Pterostilbene protects against acetaminophen-induced liver injury by restoring impaired autophagic flux

Polymethoxyflavanoids (PMFs) have exhibited a vast array of therapeutic biological properties. 5-O-Demethylnobiletin (5-DN) is one such PMF having anti-inflammatory activity, yet its role in hepatoprotection has not been studied before. Results from in vitro study revealed that 5-DN did not exert a high level of cytotoxicity on HepG2 cells at 40 μM, and it was able to rescue HepG2 cell death induced by carbon tetrachloride (CCl4). Subsequently, we investigated acute liver injury on BALB/c mice induced by CCl4 through the intraperitoneal injection of 1 mL/kg CCl4 and co-administration of 5-DN at (1 and 2 mg/kg) by oral gavage for 15 days. The results illustrated that treatment with 5-DN attenuated CCl4-induced elevated serum aminotransferase (AST)/alanine aminotransferase (ALT) ratio and significantly ameliorated severe hepatic damage such as inflammation and fibrosis evidenced through lesser aberrations in the liver histology of 5-DN dose groups. Additionally, 5-DN efficiently counteracted and equilibrated the production of ROS accelerated by CCl4 and dramatically downregulated the expression of CYP2E1 vitally involved in converting CCl4 to toxic free radicals and also enhanced the antioxidant enzymes. 5-DN treatment also inhibited cell proliferation and inflammatory pathway abnormally regulated by CCl4 treatment. Furthermore, the apoptotic response induced by CCl4 treatment was remarkably reduced by enhanced Bcl-2 expression and noticeable reduction in Bax, Bid, cleaved caspase 3, caspase 9, and apaf-1 expression. 5-DN treatment also induced the conversion of LC3 and promoted the autophagic flux. Conclusively, 5-DN exhibited hepatoprotective effects in vitro and in vivo and prevented liver fibrosis induced by CCl4.

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Ginsenoside Rb1 alleviates liver injury induced by 3‐chloro‐1,2‐propanediol by stimulating autophagic flux

Journal of Food Science ◽

10.1111/1750-3841.15968 ◽

2021 ◽

Author(s):

Jianing Lu ◽

Jing Lu ◽

Xiujuan Bu ◽

Yazhuo Li ◽

Guangcai Ge ◽

...

Keyword(s):

Liver Injury ◽

Autophagic Flux ◽

Ginsenoside Rb1

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Inhibition of monoacylglycerol lipase, an anti-inflammatory and antifibrogenic strategy in the liver

Gut ◽

10.1136/gutjnl-2018-316137 ◽

2018 ◽

Vol 68 (3) ◽

pp. 522-532 ◽

Cited By ~ 21

Author(s):

Aida Habib ◽

Dina Chokr ◽

JingHong Wan ◽

Pushpa Hegde ◽

Morgane Mabire ◽

...

Keyword(s):

Liver Injury ◽

Cannabinoid Receptor ◽

Chronic Liver ◽

Autophagic Flux ◽

Monoacylglycerol Lipase ◽

Chronic Liver Injury ◽

Fibrosis Progression ◽

Duct Ligation ◽

Anti Inflammatory ◽

The Impact

ObjectiveSustained inflammation originating from macrophages is a driving force of fibrosis progression and resolution. Monoacylglycerol lipase (MAGL) is the rate-limiting enzyme in the degradation of monoacylglycerols. It is a proinflammatory enzyme that metabolises 2-arachidonoylglycerol, an endocannabinoid receptor ligand, into arachidonic acid. Here, we investigated the impact of MAGL on inflammation and fibrosis during chronic liver injury.DesignC57BL/6J mice and mice with global invalidation of MAGL (MAGL-/-), or myeloid-specific deletion of either MAGL (MAGLMye-/-), ATG5 (ATGMye-/-) or CB2 (CB2Mye-/-), were used. Fibrosis was induced by repeated carbon tetrachloride (CCl4) injections or bile duct ligation (BDL). Studies were performed on peritoneal or bone marrow-derived macrophages and Kupffer cells.ResultsMAGL-/- or MAGLMye-/- mice exposed to CCl4 or subjected to BDL were more resistant to inflammation and fibrosis than wild-type counterparts. Therapeutic intervention with MJN110, an MAGL inhibitor, reduced hepatic macrophage number and inflammatory gene expression and slowed down fibrosis progression. MAGL inhibitors also accelerated fibrosis regression and increased Ly-6Clow macrophage number. Antifibrogenic effects exclusively relied on MAGL inhibition in macrophages, since MJN110 treatment of MAGLMye-/- BDL mice did not further decrease liver fibrosis. Cultured macrophages exposed to MJN110 or from MAGLMye-/- mice displayed reduced cytokine secretion. These effects were independent of the cannabinoid receptor 2, as they were preserved in CB2Mye-/- mice. They relied on macrophage autophagy, since anti-inflammatory and antifibrogenic effects of MJN110 were lost in ATG5Mye-/- BDL mice, and were associated with increased autophagic flux and autophagosome biosynthesis in macrophages when MAGL was pharmacologically or genetically inhibited.ConclusionMAGL is an immunometabolic target in the liver. MAGL inhibitors may show promising antifibrogenic effects during chronic liver injury.

