Bicyclol ameliorates nonalcoholic fatty liver disease in mice via inhibiting MAPKs and NF-κB signaling pathways

Zhao, Weixin; Yan, Yixiao; Xiao, Zhifeng; Wang, Meihong; Xu, Mingjiang; Wang, Zhe; Wang, Yi; Zhuang, Zaishou; Yang, Daona; Chen, Gaozhi; Liang, Guang

doi:10.1016/j.biopha.2021.111874

Cited by 17 publications

(8 citation statements)

References 26 publications

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“…In contrast, Yao et al reported that the anti-apoptosis associated with ER stress in this model might be the mechanism for bicyclol to attenuate fatty liver ( Yao et al, 2016 ). Recently, bicyclol was reported to alleviate HFD-induced NAFLD through its anti-inflammatory mechanism ( Zhao et al, 2021 ). Our results showed that the expression of lipolysis-related protein CES2 was decreased in WD or WD/CCl 4 -induced mice, and bicyclol reversed CES2 expression to improve NAFLD, which is consistent with the fact that CES2 is reduced in high fat diet-induced obese mice, diabetic db/db mice, and NASH patients, while the liver disease was alleviated after CES2 was restored ( Li et al, 2016 ; Xu et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Bicyclol, a synthetic compound that originated from the Chinese traditional herb Schisandra chinensis , is an approved drug for alleviating liver injuries accompanied by elevated transaminases caused by various etiologies, such as viruses, drugs, alcohol, chemicals, and immunogens ( Liu, 2009 ; Li et al, 2018a ; Li et al, 2018b ). A few studies reported the therapeutic efficacy of bicyclol for NAFLD in clinic ( Li et al, 2020 ) and in animal models ( Zhao et al, 2021 ), though more data are needed to show its clinical benefits and the detailed mechanisms. Berberine, an approved antibacterial agent derived from a wide variety of Chinese traditional herbs, such as Coptis chinensis and Berberis vulgaris ( Kong et al, 2020 ), has beneficial effects on NAFLD through diverse mechanisms, including the increase of insulin sensitivity, regulation of adenosine monophosphate-activated protein kinase (AMPK) pathway, improvement of mitochondrial function, and regulation of the gut microenvironment ( Zhu et al, 2016 ; Wang et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Combined Use of Bicyclol and Berberine Alleviates Mouse Nonalcoholic Fatty Liver Disease

Liu

et al. 2022

Front. Pharmacol.

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Nonalcoholic fatty liver disease (NAFLD), ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), is a liver disease worldwide without approved therapeutic drugs. Anti-inflammatory and hepatoprotective drug bicyclol and multi-pharmacological active drug berberine, respectively, have shown beneficial effects on NAFLD in murine nutritional models and patients, though the therapeutic mechanisms remain to be illustrated. Here, we investigated the combined effects of bicyclol and berberine on mouse steatosis induced by Western diet (WD), and NASH induced by WD/CCl4. The combined use of these was rather safe and better reduced the levels of transaminase in serum and triglycerides and cholesterol in the liver than their respective monotherapy, accompanied with more significantly attenuating hepatic inflammation, steatosis, and ballooning in mice with steatosis and NASH. The combined therapy also significantly inhibited fibrogenesis, characterized by the decreased hepatic collagen deposition and fibrotic surface. As per mechanism, bicyclol enhanced lipolysis and β-oxidation through restoring the p62-Nrf2-CES2 signaling axis and p62-Nrf2-PPARα signaling axis, respectively, while berberine suppressed de novo lipogenesis through downregulating the expression of acetyl-CoA carboxylase and fatty acid synthetase, along with enrichment of lipid metabolism-related Bacteroidaceae (family) and Bacteroides (genus). Of note, the combined use of bicyclol and berberine did not influence each other but enhanced the overall therapeutic role in the amelioration of NAFLD. Conclusion: Combined use of bicyclol and berberine might be a new available strategy to treat NAFLD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Combined Use of Bicyclol and Berberine Alleviates Mouse Nonalcoholic Fatty Liver Disease

Liu

et al. 2022

Front. Pharmacol.

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“…A systematic meta-analysis presented the evidence of bicyclol treatment for improving liver function and serum lipid biomarkers in patients with NAFLD, predicting that bicyclol might be an alternative agent for NAFLD (Li et al, 2020). The quality of evidence suggested that bicyclol administration significantly attenuated high-fat diet (HFD)-induced activation of inflammatory-mediated signaling pathway (MAPKs/NF-κB) and gluconeogenesis/insulin signaling pathway (Akt, PGC-1α and PEPCK) (Li H et al, 2021;Zhao W et al, 2021). Pharmacological studies displayed that bicyclol had obvious protective effects against hepatocyte injury caused by tetracycline, alcoholic and non-alcoholic fatty liver associated with cell apoptosis, endoplasmic reticulum (ER), and oxidative stress (Yao et al, 2016;Jia et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Bicyclol attenuates high fat diet-induced non-alcoholic fatty liver disease/non-alcoholic steatohepatitis through modulating multiple pathways in mice

Jia

et al. 2023

Front. Pharmacol.

