulum Chaperone BiP Proteins 0.000 description 1
- 102100021451 Endoplasmic reticulum chaperone BiP Human genes 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 102000018711 Facilitative Glucose Transport Proteins Human genes 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 102000018898 GTPase-Activating Proteins Human genes 0.000 description 1
- 108010027920 GTPase-Activating Proteins Proteins 0.000 description 1
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical class C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 1
- 108091052347 Glucose transporter family Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101150112743 HSPA5 gene Proteins 0.000 description 1
- 101000905743 Homo sapiens Cyclic AMP-dependent transcription factor ATF-4 Proteins 0.000 description 1
- 101001008429 Homo sapiens Nucleobindin-2 Proteins 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000003746 Insulin Receptor Human genes 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 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
- 229930182816 L-glutamine Natural products 0.000 description 1
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
- 108010013563 Lipoprotein Lipase Proteins 0.000 description 1
- 102100022119 Lipoprotein lipase Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090000301 Membrane transport proteins Proteins 0.000 description 1
- 102000003939 Membrane transport proteins Human genes 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 1
- 102100027441 Nucleobindin-2 Human genes 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 101100540618 Rattus norvegicus Vps52 gene Proteins 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 101150110386 SLC2A4 gene Proteins 0.000 description 1
- 108010041948 SNARE Proteins Proteins 0.000 description 1
- 102000000583 SNARE Proteins Human genes 0.000 description 1
- 101100111629 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) KAR2 gene Proteins 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- CUAMENOHJPFQQA-JCKUYFFHSA-N [(2s)-1-hydroxy-3-[(z)-octadec-9-enoxy]propan-2-yl] acetate Chemical compound CCCCCCCC\C=C/CCCCCCCCOC[C@H](CO)OC(C)=O CUAMENOHJPFQQA-JCKUYFFHSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 230000010014 adipocyte dysfunction Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- OWMVSZAMULFTJU-UHFFFAOYSA-N bis-tris Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 230000004094 calcium homeostasis Effects 0.000 description 1
- 230000003185 calcium uptake Effects 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 210000004413 cardiac myocyte Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 230000004637 cellular stress Effects 0.000 description 1
- 229940106189 ceramide Drugs 0.000 description 1
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000009109 curative therapy Methods 0.000 description 1
- 238000011461 current therapy Methods 0.000 description 1
- 208000031513 cyst Diseases 0.000 description 1
- 238000004163 cytometry Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000003413 degradative effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000000326 densiometry Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 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
- 230000004761 fibrosis Effects 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 229910052949 galena Inorganic materials 0.000 description 1
- 101150063999 gcs-1 gene Proteins 0.000 description 1
