Abstract
To investigate the effects and mechanism of diosmetin on acute hepatic failure (AHF), an AHF murine model was established through administration of lipopolysaccharides/D-galactosamine (LPS/D-GalN). In vitro, diosmetin scavenged free radicals. In vivo, diosmetin decreased mortality among mice, blocked the development of histopathological changes and hepatic damage, and suppressed levels of inflammatory mediators and cytokines. In addition, diosmetin prevented the expression of phosphorylated IKK, IκBα, and NF-κB p65 in the NF-κB signaling pathway, and JNK and p38 in the MAPK signaling pathway. Diosmetin also inhibited hepatocyte apoptosis. Thus, diosmetin exerts protective effects against endotoxin-induced acute hepatic failure in mice. The underlying mechanisms are antioxidation, NF-κB signaling inhibition, inflammatory mediator/cytokine attenuation, and hepatocyte apoptosis suppression. Diosmetin is thus a potential drug candidate for use in the treatment of acute hepatic failure.
Highlights
Acute hepatic failure (AHF) is defined as the sudden clinical syndrome of severe hepatocellular dysfunction accompanied by hepatic encephalopathy in a healthy human [1, 2]
To investigate the effects and mechanism of diosmetin on acute hepatic failure (AHF), an AHF murine model was established through administration of lipopolysaccharides/D-galactosamine (LPS/D-GalN)
LPS and D-GalN-induced hepatitis is a wellestablished model of liver injury promoted by macrophages [22]
Summary
Acute hepatic failure (AHF) is defined as the sudden clinical syndrome of severe hepatocellular dysfunction accompanied by hepatic encephalopathy in a healthy human [1, 2]. The loss of hepatocellular function leads to metabolic derangements, including clotting factor synthesis, gluconeogenesis and ureogenesis, impairment of plasma detoxification, neurologic complications, and multiorgan failure [3]. AHF has a variety of etiologies, such as viral hepatitis [4], excessive alcohol [5], and drug-induced hepatotoxicity [6]. When patients experience life-threatening liver failure, no effective therapy is available apart from liver transplantation [7]. Cell-based therapies are not appropriate for most patients. A continuing search for a promising hepatoprotective agent is necessary
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