JP5546807B2 - PPAR ligand agent - Google Patents
PPAR ligand agent Download PDFInfo
- Publication number
- JP5546807B2 JP5546807B2 JP2009157200A JP2009157200A JP5546807B2 JP 5546807 B2 JP5546807 B2 JP 5546807B2 JP 2009157200 A JP2009157200 A JP 2009157200A JP 2009157200 A JP2009157200 A JP 2009157200A JP 5546807 B2 JP5546807 B2 JP 5546807B2
- Authority
- JP
- Japan
- Prior art keywords
- ppar
- compound
- extract
- ppar ligand
- obesity
- 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.)
- Expired - Fee Related
Links
- 239000003446 ligand Substances 0.000 title claims description 77
- 239000003795 chemical substances by application Substances 0.000 title claims description 33
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 title description 61
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 title description 61
- 150000001875 compounds Chemical class 0.000 claims description 32
- 208000008589 Obesity Diseases 0.000 claims description 29
- 235000020824 obesity Nutrition 0.000 claims description 29
- 235000000346 sugar Nutrition 0.000 claims description 26
- 102000023984 PPAR alpha Human genes 0.000 claims description 25
- 108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 claims description 25
- 206010022489 Insulin Resistance Diseases 0.000 claims description 19
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 19
- 206010012601 diabetes mellitus Diseases 0.000 claims description 16
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 15
- 206010020772 Hypertension Diseases 0.000 claims description 15
- 239000004480 active ingredient Substances 0.000 claims description 5
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 229940127557 pharmaceutical product Drugs 0.000 claims description 2
- 230000000694 effects Effects 0.000 description 48
- 239000000284 extract Substances 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 238000000034 method Methods 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical group OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 16
- 230000009471 action Effects 0.000 description 16
- 238000000605 extraction Methods 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 235000013305 food Nutrition 0.000 description 13
- 108010016731 PPAR gamma Proteins 0.000 description 12
- 102100038825 Peroxisome proliferator-activated receptor gamma Human genes 0.000 description 12
- 238000004020 luminiscence type Methods 0.000 description 11
- 229940126062 Compound A Drugs 0.000 description 10
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 10
- 235000013399 edible fruits Nutrition 0.000 description 10
- 238000005259 measurement Methods 0.000 description 9
- 239000002609 medium Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 230000006872 improvement Effects 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 102100039556 Galectin-4 Human genes 0.000 description 7
- 101000608765 Homo sapiens Galectin-4 Proteins 0.000 description 7
- 108010015181 PPAR delta Proteins 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 150000002500 ions Chemical class 0.000 description 7
- 230000002265 prevention Effects 0.000 description 7
- 241000196324 Embryophyta Species 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 6
- 210000001789 adipocyte Anatomy 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000013612 plasmid Substances 0.000 description 6
- 244000280244 Luffa acutangula Species 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 5
- 231100000673 dose–response relationship Toxicity 0.000 description 5
- 238000003306 harvesting Methods 0.000 description 5
- 239000000401 methanolic extract Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- FHEYXUNYNJORPG-UHFFFAOYSA-N 2-prop-2-enyl-1-benzofuran Chemical class C1=CC=C2OC(CC=C)=CC2=C1 FHEYXUNYNJORPG-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 241000219104 Cucurbitaceae Species 0.000 description 4
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- 235000018780 Luffa acutangula Nutrition 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 4
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 150000001720 carbohydrates Chemical group 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 239000013613 expression plasmid Substances 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 210000002027 skeletal muscle Anatomy 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 150000008163 sugars Chemical class 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 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 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- LNSXRXFBSDRILE-UHFFFAOYSA-N Cucurbitacin Natural products CC(=O)OC(C)(C)C=CC(=O)C(C)(O)C1C(O)CC2(C)C3CC=C4C(C)(C)C(O)C(O)CC4(C)C3(C)C(=O)CC12C LNSXRXFBSDRILE-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 108060001084 Luciferase Proteins 0.000 description 3
- 235000009814 Luffa aegyptiaca Nutrition 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000003579 anti-obesity Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 235000009508 confectionery Nutrition 0.000 description 3
- 150000001904 cucurbitacins Chemical class 0.000 description 3
- -1 etc.) Substances 0.000 description 3
- 239000003925 fat Substances 0.000 description 3
- 235000019197 fats Nutrition 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 229930182470 glycoside Natural products 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- REFJWTPEDVJJIY-UHFFFAOYSA-N quercetin Natural products C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000011144 upstream manufacturing Methods 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- 241001438349 Adinandra nitida Species 0.000 description 2
- 240000000171 Crataegus monogyna Species 0.000 description 2
- 235000004423 Crataegus monogyna Nutrition 0.000 description 2
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- SHZGCJCMOBCMKK-JFNONXLTSA-N L-rhamnopyranose Chemical compound C[C@@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O SHZGCJCMOBCMKK-JFNONXLTSA-N 0.000 description 2
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- 244000302544 Luffa aegyptiaca Species 0.000 description 2
- 208000001145 Metabolic Syndrome Diseases 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 108010044210 PPAR-beta Proteins 0.000 description 2
- 241000218996 Passiflora Species 0.000 description 2
- 241000244268 Peucedanum japonicum Species 0.000 description 2
- 240000004760 Pimpinella anisum Species 0.000 description 2
- 235000012550 Pimpinella anisum Nutrition 0.000 description 2
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 description 2
- 108091027981 Response element Proteins 0.000 description 2
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 description 2
- 240000006028 Sambucus nigra Species 0.000 description 2
- 235000003142 Sambucus nigra Nutrition 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- 240000004482 Withania somnifera Species 0.000 description 2
- 235000001978 Withania somnifera Nutrition 0.000 description 2
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 2
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 235000013361 beverage Nutrition 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000006037 cell lysis Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 210000004748 cultured cell Anatomy 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 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 2
- 235000008995 european elder Nutrition 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- 229930182830 galactose Natural products 0.000 description 2
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 2
- 150000002338 glycosides Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000001969 hypertrophic effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 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 2
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 2
- 230000037356 lipid metabolism Effects 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 150000002772 monosaccharides Chemical class 0.000 description 2
- 235000012149 noodles Nutrition 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000012264 purified product Substances 0.000 description 2
- 229960001285 quercetin Drugs 0.000 description 2
- 235000005875 quercetin Nutrition 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000004043 responsiveness Effects 0.000 description 2
- NVLRFXKSQQPKAD-UHFFFAOYSA-N tricarbon Chemical compound [C]=C=[C] NVLRFXKSQQPKAD-UHFFFAOYSA-N 0.000 description 2
- 235000013311 vegetables Nutrition 0.000 description 2
- OGOMAWHSXRDAKZ-RUOAZZEASA-N (2s,3r,4s,5r,6r)-3,4,5-tris(phenylmethoxy)-6-(phenylmethoxymethyl)oxan-2-ol Chemical compound C([C@H]1O[C@@H]([C@@H]([C@@H](OCC=2C=CC=CC=2)[C@@H]1OCC=1C=CC=CC=1)OCC=1C=CC=CC=1)O)OCC1=CC=CC=C1 OGOMAWHSXRDAKZ-RUOAZZEASA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- AFOBQYBIRDDGAD-UHFFFAOYSA-N 2-(4-methoxyphenyl)-1-benzofuran-5-carboxylic acid Chemical compound C1=CC(OC)=CC=C1C1=CC2=CC(C(O)=O)=CC=C2O1 AFOBQYBIRDDGAD-UHFFFAOYSA-N 0.000 description 1
- 244000167222 Acanthopanax sessiliflorus Species 0.000 description 1
- 235000017615 Acanthopanax sessiliflorus Nutrition 0.000 description 1
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 239000009405 Ashwagandha Substances 0.000 description 1
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 description 1
- 235000017166 Bambusa arundinacea Nutrition 0.000 description 1
- 235000017491 Bambusa tulda Nutrition 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- 101100297347 Caenorhabditis elegans pgl-3 gene Proteins 0.000 description 1
- 241000722682 Calluna Species 0.000 description 1
- 240000002804 Calluna vulgaris Species 0.000 description 1
- 235000007575 Calluna vulgaris Nutrition 0.000 description 1
- 241000206601 Carnobacterium mobile Species 0.000 description 1
- 241000252185 Cobitidae Species 0.000 description 1
- 241001640558 Cotoneaster horizontalis Species 0.000 description 1
- 235000009917 Crataegus X brevipes Nutrition 0.000 description 1
- 235000013204 Crataegus X haemacarpa Nutrition 0.000 description 1
- 235000009685 Crataegus X maligna Nutrition 0.000 description 1
- 235000009444 Crataegus X rubrocarnea Nutrition 0.000 description 1
- 235000009486 Crataegus bullatus Nutrition 0.000 description 1
- 235000017181 Crataegus chrysocarpa Nutrition 0.000 description 1
- 235000009682 Crataegus limnophila Nutrition 0.000 description 1
- 235000002313 Crataegus paludosa Nutrition 0.000 description 1
- 235000009840 Crataegus x incaedua Nutrition 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- CVKKIVYBGGDJCR-SXDZHWHFSA-N Cucurbitacin B Natural products CC(=O)OC(C)(C)C=CC(=O)[C@@](C)(O)[C@@H]1[C@@H](O)C[C@]2(C)C3=CC[C@@H]4C(C)(C)C(=O)[C@H](O)C[C@@]4(C)[C@@H]3CC(=O)[C@@]12C CVKKIVYBGGDJCR-SXDZHWHFSA-N 0.000 description 1
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 108090000331 Firefly luciferases Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 240000008415 Lactuca sativa Species 0.000 description 1
- 108010022337 Leucine Enkephalin Proteins 0.000 description 1
- 101000741778 Mus musculus Peroxisome proliferator-activated receptor alpha Proteins 0.000 description 1
- 101000741798 Mus musculus Peroxisome proliferator-activated receptor delta Proteins 0.000 description 1
- 235000007265 Myrrhis odorata Nutrition 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 229940122054 Peroxisome proliferator-activated receptor delta agonist Drugs 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 244000082204 Phyllostachys viridis Species 0.000 description 1
- 235000015334 Phyllostachys viridis Nutrition 0.000 description 1
- 235000006521 Pleurotus eryngii var ferulae Nutrition 0.000 description 1
