JP7398207B2 - Toxic AGEs generation inhibitor - Google Patents
Toxic AGEs generation inhibitor Download PDFInfo
- Publication number
- JP7398207B2 JP7398207B2 JP2019094423A JP2019094423A JP7398207B2 JP 7398207 B2 JP7398207 B2 JP 7398207B2 JP 2019094423 A JP2019094423 A JP 2019094423A JP 2019094423 A JP2019094423 A JP 2019094423A JP 7398207 B2 JP7398207 B2 JP 7398207B2
- Authority
- JP
- Japan
- Prior art keywords
- production
- tage
- age
- toxic
- ages
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 231100000331 toxic Toxicity 0.000 title claims description 60
- 230000002588 toxic effect Effects 0.000 title claims description 60
- 239000003112 inhibitor Substances 0.000 title claims description 52
- 238000004519 manufacturing process Methods 0.000 claims description 118
- 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 claims description 53
- -1 quercetin glycoside Chemical class 0.000 claims description 49
- 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 claims description 48
- 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 claims description 48
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 claims description 48
- 235000005875 quercetin Nutrition 0.000 claims description 48
- 229960001285 quercetin Drugs 0.000 claims description 48
- PFPQMWRASYNLMZ-LGIMBNBCSA-N 2-(3,4-dihydroxyphenyl)-3-[(2s,3r,4r,5s,6r)-3,4-dihydroxy-5-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2r,3r,4r,5r,6s)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxy-5,7-dihydroxychromen-4-one Chemical group O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1OC[C@@H]1[C@@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](O)[C@H](OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 PFPQMWRASYNLMZ-LGIMBNBCSA-N 0.000 claims description 44
- 229930182470 glycoside Natural products 0.000 claims description 44
- WGCNASOHLSPBMP-UHFFFAOYSA-N Glycolaldehyde Chemical compound OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 42
- JMGZEFIQIZZSBH-UHFFFAOYSA-N Bioquercetin Natural products CC1OC(OCC(O)C2OC(OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5)C(O)C2O)C(O)C(O)C1O JMGZEFIQIZZSBH-UHFFFAOYSA-N 0.000 claims description 38
- MNQZXJOMYWMBOU-VKHMYHEASA-N D-glyceraldehyde Chemical compound OC[C@@H](O)C=O MNQZXJOMYWMBOU-VKHMYHEASA-N 0.000 claims description 18
- 102000008186 Collagen Human genes 0.000 claims description 10
- 108010035532 Collagen Proteins 0.000 claims description 10
- 229920001436 collagen Polymers 0.000 claims description 10
- 102000009027 Albumins Human genes 0.000 claims description 5
- 108010088751 Albumins Proteins 0.000 claims description 5
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 claims description 3
- 238000012360 testing method Methods 0.000 description 38
- 235000013305 food Nutrition 0.000 description 28
- 230000002401 inhibitory effect Effects 0.000 description 28
- 210000004369 blood Anatomy 0.000 description 22
- 239000008280 blood Substances 0.000 description 22
- 230000000694 effects Effects 0.000 description 22
- 239000000203 mixture Substances 0.000 description 22
- 102000004169 proteins and genes Human genes 0.000 description 21
- 108090000623 proteins and genes Proteins 0.000 description 21
- 102000008100 Human Serum Albumin Human genes 0.000 description 19
- 108091006905 Human Serum Albumin Proteins 0.000 description 19
- 238000000034 method Methods 0.000 description 19
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- 235000005493 rutin Nutrition 0.000 description 18
- IVTMALDHFAHOGL-UHFFFAOYSA-N eriodictyol 7-O-rutinoside Natural products OC1C(O)C(O)C(C)OC1OCC1C(O)C(O)C(O)C(OC=2C=C3C(C(C(O)=C(O3)C=3C=C(O)C(O)=CC=3)=O)=C(O)C=2)O1 IVTMALDHFAHOGL-UHFFFAOYSA-N 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 17
- FDRQPMVGJOQVTL-UHFFFAOYSA-N quercetin rutinoside Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 FDRQPMVGJOQVTL-UHFFFAOYSA-N 0.000 description 17
- IKGXIBQEEMLURG-BKUODXTLSA-N rutin Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@@H]1OC[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 IKGXIBQEEMLURG-BKUODXTLSA-N 0.000 description 17
- ALABRVAAKCSLSC-UHFFFAOYSA-N rutin Natural products CC1OC(OCC2OC(O)C(O)C(O)C2O)C(O)C(O)C1OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5 ALABRVAAKCSLSC-UHFFFAOYSA-N 0.000 description 17
- 229960004555 rutoside Drugs 0.000 description 17
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 16
- 239000003814 drug Substances 0.000 description 16
- 239000008103 glucose Substances 0.000 description 16
- 201000010099 disease Diseases 0.000 description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 15
- 239000000047 product Substances 0.000 description 13
- 229940079593 drug Drugs 0.000 description 12
- 239000002994 raw material Substances 0.000 description 12
- 150000001720 carbohydrates Chemical class 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- 108090000790 Enzymes Proteins 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 8
- OVSQVDMCBVZWGM-IDRAQACASA-N Hirsutrin Natural products O([C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1)C1=C(c2cc(O)c(O)cc2)Oc2c(c(O)cc(O)c2)C1=O OVSQVDMCBVZWGM-IDRAQACASA-N 0.000 description 8
- FVQOMEDMFUMIMO-UHFFFAOYSA-N Hyperosid Natural products OC1C(O)C(O)C(CO)OC1OC1C(=O)C2=C(O)C=C(O)C=C2OC1C1=CC=C(O)C(O)=C1 FVQOMEDMFUMIMO-UHFFFAOYSA-N 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
- OVSQVDMCBVZWGM-QSOFNFLRSA-N quercetin 3-O-beta-D-glucopyranoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C(C=2C=C(O)C(O)=CC=2)OC2=CC(O)=CC(O)=C2C1=O OVSQVDMCBVZWGM-QSOFNFLRSA-N 0.000 description 8
- 238000009472 formulation Methods 0.000 description 7
- GXMWXESSGGEWEM-UHFFFAOYSA-N isoquercitrin Natural products OCC(O)C1OC(OC2C(Oc3cc(O)cc(O)c3C2=O)c4ccc(O)c(O)c4)C(O)C1O GXMWXESSGGEWEM-UHFFFAOYSA-N 0.000 description 7
- 239000002537 cosmetic Substances 0.000 description 6
- 230000003247 decreasing effect Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 5
- 238000002965 ELISA Methods 0.000 description 5
- 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 5
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 description 5
- 102000007562 Serum Albumin Human genes 0.000 description 5
- 108010071390 Serum Albumin Proteins 0.000 description 5
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical compound NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- 230000036252 glycation Effects 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 235000000346 sugar Nutrition 0.000 description 5
- 230000008685 targeting Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 229920000856 Amylose Polymers 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- 229930091371 Fructose Natural products 0.000 description 4
- 239000005715 Fructose Substances 0.000 description 4
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 4
- 230000037406 food intake Effects 0.000 description 4
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 208000024827 Alzheimer disease Diseases 0.000 description 3
- 102000014914 Carrier Proteins Human genes 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 235000013361 beverage Nutrition 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 150000004676 glycans Chemical class 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 229920001282 polysaccharide Polymers 0.000 description 3
- 239000005017 polysaccharide Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 150000005846 sugar alcohols Chemical class 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 108010078791 Carrier Proteins Proteins 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 101710172711 Structural protein Proteins 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 244000269722 Thea sinensis Species 0.000 description 2
- 235000006468 Thea sinensis Nutrition 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-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
- 239000011230 binding agent Substances 0.000 description 2
- 238000009534 blood test Methods 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 235000013539 calcium stearate Nutrition 0.000 description 2
- 239000008116 calcium stearate Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000036512 infertility Effects 0.000 description 2
- 231100000535 infertility Toxicity 0.000 description 2
- 208000021267 infertility disease Diseases 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 150000002772 monosaccharides Chemical class 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 2
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 239000008057 potassium phosphate buffer Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- RRUYWEMUWIRRNB-LURJTMIESA-N (2s)-6-amino-2-[carboxy(methyl)amino]hexanoic acid Chemical compound OC(=O)N(C)[C@H](C(O)=O)CCCCN RRUYWEMUWIRRNB-LURJTMIESA-N 0.000 description 1
- LXJXRIRHZLFYRP-VKHMYHEASA-L (R)-2-Hydroxy-3-(phosphonooxy)-propanal Natural products O=C[C@H](O)COP([O-])([O-])=O LXJXRIRHZLFYRP-VKHMYHEASA-L 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- CAAMSDWKXXPUJR-UHFFFAOYSA-N 3,5-dihydro-4H-imidazol-4-one Chemical compound O=C1CNC=N1 CAAMSDWKXXPUJR-UHFFFAOYSA-N 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 108010005094 Advanced Glycation End Products Proteins 0.000 description 1
- 229920000945 Amylopectin Polymers 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 235000005956 Cosmos caudatus Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-CUHNMECISA-N D-Cellobiose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-CUHNMECISA-N 0.000 description 1
- LXJXRIRHZLFYRP-VKHMYHEASA-N D-glyceraldehyde 3-phosphate Chemical compound O=C[C@H](O)COP(O)(O)=O LXJXRIRHZLFYRP-VKHMYHEASA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 102000016942 Elastin Human genes 0.000 description 1
- 108010014258 Elastin Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- 108010073178 Glucan 1,4-alpha-Glucosidase Proteins 0.000 description 1
- 102100022624 Glucoamylase Human genes 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000051366 Glycosyltransferases Human genes 0.000 description 1
- 108700023372 Glycosyltransferases Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 108010028554 LDL Cholesterol Proteins 0.000 description 1
- 238000008214 LDL Cholesterol Methods 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 108010063312 Metalloproteins Proteins 0.000 description 1
- 102000010750 Metalloproteins Human genes 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 102000003896 Myeloperoxidases Human genes 0.000 description 1
- 108090000235 Myeloperoxidases Proteins 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 102000007999 Nuclear Proteins Human genes 0.000 description 1
- 108010089610 Nuclear Proteins Proteins 0.000 description 1
- AYRXSINWFIIFAE-UHFFFAOYSA-N O6-alpha-D-Galactopyranosyl-D-galactose Natural products OCC1OC(OCC(O)C(O)C(O)C(O)C=O)C(O)C(O)C1O AYRXSINWFIIFAE-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- 108010089430 Phosphoproteins Proteins 0.000 description 1
- 102000007982 Phosphoproteins Human genes 0.000 description 1
- OVVGHDNPYGTYIT-VHBGUFLRSA-N Robinobiose Natural products O(C[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)O1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](C)O1 OVVGHDNPYGTYIT-VHBGUFLRSA-N 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 150000004753 Schiff bases Chemical class 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 235000009470 Theobroma cacao Nutrition 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 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 1
- 108010044879 alpha-L-rhamnosidase Proteins 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 235000020279 black tea Nutrition 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000037118 bone strength Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000001058 brown pigment Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000000512 collagen gel Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 201000009101 diabetic angiopathy Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229920002549 elastin Polymers 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000013332 fish product Nutrition 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- DLRVVLDZNNYCBX-CQUJWQHSSA-N gentiobiose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)C(O)O1 DLRVVLDZNNYCBX-CQUJWQHSSA-N 0.000 description 1
- 230000002414 glycolytic effect Effects 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 235000009569 green tea Nutrition 0.000 description 1
- 235000013402 health food Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002402 hexoses Chemical class 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- OVSQVDMCBVZWGM-QCKGUQPXSA-N isoquercetin Natural products OC[C@@H]1O[C@@H](OC2=C(Oc3cc(O)cc(O)c3C2=O)c4ccc(O)c(O)c4)[C@H](O)[C@@H](O)[C@@H]1O OVSQVDMCBVZWGM-QCKGUQPXSA-N 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- ZKLLSNQJRLJIGT-UYFOZJQFSA-N keto-D-fructose 1-phosphate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)COP(O)(O)=O ZKLLSNQJRLJIGT-UYFOZJQFSA-N 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 235000020124 milk-based beverage Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 235000020333 oolong tea Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- AYEKKSTZQYEZPU-RYUDHWBXSA-N pentosidine Chemical compound OC(=O)[C@@H](N)CCCCN1C=CC=C2N=C(NCCC[C@H](N)C(O)=O)N=C12 AYEKKSTZQYEZPU-RYUDHWBXSA-N 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 150000008442 polyphenolic compounds Chemical group 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- QYNRIDLOTGRNML-UHFFFAOYSA-N primeverose Natural products OC1C(O)C(O)COC1OCC1C(O)C(O)C(O)C(O)O1 QYNRIDLOTGRNML-UHFFFAOYSA-N 0.000 description 1
- XOPPYWGGTZVUFP-DLWPFLMGSA-N primeverose Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O XOPPYWGGTZVUFP-DLWPFLMGSA-N 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000011962 puddings Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- OVVGHDNPYGTYIT-BNXXONSGSA-N rutinose Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)O1 OVVGHDNPYGTYIT-BNXXONSGSA-N 0.000 description 1
- 125000000953 rutinose group Chemical group 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 230000009759 skin aging Effects 0.000 description 1
- 235000014214 soft drink Nutrition 0.000 description 1
- 235000013322 soy milk Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 235000011496 sports drink Nutrition 0.000 description 1
- 235000014268 sports nutrition Nutrition 0.000 description 1
- NBMBWTIUOJARSX-UHFFFAOYSA-N srtrophanthobiose Natural products COC1CC(O)OC(C)C1OC1C(O)C(O)C(O)C(CO)O1 NBMBWTIUOJARSX-UHFFFAOYSA-N 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000015961 tonic Nutrition 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 229960000716 tonics Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 235000015192 vegetable juice Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 235000013618 yogurt Nutrition 0.000 description 1
Description
本発明は、Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤に関する。 The present invention relates to a toxic AGEs production inhibitor.
