Melatonin regulates L-arginine transport and NADPH oxidase in young rats with bile duct ligation: role of protein kinase C

Abstract

Background: Bile duct ligation (BDL) is a commonly used cholestatic liver disease (cLD) model. We recently found that l-arginine levels were significantly raised by melatonin in young rats with BDL. We hypothesized that protein kinase c-α (PKc-α) is involved in the increases of l-arginine in melatonintreated BDL rats. In addition, we tested whether melatonin prevents nicotinamide adenine dinucleotide phosphate (NADPh) oxidase-induced reactive oxygen species (ROs) production, in rats with BDL, through PKc. Methods: Four groups of young male rats were studied: shams (n = 6), untreated BDL rats (n = 9), melatonin-treated shams (n = 6, M), and melatonin-treated BDL rats (n = 6, BDL + M). Melatonin-treated rats received daily melatonin 1 mg/kg/d via i.p. injection. All surviving rats were killed 14 d after surgery. results: Melatonin prevented BDL-induced mortality and kidney injury. Melatonin additionally increased l-arginine concentrations in BDL liver, which is correlated with decreased PKc-α translocation. Next, melatonin increased l-arginine levels in BDL kidneys, which was correlated with decreased renal levels of arginase II. In the BDL kidney, melatonin decreased PKc-β translocation, reduced p47phox translocation, and diminished NADPh-dependent superoxide production. conclusion: Melatonin inhibits PKc-α to increase cationic amino acid transporter-1 (cAT-1)-mediated l-arginine uptake in BDL liver, whereas it inhibits PKc-β to reduce NADPhdependent superoxide production.

Serum Metabolomic Profiling in a Rat Model Reveals Protective Function of Paeoniflorin Against ANIT Induced Cholestasis

“…In urea cycle, L(D)-arginine and its downstream substrate 4-guanidinobutanoate were found to decline in the model group, whereas PeaH group significantly enhanced the contents. Previous studies demonstrate that modulation of L-arginine metabolism displays protective effects on cholestatic rats through NO synthasis and attenuating oxidative stress (Tain et al, 2013).…”

Melatonin Alleviates Liver Apoptosis in Bile Duct Ligation Young Rats

“…All rats were sacrificed 14 days after surgery. To reduce the number of animals used, we did not perform sham group receiving melatonin because we previously found that there were no significant effects of melatonin in plasma direct and total bilirubin, AST, and ALT levels in young sham operation rats [41]. …”

The melatonin immunomodulatory actions in radiotherapy

“…These enzymes have other effects involved in inflammation and redox systems, such as mitochondria following exposure to radiation, and they amplify oxidative damages induced by it (Prise and O'Sullivan 2009). Both antioxidative and anti-inflammatory effects of melatonin cause inhibition of COX-2, iNOS, and NADPH oxidase (Tain et al 2013;Cuzzocrea et al 1999;Cuzzocrea et al 1997;Pozo et al 1994). Melatonin scavenges both ROS and NO, and attenuates the formation of peroxides and peroxynitrite, and reduces the expression of transcriptional factors involved in chronic inflammation (Korkmaz et al 2009).…”