- 244000088486 Pleurotus eryngii var. ferulae Species 0.000 description 1
- 241000209504 Poaceae Species 0.000 description 1
- 102000004226 Prostaglandin-E Synthases Human genes 0.000 description 1
- 108090000748 Prostaglandin-E Synthases Proteins 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 241001495449 Robinia pseudoacacia Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 108010022394 Threonine synthase Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 1
- KUSXBOZNRPQEON-UHFFFAOYSA-N Vladinol E Natural products O1C=2C(OC)=CC(C=CCO)=CC=2C(CO)C1C1=CC=C(O)C(OC)=C1 KUSXBOZNRPQEON-UHFFFAOYSA-N 0.000 description 1
- XRLMHVZJEZXREY-JPVHLGFFSA-N [(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] 2-(4-methoxyphenyl)-1-benzofuran-5-carboxylate Chemical compound C1=CC(OC)=CC=C1C1=CC2=CC(C(=O)O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)=CC=C2O1 XRLMHVZJEZXREY-JPVHLGFFSA-N 0.000 description 1
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 230000011759 adipose tissue development Effects 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 230000002744 anti-aggregatory effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000011425 bamboo Substances 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 235000015895 biscuits Nutrition 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 235000008429 bread Nutrition 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 229940112822 chewing gum Drugs 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 235000019219 chocolate Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002485 combustion reaction Methods 0.000 description 1
- 235000012495 crackers Nutrition 0.000 description 1
- 244000038559 crop plants Species 0.000 description 1
- 229940095074 cyclic amp Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- KUSXBOZNRPQEON-ONEGZZNKSA-N dehydrodiconiferyl alcohol Chemical compound O1C=2C(OC)=CC(\C=C\CO)=CC=2C(CO)C1C1=CC=C(O)C(OC)=C1 KUSXBOZNRPQEON-ONEGZZNKSA-N 0.000 description 1
- KUSXBOZNRPQEON-BEFAXECRSA-N dehydrodiconiferyl alcohol Natural products COc1cc(ccc1O)[C@@H]2Oc3c(OC)cc(C=CCO)cc3[C@H]2CO KUSXBOZNRPQEON-BEFAXECRSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 235000011850 desserts Nutrition 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- PIGAXYFCLPQWOD-UHFFFAOYSA-N dihydrocucurbitacin I Natural products CC12C(=O)CC3(C)C(C(C)(O)C(=O)CCC(C)(O)C)C(O)CC3(C)C1CC=C1C2C=C(O)C(=O)C1(C)C PIGAXYFCLPQWOD-UHFFFAOYSA-N 0.000 description 1
- 102000004419 dihydrofolate reductase Human genes 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012581 double quantum filtered COSY Methods 0.000 description 1
- 235000015071 dressings Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940108890 emend Drugs 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 239000000469 ethanolic extract Substances 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 235000013611 frozen food Nutrition 0.000 description 1
- 235000015203 fruit juice Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 235000013402 health food Nutrition 0.000 description 1
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 1
- 238000001052 heteronuclear multiple bond coherence spectrum Methods 0.000 description 1
- 238000005570 heteronuclear single quantum coherence Methods 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 235000009200 high fat diet Nutrition 0.000 description 1
- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 235000015243 ice cream Nutrition 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 235000008446 instant noodles Nutrition 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 238000000752 ionisation method Methods 0.000 description 1
- HPIGCVXMBGOWTF-UHFFFAOYSA-N isomaltol Natural products CC(=O)C=1OC=CC=1O HPIGCVXMBGOWTF-UHFFFAOYSA-N 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- URLZCHNOLZSCCA-UHFFFAOYSA-N leu-enkephalin Chemical compound C=1C=C(O)C=CC=1CC(N)C(=O)NCC(=O)NCC(=O)NC(C(=O)NC(CC(C)C)C(O)=O)CC1=CC=CC=C1 URLZCHNOLZSCCA-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 235000013310 margarine Nutrition 0.000 description 1
- 239000003264 margarine Substances 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000010746 mayonnaise Nutrition 0.000 description 1
- 239000008268 mayonnaise Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 102000006255 nuclear receptors Human genes 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- QHGUCRYDKWKLMG-UHFFFAOYSA-N octopamine Chemical compound NCC(O)C1=CC=C(O)C=C1 QHGUCRYDKWKLMG-UHFFFAOYSA-N 0.000 description 1
- 229960001576 octopamine Drugs 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000003614 peroxisome proliferator Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 210000000229 preadipocyte Anatomy 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 108010047709 rat PPAR gamma Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000001896 rotating frame Overhauser effect spectroscopy Methods 0.000 description 1
- 235000012045 salad Nutrition 0.000 description 1
- 235000015067 sauces Nutrition 0.000 description 1
- 235000014214 soft drink Nutrition 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000013616 tea Nutrition 0.000 description 1
- 150000003548 thiazolidines Chemical class 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 238000001551 total correlation spectroscopy Methods 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- DBRXOUCRJQVYJQ-CKNDUULBSA-N withaferin A Chemical compound C([C@@H]1[C@H]([C@@H]2[C@]3(CC[C@@H]4[C@@]5(C)C(=O)C=C[C@H](O)[C@@]65O[C@@H]6C[C@H]4[C@@H]3CC2)C)C)C(C)=C(CO)C(=O)O1 DBRXOUCRJQVYJQ-CKNDUULBSA-N 0.000 description 1
- SASUFNRGCZMRFD-JCUIILOWSA-N withanolide D Chemical compound C1C(C)=C(C)C(=O)O[C@H]1[C@](C)(O)[C@@H]1[C@@]2(C)CC[C@@H]3[C@@]4(C)C(=O)C=C[C@H](O)[C@@]54O[C@@H]5C[C@H]3[C@@H]2CC1 SASUFNRGCZMRFD-JCUIILOWSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/10—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to heterocyclic rings
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/52—Adding ingredients
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- 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
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- 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
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- 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
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/42—Cucurbitaceae (Cucumber family)
-
- 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
- A61P3/04—Anorexiants; Antiobesity agents
-
- 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
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
-
- 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)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Food Science & Technology (AREA)
- Nutrition Science (AREA)
- Polymers & Plastics (AREA)
- Biotechnology (AREA)
- Mycology (AREA)
- Molecular Biology (AREA)
- Botany (AREA)
- Emergency Medicine (AREA)
- Alternative & Traditional Medicine (AREA)
- Medical Informatics (AREA)
- Microbiology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Endocrinology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Child & Adolescent Psychology (AREA)
- Medicines Containing Plant Substances (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Non-Alcoholic Beverages (AREA)
Description
本発明は、PPARリガンド剤に関する。より具体的には、肥満、肥満に伴い発症するインスリン抵抗性、高脂血症、高血圧または糖尿病を予防および/または改善する作用を有するPPARα、δおよび/またはγのリガンド剤に関する。さらに、PPARα、δおよび/またはγのリガンド作用を有する新規化合物に関する。 The present invention relates to a PPAR ligand agent. More specifically, the present invention relates to a ligand agent for PPARα, δ and / or γ having an action of preventing and / or improving obesity, insulin resistance that develops with obesity, hyperlipidemia, hypertension or diabetes. Furthermore, the present invention relates to a novel compound having a ligand action of PPARα, δ and / or γ.
ペルオキシソーム増殖剤応答性受容体(Peroxisome proliferator−activated receptors:PPARs)は、リガンド依存的に転写を制御する核内受容体で、PPARα、PPARδ(PPARβ)、PPARγの3種のサブタイプの存在が知られている。 Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate transcription in a ligand-dependent manner and are known to have three subtypes: PPARα, PPARδ (PPARβ), and PPARγ. It has been.
PPARαの主要調節臓器は肝臓であり、PPARαが活性化することにより、肝臓における脂肪の燃焼が促進され、血中・肝臓・骨格筋の中性脂肪含量が減少し、インスリン抵抗性が改善される。 The main regulatory organ of PPARα is the liver, and activation of PPARα promotes the burning of fat in the liver, reduces the triglyceride content in blood, liver and skeletal muscle, and improves insulin resistance .
PPARδはPPARβとも呼ばれ、特に骨格筋を中心とした強力なエネルギー代謝促進作用、脂肪酸燃焼促進作用をつかさどっていることが明らかとなっている。PPARδアゴニスト(GW501516)を用いた実験では、PPARδの活性化により、骨格筋の脂肪酸酸化が亢進し、高脂肪食による肥満やインスリン抵抗性も抑制されたことが示されている。 PPARδ is also referred to as PPARβ, and it has been clarified that it particularly has a strong energy metabolism promoting action mainly on skeletal muscles and a fatty acid combustion promoting action. Experiments using a PPARδ agonist (GW501516) show that activation of PPARδ promotes fatty acid oxidation of skeletal muscle and suppresses obesity and insulin resistance due to a high fat diet.
PPARγの主要調節臓器は脂肪組織である。PPARγのアゴニストであるチアゾリジン誘導体は、PPARγを介して肥大脂肪細胞のアポトーシスと前駆脂肪細胞から小型脂肪細胞への分化による生成より、肥大脂肪細胞を小型脂肪細胞に置き換えることにより、インスリン抵抗性を改善することが報告されている(非特許文献1)。 The main regulatory organ of PPARγ is adipose tissue. Thiazolidine derivatives, agonists of PPARγ, improve insulin resistance by replacing hypertrophic adipocytes with small adipocytes rather than PPARγ via apoptosis of hypertrophic adipocytes and generation from preadipocytes to small adipocytes It has been reported (Non-Patent Document 1).
このように、PPARsは生体内の糖、脂質代謝の制御に関与しているのみならず、肥満、高脂血症、高血圧、糖尿病などの生活習慣病、癌、炎症性疾患、動脈硬化症などの疾患の発症への関与が明らかとなっている(非特許文献2)。 Thus, PPARs are not only involved in the regulation of sugar and lipid metabolism in the body, but also include lifestyle-related diseases such as obesity, hyperlipidemia, hypertension, diabetes, cancer, inflammatory diseases, arteriosclerosis, etc. Involvement in the onset of other diseases has been clarified (Non-patent Document 2).
メタボリックシンドロームにおいて、肥満は他のリスクファクター、インスリン抵抗性、高脂血症、高血圧、糖尿病などの上流に位置しており、したがって、肥満を改善することにより、他のリスクファクターをも改善することが可能である。すなわち、PPARのリガンド剤はPPARを活性化することにより、生体内における脂質代謝を促進し、蓄積した脂肪を減少させることにより、肥満を予防および改善し、さらに肥満に伴い発症するインスリン抵抗性、高脂血症、高血圧、糖尿病を予防および改善することが可能である(非特許文献3)。 In the metabolic syndrome, obesity is located upstream of other risk factors, such as insulin resistance, hyperlipidemia, hypertension, diabetes, etc. Therefore, improving other obesity factors by improving obesity Is possible. That is, the ligand agent of PPAR activates PPAR, promotes lipid metabolism in the living body, reduces and accumulates fat, prevents and improves obesity, and further, insulin resistance that develops with obesity, It is possible to prevent and improve hyperlipidemia, hypertension, and diabetes (Non-patent Document 3).
ウリ科植物の抽出物の抗肥満作用が報告されている(特許文献1)。その内容は、タワシヘチマ(Luffa cylindrica L.)由来の、インスリン分泌促進作用やサイクリックAMPホスホジエステラーゼ阻害作用による肥満および糖尿病の予防および治療効果である。また、ウリ科植物、タワシヘチマ由来の有効成分であるデヒドロジコニフェリルアルコールが、PPARαおよびδの働きを活性化させ、脂肪前駆細胞からの脂肪生成を抑制すると報告されている(特許文献2および3)。 An anti-obesity effect of an extract of the Cucurbitaceae plant has been reported (Patent Document 1). Its content is the effect of preventing and treating obesity and diabetes derived from Tuffet loach ( Luffa cylindrica L.) by promoting insulin secretion and inhibiting cyclic AMP phosphodiesterase. In addition, it has been reported that dehydrodiconiferyl alcohol, which is an active ingredient derived from the cucurbitaceae plant and Tawahishi Hima, activates the functions of PPARα and δ and suppresses adipogenesis from adipose precursor cells (Patent Documents 2 and 3). ).