アミノ酸と還元糖を加熱すると褐色の色素が生成する反応は、一般にメイラード反応と呼ばれ、食品の加熱中に起こる着色や、香り・風味の変化、保存期間中の栄養価低下に関わる反応であることから食品化学の領域で注目されてきた。１９６０年代にはメイラード反応は生体内でも起きており、糖尿病の進行に伴いタンパク質の糖化反応が進行することが明らかになった。その後、タンパク質の糖化反応による終末糖化産物（Ａｄｖａｎｃｅｄ ｇｌｙｃａｔｉｏｎ ｅｎｄ ｐｒｏｄｕｃｔｓ、以下ＡＧＥｓと称する）が、アルツハイマー病等の神経疾患や、癌の増殖、転移、浸潤、老化現象、高血圧、動脈硬化症などにも関与していることが明らかになり、これら疾患の発症、進展を抑制するため、種々のＡＧＥｓ生成抑制剤が開発されてきた（例えば特許文献１、特許文献２）。 The reaction that produces a brown pigment when amino acids and reducing sugars are heated is generally called the Maillard reaction, and is a reaction that is associated with coloration, changes in aroma and flavor, and loss of nutritional value during storage of foods that occur during heating. For this reason, it has attracted attention in the field of food chemistry. In the 1960s, it was discovered that the Maillard reaction also occurs in vivo, and that the glycation reaction of proteins progresses as diabetes progresses. After that, advanced glycation end products (hereinafter referred to as AGEs) from protein glycation reactions can cause neurological diseases such as Alzheimer's disease, cancer proliferation, metastasis, invasion, aging phenomena, hypertension, arteriosclerosis, etc. It has become clear that AGEs are involved, and in order to suppress the onset and progression of these diseases, various AGEs production inhibitors have been developed (for example, Patent Document 1, Patent Document 2).
生体内でのＡＧＥｓ生成経路の全貌は未だに明らかになっていないが、近年の研究により、グルコースとタンパク質から生成するだけでなく、グルコースの代謝中間体や分解物、メイラード反応中間体などからもＡＧＥｓが生成することがわかっている（非特許文献１）。さらに、ＡＧＥｓは、防御的な意味合いで生成されると考えられるＮｏｎ－Ｔｏｘｉｃ ＡＧＥｓと、実際に病気の原因となるＴｏｘｉｃ ＡＧＥｓ（以下、ＴＡＧＥとも称する）に分類できることがわかってきた。構造が明らかにされたＮｏｎ－Ｔｏｘｉｃ ＡＧＥｓとしては、カルボキシメチルリジン、ピラリン、ペントシジン、クロスリン、イミダゾロン等が知られ、これらの構造を認識する抗体が市販されていることから、生体内のＡＧＥｓを定量するための指標として広く用いられている。しかし、例えばカルボキシルメチルリジンは生体において糖化反応ではなく、脂質過酸化により生成することが明らかになっており、Ｎｏｎ－Ｔｏｘｉｃ ＡＧＥｓを定量しても、生体の糖化の度合いを正確に評価しているとはいえない。 Although the complete picture of the AGEs production pathway in living organisms is still not clear, recent research has shown that AGEs are not only produced from glucose and proteins, but also from metabolic intermediates and decomposition products of glucose, Maillard reaction intermediates, etc. is known to be generated (Non-Patent Document 1). Furthermore, it has been found that AGEs can be classified into non-toxic AGEs, which are thought to be generated for protection, and toxic AGEs (hereinafter also referred to as TAGEs), which actually cause diseases. Non-Toxic AGEs whose structures have been clarified include carboxymethyllysine, pyralline, pentosidine, crossrin, and imidazolone, and since antibodies that recognize these structures are commercially available, it is possible to quantify AGEs in vivo. It is widely used as an indicator for However, it has been revealed that carboxylmethyllysine, for example, is produced in living organisms through lipid peroxidation rather than through glycation reactions, and quantifying non-toxic AGEs does not accurately assess the degree of glycation in living organisms. I can't say that.
ＴＡＧＥとしては、グルコースから生じたグリコールアルデヒドに由来するＡＧＥ（以下、ＧＯ－ＡＧＥという）、グルコースおよびフルクトースから生じるグリセルアルデヒドに由来するＡＧＥ（以下、ＧＥ－ＡＧＥという）、グルコース分解産物から生成するアセトアルデヒドに由来するＡＧＥ（以下、ＡＡ－ＡＧＥという）が知られている。これらのＴＡＧＥは、Ｎｏｎ－Ｔｏｘｉｃ ＡＧＥｓとは異なって、非常に強い細胞障害性を示すだけでなく、ＲＡＧＥ（ｒｅｃｅｐｔｏｒ ｆｏｒ ＡＧＥｓ）を介して糖尿病血管合併症、心血管病、非アルコール性脂肪肝炎、がん、不妊症、アルツハイマー病などの多様な疾患に関与することが近年の研究により明らかにされている（非特許文献２）。中でもＧＥ－ＡＧＥは毒性が強いこと、さらに清涼飲料や果物に多く含まれるフルクトース（果糖）からも生じることから、ＴＡＧＥの中でも特に食生活と疾患の関連という観点から注目を集めている。 TAGEs include AGE derived from glycolaldehyde generated from glucose (hereinafter referred to as GO-AGE), AGE derived from glyceraldehyde generated from glucose and fructose (hereinafter referred to as GE-AGE), and AGE generated from glucose decomposition products. AGE derived from acetaldehyde (hereinafter referred to as AA-AGE) is known. Unlike Non-Toxic AGEs, these TAGEs not only exhibit very strong cytotoxicity, but also cause diabetic vascular complications, cardiovascular disease, non-alcoholic steatohepatitis, etc. through RAGE (receptor for AGEs). Recent studies have revealed that it is involved in various diseases such as cancer, infertility, and Alzheimer's disease (Non-Patent Document 2). Among the TAGEs, GE-AGE is attracting attention because it is highly toxic and is also generated from fructose, which is abundant in soft drinks and fruits, from the perspective of the relationship between diet and disease.
本発明者らはＴＡＧＥの影響を抑えることが生活習慣病の発症、進展の予防や治療の戦略上重要であると考え、ＴＡＧＥの生成を抑制し、さらには血中ＴＡＧＥ濃度を低下させる、または上昇を抑制することのできるＴＡＧＥ生成抑制剤を提供することを本発明の課題とする。 The present inventors believe that suppressing the influence of TAGE is important as a strategy for preventing and treating the onset and progression of lifestyle-related diseases. An object of the present invention is to provide a TAGE production inhibitor that can suppress the increase in TAGE production.
本発明者らは上記課題を解決すべく鋭意検討した。その結果、以下の構成を有することにより上記課題を解決できることを見出し、本発明を完成するに至った。
本発明は、例えば以下の〔１〕～〔６〕に関する。
〔１〕式（１）で示されるケルセチン配糖体を含むＴｏｘｉｃ ＡＧＥｓ生成抑制剤。
〔式（１）中、Ｒ1およびＲ2は、それぞれ独立に糖類由来の構造である。〕
〔２〕前記式（１）中、Ｒ1がラムノース由来の構造である、〔１〕に記載のＴｏｘｉｃ ＡＧＥｓ生成抑制剤。
〔３〕前記式（１）で示されるケルセチン配糖体がα－グルコシルルチンである、〔１〕または〔２〕に記載のＴｏｘｉｃ ＡＧＥｓ生成抑制剤。
〔４〕少なくともアルブミンまたはコラーゲン由来のＴｏｘｉｃ ＡＧＥｓの生成を抑制する、〔１〕～〔３〕いずれかに記載のＴｏｘｉｃ ＡＧＥｓ生成抑制剤。
〔５〕グリセルアルデヒド、アセトアルデヒド、およびグリコールアルデヒドから選択される少なくとも一つを由来とするＴｏｘｉｃ ＡＧＥｓの生成を抑制する〔１〕～〔４〕いずれかに記載のＴｏｘｉｃ ＡＧＥｓ生成抑制剤。
〔６〕〔１〕～〔５〕いずれかに記載のＴｏｘｉｃ ＡＧＥｓ生成抑制剤を含む飲食品、医薬品、医薬部外品または化粧品。
The present inventors have made extensive studies to solve the above problems. As a result, it was discovered that the above problems could be solved by having the following configuration, and the present invention was completed.
The present invention relates to, for example, the following [1] to [6].
[1] A toxic AGEs production inhibitor containing a quercetin glycoside represented by formula (1).
[In formula (1), R 1 and R 2 are each independently a structure derived from a saccharide. ]
[2] The toxic AGEs production inhibitor according to [1], wherein in the formula (1), R 1 is a structure derived from rhamnose.
[3] The toxic AGEs production inhibitor according to [1] or [2], wherein the quercetin glycoside represented by formula (1) is α-glucosylrutin.
[4] The toxic AGEs production inhibitor according to any one of [1] to [3], which inhibits the production of at least albumin- or collagen-derived toxic AGEs.
