CN115531406A - 芒柄花苷在制备预防或治疗脂肪肝药物中的应用 - Google Patents
芒柄花苷在制备预防或治疗脂肪肝药物中的应用 Download PDFInfo
- Publication number
- CN115531406A CN115531406A CN202211282248.2A CN202211282248A CN115531406A CN 115531406 A CN115531406 A CN 115531406A CN 202211282248 A CN202211282248 A CN 202211282248A CN 115531406 A CN115531406 A CN 115531406A
- Authority
- CN
- China
- Prior art keywords
- formononetin
- fatty liver
- liver
- medicine
- mice
- 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
- HKQYGTCOTHHOMP-UHFFFAOYSA-N formononetin Chemical compound C1=CC(OC)=CC=C1C1=COC2=CC(O)=CC=C2C1=O HKQYGTCOTHHOMP-UHFFFAOYSA-N 0.000 title claims abstract description 124
- RIKPNWPEMPODJD-UHFFFAOYSA-N formononetin Natural products C1=CC(OC)=CC=C1C1=COC2=CC=CC=C2C1=O RIKPNWPEMPODJD-UHFFFAOYSA-N 0.000 title claims abstract description 62
- 239000003814 drug Substances 0.000 title claims abstract description 36
- 208000004930 Fatty Liver Diseases 0.000 title claims abstract description 22
- 206010019708 Hepatic steatosis Diseases 0.000 title claims abstract description 22
- 208000010706 fatty liver disease Diseases 0.000 title claims abstract description 20
- 231100000240 steatosis hepatitis Toxicity 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims abstract description 23
- 239000000463 material Substances 0.000 claims description 8
- 239000006187 pill Substances 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 239000003826 tablet Substances 0.000 claims description 3
- 230000000694 effects Effects 0.000 abstract description 25
- 210000004185 liver Anatomy 0.000 abstract description 17
- 206010022489 Insulin Resistance Diseases 0.000 abstract description 4
- 238000009825 accumulation Methods 0.000 abstract description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 abstract description 4
- 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 abstract description 3
- 206010067125 Liver injury Diseases 0.000 abstract description 3
- 239000008103 glucose Substances 0.000 abstract description 3
- 230000002159 abnormal effect Effects 0.000 abstract description 2
- 150000002632 lipids Chemical class 0.000 abstract description 2
- 231100000753 hepatic injury Toxicity 0.000 abstract 1
- 241000699670 Mus sp. Species 0.000 description 38
- 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 24
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 13
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 12
- 108010082126 Alanine transaminase Proteins 0.000 description 12