ウリ科の植物であるトカドヘチマ(Luffa acutangula Roxb.)は、インドから東南アジア、中国南部にかけて広く栽培され、未熟果実を野菜として利用している。果実ジュースのエーテル抽出物に細胞毒性を示すククルビタシン類(cucurbitacins)が存在するという報告(非特許文献4)、幼苗、根、完熟種子はククルビタシン類を含むという報告がある(非特許文献5)。しかし、トカドヘチマ抽出物がPPARリガンド作用を示すことは知られていない。 The cucurbitaceae plant Luffa acutangula Roxb. Is widely cultivated from India to Southeast Asia and southern China, and uses immature fruits as vegetables. There are reports that cucurbitacins that exhibit cytotoxicity exist in the ether extract of fruit juice (Non-patent Document 4), and that seedlings, roots, and mature seeds contain cucurbitacins (Non-patent Document 5). However, it is not known that Tocadohetima extract exhibits PPAR ligand action.
PPARリガンド剤は、肥満を予防および/または改善することが期待され、さらにはメタボリックシンドロームのリスクファクターであるインスリン抵抗性、高脂血症、高血圧または糖尿病などを予防および/または改善することが期待される。しかし、既存のPPARリガンド剤は、医薬品の長期投与による副作用などが危惧されるほか、食品由来のポリフェノール類などには、十分なPPARリガンド作用が得られないなどの問題点がある。 PPAR ligand agents are expected to prevent and / or improve obesity, and further prevent and / or improve insulin resistance, hyperlipidemia, hypertension, diabetes, etc., which are risk factors of metabolic syndrome Is done. However, existing PPAR ligand agents have problems such as side effects due to long-term administration of pharmaceuticals, and food-derived polyphenols cannot obtain sufficient PPAR ligand action.
本発明の目的は、安全で、優れたPPARリガンド剤を提供することである。 An object of the present invention is to provide a safe and excellent PPAR ligand agent.
本発明者らは、上記課題を解決するため、長期摂取しても安全で副作用の少ないPPARリガンドを天然由来の420種類の植物に求め、鋭意探索した結果、トカドヘチマの抽出物に高いPPARリガンド活性があることを見出した。さらに、トカドヘチマ抽出物中から新規化合物である式(1): In order to solve the above problems, the present inventors have sought 420 kinds of naturally-derived PPAR ligands that are safe and have few side effects even when ingested for a long period of time, and as a result of diligent search, the extract of Tocadohetica has high PPAR ligand activity. Found that there is. Furthermore, the formula (1), which is a novel compound from Tocadohetima extract:
(Rは糖である)
で表わされる化合物を精製し、この化合物が強いPPARリガンド作用を有することを見出した。本発明はこれらの知見に基づいて完成したものである。
(R is sugar)
The compound represented by (2) was purified and found to have a strong PPAR ligand action. The present invention has been completed based on these findings.
すなわち本発明は、次の[1]〜[7]である。
[1] トカドヘチマの溶媒抽出物を有効成分とするPPARα、δおよび/またはγのリガンド剤。
[2] 溶媒がアルコール類または含水アルコール類である、[1]記載のPPARα、δおよび/またはγのリガンド剤。
[3] 有効成分として、式(1):
That is, the present invention includes the following [1] to [7].
[1] A ligand agent of PPARα, δ and / or γ containing a solvent extract of tocadohetima as an active ingredient.
[2] The ligand agent for PPARα, δ and / or γ according to [1], wherein the solvent is an alcohol or a hydrous alcohol.
[3] As an active ingredient, the formula (1):
(RはHまたは糖である)
で表される化合物を含む、[1]または[2]記載のPPARα、δおよび/またはγのリガンド剤。
[4] 肥満、肥満に伴い発症するインスリン抵抗性、高脂血症、高血圧または糖尿病を予防および/または改善するための、[1]〜[3]のいずれかに記載のPPARα、δおよび/またはγのリガンド剤。
[5] 飲食品の形態である、[4]記載のPPARα、δおよび/またはγのリガンド剤。
[6] 医薬品の形態である、[4]記載のPPARα、δおよび/またはγのリガンド剤。
[7] 式(1):
(R is H or sugar)
A PPARα, δ and / or γ ligand agent according to [1] or [2], which comprises a compound represented by the formula:
[4] PPARα, δ and / or [1] for preventing and / or improving obesity, insulin resistance, hyperlipidemia, hypertension or diabetes that develops with obesity Or a ligand agent for γ.
[5] The PPARα, δ and / or γ ligand agent according to [4], which is in the form of a food or drink.
[6] The PPARα, δ and / or γ ligand agent according to [4], which is in the form of a pharmaceutical product.
[7] Formula (1):
(Rは糖である)
で表される化合物。
(R is sugar)
A compound represented by
本発明のPPARリガンド剤は、PPARα、δおよびγに対して優れたリガンド活性を示し、かつ、食物として摂取されている植物由来であり、安全性が高い。したがって、本発明により、優れたPPARリガンド剤が提供され、肥満、肥満に伴うインスリン抵抗性、高脂血症、高血圧、糖尿病などを予防および/または改善に有効な飲食物、医薬品の形態であるPPARリガンド剤が提供される。 The PPAR ligand agent of the present invention exhibits excellent ligand activity for PPARα, δ, and γ, and is derived from a plant that is ingested as food, and has high safety. Therefore, according to the present invention, an excellent PPAR ligand agent is provided, which is a form of food, beverage, or medicine effective for preventing and / or improving obesity, insulin resistance associated with obesity, hyperlipidemia, hypertension, diabetes and the like. A PPAR ligand agent is provided.
以下、本発明の実施の形態について、詳細に説明する。
<PPARリガンド剤>
本発明のPPARリガンド剤は、トカドヘチマ抽出物または該抽出物中の特定の化合物を有効成分として含有する。
Hereinafter, embodiments of the present invention will be described in detail.
<PPAR ligand agent>
The PPAR ligand agent of the present invention contains a tocadohetima extract or a specific compound in the extract as an active ingredient.
トカドヘチマ抽出物
原料となるトカドヘチマ(Luffa acutangula Roxb.)はウリ科の植物である。トカドヘチマはインドから東南アジア、中国南部にかけて広く栽培され、未熟果実を野菜として利用している(世界有用植物事典 平凡社 p. 637、熱帯の野菜 農林水産省熱帯農業研究センター p. 37-39)。
Tocadohetima ( Luffa acutangula Roxb.), Which is a raw material for Tokadohema extract , is a plant of the Cucurbitaceae family. Tokadohema is widely cultivated from India to Southeast Asia and southern China, and uses immature fruits as vegetables (World useful plant encyclopedia Heibonsha p. 637, Tropical vegetable research center for tropical agriculture, Ministry of Agriculture, Forestry and Fisheries p. 37-39).
トカドヘチマ抽出物の原料は、未熟果実を用いるのが好ましいが、これら以外の部位、果皮、葉、花、地上部、全草などのいずれかを、またはいずれも用いることができる。
抽出に用いる溶媒としては、炭素数1〜4の低級アルコール類(たとえばメタノール、エタノール、プロパノール、ブタノールなど)、液状多価アルコール(例えば、1,3−ブチレングリコール、プロピレングリコール、グリセリンなど)、ケトン類(たとえば、アセトン、メチルエチルケトンなど)、エステル類(例えば、酢酸エチル、酢酸ブチルなど)などが挙げられる。これらは、単独または2種以上を混合して用いることもできる。本発明においては、含水アルコール類またはアルコール類を用いるのが好ましく、特に含水低級アルコール類または低級アルコール類が好ましい。
It is preferable to use immature fruits as the raw material for the Tocadohetima extract, but any part other than these, such as fruit skin, leaves, flowers, above-ground parts, whole grasses, etc. can be used.
Solvents used for extraction include lower alcohols having 1 to 4 carbon atoms (for example, methanol, ethanol, propanol, butanol, etc.), liquid polyhydric alcohols (for example, 1,3-butylene glycol, propylene glycol, glycerin, etc.), ketones (For example, acetone, methyl ethyl ketone, etc.), esters (for example, ethyl acetate, butyl acetate, etc.) and the like. These may be used alone or in combination of two or more. In the present invention, water-containing alcohols or alcohols are preferably used, and water-containing lower alcohols or lower alcohols are particularly preferable.
溶媒抽出する場合、トカドヘチマは生のまま、または乾燥させたもののいずれを用いても良く、抽出する際の植物体は原型のまま、切断したもの、粉砕したもの、粉末化したものなどいずれを用いても良い。抽出温度は5〜80℃の範囲で適宜に、更に加圧、減圧などの条件も適宜に設定することが可能であるが、抽出溶媒の安全性、抽出成分の安定性の点から、温度としては室温が好ましい。抽出時間は0.1時間〜1ヶ月の範囲で適宜に設定することが可能であるが、好ましくは0.5時間〜7日である。植物体と抽出溶媒の比率は1〜1000倍(W/V)の範囲で任意に設定することが可能であるが、好ましくは1〜100倍(W/V)である。 When solvent extraction is performed, either the raw tokadohema may be used as it is or dried, and the plant body used for extraction may be the original, cut, crushed, powdered, etc. May be. The extraction temperature can be appropriately set within the range of 5 to 80 ° C., and further conditions such as pressurization and decompression can be set as appropriate. However, from the viewpoint of the safety of the extraction solvent and the stability of the extraction components, Is preferably room temperature. The extraction time can be appropriately set in the range of 0.1 hour to 1 month, preferably 0.5 hour to 7 days. Although the ratio of a plant body and an extraction solvent can be arbitrarily set in the range of 1 to 1000 times (W / V), it is preferably 1 to 100 times (W / V).
2−アリルベンゾフラン類縁体
本発明のリガンド剤は、式(1)
2-allylbenzofuran analog The ligand agent of the present invention has the formula (1)
(RはHまたは糖である)
で表される2−アリルベンゾフラン類縁体を含む。
R部分の糖は、3炭糖〜7炭糖のいずれであってもよく、また単糖に限らず複数個結合した糖であってもよい。好ましい例としては、構成糖としてはグルコース、ラムノース、アラビノース、キシロース、またはガラクトースであり、それらが1〜8個結合したものが挙げられる。特に好ましくは、糖はグルコースである。
(R is H or sugar)
The 2-allyl benzofuran analog represented by these is included.
The sugar at the R moiety may be any of tricarbon sugar to 7 carbon sugar, and is not limited to a monosaccharide but may be a sugar in which a plurality of sugars are bonded. Preferable examples include glucose, rhamnose, arabinose, xylose, or galactose as constituent sugars, and those in which 1 to 8 of them are bound. Particularly preferably, the sugar is glucose.
