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Hepatic sinusoidal obstruction syndrome (HSOS) is a rare liver disease with considerable morbidity and mortality. (-)-Epicatechin (EPI) is a natural flavonol. This study aims to investigate the protection of EPI against monocrotaline (MCT)-induced HSOS and its engaged mechanism. Results of serum alanine/aspartate aminotransferases (ALT/AST) activities, total bilirubin (TBil) and bile acids (TBA) amounts, liver histological evaluation, scanning electron microscope observation and hepatic metalloproteinase-9 (MMP-9) expression all demonstrated the protection by EPI against MCT-induced HSOS in rats. EPI attenuated liver oxidative injury induced by MCT. EPI enhanced the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and increased the expression of its downstream antioxidant genes in rats. Molecular docking results implied the potential interaction of EPI with the Nrf2 binding site in kelch-like ECH-associated protein-1 (Keap1). The EPI-provided protection against MCT-induced HSOS was diminished in Nrf2 knock-out mice when mice were treated with MCT for 24 h but not for 48 h. However, EPI reduced the increased liver myeloperoxidase (MPO) activity, hepatic infiltration of immune cells, pro-inflammatory cytokines expression and nuclear factor κB (NFκB) activation in both wild-type and Nrf2 knock-out mice when mice were treated with MCT for 48 h. EPI reduced the elevated serum heat shock protein 60 (HSP60) content, and reversed the decreased mitochondria expression of HSP60 and Lon in livers from MCT-treated rats. Furthermore, the MCT-induced HSOS was markedly alleviated in mice treated with anti-HSP60 antibody. Taken together, this study demonstrates that EPI attenuates MCT-induced HSOS by reducing liver oxidative injury via activating Nrf2 antioxidant pathway and inhibiting liver inflammatory injury through abrogating NFκB signaling pathway initiated by HSP60.

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Highlights • EPI attenuates MCT-induced HSOS in rats. • EPI inhibits MCT induced liver oxidative injury in rats. • Nrf2 is important for the EPI-provided protection against MCT-induced HSOS. • EPI also abrogates MCT-induced liver inflammatory injury. • EPI reduced the release of HSP60.

Titel:	(-)-Epicatechin attenuates hepatic sinusoidal obstruction syndrome by inhibiting liver oxidative and inflammatory injury
Autor/in / Beteiligte Person:	Wang, Zhengtao ; Sheng, Yuchen ; Hao, Zhanxia ; Ji, Lili ; Jing, Xiaoqi ; Huang, Zhenlin ; Zhang, Jiaqi
Link:	View record in OpenAIRE (Volltext) http://europepmc.org/articles/PMC6395886
Zeitschrift:	Redox Biology, Jg. 22 (2019-02-01)
Veröffentlichung:	Elsevier, 2019
Medientyp:	unknown
ISSN:	2213-2317 (print)
Schlagwort:	0301 basic medicine Male Models, Molecular MDA, malondialdehydeand Nrf2, Nuclear factor erythroid 2-related factor 2 GSH, reduced glutathione Clinical Biochemistry Hepatic Veno-Occlusive Disease Molecular Conformation MPO, myeloperoxidase HO-1, heme oxygenase 1 Pharmacology HSOS Biochemistry Antioxidants Catechin Liver disease chemistry.chemical_compound H2DCFDA, 2′-7′-dichlorodihydrofluorescein diacetate Mice 0302 clinical medicine lcsh:QH301-705.5 lcsh:R5-920 Monocrotaline biology (-)-Epicatechin HSCT, hematopoietic stem-cell transplantation EPI, (-)-epicatechin TBA, bile acids DILI, drug-induced liver injury Liver Myeloperoxidase LPO, lipid peroxidation Signal transduction HSP60, heat shock protein 60 Inflammation Mediators lcsh:Medicine (General) Oxidation-Reduction Research Paper Signal Transduction ALT/AST, alanine/aspartate aminotransferases MCT, monocrotaline Bilirubin TBil, total bilirubin NF-E2-Related Factor 2 H&E, hematoxylin-eosin HSOS, hepatic sinusoidal obstruction syndrome Mice, Transgenic Oxidative phosphorylation Nrf2 03 medical and health sciences Structure-Activity Relationship ROS, reactive oxygen species Heat shock protein Keap1, kelch-like ECH-associated protein-1 GST, glutathione-S-transferase medicine Animals GCLC, catalytic subunit of glutamate-cysteine ligase TALEN, transcription activator-like effector nucleases HPAs, hepatotoxic pyrrolizidine alkaloids MMP-9, metalloproteinase-9 GCLM, modify subunit of glutamate-cysteine ligase Organic Chemistry Chaperonin 60 medicine.disease NQO1, NAD(P)H: quinone oxidoreductase 1 KEAP1 Rats HSECs, hepatic sinusoidal endothelial cells Disease Models, Animal Oxidative Stress 030104 developmental biology NFκB, nuclear factor κB lcsh:Biology (General) chemistry i.g., intragastrical administration biology.protein MOF, multi-organ failure NAFLD, nonalcoholic fatty liver disease Reactive Oxygen Species 030217 neurology & neurosurgery TBIL Biomarkers NFκB
Sonstiges:	Nachgewiesen in: OpenAIRE Sprachen: English Language: English Rights: OPEN

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(-)-Epicatechin attenuates hepatic sinusoidal obstruction syndrome by inhibiting liver oxidative and inflammatory injury