[5] The Toxic AGEs production inhibitor according to any one of [1] to [4], which suppresses the production of Toxic AGEs derived from at least one selected from glyceraldehyde, acetaldehyde, and glycolaldehyde.
[6] A food or drink, a pharmaceutical, a quasi-drug, or a cosmetic containing the Toxic AGEs production inhibitor according to any one of [1] to [5].
本発明によれば、ＴＡＧＥの生成を抑制するＴｏｘｉｃ ＡＧＥｓ生成抑制剤を提供できる。 According to the present invention, it is possible to provide a toxic AGEs production inhibitor that suppresses the production of TAGE.
次に本発明のＴｏｘｉｃ ＡＧＥｓ生成抑制剤について具体的に説明する。なお、Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤を、ＴＡＧＥ生成抑制剤とも記す。
本発明のＴｏｘｉｃ ＡＧＥｓ生成抑制剤は、式（１）で示されるケルセチン配糖体を含む。
〔式（１）中、Ｒ1およびＲ2は、それぞれ独立に糖類由来の構造である。〕
Next, the Toxic AGEs production inhibitor of the present invention will be specifically explained. Note that the toxic AGEs production inhibitor is also referred to as a TAGE production inhibitor.
The toxic AGEs production inhibitor of the present invention contains a quercetin glycoside represented by formula (1).
[In formula (1), R 1 and R 2 are each independently a structure derived from a saccharide. ]
〈ケルセチン配糖体〉
式（１）で表されるケルセチン配糖体は、ポリフェノールの一種であるケルセチンの３位の水酸基にグルコースがβ結合し、前記グルコースの４位および５位の水酸基に糖類が結合した化合物である。式（１）で表されるケルセチン配糖体としては、１種のケルセチン配糖体のみで用いてもよく、複数種のケルセチン配糖体の混合物を用いてもよい。また、ＴＡＧＥ生成抑制剤は、本発明の効果を損なわない範囲で前記ケルセチン配糖体以外の成分（その他の成分）を含んでもよく、例えばイソケルシトリン（イソケルセチン）、ケルセチン、ルチン等を含んでもよい。
<Quercetin glycosides>
The quercetin glycoside represented by formula (1) is a compound in which glucose is β-bonded to the hydroxyl group at the 3-position of quercetin, which is a type of polyphenol, and saccharide is bonded to the hydroxyl group at the 4- and 5-positions of the glucose. . As the quercetin glycoside represented by formula (1), only one type of quercetin glycoside may be used, or a mixture of multiple types of quercetin glycosides may be used. Furthermore, the TAGE production inhibitor may contain components other than the quercetin glycosides (other components) within a range that does not impair the effects of the present invention, such as isoquercitrin (isoquercetin), quercetin, rutin, etc. But that's fine.
〈Ｒ1およびＲ2〉
式（１）中のＲ1およびＲ2は、それぞれ独立に糖類由来の構造である。糖類由来の構造としては、通常は糖類の有する複数のＯＨ基のうち、一つが脱離した構造が挙げられる。前記糖類としては例えば、グルコース、ラムノース、フルクトース、マンノース、ガラクトース等のヘキソース、キシロース、アラビノース等のペントース等の単糖類、スクロース、ラクトース、プリメベロース、ゲンチオビオース、ルチノース、ストロファントビオース、セロビオース、アミロース、アミロペクチン、セルロース等の多糖類、エリスリトール、キシリトール等の糖アルコール、あるいはそれらの誘導体を用いることができる。原料の入手容易性や反応効率、ケルセチン配糖体の安定性、ＴＡＧＥ生成抑制効果の観点から、Ｒ1およびＲ2は単糖または多糖であることが好ましい。Ｒ1はラムノース由来の構造であることが好ましい。また、Ｒ2はグルコース由来の構造またはアミロース由来の構造であることが好ましい。
<R 1 and R 2 >
R 1 and R 2 in formula (1) are each independently a structure derived from a saccharide. Examples of structures derived from saccharides include structures in which one of the plurality of OH groups possessed by saccharides is removed. Examples of the saccharides include hexoses such as glucose, rhamnose, fructose, mannose, and galactose; monosaccharides such as pentoses such as xylose and arabinose; sucrose, lactose, primeverose, gentiobiose, rutinose, strophantobiose, cellobiose, amylose, and amylopectin. , polysaccharides such as cellulose, sugar alcohols such as erythritol and xylitol, or derivatives thereof. From the viewpoint of availability of raw materials, reaction efficiency, stability of quercetin glycosides, and TAGE production inhibiting effect, R 1 and R 2 are preferably monosaccharides or polysaccharides. Preferably, R 1 has a structure derived from rhamnose. Furthermore, R 2 is preferably a structure derived from glucose or amylose.
原料の入手容易性や反応効率、ケルセチン配糖体の安定性、ＴＡＧＥ生成抑制効果の観点から、Ｒ1がラムノース由来の構造である場合は、前記ケルセチン配糖体は式（１－１）で示されるものが好ましい。
〔式（１－１）中、Ｒ2は糖類由来の構造である。〕
From the viewpoint of availability of raw materials, reaction efficiency, stability of quercetin glycoside, and TAGE production suppressing effect, when R 1 is a structure derived from rhamnose, the quercetin glycoside has the formula (1-1). Those shown are preferred.
[In formula (1-1), R 2 is a structure derived from a saccharide. ]
原料の入手容易性や反応効率、ケルセチン配糖体の安定性、ＴＡＧＥ生成抑制効果の観点から、Ｒ2がグルコース由来の構造またはアミロース由来の構造である場合は、前記ケルセチン配糖体は式（１－２）で示されるものがより好ましい。なお、アミロースは、グルコースがα１→４結合により結合した多糖である。
〔式（１－２）中、Ｒ1は糖類由来の構造である。また、ｎは１以上の整数である。〕
From the viewpoints of availability of raw materials, reaction efficiency, stability of quercetin glycosides, and TAGE production inhibiting effect, when R 2 is a glucose-derived structure or an amylose-derived structure, the quercetin glycosides have the formula ( Those shown in 1-2) are more preferred. Note that amylose is a polysaccharide in which glucose is linked through α1→4 bonds.
[In formula (1-2), R 1 is a structure derived from a saccharide. Further, n is an integer of 1 or more. ]
原料の入手容易性や反応効率、ケルセチン配糖体の安定性、ＴＡＧＥ生成抑制効果の観点から、式（１－２）中、ｎ＝１、またはｎ＝２～２０が好ましく、ｎ＝１、またはｎ＝２～１０がより好ましく、ｎ＝１がさらに好ましい。 From the viewpoint of availability of raw materials, reaction efficiency, stability of quercetin glycosides, and TAGE production suppressing effect, in formula (1-2), n = 1 or n = 2 to 20 is preferable, n = 1, Alternatively, n=2 to 10 is more preferable, and n=1 is even more preferable.
原料の入手容易性や反応効率、ケルセチン配糖体の安定性、ＴＡＧＥ生成抑制効果の観点から、前記ケルセチン配糖体は式（１－３）で示されるものが特に好ましい。
原料の入手容易性や反応効率、ケルセチン配糖体の安定性、ＴＡＧＥ生成抑制効果の観点から、式（１－３）中、ｎ＝１、またはｎ＝２～２０が好ましく、ｎ＝１、またはｎ＝２～１０がより好ましく、ｎ＝１がさらに好ましい。 From the viewpoint of raw material availability, reaction efficiency, stability of quercetin glycosides, and TAGE production suppressing effect, in formula (1-3), n = 1 or n = 2 to 20 is preferable, n = 1, Alternatively, n=2 to 10 is more preferable, and n=1 is even more preferable.
式（１－３）のケルセチン配糖体は総称して、α－グルコシルルチンとも呼ばれる。また、α－グルコシルルチンの中でも、式（１－３）中、ｎ＝１であるケルセチン配糖体は、α－モノグルコシルルチンとも呼ばれる。 Quercetin glycosides of formula (1-3) are also collectively called α-glucosylrutin. Furthermore, among α-glucosyl rutins, quercetin glycoside in which n=1 in formula (1-3) is also called α-monoglucosyl rutin.
式（１）で表されるケルセチン配糖体としては、α－モノグルコシルルチンが主成分であることが好ましく、式（１）で表されるケルセチン配糖体中として、α－モノグルコシルルチンが５０～１００質量％含まれることがより好ましく、６５～８５質量％含まれることがさらに好ましい。 As the quercetin glycoside represented by formula (1), it is preferable that α-monoglucosyl rutin is the main component. It is more preferably contained in an amount of 50 to 100% by mass, and even more preferably 65 to 85% by mass.
前記糖に含まれている水酸基は、他の基により修飾されていてもよい。 The hydroxyl group contained in the sugar may be modified with another group.
〈ケルセチン配糖体の製造方法〉
前記ケルセチン配糖体は、天然物由来のものでもよく、合成品であってもよい。天然物を原料とする場合には、原料となる動植物から、公知の抽出方法によって得られる抽出物をそのまま用いてもよく、さらに分離精製を行ってもよい。
<Method for producing quercetin glycosides>
The quercetin glycoside may be derived from a natural product or may be a synthetic product. When a natural product is used as a raw material, an extract obtained from the raw material animal or plant by a known extraction method may be used as it is, or it may be further separated and purified.
前記ケルセチン配糖体が合成品である場合には、原料となる化合物は制限されず、公知の手法を用いて製造することができ、未反応の原料や副生成物、不純物を含んでもよい。前記ケルセチン配糖体は、原料の入手容易性や反応効率、ケルセチン配糖体の安定性、ＴＡＧＥ生成抑制効果の観点からケルセチン、イソケルシトリンまたはルチンに糖類を結合させて製造することが好ましく、ルチンに糖類を結合させることがさらに好ましい。また、糖類を結合させた後、糖類の結合を特異的に切断し、目的とする分子種のケルセチン配糖体を得ることがより好ましい。糖類の結合または切断には、例えば酵素法、有機化学的な方法や生物変換による方法等を用いることができるが、原料のケルセチン、イソケルシトリンまたはルチンに１種または複数の酵素を作用させることが好ましく、特許第２８１６０３０号公報に記載の酵素処理がさらに好ましい。 When the quercetin glycoside is a synthetic product, the compound serving as the raw material is not limited, and can be produced using a known method, and may contain unreacted raw materials, by-products, and impurities. The quercetin glycoside is preferably produced by bonding saccharides to quercetin, isoquercitrin, or rutin from the viewpoint of raw material availability, reaction efficiency, stability of quercetin glycoside, and TAGE production suppressing effect, It is more preferable to bind sugars to rutin. Furthermore, after binding the saccharide, it is more preferable to specifically cleave the saccharide bond to obtain the desired molecular species of quercetin glycoside. For example, enzymatic methods, organic chemical methods, bioconversion methods, etc. can be used to bond or cleave sugars, but it is possible to use one or more enzymes to act on the raw material quercetin, isoquercitrin, or rutin. is preferred, and the enzyme treatment described in Japanese Patent No. 2816030 is more preferred.
