CN109771411A - Dihydroquercetin is used to prepare the purposes in the drug for the treatment of fatty liver - Google Patents
Dihydroquercetin is used to prepare the purposes in the drug for the treatment of fatty liver Download PDFInfo
- Publication number
- CN109771411A CN109771411A CN201811412574.4A CN201811412574A CN109771411A CN 109771411 A CN109771411 A CN 109771411A CN 201811412574 A CN201811412574 A CN 201811412574A CN 109771411 A CN109771411 A CN 109771411A
- Authority
- CN
- China
- Prior art keywords
- dihydroquercetin
- group
- liver
- alcohol
- purposes
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- XCGZWJIXHMSSQC-UHFFFAOYSA-N dihydroquercetin Natural products OC1=CC2OC(=C(O)C(=O)C2C(O)=C1)c1ccc(O)c(O)c1 XCGZWJIXHMSSQC-UHFFFAOYSA-N 0.000 title claims abstract description 103
- CXQWRCVTCMQVQX-LSDHHAIUSA-N (+)-taxifolin Chemical compound C1([C@@H]2[C@H](C(C3=C(O)C=C(O)C=C3O2)=O)O)=CC=C(O)C(O)=C1 CXQWRCVTCMQVQX-LSDHHAIUSA-N 0.000 title claims abstract description 101
- 208000010706 fatty liver disease Diseases 0.000 title claims abstract description 37
- 231100000240 steatosis hepatitis Toxicity 0.000 title claims abstract description 20
- 208000004930 Fatty Liver Diseases 0.000 title claims abstract description 16
- 206010019708 Hepatic steatosis Diseases 0.000 title claims abstract description 16
- 239000003814 drug Substances 0.000 title claims abstract description 13
- 229940079593 drug Drugs 0.000 title claims description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 230000001476 alcoholic effect Effects 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 84
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound 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 14
- 231100000753 hepatic injury Toxicity 0.000 claims description 8
- 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 7
- 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 7
- 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 7
- 229960001285 quercetin Drugs 0.000 claims description 7
- 235000005875 quercetin Nutrition 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 206010067125 Liver injury Diseases 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 230000036541 health Effects 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 210000004185 liver Anatomy 0.000 abstract description 44
- 206010061218 Inflammation Diseases 0.000 abstract description 22
- 230000004054 inflammatory process Effects 0.000 abstract description 22
- 208000007082 Alcoholic Fatty Liver Diseases 0.000 abstract description 21
- 206010016262 Fatty liver alcoholic Diseases 0.000 abstract description 21
- 208000026594 alcoholic fatty liver disease Diseases 0.000 abstract description 21
- 230000000694 effects Effects 0.000 abstract description 17
- 208000022309 Alcoholic Liver disease Diseases 0.000 abstract description 11
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 abstract description 8
- 208000000501 Lipidoses Diseases 0.000 abstract description 5
- 206010024585 Lipidosis Diseases 0.000 abstract description 5
- -1 dihydroquercetin glycosides Chemical class 0.000 abstract description 5
- 239000004615 ingredient Substances 0.000 abstract description 5
- 231100000419 toxicity Toxicity 0.000 abstract description 3
- 230000001988 toxicity Effects 0.000 abstract description 3
- 229930182470 glycoside Natural products 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- 235000019441 ethanol Nutrition 0.000 description 74
- 150000002632 lipids Chemical class 0.000 description 29
- 241000699666 Mus <mouse, genus> Species 0.000 description 26
- 210000002966 serum Anatomy 0.000 description 26
- 125000003158 alcohol group Chemical group 0.000 description 23
- 235000002639 sodium chloride Nutrition 0.000 description 22
- 235000013305 food Nutrition 0.000 description 21
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 17
- 230000001154 acute effect Effects 0.000 description 13
- 210000005229 liver cell Anatomy 0.000 description 13
- 102000003777 Interleukin-1 beta Human genes 0.000 description 12
- 108090000193 Interleukin-1 beta Proteins 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 230000001965 increasing effect Effects 0.000 description 12
- 102100035904 Caspase-1 Human genes 0.000 description 10
- 108090000426 Caspase-1 Proteins 0.000 description 10
- 108010074436 Sterol Regulatory Element Binding Protein 1 Proteins 0.000 description 10
- 102100026839 Sterol regulatory element-binding protein 1 Human genes 0.000 description 10
- 102000000874 Pyrin Domain-Containing 3 Protein NLR Family Human genes 0.000 description 9
- 108010001946 Pyrin Domain-Containing 3 Protein NLR Family Proteins 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- 230000000474 nursing effect Effects 0.000 description 8
- 102100026715 Serine/threonine-protein kinase STK11 Human genes 0.000 description 7
- 101710181599 Serine/threonine-protein kinase STK11 Proteins 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- JTSLALYXYSRPGW-UHFFFAOYSA-N n-[5-(4-cyanophenyl)-1h-pyrrolo[2,3-b]pyridin-3-yl]pyridine-3-carboxamide Chemical compound C=1C=CN=CC=1C(=O)NC(C1=C2)=CNC1=NC=C2C1=CC=C(C#N)C=C1 JTSLALYXYSRPGW-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 230000007423 decrease Effects 0.000 description 6
- 230000003247 decreasing effect Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000011049 filling Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 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
- 241000282414 Homo sapiens Species 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 230000008021 deposition Effects 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 230000035611 feeding Effects 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 210000004969 inflammatory cell Anatomy 0.000 description 4
- 230000008520 organization Effects 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 230000007863 steatosis Effects 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 238000001262 western blot Methods 0.000 description 4
- 238000011740 C57BL/6 mouse Methods 0.000 description 3
- 229920002774 Maltodextrin Polymers 0.000 description 3
- 239000005913 Maltodextrin Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- NPGIHFRTRXVWOY-UHFFFAOYSA-N Oil red O Chemical compound Cc1ccc(C)c(c1)N=Nc1cc(C)c(cc1C)N=Nc1c(O)ccc2ccccc12 NPGIHFRTRXVWOY-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- 238000004043 dyeing Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 150000004676 glycans Chemical class 0.000 description 3
- 230000008595 infiltration Effects 0.000 description 3
- 238000001764 infiltration Methods 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 229940035034 maltodextrin Drugs 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 238000006384 oligomerization reaction Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 229940032147 starch Drugs 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 206010048998 Acute phase reaction Diseases 0.000 description 2
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 2
- 108010082126 Alanine transaminase Proteins 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 206010019663 Hepatic failure Diseases 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 108090000364 Ligases Proteins 0.000 description 2
- 102000003960 Ligases Human genes 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- SEBFKMXJBCUCAI-UHFFFAOYSA-N NSC 227190 Natural products C1=C(O)C(OC)=CC(C2C(OC3=CC=C(C=C3O2)C2C(C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 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
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 229930003935 flavonoid Natural products 0.000 description 2
- 150000002215 flavonoids Chemical class 0.000 description 2
- 235000017173 flavonoids Nutrition 0.000 description 2
- 230000030279 gene silencing Effects 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 210000003494 hepatocyte Anatomy 0.000 description 2
- 235000009200 high fat diet Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 208000007903 liver failure Diseases 0.000 description 2
- 231100000835 liver failure Toxicity 0.000 description 2