- 239000006481 glucose medium Substances 0.000 description 1
- UPWGQKDVAURUGE-UHFFFAOYSA-N glycerine monooleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC(CO)CO UPWGQKDVAURUGE-UHFFFAOYSA-N 0.000 description 1
- 101150028578 grp78 gene Proteins 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 210000002064 heart cell Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000002473 insulinotropic effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000007154 intracellular accumulation Effects 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 230000010189 intracellular transport Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- XCAUINMIESBTBL-UHFFFAOYSA-N lead(ii) sulfide Chemical compound [Pb]=S XCAUINMIESBTBL-UHFFFAOYSA-N 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 235000020778 linoleic acid Nutrition 0.000 description 1
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 1
- 229960004488 linolenic acid Drugs 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229950004994 meglitinide Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 230000004065 mitochondrial dysfunction Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 235000021281 monounsaturated fatty acids Nutrition 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229920002113 octoxynol Polymers 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 210000002571 pancreatic alpha cell Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical group O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000012846 protein folding Effects 0.000 description 1
- 210000000512 proximal kidney tubule Anatomy 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000016914 response to endoplasmic reticulum stress Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 210000003660 reticulum Anatomy 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000009962 secretion pathway Effects 0.000 description 1
- 210000004739 secretory vesicle Anatomy 0.000 description 1
- NRWMBHYHFFGEEC-UHFFFAOYSA-N selachyl alcohol Natural products CCCCCCCCC=CCCCCCCCCOCC(O)CO NRWMBHYHFFGEEC-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000006354 stress signaling Effects 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 210000003412 trans-golgi network Anatomy 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7024—Esters of saccharides
-
- 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
- A23L33/115—Fatty acids or derivatives thereof; Fats or oils
- A23L33/12—Fatty acids or derivatives thereof
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
-
- 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
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
-
- 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
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/12—Mucolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Emergency Medicine (AREA)
- Diabetes (AREA)
- Molecular Biology (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Obesity (AREA)
- Mycology (AREA)
- Polymers & Plastics (AREA)
- Food Science & Technology (AREA)
- Nutrition Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Heart & Thoracic Surgery (AREA)
- Pulmonology (AREA)
- Gastroenterology & Hepatology (AREA)
- Hospice & Palliative Care (AREA)
- Endocrinology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Furan Compounds (AREA)
Description
Aは窒素または酸素原子、好ましくは酸素原子であり、
nは2または3に等しく、好ましくはnは2に等しく、かつ、
Rは任意の化学基である]
で示される化合物であって、対象において、脂質異常症、典型的には上記で定義したような脂質異常症の予防または治療に用いるための化合物に関する。
図の凡例