- 235000012000 cholesterol Nutrition 0.000 description 12
- 210000002966 serum Anatomy 0.000 description 12
- 235000005911 diet Nutrition 0.000 description 11
- 230000037213 diet Effects 0.000 description 10
- 238000010186 staining Methods 0.000 description 10
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 9
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 8
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 8
- 108010028554 LDL Cholesterol Proteins 0.000 description 6
- 210000000593 adipose tissue white Anatomy 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 108090000340 Transaminases Proteins 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 102000014898 transaminase activity proteins Human genes 0.000 description 4
- 229930183931 Filipin Natural products 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- 238000013231 NASH rodent model Methods 0.000 description 3
- 230000035508 accumulation Effects 0.000 description 3
- 210000005252 bulbus oculi Anatomy 0.000 description 3
- 208000019425 cirrhosis of liver Diseases 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 210000000918 epididymis Anatomy 0.000 description 3
- 201000010063 epididymitis Diseases 0.000 description 3
- IMQSIXYSKPIGPD-NKYUYKLDSA-N filipin Chemical compound CCCCC[C@H](O)[C@@H]1[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@H](O)\C(C)=C\C=C\C=C\C=C\C=C\[C@H](O)[C@@H](C)OC1=O IMQSIXYSKPIGPD-NKYUYKLDSA-N 0.000 description 3
- 229950000152 filipin Drugs 0.000 description 3
- IMQSIXYSKPIGPD-UHFFFAOYSA-N filipin III Natural products CCCCCC(O)C1C(O)CC(O)CC(O)CC(O)CC(O)CC(O)CC(O)C(C)=CC=CC=CC=CC=CC(O)C(C)OC1=O IMQSIXYSKPIGPD-UHFFFAOYSA-N 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 230000006372 lipid accumulation Effects 0.000 description 3
- 210000005228 liver tissue Anatomy 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000007882 cirrhosis Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 238000002224 dissection Methods 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- -1 fibrates Substances 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 2
- 231100000234 hepatic damage Toxicity 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 230000008818 liver damage Effects 0.000 description 2
- 229940048380 lovastatin 60 mg Drugs 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 229960001412 pentobarbital Drugs 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 description 1