- 210000005228 liver tissue Anatomy 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 206010036067 polydipsia Diseases 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000003223 protective agent Substances 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- SEBFKMXJBCUCAI-HKTJVKLFSA-N silibinin Chemical compound C1=C(O)C(OC)=CC([C@@H]2[C@H](OC3=CC=C(C=C3O2)[C@@H]2[C@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-HKTJVKLFSA-N 0.000 description 2
- 229960004245 silymarin Drugs 0.000 description 2
- 235000017700 silymarin Nutrition 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- YUXKOWPNKJSTPQ-AXWWPMSFSA-N (2s,3r)-2-amino-3-hydroxybutanoic acid;(2s)-2-amino-3-hydroxypropanoic acid Chemical compound OC[C@H](N)C(O)=O.C[C@@H](O)[C@H](N)C(O)=O YUXKOWPNKJSTPQ-AXWWPMSFSA-N 0.000 description 1
- 230000006269 (delayed) early viral mRNA transcription Effects 0.000 description 1
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- YGZFYDFBHIDIBH-UHFFFAOYSA-N 2-[bis(2-hydroxyethyl)amino]icosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCC(CO)N(CCO)CCO YGZFYDFBHIDIBH-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- AEDQNOLIADXSBB-UHFFFAOYSA-N 3-(dodecylazaniumyl)propanoate Chemical compound CCCCCCCCCCCCNCCC(O)=O AEDQNOLIADXSBB-UHFFFAOYSA-N 0.000 description 1
- 102100032814 ATP-dependent zinc metalloprotease YME1L1 Human genes 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000000452 Acetyl-CoA carboxylase Human genes 0.000 description 1
- 108010016219 Acetyl-CoA carboxylase Proteins 0.000 description 1
- 102100031786 Adiponectin Human genes 0.000 description 1
- 108010076365 Adiponectin Proteins 0.000 description 1
- 244000291564 Allium cepa Species 0.000 description 1
- 235000002732 Allium cepa var. cepa Nutrition 0.000 description 1
- 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 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108010018763 Biotin carboxylase Proteins 0.000 description 1
- RZYKUPXRYIOEME-UHFFFAOYSA-N CCCCCCCCCCCC[S] Chemical compound CCCCCCCCCCCC[S] RZYKUPXRYIOEME-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 206010019837 Hepatocellular injury Diseases 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 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 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- BAWFJGJZGIEFAR-NNYOXOHSSA-O NAD(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-O 0.000 description 1
- 102000012064 NLR Proteins Human genes 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102100032361 Pannexin-1 Human genes 0.000 description 1
- 101710165201 Pannexin-1 Proteins 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 101800000795 Proadrenomedullin N-20 terminal peptide Proteins 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 240000001416 Pseudotsuga menziesii Species 0.000 description 1
- 235000005386 Pseudotsuga menziesii var menziesii Nutrition 0.000 description 1
- 241001480055 Quercus mongolica Species 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- ZONYXWQDUYMKFB-UHFFFAOYSA-N SJ000286395 Natural products O1C2=CC=CC=C2C(=O)CC1C1=CC=CC=C1 ZONYXWQDUYMKFB-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000320380 Silybum Species 0.000 description 1
- 235000010841 Silybum marianum Nutrition 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 1
- 241000218636 Thuja Species 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 206010046274 Upper gastrointestinal haemorrhage Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000035508 accumulation Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000009692 acute damage Effects 0.000 description 1
- 230000004658 acute-phase response Effects 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002300 anti-fibrosis Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- ZROGCCBNZBKLEL-MPRHSVQHSA-N astilbin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@H]1C(=O)C2=C(O)C=C(O)C=C2O[C@@H]1C1=CC=C(O)C(O)=C1 ZROGCCBNZBKLEL-MPRHSVQHSA-N 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 108010051210 beta-Fructofuranosidase Proteins 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000006567 cellular energy metabolism Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000019439 energy homeostasis Effects 0.000 description 1
- 229940031098 ethanolamine Drugs 0.000 description 1
- 230000004129 fatty acid metabolism Effects 0.000 description 1
- 230000004136 fatty acid synthesis Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 229930003949 flavanone Natural products 0.000 description 1
- 150000002207 flavanone derivatives Chemical class 0.000 description 1
- 235000011981 flavanones Nutrition 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000004459 forage Substances 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 231100000437 hepatocellular injury Toxicity 0.000 description 1
- 235000008216 herbs Nutrition 0.000 description 1
- 230000001744 histochemical effect Effects 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000001573 invertase Substances 0.000 description 1
- 235000011073 invertase Nutrition 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000006372 lipid accumulation Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 101150115478 lkb1 gene Proteins 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 235000004213 low-fat Nutrition 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- LTYOQGRJFJAKNA-IJCONWDESA-N malonyl-coenzyme a Chemical compound O[C@@H]1[C@@H](OP(O)(O)=O)[C@H](CO[P@](O)(=O)O[P@@](O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CC(O)=O)O[C@H]1N1C2=NC=NC(N)=C2N=C1 LTYOQGRJFJAKNA-IJCONWDESA-N 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- WVJKHCGMRZGIJH-UHFFFAOYSA-N methanetriamine Chemical compound NC(N)N WVJKHCGMRZGIJH-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 1
- 235000021590 normal diet Nutrition 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- PIRWNASAJNPKHT-SHZATDIYSA-N pamp Chemical compound C([C@@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)N)C(C)C)C1=CC=CC=C1 PIRWNASAJNPKHT-SHZATDIYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000003950 pathogenic mechanism Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 235000010204 pine bark Nutrition 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 238000007447 staining method Methods 0.000 description 1
- 235000000891 standard diet Nutrition 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 102000014898 transaminase activity proteins Human genes 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to dihydroquercetins or its pharmaceutically acceptable salt in the purposes for treating fatty liver.Specifically, the dihydroquercetin or its pharmaceutically acceptable salt the purposes for the treatment of alcoholic fatty liver and the dihydroquercetin or its pharmaceutically acceptable salt treatment nonalcoholic fatty liver purposes.The present invention relates to the wider medical usage of dihydroquercetin glycosides, it is made to be applied in preparation treatment alcoholic liver medicine.It can be in the therapeutic effect of the initial stage of alcoholic liver disease by dihydroquercetin;Meanwhile the ingredient has the characteristics that small toxicity, and has significant relaxation effect to lipidosis in alcoholic liver disease and inflammatory reaction.
Description
Technical field
The present invention relates to the purposes that a kind of dihydroquercetin or its pharmaceutically acceptable salt are used to prepare treatment fatty liver.
The present invention relates to the wider medical usage of dihydroquercetin glycosides, answer it in preparation treatment alcoholic liver medicine
With.
Background technique
Flavone compound is a large amount of ingredients being widely present in most of Chinese traditional herbs, and dihydroquercetin is in ocean
The most abundant flavanone found in green onion, milk thistle and star-spangled banner pine bark (Pseudotsuga taxifolia).Dihydroquercetin
It is widely used in food and care industry as food additives, and studies have shown that dihydroquercetin has a variety of pharmacology
Activity, such as antiviral, anti-inflammatory, anti-oxidant and anti-fibrosis.So far, main research is around dihydroquercetin
Potent oxidation resistance, dihydroquercetin can be by inhibiting fatty acid synthetase to the rouge of prostate cancer and breast cancer cell
Fat generation shows effective rejection characteristic.In addition, dihydroquercetin is found in approved hepatic silymarin
A kind of unique flavonoids.