本発明者らは、外因性源(食事)または内因性源(低酸素症、もしくは突然変異による脂肪酸不飽和化ステップの変化)のSFAが、細胞膜を作っているリン脂質に蓄積し、従ってタンパク質分泌経路に介入する細胞内オルガネラの機能性を改変することにより多数の過程を破壊する(図1を参照のこと)ことを示した。
Aは典型的には酸素原子、またはNR1基であり(ここに、R1=H、もしくはOHで適宜置換されたC1−C6アルキルである)、好ましくはAは酸素原子、またはNH、NCH3もしくはNCH2CH2OHであり、より好ましくはAは酸素原子であり、
n=2または3、好ましくはn=2であり、
Rは任意の化学基であり、基(CHR)ごとに異なり得る]
で示される化合物である。
式(I)において、ジグザグで分断されている結合は、極性頭部と不飽和脂肪酸の炭素鎖との間の結合を表し、式(I)のC=O基は不飽和脂肪酸のC=Oである。
好ましくは、Rは炭素、水素および酸素原子のみを含む基である。
好ましくは、Rは炭素、水素および酸素原子のみを含む飽和基である。
好ましくは、(CHR)n−OH基はグリセロール、エリトリトールまたはマンノースのような単糖の誘導体である。
(i)酵母サッカロマイセス・セレヴィシエの脂肪中毒を起こしたhem1Δ変異体の生育を回復させる、
(ii)小胞体ストレス応答(UPR)を低減または抑制する、
(iii)酵母サッカロマイセス・セレヴィシエの4重変異体(QM)に毒性を示さない、および/または、
(iv)脂肪中毒を起こした哺乳類細胞のアポトーシス死を低減または抑制する。
表1に記載されているサッカロマイセス・セレヴィシエ酵母株は、細胞のリン脂質の脂肪酸含有量の解析のため、および、小胞体ストレス応答(UPR)誘発試験のため、毒性を実証するための様々な生育回復試験のために用いる。
UPR活性化状態、および脂肪中毒により誘導される細胞死もまた、ラットの膵β細胞株BRIN−BD11においても解析した。
さらに、カルシウム動員試験はヒト上皮細胞CFBEにおいて実施し、インスリン成熟実験はマウスの膵β細胞株MIN6において実施した。
hem1Δ突然変異を持つ株を、液体YPGA培地(80μg/ml δ−アミノレブリン酸(ALA)を添加したYPG(1%酵母エキス(w/v)、1%ペプトン(w/v)、および2%グルコース(w/v))中、好気条件下、28℃で振とう培養する。飽和脂肪酸(SFA)による脂肪中毒は、YPG+培地(この条件下でもたらされるステロールの枯渇を相殺するために、80μg/ml エルゴステロールを添加したYPG)に移すことにより、不飽和脂肪酸(UFA)−その合成はヘム(特にOle1p酵素の補欠分子族)の存在に依存する−が枯渇することにより、引き起こされる。脂肪中毒は、cm2当たり3500の細胞(YPGA中にて前培養したhem1Δ)を移すことにより2%寒天(w/v)を含む固形YPG+培地上で、あるいは2・106細胞/ml YPG+を植菌することにより液体培地中にて、誘導し得る。古典的に、SFA脂肪中毒の効果は、YPG+培地に移してから7時間後に解析する。SFA脂肪中毒の有害効果に対抗する化合物の能力は、順に、細胞を播種した後、この化合物をYPG+トランスファー培地上(または該培地中)に加え、引き続いて評価する。
1)脂質試薬の調製:
脂質種は、エタノール中にて調製した後、37℃で1時間インキュベートすることにより、ウシ血清アルブミン(BSA、初めは脂肪酸を枯渇している)と複合体を形成させる。当体積のエタノールを加え、全量を70℃に加熱して均一にすることにより、パルミチン酸の原液を得る。OAGおよびLPA溶液は、室温で100%エタノール中にて調製する。哺乳類細胞のインキュベーションには、培地中のBSAおよびエタノールの終末濃度をそれぞれ、1%および0.5%(w/v)に保つ。
ラットの膵β細胞株(BRIN−BD11)を、11mM グルコースを含み、かつ、10%(v/v)ウシ胎仔血清(FCS)、2mM L−グルタミン、100U/ml ペニシリン、および100μg/ml ストレプトマイシンを添加した完全RPMI−1640培地中にて培養する。各実験ごとに、初めに、細胞を、6−ウェルプレート内に0.5・105細胞/mlの密度で24時間播種する。その後、完全培地を、FCSは含まないがBSAと複合体を形成させた所望の濃度の対象脂質試薬を含む等価物に置き換える。対照条件下でも、同じ量のBSAおよびエタノールを用いる。インキュベーションの終わりに全ての細胞(死細胞および生細胞)を集め、300gで5分間遠心分離する。次いで細胞ペレットを200μlの培地に再懸濁し、次いで20μg/ml ヨウ化プロピジウム(PI)溶液を含む200μlのFACS緩衝液(リン酸緩衝生理食塩水(PBS)、2%(v/v)FCS、10mM アジ化ナトリウム)を加えることにより、PIを用いて、死細胞(完全性が失われた細胞膜を持つ)のDNAを染色する。氷上で10分間インキュベートした後、このようにして得たサンプルをフローサイトメトリーにより解析する。定量には、Beckman Coulter EPICS XL MCLを用い、DNAにインターカレートしたPIの発光の検出には、FL3チャンネルを用い、解析は、EXPO32 ADCソフトウェア(Applied Cytometry Systems、V 1.1 build 207)を用いて実施する。
BRIN−BD11細胞を、T25フラスコ内に0.5・105細胞/mlの密度で24時間播種する。次いで、上記で示したように、完全培地を、FCSは含まないが対象脂質試薬を含む同等のものに置き換える。6時間インキュベートした後、プロテアーゼおよびホスファターゼ阻害剤を含む溶解緩衝液(20mM Tris、150mM NaCl、1mM EDTA、および1%(v/v)Triton−X)を用いて、総タンパク質を抽出する。次いでこれらのタンパク質を12%NuPAGE(登録商標) Novex(登録商標) ビス−トリスゲル(Invitrogen)アクリルアミド・ゲル上で電気泳動した後、PVDF膜に転写し、次いで1/1000に希釈した抗−リン酸化−eIF2α抗体(Cell Signaling(New England Biolabs))を用いてプローブする。次に、緩衝液Re−Blot Plus−Strong(Millipore)を用いて膜をストリップした後、1/1000に希釈した抗−総eIF2α抗体(Cell Signaling(New England Biolabs)を用いて2回目のプローブをする。リン酸化された、またはリン酸化されていない形態のeIF2αタンパク質の相対存在量の密度解析は、Quantify Oneソフトウェア(Biorad UK Ltd)と組み合わせた、Fluor−S MultiImager解析システムを用いて実施する。
BRIN−BD11細胞の脂肪中毒について上記した方法で、MIN6細胞株を、10%(v/v)ウシ胎仔血清(FCS)、15mM HEPES、100U/ml ペニシリン、および100μg/ml ストレプトマイシンを添加した、完全DMEM−High グルコース培地(6mM)中にて培養し、脂肪中毒を、対象化合物の添加ありまたはなしで、BSA(終末濃度0.92%(w/v))に結合している400μM パルミチン酸に48時間暴露することにより、誘導する(Boslem et al., 2011を参照のこと)。次いで細胞を集め、プロインスリンからインスリンへの成熟を観察するために、抗インスリン抗体を用いて、上記で示したようにウェスタンブロットを実施する。
