A 35 kDa Phyllanthus niruri protein suppresses indomethacin mediated hepatic impairments: Its role in Hsp70, HO-1, JNKs and Ca2+dependent inflammatory pathways.
The present study has been conducted to explore a novel strategy to modulate the unfavourable effects of indomethacin by Phyllanthus niruri protein (PNP) and the underlying mechanism PNP exploits for the amelioration of that pathophysiology. In hepatocytes, indomethacin enhanced reactive oxygen species (ROS), reduced intracellular antioxidant capacity, up regulated mitogen activated protein kinase (MAPKs), disrupted mitochondrial membrane potential, activated apoptotic pathways and there by reduced the viability of the hepatocytes. Simultaneous treatment with PNP modulated these detrimental actions of the drug and retained cell viability. Similarly, in mice, indomethacin elevated serum marker enzymes (e.g. Alanine Transaminase), decreased antioxidant enzyme activities, elevated oxidations of lipids and proteins, increased intracellular calcium overload mediated endoplasmic reticular stress (ER stress) pathways, up regulated the pro-inflammatory cytokines and there by leading to the mitochondrial dependent caspase-3 activation and poly-ADP ribose polymerase (PARP) cleavage. Moreover investigation of these inherent molecular pathways exhibited that these alterations are associated with up regulation of MAPKs, inducible nitric oxide synthase (iNOS), heme oxygenase-1 and down regulation of survival proteins. However, PNP suppressed those apoptotic indices as evidenced from histopathological studies and DNA fragmentation analysis. Combining, results suggest that PNP could possibly provide a protection against indomethacin-induced hepatic pathophysiology.
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, 700054, India.
Sudip
S
Bhattacharyya
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, 700054, India.
Sharmistha
S
Banerjee
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, 700054, India.
Chirajyoti
C
Guha
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, 700054, India.
Shatadal
S
Ghosh
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, 700054, India. Electronic address: parames@jcbose.ac.in.
Parames C
PC
Sil
D000818:Animals; D002118:Calcium / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006505:Hepatitis / Q000188:drug therapy / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007213:Indomethacin / Q000009:adverse effects*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D029803:Phyllanthus / Q000737:chemistry*; D010940:Plant Proteins / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
D018840:HSP70 Heat-Shock Proteins; D008565:Membrane Proteins; D010940:Plant Proteins; D017382:Reactive Oxygen Species; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D048670:MAP Kinase Kinase 4; D002118:Calcium; D007213:Indomethacin
Ca2+ overload; ER stress; Hepatoprotection; Indomethacin; Inflammation; Phyllanthus niruri protein; i-NOS