上記特許第２８１６０３０号公報に記載の酵素処理について概説すれば、以下の通りである。（１）糖供与体の共存下でルチンに糖転移酵素を作用させ、ルチンのグルコース単位にα-１,４結合によりグルコースを付加することにより、α－グルコシルルチンが生成し、未反応のルチンとα－グルコシルルチンを含有する組成物が得られる。（２）上記（１）により生成したα－グルコシルルチンにグルコアミラーゼ等を作用させ、ルチンのグルコース単位に結合しているグルコース鎖から１分子だけを残して他のグルコースを切断することにより、α－モノグルコシルルチンが生成し、未反応のままのルチンとα－モノグルコシルルチンを含有する組成物が得られる。（３）未反応のままのルチンにα-Ｌ-ラムノシダーゼを作用させ、ルチンのルチノース単位に含まれるラムノースを切断することによりイソケルシトリンが生成し、イソケルシトリンとα－モノグルコシルルチンを含有する組成物が得られる。 An overview of the enzyme treatment described in the above-mentioned Japanese Patent No. 2816030 is as follows. (1) By allowing glycosyltransferase to act on rutin in the presence of a sugar donor and adding glucose to the glucose unit of rutin through an α-1,4 bond, α-glucosylrutin is produced, and unreacted rutin A composition containing α-glucosylrutin and α-glucosylrutin is obtained. (2) By treating the α-glucosylrutin produced in (1) above with glucoamylase, etc., and cutting off the other glucose from the glucose chain bound to the glucose unit of rutin, leaving only one molecule, α - Monoglucosylrutin is produced, and a composition containing unreacted rutin and α-monoglucosylrutin is obtained. (3) Isoquercitrin is generated by allowing α-L-rhamnosidase to act on unreacted rutin and cleaving the rhamnose contained in the rutinose unit of rutin, which contains isoquercitrin and α-monoglucosyl rutin. A composition is obtained.
前記酵素処理は、目的とするＴｏｘｉｃ ＡＧＥｓ生成抑制剤の態様に合わせて、組み合わせ、順番等を適宜調整することが可能である。また、複数種の酵素を同時に添加することで、１つの工程で複数の酵素反応を並行して進める態様であってもよい。また、このような酵素処理工程の後にまたはその途中に、必要に応じてその他の処理を行ってもよい。例えば、沈殿物を除去するための濾過処理、沈殿物が生じない程度の濃縮処理、イオン交換樹脂を用いた脱塩処理、その他の夾雑物を除去するための精製処理、さらにこれらの液状物から固形物を調製するための乾燥または凍結乾燥処理などが挙げられる。 The combination, order, etc. of the enzyme treatment can be adjusted as appropriate depending on the desired form of the Toxic AGEs production inhibitor. Alternatively, a mode may be adopted in which a plurality of enzyme reactions are carried out in parallel in one step by adding a plurality of types of enzymes at the same time. Furthermore, other treatments may be performed as necessary after or during the enzyme treatment step. For example, filtration treatment to remove precipitates, concentration treatment to the extent that no precipitates are formed, desalting treatment using ion exchange resin, purification treatment to remove other impurities, and further processing from these liquid materials. Examples include drying or freeze-drying treatments to prepare solids.
上述のような製造方法により得られる組成物は「酵素処理ルチン」として一般的に製造販売されており、本発明ではそのような商品を使用することができる。例えば、東洋精糖(株)製の商品「αＧルチンＰＳ」は、α－モノグルコシルルチン７５質量％、イソケルシトリン１５質量％を含有する組成物である。また、同じく東洋精糖(株)製の商品「αＧルチンＰ」は、α－グルコシルルチン７０質量％、ルチン１５質量％を含有する組成物である。 The composition obtained by the above production method is generally manufactured and sold as "enzyme-treated rutin," and such products can be used in the present invention. For example, the product "αG Rutin PS" manufactured by Toyo Seito Co., Ltd. is a composition containing 75% by mass of α-monoglucosylrutin and 15% by mass of isoquercitrin. Furthermore, the product "αG Rutin P", also manufactured by Toyo Seito Co., Ltd., is a composition containing 70% by mass of α-glucosylrutin and 15% by mass of rutin.
〈Ｔｏｘｉｃ ＡＧＥｓ〉
本発明におけるＴｏｘｉｃ ＡＧＥｓは、グリセルアルデヒド、アセトアルデヒド、またはグリコールアルデヒドに由来するＡＧＥｓである。
<Toxic AGEs>
Toxic AGEs in the present invention are AGEs derived from glyceraldehyde, acetaldehyde, or glycolaldehyde.
グリセルアルデヒドに由来するＡＧＥ（ＧＥ-ＡＧＥ）とは、グリセルアルデヒドとタンパク質が反応して生成されるＡＧＥである。生体内において、グリセルアルデヒドが生じる経路は、全ては明らかになってはいないが、例えば、グルコースが解糖系において代謝されて生じるグリセルアルデヒド３－リン酸を経てグリセルアルデヒドを生じる経路、フルクトースがフルクトース１－リン酸を経てグリセルアルデヒドを生じる経路等があげられる。ＧＥ-ＡＧＥを検出する方法は制限されないが、例えば、グリセルアルデヒドと血清アルブミンを反応させて生成されたＧＥ-ＡＧＥを実験動物に免疫して得られたＧＥ-ＡＧＥ特異的な抗体を用いて行うＥＬＩＳＡ等である。 AGE derived from glyceraldehyde (GE-AGE) is an AGE produced by the reaction of glyceraldehyde and protein. Although not all of the routes by which glyceraldehyde is produced in vivo are clear, for example, the pathway which produces glyceraldehyde through glyceraldehyde 3-phosphate produced when glucose is metabolized in the glycolytic system; Examples include a pathway in which fructose generates glyceraldehyde via fructose 1-phosphate. The method for detecting GE-AGE is not limited, but for example, using a GE-AGE-specific antibody obtained by immunizing an experimental animal with GE-AGE produced by reacting glyceraldehyde with serum albumin. ELISA etc. are carried out.
アセトアルデヒドに由来するＡＧＥ（ＡＡ-ＡＧＥ）は、アセトアルデヒドとタンパク質が反応して生成されるＡＧＥである。生体内において、アセトアルデヒドが生じる経路は、全ては明らかになってはいないが、例えば、グルコース分解産物から生成する経路等があげられる。ＡＡ-ＡＧＥを検出する方法は制限されないが、例えば、アセトアルデヒドと血清アルブミンを反応させて生成されたＡＡ-ＡＧＥを実験動物に免疫して得られたＡＡ-ＡＧＥ特異的な抗体を用いて行うＥＬＩＳＡ等である。 AGE derived from acetaldehyde (AA-AGE) is an AGE produced by the reaction of acetaldehyde and protein. Although not all of the routes by which acetaldehyde is produced in vivo are clear, examples include the route by which acetaldehyde is produced from glucose decomposition products. The method for detecting AA-AGE is not limited, but for example, ELISA using an AA-AGE-specific antibody obtained by immunizing a laboratory animal with AA-AGE produced by reacting acetaldehyde and serum albumin. etc.
グリコールアルデヒドに由来するＡＧＥ（ＧＯ-ＡＧＥ）は、グリコールアルデヒドとタンパク質が反応して生成されるＡＧＥである。生体内において、グリコールアルデヒドが生じる経路は、全ては明らかになってはいないが、例えば、グルコースとタンパク質から生じたシッフ塩基を経る経路や、活性化されたリンパ球系細胞においてミエロペルオキシダーゼを介してセリンから生成される経路等があげられる。ＧＯ-ＡＧＥを検出する方法は制限されないが、例えば、グリコールアルデヒドと血清アルブミンを反応させて生成されたＧＯ-ＡＧＥを実験動物に免疫して得られたＧＯ-ＡＧＥ特異的な抗体を用いて行うＥＬＩＳＡ等である。 AGE derived from glycolaldehyde (GO-AGE) is an AGE produced by the reaction of glycolaldehyde and protein. Although not all of the routes by which glycolaldehyde is produced in vivo are clear, for example, it is produced via Schiff bases generated from glucose and proteins, and via myeloperoxidase in activated lymphoid cells. Examples include the pathway generated from serine. The method for detecting GO-AGE is not limited, but for example, GO-AGE produced by reacting glycolaldehyde with serum albumin may be used to immunize an experimental animal with a GO-AGE-specific antibody. ELISA etc.
＜ＴＡＧＥ生成の由来となるタンパク質＞
ＴＡＧＥ生成の由来となるタンパク質は、そのすべてが判明しているわけではないが、心臓、脳、皮膚等の臓器、毛髪等の付属器や血液等に存在するタンパク質、すなわち生体に存在するすべてのタンパク質が由来になると考えられる。組成によって分類すれば、アミノ酸のみで構成される単純タンパク質だけでなく、糖タンパク質、リポタンパク質、リンタンパク質、核タンパク質、金属タンパク質など、アミノ酸以外の成分を含む複合タンパク質、ゼラチンやペプトン等の誘導タンパク質も含む。機能によって分類すれば、例えば、Ｇタンパク質等の膜タンパク質、血清アルブミン等の輸送タンパク質、コラーゲン、エラスチン等の構造タンパク質、アクチン等の運動タンパク質グロブリン等の抗体タンパク質、酵素タンパク質、色素タンパク質、結合タンパク質、受容体タンパク質などが挙げられる。
本発明のＴｏｘｉｃ ＡＧＥｓ生成抑制剤は、皮膚または血液に存在するタンパク質、構造タンパク質、または輸送タンパク質由来のＴｏｘｉｃ ＡＧＥｓの生成を阻害することが好ましく、少なくともアルブミンまたはコラーゲン由来のＴｏｘｉｃ ＡＧＥｓの生成を阻害することがさらに好ましい。
<Protein from which TAGE production is derived>
Although not all of the proteins from which TAGE production is derived are known, they include all proteins present in organs such as the heart, brain, and skin, appendages such as hair, and blood, that is, all of the proteins present in living organisms. It is thought that it originates from protein. Classified by composition, there are not only simple proteins composed only of amino acids, but also complex proteins containing components other than amino acids, such as glycoproteins, lipoproteins, phosphoproteins, nuclear proteins, and metalloproteins, and derived proteins such as gelatin and peptone. Also included. Classified by function, for example, membrane proteins such as G protein, transport proteins such as serum albumin, structural proteins such as collagen and elastin, motor proteins such as actin, antibody proteins such as globulin, enzyme proteins, pigment proteins, binding proteins, Examples include receptor proteins.
The Toxic AGEs production inhibitor of the present invention preferably inhibits the production of Toxic AGEs derived from proteins, structural proteins, or transport proteins present in the skin or blood, and at least inhibits the production of Toxic AGEs derived from albumin or collagen. It is even more preferable.
〈Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤〉
本発明におけるＴｏｘｉｃ ＡＧＥｓ生成抑制剤とは、ＴＡＧＥの生成を抑制する作用を有する成分を含む剤をいい、式（１）で示されるケルセチン配糖体を含んでいる。
より具体的にはＧＥ-ＡＧＥ、ＡＡ-ＡＧＥ、またはＧＯ-ＡＧＥの生成を抑制する作用を有する成分を含む剤をいう。
<Toxic AGEs production inhibitor>
The toxic AGEs production inhibitor in the present invention refers to an agent containing a component having an effect of inhibiting the production of TAGE, and includes a quercetin glycoside represented by formula (1).
More specifically, it refers to an agent containing a component that has the effect of suppressing the production of GE-AGE, AA-AGE, or GO-AGE.
