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5-O-Demethylnobiletin Alleviates CCl₄-Induced Acute Liver Injury by Equilibrating ROS-Mediated Apoptosis and Autophagy Induction.

ABSTRACT: 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 ?M, 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.

SUBMITTER: Chang SN

PROVIDER: S-EPMC7865239 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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5-O-Demethylnobiletin Alleviates CCl<sub>4</sub>-Induced Acute Liver Injury by Equilibrating ROS-Mediated Apoptosis and Autophagy Induction.

Chang Sukkum Ngullie SN Kim Se Ho SH Dey Debasish Kumar DK Park Seon Min SM Nasif Omaima O Bajpai Vivek K VK Kang Sun Chul SC Lee Jintae J Park Jae Gyu JG

International journal of molecular sciences 20210122 3

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 (CCl<sub>4</sub>). Subsequently, we investigated acute liver injury on BA ...[more]

PMID: 33499185

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Project description:Liver-resident macrophages (Kupffer cells, KCs) and autophagy play critical roles in the pathogenesis of toxin-induced liver injury. Recent evidence indicates that autophagy can regulate macrophage M1/M2 polarization under different inflammatory conditions. Polyamines, including putrescine, spermidine, and spermine (SPM), are polycations with anti-oxidative, anti-aging, and cell autophagy induction properties. This study aimed to determine the mechanisms by which SPM protects against thioacetamide (TAA)-induced acute liver injury in a mouse model. Pretreatment with SPM significantly alleviated liver injury and reduced intrahepatic inflammation in TAA-induced liver injury compared to controls. SPM markedly inhibited M1 polarization, but promoted M2 polarization of KCs obtained from TAA-exposed livers, as evidenced by decreased IL-1β and iNOS gene induction but increased Arg-1 and Mrc-1 gene induction accompanied by decreased STAT1 activation and increased STAT6 activation. Furthermore, pretreatment with SPM enhanced autophagy, as revealed by increased LC3B-II levels, decreased p62 protein expression, and increased ATG5 protein expression in TAA-treated KCs. Knockdown of ATG5 in SPM-pretreated KCs by siRNA resulted in a significant increase in pro-inflammatory TNF-α and IL-6 secretion and decreased anti-inflammatory IL-10 secretion after TAA treatment, while no significant changes were observed in cytokine production in the TAA treatment alone. Additionally, the effect of SPM on regulation of KC M1/M2 polarization was abolished by ATG5 knockdown in TAA-exposed KCs. Finally, in vivo ATG5 knockdown in KCs abrogated the protective effect of SPM against TAA-induced acute liver injury. Our results indicate that SPM-mediated autophagy inhibits M1 polarization, while promoting M2 polarization of KCs in TAA-treated livers via upregulation of ATG5 expression, leading to attenuated liver injury. This study provides a novel target for the prevention of acute liver injury.

Dataset Information

5-O-Demethylnobiletin Alleviates CCl₄-Induced Acute Liver Injury by Equilibrating ROS-Mediated Apoptosis and Autophagy Induction.

Publications

5-O-Demethylnobiletin Alleviates CCl<sub>4</sub>-Induced Acute Liver Injury by Equilibrating ROS-Mediated Apoptosis and Autophagy Induction.

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5-O-Demethylnobiletin Alleviates CCl4-Induced Acute Liver Injury by Equilibrating ROS-Mediated Apoptosis and Autophagy Induction.

Publications

5-O-Demethylnobiletin Alleviates CCl<sub>4</sub>-Induced Acute Liver Injury by Equilibrating ROS-Mediated Apoptosis and Autophagy Induction.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

5-O-Demethylnobiletin Alleviates CCl₄-Induced Acute Liver Injury by Equilibrating ROS-Mediated Apoptosis and Autophagy Induction.