Rが糖の場合、糖中のいずれのOH基が結合した化合物であってもよいが、C−1位のOH基が結合したものが好ましい。
上記化合物は、トカドヘチマから抽出・精製することにより得ることができる。抽出・精製方法は、当業者の知識に基づいて適宜実施することができる。例示としては、抽出物を実施例8〜12に示す方法で精製することにより得ることができる。
When R is a saccharide, it may be a compound to which any OH group in the saccharide is bonded, but a compound having an OH group at the C-1 position is preferable.
The above compound can be obtained by extraction and purification from tocadohecima. The extraction / purification method can be appropriately performed based on the knowledge of those skilled in the art. For example, the extract can be obtained by purifying the extract by the methods shown in Examples 8 to 12.
上記化合物は、強いPPARα、δおよびγリガンド作用を有する。
なお、WO 2003051860には、本発明に用いられる2−アリルベンゾフラン類縁体と構造類似のCAS 551002−33−6が開示されている。しかし、該物質のエストロジェン作用を標榜しており、PPARリガンド作用や抗肥満効果に関しては開示されていない。また、WO 2009064251には、2−アリルベンゾフラン類縁体(RがH)が開示されている。しかし、該物質を部分構造とするプロスタグランジンE合成酵素阻害作用を標榜しており、PPARリガンド作用や抗肥満効果に関しては開示されていない。
The above compounds have strong PPARα, δ and γ ligand actions.
WO 2003051860 discloses CAS 551002-33-6, which is structurally similar to the 2-allylbenzofuran analog used in the present invention. However, the estrogen action of the substance is advocated and no PPAR ligand action or anti-obesity effect is disclosed. WO 2009064251 discloses a 2-allylbenzofuran analog (R is H). However, the prostaglandin E synthase inhibitory action with the substance as a partial structure is advocated, and no PPAR ligand action or anti-obesity effect is disclosed.
PPARリガンド活性の評価
PPARリガンド活性は、当業者が通常用いる方法で測定することができる。たとえば、培養細胞にPPARα、δまたはγを発現させると同時に、PPARの活性化に反応して蛍光シグナル等の測定用シグナルを発する系を発現させ、試験物を投与して、測定用シグナルの強度を測定することにより、PPARリガンド活性を定量化することができる。具体的には、実施例1〜3に示す方法で評価することができる。
Evaluation of PPAR Ligand Activity PPAR ligand activity can be measured by methods commonly used by those skilled in the art. For example, PPARα, δ, or γ is expressed in cultured cells, and at the same time, a system that emits a measurement signal such as a fluorescence signal in response to PPAR activation is expressed. Can be used to quantify PPAR ligand activity. Specifically, it can be evaluated by the methods shown in Examples 1 to 3.
PPARリガンド剤
本発明のPPARリガンド剤は、PPARの生体内分布や生理活性に応じて、ペルオキシソーム増殖剤応答性受容体が関連する疾患の予防および/または改善のために用いることができる。具体的には、本発明のPPARリガンド剤は、肥満、肥満に伴い発症するインスリン抵抗性、高脂血症、高血圧または糖尿病の予防および/または改善に有効である。
PPAR Ligand Agent The PPAR ligand agent of the present invention can be used for prevention and / or improvement of diseases associated with peroxisome proliferator-responsive receptors, depending on the biodistribution and physiological activity of PPAR. Specifically, the PPAR ligand agent of the present invention is effective for the prevention and / or improvement of obesity, insulin resistance that develops with obesity, hyperlipidemia, hypertension or diabetes.
本発明において、肥満の予防とは、肥満または肥満症であるとされる状態になるのを防ぐ又は遅らせることをいう。また、肥満の改善とは、肥満または肥満症であるとされる状態を改善することをいう。 In the present invention, prevention of obesity refers to preventing or delaying the occurrence of obesity or obesity. Moreover, the improvement of obesity means improving the state considered to be obesity or obesity.
本発明において、インスリン抵抗性とは、肝臓・脂肪細胞・骨格筋で、インスリンの主な作用である糖の吸収促進作用が弱っている状態をいう。インスリン抵抗性の予防とは、SSPG(Steady-state plasma glucose)法などによるインスリン抵抗性の指標となる値がより悪化するのを防ぐ又は遅らせることを指す。インスリン抵抗性の改善とは、上記のインスリン抵抗性の指標となる値をより改善することをいう。 In the present invention, insulin resistance refers to a state where the absorption promotion action of sugar, which is the main action of insulin, is weak in the liver, adipocytes, and skeletal muscle. Prevention of insulin resistance refers to preventing or delaying further deterioration of a value serving as an index of insulin resistance by the SSPG (Steady-state plasma glucose) method or the like. Improvement of insulin resistance means improvement of a value that serves as an index of insulin resistance.
本発明において、高脂血症の予防とは、高脂血症の状態又は境界域の状態になるのを防ぐ又は遅らせることをいう。また、高脂血症の改善とは、上記に示す高脂血症の状態または境界域の状態から、正常域と定義している状態に近づけることをいう。 In the present invention, prevention of hyperlipidemia refers to preventing or delaying hyperlipidemia or borderline conditions. Further, the improvement of hyperlipidemia refers to bringing the state of hyperlipidemia or boundary region described above closer to the state defined as the normal region.
本発明において、高血圧の予防とは、高血圧とされる状態または境界域の状態になるのを防ぐ又は遅らせることをいう。また、高血圧の改善とは、高血圧とされる状態または境界域の状態から、正常域と定義している状態に近づけることをいう。 In the present invention, prevention of hypertension refers to preventing or delaying the occurrence of hypertension or borderline conditions. In addition, improvement of hypertension refers to bringing a state defined as a normal range closer to a state defined as a normal range from a state considered to be high blood pressure or a state of a boundary region.
本発明において、糖尿病の予防とは、糖尿病の状態または境界域の状態になるのを防ぐ又は遅らせることをいう。また、糖尿病の改善とは、糖尿病の状態または境界域の状態から、正常域と定義している状態に近づけることをいう。 In the present invention, prevention of diabetes refers to preventing or delaying diabetic state or borderline state. Further, the improvement of diabetes refers to the approach of a state defined as a normal range from a diabetic state or a boundary state.
本発明のPPARリガンド剤は、PPARα、δ、γのいずれをも活性化する効果を有する。本発明のPPARリガンド剤は、PPARγに対してもリガンド作用を有することから、トカドヘチマ抽出物の作用はタワシヘチマの作用と明確に区別される。 The PPAR ligand agent of the present invention has an effect of activating any of PPARα, δ, and γ. Since the PPAR ligand agent of the present invention also has a ligand action on PPARγ, the action of Tocadohetima extract is clearly distinguished from the action of Tawashi loofah.
本発明のPPARリガンド剤は、飲食品および医薬品として利用することができるが、その形態は限定されず、健康食品、栄養補助食品、栄養機能食品、特定保健用食品などの飲食品および医薬品として用いることができる。 The PPAR ligand agent of the present invention can be used as foods and drinks and pharmaceuticals, but the form is not limited, and is used as foods and drinks and pharmaceuticals such as health foods, nutritional supplements, functional nutritional foods, and foods for specified health use. be able to.
飲食品としては、チューインガム、チョコレート、キャンディー、ゼリー、ビスケット、クラッカーなどの菓子類、アイスクリーム、氷菓などの冷菓類、 茶、清涼飲料、栄養ドリンク、美容ドリンクなどの飲料、うどん、中華麺、スパゲティー、即席麺などの麺類、蒲鉾、竹輪、はんぺんなどの練り製品、ドレッシング、マヨネーズ、ソースなどの調味料、マーガリン、バター、サラダ油などの油脂類、パン、ハム、スープ、レトルト食品、冷凍食品など、すべての飲食品に使用することができる。これら肥満、肥満に伴い発症するインスリン抵抗性、高脂血症、高血圧、糖尿病を予防および/または改善する組成物を摂取する場合、その摂取量は当該抽出物として成人一人一日当たり、好ましくは0.01〜1000mg/kg体重、より好ましくは1〜300mg/kg体重である。 Foods and drinks include chewing gum, chocolate, candy, jelly, biscuits, crackers and other confectionery, ice cream, frozen desserts such as ice confectionery, tea, soft drinks, nutrition drinks, beauty drinks, udon, Chinese noodles, spaghetti , Noodles such as instant noodles, kneaded products such as rice cakes, bamboo rings, hampen, seasonings such as dressing, mayonnaise, sauces, fats and oils such as margarine, butter, salad oil, bread, ham, soup, retort food, frozen food, etc. Can be used for food and drink. When the composition for preventing and / or improving obesity, insulin resistance, hyperlipidemia, hypertension, and diabetes that develops due to obesity is ingested, the amount of intake is per adult day, preferably 0 as the extract. 0.01 to 1000 mg / kg body weight, more preferably 1 to 300 mg / kg body weight.
医薬品として用いる場合は、その剤形は特に限定されず、例えば、カプセル剤、錠剤、顆粒剤、注射剤、座薬、貼付剤などが挙げられる。製剤化においては、薬剤学的に許容される他の製剤素材、例えば、賦形剤、崩壊剤、滑沢剤、結合剤、酸化防止剤、着色剤、凝集防止剤、吸収促進剤、溶解補助剤、安定化剤などを適宜添加して調製することができる。これら製剤を当該抽出物換算で成人一人一日当たり、好ましくは0.01〜1000mg/kg体重、より好ましくは1〜300mg/kg体重を1回ないし数回に分けて投与する。 When used as a pharmaceutical, the dosage form is not particularly limited, and examples thereof include capsules, tablets, granules, injections, suppositories, and patches. In formulation, other pharmaceutically acceptable formulation materials such as excipients, disintegrants, lubricants, binders, antioxidants, colorants, anti-aggregation agents, absorption enhancers, solubilizers An agent, a stabilizer and the like can be added as appropriate. These preparations are administered in an amount of from 0.01 to 1000 mg / kg body weight, more preferably from 1 to 300 mg / kg body weight per day per adult, in terms of the extract.
<新規化合物>
本発明は、トカドヘチマから得られる新規化合物に関する。具体的には、
式(1):
<New compound>
The present invention relates to a novel compound obtained from tocadohecima. In particular,
Formula (1):
(Rは糖である)
で表される化合物である。
R部分の糖は、3炭糖〜7炭糖のいずれであってもよく、また単糖に限らず複数個結合した糖であってもよい。好ましい例としては、構成糖としてはグルコース、ラムノース、アラビノース、キシロース、またはガラクトースであり、それらが1〜8個結合したものが挙げられる。特に好ましくは、糖はグルコースである。
(R is sugar)
It is a compound represented by these.
The sugar at the R moiety may be any of tricarbon sugar to 7 carbon sugar, and is not limited to a monosaccharide but may be a sugar in which a plurality of sugars are bonded. Preferable examples include glucose, rhamnose, arabinose, xylose, or galactose as constituent sugars, and those in which 1 to 8 of them are bound. Particularly preferably, the sugar is glucose.