ＴＡＧＥの中でもＧＥ-ＡＧＥは毒性が強く、疾病の発症、進展とも強く関連していることから、本発明のＴｏｘｉｃ ＡＧＥｓ生成抑制剤はＧＥ-ＡＧＥの生成を抑制する作用を有することが好ましい。すなわち、本発明のＴｏｘｉｃ ＡＧＥｓ生成抑制剤は、ＧＥ-ＡＧＥ生成抑制剤であることが、好ましい態様の一つである。 Among TAGEs, GE-AGE is highly toxic and is strongly associated with the onset and progression of diseases. Therefore, the toxic AGEs production inhibitor of the present invention preferably has an effect of inhibiting the production of GE-AGE. That is, one preferred embodiment of the Toxic AGEs production inhibitor of the present invention is a GE-AGE production inhibitor.
本発明におけるＡＧＥｓ生成抑制作用の評価方法は、有効成分によってＡＧＥｓ生成が抑制される作用の有無が判断できれば特に制限されない。例えば、文献「Ｊ Ｂｉｏｌ Ｃｈｅｍ ２７２：８７２３－８７３０、１９９７」に記載の蛍光強度による評価方法、文献「Ｄｉａｂｅｔｅｓ Ｃａｒｅ ３５：２６１８－２６２５、２０１２」に記載のＥＬＩＳＡ法等が挙げられる。実験操作が簡便であることから、蛍光強度による評価方法が好ましい。 The method for evaluating the effect of inhibiting AGEs production in the present invention is not particularly limited as long as it can be determined whether or not the active ingredient has an effect of inhibiting AGEs production. Examples include the evaluation method based on fluorescence intensity described in the literature "J Biol Chem 272:8723-8730, 1997" and the ELISA method described in the literature "Diabetes Care 35:2618-2625, 2012". An evaluation method based on fluorescence intensity is preferred because experimental operations are simple.
＜Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤の配合＞
本発明のＴｏｘｉｃ ＡＧＥｓ生成抑制剤は、前記ケルセチン配糖体を含むものであればよく、前記ケルセチン配糖体のみからなるものであってもよいし、前記ケルセチン配糖体によるＴＡＧＥ生成抑制効果を妨げない限り、さらに賦形剤、安定化剤や湿潤剤や乳化剤等の公知の任意成分を含有してもよい。
<Combination of toxic AGEs generation inhibitor>
The toxic AGEs production inhibitor of the present invention may contain the quercetin glycoside, may consist only of the quercetin glycoside, or may suppress the TAGE production inhibitory effect of the quercetin glycoside. As long as they do not interfere, the composition may further contain known optional components such as excipients, stabilizers, wetting agents, and emulsifiers.
Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤に含まれる前記ケルセチン配糖体の割合は特に限定されない。例えば、本発明のＴｏｘｉｃ ＡＧＥｓ生成抑制剤が含む、前記ケルセチン配糖体の含有量の下限としては例えば、３０質量％、４０質量％、４５質量％、５０質量％、６０質量％、７０質量％が挙げられる。また、本発明のＴｏｘｉｃ ＡＧＥｓ生成抑制剤が含む、前記ケルセチン配糖体の含有量の上限としては例えば、１００質量％、９９質量％、９８質量％、９５質量％、９０質量％、８５質量％が挙げられる。本発明のＴｏｘｉｃ ＡＧＥｓ生成抑制剤が含む、前記ケルセチン配糖体の含有量の範囲としては、前記下限と上限とを任意に組み合わせた範囲を任意に設定することができ、例えば３０～１００質量％、６０～１００質量％、６０～９０質量％等の範囲を設定することができる。 The proportion of the quercetin glycoside contained in the toxic AGEs production inhibitor is not particularly limited. For example, the lower limit of the content of the quercetin glycoside contained in the Toxic AGEs production inhibitor of the present invention is, for example, 30% by mass, 40% by mass, 45% by mass, 50% by mass, 60% by mass, 70% by mass. can be mentioned. Further, the upper limit of the content of the quercetin glycoside contained in the Toxic AGEs production inhibitor of the present invention is, for example, 100% by mass, 99% by mass, 98% by mass, 95% by mass, 90% by mass, 85% by mass. can be mentioned. The range of the content of the quercetin glycoside contained in the toxic AGEs production inhibitor of the present invention can be arbitrarily set to any combination of the lower limit and upper limit, for example, 30 to 100% by mass. , 60 to 100% by mass, 60 to 90% by mass, and the like.
ケルセチン配糖体を含むＴｏｘｉｃ ＡＧＥｓ生成抑制剤としては、例えば、以下の市販品をあげることができる。東洋精糖(株)製の商品「αＧルチンＰＳ」は、α－モノグルコシルルチン７５質量％、イソケルシトリン１５質量％を含有する組成物である。また、同じく東洋精糖(株)製の商品「αＧルチンＰ」は、α－グルコシルルチン７０質量％、ルチン１５質量％を含有する組成物であり、これら商品をＴｏｘｉｃ ＡＧＥｓ生成抑制剤として使用することができる。 Examples of toxic AGEs production inhibitors containing quercetin glycosides include the following commercially available products. The product "αG Rutin PS" manufactured by Toyo Seito Co., Ltd. is a composition containing 75% by mass of α-monoglucosylrutin and 15% by mass of isoquercitrin. In addition, the product "αG Rutin P", also manufactured by Toyo Seito Co., Ltd., is a composition containing 70% by mass of α-glucosylrutin and 15% by mass of rutin, and these products can be used as toxic AGEs production inhibitors. Can be done.
＜Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤の用途＞
Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤は、ＧＥ-ＡＧＥ、ＡＡ-ＡＧＥ、およびＧＯ-ＡＧＥの生成を抑制する作用を有するので、例えば、生体におけるＴＡＧＥ量を低下、または増加を抑制する目的で、単回または複数回生体に投与することができる。
Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤は、血清アルブミンを対象としてＧＥ-ＡＧＥ、ＡＡ-ＡＧＥ、およびＧＯ-ＡＧＥの生成を抑制する作用を有する。また、ヒトへの長期間にわたる継続的な経口投与により血中ＴＡＧＥ濃度を低下、または増加を抑制させる効果を有する。したがって、前記Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤は、血中ＴＡＧＥ濃度の増加に起因する疾病の予防または改善に有用であり、例えば、糖尿病、心血管病、非アルコール性脂肪肝炎、がん、不妊症、アルツハイマー病等の発症、進展の予防に寄与する。
<Applications of Toxic AGEs generation inhibitor>
Toxic AGEs production inhibitors have the effect of suppressing the production of GE-AGE, AA-AGE, and GO-AGE, so for example, they can be administered once or multiple times for the purpose of reducing the amount of TAGE in living organisms or suppressing the increase. It can be administered to a regenerating body.
Toxic AGEs production inhibitors have the effect of inhibiting the production of GE-AGE, AA-AGE, and GO-AGE in serum albumin. In addition, continuous oral administration over a long period of time to humans has the effect of lowering or suppressing the increase in blood TAGE concentration. Therefore, the toxic AGEs production inhibitor is useful for preventing or ameliorating diseases caused by an increase in blood TAGE concentration, such as diabetes, cardiovascular disease, nonalcoholic steatohepatitis, cancer, infertility, and Alzheimer's disease. Contributes to preventing the onset and progression of diseases.
Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤は、コラーゲンを対象としてＧＥ-ＡＧＥの生成を抑制する作用を有する。したがって、前記Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤は、コラーゲンのＴＡＧＥ量増加に起因する疾病の予防または改善に有用であり、例えば、皮膚の老化、動脈硬化症、骨粗鬆症、骨強度低下、変形性関節症等の発症、進展の予防に寄与する。 Toxic AGEs production inhibitors have the effect of inhibiting the production of GE-AGEs targeting collagen. Therefore, the toxic AGEs production inhibitor is useful for preventing or ameliorating diseases caused by an increase in the amount of TAGE in collagen, such as skin aging, arteriosclerosis, osteoporosis, decreased bone strength, osteoarthritis, etc. Contributes to prevention of onset and progression.
Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤の投与量は、ＴＡＧＥ生成が関与する疾患の種類や症状の程度によって適宜選択すればよい。例えば、前記Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤を経口投与する場合は、ＴＡＧＥ生成抑制効果の観点から前記ケルセチン配糖体として一日あたり５０ｍｇ～６００ｍｇが好ましく、１００ｍｇ～３００ｍｇがさらに好ましい。また、前記一日あたり投与量を、例えば１日あたり１～３回にわけて投与することができ、２または３回にわけて投与するのが好ましい。 The dosage of the toxic AGEs production inhibitor may be appropriately selected depending on the type of disease in which TAGE production is involved and the severity of the symptoms. For example, when the toxic AGEs production inhibitor is orally administered, the amount of the quercetin glycoside per day is preferably 50 mg to 600 mg, more preferably 100 mg to 300 mg, from the viewpoint of the TAGE production inhibiting effect. Further, the above-mentioned daily dosage can be administered, for example, in 1 to 3 divided doses per day, preferably in 2 or 3 divided doses.
Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤の投与期間は、ＴＡＧＥ生成が関与する疾患の種類や症状の程度によって適宜選択すればよい。ＴＡＧＥ生成抑制効果の観点から、好ましくは７～８０日、より好ましくは１４日～６０日である。 The administration period of the toxic AGEs production inhibitor may be appropriately selected depending on the type of disease and the severity of the symptoms in which TAGE production is involved. From the viewpoint of TAGE production inhibiting effect, the period is preferably 7 to 80 days, more preferably 14 to 60 days.
Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤は、ヒトに少量を投与することで、ＴＡＧＥ生成を効率良く抑制することができる。ＴＡＧＥ生成が関与する疾患の種類や症状の程度にもよるが、前記効果は、特に血中のＴＡＧＥ濃度が例えば２０μｇ／ｍＬ以上、より好ましくは２５μｇ／ｍＬであるヒトに対して効果を発揮する。 Toxic AGEs production inhibitors can efficiently suppress TAGE production by administering a small amount to humans. Although it depends on the type of disease and the severity of symptoms in which TAGE production is involved, the above effects are particularly effective for humans whose blood TAGE concentration is, for example, 20 μg/mL or more, more preferably 25 μg/mL. .
＜Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤を含む製剤＞
Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤は、そのまま生体に投与してもよいし、前記Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤の有効量を薬学的に許容する担体とともに配合した製剤として投与してもよい。投与方法は特に制限されず、経口、または非経口とすることができる。製剤としては、例えば、飲食品、医薬品、医薬部外品、化粧品、飼料、ペットフードが挙げられ、飲食品、医薬品、医薬部外品、または化粧品が好ましい。
<Preparation containing toxic AGEs production inhibitor>
The toxic AGEs production inhibitor may be administered to a living body as it is, or may be administered as a preparation containing an effective amount of the toxic AGEs production inhibitor together with a pharmaceutically acceptable carrier. The method of administration is not particularly limited, and can be oral or parenteral. Examples of the formulation include food and beverages, pharmaceuticals, quasi-drugs, cosmetics, feeds, and pet foods, with food and beverages, pharmaceuticals, quasi-drugs, and cosmetics being preferred.
