Scoparone improves hepatic inflammation and autophagy in mice with nonalcoholic steatohepatitis by regulating the ROS/P38/Nrf2 axis and PI3K/AKT/mTOR pathway in macrophages

Liu, Beibei; Deng, Xiaoling; Jiang, Qianqian; Li, Guixin; Zhang, Junli; Zhang, Ning; Xin, Shengliang; Xu, Ke

doi:10.1016/j.biopha.2020.109895

Cited by 98 publications

(61 citation statements)

References 47 publications

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“…Oxidative stress is believed to play an important role in advanced liver failure. Previous studies have revealed that reactive oxygen species (ROS) play a role in hepatic inflammation [ 10 ], and ROS also promote HMGB1 secretion [ 11 ]. It has also been suggested that ROS in hepatocytes play important roles in the pathogenesis of liver failure; injured/dead hepatocytes greatly increase oxidative stress, which in turn contributes to further hepatocyte loss and impedes regeneration, culminating in a vicious cycle [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Serum superoxide dismutase level is a potential biomarker of disease prognosis in patients with HEV-induced liver failure

Wang

Yao

et al. 2022

BMC Gastroenterol

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Background Viral hepatitis E clinically ranges from self-limiting hepatitis to lethal liver failure. Oxidative stress has been shown to mediate hepatic inflammation during HBV-induced liver failure. We investigated whether a biomarker of oxidative stress may be helpful in assessing severity and disease outcomes of patients with HEV-induced liver failure. Methods Clinical data were obtained from patients with HEV-induced acute viral hepatitis (AVH, n = 30), acute liver failure (ALF, n = 17), and acute-on-chronic liver failure (ACLF, n = 36), as well as from healthy controls (HC, n = 30). The SOD and HMGB1 levels were measured in serum by ELISA. HL-7702 cells were cultured and stimulated by serum from HEV-infected patients or by HMGB1; oxidative status was investigated by CellROX and apoptosis was investigated by flow cytometry. Results Patients with HEV-induced liver failure (including ALF and ACLF) showed increased SOD levels compared with HEV-AVH patients and healthy controls. SOD levels > 400 U/mL were associated with a significantly higher risk of mortality in HEV-ALF and HEV-ACLF patients. Serum from HEV-infected patients led to ROS accumulation, HMGB1 secretion, and apoptosis in HL-7702 cells. Antioxidant treatment successfully inhibited HEV-induced HMGB1 secretion, and HMGB1 promoted apoptosis in HL-7702 cells. Conclusion HEV increased oxidative stress in the pathogenesis of HEV-induced hepatic diseases. Early testing of serum SOD may serve as a predictor of both HEV-ALF and HEV-ACLF outcomes. Moreover, development of strategies for modulating oxidative stress might be a potential target for treating HEV-induced liver failure patients.

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Section: Introductionmentioning

confidence: 99%

Serum superoxide dismutase level is a potential biomarker of disease prognosis in patients with HEV-induced liver failure

Wang

Yao

et al. 2022

BMC Gastroenterol

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“…Autophagy plays a vital role in NASH [ 50 , 72 ]. Because the suppression of autophagic ﬂux is associated with increased ER stress in the livers of patients with NASH [ 49 ], an increase of autophagic flux improves NASH [ 73 , 74 ] and hepatic fibrosis [ 75 ] in mouse experimental models. Furthermore, it was shown that chemical chaperone 4-PBA, an ER stress inhibitor, ameliorates lipid accumulation and lipotoxicity in human hepatoma cells by activating autophagy [ 76 ].…”