R部分が糖である化合物は、化学的に合成することができる。たとえば、N,N‘−ジシクロヘキシルカルボジイミド(DCC)中、2、3、4、6−テトラ−O−ベンジル−D−グルコピラノースをR部分がHの化合物とカップリングさせたのち、通常の水素化分解によってベンジル基を除去する。例えば、酢酸やアルコールなどのプロトン性極性溶媒中で、あるいはベンゼン、トルエン、酢酸エチルなどの非極性溶媒中で、パラジウム炭素やパラジウム黒、あるいはプラチナ炭素やプラチナ黒などを触媒として水素の存在で脱ベンジル化し、R部分がグルコースの化合物に導くことができる。 A compound in which the R moiety is a sugar can be chemically synthesized. For example, in N, N′-dicyclohexylcarbodiimide (DCC), 2, 3, 4, 6-tetra-O-benzyl-D-glucopyranose is coupled with a compound in which the R moiety is H, followed by conventional hydrogenation. The benzyl group is removed by decomposition. For example, in a protic polar solvent such as acetic acid or alcohol, or in a nonpolar solvent such as benzene, toluene, or ethyl acetate, palladium carbon or palladium black, or platinum carbon or platinum black is used as a catalyst to remove hydrogen. Benzylated and the R moiety can lead to a glucose compound.
R部分の糖は、糖中のいずれのOH基が結合した化合物であってもよいが、C−1位のOH基が結合したものが好ましい。
上記化合物は、トカドヘチマから抽出・精製することにより得ることができる。抽出・精製方法は、当業者の知識に基づいて適宜実施することができる。例示としては、抽出物を実施例8〜12に示す方法で精製することにより得ることができる。また、化学合成によっても得ることができる。
The saccharide at the R moiety may be a compound to which any OH group in the saccharide is bonded, but preferably has a OH group at the C-1 position bonded thereto.
The above compound can be obtained by extraction and purification from tocadohecima. The extraction / purification method can be appropriately performed based on the knowledge of those skilled in the art. For example, the extract can be obtained by purifying the extract by the methods shown in Examples 8 to 12. It can also be obtained by chemical synthesis.
上記化合物は、強いPPARα、δおよびγリガンド作用を有する。
以下に本発明を実施例により詳細に説明するが、本発明はこれらに限定されるものではない。
The above compounds have strong PPARα, δ and γ ligand actions.
EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.
実施例1 PPARγリガンド活性の測定方法
PPARγリガンド活性測定用CHO細胞を以下の方法で取得した。
PPARレポータープラスミド(pPPRE-Luc)は、SV40プロモーター遺伝子、蛍ルシフェラーゼ遺伝子を含むレポータープラスミド pGL3(Promega社)のSV40プロモーター遺伝子の上流にPPAR応答配列(PPRE)を3回組み込んだレポータープラスミドである。PPARγ発現プラスミド(pKD-rPPARγ)はSV40プロモーターによる哺乳類細胞用発現プラスミドにラットPPARγ遺伝子を組み込んだプラスミドである。 pPPRE-LucとpKD-rPPARγを、Lipofectamine(Invitorgen社)を用いてCHO(dhfr-)細胞(チャイニーズハムスター卵巣由来細胞ジヒドロ葉酸還元酵素欠損株)にコトランスフェクションした。チミジンをほとんど含有しない透析ウシ胎児血清(Gibco社)を含むDMEM培地(Dulbecco‘s Modified Eagle Medium、Gibco社)で細胞を培養することにより、pPPRE-Luc と pKD-rPPARγを保持する安定形質転換株(CHO/PPARγ/PPRE)を取得した。
Example 1 Method for Measuring PPARγ Ligand Activity CHO cells for measuring PPARγ ligand activity were obtained by the following method.
The PPAR reporter plasmid (pPPRE-Luc) is a reporter plasmid in which the PPAR response element (PPRE) is incorporated three times upstream of the SV40 promoter gene of the reporter plasmid pGL3 (Promega) containing the SV40 promoter gene and the firefly luciferase gene. The PPARγ expression plasmid (pKD-rPPARγ) is a plasmid in which the rat PPARγ gene is incorporated into an expression plasmid for mammalian cells using the SV40 promoter. pPPRE-Luc and pKD-rPPARγ were co-transfected into CHO (dhfr-) cells (Chinese hamster ovary-derived cell dihydrofolate reductase-deficient strain) using Lipofectamine (Invitrogen). A stable transformant that retains pPPRE-Luc and pKD-rPPARγ by culturing cells in DMEM medium (Dulbecco's Modified Eagle Medium, Gibco) containing dialyzed fetal calf serum (Gibco) containing almost no thymidine (CHO / PPARγ / PPRE) was obtained.
上記細胞を96穴培養プレートに1x104 Cells/well となるように播種し、37℃、5% CO2条件下で24時間培養した。培地には、10% FBS(ウシ胎仔血清;Equitech−Bio社)、0.3g/l−Glutamine(日水製薬)、10ml/l MEM用非必須アミノ酸溶液(大日本住友製薬)を含むDMEM(日水製薬)を用いた。24時間培養後、試験物を含む培地に交換し、24時間培養した。溶媒対照にはジメチルスルホキシドを用い、培地に1/100量添加した。細胞をリン酸緩衝生理食塩水(PBS−)で洗浄した後、細胞溶解液(Cell Culture Lysis Reagent:Promega社)で細胞を溶解させ、Luciferase Assay Reagent(Promega社)を添加してマルチラベルカウンター(Wallac社)にてルシフェラーゼの発光強度を測定した。また、PPARγの合成アゴニストであるシグリチゾン(Ciglitizone)(Sigma社、濃度25μM)をポジティブコントロールとして用いた。リガンド活性の評価は、コントロール(溶媒対照)の発光強度に対する試験物の発光強度の比を試験物のPPARγリガンド活性発光度比とし、1.3以上を示したものについて、PPARγのリガンド活性があると判断した。 The cells were seeded in a 96-well culture plate at 1 × 10 4 Cells / well and cultured at 37 ° C. and 5% CO 2 for 24 hours. The medium includes 10% FBS (fetal calf serum; Equitech-Bio), 0.3 g / l-Glutamine (Nissui Pharmaceutical), 10 ml / l MEM containing a non-essential amino acid solution for MEM (Dainippon Sumitomo Pharma) Nissui Pharmaceutical) was used. After culturing for 24 hours, the medium was replaced with a medium containing the test substance, and cultured for 24 hours. Dimethyl sulfoxide was used as a solvent control, and 1/100 amount was added to the medium. After the cells were washed with phosphate buffered saline (PBS-), the cells were lysed with a cell lysis solution (Cell Culture Lysis Reagent: Promega), Luciferase Assay Reagent (Promega) was added, and a multi-label counter (Promega) was added. The luminescence intensity of luciferase was measured by Wallac). In addition, ciglitisone (Sigma, concentration 25 μM), a synthetic agonist of PPARγ, was used as a positive control. Evaluation of the ligand activity is based on the ratio of the luminescence intensity of the test substance to the luminescence intensity of the control (solvent control) as the PPARγ ligand activity luminescence intensity ratio of the test article. It was judged.
実施例2 PPARδリガンド活性の測定方法
HepG2細胞(ヒト肝臓癌由来の培養細胞)を96穴培養プレートに1x104 cells/wellとなるように播種し、37℃、5% CO2条件下で24時間培養した。培地には、10% FBS(ウシ胎仔血清;Equitech−Bio社)、0.3g/l L−Glutamine(日水製薬)を含むRPMI1640(日水製薬)を用いた。その細胞をOPTI−MEM(Gibco社)で洗浄した後、pBIND/GAL4::mPPARδとpG5luc(Promega社)を用いてトランスフェクションした。なお、pBIND/GAL4::mPPARδは、酵母由来転写因子GAL4融合タンパク発現プラズミドであるpBIND(Promega社)にマウスPPARδ遺伝子を挿入したプラスミドであり、pG5lucはルシフェラーゼ遺伝子の上流にGAL4の応答配列(UAS)を5回組み込んだレポーター・プラスミドである(Cell,1995年,83巻,803〜812頁などに記載の方法で作成可能)。トランスフェクションの約24時間後、試験物を含む培地に交換し、24時間培養した。溶媒対照にはジメチルスルホキシドを用い、培地に1/100量添加した。細胞をリン酸緩衝生理食塩水(PBS−)で洗浄した後、細胞溶解液(Cell Culture Lysis Reagent:Promega社)で細胞を溶解させ、Luciferase Assay Reagent(Promega社)を添加してマルチラベルカウンター(Wallac社)にてルシフェラーゼの発光強度を測定した。また、PPARδの合成アゴニストであるL−165041(Sigma社、濃度25μM)をポジティブコントロールとして用いた。リガンド活性の評価は、コントロール(溶媒対照)の発光強度に対する試験物の発光強度の比を試験物のPPARδリガンド活性発光度比とし、1.3以上を示したものについて、PPARδのリガンド活性があると判断した。
Example 2 Method for Measuring PPARδ Ligand Activity HepG2 cells (cultured cells derived from human liver cancer) were seeded in a 96-well culture plate so as to be 1 × 10 4 cells / well, and the condition was maintained at 37 ° C. and 5% CO 2 for 24 hours. Cultured. RPMI1640 (Nissui Pharmaceutical) containing 10% FBS (fetal bovine serum; Equitech-Bio), 0.3 g / l L-Glutamine (Nissui Pharmaceutical) was used as the medium. The cells were washed with OPTI-MEM (Gibco) and then transfected with pBIND / GAL4 :: mPPARδ and pG5luc (Promega). PBIND / GAL4 :: mPPARδ is a plasmid in which the mouse PPARδ gene is inserted into pBIND (Promega), a yeast-derived transcription factor GAL4 fusion protein expression plasmid, and pG5luc is a GAL4 response element (UAS) upstream of the luciferase gene. ) Is incorporated 5 times (can be prepared by the method described in Cell, 1995, 83, 803-812, etc.). About 24 hours after transfection, the medium was replaced with a medium containing the test substance and cultured for 24 hours. Dimethyl sulfoxide was used as a solvent control, and 1/100 amount was added to the medium. After washing the cells with phosphate buffered saline (PBS-), the cells were lysed with a cell lysis solution (Cell Culture Lysis Reagent: Promega), Luciferase Assay Reagent (Promega) was added, and a multi-label counter (Promega) was added. The luminescence intensity of luciferase was measured by Wallac). Moreover, L-165041 (Sigma, concentration 25 μM), which is a synthetic agonist of PPARδ, was used as a positive control. Evaluation of the ligand activity is based on the ratio of the luminescence intensity of the test substance to the luminescence intensity of the control (solvent control) as the PPARδ ligand activity luminescence intensity ratio of the test article. It was judged.