経口の場合、前記製剤は、飲食品（特定保健用食品、栄養機能食品、機能性表示食品等の保健機能食品や、その他のいわゆる健康食品やサプリメントを含む。）、医薬品、医薬部外品、飼料、ペットフード等であってもよい。前記製剤は、ＴＡＧＥ生成抑制効果を効果的に発現させるために、医薬品、医薬部外品または飲食品として経口投与することが好ましい。
非経口の場合、前記製剤は、注射剤、皮膚外用剤、坐剤等の医薬品、医薬部外品、または化粧品とすることができ、ＴＡＧＥ生成抑制効果を効果的に発現させるために、皮膚外用剤、医薬部外品、または化粧品とすることが好ましい。
In the case of oral administration, the above-mentioned preparations include foods and drinks (including foods with health claims such as foods for specified health uses, foods with nutritional function claims, foods with functional claims, and other so-called health foods and supplements), pharmaceuticals, quasi-drugs, It may be feed, pet food, etc. The preparation is preferably orally administered as a drug, quasi-drug, or food or drink in order to effectively exhibit the TAGE production inhibiting effect.
In the case of parenteral administration, the preparation can be a pharmaceutical, quasi-drug, or cosmetic such as an injection, an external preparation for skin use, or a suppository. It is preferable to use it as a drug, a quasi-drug, or a cosmetic.
前記製剤は、固形または液状（ペースト状を含む）にすることができる。剤形は制限されず、具体的には、固形製剤として、粉末剤、顆粒剤、錠剤、カプセル剤、トローチ等が挙げられる。また、液状製剤として内用液剤、外用液剤、懸濁剤、乳剤、シロップ剤、ドリンク剤、注射液、輸液等が例示され、これら剤形やその他の剤形が目的に応じて適宜選択される。投与が容易で、ＴＡＧＥ生成抑制効果を発揮しやすいことから、錠剤、またはカプセル剤とするのが好ましい。 The formulation can be in solid or liquid form (including paste form). The dosage form is not limited, and specific examples of solid preparations include powders, granules, tablets, capsules, and troches. In addition, examples of liquid preparations include internal solutions, external solutions, suspensions, emulsions, syrups, drinks, injections, and infusions, and these and other dosage forms are selected as appropriate depending on the purpose. . It is preferable to use tablets or capsules because they are easy to administer and exhibit the TAGE production inhibiting effect.
固形製剤においては賦形剤、結合剤、崩壊剤、潤沢剤、矯味剤、安定化剤などの補助剤を用いてもよい。固形製剤における賦形剤の好適な例としては、例えば乳糖、Ｄ－マンニトール、デンプンなどが挙げられる。結合剤の好適な例としては、例えば、結晶セルロース、白糖、Ｄ－マンニトール、糖アルコール、デキストリン、ヒドロキシプロピルセルロース等が挙げられる。崩壊剤の好適な例としては、例えば、デンプン、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム等が挙げられる。潤沢剤の好適な例としては、例えばステアリン酸カルシウム等が挙げられる。 In solid preparations, adjuvants such as excipients, binders, disintegrants, lubricants, flavoring agents, and stabilizers may be used. Suitable examples of excipients in solid preparations include lactose, D-mannitol, starch, and the like. Suitable examples of the binder include crystalline cellulose, white sugar, D-mannitol, sugar alcohol, dextrin, hydroxypropylcellulose, and the like. Suitable examples of disintegrants include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, and the like. Suitable examples of lubricants include, for example, calcium stearate.
液状製剤において、溶媒としては有効成分である前記ケルセチン配糖体を溶解させることができ、生体安全性が高いものが選択される。溶媒の好適な例としては、例えば、精製水、エタノール、プロピレングリコールなどが挙げられる。また、液状製剤は、溶解補助剤、懸濁剤、等張化剤、緩衝剤、抗酸化剤等の補助成分を含んでいてもよい。
。
In the liquid preparation, a solvent is selected that can dissolve the quercetin glycoside, which is an active ingredient, and has high biosafety. Suitable examples of the solvent include purified water, ethanol, propylene glycol, and the like. The liquid preparation may also contain auxiliary ingredients such as a solubilizing agent, a suspending agent, a tonicity agent, a buffering agent, and an antioxidant.
.
前記製剤は、前記固形製剤、前記液状製剤の他にも、例えば、果実飲料、ウーロン茶、緑茶、紅茶、ココア、野菜ジュース、青汁、豆乳、乳飲料、乳酸飲料、ニアウォーター、スポーツドリンク、栄養ドリンク等の飲料類、ゼリー、プリン、ヨーグルト等の洋菓子類、和菓子、調味料、魚肉加工品、畜産加工品等の飲食品；乳液、美容液、ローション、クリーム、パック、ファンデーション、化粧下地、口紅、洗顔料、シャンプー、ヘアトニック等の医薬品、医薬部外品または化粧品であってもよい。 In addition to the solid preparations and liquid preparations, the preparations include, for example, fruit drinks, oolong tea, green tea, black tea, cocoa, vegetable juice, green juice, soy milk, milk drinks, lactic acid drinks, near water, sports drinks, and nutrition. Beverages such as drinks, Western sweets such as jelly, pudding, yogurt, Japanese sweets, seasonings, processed fish products, processed livestock products, etc.; Emulsions, serums, lotions, creams, packs, foundations, makeup bases, lipsticks. , pharmaceuticals, quasi-drugs, or cosmetics such as facial cleansers, shampoos, and hair tonics.
上記Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤を含む製剤は、これらの製剤について一般的に用いられている手法に従って前記Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤を添加することにより製造することができる。前記Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤は、製剤の製造工程の初期に添加されるか、製造工程の中期または終期に添加されればよく、また添加の手法は、混和、混練、溶解、浸漬、散布、噴霧、塗布等から適切なものを製剤の態様に応じて選択すればよい。 A formulation containing the above toxic AGEs production inhibitor can be produced by adding the above toxic AGEs production inhibitor according to a method commonly used for these formulations. The toxic AGEs generation inhibitor may be added at the beginning of the manufacturing process of the preparation, or at the middle or end of the manufacturing process, and the addition method may be mixing, kneading, dissolving, dipping, spraying, or spraying. , application, etc., depending on the form of the formulation.
前記Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤の有効成分である前記ケルセチン配糖体は、水溶性が良好であるため、水または水分の多い製剤に添加する際も、均一に溶解または分散させることが可能である。 Since the quercetin glycoside, which is an active ingredient of the toxic AGEs production inhibitor, has good water solubility, it can be uniformly dissolved or dispersed even when added to water or a water-rich preparation.
前記Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤の製剤への配合量は、ＴＡＧＥ生成が関与する疾患の種類や症状の程度によって適宜選択すればよいが、投与の容易性や製剤中での安定性の観点から前記ケルセチン配糖体として、２０～６０質量％が好ましく、３０～５０質量％がさらに好ましい。 The amount of the toxic AGEs production inhibitor to be added to the formulation may be appropriately selected depending on the type of disease and the severity of symptoms in which TAGE production is involved, but from the viewpoint of ease of administration and stability in the formulation, the amount of the quercetin The amount of glycoside is preferably 20 to 60% by mass, more preferably 30 to 50% by mass.
以下、本発明を実施例に基づいて更に具体的に説明するが、本発明はこれら実施例に限定されない。 Hereinafter, the present invention will be explained in more detail based on Examples, but the present invention is not limited to these Examples.
［実施例１］アルブミンを対象としたＧＥ－ＡＧＥ生成試験
（方法）
ケルセチン配糖体によるＴＡＧＥ阻害作用の評価は、生成したＴＡＧＥの蛍光強度を測定する方法で行った。
０．２Ｍリン酸水素二カリウム溶液と０．１Ｍリン酸二水素カリウム溶液を混合して調製したリン酸カリウム緩衝液（ｐＨ７．４）に、ヒト血清アルブミン（和光純薬工業社製、終濃度０．５％）３ｍＬとグリセルアルデヒド（ナカライテスク社製、終濃度１０ｍＭ）３ｍＬを添加し、混合した。この混合液（ブランク）に、ケルセチン配糖体としてαＧルチンＰＳ（東洋精糖社製）３ｍＬ（溶媒：リン酸カリウム緩衝液）を終濃度が３０ｐｐｍ、６０ｐｐｍ、１２０ｐｐｍとなるように添加混合した。これらのサンプルを振盪機にセットし、１０日間３７℃でインキュベーションした。３日目と１０日目にサンプルを１．０ｍＬ採取し、４０％トリクロロ酢酸０．３３ｍＬを加えてタンパク質を凝固させた後、遠心分離して上澄み液を除去した。沈殿したタンパク質をリン酸カリウム緩衝液で溶解して測定用サンプルとした。測定用サンプルはマイクロプレートにＮ＝４で分注し、蛍光プレートリーダー（モレキュラーデバイスジャパン社製）を用い、励起波長３７０ｎｍで４４０ｎｍの蛍光強度を測定した。αＧルチンＰＳを添加していないサンプル（ブランク）の蛍光強度を１００として、各サンプルのＴＡＧＥ生成率（％）を算出した。なお、グリセルアルデヒドを終濃度で１０ｍＭ、３０ｍＭ、５０ｍＭ、ヒト血清アルブミンを終濃度で０．２％、０．５％とした予備試験を行い、最適な試験条件を検討した上で、上記の本試験を行った。
[Example 1] GE-AGE production test targeting albumin (method)
The TAGE inhibitory effect of quercetin glycosides was evaluated by measuring the fluorescence intensity of the generated TAGE.
Human serum albumin (manufactured by Wako Pure Chemical Industries, Ltd., final concentration 0.5%) and 3 mL of glyceraldehyde (manufactured by Nacalai Tesque, final concentration 10 mM) were added and mixed. To this mixture (blank), 3 mL of αG rutin PS (manufactured by Toyo Seito Co., Ltd.) as a quercetin glycoside (solvent: potassium phosphate buffer) was added and mixed at final concentrations of 30 ppm, 60 ppm, and 120 ppm. These samples were placed on a shaker and incubated at 37°C for 10 days. 1.0 mL of samples were collected on the 3rd and 10th day, 0.33 mL of 40% trichloroacetic acid was added to coagulate the protein, and the supernatant was removed by centrifugation. The precipitated protein was dissolved in potassium phosphate buffer to prepare a sample for measurement. Samples for measurement were dispensed into a microplate at N=4, and the fluorescence intensity at 440 nm was measured at an excitation wavelength of 370 nm using a fluorescence plate reader (manufactured by Molecular Devices Japan). The TAGE production rate (%) of each sample was calculated by setting the fluorescence intensity of the sample (blank) to which αG-rutin PS was not added as 100. In addition, after conducting a preliminary test using glyceraldehyde at a final concentration of 10mM, 30mM, and 50mM and human serum albumin at a final concentration of 0.2% and 0.5%, and considering the optimal test conditions, the above The main test was conducted.
（結果）
結果を図１に示す。３日目、１０日目においてαＧルチンＰＳの濃度依存的にＴＡＧＥの生成率が低くなっており、αＧルチンＰＳはＧＥ－ＡＧＥの生成抑制効果を有することがわかる。
(result)
The results are shown in Figure 1. On the 3rd and 10th days, the production rate of TAGE decreased depending on the concentration of αG-rutin PS, indicating that αG-rutin PS has the effect of suppressing the production of GE-AGE.
