Application of combination of FXR (Farnesoid X Receptor) agonist and SIRT1 (Sirtuin1) agonist for preparing anti-hepatic fibrosis drug

An anti-hepatic fibrosis and agonist technology, which is applied in the direction of drug combinations, active ingredients of hydroxyl compounds, medical preparations containing active ingredients, etc., can solve the problem of OCA’s inability to significantly activate the FXR pathway to prevent fibrosis, down-regulation of expression levels, liver There is no significant improvement in fibrosis indicators and other issues

Active Publication Date: 2019-02-05
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Some previous animal experiments showed that FXR agonists such as OCA have significant curative effect on liver fibrosis (Fiorucci S, Antonelli E, Rizzo G, et al. The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology.2004Nov;127(5):1497-512.Fiorucci S1,Rizzo G,Antonelli E,et al.A farnesoid x receptor-small heterodimer partner regulatory cascademodulates tissue metalloproteinase inhibitor-1and matrix metalloprotease reselllution in ate hepatic stasis liverfibrosis.J Pharmacol Exp Ther.2005Aug; 314(2):584-95.); However, the results of two recent clinical studies showed that compared with placebo, OCA did not significantly improve the indicators of liver fibrosis in patients (Nevens F, Andreone P, Mazzella G, et al. A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis. N Engl J Med. 2016 Aug 18; 375(7): 631-43; Kowdley KV, Luketic V, Chapman R , et al.A randomized trial of obeticholic acid monotherapy patients with primary biliary cholangitis.Hepatology.2018May;67(5):1890-1902.)
An important reason for the clinical failure of OCA is that the expression level of FXR, the target of OCA, is significantly down-regulated in the liver of patients with liver injury, which in turn leads to the inability of OCA to significantly activate the FXR pathway and exert its anti-fibrosis effect

Method used

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  • Application of combination of FXR (Farnesoid X Receptor) agonist and SIRT1 (Sirtuin1) agonist for preparing anti-hepatic fibrosis drug
  • Application of combination of FXR (Farnesoid X Receptor) agonist and SIRT1 (Sirtuin1) agonist for preparing anti-hepatic fibrosis drug
  • Application of combination of FXR (Farnesoid X Receptor) agonist and SIRT1 (Sirtuin1) agonist for preparing anti-hepatic fibrosis drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1 SRT1720 can significantly reverse the downregulation of FXR protein level

[0030] 1 Experimental materials

[0031] The HepG2 cell line used in the present invention was purchased from Shanghai Cell Bank;

[0032] The SRT1720 used in the present invention was purchased from MCE Company.

[0033] 2 Experimental methods

[0034] 2.1 Cell culture

[0035] Cells were grown in T25 cell culture flasks (Costar) and cultured at 37°C, 5% CO2 and 90% relative humidity. The culture medium is DMEM medium containing 10% fetal bovine serum (FBS), supplemented with 1 unit / ml of penicillin and 1 μg / ml of streptomycin. The cells are all adherent cells, the medium was changed every other day, and the cells were subcultured in bottles every three days.

[0036] 2.2 Western blot

[0037] 1) Place the cells on ice after collection, add 100 μl of RIPA cell lysate, 1% Protease Inhibitor Cocktail (Sigma), and 1% phosphatase inhibitor to each 20 μl of cell volume, fully blow of...

Embodiment 2

[0050] Example 2 The effect of SRT1720 combined with OCA on liver fibrosis

[0051] 1 Experimental materials

[0052] Experimental mice (C57BL / 6) were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.;

[0053] CCl 4 Purchased from Shanghai Lingfeng Chemical Reagent Company, mineral oil was purchased from Sigma-Aldrich Company, TrizolRNAiso plus was purchased from Takara Company, reverse transcription kit and SYBR Green were purchased from Applied Biosystems Company, and the primers used were synthesized by Life Company.

[0054] All other biological materials / reagents can be obtained from commercial sources.

[0055] All the other experimental materials are the same as in Example 1.

[0056] 2 Experimental methods

[0057] 2.1 The effect of SRT1720 combined with OCA on CCl 4 Induced liver fibrosis in mice.

[0058] Before the experiment, the C57BL / 6 mice were adaptively fed for one week at a room temperature of 22-26°C, a relative humidity of...

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Abstract

The invention discloses application of combination of FXR (Farnesoid X Receptor) agonist and SIRT1 (Sirtuin1) agonist for preparing an anti-hepatic fibrosis drug. Compared with the prior art, the invention discloses the application of the combination of FXR agonist and SIRT1 agonist for preparing the anti-hepatic fibrosis drug. Under a liver injury state, an FXR expression level is obviously lowered, in addition, the SIRT1 agonist can obviously inhibit FXR protein reduction, and therefore, the FXR agonist and the SIRT1 agonist are combined for treating hepatic fibrosis so as to perform an important role.

Description

technical field [0001] The invention relates to the application of the combination of FXR agonist and SIRT1 agonist in the preparation of anti-hepatic fibrosis medicine, which belongs to the technical field of new application of medicine. Background technique [0002] The incidence of liver diseases, especially viral hepatitis, fatty liver disease, liver fibrosis and liver cancer, remains high worldwide. For example, the incidence rate of NAFLD among ordinary adults in Europe and America is 20-33%, and the incidence rate among obese people reaches 60-90%; in China, the incidence rate is about 15% (Fan J G, Farrell G C. non-alcoholic fatty liver disease in China. Journal of Hepatology, 2009, 50(1):204-10.). Liver fibrosis (Fibrosis) is a pathological state, which refers to the transitional deposition of fibrous connective tissue in the liver. Liver fibrosis is an intermediate link in the further development of chronic liver diseases such as chronic viral hepatitis, metaboli...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61K31/05A61K31/575A61P1/16
CPCA61K31/05A61K31/575A61K45/06A61P1/16A61K2300/00
Inventor 郝海平王洪崔双王广基潘晓洁周济宇何青娴章鹏飞郭怡彤黄宁宁
Owner CHINA PHARM UNIV
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