- 244000303040 Glycyrrhiza glabra Species 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229940122355 Insulin sensitizer Drugs 0.000 description 1
- 238000013232 NAFLD rodent model Methods 0.000 description 1
- 238000013234 NASH mouse model Methods 0.000 description 1
- 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 1
- 101710098398 Probable alanine aminotransferase, mitochondrial Proteins 0.000 description 1
- 241000519995 Stachys sylvatica Species 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 238000008050 Total Bilirubin Reagent Methods 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 230000000081 effect on glucose Effects 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 230000009795 fibrotic process Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 235000019137 high fructose diet Nutrition 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 235000011477 liquorice Nutrition 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 208000018191 liver inflammation Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 238000007410 oral glucose tolerance test Methods 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 150000004291 polyenes Chemical class 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000013235 rat NASH model Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 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 1
- 229960004245 silymarin Drugs 0.000 description 1
- 235000017700 silymarin Nutrition 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 description 1
- 229960001661 ursodiol Drugs 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Gastroenterology & Hepatology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了芒柄花苷在制备预防或治疗脂肪肝药物中的应用。相对于现有技术，本发明发现芒柄花苷能够用于预防或治疗脂肪肝，尤其是非酒精性脂肪肝，效果显著。研究证实芒柄花苷能够减轻肝脏脂肪变性，缓解肝脏脂质的异常积累，改善胰岛素抵抗及葡萄糖抵抗，减轻肝损伤。
Description
技术领域
本发明涉及芒柄花苷的医药用途，尤其涉及一种芒柄花苷在制备预防或治疗脂肪肝药物中的应用，属于天然药物领域。
背景技术
非酒精性脂肪肝(NAFLD)是一种非酒精作用引起，以肝脏脂肪变性和胰岛素抵抗为病理特征的一系列综合征。临床上又将其分为单纯性脂肪肝、脂肪肝炎以及与之相关的肝硬化和肝细胞癌。随着生活水平的提高及膳食结构的改变，非酒精性脂肪肝的发病率逐年上升。NAFLD在西方普通人群中的发病率接近20％～30％，其中约20％的病人发展成NASH，NASH中近20％的病人可进展为肝硬化，甚至发生终末期的肝功能衰竭。据文献报道，治疗NAFLD的药物主要有以下几种：胰岛素增敏剂：二甲双胍等双胍类、吡格列酮等噻唑烷二酮类；调脂药物：他汀类、贝特类，烟酸；保肝药：还原型谷胱甘肽、维生素E、多烯磷脂胆碱、熊去氧胆酸、水飞蓟素等等。而芒柄花苷(Ononin)是否具有预防和治疗非酒精性脂肪肝的作用未见任何报道。
芒柄花苷是传统中药甘草中的活性成分，已有文献报道了其对心血管疾病防治活性。
发明内容
发明目的：本发明旨在提供一种芒柄花苷在制备预防或治疗脂肪肝药物中的应用。
技术方案：本发明的芒柄花苷在制备预防或治疗脂肪肝药物中的应用。
进一步地，所述的脂肪肝为非酒精性脂肪肝。
进一步地，所述的药物为芒柄花苷作为唯一活性成分或包含芒柄花苷的药物组合物。
更进一步地，药物的剂型为颗粒剂、散剂、片剂、胶囊剂、丸剂、口服液、汤剂或滴丸剂。