［実施例２］アルブミンを対象としたＡＡ－ＡＧＥ生成試験
（方法）
グリセルアルデヒドの代わりにアセトアルデヒド（ナカライテスク社製、終濃度５０ｍＭ）を用いた以外は、実施例１と同様にして試験を行った。なお、アセトアルデヒドを終濃度で１０ｍＭ、３０ｍＭ、５０ｍＭ、ヒト血清アルブミンを終濃度で０．２％、０．５％とした予備試験を行い、最適な試験条件を検討した上で、上記の本試験を行った。
[Example 2] AA-AGE production test targeting albumin (method)
The test was conducted in the same manner as in Example 1, except that acetaldehyde (manufactured by Nacalai Tesque, final concentration 50 mM) was used instead of glyceraldehyde. In addition, we conducted a preliminary test using acetaldehyde at a final concentration of 10mM, 30mM, and 50mM and human serum albumin at a final concentration of 0.2% and 0.5%, and after considering the optimal test conditions, we performed the above main test. I did it.
（結果）
結果を図２に示す。３日目、１０日目においてαＧルチンＰＳの濃度依存的にＴＡＧＥの生成率が低くなっており、αＧルチンＰＳはＡＡ－ＡＧＥの生成抑制効果を有することがわかる。
(result)
The results are shown in Figure 2. On the 3rd and 10th days, the production rate of TAGE decreased depending on the concentration of αG-rutin PS, indicating that αG-rutin PS has an effect of inhibiting the production of AA-AGE.
［実施例３］アルブミンを対象としたＧＯ－ＡＧＥ生成試験
（方法）
グリセルアルデヒドの代わりにグリコールアルデヒド（ナカライテスク社製、終濃度１０ｍＭ、または３０ｍＭ）を用い、ヒト血清アルブミンの終濃度を０．２％または０．５％の２点とした以外は、実施例１と同様にして試験を行った。
[Example 3] GO-AGE production test targeting albumin (method)
Example except that glycolaldehyde (manufactured by Nacalai Tesque, final concentration 10mM or 30mM) was used instead of glyceraldehyde, and the final concentration of human serum albumin was set at two points, 0.2% or 0.5%. The test was conducted in the same manner as in 1.
（結果）
グリコールアルデヒド１０ｍＭ、ヒト血清アルブミン０．５％での結果を図３に示す。また、グリコールアルデヒド１０ｍＭでの結果を図４、グリコールアルデヒド３０ｍＭでの結果を図５に示す。さらに、ヒト血清アルブミン０．２％での結果を図６、ヒト血清アルブミン０．５％での結果を図７に示す。
図４、５より、３日目、１０日目においてヒト血清アルブミンの濃度が高いほど、ＴＡＧＥ生成率は高くなる傾向にあり、ＴＡＧＥ生成は、ヒト血清アルブミン濃度依存的であることがわかる。また、αＧルチンＰＳの濃度依存的にＴＡＧＥの生成率が低くなっており、αＧルチンＰＳはＧＯ－ＡＧＥの生成抑制効果を有することがわかる。
図６、７より、３日目、１０日目においてグリコールアルデヒドの濃度が高いほど、ＴＡＧＥ生成率は高くなっており、ＴＡＧＥ生成は、グリコールアルデヒド濃度依存的であることがわかる。また、αＧルチンＰＳの濃度依存的にＴＡＧＥの生成率が低くなっており、αＧルチンＰＳはＧＯ－ＡＧＥの生成抑制効果を有することがわかる。
(result)
The results with 10 mM glycolaldehyde and 0.5% human serum albumin are shown in FIG. Further, the results with 10 mM glycolaldehyde are shown in FIG. 4, and the results with 30 mM glycolaldehyde are shown in FIG. Furthermore, the results with 0.2% human serum albumin are shown in FIG. 6, and the results with 0.5% human serum albumin are shown in FIG.
From FIGS. 4 and 5, it can be seen that the higher the concentration of human serum albumin is on the 3rd and 10th day, the higher the TAGE production rate tends to be, indicating that TAGE production is dependent on the human serum albumin concentration. Furthermore, the production rate of TAGE decreased depending on the concentration of αG-rutin PS, indicating that αG-rutin PS has the effect of inhibiting the production of GO-AGE.
From FIGS. 6 and 7, it can be seen that the higher the glycolaldehyde concentration on the 3rd and 10th day, the higher the TAGE production rate, and that the TAGE production is dependent on the glycolaldehyde concentration. Furthermore, the production rate of TAGE decreased depending on the concentration of αG-rutin PS, indicating that αG-rutin PS has the effect of inhibiting the production of GO-AGE.
［実施例４］コラーゲンを対象としたＧＥ－ＡＧＥ生成試験
（方法）
コラーゲン抗糖化アッセイキットグリセルアルデヒド（コスモバイオ社製、ＮＯ．ＡＫ－７１）を用いて、糖化したコラーゲンが発する蛍光（励起波長３７０ｎｍ、蛍光波長４４０ｎｍ）を指標として、ＧＥ－ＡＧＥ生成を評価した。コラーゲンゲルに緩衝液、緩衝液に溶解したαＧルチンＰＳ、または緩衝液に溶解したアミノグアニジンを添加した後、グリセルアルデヒドを終濃度５０ｍＭで添加し、３７℃のインキュベーター中に２４時間静置してから蛍光プレートリーダー（モレキュラーデバイスジャパン社製）にて蛍光強度を測定した。測定した蛍光強度から反応０時間での蛍光強度を差し引いて、糖化度とした。なお、アミノグアニジンは、ＡＧＥ生成抑制効果を有することが広く知られており、ＡＧＥ生成抑制効果のポジティブコントロールとして用いた。
[Example 4] GE-AGE production test targeting collagen (method)
Using collagen anti-glycation assay kit glyceraldehyde (manufactured by Cosmo Bio, NO. AK-71), GE-AGE production was evaluated using the fluorescence emitted by glycated collagen (excitation wavelength 370 nm, fluorescence wavelength 440 nm) as an indicator. . After adding a buffer solution, αG-rutin PS dissolved in the buffer solution, or aminoguanidine dissolved in the buffer solution to the collagen gel, glyceraldehyde was added at a final concentration of 50 mM, and the mixture was left standing in an incubator at 37°C for 24 hours. Then, the fluorescence intensity was measured using a fluorescence plate reader (manufactured by Molecular Devices Japan). The fluorescence intensity at 0 hours of reaction was subtracted from the measured fluorescence intensity to determine the degree of saccharification. Note that aminoguanidine is widely known to have an AGE production inhibitory effect, and was used as a positive control for the AGE production inhibitory effect.
（結果）
結果を図８に示す。αＧルチンＰＳ、およびアミノグアニジンの濃度依存的に糖化度が低くなっており、αＧルチンＰＳ、およびアミノグアニジンはＧＥ－ＡＧＥ生成抑制効果を有することがわかる。また、αＧルチンＰＳは、同一濃度で比較するとアミノグアニジンよりもＧＥ－ＡＧＥ生成抑制効果に優れることが分かる。
(result)
The results are shown in FIG. It can be seen that the degree of glycation of αG rutin PS and aminoguanidine decreases depending on the concentration, indicating that αG rutin PS and aminoguanidine have the effect of suppressing GE-AGE production. Furthermore, when compared at the same concentration, αG-rutin PS is found to be more effective in suppressing GE-AGE production than aminoguanidine.
［実施例５］試験食品摂取によるヒト試験
（方法）
３０歳以上６５歳未満の男性１２人を対象に、αＧルチンＰＳを配合した試験食品を８週間摂取させて、血中ＴＡＧＥ濃度の変化を調べた。なお、試験はヘルシンキ宣言に基づく倫理的原則、「人を対象とする医学系研究に関する倫理指針」および「個人情報の保護に関する法律」を遵守し、試験の参加について被験者本人の自由意思に基づいた同意を文書により取得した上で実施した。
[Example 5] Human test by ingestion of test food (Method)
Twelve men aged 30 to 65 were given a test food containing αG-rutin PS for 8 weeks, and changes in blood TAGE concentration were investigated. The study complied with ethical principles based on the Declaration of Helsinki, the "Ethical Guidelines for Medical Research Involving Human Subjects" and the "Act on the Protection of Personal Information," and the participation in the study was based on the free will of the subjects themselves. The study was conducted after obtaining written consent.
〔試験食品〕
試験食品としてはαＧルチンＰＳ錠（東洋精糖社製）を用いた。本試験食品は２００ｍｇ／粒の錠剤であり、１回３粒を１日１回摂取させた。本試験食品の組成を以下に示す。
（組成）
αＧルチンＰＳ ５０．０％
結晶セルロース ２５．０％
糖アルコール ２３．０％
ステアリン酸カルシウム ２．０％
合計 １００．０％
[Test food]
αG Rutin PS tablets (manufactured by Toyo Seito Co., Ltd.) were used as the test food. This test food was a 200 mg/tablet tablet, and three tablets were ingested once a day. The composition of this test food is shown below.
(composition)
αG Rutin PS 50.0%
Crystalline cellulose 25.0%
Sugar alcohol 23.0%
Calcium stearate 2.0%
Total 100.0%
〔被験者〕
被験者は、３０歳以上６５歳未満の男性１２人とし、以下の除外基準に該当する者を除いて選定した。
１．現在、重篤な疾患により投薬または通院治療を行っている者
２．試験食品にアレルギー発症のおそれがある者
３．試験に影響を及ぼす可能性のある薬剤を使用している者
４．極端な偏食をしている者
５．食事、睡眠などの生活習慣が極度に不規則な者
６．現在、他の臨床試験に参加している、もしくは過去３か月以内に他の治験に参加した者
７．その他、試験責任医師が試験の対象として不適当と判断した者
〔subject〕
The subjects were 12 men aged 30 to 65, excluding those who met the following exclusion criteria.
1. Persons currently receiving medication or outpatient treatment for a serious illness 2. 3. Persons who are at risk of developing an allergy to the test food. 4. Persons using drugs that may affect the test. 5. People who are extremely picky eaters. 6. Persons with extremely irregular lifestyle habits such as eating and sleeping. 7. Those who are currently participating in another clinical trial or have participated in another clinical trial within the past 3 months. Others who are judged by the study director to be unsuitable for the study.
〔試験手順〕
試験は非盲検試験とし、試験食品摂取前、摂取２週間後、４週間後、８週間後に被験者に来院してもらい、医師の監督のもと、身長、体重、血圧、脈拍の測定および採血を行った。
〔Procedure of test〕
The study was an open-label study, and subjects were asked to visit the hospital before ingesting the test food, and 2 weeks, 4 weeks, and 8 weeks after ingesting the test food, and under the supervision of a doctor, their height, weight, blood pressure, and pulse were measured, and blood was drawn. I did it.
〔測定方法〕
血液中の各測定項目は、常法により測定した。
血中ＴＡＧＥ濃度は、採血で得られた血液から血清を分離し、ＥＬＩＳＡ法で測定後、Ｇｌｙｃｅｒｙｌａｌｄｅｈｙｄｅ－ＡＧＥ－ＢＳＡを標準物質として濃度を求めた。
〔Measuring method〕
Each measurement item in the blood was measured by a conventional method.
Blood TAGE concentration was determined by separating serum from blood obtained by blood sampling, measuring by ELISA method, and determining the concentration using glycerylaldehyde-AGE-BSA as a standard substance.
（結果）
身長、体重、血圧、脈拍数の１２名の平均値と標準誤差を表１に示す。また、血液検査結果の１２名の平均値と標準誤差を表２に示す。
(result)
Table 1 shows the average values and standard errors of height, weight, blood pressure, and pulse rate for the 12 participants. In addition, Table 2 shows the average values and standard errors of the blood test results for the 12 people.