Whether there is excessive drinking history according to Patients with Fatty Liver, is broadly divided into alcoholic fatty liver and non-alcoholic fatty
Liver.Nonalcoholic fatty liver is mainly related to insulin resistance, metabolic syndrome, and illness rate is higher in obese people.
Clinically nonalcoholic fatty liver can be divided into acute and chronic.Although acute nonalcoholic fatty liver disease is more rare, by
It can lead to the diseases such as some renal failures in acute nonalcoholic fatty liver, therefore cannot ignore.Chronic non-alcoholic fatty
Liver is more common compared to for acute, and the state of an illness slowly develops and hidden the characteristics of being, and will increase the wind for suffering from cardiovascular and cerebrovascular disease
Danger.Acute alcoholic fatty liver, which refers to, once to be drunk excessive alcohol or spills alcoholic liver disease caused by class beverage.Often it is accompanied by
Hepatic cell fattydegeneration, hepatocellular injury and inflammatory cell infiltration can be further development of liver fibrosis, liver if continuing to drink
Hardening even liver cancer, and can concurrent liver failure and upper gastrointestinal bleeding etc..It is bad that extensive liver cell can be induced when serious excessive drinking
Extremely or even liver failure.Although pathogenesis and protective agents of many researchers to alcoholic fatty liver for many years
It has made extensive and intensive studies, but since the organism metabolism process of alcohol is extremely complex, Different Individual is to Ethanol intake
Response difference is larger, and the definite occurrence and development process of alcoholic liver disease and pathomechanism are also indefinite so far, and also shortage makes us full
The intervention means of meaning include effectively protective agents, and therefore, the therapeutic agent for urgently finding natural alcoholic liver disease becomes ten
Divide important.
Summary of the invention
In view of prior art disadvantage, the purpose of the present invention is to provide dihydroquercetins or its pharmaceutically acceptable salt to exist
The purposes for treating fatty liver.
Purposes of the present invention, the dihydroquercetin or its pharmaceutically acceptable salt are in treatment alcoholic fatty liver
Purposes.
Purposes of the present invention, the dihydroquercetin or its pharmaceutically acceptable salt are in treatment non-alcoholic fatty
The purposes of liver.
Purposes of the present invention, wherein dihydroquercetin or its pharmaceutically acceptable salt are included in single formulation
In.
Purposes of the present invention, wherein dihydroquercetin or its pharmaceutically acceptable salt are configured to medicine group respectively
It closes object and is applied in combination.
Purposes of the present invention, wherein the dihydroquercetin or its pharmaceutically acceptable salt concentration are
121.8mg/ daily/60kg or more.
Purposes of the present invention, wherein the dihydroquercetin or its pharmaceutically acceptable salt concentration are dihydro Mongolian oak
Skin element administration concentration is 25mg/kg~100mg/kg.
The second aspect of the present invention provides a kind of dihydroquercetin or its pharmaceutically acceptable salt in preparation prevention and controls
Treat the purposes in the drug of alcoholic liver injury.
A kind of dihydroquercetin of the third aspect of the present invention or its pharmaceutically acceptable salt are in preparation prevention and treatment wine
Purposes in the health care product of essence hepatic injury.
A kind of dihydroquercetin of the fourth aspect of the present invention or its pharmaceutically acceptable salt are in preparation prevention and treatment wine
Purposes in the drink of essence hepatic injury.
It is found after the present inventor concentrates on studies, dihydroquercetin can be changed by LKB1-AMPK signal path
Lipidosis caused by kind alcohol exposure;Dihydroquercetin can improve alcohol exposure by NLRP3 inflammation corpusculum signal path
Cause inflammatory reaction.There can be relaxation effect in the initial stage of alcoholic liver disease by dihydroquercetin;Meanwhile the ingredient
Have the characteristics that small toxicity, and has significant relaxation effect to lipidosis in alcoholic liver disease and inflammatory reaction.Specifically,
Dihydroquercetin to alcoholic fatty liver caused by alcohol have good inhibiting effect, while to alcoholic fatty liver with
Inflammation has good improvement result, and cheap.Dihydroquercetin can be by inhibiting fatty acid synthetase to prostate
The fat of cancer and breast cancer cell, which generates, shows effective rejection characteristic, in addition, dihydroquercetin is in approved liver protection
The unique a kind of flavonoids found in drug silymarin.
Detailed description of the invention
Fig. 1 shows dihydroquercetin to the testing result of chmice acute alcoholic fatty liver model biochemical indicator;
Influence Fig. 2 shows dihydroquercetin to carousing alcoholic fatty liver mouse liver tectology;
Fig. 3 shows influence of the dihydroquercetin to acute alcoholic fatty liver mouse liver tectology;
Fig. 4 shows the influence of inflammation corpusculum activation of the dihydroquercetin to chmice acute alcoholic fatty liver;
It is horizontal that Fig. 5 shows lipopexia and inflammatory factor expression in the HepG2 cell that dihydroquercetin stimulates alcohol
It influences;
Fig. 6 shows the influence of lipopexia in dihydroquercetin P2X7R dependence regulation alcohol stimulation HepG2 cell;
Fig. 7 shows influence of the dihydroquercetin to every biochemical indicator of mice serum and liver;
Fig. 8 shows influence (200 times) of the dihydroquercetin to murine liver tissue oil red fat stains.
Specific embodiment
In the following, a detailed description of the technical solution in the embodiment of the present invention is provided, it is clear that described embodiment is only
It is a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, ordinary skill people
Member's every other embodiment obtained without making creative work, shall fall within the protection scope of the present invention.
It should be noted that in the present invention, term " basic " or the meaning that " complete " " substantially " is not precluded.Such as one
A ingredient substantially free Y, is also possible to be entirely free of Y.In the case where limiting specific value, refer to the specific value
With the range to float up and down based on the specific value, floating range can be +/- the 5% of the specific value, +/-
4%, +/- 3%, +/- 2%, +/- 1%, +/- 0.5%, +/- 0.2%, +/- 0.1%, +/- 0.05%, +/- 0.01% etc..Such as
Fruit needs, " basic " or " substantially " can above floating range replace or deleted from of the invention define.
" containing " had both included the factor mentioned, and also allowed to include additional, uncertain factor.
" about ", " about ", " left and right " in the case where limiting specific value, refer to the specific value have with the specific number
The range to float up and down based on value, floating range can be +/- the 5% of the specific value, and +/- 4%, +/- 3%, it is +/-
2%, +/- 1%, +/- 0.5%, +/- 0.2%, +/- 0.1%, +/- 0.05%, +/- 0.01% etc..
"and/or" indicates respectively be used alone by multiple terms of its connection, mutually can also arbitrarily combine.
In the present invention, the numberical range used for simplicity not only includes its endpoint value, also includes its all son
Range and individual numerical value all within the scope of this.For example, numberical range 1-6 not only includes subrange, such as 1-3,1-4,1-
5,2-4,2-6,3-6 etc., also including individual numerical value within the scope of this, such as 1,2,3,4,5,6.