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Genipin Ameliorates Carbon Tetrachloride-Induced Liver Injury in Mice via the Concomitant Inhibition of Inflammation and Induction of Autophagy

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/3729051 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 6

Author(s):

Ya Wang ◽

Tianming Zhao ◽

You Deng ◽

Lijun Hou ◽

Xiaofei Fan ◽

...

Keyword(s):

Carbon Tetrachloride ◽

Liver Injury ◽

Inflammatory Response ◽

Protective Effect ◽

P38 Mapk ◽

Mapk Signaling ◽

Autophagic Flux ◽

Mice Model ◽

Stat3 Signaling Pathway ◽

Liver Changes

Genipin, as the most effective ingredient of various traditional medications, encompasses antioxidative, anti-inflammatory, and antibacterial capacities. More recently, it is suggested that genipin protects against septic liver damage by restoring autophagy. The purpose of the current study was to explore the protective effect of genipin against carbon tetrachloride- (CCl4-) induced acute liver injury (ALI) and its underlying molecular machinery. Our results indicated that treatment with genipin significantly reduced CCl4-induced hepatotoxicity by ameliorating histological liver changes, decreasing the aspartate aminotransferase and alanine transaminase levels, alleviating the secretion of inflammatory cytokines, and promoting autophagic flux. Moreover, genipin effectively induced the conversion of LC3 and inhibition of p62 accumulation. The liver expressions of ATG5, ATG7, and ATG12 were significantly increased by genipin pretreatment in the ALI mice model. This protective effect may be mediated by the inhibition of mTOR and the activation of p38 MAPK signaling pathways. Meanwhile, genipin attenuated CCl4-induced inflammatory response by inhibiting the NF-κB and STAT3 signaling pathway. In addition, pretreatment with autophagy inhibitor 3-methyladenine (3-MA) or inhibition of p38 MAPK by SB203580 abolished the hepatoprotective effect of genipin. Taken together, our study implicates that genipin has a protective potential against CCl4-induced hepatotoxicity, which might be strongly associated with the induction of autophagy and the attenuation of inflammatory response.

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Effects of Steroids on Fetal Rat Liver

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100063664 ◽

1969 ◽

Vol 27 ◽

pp. 350-351

Author(s):

F. G. Zaki

Keyword(s):

Liver Injury ◽

Rat Liver ◽

Fetal Liver ◽

Dosage Level ◽

Maternal Plasma ◽

Methyl Prednisolone ◽

Fetal Rat ◽

Toxic Agents ◽

Fetal Rat Liver ◽

Neonatal Liver

Fetal and neonatal liver injury induced by agents circulating in maternal plasma, even though well recognized, its morphological manifestations are not yet established. As part of our studies of fetal and neonatal liver injury induced by maternal nutritional disorders, metabolic impairment and toxic agents, the effects of two anti-inflammatory steroids have been recently inves tigated.Triamcinolone and methyl prednisolone were injected each in a group of rats during pregnancy at a-dosage level of 2 mgm three times a week. Fetal liver was studied at 18 days of gestation. Litter size and weight markedly decreased than those of control rats. Stillbirths and resorption were of higher incidence in the triamcinolone group than in those given the prednisolone.

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