ヒト上皮細胞系、CFBEを、ガラスボトムディッシュ上、10%ウシ胎仔血清(FCS)、100 IU/ml ペニシリン、100μg/ml ストレプトマイシン、および0.5μg/ml ピューロマイシンを添加したMEM+GlutaMAX(商標)−1培地(αMEM;Invitrogen)中にて培養する。初めに、細胞に、3μM 蛍光カルシウムプローブ、フルオ−4−アセトキシメチル エステル(FluoProbes(登録商標))を室温で20分間添加した。次いで、Zeiss Axio Observer Z1倒立顕微鏡を用いて、250msシーケンスのレーザー刺激で4分間、対象領域について蛍光強度の変化を取得することにより、カルシウム動員を記録する。次いで、Carl Zeiss AxioVision Release 4.8.2ソフトウェア、および関連する生理取得モジュールを用いて、集めたデータを解釈する。最後に、時間t(F)での各ピクセルにおける強度を、刺激(F0)前の該ピクセルにおける蛍光強度で割ることにより、強度プロファイルを標準化する。このようにして得られた画像((F−F0)/F0)により、全記録にわたるカルシウム強度/動員のプロファイルを得ることができる(Vachel et al., 2013を参照のこと)。
1)化合物のスクリーニング:
SFA脂肪中毒の誘導(固形培地上で培養したhem1Δに対する)に続いて、ジメチルスルホキシド(DMSO)またはエタノール(EtOH)中に様々な化合物を10mMで含む溶液の5μl滴を、寒天の表面上に沈着させる。脂質により誘導される細胞の生育の停止に対抗する化合物の能力は、該化合物の沈着部位に、28℃で培養した3日後に、hem1Δコロニーのハローが出現することにより、推定する(Deguil et al., 2011を参照のこと)。
野生型(WT)および4重変異(QM)株を、同時に、液体YPG培地中、好気条件下、28℃で振とう培養した後、cm2当たり3500の細胞をYPG+2%寒天(w/v)に播種する。このように固形培地に移した後、DMSOまたはEtOH中に様々な化合物を1、10、および100mMで含む溶液の1μl滴を、寒天表面上に沈着させる。別に、DMSOおよびEtOHもまた、これら2つの溶媒の内因性の毒性を評価するために、沈着させる。28℃で培養した3日後に、純粋溶媒の沈着に対して得られた生育阻害のハロー直径を、様々な濃度の試験化合物の沈着についてのものと比べることにより、試験化合物の毒性を評価する。WT株とは異なり、QM株は、過剰な外因性のオレイン酸を脂肪滴内の中性脂肪(トリグリセリド(TG)またはエステル化ステロール(ES))の形態で緩衝する能力がない。従って、WT株に対して毒性がない場合に、QM株に対しては化合物の毒性が観察されることは、この化合物が、酵母により遊離脂肪酸源として認識されていることを示している。
hem1Δ株を、2・106細胞/mlの初期細胞濃度から、液体培地(YPGA、YPG+、またはYPG++200μM 試験化合物)中、好気条件下、28℃で7時間振とう培養する。総脂質の抽出を実施するため、培養の終わりに108の細胞を集める。細胞を4℃で1mlの蒸留水中に懸濁した後、500μlのガラスビーズ(φ0.6mM)を加え、次いで全量を振とう機内で5000rpmで20秒の3回のシーケンス(3回の各シーケンス間、チューブを氷上で保つ)に供する。その結果得られた細胞溶解物にビーズ洗浄溶液(1ml)を添加し、次いで40mlガラスチューブ(Corex(商標))に移した後、2:1(v/v)のメタノール:クロロホルム比を用いて脂質抽出を実施する。初めに6mlのメタノールを加えて全量を30秒間ボルテックスし、次いで65℃で15分間インキュベートする。混合液を室温に冷却したら、3mlのクロロホルムを加え、次いで全量を再び30秒間ボルテックスした後、抽出を16時間進行させる。その後、サンプルを10000gで12分間遠心分離した後、上清を新しいCorex(商標)チューブに移す。2mlのクロロホルム、次いで4mlの蒸留水を加えた後、全量を30秒間ボルテックスし、次いで3000gで8分間遠心分離する。得られた上層を除去した後、下層の有機相をガラス溶血チューブ内に集める。最後に、総細胞脂質サンプルを得るため、窒素気流下、80℃で溶媒を留去する。
総細胞脂質サンプルを、30秒間ボルテックスしながら、1mlのジクロロメタンに再懸濁する。3mlのメタノール、次いで2mlのジクロロメタンを連続して用いて予め調整したシリカカラム(BOND ELUT−SI、100mg 1ml)上に、全量を沈着させる。次いで、カラムにより保持されているフラクションを、2mlのジクロロメタン、次いで3mlのアセトンを連続して用いて洗浄する。最後に、2mlの50:45:5(v/v/v)クロロホルム/メタノール/水混合液をカラム上に沈着させ、その結果溶出されたリン脂質をガラス溶血チューブ内に集める。細胞リン脂質サンプルを得るため、窒素下、80℃で溶媒を留去する。
100μlの混合液Mix−(2:1:1(v/v/v)イソプロパノール/アセトニトリル/水+1%(v/v)トリエチルアミン)、または混合液Mix+(2:1:1(v/v/v)イソプロパノール/アセトニトリル/水+1%(v/v)ギ酸)に再懸濁したら、サンプルを、エレクトロスプレーイオン化質量分析(ESI−MS)により、ネガティブまたはポジティブモードでそれぞれ解析し、得られた結果を、様々なリン脂質種の脂肪酸含有量を分析するために用いる。
プラスミドpPW344[2μ URA3 4×UPRE−lacZ(Patil et al., 2004)を参照のこと)]により形質転換したhem1Δ株を、2・106細胞/mlの初期細胞濃度から、液体培地(YPGA、YPG+、またはYPG++200μM 試験化合物)中、好気条件下、28℃で7時間振とう培養する。lacZ導入遺伝子の発現(UPR活性化の場合)から得られたβ−ガラクトシダーゼ(β−gal)活性を定量するために、培養の終わりに108の細胞を集める。初めに、細胞を1.5mlのZバッファー(60mM Na2HPO4、40mM NaH2PO4、10mM KCl、1mM MgSO4、および50mM β−メルカプトエタノール;溶液のpHは7)に再懸濁し、次いでこの懸濁液の1/15を、OD600nm測定を実施するのに用いる。次に、懸濁液に、100μlの0.1%(v/v)ドデシル硫酸ナトリウム(SDS)、および200μlのクロロホルムを添加し、次いで連続する2回の30秒シーケンスでボルテックスする。デカンテーションした後、このようにして得られた溶液の400μl(体積 V)をガラス溶血チューブに移し、次いで600μlのZバッファーを添加する。次いで4mg/mlの基質オルト−ニトロフェニル−β−ガラクトシド(ONPG)を含む200マイクロリッターのZバッファーを加えた後、全量をボルテックスを用いて均質にし、次いで反応を開始させるために30℃の水浴内でインキュベートする。全量が淡黄色がかったら、500μlの1M Na2CO3を加えることにより、室温で反応をクエンチする(時間tにて)。最後に、サンプルを800gで5分間遠心分離し、次いで上清を新しいガラス溶血チューブ内に集めた後、反応生成物(o−ニトロフェノール)および細胞残渣を、分光分析により、420nmおよび550nmの波長でそれぞれ分析する。各サンプルについて、任意単位で表される式U=(1000×[OD420nm−(1.75×OD550nm)])/(t×V×OD600nm)を用いて、β−gal活性(U)を計算する。
- Alkhateeb H, Chabowski A, Glatz JFC, Luiken JFP, Bonen A (2007) Two phases of palmitate-induced insulin resistance in skeletal muscle: impaired GLUT4 translocation is followed by a reduced GLUT4 intrinsic activity. American Journal of Physiology - Endocrinology And Metabolism 293: E783-E793
- Bigay J, Casella JF, Drin G, Mesmin B, Antonny B. ArfGAP1 responds to membrane curvature through the folding of a lipid packing sensor motif. EMBO J. 2005 Jul 6; 24(13):2244-53.
