Acta Pharmaceutica Sinica B
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2019
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IF 5.808
Yayun Liu,Wei Xu,Ting Zhai,Jiaojiao You,Yong Chen
Non-alcoholic steatohepatitis (NASH) is a chronic metabolic syndrome and the CFLAR-JNK pathway can reverse the process of NASH. Although silibinin is used for the treatment of NASH in clinical, its effect on CFLAR-JNK pathway in NASH remains unclear. This study aimed to investigate the effect of silibinin on CFLAR-JNK pathway in NASH models both in vivo and in vitro . The in vivo study was performed using male C57BL/6 mice fed with methionine– choline-deficient diet and simultaneously treated with silibinin for 6 weeks. The in vitro study was performed by using mouse NCTC-1469 cells which were respectively pretreated with oleic acid plus palmitic acid, and adenovirus-down Cflar for 24 h, then treated with silibinin for 24 h. After the drug treatment, the key indicators involved in CFLAR-JNK pathway including hepatic injury, lipid metabolism and oxidative stress were determined. Silibinin significantly activated CFLAR and inhibited the phosphorylation of JNK, up-regulated the mRNA expression of Pparα, Fabp5, Cpt1α, Acox, Scd-1, Gpat and Mttp , reduced the activities of serum ALT and AST and the contents of hepatic TG, TC and MDA, increased the expression of NRF2 and the activities of CAT, GSH-Px and HO-1, and decreased the activities and expression of CYP2E1 and CYP4A in vivo . These effects were confirmed by the in vitro experiments. Silibinin prevented NASH by regulating CFLAR-JNK pathway, and thereby on one hand promoting the β -oxidation and efflux of fatty acids in liver to relieve lipid accumulation, and on the other hand inducing antioxidase activity (CAT, GSH-Px and HO-1) and inhibiting pro-oxidase activity (CYP2E1 and CYP4A) to relieve oxidative stress.
研究领域:
药理学
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肝病学
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代谢性疾病
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产品关联
DOI
PubMed
高影响因子
MEDICINAL CHEMISTRY RESEARCH
·
2022
·Vol. 31
·期 12
·2209-2219
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IF 2.351
Chen Yu,Zhang Shaojun,Lu Yanxia,Li Lujun,Shi Yu,Lei Yueyue,Yang Xinyu,Wu Zhengzhi
Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease associated with hepatic lipid accumulation, insulin resistance, oxidative stress, and inflammation. The CFLAR-JNK pathway plays a decisive role in the development of NAFLD. EJ1 is a new hexacyclic triterpenic acid isolated from Euscaphis japonica , a traditional herbal medicine with anti-NAFLD effect. The present study was aimed to evaluate the hepatoprotective effect of EJ1 against NAFLD in vitro and the underlying mechanisms. The biochemical parameters related to lipid accumulation, insulin resistance, oxidative stress, and inflammation in oleic acid-induced HepG2 cellular model of NAFLD were measured. In this study, EJ1 was found to significantly decrease TG and TC contents. Meanwhile, EJ1 increased hepatocellular glucose uptake and improved insulin resistance by increasing the phosphorylation levels of pIRS1, pAKT and PI3K. Furthermore, EJ1 decreased the intracellular ROS and MDA, promoted the antioxidant enzymes activity including SOD and GSH-Px. Moreover, EJ1 reduced the levels of cellular NO and mRNA of TNF-α, IL-6 and IL-8. Further investigation showed that EJ1 treatment led to up-regulation of CFLAR protein expression and down-regulation of JNK protein phosphorylation. These results revealed that EJ1 has the potential to alleviate lipid accumulation, insulin resistance, oxidative stress, and inflammatory responses in OA-treated HepG2 cellular model of NAFLD, representing a promising leading compound for NAFLD, possibly by activating the CFLAR-JNK pathway.
Graphical abstract
研究领域:
药理学
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细胞生物学
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分子生物学
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肝病学
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产品关联
DOI
高影响因子
Chinese Herbal Medicines
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2019
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IF 0
Ya-yun Liu,Jiao-jiao You,Wei Xu,Ting Zhai,Chun-yuan Du,Yong Chen,Feng-mei Han
Objective The present work was to investigate the protective effects of the aqueous extract of Gynura procumbens (GPAE) against nonalcoholic steatohepatitis (NASH) in mice and NCTC-1469 cells. Methods C57BL/6J mice were fed with methionine and choline-deficient (MCD) diet and administered simultaneously with GPAE (500 and 1000 mg/kg/d, respectively) by gavage for six weeks. The biomarkers of NASH in serum and liver were determined. NCTC-1469 cells were pretreated with 0.25 mmol/L palmitic acid (PA) plus 0.5 mmol/L oleic acid (OA) for 24 h or treated with adenovirus expressing short-hairpin RNA against CFLAR (Ad-shCFLAR) for 24 h and then treated with GPAE (80 and 160 µg/mL, respectively) for 24 h, and the content of cellular biomarkers of NASH was detected. Results In mice treated with MCD , GPAE could decrease the levels of serum ALT , AST, the content of hepatic TG , TC and MDA , repress the activities and protein expression of CYP2E1 and CYP4A and the phosphorylation of JNK, increase the activities of HO-1, CAT and GSH-Px, up-regulate the mRNA expression of PPARα, FABP5, CPT1α, ACOX, SCD-1, mGPAT, MTTP and the protein expression of CFLAR and NRF2. In NCTC-1469 cells treated with PA and OA, GPAE could decrease the content of cellular TG and ROS , promote the uptake of 2-NBDG, up-regulate the protein expression of CFLAR and NRF2. In NCTC-1469 cells treated with Ad-sh CFLAR , GPAE up-regulated the mRNA and protein expression of CFLAR, down-regulated the phosphorylation of JNK, and increased the protein expression of NRF2 and pIRS1 . Conclusion These results indicated that the activation on CFLAR-JNK pathway might be the main anti-NASH mechanism of GPAE, which on the one hand promote the β-oxidation and efflux of fatty acids in liver, and finally reduce hepatic lipid accumulation , on the other hand increase the activities of anti-oxidant enzymes and inhibit the activities of ROS generation enzymes by activating NRF2, and therefore attenuates hepatic oxidative stress damage.
研究领域:
药理学
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肝病学
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分子生物学
✓ 已验证
产品关联
DOI
危险品化学品经营许可证（带存储）