title: Picroliv modulates antioxidant status and down-regulates AP1 transcription factor after hemorrhage and resuscitation.
abstract: Resuscitation from hemorrhagic shock initiates profound changes in the liver that are likely to contribute to end organ damage and resultant dysfunction after shock. Extensive research in this area has indicated the potential of free radical scavenging strategy for better management of the pathophysiology following hemorrhage-resuscitation (H/R) injury. We studied the effect of a novel pharmacological agent, picroliv, on hepatocellular injury and redox status, as well as its possible mechanism of action in a H/R model in adult rats. Anesthetized rats were subjected to hemorrhagic shock by bleeding 30 mL/kg body weight. After 60 min of shock, rats were resuscitated with twice the shed blood volume of lactated Ringer's solution and were sacrificed 2 h after resuscitation. We observed that picroliv (12 mg/kg) pretreatment, given orally for 7 days, resulted in a significant decrease in serum aspartate transaminase and gamma-glutamyl transpeptidase levels. Picroliv also inhibited the lipid peroxidation and nitric oxide release that occurred after H/R and altered the activity of glutathione reductase in a favorable manner, thereby suggesting better antioxidant status. Picroliv significantly down-regulated the stress-sensitive transcription factor AP1 and decreased the level of c-fos mRNA as well as c-jun and c-fos proteins in liver tissue, indicating that its actions could be mediated through AP1 and associated signal transduction pathways. These findings suggest that picroliv has the potential to be developed as a protective agent against H/R injury.
authors.affiliation: Center for Combat Casualty Care and Life Sustainment Research, Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, 20814, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Seth
authors.forename: Shirin V
authors.initials: SV
authors.lastname: Sundar
authors.forename: Ranjana K
authors.initials: RK
authors.lastname: Seth
authors.forename: Gurmel S
authors.initials: GS
authors.lastname: Sidhu
authors.forename: Shekhar C
authors.initials: SC
authors.lastname: Sharma
authors.forename: Dinesh K
authors.initials: DK
authors.lastname: Kulshreshtha
authors.forename: Radha K
authors.initials: RK
authors.lastname: Maheshwari
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D000981:Antiprotozoal Agents / Q000494:pharmacology; D001219:Aspartate Aminotransferases / Q000097:blood; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D002934:Cinnamates / Q000494:pharmacology*; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D005609:Free Radicals; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D006027:Glycosides / Q000494:pharmacology*; D006470:Hemorrhage / Q000378:metabolism*; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000096:biosynthesis*; D015533:Transcriptional Activation; D014641:Vanillic Acid / Q000494:pharmacology*; D005723:gamma-Glutamyltransferase / Q000097:blood
chemical_list: D000975:Antioxidants; D000981:Antiprotozoal Agents; D002934:Cinnamates; D005609:Free Radicals; D006027:Glycosides; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; C057463:kutkin; D009569:Nitric Oxide; D012313:RNA; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D005978:Glutathione; D014641:Vanillic Acid