実施例3 PPARαリガンド活性の測定方法
実施例2に記載の方法のうち、融合タンパク発現プラスミドとして、pBIND/GAL4::mPPARδの代わりに、pBIND/GAL4::mPPARαを用いる以外は、実施例2と同様に実施し、PPARαリガンド活性の測定を行った。なお、pBIND/GAL4::mPPARαとは、pBIND(Promega社)にマウスPPARα遺伝子を挿入したプラスミドである。また、PPARαの合成アゴニストであるWY−14643(Sigma社、濃度25μM)をポジティブコントロールとして用いた。リガンド活性の評価は、コントロール(溶媒対照)の発光強度に対する試験物の発光強度の比を試験物のPPARαリガンド活性発光度比とし、1.3以上を示したものについて、PPARαのリガンド活性があると判断した。
Example 3 Method for Measuring PPARα Ligand Activity Of the methods described in Example 2, except that pBIND / GAL4 :: mPPARα is used instead of pBIND / GAL4 :: mPPARδ as a fusion protein expression plasmid, In the same manner, PPARα ligand activity was measured. Note that pBIND / GAL4 :: mPPARα is a plasmid in which the mouse PPARα gene is inserted into pBIND (Promega). Moreover, WY-14463 (Sigma, concentration 25 μM), which is a synthetic agonist of PPARα, was used as a positive control. The evaluation of the ligand activity is based on the ratio of the luminescence intensity of the test substance to the luminescence intensity of the control (solvent control) as the PPARα ligand activity luminescence intensity ratio of the test article. It was judged.
実施例4 試験物のPPARリガンド活性
植物420種の乾燥物をそれぞれ破砕し、破砕物1gに対して10倍量の70容量%エタノールに浸し、室温下、1日1回撹拌操作を加えて7日間抽出した。遠心分離後の上澄みを減圧濃縮後、凍結乾燥し、抽出物を得た。抽出物をジメチルスルホキシドに溶かして10mg/mlとし、実施例1−3の方法に従ってPPARリガンド活性を測定した。セイヨウニワトコ(Sambucus nigra L.(花))、アギタケ(Pleurotus ferulae(子実体))、アシュワガンダ(Withania somnifera Dunal(根))、アニス(Pimpinella anisum L.(種子))、ギョリュウモドキ(Calluna vulgaris(L.)Hull.(花))、サクナ(Peucedanum japonicum Thunb.(地上部))、セイヨウサンザシ(Crataegus monogyna Jaquin emend.Lindman(果実))、セキガイチャ(Adinandra nitida(葉))、タワシヘチマ(Luffa cylindrica L.(果実))、チャボトケイソウ(Passiflora incarnate L.(地上部))、トカドヘチマ(Luffa acutangula Roxb.(果実))、ハリエンジュ(Robinia pseudoacacia L.(花))、マンシュウウコギ(Acanthopanax sessiliflorus(Rupr.et Maxim.)Seem.(葉))に活性が認められた。中でも、トカドヘチマ抽出物が活性スペクトル上、とくに優れていた。結果を表1に示す。
Example 4 420 dry samples of PPAR ligand-active plants as test samples were each crushed, soaked in 10 volumes of 70% by volume ethanol with respect to 1 g of the crushed product, and stirred at room temperature once a day to add 7 Extracted for days. The supernatant after centrifugation was concentrated under reduced pressure and lyophilized to obtain an extract. The extract was dissolved in dimethyl sulfoxide to 10 mg / ml, and PPAR ligand activity was measured according to the method of Example 1-3. Sambucus nigra (Sambucus nigra L. (flower)), Agitake (Pleurotus ferulae (fruiting bodies)), Ashwagandha (Withania somnifera Dunal (root)), anise (Pimpinella anisum L. (seed)), Calluna (Calluna vulgaris (L .) Hull. (Hana)), Peucedanum japonicum (Peucedanum japonicum Thunb. (above-ground part)), hawthorn (Crataegus monogyna Jaquin emend.Lindman (fruit)), Adinandra nitida (Adinandra nitida (leaf)), Tawashihechima (Luffa cylindrica L. (fruit)), passiflora passion flower (passiflora in arnate L. (above-ground)), Luffa Acutangula (Luffa acutangula Roxb. (fruit)), locust (Robinia pseudoacacia L. (flower)), Man Shu Acanthopanax (Acanthopanax sessiliflorus (Rupr.et Maxim.) Seem. to (leaves)) Activity was observed. Among them, the tocadohetima extract was particularly excellent on the activity spectrum. The results are shown in Table 1.
実施例5 トカドヘチマ抽出物の部位の違いによるPPARリガンド活性
236(ID2380)未熟果実(9月収穫)、421(ID2379)根、茎、葉(9月収穫)、433(ID4715)根、茎、葉(10月下旬収穫)の乾燥物をブレンダー(ラボミルサーLM−PLUS,大阪ケミカル株式会社製)で粉砕後、15gに5倍量のメタノールを添加し、室温で一週間浸漬した。東洋ろ紙No.2で吸引ろ過し、ろ液を減圧乾固し、抽出物を得た。固形分回収率は、それぞれ6.2%、4.1%、3.1%であった。抽出物をジメチルスルホキシドに溶かして10mg/mlとし、実施例1−3の方法に従ってPPARリガンド活性を測定した。結果を表2〜4及び図1〜3に示す。
Example 5 PPAR Ligand Activity 236 (ID2380) Immature Fruit (September Harvest), 421 (ID2379) Root, Stem, Leaf (September Harvest), 433 (ID4715) Root, Stem, Leaf The dried product (harvested in late October) was pulverized with a blender (Lab Miller LM-PLUS, manufactured by Osaka Chemical Co., Ltd.), 5 times the amount of methanol was added to 15 g, and the mixture was immersed at room temperature for one week. Toyo Filter Paper No. The mixture was suction filtered through 2, and the filtrate was dried under reduced pressure to obtain an extract. The solid content recovery rates were 6.2%, 4.1%, and 3.1%, respectively. The extract was dissolved in dimethyl sulfoxide to 10 mg / ml, and PPAR ligand activity was measured according to the method of Example 1-3. The results are shown in Tables 2 to 4 and FIGS.
最大用量の100μg/mlでは細胞障害性を示したが、根・茎・葉および未熟果実にほぼ同等の活性が観察された。
実施例6 トカドヘチマ抽出物の抽出溶媒の違いによるPPARリガンド活性
トカドヘチマ乾燥物をブレンダーで粉砕後、熱水、70容量%エタノール、メタノールの3種類の溶媒で抽出した。抽出条件(固形分収率)は、熱水:10倍量、80℃、30分(28%)、70容量%エタノール:10倍量、室温一週間(21%)、メタノール:5倍量、室温一週間(6%)である。得られた乾燥抽出物をジメチルスルホキシドに溶かして10mg/mlとし、実施例1−3の方法に従ってPPARリガンド活性を測定した。結果を表5〜7及び図4〜6に示す。
The maximum dose of 100 μg / ml showed cytotoxicity, but almost the same activity was observed in roots, stems, leaves and immature fruits.
Example 6 PPAR Ligand-Activated Tocadohetima Dried Product Due to Difference in Extraction Solvent of Tocadohetima Extract After pulverizing with a blender, it was extracted with three kinds of solvents: hot water, 70 vol% ethanol, and methanol. Extraction conditions (solid content yield) are as follows: hot water: 10 times, 80 ° C., 30 minutes (28%), 70 vol% ethanol: 10 times, room temperature for one week (21%), methanol: 5 times, Room temperature for one week (6%). The obtained dried extract was dissolved in dimethyl sulfoxide to 10 mg / ml, and PPAR ligand activity was measured according to the method of Example 1-3. The results are shown in Tables 5 to 7 and FIGS.
実施例7 トカドヘチマ抽出物の抽出条件の違いによるPPARリガンド活性
トカドヘチマ乾燥物をブレンダーで粉砕後、2gに対して10倍量の含水量の異なるエタノール(10容量%、30容量%、50容量%、70容量%、90容量%エタノール)を添加し、室温で抽出した。1日後、3日後、5日後、7日後に遠心分離し、抽出液を得た。それぞれの抽出液を減圧濃縮、凍結乾燥し、固形分を得た。70容量%エタノール、7日間浸漬条件の固形分抽出効率(17.6%)を1.00とした相対抽出効率を求めた。結果を表8に示す。また、得られた乾燥抽出物をジメチルスルホキシドに溶かして50mg/mlとし、実施例1−3の方法に従ってPPARリガンド活性を測定した。結果を表9〜11に示す。
Example 7 PPAR Ligand-Activated Tocadohetima Dried Product Due to Differences in Extraction Conditions of Tocadohetima Extract After grinding with a blender, ethanol (10 vol%, 30 vol%, 50 vol%, 70 volume%, 90 volume% ethanol) was added and extracted at room temperature. Centrifugation was performed after 1 day, 3 days, 5 days, and 7 days to obtain an extract. Each extract was concentrated under reduced pressure and lyophilized to obtain a solid content. The relative extraction efficiency was determined with a solid content extraction efficiency (17.6%) of 70 vol% ethanol and 7 days immersion conditions being 1.00. The results are shown in Table 8. Further, the obtained dried extract was dissolved in dimethyl sulfoxide to give 50 mg / ml, and PPAR ligand activity was measured according to the method of Example 1-3. The results are shown in Tables 9-11.
実施例8
成分の分画
トカドヘチマのメタノールエキス310mgにメタノール4mlを添加した試料をBond−Elut−C8 1ml(Varians社)5本に分けて負荷し、それぞれメタノール2ml、アセトニトリル1mlで溶出し、湿重量290mgを得た。この前処理ののち、ジメチルスルホキシド200μl、メタノール100μlを添加した試料をパックドカラムに付し、5ml/0.5分ずつ採取した。結果を図7に示す。
Example 8
A sample obtained by adding 4 ml of methanol to 310 mg of the component fraction Tocadochema methanol extract was loaded into 5 parts of Bond-Elut-C8 (Varians) and eluted with 2 ml of methanol and 1 ml of acetonitrile, respectively, to obtain a wet weight of 290 mg. It was. After this pretreatment, a sample to which 200 μl of dimethyl sulfoxide and 100 μl of methanol were added was applied to a packed column and sampled at a rate of 5 ml / 0.5 minutes. The results are shown in FIG.
分取条件
システム:Gilson(登録商標)305型および303型
カラム:DevelosilTM C30−UG−5(20*250mm+20*50mm、野村化学株式会社製)
移動相:A:蒸留水、B:アセトニトリル
プログラム:0分(0% B)、76分(100% B)、114分(100% B)
流速:10ml/分
検出波長:280nm
フラクションコレクター:Gilson(登録商標) FC204型
実施例9 分画物のPPARリガンド活性測定
実施例8で得られたフラクション81−130から各々200μl採取し、減圧濃縮してジメチルスルホキシド100μlに再溶解した。実施例1−3の方法にしたがって測定した結果、フラクション93、94、124―127に活性が認められた(図8)。
Preparative conditions System: Gilson <(R)> 305 and 303 columns: Develosil < TM > C30-UG-5 (20 * 250 mm + 20 * 50 mm, manufactured by Nomura Chemical Co., Ltd.)
Mobile phase: A: distilled water, B: acetonitrile program: 0 min (0% B), 76 min (100% B), 114 min (100% B)
Flow rate: 10 ml / min Detection wavelength: 280 nm
Fraction collector: Gilson (registered trademark) FC204 type
Example 9 Measurement of PPAR Ligand Activity of Fractions 200 μl of each fraction was collected from fractions 81-130 obtained in Example 8, concentrated under reduced pressure, and redissolved in 100 μl of dimethyl sulfoxide. As a result of measurement according to the method of Example 1-3, the activity was recognized in fractions 93, 94, and 124-127 (FIG. 8).