The dihydroquercetin is the compound that the double bond between 2 of the pyranoid ring of Quercetin and 3 is reduced, at this
In invention, the example of the pharmaceutically acceptable salt of the dihydroquercetin includes and salt formed by inorganic base and organic base institute
At salt, with salt etc. formed by basic amino acid.
Example with salt formed by inorganic base includes and alkali metal (such as sodium, potassium etc.), alkaline-earth metal (such as calcium, magnesium etc.)
And salt formed by aluminium, ammonium etc..Example with salt formed by organic base include with trimethylamine, triethylamine, pyridine, picoline,
Ethanol amine, diethanol amine, triethanolamine, dicyclohexylamine, N, salt formed by N- dibenzyl-ethylenediamin etc..With basic amino acid institute
At the example of salt include and arginine, lysine.
Medicament of the invention can be formulated into, such as pharmaceutical composition, such as tablet (including sugar coated tablet, film coating
Piece), powder, granule, capsule (including soft capsule), liquid agent, injection, suppository, sustained release preparation is (for example, be sustained micro- glue
Capsule) or quick releasing formulation, and safely oral administration or parenteral administration (for example, part, rectum, intravenous administration etc.).Institute
Stating injection can be used in administration in intravenous, intramuscular, subcutaneous or organ, or can be directly applied to lesion.
The pharmacologically acceptable carrier that can be used in preparing medicament of the invention includes conventional use of various
Organic or inorganic carrier substance, such as the excipient for solid pharmaceutical preparation, lubricant, adhesive and disintegrating agent are used for liquid system
Solvent, solubilizer, suspending agent, isotonic agent, buffer and soothing agent of agent etc..In addition, if necessary, can also use appropriate
Universal additive, such as preservative, antioxidant, colorant, sweetener, adsorbent, wetting agent etc..
In the present invention, the example of the excipient includes: lactose, sucrose, PEARLITOL 25C, starch, cornstarch, crystallization
Cellulose, light anhydrous silicic acid etc..
In the present invention, the example of the lubricant includes magnesium stearate, calcium stearate, talcum, colloidal silicon dioxide etc..
In the present invention, the example of described adhesive includes avicel cellulose, sucrose, PEARLITOL 25C, dextrin, hydroxypropyl fibre
Tie up element, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, starch, gelatin, methylcellulose, sodium carboxymethylcellulose etc..
In the present invention, the example of the disintegrating agent includes starch, carboxymethyl cellulose, calcium carboxymethylcellulose, carboxylic first
Base sodium starch, L- hydroxypropyl cellulose etc..
In the present invention, the example of the solvent includes water for injection, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn
Oil, olive oil etc..
In the present invention, the example of the solubilizer includes polyethylene glycol, propylene glycol, PEARLITOL 25C, Ergol, second
Alcohol, Trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate etc..
In the present invention, the example of the suspending agent includes: surfactant, such as stearyl triethanolamine, lauryl sulphur
Sour sodium, lauryl amino propionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate etc.;Hydrophilic polymer, such as
Polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose,
Hydroxypropyl cellulose etc.;Etc..
In the present invention, the example of the isotonic agent includes glucose, D-glucitol, sodium chloride, glycerol, PEARLITOL 25C
Deng.
In the present invention, the example of the buffer include such as phosphate, acetate, carbonate, citrate it is slow
Electuary etc..
In the present invention, the dihydroquercetin significantly inhibits the liver cell lipopexia of AMPK mediation and P2X7R is mediated
Inflammatory response.The dihydroquercetin has no the side reaction for fat deposition and inflammation under 25mg/kg dosage.According to medicine
Object human trial safety risk management planning guide principle (U.S. FDA U.S. sanitary and the formulation of public service portion) for the first time, for
Adult healthy volunteer, it is every that the mouse dosage of 25mg/kg dihydroquercetin is equivalent to 121.8mg/ in clinical phase test
It/dosage of 60kg normal adult is the optimal dose that human body is normally taken in daily.
Embodiment
The present invention uses 10 week old, and the male C57BL/6 mouse of 20~25g of weight is purchased from this experimental animal section of Changchun hundred million
Skill Co., Ltd (Jilin, China), all mouse keep the periodicity of illumination round the clock of 12h/12h during test, and living environment is kept
In temperature ± 23 ± 2 DEG C, humidity 55 ± 5%.Guarantee balanced standard diet and sufficient drinking public water supply.In the present invention,
C57BL/6 mouse adapts to be randomly divided into six groups after a week: normal group, alcohol group is administered alone group, and alcohol adds low dose group, wine
Finishing middle dose group, alcohol increase dosage group, every group of 10 mouse.Method is as follows: normal group gives solid feed;It is administered alone
Group gives dihydroquercetin by 25mg/ml weight;Alcohol group gives 33% alcohol;Be administered low middle high dose group by 1mg/ml,
5mg/ml, 25mg/ml weight give 33% alcohol after giving dihydroquercetin respectively;Dihydroquercetin and alcohol are total every 12 hours
To 3 times, give for the 3rd time after 4 hours of dihydroquercetin and alcohol to heart puncturing extracting blood after all mouse etherizations, and
Anatomical isolation liver.Serum is left and taken after blood 3000rpm centrifugation, liver great Ye, which is immersed in neutral formalin solution, to be retained,
Liver leaflet is dispensed into -80 DEG C of keepings in 1.5ml centrifuge tube.
In C57BL/6 chmice acute alcoholic hepatic injury model, normal group mouse liver lobuli hepatis structure is complete;Alcohol group
Occur a large amount of fat bubbles not of uniform size around mouse liver portal area, liver cell balloon sample, which becomes apparent, waits pathological changes;It gives
Medicine group is significantly reduced with the increase steatosis of administration concentration, has been approached normal group.
Alcohol is considered causing fatty liver by changing liver NADH/NAD+ ratio, that is, inhibits fatty acid oxidation and stimulation
Fat generates.It has recently been demonstrated that Ethanol intake may directly affect the activity of AMP deopendent protein kinase (AMPK).
AMPK is a kind of protein kinase that energy and metabolic balance are adjusted in liver, heart, skeletal muscle, is that adiponectin plays biology
The key signal molecule of effect.The activation of liver AMPK can increase fatty acid oxidation, reduce the synthesis of fat, inhibit glycogen and gallbladder
Sterol synthesis adjusts energy homeostasis balance.AMPK is called " switch for adjusting cellular energy metabolism ", and AMPK is that liver adjusts rouge
The important target spot of matter metabolic balance.The mouse AMPK activity inhibited of feeding ethyl alcohol, AMPK can be by inhibiting acetyl-coa carboxylase
Enzyme (ACC) reduces malonyl coenzyme A to control fatty acid metabolism.AMPK also can be by inhibiting SREBP-1 to inhibit fatty acid
Synthesis, a kind of transcription factor that lipid can be promoted to generate related gene.Research finds that the activation of AMPK needs upstream kinases pair
Thr172 carries out phosphorylation to complete on AMPK α subunit activation ring.LKB1 is called STK11 (Serine Threonine
Protein Linase 11) it is the silk gas acid/Serineprotein kinase family member encoded by lkb1 gene, it is a kind of suppression
Cancer factor.When body is by that stress lead to energy consumption, LKB1 with phosphorylation and can activate AMPK, come alleviate stress, protection
Animal body.Identical conclusion can also be obtained in the present invention, it is aobvious in the western blot result of acute alcohol mouse liver injury models
The decline of alcohol group AMPK and LKB1 expression, the raising of ACC and SREBP-1 expression are shown.Dihydroquercetin administration group is with giving
The increase AMPK and LKB1 of concentration express significantly raised, ACC and the apparent decline of SREBP-1 expression.