表１より、体重、ＢＭＩ、血圧、脈拍に有意な差はなかった。表２より、各種血液検査値の中で、有意差、または有意傾向のある変化は、ＬＤＬ－コレステロール値の上昇と、ＴＡＧＥ値の減少のみであった。血中ＴＡＧＥ濃度は、摂取開始時に比べ、２週後、４週後、８週後において減少する傾向にあった。 From Table 1, there were no significant differences in body weight, BMI, blood pressure, and pulse rate. From Table 2, among the various blood test values, the only significant differences or changes with a tendency to significance were an increase in LDL-cholesterol value and a decrease in TAGE value. The blood TAGE concentration tended to decrease after 2 weeks, 4 weeks, and 8 weeks compared to the beginning of intake.
１２名の各被験者における血中ＴＡＧＥ濃度の変化を表３に示す。また、表３をグラフ化したものを図９（被験者Ａ、Ｂ、Ｃ、Ｄ）、図１０（被験者Ｅ、Ｆ、Ｇ、Ｈ）、図１１(被験者Ｉ、Ｊ、Ｋ、Ｌ)、図１２（被験者１２名の平均値）に示す。 Table 3 shows the changes in blood TAGE concentration in each of the 12 subjects. In addition, graphs of Table 3 are shown in Fig. 9 (subjects A, B, C, D), Fig. 10 (subjects E, F, G, H), Fig. 11 (subjects I, J, K, L), Fig. 12 (average value of 12 subjects).
表３、図１２において、摂取開始時に比べ、試験食品摂取後は平均血中ＴＡＧＥ濃度が減少する傾向にあり、特に摂取４週間後においては有意に血中ＴＡＧＥ濃度が低下している。このことから、αＧルチンＰＳには血中ＴＡＧＥ濃度を低下、または上昇を抑制する効果があることがわかった。また、摂取開始時の血中ＴＡＧＥ濃度が特に高い被験者Ｅ、被験者Ｈ、被験者Ｉにおいて、試験食品摂取により血中ＴＡＧＥ濃度が大きく低下していた。αＧルチンＰＳによる効果は、血中ＴＡＧＥ濃度が高い場合にその効果が現れやすいものと推測された。 In Table 3 and FIG. 12, there is a tendency for the average blood TAGE concentration to decrease after ingestion of the test food compared to the time at the start of ingestion, and in particular, the blood TAGE concentration decreases significantly after 4 weeks of ingestion. From this, it was found that αG-rutin PS has the effect of lowering or suppressing the increase in blood TAGE concentration. Furthermore, in Subject E, Subject H, and Subject I, whose blood TAGE concentration was particularly high at the start of intake, the blood TAGE concentration significantly decreased after ingesting the test food. It was speculated that the effect of αG-rutin PS would be more likely to appear when the blood TAGE concentration is high.
Claims (2)
前記ケルセチン配糖体がα－グルコシルルチンであり、
グリセルアルデヒド、アセトアルデヒド、およびグリコールアルデヒドから選択される少なくとも一つを由来とするＴｏｘｉｃ ＡＧＥｓの生成を抑制する、
ヒトへ経口投与するための、Ｔｏｘｉｃ ＡＧＥｓ生成抑制剤。 A toxic AGEs production inhibitor containing quercetin glycoside,
the quercetin glycoside is α-glucosylrutin;
suppressing the production of Toxic AGEs derived from at least one selected from glyceraldehyde, acetaldehyde, and glycolaldehyde;
A toxic AGEs production inhibitor for oral administration to humans.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2019094423A JP7398207B2 (en) | 2019-05-20 | 2019-05-20 | Toxic AGEs generation inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2019094423A JP7398207B2 (en) | 2019-05-20 | 2019-05-20 | Toxic AGEs generation inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2020188689A JP2020188689A (en) | 2020-11-26 |
| JP7398207B2 true JP7398207B2 (en) | 2023-12-14 |
Family
ID=73452965
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2019094423A Active JP7398207B2 (en) | 2019-05-20 | 2019-05-20 | Toxic AGEs generation inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP7398207B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP7318082B2 (en) * | 2021-04-01 | 2023-07-31 | ライオン株式会社 | glycative stress inhibitor |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004059522A (en) | 2002-07-30 | 2004-02-26 | Fancl Corp | Long-acting rutin preparation |
| JP2014094966A (en) | 2010-02-10 | 2014-05-22 | Oriza Yuka Kk | Age production inhibitor |
| CN104000813A (en) | 2014-05-26 | 2014-08-27 | 徐州医学院 | Preventive and therapeutic effect of quercetin to diabetic cataract |
| WO2015083554A1 (en) | 2013-12-02 | 2015-06-11 | 株式会社林原 | 4G-O-α-D-GLUCOPYRANOSYLRUTIN CRYSTAL AND APPLICATION THEREOF |
| JP2017057163A (en) | 2015-09-16 | 2017-03-23 | 一般社団法人Ａｇｅ研究協会 | Ages formation inhibitor, drug for preventing/treating ages related disease, and supplement, functional food, and cosmetic compositions |
| JP2017145236A (en) | 2016-02-17 | 2017-08-24 | 一般社団法人Ａｇｅ研究協会 | Ages-related reaction inhibitor, prophylactic/therapeutic agent for ages-related diseases, and supplement, functional food, and cosmetic composition |
| JP2019043952A (en) | 2017-09-06 | 2019-03-22 | 東洋精糖株式会社 | AGENTS FOR IMPROVING INTESTINAL ENVIRONMENT AND INHIBITORS OF β-GLUCURONIDASE |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1302712B (en) * | ||||
| KR101253354B1 (en) * | 2006-08-09 | 2013-04-11 | (주)아모레퍼시픽 | Composition containing flavonol glycosides of green tea for inhibiting protein glycation reaction |
-
2019
- 2019-05-20 JP JP2019094423A patent/JP7398207B2/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004059522A (en) | 2002-07-30 | 2004-02-26 | Fancl Corp | Long-acting rutin preparation |
| JP2014094966A (en) | 2010-02-10 | 2014-05-22 | Oriza Yuka Kk | Age production inhibitor |
| WO2015083554A1 (en) | 2013-12-02 | 2015-06-11 | 株式会社林原 | 4G-O-α-D-GLUCOPYRANOSYLRUTIN CRYSTAL AND APPLICATION THEREOF |
| CN104000813A (en) | 2014-05-26 | 2014-08-27 | 徐州医学院 | Preventive and therapeutic effect of quercetin to diabetic cataract |
| JP2017057163A (en) | 2015-09-16 | 2017-03-23 | 一般社団法人Ａｇｅ研究協会 | Ages formation inhibitor, drug for preventing/treating ages related disease, and supplement, functional food, and cosmetic compositions |
| JP2017145236A (en) | 2016-02-17 | 2017-08-24 | 一般社団法人Ａｇｅ研究協会 | Ages-related reaction inhibitor, prophylactic/therapeutic agent for ages-related diseases, and supplement, functional food, and cosmetic composition |
| JP2019043952A (en) | 2017-09-06 | 2019-03-22 | 東洋精糖株式会社 | AGENTS FOR IMPROVING INTESTINAL ENVIRONMENT AND INHIBITORS OF β-GLUCURONIDASE |
Non-Patent Citations (6)
| Title |
|---|
| Chi-Hao WU et al.，Inhibitory Effect of Naturally Occurring Flavonoids on the Formation of Advanced Glycation Endproducts，Journal of Agricultural and Food Chemistry，2005年03月25日，Vol. 53, No. 8，pp. 3167-3173，DOI:10.1021/jf048550u |
| Hiroaki MURAMOTO et al.，Serum levels of advanced glycation end-products (AGEs) in dialysis patients，Nihon Toseki Igakkai Zasshi，2013年，Vol. 46, No. 5，pp.467-473，DOI: doi.org/10.4009/jsdt.46.467 |
| Takashi NAGASAWA et al.，Dietary G-rutin suppresses glycation in tissue proteins of streptozotocin-induced diabetic rats，Molecular and Cellular Biochemistry，Vol. 252, No. 1/2，2003年，pp.141-147 |
| Takashi NAGASAWA et al.，Inhibition of glycation reaction in tissue protein incubations by water soluble rutin derivative，Molecularand Cellular Biochemistry，2003年，Vol. 249、No. 1/2，pp.3-10，DOI: 10.1023/A:1024793429244 |
| Takashi NAGASAWA et al.，Suppression of early and advanced glycation by dietary water-soluble rutin derivative in diabetic rats，International Congress Series，2002年11月，Vol. 1245，pp.403-405，DOI:10.1016/S0531-5131(02)00949-4 |
| 糖化ストレスとアンチエイジング：１０．糖化ストレスと肝疾患，Glycative Stress Research［オンライン］，2018年，5(4)，pp. 177-180 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2020188689A (en) | 2020-11-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20160058782A1 (en) | Maillard reaction inhibitor | |
| KR100945825B1 (en) | Method of utilizing physiological activity of rare saccharide and compositions containing rare saccharide | |
| JP5207611B2 (en) | Saccharification inhibitor | |
| KR102567721B1 (en) | Composition for Prevention or Treatment of Metabolic Disorders or Muscular Diseases Comprising Extracellular Vesicles Derived from Lactobacillus bacteria | |
| JP7136765B2 (en) | Autophagy inducers and their uses | |
| JP2014037399A (en) | Anti-glycation agent and method for producing the same | |
| EP3035949B1 (en) | Sugar cane derived extracts and uses | |
| TWI671073B (en) | Agent for treating inflammatory diseases, which contains adenosine n1-oxide | |
| KR20230152614A (en) | Composition for improving cognitive function speed | |
| US20160279156A1 (en) | Composition for preventing or treating colon cancer, containing 3,6-anhydrol-galactose | |
| JP7398207B2 (en) | Toxic AGEs generation inhibitor | |
| JP2012219014A (en) | Anti-saccharification agent including soybean extract | |
| WO2003101466A1 (en) | Rubrofusarin glycoside-containing composition | |
| WO2009155097A1 (en) | Natural product inhibitors of 3dg | |
| JP2017145236A (en) | Ages-related reaction inhibitor, prophylactic/therapeutic agent for ages-related diseases, and supplement, functional food, and cosmetic composition | |
| JP2015010067A (en) | Liver function improvement formulation | |
| CN103372024A (en) | An inhibitor of the production of advanced glycation end products | |
| JP6170653B2 (en) | In vivo Maillard reaction inhibitor composition containing tranexamic acid | |
| JP6012138B2 (en) | Anti-glycation agent | |
| KR20170033101A (en) | Composition for improving liver function comprising citrulline as an active ingredient | |
| US9061022B2 (en) | Pharmaceutical composition for treating wounds or revitalizing skin comprising Euphorbia kansui extracts, fractions thereof or diterpene compounds separated from the fractions as active ingredient | |
| KR102318957B1 (en) | Composition for Prevention and Treatment of Metabolic Diseases Comprising Ginsenoside MC or MC1 | |
| JP6003018B2 (en) | Hepatoprotective agent, pharmaceutical composition, and composition for protecting cells, etc. | |
| KR102250906B1 (en) | Composition for Prevention and Treatment of Inflammatory Diseases Comprising Ginsenoside MC1 | |
| JP7455350B2 (en) | Damage inhibitors, cosmetics, and food and beverages caused by air pollutants |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20220311 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230404 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230529 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230711 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20230828 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20231020 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20231020 |
|
| 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: 20231114 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20231204 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 7398207 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |