title: 14-Deoxyandrographolide targets adenylate cyclase and prevents ethanol-induced liver injury through constitutive NOS dependent reduced redox signaling in rats.
abstract: 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 γ-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.
authors.affiliation: Cell Biology & Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Samir
authors.initials: S
authors.lastname: Mandal
authors.forename: Vinod K
authors.initials: VK
authors.lastname: Nelson
authors.forename: Sibabrata
authors.initials: S
authors.lastname: Mukhopadhyay
authors.forename: Sukdeb
authors.initials: S
authors.lastname: Bandhopadhyay
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Maganti
authors.forename: Nanda
authors.initials: N
authors.lastname: Ghoshal
authors.forename: Gargi
authors.initials: G
authors.lastname: Sen
authors.forename: Tuli
authors.initials: T
authors.lastname: Biswas
mesh_terms: D000262:Adenylyl Cyclases / Q000737:chemistry / Q000378:metabolism*; D035685:Andrographis / Q000737:chemistry; D000818:Animals; D000975:Antioxidants / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000819:agonists / Q000378:metabolism; D004224:Diterpenes / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005721:Glutamate-Cysteine Ligase / Q000737:chemistry / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009569:Nitric Oxide / Q000819:agonists / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D018515:Plant Leaves / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems / Q000187:drug effects*
chemical_list: C114791:14-deoxyandrographolide; D000975:Antioxidants; D004224:Diterpenes; D009569:Nitric Oxide; D000242:Cyclic AMP; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D000262:Adenylyl Cyclases; D005721:Glutamate-Cysteine Ligase
keywords: 14-Deoxyandrographolide; Adenylate cyclase; Chronic alcoholism; Constitutive nitric oxide synthase; Hepatotoxicity; γ-Glutamylcysteine synthetase