実施例10 成分のPPARリガンド活性
実施例8で得られた活性画分のうち、フラクション93、94、および124、125の用量反応性を実施例1−3の方法にしたがって測定した。結果を表12および図9〜12に示す。活性を示す最大有効希釈倍率はフラクション93、94では1300倍、124、125では12000倍であった。アッセイ時に用いた試料はフラクションを2倍濃縮したものなので、もとの試料ではそれぞれ650倍、6000倍希釈となる。該当フラクションを減圧濃縮、凍結乾燥し、得られた重量が0.2mgであることを考慮すると、有効濃度は、
フラクション93、94:0.2mg/10ml/650=0.00003mg/ml=0.03μg/ml
フラクション124、125:0.2mg/10ml/6000=0.000003mg/ml=0.003μg/ml
Example 10 PPAR Ligand Activity of Components Of the active fraction obtained in Example 8, the dose responsiveness of fractions 93, 94, and 124, 125 was measured according to the method of Example 1-3. The results are shown in Table 12 and FIGS. The maximum effective dilution factor showing activity was 1300 times for fractions 93 and 94, and 12000 times for 124 and 125. Since the sample used at the time of the assay is a fraction concentrated twice, the original sample is diluted 650 times and 6000 times, respectively. Considering that the relevant fraction is concentrated under reduced pressure and lyophilized and the weight obtained is 0.2 mg, the effective concentration is
Fraction 93, 94: 0.2 mg / 10 ml / 650 = 0.00003 mg / ml = 0.03 μg / ml
Fraction 124, 125: 0.2 mg / 10 ml / 6000 = 0.000003 mg / ml = 0.003 μg / ml
実施例11 精製物の活性
実施例8で得られたフラクョン124,125をDevelosilTM C30−UG−5に付し、50V/V%アセトニトリル−0.1%ギ酸で溶出し、化合物A(RはH)を得た(図15)。また、実施例8で得られたフラクョン93,94をDevelosilTM C30−UG−5に付し、30V/V%アセトニトリル−0.1%ギ酸で溶出し、化合物B(RはGlc)を得た(図16)。化合物A(RはH)の極大吸収は251nmおよび304nm、化合物B(RはGlc)の極大吸収は256nmおよび304nmであった(図13,14)。PPARリガンド活性を測定した結果を表13に示す。
Example 11 Activity of Purified Product Fractions 124 and 125 obtained in Example 8 were subjected to Develosil ™ C30-UG-5 and eluted with 50 V / V% acetonitrile-0.1% formic acid to obtain compound A (R is H) was obtained (FIG. 15). Further, fractions 93 and 94 obtained in Example 8 were subjected to Develosil ™ C30-UG-5 and eluted with 30 V / V% acetonitrile-0.1% formic acid to obtain compound B (R is Glc). (FIG. 16). The maximum absorption of Compound A (R is H) was 251 nm and 304 nm, and the maximum absorption of Compound B (R was Glc) was 256 nm and 304 nm (FIGS. 13 and 14). The results of measuring the PPAR ligand activity are shown in Table 13.
糖部分の無い物質(アグリコン)よりも配糖体の方が吸収されやすいことが知られている。例えば、ケルセチン配糖体の方が糖部分のないケルセチンよりも生物学的利用率が高いことが知られている(Free Radic. Res. 31(6):569−573; 1999)。また、糖部分の無い物質(アグリコン)よりも配糖体の方が極性が高く、より水に溶けやすいという性質を有する。これらの性質からも、化合物Bは優れたPPARリガンド剤であるといえる。 It is known that glycosides are more easily absorbed than substances without sugar moieties (aglycones). For example, it is known that quercetin glycoside has a higher bioavailability than quercetin without a sugar moiety (Free Radic. Res. 31 (6): 569-573; 1999). In addition, glycosides are more polar than substances without a sugar moiety (aglycone), and are more soluble in water. From these properties, it can be said that Compound B is an excellent PPAR ligand agent.
実施例12 精製物の質量分析
Q−TOF Premier(Micromass社製、UK)を用いて、以下の条件で精密質量分析(LC−MSおよびLC−MS/MS)を行った;
カラム:DevelosilTM C30−UG−5(3mm*150mm、野村化学株式会社製)、カラム温度:40℃
移動相:50V/V%アセトニトリル−0.1%ギ酸、流速:0.25ml/分
イオン化法:ESI、イオンソース;Z−スプレー
Capillary voltage:2.7kV(ネガティブ、Vモード)、3.0kV(ポジティブ、Vモード、)
Cone voltage:
38V{ネガティブモード、化合物A(RはH)のMSおよび化合物A(RはH)のm/z 267.07のMS/MS測定時}
40V{ポジティブモード、化合物A(RはH)のMSおよび化合物A(RはH)のm/z 269.08のMS/MS測定時}
24V{ネガティブモード、化合物B(RはGlc)のMS測定時}
20V{ネガティブモード、化合物B(RはGlc)のm/z 429.12のMS/MS測定時}
Collision energy:
20−30eV{ネガティブモード、化合物A(RはH) の m/z 267.07のMS/MS測定時}
25−30eV{ポジティブモード、化合物A(RはH) の m/z 269.08のMS/MS測定時}
20 eV{ネガティブモード、化合物B(RはGlc) の m/z 429.12のMS/MS測定時}
Source Temp:100℃(ネガティブモード、ポジティブモード)
Desolvation Temp:300℃(ネガティブモード、ポジティブモード)
ロックスプレーによる質量補正を行い、リファレンスにはロイシンエンケファリン(m/z 554.2615(ネガティブモード)、m/z 556.2771(ポジティブモード))を用いた。
<化合物A>(RはH)
ネガティブモード:
MS:m/z 267.0650[M−H]−、C16H11O4(理論m/z 267.0657、誤差―2.6ppm)
MS/MS(プレカーサーイオン m/z 267.07):
フラグメントイオン m/z 208.0526、m/z 223.0756
ポジティブモード:
MS:m/z 269.0808[M+H]+、C16H13O4(理論m/z 269.0814、誤差−2.2ppm)
MS/MS(プレカーサーイオンm/z 269.08):
フラグメントイオンm/z 165.0703、m/z 181.0656、
m/z 195.0800、m/z 209.0606、m/z 223.0760、m/z 241.0858
<化合物B>(RはGlc)
ネガティブモード:
MS:m/z 429.1185[M−H]−、C22H21O9(理論m/z 429.1186、誤差−0.2ppm)
MS/MS(プレカーサーイオン m/z 429.12):
フラグメントイオン m/z 223.0756、m/z 267.0640
ポジティブモードの精密質量のMSとMS/MSは分析せず。
Example 12 Mass Spectrometry of Purified Product Using Q-TOF Premier (Micromass, UK), accurate mass spectrometry (LC-MS and LC-MS / MS) was performed under the following conditions;
Column: Develosil ™ C30-UG-5 (3 mm * 150 mm, manufactured by Nomura Chemical Co., Ltd.), column temperature: 40 ° C.
Mobile phase: 50 V / V% acetonitrile-0.1% formic acid, flow rate: 0.25 ml / min Ionization method: ESI, ion source; Z-spray Capillary voltage: 2.7 kV (negative, V mode), 3.0 kV ( Positive, V mode,)
Cone voltage:
38 V {negative mode, MS of compound A (R is H) and MS / MS of compound A (R is H) m / z 267.07}
40V {positive mode, MS of compound A (R is H) and MS / MS of compound A (R is H) m / z 269.08}
24V {Negative mode, MS measurement of compound B (R is Glc)}
20 V {in negative mode, MS / MS measurement of m / z 429.12 of compound B (R is Glc)}
Collision energy:
20-30 eV {in negative mode, MS / MS measurement of m / z 267.07 of compound A (R is H)}
25-30 eV {positive mode, compound A (R is H) m / z 269.08 MS / MS measurement}
20 eV {negative mode, Compound B (R is Glc) m / z 429.12 MS / MS measurement}
Source Temp: 100 ° C (negative mode, positive mode)
Desolation Temp: 300 ° C (negative mode, positive mode)
The mass was corrected by rock spray, and leucine enkephalin (m / z 554.2615 (negative mode), m / z 556.2771 (positive mode)) was used as a reference.
<Compound A> (R is H)
Negative mode:
MS: m / z 267.0650 [M−H] − , C 16 H 11 O 4 (theoretical m / z 267.0657, error −2.6 ppm)
MS / MS (Precursor ion m / z 267.07):
Fragment ions m / z 208.0526, m / z 223.0756
Positive mode:
MS: m / z 269.0808 [M + H] + , C 16 H 13 O 4 (theoretical m / z 269.814, error −2.2 ppm)
MS / MS (Precursor ion m / z 269.08):
Fragment ion m / z 165.0703, m / z 181.0656,
m / z 195.0800, m / z 209.0606, m / z 223.0760, m / z 241.0858
<Compound B> (R is Glc)
Negative mode:
MS: m / z 429.1185 [M−H] − , C 22 H 21 O 9 (theoretical m / z 429.1186, error −0.2 ppm)
MS / MS (Precursor ion m / z 429.12):
Fragment ions m / z 223.0756, m / z 267.0640
MS and MS / MS of positive mass in positive mode are not analyzed.
実施例13 構造解析
実施例11で得られた化合物A,化合物Bの試料をメタノール−D4に溶解し、溶媒を内部標準として、DMX−750 spectrometer(BRUKER BIOSPIN, Germany)を用いて測定した。測定項目は1H NMR、1H{13C}−HSQC、1H{13C}−HMBC、TOCSY、DQF−COSY、NOESYおよびROESYである。
化合物A(RはH): 2−(4−methoxyphenyl)benzofuran−5−carboxylic acid
δH(Hz):8.18(C−4H,1H、d、J=1.4)、7.92(C−6H,1H、dd、J=8.5,1.4)、7.83(C−2‘H,C−6’H、2H、d、J=8.8)、7.43(C−7H,1H、d、J=8.5)、7.06(C−3H,1H、s)、7.02(C−3‘H,C−5’H,2H、d、J=8.8)、3.86(C−4’−OCH3、3H、s)
δC: 157.6(C2)、101.1(C3)、134.4(C3a)、123.4(C4),130.4(C5)、126.7(C6)、110.5(C7)、157.4(C7a)、167.9(C8)、124.5(C1‘)、127.4(C2’,C6‘)、115(C3’,C5‘)、161.7(C4’)、56(C4‘−OCH3)
化合物B(RはGlc): 5−[(β−D−glucopyranosyloxy)carbonyl]−2−(4−methoxyphenyl)benzofuran
GlcのC−1位の水素(C−1”H、δH5.75)とカルボキシル基の炭素(C−8、δc167)とのつながりを示す1H{13C}−HMBCスペクトルデータから、GlcのC−1位のOHが結合していると結論した。また、グルコース C−1位の水素(C−1”H、δH5.75)の結合定数、J=8.1 Hzであることから、β結合であることが分かった。
δH(Hz):8.37(C−4H,1H、d、J=1.7)、8.04(C−,1H、dd、J=8.6,1.7)、7.86(C−2‘H,C−6’H,2H、d、J=8.8)、7.60(C−7H,1H、d、J=8.6)、7.14(C−3H,1H、s)、7.04(C−3‘H,C−5’H,2H、d、J=8.8)、3.56(C4’−OCH3,3H、s); 5.75(C−1“H,1H、d、J=8.1)、3.87(C−6”H,1H、dd、J=12.3、2.0)、3.72(C−6“H,1H、dd、J=12.3、5.2)、3.55(C−2”H,1H、dd、J=9.1、8.1)、3.51(C−3“H、1H、J=9.1、8.7)、3.47(C−5”H、1H、m)、3.43(C−4“H、1H、dd、J=9.6、8.7)
δC:159.5(C2)、101(C3)、131(C3a)、124.5(C4),126(C5)、127(C6)、112(C7)、159(C7a)、167(C8)、124(C1‘)、128(C2’,C6‘)、116(C3’,C5‘)、162(C4’)、56(C4‘−OCH3);96(C1“)、74(C2”)、78(C3“)、71(C4”)、79(C5“)、62.4(C6”)
Example 13 Structural Analysis Example Compound obtained in 11 A, a sample of compound B was dissolved in methanol -D 4, the solvent as internal standard, was measured using a DMX-750 spectrometer (BRUKER BIOSPIN, Germany). Measurement items are 1 H NMR, 1 H { 13 C} -HSQC, 1 H { 13 C} -HMBC, TOCSY, DQF-COSY, NOESY, and ROESY.