更进一步地，药物组合物是以芒柄花苷作为活性成分，加上药学上可接受的辅料所制成的药物。
更进一步地，药物组合物中芒柄花苷的含量为0.1-99wt％。
进一步地，芒柄花苷的给药量为40-80mg/kg。
本发明所述芒柄花苷在治疗脂肪肝时，可以单独使用，也可以与其他药物配合同时使用，或者与其他药物一起制成复方制剂使用，都可以达到治疗脂肪肝的目的。
本发明所述药学上可接受的辅料，是指制备不同剂型时加入所需的各种常规辅料，例如稀释剂、黏合剂、崩解剂、助流剂、润滑剂、矫味剂、包合材料、吸附材料等以常规的制剂方法制备成任何一种常用的口服制剂，例如可以是颗粒剂、散剂、片剂、胶囊剂、丸剂、口服液、汤剂、滴丸剂等。
本发明通过药理实验发现了芒柄花苷对高脂、高胆固醇、高果糖饮食(HFFC)诱导的类似于人类的非酒精性脂肪性肝炎模型(NASH)小鼠具有良好的治疗效果。非酒精性脂肪性肝炎(NASH)是NAFLD的活性形式，具有肝脏坏死性炎症和更快的纤维化进程。对此动物实验进行系统研究，发现：芒柄花苷通过减少肝脏脂肪变性，减轻肝损伤，成功地减弱了NASH的发展。
有益效果：与现有技术相比，本发明具有如下显著优点：芒柄花苷能够用于预防或治疗脂肪肝，尤其是非酒精性脂肪肝，效果显著。研究证实芒柄花苷能够减轻肝脏脂肪变性，炎症以及纤维化，缓解肝脏脂质的异常积累，减少氧化应激。
附图说明
图1为芒柄花苷对各组小鼠体重的影响；
图2为芒柄花苷对各组小鼠肝重的影响；
图3为芒柄花苷对各组小鼠白色脂肪(WAT)质量的影响；
图4为芒柄花苷对各组小鼠肝脏的H&E、油红(O-red)、菲律宾(Filipin)染色及WAT的O-Red染色的影响；
图5为各组小鼠肝脏Filipin染色相对定量；
图6为芒柄花苷对各组小鼠心、脾、肺、肾、肌苏木精-伊红(H&E)染色的影响；
图7为芒柄花苷对各组小鼠肝内总胆固醇(TC)水平的影响；
图8为芒柄花苷对各组小鼠肝内总甘油三酯(TG)水平的影响；
图9为芒柄花苷对各组小鼠肝内谷丙转氨酶(ALT)水平的影响；
图10为芒柄花苷对各组小鼠肝内谷草转氨酶(AST)水平的影响；
图11为芒柄花苷对各组小鼠血清中总胆固醇(TC)水平的影响；
图12为芒柄花苷对各组小鼠血清中总甘油三酯(TG)水平的影响；
图13为芒柄花苷对各组小鼠血清中谷丙转氨酶(ALT)水平的影响；
图14为芒柄花苷对各组小鼠血清中谷草转氨酶(AST)水平的影响；
图15为芒柄花苷对各组小鼠血清中低密度脂蛋白胆固醇(LDL-c)水平的影响；
图16为芒柄花苷对各组小鼠口服葡萄糖耐量(OGTT)的影响；
图17为口服葡萄糖耐量实验曲线下面积统计；
图18为芒柄花苷对各组小鼠胰岛素耐量(ITT)的影响；
图19为胰岛素耐量实验曲线下面积统计。
具体实施方式
下面结合附图对本发明的技术方案作进一步说明。
下述实施例中的实验方法，如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1
研究芒柄花苷对小鼠非酒精性脂肪肝模型组织学的影响
实验动物及方法：C57BL小鼠，SPF级，雄性，6周龄，体重(22±2)g。小鼠适应性饲养2周后随机分成五组，空白对照组10只，给予正常对照饲料；模型组15只，给予HFFC(高脂肪酸、高胆固醇、高果糖)饮食；低剂量组、高剂量组及阳性药组各10只，此三组在给予HFFC饮食的同时分别给予芒柄花苷40mg/kg/day、芒柄花苷80mg/kg/day、洛伐他汀阳60mg/kg/day。各给药组均每日灌胃给药，给药10周，每周记录小鼠体重。实验期间12h光照12h黑夜，小鼠自由饮食饮水。连续喂养10周后，0.2％戊巴比妥钠(0.2ml/10g)腹腔注射麻醉，摘眼球取血，随后脱颈处死，随后解剖获得小鼠各个组织，完成后续实验分析。
药物配置方法：各给药组药物均混悬于0.5％的CMC-Na溶液，保证体系均一。
观察指标：
a动物的一般情况：体重、进食量；
b组织形态大小：肝、附睾白脂；
c病理学检查：HE染色、油红染色、菲律宾染色；
结果见图1、图2、图3、图4、图5、图6；
结果分析：在整个实验过程中，模型组小鼠的体重显著性高于空白对照组，而各个给药组小鼠体中相比于模型组有表现出明显下调；在对小鼠各组织的分析中，造模组小鼠的肝脏出现脂质堆积所导致的白色化及白斑，且附睾白脂含量明显增加，说明HFFC饮食成功诱导形成了NASH模型。而在给药组中，心、脾、肺、肾、肌等组织的H&E染色未见明显毒性，且肝脏的白色化明显减轻，附睾白脂含量也发生显著下调。在染色分析中，HE染色及油红染色均可观察到给药组肝脏中的脂质堆积相比于模型组均明显减轻，经统计学分析其间存在显著性差异；菲律宾染色可观察到模型组肝内胆固醇堆积明显上调，而各个给药组的胆固醇堆积发生明显下调。以上均结果均说明芒柄花苷在对小鼠HFFC饮食诱导的NASH模型的治疗中有显著性活性。
实施例2
研究芒柄花苷对小鼠非酒精性脂肪肝模型生化指标的影响
实验动物及方法：C57BL小鼠，SPF级，雄性，6周龄，体重(22±2)g。小鼠适应性饲养2周后随机分成五组，空白对照组10只，给予正常对照饲料；模型组15只，给予HFFC(高脂肪酸、高胆固醇、高果糖)饮食；低剂量组、高剂量组及阳性药组各10只，此三组在给予HFFC饮食的同时分别给予芒柄花苷40mg/kg/day、芒柄花苷80mg/kg/day、洛伐他汀阳60mg/kg/day。各给药组均每日灌胃给药，给药10周，每周记录小鼠体重。实验期间12h光照12h黑夜，小鼠自由饮食饮水。连续喂养10周后，0.2％戊巴比妥钠(0.2ml/10g)腹腔注射麻醉，摘眼球取血，随后脱颈处死，随后解剖获得小鼠各个组织，完成后续实验分析。
药物配置方法：各给药组药物均混悬于0.5％的CMC-Na溶液，保证体系均一。
观察指标：