In order to further confirm, it is respectively 100nM, 25nM, 12.5nM bis- that HepG2 cell, which gives concentration, in vitro experiment
Large dosage of alcohol inducing hepatocyte damage is given at hydrogen Quercetin, interval after 1 hour, albumen is scraped after 24 hours in -80 DEG C of keepings.
Also the identical conclusion of above-mentioned experiment in vivo is obtained in experiment in vitro, illustrates that dihydroquercetin can be influenced by adjusting the note living of enzyme
Lipid metaboli inhibits the synthesis of liver fat.
Alcoholic liver disease (ALD) is characterized in that liver lipid accumulation (steatosis) and inflammatory reaction, increases inflammatory cell
The expression of the factor.Two kinds in these cell factors, interleukin-1 ' beta ' (IL-1 β) and IL-18 are needed through NOD sample receptor
(NLR) member of family activates caspase-1 (caspase-1).When inflammatory reaction, local Extracellular ATP concentration is increased,
In conjunction with and activate P2X7R receptor formed duct, lead to K+Outflow and Ca2+Interior stream, cell membrane potential change, and make the dye being coupled with it
Material absorption duct pannexin-1 is open to form duct, allows bacterial product by entering cell with Extracellular ATP, while promoting core
Thuja acid combination oligomerization domain sample receptor family (Nucleotide-binding oligomerization domain like
Receptors, NLRs) inflammation corpusculum NLRP3 assembly, the pathogen-associated molecular patterns such as NLRP3 and virus, opsonigenous substance
(Pathogen Associated Molecular pattern, PAMP) changes in conjunction with rear conformation, its functional structure of exposure
Domain, then oligomerization, and Caspase-1 precursor is raised by The homotype interaction, lead to its conformational change, generates activity
Caspase-1, that is, IL-1 invertase, be responsible for for inactive IL-1 β, IL-18 precursor being cut into the functional inflammatory cell of tool because
Son.The expression of P2X7R and NLRP3 obviously increases around central vein in alcohol group;Administration group compared with alcohol group, the two
Expression is remarkably decreased;Compared with normal group, the expression of the two does not change significantly dihydroquercetin control group.Alcohol group with
Normal group compares, and the content of IL-1 β dramatically increases in serum;For administration group compared with alcohol group, the content of -1 β of serum IL is significant
Decline.The expression of Pro-IL-1 β and Caspase-1 in liver organization are observed, in alcohol group Pro-IL-1 β and
The expression of Caspase-1 significantly increases, and the expression of Pro-IL-1 β and Caspase-1 are obviously pressed down in liver organization after administration
System.HepG2 cell gives LPS after giving dihydroquercetin one hour, ATP is given after 24 hours, -80 DEG C of albumen are scraped after 30 minutes
It takes care of, is also obtained for above-mentioned identical conclusion in experiment in vitro.
Fig. 1 shows biochemical indicator testing result, in the present invention, the measurement of Triglycerides in Serum (Serum TG) according to
Following methods carry out: eyeball of mouse takes blood, stands, and 3000 turns/min is centrifuged 10min, isolates serum.
1) gradient dilution is carried out with the titer of 200mg/ml concentration, prepares 0mg/ml, 6.25mg/ml, 12.5mg/ altogether
The standard of ml, 25mg/ml, 50mg/ml, 100mg/ml, 200mg/ml various concentration is put into the Tube of 7 different 1.5ml
In.250 μ l working reagents are added in the Tube of each 1.5ml.It is and 250 μ l working reagents is only added in the Tube of blank.Into
Row is vortexed, after centrifugation, is put into 37 DEG C of water-baths 15 minutes.After 15 minutes, 500 μ l distilled water are added in each Tube, into
Row is vortexed, is centrifuged, and makes to be uniformly mixed.
2) in sample Tube, 48 different blood of 250 μ l working reagents and 5 μ l are put into the Tube of each 1.5ml
Clearly.After being vortexed, being centrifuged, it is put into 37 DEG C of water-baths 15 minutes.After 15 minutes, 500 μ l distilled water are added in each Tube,
It is being vortexed, is being centrifuged, making to be uniformly mixed.
3) after mixing, equipped with 7 standards, 1 blank, 48 samples the Tube of totally 56 1.5ml in every time
200 μ l to be inhaled to be added in 3 secondary orifices of 96 orifice plates, 96 orifice plates after adding are put into micropore board detector, wavelength 500nm is set, into
Row detection.
In the present invention, the measurement of triglycerides (Serum TG) carries out in accordance with the following methods in liver:
1) it after every 100mg liver adds 9 times of physiological saline, is homogenized.
2) in every 100 μ l homogenate suspension, the mixed liquor of 375 μ l chloroforms and 125 μ l methanol is added.It is vortexed 20 minutes.
3) 125 μ l chloroforms are added, are vortexed 20 minutes.
4) 125 μ l distilled water are added, are vortexed 15 minutes.
5) 1200 turns/min is centrifuged 5 minutes at room temperature.
6) it collects in 40 μ l to new 1.5mlTube of subnatant.
7) gradient dilution is carried out with the titer of 200mg/ml concentration, prepares 0mg/ml, 6.25mg/ml, 12.5mg/ altogether
The standard of ml, 25mg/ml, 50mg/ml, 100mg/ml, 200mg/ml various concentration is put into the Tube of 7 different 1.5ml
In.750 μ l working reagents are added in the Tube of each 1.5ml.It is and distilled water is only added in the Tube of blank.Be vortexed,
After centrifugation, it is protected from light and is put into 37 DEG C of water-baths 20 minutes.
8) in sample Tube, 48 different blood of 750 μ l working reagents and 7.5 μ l are put into the Tube of each 1.5ml
Clearly.After being vortexed, being centrifuged, it is put into 37 DEG C of water-baths 15 minutes.
9) after mixing, equipped with 7 standards, 1 blank, sample the Tube of totally 56 1.5ml in inhale 200 every time
μ l is added in 3 secondary orifices of 96 orifice plates, and 96 orifice plates after adding are put into micropore board detector, is set wavelength 500nm, is examined
It surveys.