Compound A (R is H) : 2- (4-methoxyphenyl) benzofuran-5-carboxylic acid
δ H (Hz): 8.18 (C-4H, 1H, d, J = 1.4), 7.92 (C-6H, 1H, dd, J = 8.5, 1.4), 7. 83 (C-2′H, C-6′H, 2H, d, J = 8.8), 7.43 (C-7H, 1H, d, J = 8.5), 7.06 (C− 3H, 1H, s), 7.02 (C-3′H, C-5′H, 2H, d, J = 8.8), 3.86 (C-4′-OCH3, 3H, s)
δ C : 157.6 (C2), 101.1 (C3), 134.4 (C3a), 123.4 (C4), 130.4 (C5), 126.7 (C6), 110.5 (C7) ), 157.4 (C7a), 167.9 (C8), 124.5 (C1 ′), 127.4 (C2 ′, C6 ′), 115 (C3 ′, C5 ′), 161.7 (C4 ′) ), 56 (C4′-OCH3)
Compound B (R is Glc) : 5-[(β-D-glucopyranosyloxy) carbonyl] -2- (4-methoxyphenyl) benzofuran
From 1 H { 13 C} -HMBC spectrum data showing the connection between hydrogen at C-1 position of Glc (C-1 ″ H, δ H 5.75) and carbon of carboxyl group (C-8, δc 167), It was concluded that the OH at the C-1 position of Glc was bonded, and the binding constant of hydrogen at the C-1 position (C-1 ″ H, δ H 5.75) at J = 8.1 Hz. There was a β bond.
δ H (Hz): 8.37 (C-4H, 1H, d, J = 1.7), 8.04 (C-, 1H, dd, J = 8.6, 1.7), 7.86 (C-2′H, C-6′H, 2H, d, J = 8.8), 7.60 (C-7H, 1H, d, J = 8.6), 7.14 (C-3H , 1H, s), 7.04 (C-3′H, C-5′H, 2H, d, J = 8.8), 3.56 (C4′-OCH3, 3H, s); 5.75 (C-1 “H, 1H, d, J = 8.1), 3.87 (C-6” H, 1H, dd, J = 12.3, 2.0), 3.72 (C-6 “H, 1H, dd, J = 12.3, 5.2), 3.55 (C-2” H, 1H, dd, J = 9.1, 8.1), 3.51 (C-3 “H, 1H, J = 9.1, 8.7), 3.47 (C-5” H, 1H, m), 3.43 (C-4 “H, 1H, d) d, J = 9.6, 8.7)
δ C: 159.5 (C2), 101 (C3), 131 (C3a), 124.5 (C4), 126 (C5), 127 (C6), 112 (C7), 159 (C7a), 167 (C8 ), 124 (C1 ′), 128 (C2 ′, C6 ′), 116 (C3 ′, C5 ′), 162 (C4 ′), 56 (C4′-OCH3); 96 (C1 ″), 74 (C2 ″) ), 78 (C3 "), 71 (C4"), 79 (C5 "), 62.4 (C6")
本発明により、優れたPPARリガンド剤が提供され、肥満、肥満に伴うインスリン抵抗性、高脂血症、高血圧、糖尿病などの予防および/または改善に有効な飲食物、医薬品の形態であるPPARリガンド剤が提供される。 INDUSTRIAL APPLICABILITY According to the present invention, an excellent PPAR ligand agent is provided, and is a PPAR ligand that is in the form of food, beverage, or medicine effective in preventing and / or improving obesity, insulin resistance associated with obesity, hyperlipidemia, hypertension, diabetes, etc. An agent is provided.
Claims (4)
で表される化合物を含む、PPARα、δおよび/またはγのリガンド剤。 As an active ingredient, the formula (1):
A ligand agent for PPARα, δ and / or γ, which comprises a compound represented by:
で表される化合物。
Formula (1):
A compound represented by
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2009157200A JP5546807B2 (en) | 2009-07-01 | 2009-07-01 | PPAR ligand agent |
PCT/JP2010/060834 WO2011001913A1 (en) | 2009-07-01 | 2010-06-25 | Ppar ligand |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2009157200A JP5546807B2 (en) | 2009-07-01 | 2009-07-01 | PPAR ligand agent |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2011012011A JP2011012011A (en) | 2011-01-20 |
JP5546807B2 true JP5546807B2 (en) | 2014-07-09 |
Family
ID=43410989
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2009157200A Expired - Fee Related JP5546807B2 (en) | 2009-07-01 | 2009-07-01 | PPAR ligand agent |
Country Status (2)
Country | Link |
---|---|
JP (1) | JP5546807B2 (en) |
WO (1) | WO2011001913A1 (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW201309313A (en) * | 2011-02-14 | 2013-03-01 | Amino Up Chemical Co Ltd | Adiponectin production promoter, and pharmaceutical composition, food and drink, and fodder containing adiponectin production promoter |
JP2012171932A (en) * | 2011-02-23 | 2012-09-10 | Kao Corp | Aromatase activator |
JP6909569B2 (en) * | 2016-09-16 | 2021-07-28 | オリザ油化株式会社 | Skin quality improver |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20020010581A (en) * | 1999-03-11 | 2002-02-04 | 사단호진 산교 소죠켄큐쇼 | Novel ligands of nuclear receptors ppar's |
JP5248023B2 (en) * | 2007-01-31 | 2013-07-31 | ユニチカ株式会社 | Calcium absorption promoting composition |
TW200930369A (en) * | 2007-11-15 | 2009-07-16 | Astrazeneca Ab | Bis-(sulfonylamino) derivatives in therapy |
-
2009
- 2009-07-01 JP JP2009157200A patent/JP5546807B2/en not_active Expired - Fee Related
-
2010
- 2010-06-25 WO PCT/JP2010/060834 patent/WO2011001913A1/en active Application Filing
Also Published As
Publication number | Publication date |
---|---|
JP2011012011A (en) | 2011-01-20 |
WO2011001913A1 (en) | 2011-01-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5550365B2 (en) | Pharmacological composition of amachazul extract and damlin A, B | |
US20200055835A1 (en) | Use of tricyclic sesquiterpene lactones in the treatment of obesity and related diseases and non-therapeutic treatable conditions | |
Legault et al. | Antioxidant and anti-inflammatory activities of quercetin 7-O-β-D-glucopyranoside from the leaves of Brasenia schreberi | |
Křen et al. | Silybin and its congeners: From traditional medicine to molecular effects | |
KR20180079174A (en) | Composition comprising 3,5-dicaffeoylquinic acid or extract of chrysanthemum as an effective ingredient for preventing or treating of muscular disorder or improvement of muscular functions | |
Luyen et al. | Chemical constituents of Triticum aestivum and their effects on adipogenic differentiation of 3T3-L1 preadipocytes | |
Qin et al. | A new compound isolated from the reduced ribose–tryptophan maillard reaction products exhibits distinct anti-inflammatory activity | |
Lee et al. | Chemical constituents from the aerial parts of Aster koraiensis with protein glycation and aldose reductase inhibitory activities | |
KR20160139072A (en) | Pharmaceutical composition comprising Ptentilla Chinensis extract or isolated polyphenolic compounds for prevention or treatment of metabolic disease | |
Sung et al. | Bioassay-guided isolation of anti-adipogenic compounds from defatted pepper (Capsicum annuum L.) seeds | |
JP5546807B2 (en) | PPAR ligand agent | |
KR100743852B1 (en) | Glycoside having 4-methylergost-7-en-3-ol skeleton and drug for ameliorating hyperglycemia | |
JP6599592B2 (en) | α-Glucosidase activity inhibitor | |
KR101034624B1 (en) | Chalcone compounds as activators of DDAH promoter from Glycyrrhiza uralensis and compositions for prevention and treatment of islet cellular apoptosis and diabetic nephropathy containing the same as an active ingredient | |
KR100902338B1 (en) | A composition that is comprising extracts, fractions or isolated single compounds of Robinia pseudo?acacia var. umbraculifera | |
El-Mesallamy et al. | Reno-protective effect of methanolic extract of Stevia rebaudiana Bertoni and bioactive phenolic compounds in type-1-diabetes | |
KR20080059336A (en) | Food or drink for improving pancreatic functions | |
US11752187B2 (en) | Anti-obesity composition including Geumhwagyu extract as active ingredient | |
JP2004002231A (en) | Composition comprising rubrofusarin glycoside | |
KR101548605B1 (en) | Compositions comprising fractions of Panax ginseng or ginsenosides isolated therefrom for prevention or treatment of disease through activation of sirtuins | |
KR101715676B1 (en) | a novel compound (KS 513) isolated from the extract of Pseudolysimachion rotundum var. subintegrum and the composition comprising the same as an active ingredient for preventing or treating allergy disease, inflammatory disease, asthma or chronic obstructive pulmonary disease | |
JPWO2004045632A1 (en) | Peroxisome proliferator-responsive receptor ligand agent | |
KR101231583B1 (en) | Composition for Improving Obesity Using Effective Compounds Isolated from Wheat Bran | |
KR101630820B1 (en) | Pharmaceutical composition for blood vessel disease prevention or treatment comprising substance extracted from Hericium erinacium | |
KR101658515B1 (en) | A composition comprising extract of Platycodon grandiflorum or saponin compounds isolated therefrom for preventing vascular aging |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20111208 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20130702 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130823 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20130910 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20131106 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20131122 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140206 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20140325 |
|
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: 20140415 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20140514 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5546807 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 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
LAPS | Cancellation because of no payment of annual fees |