a肝脏脂类蓄积相关指标：肝脏TG、TC；
b肝功能相关指标：肝脏ALT、AST，血清ALT、AST；
c血脂相关指标：血清TC、TG、LDL-c；
d其他生理指标：OGTT、ITT；
检测方法：
小鼠饲养至第八、九周时，分别进行OGTT(口服葡萄糖耐量)及ITT(胰岛素耐量)的实验。
摘眼球获得小鼠全血后室温静止4-6h后，以3000r/min超速离心10min后吸取血清，使用试剂盒检测各组小鼠血清谷丙转氨酶(ALT)、谷草转氨酶(AST)、总甘油三酯(TG)、总胆固醇(T-CHO)、低密度脂蛋白胆固醇(LDL-c)含量的变化。
获得小鼠肝组织后，准确称取一定量肝组织，加入适量无水乙醇及磁珠，以60MHz，4min参数进行磁力破碎后12000r/min超速离心10min，吸取上清，使用试剂盒检测各组小鼠肝脏组织总谷丙转氨酶(ALT)、谷草转氨酶(AST)、甘油三酯(TG)、总胆固醇(T-CHO)含量的变化。
结果见图7、图8、图9、图10、图11、图12、图13、图14、图15、图16、图17、图18、图19；
实验结果分析：芒柄花苷给药至8-9周时，可见其对葡萄糖耐受及胰岛素耐受均有显著性的改善作用。并且芒柄花苷能显著下调HFFC饮食诱导的NASH模型鼠肝内及血清中的总胆固醇、总甘油三酯及谷丙转氨酶、谷草转氨酶的水平，对血清中LDL-c水平也有显著性的抑制作用。以上结果提示芒柄花苷对于HFFC诱导的NASH小鼠模型的糖脂代谢有良好的改善作用，并且能显著性改善NASH模型中的肝损伤。
综上所述：基于HFFC饮食诱导的C57BL/6J小鼠非酒精性脂肪肝模型，发现芒柄花苷可以显著性改善各项病理指标，包括有血清中总胆固醇、总甘油三酯、谷丙转氨酶、谷草转氨酶、总胆汁酸、总胆红素及总碱性磷酸酶水平，肝脏中总胆固醇、总甘油三酯、谷丙转氨酶及谷草转氨酶水平。
这些数据均表明此种化合物具有较好的治疗和预防非酒精性脂肪肝的活性，并一定程度能够改善胰岛素耐受的症状，可作为治疗或控制NAFLD、NASH的潜在药物，但其作用具体作用机理还需进一步研究，以上结论均为其未来的相关研究及开发提供了一定的参考依据。
Claims (7)
1.芒柄花苷在制备预防或治疗脂肪肝药物中的应用。
2.根据权利要求1所述的芒柄花苷在制备预防或治疗脂肪肝药物中的应用，其特征在于，所述的脂肪肝为非酒精性脂肪肝。
3.根据权利要求1所述的芒柄花苷在制备预防或治疗脂肪肝药物中的应用，其特征在于，所述的药物为芒柄花苷作为唯一活性成分或包含芒柄花苷的药物组合物。
4.根据权利要求3所述的芒柄花苷在制备预防或治疗脂肪肝药物中的应用，其特征在于，药物的剂型为颗粒剂、散剂、片剂、胶囊剂、丸剂、口服液、汤剂或滴丸剂。
5.根据权利要求3所述的芒柄花苷在制备预防或治疗脂肪肝药物中的应用，其特征在于，药物组合物是以芒柄花苷作为活性成分，加上药学上可接受的辅料所制成的药物。
6.根据权利要求3所述的芒柄花苷在制备预防或治疗脂肪肝药物中的应用，其特征在于，药物组合物中芒柄花苷的含量为0.1-99wt％。
7.根据权利要求1所述的芒柄花苷在制备预防或治疗脂肪肝药物中的应用，其特征在于，芒柄花苷的给药量为40-80mg/kg。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211282248.2A CN115531406A (zh) | 2022-10-19 | 2022-10-19 | 芒柄花苷在制备预防或治疗脂肪肝药物中的应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211282248.2A CN115531406A (zh) | 2022-10-19 | 2022-10-19 | 芒柄花苷在制备预防或治疗脂肪肝药物中的应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115531406A true CN115531406A (zh) | 2022-12-30 |
Family
ID=84735729
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211282248.2A Pending CN115531406A (zh) | 2022-10-19 | 2022-10-19 | 芒柄花苷在制备预防或治疗脂肪肝药物中的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115531406A (zh) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107854522A (zh) * | 2017-09-13 | 2018-03-30 | 北京宜生堂医药科技研究有限公司 | 一种组合物及其制备方法和用途 |
| CN110090209A (zh) * | 2019-06-11 | 2019-08-06 | 中日友好医院 | 刺芒柄花素在治疗非酒精性脂肪肝中的应用 |
| KR20210063046A (ko) * | 2019-11-22 | 2021-06-01 | 대한민국(농촌진흥청장) | 이소플라본이 증가된 증숙 황기 추출물을 유효성분으로 포함하는 간기능 개선용 조성물 |
-
2022
- 2022-10-19 CN CN202211282248.2A patent/CN115531406A/zh active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107854522A (zh) * | 2017-09-13 | 2018-03-30 | 北京宜生堂医药科技研究有限公司 | 一种组合物及其制备方法和用途 |