The ALT (glutamic-pyruvic transaminase) and AST (glutamic-oxalacetic transaminease) be in human body sugar and the mutual phase transition of protein needed for
Enzyme.The degree of impairment of the ALT and AST reflection liver cell, ALT reflect liver cell acute injury.The AST reflection liver is thin
Cellular damage degree.TG (triglyceride) is also known as fat, is to be synthesized by food fat with liver, is long chain fatty acids and glycerol shape
At fat molecule, be most important one kind of blood lipid in blood.Serum is obtained after mouse blood centrifugation, is analyzed with full-automatic biochemical
Instrument has detected the level of serum alt, AST and TG respectively.As can be seen that alcohol nursing group more normally organizes phase from Figure 1A
Than the horizontal significant raising (###P < 0.01) of serum alt;Dihydroquercetin administration group serum alt and alcohol nursing group phase
Than being remarkably decreased (* * * P < 0.001).As can be seen that more normal group of AST level of alcohol nursing group than more significant raising in Figure 1B
(###P < 0.001);Administration group serum AST is decreased obviously (* * * P < 0.01) compared with alcohol nursing group.Fig. 1 C is in mice serum
The testing result of TG content, it can be seen that alcohol group is compared with normal group, content apparent increase (the ##P < of TG in serum
0.01);Administration group is compared with alcohol nursing group, and the content of TG is substantially reduced (* * * P < 0.01) in serum.Fig. 1 D is Mouse Liver
Dirty tissue T G content results.Alcohol nursing group liver TG content, which is more normally organized, rises (##P < 0.01) compared to obvious;Administration group compared with
Alcohol nursing group is compared and is decreased obviously (* * P < 0.01).
These results suggest that carousing mice alcoholic fatty liver model modeling success, dihydroquercetin is to alcohol fatty
Liver has excellent protective effect.
As shown in Fig. 2, HE coloration result can be seen that normal group lobuli hepatis structure complete, no inflammation cellular infiltration;Alcohol
Occurs obvious fat bubble not of uniform size around the portal area of nursing group, ballooning degeneration of liver cells is obvious;Administration group fat bubble is bright
Aobvious to become smaller and quantity is reduced, ballooning degeneration of liver cells phenomenon mitigates, and high dose administration group lobuli hepatis structure has been approached normal group;Two
Steatosis (Fig. 2A) is had no in hydrogen Quercetin control group.Oil red O stain is that the property of lipid is soluble in using dyestuff to observe
The content of tissue lipid.Find out from result, alcohol group cytolipin content is significantly raised;Give the mouse of dihydroquercetin with
The raising liver cell lipid content of administration concentration significantly decreases compared with alcohol group;Dihydroquercetin control group has no liver cell rouge
The increase (Fig. 2 B) of fat content.
Fig. 3 shows influence of the dihydroquercetin to acute alcoholic fatty liver mouse liver tectology, HE dyeing knot
It is complete that fruit can be seen that normal group mouse liver lobuli hepatis structure;There are a large amount of sizes around portal area in alcohol group mouse liver
Different fat bubble, liver cell balloon sample become apparent;Administration group is significantly reduced with the increase steatosis of administration concentration,
Close to normal group (Fig. 3 A).Oil red O stain be soluble in using dyestuff the property of lipid come in tissue visualization lipid content it is more
It is few.Fig. 3 B is oil red coloration result, as can be seen that alcohol group dyed color is obviously relatively normally organized deeply from experimental result;Administration
Oil red O stain obviously shoals afterwards, illustrates that the liver lipids content of mouse after being administered significantly declines.
As shown in Figure 3 C, alcohol can stimulate SREBP-1 to activate.From the point of view of the immune group coloration result of SREBP-1, give
The expression of SREBP-1 is significantly raised around mouse liver tissue central vein after alcohol forage feed 4 weeks;Administration group and alcohol group
It is obviously shallower compared to the coloration result of SREBP-1.
In addition, we, which are metabolized closely related protein expression with lipid synthesis to AMPK, LKB1 and ACC etc., has carried out albumen
Blot experiment, Fig. 3 E are protein blot experiment as a result, carry out gray analysis to it with quantity one software, can be with from Fig. 3 E
Find out, the expression of alcohol group AMPK, LKB1 significantly reduces (###P < 0.001), and the expression of ACC is more normally organized to be increased compared to significant
Add (###P < 0.001);Administration group is compared with alcohol group, and the expression of AMPK, LKB1 significantly increase (* * * P < 0.001), ACC's
Expression significantly reduces (* * * P < 0.001).
Fig. 4 shows influence of the dihydroquercetin to the activation of the inflammation corpusculum of chmice acute alcoholic fatty liver, using immune
The expression of acute alcohol stomach-filling model mice P2X7R and NLRP3 are observed by histochemical staining method.From Fig. 4 A and Fig. 4 B
In as can be seen that in alcohol group the expression of P2X7R and NLRP3 obviously increased around central vein;Administration group and alcohol group phase
Than the expression of the two is remarkably decreased;Compared with normal group, the expression of the two does not become significantly dihydroquercetin control group
Change.It can inhibit the expression of inflammatory factor caused by alcohol to verify dihydroquercetin, we test detection blood by ELISA
The content of IL-1 β in clear.By alcohol group it can be seen from Fig. 4 C compared with normal group, the content of IL-1 β is dramatically increased in serum
(###P < 0.001);Administration group is compared with alcohol group, and the content of IL-1 β is remarkably decreased (* * * P < 0.001) in serum.It utilizes
Western blotting observes the expression of Pro-IL-1 β and Caspase-1 in liver organization, as a result as shown in Figure 4 D: wine
The expression of Pro-IL-1 β and Caspase-1 significantly increase in smart group, Pro-IL-1 β and Caspase-1 in liver organization after administration
Expression be obviously suppressed.
It is horizontal that Fig. 5 shows lipopexia and inflammatory factor expression in the HepG2 cell that dihydroquercetin stimulates alcohol
It influences.The result of AMPK α, ACC and IL-1 β protein expression in the HepG2 cell stimulated using Western blotting detection alcohol.
Alcohol group is substantially reduced with the expression for normally organizing compared to AMPK α as can be seen from the results, ACC and IL-1 β expression is significant to rise
It is high.The expression of AMPK α significantly increases after administration, the expression of ACC and IL-1 β significantly reduces.
Fig. 6 shows the influence of lipopexia in dihydroquercetin P2X7R dependence regulation alcohol stimulation HepG2 cell.Rouge
Polysaccharide (LPS) is the main component of gram-negative bacteria cell wall, can act on inflammation and immunocyte, such as monokaryon/macrophage
Cell, endothelial cell etc., acute-phase response (acute phase reac-tion, APR) in inductor.P2X7R is extracellular
The ion-channel ligands of ATP activation, and ATP is the classical activator of NLRP3 inflammation body, research confirms, P2X7R is mediating ATP
Endogenous danger signal activating immune cell NLRP3 inflammation body intracellular promotes activity IL-18 and IL-1 β secretion, booster immunization thin
Born of the same parents' inflammation responsing reaction plays an important role.It can be seen that LPS+ATP group is compared with normally organizing from Fig. 6 A western blot result
The expression of P2X7R and pro-IL-1 β is significantly raised, administration group with LPS+ATP group compare with to want concentration increase P2X7R with
The expression of pro-IL-1 β gradually decreases.In addition, we are observed after silencing P2X7R with immunofluorescence dyeing in HepG2 cell
The expression of SREBP-1.It can be seen that the alcohol group of control group is with normally organizing the red fluorescence compared to SREBP-1 from Fig. 6 B result
It is remarkably reinforced, normal group of silencing P2X7R, the red fluorescence of model group and administration group SREBP-1 are obviously reduced.
Hereinafter, the dihydroquercetin or its pharmaceutically acceptable salt are treating non-alcohol during the present invention will be described in detail
The purposes of property fatty liver.