- Boslem E, MacIntosh G, Preston AM, Bartley C, Busch AK, Fuller M, Laybutt DR, Meikle PJ, Biden TJ. A lipidomic screen of palmitate-treated MIN6 β-cells links sphingolipid metabolites with endoplasmic reticulum (ER) stress and impaired protein trafficking. Biochem J. 2011 Apr 1; 435(1):267-76.
- Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. (2003) β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes. Vol. 52, pp. 102-110.
- Cnop M, Hannaert JC, Hoorens A, Eizirik DL, Pipeleers DG (2001) Inverse Relationship Between Cytotoxicity of Free Fatty Acids in Pancreatic Islet Cells and Cellular Triglyceride Accumulation. Diabetes 50: 1771-1777.
- Cunha DA, Hekerman P, Ladriere L, Bazarra-Castro A, Ortis F, Wakeham MC, Moore F, Rasschaert J, Cardozo AK, Bellomo E, Overbergh L, Mathieu C, Lupi R, Hai T, Herchuelz A, Marchetti P, Rutter GA, Eizirik DL, Cnop M. (2008) Initiation and execution of lipotoxic ER stress in pancreatic {beta}-cells. Vol. 121, pp. 2308-2318.
- Deguil J, Pineau L, Rowland Snyder EC, Dupont S, Beney L, Gil A, Frapper G, Ferreira T (2011) Modulation of Lipid-Induced ER Stress by Fatty Acid Shape. Traffic 12: 349-362
- Dhayal S, Morgan NG (2011) Structure-activity relationships influencing lipid-induced changes in eIF2alpha phosphorylation and cell viability in BRIN-BD11 cells. FEBS Lett 585: 2243-2248
- Diakogiannaki E, Morgan NG. (2008) Differential regulation of the ER stress response by long-chain fatty acids in the pancreatic β-cell. Vol. 036, pp. 959-962.
- Diakogiannaki E, Welters HJ, Morgan NG. (2008) Differential regulation of the endoplasmic reticulum stress response in pancreatic {beta}-cells exposed to long-chain saturated and monounsaturated fatty acids. Vol. 197, pp. 553-563.
- Egnatchik RA, Leamy AK, Jacobson DA, Shiota M, Young JD. ER calcium release promotes mitochondrial dysfunction and hepatic cell lipotoxicity in response to palmitate overload. Mol Metab. 2014 May 22; 3(5):544-53.
- Guo W, Wong S, Xie W, Lei T, Luo Z. (2007) Palmitate modulates intracellular signaling, induces endoplasmic reticulum stress, and causes apoptosis in mouse 3T3-L1 and rat primary preadipocytes. Vol. 293, pp. E576-586.
- Iwasaki Y, Saito O, Tanabe M, Inayoshi K, Kobata K, Uno S, Morita A, Watanabe T. Monoacylglycerols activate capsaicin receptor, TRPV1. Lipids. 2008 Jun; 43(6):471-83.
- Kato T, Shimano H, Yamamoto T, Ishikawa M, Kumadaki S, Matsuzaka T, Nakagawa Y, Yahagi N, Nakakuki M, Hasty AH, Takeuchi Y, Kobayashi K, Takahashi A, Yatoh S, Suzuki H, Sone H, Yamada N. (2008) Palmitate Impairs and Eicosapentaenoate Restores Insulin Secretion Through Regulation of SREBP-1c in Pancreatic Islets. Vol. 57, pp. 2382-2392.
- Katsoulieris E, Mabley JG, Samai M, Green IC, Chatterjee PK (2009) [alpha]-Linolenic acid protects renal cells against palmitic acid lipotoxicity via inhibition of endoplasmic reticulum stress. European Journal of Pharmacology 623: 107-112
- Kincaid MM, Cooper AA (2007) ERADicate ER Stress or Die Trying. Antioxid Redox Signal
- Kohlwein SD, Petschnigg J (2007) Lipid-induced cell dysfunction and cell death: lessons from yeast. Current hypertension reports 9: 455-461
- Laybutt DR, Preston AM, Akerfeldt MC, Kench JG, Busch AK, Biankin AV, Biden TJ (2007) Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia 50: 752-763
- Listenberger LL, Han X, Lewis SE, Cases S, Farese RV, et al. (2003) Triglyceride accumulation protects against fatty acid-induced lipotoxicity. PNAS 100: 3077-3082
- Martin AC, Cooper DM. Capacitative and 1-oleyl-2-acetyl-sn-glycerol-activated Ca(2+) entry distinguished using adenylyl cyclase type 8. Mol Pharmacol. 2006 Aug;70(2):769-77
- Patil CK, Li H, Walter P. Gcn4p and novel upstream activating sequences regulate targets of the unfolded protein response. PLoS Biol. 2004 Aug;2(8):E246
- Payet LA, Pineau L, Snyder EC, Colas J, Moussa A, Vannier B, Bigay J, Clarhaut J, Becq F, Berjeaud JM, Vandebrouck C, Ferreira T. Saturated fatty acids alter the late secretory pathway by modulating membrane properties. Traffic. 2013 Sep 6.
