ACS Omega
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2025
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IF 4.3
Mingmin Li,Liang Qi,Jin Huang,Haonan Li,Wei Cheng,Zihan Shi,Xianxing Jiang,Yifeng Zhou,Wanxiang Jiang
Liver fibrosis can progress to cirrhosis and hepatocellular carcinoma. Currently, there is no effective drug for liver fibrosis. The peptide 6 (T6) is an endogenous peptide derived from human intrauterine adhesion tissues and has antifibrotic potential. Here, to improve the long-term efficacy and activity of T6, we conducted the rational modified of T6 through studying structure–activity, and synthesized a series of analogues. Among them, S6 and S6-FA exhibited optimal antihepatic fibrosis activity, and S6-FA had a stronger long-acting effect than T6 and S6. The two analogues inhibited the expression of α-SMA and Collagen 1 in TGF-β-induced LX2 cells model and CCl4-induced mouse model of liver fibrosis. Besides, we discovered that S6 and S6-FA remarkably reduced the AST and ALT serum levels. Mechanistic studies have demonstrated that analogues inhibited liver fibrosis through inhibiting Erk, Smad and P65 pathways. This study provided that the novel peptide S6 and S6-FA is potential candidate compounds for treating liver fibrosis.
研究领域:
医学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2023
·
IF 5.2
Yanping Fan,Meilan Xue,Tianhu Shan,Yixian Bai,Huaqi Zhang,Man Liu,Peng Wang,Xi Liang,Hui Liang
Alcoholic liver fibrosis (ALF) is a reversible pathological change in the liver caused by chronic alcohol consumption and is associated with the activation of hepatic stellate cells . Recent findings suggest that niacin can lower triglyceride levels and exert potent antioxidant effects in liver damage. However, the therapeutic effects and molecular mechanisms of niacin in liver fibrosis remain unclear. Therefore, this study aimed to investigate the effects and mechanisms of niacin in ALF using in vivo and in vitro experiments. To establish a murine model of ALF, male C57BL/6N mice were fed a Lieber–DeCarli liquid diet containing 4 % (vol/vol) ethanol and injected with carbon tetrachloride twice weekly (2 mL/kg) for 8 weeks. L-02 and LX2 cells were treated with 400 μM acetaldehyde for 24 h to establish an in vitro ALF model. Serum parameters were examined to investigate the protective effects of niacin against ALF, and network pharmacology was used to identify potential targets and pathways of niacin. Niacin protects against ALF by suppressing the serum levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase , and alkaline phosphatase . Additionally, niacin treatment ameliorated liver fibrosis by improving the antioxidant system, inhibiting heat shock protein 90 (HSP90) activation, promoting signal transducer and activator of transcription 3 (STAT3) ubiquitination , and suppressing the JAK1/STAT3 signaling pathway . Collectively, this study provides experimental evidence that niacin protects against ALF by downregulating the HSP90/JAK1/STAT3 signaling pathway.
研究领域:
药理学
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肝病学
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分子生物学
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细胞生物学
✓ 已验证
产品关联
DOI
高影响因子
METABOLISM-CLINICAL AND EXPERIMENTAL
·
2021
·
IF 8.697
Suling Huang,Yanwei Wu,Zhuohui Zhao,Bing Wu,Kai Sun,Haoyu Wang,Li Qin,Fang Bai,Ying Leng,Wei Tang
Objective Obeticholic acid (OCA) has been proved to play potential therapeutic effect on nonalcoholic steatohepatitis (NASH). Up to now, the study of OCA on NLRP3 inflammasome activation in macrophage is still blank and merits great attention. Here, we aimed to better characterize the role and mechanism of OCA on NASH treatment focusing on NLRP3 inflammasome activation in macrophages. Methods The effects of OCA on inflammasome activation were investigated in BMDM , Kupffer cell , BMDC and LX2 cell. Preconditioned media from BMDM culture was used to treat primary hepatocytes to explore the effects of macrophage NLRP3 inflammasome activation on the function of hepatocytes. In vivo, high fat diet plus CCl 4 (DIO + CCl 4 ) induced murine NASH model and choline-deficient and amino acid-defined (CDA) diet-induced NASH mice were used to verify the inhibitory effect of OCA on inflammasome activation in liver macrophages and recapitulate its protective role on NASH progressing. To clear up the effect of OCA on macrophage is FXR dependent or not, FXR siRNA was introduced into BMDMs. Results OCA blockaded NLRP3 inflammasome in BMDMs by impacting on the activation stage and disrupting ASC oligomerization . Preconditioned supernatant from LPS + ATP treated BMDMs increased mRNA expression of lipogenic enzymes and lipid content, whereas preconditioned supernatant from OCA treated BMDM blocked these effects in both normal and the FXR knockdown hepatocytes. In DIO + CCl 4 mice, the population of inflammatory myeloid lineage cells in livers was decreased upon OCA treatment. Accordingly, the level of IL-1β and IL-18 in liver, the hepatic expression of ASC, pro-caspase-1 and active caspase-1, the expression of caspase 1 p20 in liver macrophages were also reduced. Similar results were obtained in CDA diet-fed mice. Furthermore, OCA maintained the inhibition on NLRP3 inflammasome activation in FXR knockdown BMDMs, suggesting FXR could be dispensable in this effect. Conclusions This finding brings up a new mechanism of OCA on NASH treatment, suggested by direct inhibition on NLRP3 inflammasome activation in macrophage, further suppression on inflammasome activation-elicited hepatic lipid accumulation , and contributing to the amelioration of NASH.
研究领域:
药理学
·
免疫学
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肝病学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）