The present invention uses kunming mice, 18~20g of weight.At 25 DEG C of constant temperature, humidity 50%, 12h is dark, 12h illumination
Animal housing's raising, feeding manner is using three-dimensional cage raising.It is randomly divided into 10 groups: normal group (N, n=6), control feed group
(LFD, n=6), high lipid food group (HFD, n=6), high lipid food combine alcohol carousing group (HFD+ETOH, n=6), low dosage
Dihydroquercetin increases rouge Combined fodder alcohol carousing group (HFD+ETOH+TAX25, n=6), and middle dosage dihydroquercetin is increased
Rouge Combined fodder alcohol carousing group (HFD+ETOH+TAX50, n=6), high dose dihydroquercetin increase rouge Combined fodder alcohol
Carousing group (HFD+ETOH+TAX100, n=6) and high dose dihydroquercetin group (TAX100, n=6).Under standard environment into
After 4 days adaptive feedings of row, normal group and high dose dihydroquercetin group feed normal diet, and control feed group feeds low fat feed,
Remaining 5 groups are respectively fed 60% high lipid food, and the every group of drinking-water that all freers is raised 4 days again.
Above-mentioned mouse is randomly divided into 10 groups: normal group, control feed group, high lipid food group, high lipid food joint alcohol
Carousing group, low dosage dihydroquercetin increase rouge Combined fodder alcohol carousing group, and middle dosage dihydroquercetin adds high lipid food to join
Alcohol carousing group is closed, high dose dihydroquercetin increases rouge Combined fodder alcohol carousing group, high dose dihydroquercetin group.
In the present invention, the dihydroquercetin that low dosage dihydroquercetin increases rouge Combined fodder alcohol carousing group is administered dense
Degree is 25mg/kg, to increase rouge Combined fodder alcohol carousing group dihydroquercetin administration concentration be 50mg/ to middle dosage dihydroquercetin
Kg, high dose dihydroquercetin increase rouge Combined fodder alcohol carousing group and high dose dihydroquercetin group administration concentration is
100mg/kg。
Draw it was found by the inventors of the present invention that dihydroquercetin can improve alcohol exposure by LKB1-AMPK signal path
The lipidosis risen;Dihydroquercetin can improve alcohol exposure by NLRP3 inflammation corpusculum signal path and cause inflammatory reaction.
It can be in the therapeutic effect of the initial stage of alcoholic liver disease by dihydroquercetin;Meanwhile the ingredient has the spy of small toxicity
Point, and have significant relaxation effect to lipidosis in alcoholic liver disease and inflammatory reaction.Specifically, dihydroquercetin is to wine
Alcoholic fatty liver caused by essence has a good inhibiting effect, at the same to alcoholic fatty liver with inflammation have it is certain
Improvement result, and it is cheap.
Specify that dihydroquercetin passes through the activity influence Fatty synthesis and fat oxidation of AMPK according to the present invention, to press down
The accumulation of liver fat caused by preparing alcohol;Dihydroquercetin is to P2X7R-Caspase-1-NLRP3 inflammation corpusculum caused by alcohol
Activation have certain inhibitory effect;Dihydroquercetin makees alcoholic fatty liver caused by alcohol with good inhibition
With, at the same to alcoholic fatty liver with inflammation tool have some improvement.
Fig. 7 indicates influence and dihydroquercetin of the dihydroquercetin to triglycerides in mice serum and liver to small
The influence of transaminase in mouse serum, as shown in figs. 7 a-b, after mouse gives alcohol and maltodextrin stomach-filling respectively, normal group with
The active no significant difference of glutamic-oxalacetic transaminease (AST) activity and glutamic-pyruvic transaminase (ALT) of control feed group.High lipid food joint
Alcohol carousing group P < 0.05 compared with ALT activity with the AST of high lipid food group, there is significant difference.High, medium and low dosage dihydro
Although Quercetin, which is increased compared with rouge Combined fodder alcohol carousing group combines alcohol carousing group with high lipid food, not to be had statistically
Significant difference, but have the visible trend for increasing AST and the decline of ALT activity with dihydroquercetin concentration.Mouse point
After not giving alcohol and maltodextrin stomach-filling, as seen in figure 7 c, normal group, control feed group and high dose dihydroquercetin group it
Between serum TG content there is no apparent difference.It is each that the serum TG content of high lipid food joint alcohol carousing group is apparently higher than other
Group is also increased compared with normal group, illustrates modeling success.In addition, high, medium and low dosage dihydroquercetin adds high lipid food
Serum TG content is all declined compared with joint alcohol carousing group combines alcohol carousing group with high lipid food, and is shown according to two
The concentration of hydrogen Quercetin, which increases serum TG content, successively downward trend.Mouse gives alcohol and maltodextrin stomach-filling respectively
Afterwards, as illustrated in fig. 7d, liver TG content is without apparent poor between normal group, control feed group and high dose dihydroquercetin group
Not.The liver TG content of high lipid food joint alcohol carousing group is apparently higher than high lipid food group, is also risen compared with normal group
Height illustrates modeling success.It is shown in addition, high, medium and low dosage dihydroquercetin increases rouge Combined fodder alcohol carousing group each group
Increasing liver TG content according to the concentration of dihydroquercetin has successively downward trend.
In the present invention, monoglyceride (TG) content in high lipid food group hepatic tissue and serum is with normal group than more significant
It increases, shows that high fat diet can cause fatty liver.But compared with combining alcohol carousing group with high lipid food, its fatty liver journey of the latter
It spends more obvious.It follows that the damage to liver cell, which becomes apparent from, to be also easier to lead when high fat diet and alcohol intake synergy
Cause fatty liver.Various dose dihydroquercetin is increased TG content in rouge Combined fodder alcohol carousing group serum and is combined with high lipid food
Alcohol carousing group compares, and TG content has the tendency that being substantially reduced.This show joint alcohol high in fat carouse in the case where, two
Hydrogen Quercetin can effectively improve fat deposition in liver, enhance liver cell free radical resisting attacking ability, play certain protection liver
Effect.Increase content of triglyceride feeding more high in fat in rouge Combined fodder alcohol carousing group liver in various dose dihydroquercetin
Material joint alcohol carousing group is increased, but is increased according to dihydroquercetin dosage and reduced, and shows dihydro quercitrin
Element also has curative effect.
Through the invention, the liver that alcohol carousing group is combined in HE dyeing with oil red fat stains as a result, high lipid food is carried out
Interior fat drips deposition, inflammatory cell infiltration show mouse alcoholic fatty liver modeling success.And the difference fed with high lipid food
Fat deposition makes moderate progress with the increase of dihydroquercetin administration concentration in the liver of concentration dihydroquercetin stomach-filling mouse,
Although liver does not return to normal level, but it can illustrate that dihydroquercetin has certain treatment in alcoholic fatty liver
Effect.
The inventors discovered that although various concentration dihydroquercetin increases rouge, Combined fodder alcohol carousing group can reduce wine
The biochemical indicator of essence fatty liver and liver cell prevent to tend to normalization, these indexs and prevention fail to be completely recovered to normal water
It is flat, but dihydroquercetin, in terms for the treatment of alcoholic fatty liver and nonalcoholic fatty liver, right and wrong are often with potential day
Right antioxidant.