| CN110090209A (zh) * | 2019-06-11 | 2019-08-06 | 中日友好医院 | 刺芒柄花素在治疗非酒精性脂肪肝中的应用 |
| KR20210063046A (ko) * | 2019-11-22 | 2021-06-01 | 대한민국(농촌진흥청장) | 이소플라본이 증가된 증숙 황기 추출물을 유효성분으로 포함하는 간기능 개선용 조성물 |
Non-Patent Citations (2)
| Title |
|---|
| JIA LIU 等: "A diet formula of Puerariae radix, Lycium barbarum, Crataegus pinnatifida, and Polygonati rhizoma alleviates insulin resistance and hepatic steatosis in CD-1 mice and HepG2 cells", FOOD FUNCT., vol. 5, pages 5 * |
| JIAYAO YANG 等: "Protective Effect of Fuzi Lizhong Decoction against Non-alcoholic Fatty Liver Disease via Anti-inflammatory Response through Regulating p53 and PPARG Signaling", BIOL. PHARM. BULL., vol. 43, pages 1 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109789119A (zh) | 用于治疗或预防纤维化、硬化疾病或障碍的含fxr激动剂的复合组合物 | |
| US11058703B2 (en) | Application of triacetyl-3-hydroxyphenyladenosine in preparation of pharmaceutical drug for preventing or treating non-alcoholic fatty liver disease | |
| CN101181373A (zh) | 丹皮有效部位药物组合物、其制备方法及应用 | |
| KR101461252B1 (ko) | 지방간 또는 비알코올성 지방성 간염의 예방 및/또는 치료를 위한 의약 | |
| CN110946986B (zh) | 一种寡肽在制备防治非酒精性脂肪肝病药物中的应用 | |
| JP7271693B2 (ja) | ハイドロキノン誘導体を含む肥満又は非アルコール性脂肪肝炎の予防又は治療用薬学組成物 | |
| CN101057674B (zh) | 一种用于防治糖尿病的组合物 | |
| KR20100088794A (ko) | 새송이버섯 추출물을 유효성분으로 함유하는 제 2형 당뇨병에 의한 지질대사 장애 및 당뇨합병증 질환의 예방 및 치료용 조성물 | |
| CN115531406A (zh) | 芒柄花苷在制备预防或治疗脂肪肝药物中的应用 | |
| CN111686239B (zh) | 抗真菌化合物的应用 | |
| KR20070044198A (ko) | 푸마르산 및 푸마르산 유도체를 유효성분으로 함유하는대사증후군 치료제 | |
| CN106619605A (zh) | 补骨脂宁的医药用途 | |
| US9345681B2 (en) | Anti-obesity agent comprising high-purity EPA | |
| CN105748448A (zh) | D手性肌醇在制备抗肝纤维化药物中的应用 | |
| TWI620815B (zh) | 用於改善非酒精性脂肪變性肝炎的樟芝菌絲體發酵物、其製備方法及其用途 | |
| KR101572311B1 (ko) | 2-아미노-2-노보네인카르복실산을 함유하는 비만 예방 또는 치료용 조성물 | |
| CN103735549A (zh) | 盐酸去亚甲基小檗碱在制备治疗非酒精性脂肪肝病药物中的应用 | |
| CN109512808B (zh) | 棕榈酸甲酯在制备预防或治疗脂肪肝药物中的应用 | |
| WO2022135461A1 (zh) | Magl抑制剂在制备预防或治疗脂肪性肝病药物中的用途 | |
| US20220079975A1 (en) | Method for mitigation of non-alcoholic fatty liver disease by use of a composition comprising small-molecule fucoidan and fucoxanthin | |
| CN112641779B (zh) | Gw441756在制备预防和/或治疗脂肪肝药物中的应用 | |
| CN102631370A (zh) | 一种预防或改善高脂血症及补充维生素d的组合物 | |
| CN116747226A (zh) | 黄柏碱在制备治疗和/或预防非酒精性脂肪肝炎药物中的应用 | |
| US20230190682A1 (en) | Pharmaceutical composition for preventing or treating metabolic diseases | |
| CN113082033A (zh) | Fr180204在制备预防和/或治疗非酒精性脂肪性肝病或肝炎药物中的应用 |
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 |