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Introduction: The pathological progression of non-alcoholic fatty liver disease (NAFLD) is driven by multiple factors, and non-alcoholic steatohepatitis (NASH) represents its progressive form. In our previous studies, we found that bicyclol had beneficial effects on NAFLD/ NASH. Here we aim to investigate the underlying molecular mechanisms of the bicyclol effect on NAFLD/NASH induced by high-fat diet (HFD) feeding.Methods: A mice model of NAFLD/NASH induced by HFD-feeding for 8 weeks was used. As a pretreatment, bicyclol (200 mg/kg) was given to mice by oral gavage twice daily. Hematoxylin and eosin (H&E) stains were processed to evaluate hepatic steatosis, and hepatic fibrous hyperplasia was assessed by Masson staining. Biochemistry analyses were used to measure serum aminotransferase, serum lipids, and lipids in liver tissues. Proteomics and bioinformatics analyses were performed to identify the signaling pathways and target proteins. Data are available via Proteome X change with identifier PXD040233. The real-time RT-PCR and Western blot analyses were performed to verify the proteomics data.Results: Bicyclol had a markedly protective effect against NAFLD/NASH by suppressing the increase of serum aminotransferase, hepatic lipid accumulation and alleviating histopathological changes in liver tissues. Proteomics analyses showed that bicyclol remarkably restored major pathways related to immunological responses and metabolic processes altered by HFD feeding. Consistent with our previous results, bicyclol significantly inhibited inflammation and oxidative stress pathway related indexes (SAA1, GSTM1 and GSTA1). Furthermore, the beneficial effects of bicyclol were closely associated with the signaling pathways of bile acid metabolism (NPC1, SLCOLA4 and UGT1A1), cytochrome P450-mediated metabolism (CYP2C54, CYP3A11 and CYP3A25), biological processes such as metal ion metabolism (Ceruloplasmin and Metallothionein-1), angiogenesis (ALDH1A1) and immunological responses (IFI204 and IFIT3).Discussion: These findings suggested that bicyclol is a potential preventive agent for NAFLD/NASH by targeting multiple mechanisms in future clinical investigations.

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“…The results above suggested that dietary high fat induced oxidative stress via the suppression of the NF-κB/NO signal pathway. Some research supported the notion that the NF-κB signal pathway also plays a crucial regulatory role in NAFLD induced by high-fat diets [ 58 , 59 ]. In vertebrates, NF-κB is activated by high-fat diets to induce inflammation.…”

Section: Discussionmentioning

confidence: 96%

High-Fat-Diet-Induced Oxidative Stress in Giant Freshwater Prawn (Macrobrachium rosenbergii) via NF-κB/NO Signal Pathway and the Amelioration of Vitamin E

Sun

Shan

et al. 2022

Antioxidants

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Lipids work as essential energy sources for organisms. However, prawns fed on high-fat diets suffer from oxidative stress, whose potential mechanisms are poorly understood. The present study aimed to explore the regulation mechanism of oxidative stress induced by high fat and the amelioration by vitamin E (VE) of oxidative stress. Macrobrachium rosenbergii were fed with two dietary fat levels (LF 9% and HF 13%) and two VE levels (200 mg/kg and 600 mg/kg) for 8 weeks. The results showed that the HF diet decreased the growth performance, survival rate and antioxidant capacity of M. rosenbergii, as well as inducing hypertrophied lipid droplets, lipophagy and apoptosis. A total of 600 mg/kg of VE in the HF diet alleviated the negative effects induced by HF. In addition, the HF diet suppressed the expression of toll-dorsal and imd-relish signal pathways. After the relish and dorsal pathways were knocked down, the downstream iNOS and NO levels decreased and the MDA level increased. The results indicated that M. rosenbergii fed with a high-fat diet could cause oxidative damage. Its molecular mechanism may be attributed to the fact that high fat suppresses the NF-κB/NO signaling pathway mediating pro-oxidant and antioxidant targets for regulation of oxidative stress. Dietary VE in an HF diet alleviated hepatopancreas oxidative stress and apoptosis.

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Bicyclol ameliorates nonalcoholic fatty liver disease in mice via inhibiting MAPKs and NF-κB signaling pathways

Cited by 17 publications

References 26 publications

Combined Use of Bicyclol and Berberine Alleviates Mouse Nonalcoholic Fatty Liver Disease

Combined Use of Bicyclol and Berberine Alleviates Mouse Nonalcoholic Fatty Liver Disease

Bicyclol attenuates high fat diet-induced non-alcoholic fatty liver disease/non-alcoholic steatohepatitis through modulating multiple pathways in mice

High-Fat-Diet-Induced Oxidative Stress in Giant Freshwater Prawn (Macrobrachium rosenbergii) via NF-κB/NO Signal Pathway and the Amelioration of Vitamin E

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