title: Demethyleneberberine, a natural mitochondria-targeted antioxidant, inhibits mitochondrial dysfunction, oxidative stress, and steatosis in alcoholic liver disease mouse model.
abstract: Excessive alcohol consumption induces oxidative stress and lipid accumulation in the liver. Mitochondria have long been recognized as the key target for alcoholic liver disease (ALD). Recently, the artificial mitochondria-targeted antioxidant MitoQ has been used to treat ALD effectively in mice. Here, we introduce the natural mitochondria-targeted antioxidant demethyleneberberine (DMB), which has been found in Chinese herb Cortex Phellodendri chinensis. The protective effect of DMB on ALD was evaluated with HepG2 cells and acutely/chronically ethanol-fed mice, mimicking two common patterns of drinking in human. The results showed that DMB, which is composed of a potential antioxidant structure, could penetrate the membrane of mitochondria and accumulate in mitochondria either in vitro or in vivo. Consequently, the acute drinking-caused oxidative stress and mitochondrial dysfunction were significantly ameliorated by DMB. Moreover, we also found that DMB suppressed CYP2E1, hypoxia inducible factor α, and inducible nitric oxide synthase, which contributed to oxidative stress and restored sirtuin 1/AMP-activated protein kinase/peroxisome proliferator-activated receptor-γ coactivator-1α pathway-associated fatty acid oxidation in chronic ethanol-fed mice, which in turn ameliorated lipid peroxidation and macrosteatosis in the liver. Taking these findings together, DMB could serve as a novel and potential therapy for ALD in human beings.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing, China; and Institute of Toxicology, Jiangsu Provincial Center for Disease Prevention and Control, Nanjing, China.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing, China; and Institute of Toxicology, Jiangsu Provincial Center for Disease Prevention and Control, Nanjing, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Qiang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing, China; and Institute of Toxicology, Jiangsu Provincial Center for Disease Prevention and Control, Nanjing, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing, China; and Institute of Toxicology, Jiangsu Provincial Center for Disease Prevention and Control, Nanjing, China.
authors.forename: Dongshen
authors.initials: D
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing, China; and Institute of Toxicology, Jiangsu Provincial Center for Disease Prevention and Control, Nanjing, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing, China; and Institute of Toxicology, Jiangsu Provincial Center for Disease Prevention and Control, Nanjing, China.
authors.forename: Cuisong
authors.initials: C
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing, China; and Institute of Toxicology, Jiangsu Provincial Center for Disease Prevention and Control, Nanjing, China.
authors.forename: Xie
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing, China; and Institute of Toxicology, Jiangsu Provincial Center for Disease Prevention and Control, Nanjing, China.
authors.forename: Ruiyan
authors.initials: R
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing, China; and Institute of Toxicology, Jiangsu Provincial Center for Disease Prevention and Control, Nanjing, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing, China; and Institute of Toxicology, Jiangsu Provincial Center for Disease Prevention and Control, Nanjing, China ybzhang@cpu.edu.cn.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001599:Berberine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004195:Disease Models, Animal; D000431:Ethanol / Q000009:adverse effects; D005227:Fatty Acids / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors; D008108:Liver Diseases, Alcoholic / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000975:Antioxidants; D005227:Fatty Acids; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D001599:Berberine; C477155:demethyleneberberine; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1; D052247:Nitric Oxide Synthase Type II; D055372:AMP-Activated Protein Kinases; D056564:Sirtuin 1