*Last two authors contributed equally to this work.
BACKGROUND AND PURPOSELiver 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.
EXPERIMENTAL APPROACHApoptotic 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 Dgalactosamine/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.
KEY RESULTSHesperetin 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.
CONCLUSION AND IMPLICATIONSHesperetin 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.
AbbreviationsALT, alanine aminotransferase; AST, aspartate aminotransferase; CM, cytokine mixture; CMC-Na, sodium carboxymethylcellulose; ConA, concanavalin A; D-GalN, D-galactosamine; FasL, Fas ligand; GCDCA, glycochenodeoxycholic acid; HE, haematoxylin-eosin; HO1, haem oxygenase 1; iNOS, inducible NOS; TBil, total bilirubin; TLR, toll-like receptor; TUDCA, tauroursodeoxycholic acid
IntroductionHesperetin is a natural compound belonging to the flavanone class of flavonoids. It is the aglycone of hesperidin (β-7-rutinoside of hesperetin), a predominant flavonoid component of citrus fruits (Figure 1). It is now well accepted that low consumption of high fat foods and an increased intake of fruit and vegetables will reduce the risk of some lifethreatening diseases and maintain a good health status (Parr and Bolwell, 2000). Worldwide, the dietary intake of citrus fruit products, and hence flavanones, is increasing every year (Khan et al., 2014). In Western countries, the intake of hesperetin is largely dependent on dietary habits (Knekt et al., 2002), whereas hesperetin is also known as a major active ingredient in the Chinese traditional medic...