Section: Discussionmentioning

confidence: 99%

PERK prevents hepatic lipotoxicity by activating the p62-ULK1 axis-mediated noncanonical KEAP1-Nrf2 pathway

et al. 2022

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Hepatic lipotoxicity is a crucial factor in nonalcoholic steatohepatitis resulting from excessive saturated fatty acid-induced reactive oxygen species (ROS)-mediated cell death, which is associated with the accumulation of endoplasmic reticulum (ER) stress in the liver. The unfolded protein response (UPR) alleviates ER stress by restoring ER protein folding homeostasis. However, whether UPR contributes ROS elimination under lipotoxicity remains unclear. The Kelch like ECH-associated protein 1 (KEAP1)-nuclear factor, erythroid 2 like 2 (Nrf2) pathway provides antioxidant defense against lipotoxic stress by eliminating ROS and can be activated by the p62-Unc-51 like autophagy activating kinase 1 (ULK1) axis. However, the upstream molecular regulator of the p62-ULK1 axis-induced KEAP1-Nrf2 pathway in the same context remains unidentified. Here, we demonstrated that PKR-like ER kinase (PERK), a UPR sensor, directly phosphorylates p62 and ULK1, thereby activating the noncanonical KEAP1-Nrf2 pathway. We also elucidated the molecular mechanism underlying the PERK-mediated p62-ULK1 axis-dependent noncanonical KEAP1-Nrf2 pathway, which could represent a promising therapeutic strategy against hepatic lipotoxicity.

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“…The changes were strikingly reversed by administration of H 2 S. It has been demonstrated that the PI3K/Akt/mTOR cascade plays a role in the development of NAFLD and ROS elevation can lead to the activation of PI3K/AKT/mTOR cascade (Chen et al, 2017;Urasaki et al, 2018). A recent study indicates that scoparone could improve hepatic autophagy and inflammation in non-alcoholic steatohepatitis mice through the regulation of the ROS/p38/nuclear factor erythroid 2-related factor 2 (Nrf2) axis and PI3K/AKT/mTOR cascade in macrophages (Liu et al, 2020a). Another study suggests that S-propargyl-cysteine (SPRC, an H 2 S donor) decreases intracellular ROS levels in OA-induced HepG2 cells by upregulating AKT phosphorylation, Nrf2 translocation, and the expression levels of CSE and heme oxygenase-1 (HO-1).…”

Section: Discussionmentioning

confidence: 99%

Hydrogen Sulfide Attenuates High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease by Inhibiting Apoptosis and Promoting Autophagy via Reactive Oxygen Species/Phosphatidylinositol 3-Kinase/AKT/Mammalian Target of Rapamycin Signaling Pathway

Zhong

Wang

et al. 2020

Front. Pharmacol.

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Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease worldwide. Hydrogen sulfide (H2S) is involved in a wide range of physiological and pathological processes. Nevertheless, the mechanism of action of H2S in NAFLD development has not been fully clarified. Here, the reduced level of H2S was observed in liver cells treated with oleic acid (OA). Administration of H2S increased the proliferation of OA-treated cells. The results showed that H2S decreased apoptosis and promoted autophagy through reactive oxygen species (ROS)-mediated phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) cascade in OA-treated cells. In addition, administration of H2S relieved high-fat diet (HFD)-induced NAFLD via inhibition of apoptosis and promotion of autophagy. These findings suggest that H2S could ameliorate HFD-induced NAFLD by regulating apoptosis and autophagy through ROS/PI3K/AKT/mTOR signaling pathway. Novel H2S-releasing donors may have therapeutic potential for the treatment of NAFLD.

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Scoparone improves hepatic inflammation and autophagy in mice with nonalcoholic steatohepatitis by regulating the ROS/P38/Nrf2 axis and PI3K/AKT/mTOR pathway in macrophages

Cited by 98 publications

References 47 publications

Serum superoxide dismutase level is a potential biomarker of disease prognosis in patients with HEV-induced liver failure

Serum superoxide dismutase level is a potential biomarker of disease prognosis in patients with HEV-induced liver failure

PERK prevents hepatic lipotoxicity by activating the p62-ULK1 axis-mediated noncanonical KEAP1-Nrf2 pathway

Hydrogen Sulfide Attenuates High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease by Inhibiting Apoptosis and Promoting Autophagy via Reactive Oxygen Species/Phosphatidylinositol 3-Kinase/AKT/Mammalian Target of Rapamycin Signaling Pathway

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