- Petschnigg J, Moe OW, Stagljar I (2011) Using yeast as a model to study membrane proteins. Current opinion in nephrology and hypertension 20: 425-432
- Petschnigg J, Wolinski H, Kolb D, Zellnig Gn, Kurat CF, Natter K, Kohlwein SD (2009) Good Fat, Essential Cellular Requirements for Triacylglycerol Synthesis to Maintain Membrane Homeostasis in Yeast. J Biol Chem 284: 30981-30993
- Pineau L, Bonifait L, Berjeaud J-M, Alimardani-Theuil P, Berges T, Ferreira T (2008) A Lipid-mediated Quality Control Process in the Golgi Apparatus in Yeast. Mol Biol Cell 19: 807-821
- Pineau L, Colas J, Dupont S, Beney L, Fleurat-Lessard P, Berjeaud JM, Berges T, Ferreira T (2009) Lipid-Induced ER Stress: Synergistic Effects of Sterols and Saturated Fatty Acids. Traffic
- Pineau L, Ferreira T (2010) Lipid-induced ER stress in yeast and β cells: parallel trails to a common fate. FEMS Yeast Research
- Poon PP, Nothwehr SF, Singer RA, Johnston GC. The Gcs1 and Age2 ArfGAP proteins provide overlapping essential function for transport from the yeast trans-Golgi network. J Cell Biol. 2001 Dec 24; 155(7):1239-50
- Robinson M, Poon PP, Schindler C, Murray LE, Kama R, Gabriely G, Singer RA, Spang A, Johnston GC, Gerst JE. The Gcs1 Arf-GAP mediates Snc1,2 v-SNARE retrieval to the Golgi in yeast. Mol Biol Cell. 2006 Apr; 17(4):1845-58
- Schneider MF, Marsh D, Jahn W, Kloesgen B, Heimburg T. Network formation of lipid membranes: triggering structural transitions by chain melting. Proc Natl Acad Sci U S A. 1999 Dec 7; 96(25):14312-7
- Stein DT, Stevenson BE, Chester MW, Basit M, Daniels MB, Turley SD, McGarry JD (1997) The insulinotropic potency of fatty acids is influenced profoundly by their chain length and degree of saturation. The Journal of Clinical Investigation 100: 398-403
- Stutzmann GE, Mattson MP. Endoplasmic reticulum Ca(2+) handling in excitable cells in health and disease. Pharmacol Rev. 2011 Sep; 63(3):700-27
- Wei Y, Wang D, Topczewski F, Pagliassotti MJ. (2006) Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. Vol. 291, pp. E275-281.
- Zhang K, Kaufman RJ. (2006) The unfolded protein response: A stress signaling pathway critical for health and disease. Vol. 66, pp. S102-109.
- Vachel L, Norez C, Becq F, Vandebrouck C. Effect of VX-770 (ivacaftor) and OAG on Ca2+ influx and CFTR activity in G551D and F508del-CFTR expressing cells. J. Cyst. Fibros. 2013 Dec;12(6):584-91.
Claims (7)
- マンニド モノオレート、3−ヒドロキシ−2,2−ビス(ヒドロキシメチル)プロピル オレート、およびN,N−ジエタノールオレアミドから選ばれる化合物を含む、対象において2型糖尿病の予防または治療に用いるための剤。
- 化合物が、2型糖尿病の予防または治療に伝統的に用いられる別の化合物と組み合わせて使用される、請求項1に記載の剤。
- 別の化合物が、ビグアナイド、グリタゾン、スルホンアミドをベースとする血糖降下薬、グリニド、DPP−4阻害剤、インクレチン模倣薬、およびα−グルコシダーゼ阻害剤から選ばれる、請求項2に記載の剤。
- 対象が動物である、請求項1〜3のいずれか一項に記載の剤。
- 対象が哺乳類である、請求項4に記載の剤。
- 対象がヒトである、請求項4に記載の剤。
- 医薬組成物、機能性食品または食品サプリメントである、請求項1〜6のいずれか一項に記載の剤。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR13/02334 | 2013-10-08 | ||
FR1302334A FR3011467B1 (fr) | 2013-10-08 | 2013-10-08 | Composes et compositions comprenant de tels composes pour la prevention ou le traitement des dyslipidemies |
PCT/FR2014/052546 WO2015052433A1 (fr) | 2013-10-08 | 2014-10-08 | Composes et compositions comprenant de tels composes pour la prévention ou le traitement des dyslipidémies |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2016535725A JP2016535725A (ja) | 2016-11-17 |
JP6502335B2 true JP6502335B2 (ja) | 2019-04-17 |
Family
ID=50023610
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016521712A Active JP6502335B2 (ja) | 2013-10-08 | 2014-10-08 | 脂質異常症の予防または治療のための化合物および該化合物を含む組成物 |
JP2016521780A Active JP6594866B2 (ja) | 2013-10-08 | 2014-10-08 | 低酸素症による脂肪毒性の予防および/または処置のための治療用組成物の調製における化合物の使用、並びに低酸素症による脂肪毒性の予防および/または処置のための治療用組成物 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016521780A Active JP6594866B2 (ja) | 2013-10-08 | 2014-10-08 | 低酸素症による脂肪毒性の予防および/または処置のための治療用組成物の調製における化合物の使用、並びに低酸素症による脂肪毒性の予防および/または処置のための治療用組成物 |
Country Status (11)
Country | Link |
---|---|
US (2) | US9821000B2 (ja) |
EP (2) | EP3065733B1 (ja) |