More than, it is to be understood that referring to the appended Detailed description of the invention present invention, still, invention of the invention is claimed
Range is not limited to embodiment above-mentioned and/or attached drawing.In addition, it is desirable to understand, it is claimed for being recorded in invention
Conspicuous improvement, change and modification also belong to invention of the invention and model are claimed for the technical staff of the invention of range
It encloses.
Claims (10)
1. dihydroquercetin or its pharmaceutically acceptable salt are in the purposes for treating fatty liver.
2. purposes according to claim 1, the dihydroquercetin or its pharmaceutically acceptable salt are in treatment Alcoholic
The purposes of fatty liver.
3. purposes according to claim 1, the dihydroquercetin or its pharmaceutically acceptable salt are treating non-alcohol
The purposes of property fatty liver.
4. purposes according to claim 1, wherein be included in dihydroquercetin or its pharmaceutically acceptable salt single
In preparation.
5. purposes according to claim 1, wherein dihydroquercetin or its pharmaceutically acceptable salt to be configured to respectively
Pharmaceutical composition is simultaneously applied in combination.
6. purposes according to claim 2, wherein the dihydroquercetin or its pharmaceutically acceptable salt concentration are
121.8mg/ daily/60kg or more.
7. purposes according to claim 3, wherein the dihydroquercetin or its pharmaceutically acceptable salt concentration are two
Hydrogen Quercetin administration concentration is 25mg/kg~100mg/kg.
8. a kind of dihydroquercetin or its pharmaceutically acceptable salt are in the drug that preparation prevents and treats alcoholic liver injury
Purposes.
9. the health care product that a kind of dihydroquercetin or its pharmaceutically acceptable salt prevent and treat alcoholic liver injury in preparation
In purposes.
10. a kind of dihydroquercetin or its pharmaceutically acceptable salt are in the drink that preparation prevents and treats alcoholic liver injury
Purposes.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811412574.4A CN109771411A (en) | 2018-11-19 | 2018-11-19 | Dihydroquercetin is used to prepare the purposes in the drug for the treatment of fatty liver |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811412574.4A CN109771411A (en) | 2018-11-19 | 2018-11-19 | Dihydroquercetin is used to prepare the purposes in the drug for the treatment of fatty liver |
Publications (1)
Publication Number | Publication Date |
---|---|
CN109771411A true CN109771411A (en) | 2019-05-21 |
Family
ID=66496411
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201811412574.4A Pending CN109771411A (en) | 2018-11-19 | 2018-11-19 | Dihydroquercetin is used to prepare the purposes in the drug for the treatment of fatty liver |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN109771411A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113559113A (en) * | 2021-04-02 | 2021-10-29 | 广东昊邦医药健康有限责任公司 | Application of NAD + supplement in preparation of medicine for treating acute alcoholic liver injury |
CN114007604A (en) * | 2019-06-25 | 2022-02-01 | 独立行政法人国立病院机构 | Hepatic fibrosis inhibitor and brown fat cell activator containing taxifolin |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102477453A (en) * | 2010-11-22 | 2012-05-30 | 天津药物研究院 | Method of preparing taxifolin monomer from engelhardtia leaf and application |
-
2018
- 2018-11-19 CN CN201811412574.4A patent/CN109771411A/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102477453A (en) * | 2010-11-22 | 2012-05-30 | 天津药物研究院 | Method of preparing taxifolin monomer from engelhardtia leaf and application |
Non-Patent Citations (3)
Title |
---|
YU ZHANG等: "Amelioration of Alcoholic Liver Steatosis by Dihydroquercetin through the Modulation of AMPK-Dependent Lipogenesis Mediated by P2X7R−NLRP3-Inflammasome Activation", 《J. AGRIC. FOOD CHEM》 * |
张超等: "槲皮素治疗非酒精性脂肪性肝病的作用机制研究进展", 《中药新药与临床药理》 * |
郑今花: "二氢槲皮素基于NLRP3炎症小体通路调控酒精性脂肪肝与炎症的机制研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114007604A (en) * | 2019-06-25 | 2022-02-01 | 独立行政法人国立病院机构 | Hepatic fibrosis inhibitor and brown fat cell activator containing taxifolin |
EP3991728A4 (en) * | 2019-06-25 | 2023-08-09 | National Hospital Organization | Hepatic fibrosis-inhibiting agent and brown fat cell-activating agent containing taxifolin |
CN113559113A (en) * | 2021-04-02 | 2021-10-29 | 广东昊邦医药健康有限责任公司 | Application of NAD + supplement in preparation of medicine for treating acute alcoholic liver injury |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3641819B1 (en) | Use of cannabidiol in the treatment of tuberous sclerosis complex | |
CN106794986A (en) | Deuterate or non-deuterate molecule and pharmaceutical preparation | |
CN102958362A (en) | Resveratrol-containing compositions and methods of use | |
TW200932245A (en) | Methods and compositions for inhibiting angiogenesis | |
CN107949394A (en) | It is used to prevent or treats metabolic syndrome or for oxidation resistant composition comprising black soya bean leaf extract and from its separated flavonol glycosides is as active component | |
CN107441104A (en) | PDS Rb components prevent and treat the medical usage of diabetic complication and metabolic disorder relevant disease | |
CN105899211A (en) | Treatment of hepatic fibrosis using an inhibitor of CBP/catenin | |
CN109771411A (en) | Dihydroquercetin is used to prepare the purposes in the drug for the treatment of fatty liver | |
CN107613968A (en) | Prevention or the pharmaceutical composition for the treatment of fatty liver | |
CN113082039B (en) | Composition for treating sorafenib drug-resistant tumor and application thereof | |
CN103191115A (en) | Application of pyrroloquinoline quinone (PQQ) in treatment and/or improvement of diabetic foot | |
CN113018293A (en) | New application of quercetin and kaempferol | |
CN103037901B (en) | Suppress CD36 with obesity controlling and insulin sensitivity | |
JP2005325096A (en) | Monoamine reintake inhibitor compounded with grifola frondosa | |
CN107427546A (en) | Composition and its medicinal application containing interwined dragon conopsea extraction | |
WO2017157248A1 (en) | Use of triacetyl-3-hydroxyphenyladenosine in preparing pharmaceuticals for treatment of atherosclerosis | |
CN108619245A (en) | A kind of new application of Guava Leaf and guava leaf total flavonoid | |
KR101093930B1 (en) | Novel use of scoparone | |
KR20120115963A (en) | Composition for prevention or treatment of cardiovascular disease containing extracts of dioscorea batatas decne | |
CN104582730B (en) | A kind of method improving Metabolism of Mitochondria function and application | |
CN109481424A (en) | Isoliquiritigenin, pharmaceutical composition and its application in treatment diabetic nephropathy | |
CN1695604A (en) | Medication for treating nerve regression disease of hyperkinetic syndrome of attention defect and depression | |
CN111249271A (en) | Medicament for treating diabetes and preparation method and application thereof | |
CN110051671B (en) | Application of purslane amide E in preparation of medicine for treating ischemic heart disease | |
Smit | An investigation into the effects of aspalathin on myocardial glucose transport using cardiomyocytes from control and obesity-induced insulin resistant rats, and terminally differentiated H9c2 cells |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190521 |
|
RJ01 | Rejection of invention patent application after publication |