title: The protective effect of the natural compound hesperetin against fulminant hepatitis in vivo and in vitro.
abstract: Liver diseases are mostly accompanied by inflammation and hepatocyte death. Therapeutic approaches targeting both hepatocyte injury and inflammation are not available. Natural compounds are considered as potential treatment for inflammatory liver diseases. Hesperetin, a flavonoid component of citrus fruits, has been reported to have anti-inflammatory properties. The aim of this study was to evaluate the cytoprotective and anti-inflammatory properties of hesperetin both in vitro and in models of fulminant hepatitis.
  
  
  
  Apoptotic cell death and inflammation were induced in primary cultures of rat hepatocytes by bile acids and cytokine mixture respectively. Apoptosis was quantified by caspase-3 activity and necrosis by LDH release. The concanavalin A (ConA) and D-galactosamine/LPS (D-GalN/LPS) were used as models of fulminant hepatitis. Liver injury was assessed by alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, liver histology and TUNEL assay and inflammation by inducible NOS (iNOS) expression.
  
  
  
  Hesperetin blocked bile acid-induced apoptosis and cytokine-induced inflammation in rat hepatocytes. Moreover, hesperetin improved liver histology and protected against hepatocyte injury in ConA- and D-GalN/LPS-induced fulminant hepatitis, as assessed by TUNEL assay and serum AST and ALT levels. Hesperetin also reduced expression of the inflammatory marker iNOS and the expression and serum levels of TNFα and IFN-γ, the main mediators of cell toxicity in fulminant hepatitis.
  
  
  
  Hesperetin has anti-inflammatory and cytoprotective actions in models of acute liver toxicity. Hesperetin therefore has therapeutic potential for the treatment of inflammatory liver diseases accompanied by extensive hepatocyte injury, such as fulminant hepatitis.
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou, China.|Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Xueting
authors.initials: X
authors.lastname: Bai
authors.affiliation: Health Care Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, China.
authors.forename: Peixuan
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou, China.
authors.forename: Qiaoling
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Laboratory of Molecular Cardiology, The First Affiliated Hospital of Shantou University Medical College, Shantou, China.
authors.forename: Bozhi
authors.initials: B
authors.lastname: Cai
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Manon
authors.initials: M
authors.lastname: Buist-Homan
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou, China.
authors.forename: He
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou, China.
authors.forename: Jiyang
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou, China.
authors.forename: Daifei
authors.initials: D
authors.lastname: Shen
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou, China.
authors.forename: Xiajiong
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Klaas Nico
authors.initials: KN
authors.lastname: Faber
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Han
authors.initials: H
authors.lastname: Moshage
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou, China.
authors.forename: Ganggang
authors.initials: G
authors.lastname: Shi
mesh_terms: D000818:Animals; D001688:Biological Products / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D003208:Concanavalin A / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005688:Galactosamine / Q000008:administration & dosage; D006569:Hesperidin / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000008:administration & dosage; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D008297:Male; D020011:Protective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001688:Biological Products; D008070:Lipopolysaccharides; D020011:Protective Agents; D003208:Concanavalin A; D005688:Galactosamine; D006569:Hesperidin; C013015:hesperetin