JP (2) | JP6502335B2 (ja) |
CN (2) | CN105828814B (ja) |
AU (2) | AU2014333636B2 (ja) |
BR (1) | BR112016007536B1 (ja) |
CA (2) | CA2927951C (ja) |
ES (2) | ES2674869T3 (ja) |
FR (1) | FR3011467B1 (ja) |
PL (1) | PL3065732T3 (ja) |
WO (2) | WO2015052237A1 (ja) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HUE049976T2 (hu) | 2005-12-28 | 2020-11-30 | Vertex Pharma | N-[2,4-bisz(1,1-dimetil-etil)-5-hidroxi-fenil]-1,4-dihidro-4-oxo-kinolin-3-karboxamid amorf alakjának gyógyászati kompozíciói |
US9744542B2 (en) | 2013-07-29 | 2017-08-29 | Apeel Technology, Inc. | Agricultural skin grafting |
JP6746569B2 (ja) | 2014-10-07 | 2020-08-26 | バーテックス ファーマシューティカルズ インコーポレイテッドVertex Pharmaceuticals Incorporated | 嚢胞性線維症膜貫通コンダクタンス制御因子のモジュレーターの共結晶 |
EP3673738B1 (en) | 2015-05-20 | 2024-02-28 | Apeel Technology, Inc. | Plant extract compositions and methods of preparation thereof |
ES2935595T3 (es) | 2015-09-16 | 2023-03-08 | Apeel Tech Inc | Método de formación de un recubrimiento protector aplicando compuestos de glicéridos de ácidos grasos a una superficie |
EP3386303B1 (en) | 2015-12-10 | 2020-03-11 | Apeel Technology, Inc. | Process for depolymerising cutin |
WO2017132281A1 (en) | 2016-01-26 | 2017-08-03 | Apeel Technology, Inc. | Method for preparing and preserving sanitized products |
WO2018094269A1 (en) | 2016-11-17 | 2018-05-24 | Apeel Technology, Inc. | Compositions formed from plant extracts and methods of preparation thereof |
WO2020212915A1 (en) * | 2019-04-16 | 2020-10-22 | Enzychem Lifesciences | Compositions and methods for treating diabetes |
KR102218540B1 (ko) * | 2019-04-16 | 2021-02-22 | 주식회사 엔지켐생명과학 | 모노아세틸디아실글리세롤 화합물을 함유하는 당뇨병 치료용 조성물 및 당뇨병의 치료 방법 |
IL296033A (en) | 2020-03-04 | 2022-10-01 | Apeel Tech Inc | Coated agricultural products and appropriate methods |
IL302360A (en) | 2020-10-30 | 2023-06-01 | Apeel Tech Inc | Preparations and methods of their preparation |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5914520B2 (ja) * | 1977-07-29 | 1984-04-04 | カネボウ株式会社 | 二層型液状シヤンプ− |
JPS5953421A (ja) * | 1983-02-15 | 1984-03-28 | Ajinomoto Co Inc | コレステロ−ル低下または上昇抑制剤 |
EP0104043A3 (en) * | 1982-09-20 | 1984-06-06 | Ajinomoto Co., Inc. | Foodstuffs and pharmaceuticals |
WO2001017472A1 (en) | 1999-09-08 | 2001-03-15 | Watson Pharmaceuticals, Inc. | Using quaternary ammonium salts for transdermal drug delivery |
ATE330575T1 (de) * | 2000-04-03 | 2006-07-15 | 3M Innovative Properties Co | Dentalmaterialien mit verlängerter verarbeitungszeit, kits und verfahren |
IL142537A0 (en) * | 2001-04-11 | 2002-03-10 | Yeda Res & Dev | Pharmaceutical compositions for the treatment of autoimmune diseases |
WO2003040354A1 (en) | 2001-07-09 | 2003-05-15 | Alexion Pharmaceuticals, Inc. | Capacitative calcium entry mechanism in porcine oocytes |
US7132800B2 (en) * | 2001-11-15 | 2006-11-07 | Koninklijke Philips Electronics, N.V. | High-pressure discharge lamp |
US7700583B2 (en) * | 2003-04-11 | 2010-04-20 | High Point Pharmaceuticals, Llc | 11β-hydroxysteroid dehydrogenase type 1 active compounds |
GB0425658D0 (en) * | 2004-11-22 | 2004-12-22 | Stanford Rook Ltd | Immunotherapeutic agent |
US20090124608A1 (en) * | 2006-10-16 | 2009-05-14 | Board Of Trustees Of The University Of Arkansas | CB2 Receptor Modulators In Neurodegenerative Diseases And Applications Of The Same |
EP2445494A4 (en) * | 2009-06-24 | 2012-12-12 | Univ Koebenhavn | TREATMENT OF INSULIN RESISTANCE AND FATIBILITY BY STIMULATING GLP-1 RELEASE |
EP2629773A2 (en) * | 2010-10-19 | 2013-08-28 | Elcelyx Therapeutics, Inc. | Chemosensory receptor ligand-based therapies |
-
2013
- 2013-10-08 FR FR1302334A patent/FR3011467B1/fr active Active
-
2014
- 2014-10-08 ES ES14781242.4T patent/ES2674869T3/es active Active
- 2014-10-08 AU AU2014333636A patent/AU2014333636B2/en active Active
- 2014-10-08 PL PL14781242T patent/PL3065732T3/pl unknown
- 2014-10-08 JP JP2016521712A patent/JP6502335B2/ja active Active
- 2014-10-08 CA CA2927951A patent/CA2927951C/en active Active
