Aims

To support the free and open dissemination of research findings and information on alcoholism and alcohol-related problems. To encourage open access to peer-reviewed articles free for all to view.

For full versions of posted research articles readers are encouraged to email requests for "electronic reprints" (text file, PDF files, FAX copies) to the corresponding or lead author, who is highlighted in the posting.

___________________________________________

Wednesday, June 19, 2013

14-Deoxyandrographolide targets adenylate cyclase and prevents ethanol-induced liver injury through constitutive NOS dependent reduced redox signaling in rats




Chronic alcoholism is one of the most common causes of liver diseases worldwide. Nitric oxide (NO) has been proposed to have potential for clinical application against chronic hepatocellular injuries. However, mechanisms underlying hepatoprotective functions of NO in ethanol-induced apoptosis are largely unknown.

Sprauge–Dawley rats were exposed to ethanol for 8 weeks. Half of the ethanol-fed animals received 14-deoxyandrographolide (14-DAG) treatment for the last 4 weeks of study. Preventive effect of 14-DAG against ethanol-induced hepatotoxicity involved constitutive nitric oxide synthase (cNOS) activation followed by up-regulation of ╬│-glutamylcysteine synthetase activity and reduced oxidative stress.

Enhanced interaction of cNOS with caveolin-1 caused down-regulation of enzyme activity and led to depletion of NO in the hepatocytes of ethanol-fed animals. 14-DAG acted as activator of adenylate cyclase and modulated cyclic AMP (cAMP) mediated expression of caveolin-1 and calmodulin. This eventually favored activation of cNOS through inhibition of cNOS-caveolin-1 interaction.

Our results suggest that, protective effect of 14-DAG against ethanol-induced hepatic injury is based on its ability to reduce oxidative stress through cNOS dependent improvement of redox status.

14-DAG mediated activation of adenylate cyclase-cAMP signaling leading to up-regulation of cNOS may provide a promising approach in the prevention of liver diseases during chronic alcoholism.


Read Full Abstract

Request Reprint E-Mail:    sengargi@hotmail.com