- 2014-10-08 BR BR112016007536-6A patent/BR112016007536B1/pt active IP Right Grant
- 2014-10-08 JP JP2016521780A patent/JP6594866B2/ja active Active
- 2014-10-08 AU AU2014333853A patent/AU2014333853A1/en not_active Abandoned
- 2014-10-08 CN CN201480055571.3A patent/CN105828814B/zh active Active
- 2014-10-08 WO PCT/EP2014/071543 patent/WO2015052237A1/fr active Application Filing
- 2014-10-08 EP EP14790233.2A patent/EP3065733B1/fr active Active
- 2014-10-08 CA CA2926582A patent/CA2926582C/fr active Active
- 2014-10-08 EP EP14781242.4A patent/EP3065732B1/fr active Active
- 2014-10-08 US US15/027,738 patent/US9821000B2/en active Active
- 2014-10-08 US US15/028,139 patent/US10231985B2/en active Active
- 2014-10-08 ES ES14790233.2T patent/ES2682973T3/es active Active
- 2014-10-08 WO PCT/FR2014/052546 patent/WO2015052433A1/fr active Application Filing
- 2014-10-08 CN CN201480055631.1A patent/CN105744934B/zh active Active
Also Published As
Publication number | Publication date |
---|---|
EP3065732B1 (fr) | 2018-04-11 |
PL3065732T3 (pl) | 2019-03-29 |
US20160287542A1 (en) | 2016-10-06 |
CA2927951C (en) | 2022-08-30 |
CA2926582A1 (fr) | 2015-04-16 |
CA2926582C (fr) | 2023-07-25 |
JP2016535727A (ja) | 2016-11-17 |
ES2674869T3 (es) | 2018-07-04 |
CN105828814B (zh) | 2019-04-19 |
FR3011467A1 (fr) | 2015-04-10 |
AU2014333636A1 (en) | 2016-05-05 |
US10231985B2 (en) | 2019-03-19 |
AU2014333636B2 (en) | 2019-12-05 |
WO2015052237A1 (fr) | 2015-04-16 |
CA2927951A1 (en) | 2015-04-16 |
CN105828814A (zh) | 2016-08-03 |
JP2016535725A (ja) | 2016-11-17 |
JP6594866B2 (ja) | 2019-10-23 |
ES2682973T3 (es) | 2018-09-24 |
BR112016007536A2 (pt) | 2017-09-26 |
EP3065733A1 (fr) | 2016-09-14 |
US9821000B2 (en) | 2017-11-21 |
BR112016007536B1 (pt) | 2020-10-13 |
EP3065732A1 (fr) | 2016-09-14 |
US20160256429A1 (en) | 2016-09-08 |
CN105744934B (zh) | 2019-08-20 |
AU2014333853A1 (en) | 2016-05-12 |
CN105744934A (zh) | 2016-07-06 |
BR112016007536A8 (pt) | 2018-01-30 |
FR3011467B1 (fr) | 2016-02-12 |
WO2015052433A1 (fr) | 2015-04-16 |
EP3065733B1 (fr) | 2018-05-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6502335B2 (ja) | 脂質異常症の予防または治療のための化合物および該化合物を含む組成物 | |
Mailhot et al. | CFTR depletion results in changes in fatty acid composition and promotes lipogenesis in intestinal Caco 2/15 cells | |
Liu et al. | Oleic acid protects insulin-secreting INS-1E cells against palmitic acid-induced lipotoxicity along with an amelioration of ER stress | |
US20050101542A1 (en) | Combination therapy for controlling appetites | |
US10881642B2 (en) | Autophagy enhancer and use thereof | |
Bonfleur et al. | Primary hypercholesterolaemia impairs glucose homeostasis and insulin secretion in low-density lipoprotein receptor knockout mice independently of high-fat diet and obesity | |
Li et al. | GLP-1 induces the expression of FNDC5 derivatives that execute lipolytic actions | |
Baranowski et al. | Pioglitazone induces de novo ceramide synthesis in the rat heart | |
JP2017511387A (ja) | 脂質蓄積障害の治療のための方法および組成物 | |
AU2022283770B2 (en) | Cyclic plasmenylethanolamines | |
White | Obesity-linked insulin resistance, inflammation, and omega-3 fatty acids: exploring the anti-diabetic potential of novel omega-3 derived pro-resolution mediators | |
Pearson | Ceramide Accumulation in the Alpha Cell Drives Glucagon Secretion and Hyperglycemia | |
Garić | Regulation of Inflammation in Cystic Fibrosis | |
Mokhtar | The Role of Perilipin 5 (PLIN5) in Muscle Metabolism |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20171003 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20180612 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180911 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190205 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190221 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20190305 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20190320 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6502335 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |