Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0034200
Title: Natural terpenes prevent mitochondrial dysfunction, oxidative stress and release of apoptotic proteins during nimesulide-hepatotoxicity in rats
Authors: Singh B.K. 
Tripathi M. 
Chaudhari B.P.
Pandey P.K.
Kakkar P.
Keywords: 8 hydroxyguanine
alanine aminotransferase
apoptosis inducing factor
aspartate aminotransferase
bilirubin
biological marker
camphene
caspase 3
caspase 9
copper zinc superoxide dismutase
cytochrome c
DNA
endonuclease G
geraniol
glutathione
glutathione peroxidase
glutathione reductase
inducible nitric oxide synthase
manganese superoxide dismutase
messenger RNA
mitochondrial nitric oxide synthase
neuronal nitric oxide synthase
nimesulide
reactive nitrogen species
reactive oxygen metabolite
reduced nicotinamide adenine dinucleotide phosphate
silymarin
terpene derivative
unclassified drug
antioxidant
apoptosis regulatory protein
biological product
caspase 3
caspase 9
nimesulide
nucleotide
oxidizing agent
sulfonamide
terpene
alanine aminotransferase blood level
animal cell
animal experiment
animal model
animal tissue
antioxidant activity
article
aspartate aminotransferase blood level
bilirubin blood level
body weight
cell membrane permeability
controlled study
disorders of mitochondrial functions
DNA damage
drug megadose
drug structure
enzyme activity
enzyme inhibition
histopathology
immunoblotting
in vivo study
liver toxicity
macromolecule
male
membrane depolarization
mitochondrial energy transfer
mitochondrion swelling
molecular mechanics
nonhuman
oxidative stress
protein expression
protein secretion
protein synthesis inhibition
rat
Sprague Dawley rat
structure analysis
animal
cell death
cell protection
cytology
drug effect
electron transport
genetic transcription
homeostasis
lipid metabolism
liver
metabolism
mitochondrial membrane potential
mitochondrion
pathology
permeability
protein degradation
secretion
Rattus
Animals
Antioxidants
Apoptosis Regulatory Proteins
Biological Agents
Caspase 3
Caspase 9
Cell Death
Cytoprotection
DNA Damage
Electron Transport
Homeostasis
Lipid Metabolism
Liver
Male
Membrane Potential, Mitochondrial
Mitochondria
Nucleotides
Oxidants
Oxidative Stress
Permeability
Proteolysis
Rats
Rats, Sprague-Dawley
Sulfonamides
Terpenes
Transcription, Genetic
Issue Date: 2012
Citation: Singh B.K., Tripathi M., Chaudhari B.P., Pandey P.K., Kakkar P. (2012). Natural terpenes prevent mitochondrial dysfunction, oxidative stress and release of apoptotic proteins during nimesulide-hepatotoxicity in rats. PLoS ONE 7 (4) : e34200. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0034200
Rights: Attribution 4.0 International
Abstract: Nimesulide, an anti-inflammatory and analgesic drug, is reported to cause severe hepatotoxicity. In this study, molecular mechanisms involved in deranged oxidant-antioxidant homeostasis and mitochondrial dysfunction during nimesulide-induced hepatotoxicity and its attenuation by plant derived terpenes, camphene and geraniol has been explored in male Sprague-Dawley rats. Hepatotoxicity due to nimesulide (80 mg/kg BW) was evident from elevated SGPT, SGOT, bilirubin and histo-pathological changes. Antioxidants and key redox enzymes (iNOS, mtNOS, Cu/Zn-SOD, Mn-SOD, GPx and GR) were altered significantly as assessed by their mRNA expression, Immunoblot analysis and enzyme activities. Redox imbalance along with oxidative stress was evident from decreased NAD(P)H and GSH (56% and 74% respectively; P&0.001), increased superoxide and secondary ROS/RNS generation along with oxidative damage to cellular macromolecules. Nimesulide reduced mitochondrial activity, depolarized mitochondria and caused membrane permeability transition (MPT) followed by release of apoptotic proteins (AIF; apoptosis inducing factor, EndoG; endonuclease G, and Cyto c; cytochrome c). It also significantly activated caspase-9 and caspase-3 and increased oxidative DNA damage (level of 8-Oxoguanine glycosylase; P&0.05). A combination of camphene and geraniol (CG; 1:1), when pre-administered in rats (10 mg/kg BW), accorded protection against nimesulide hepatotoxicity in vivo, as evident from normalized serum biomarkers and histopathology. mRNA expression and activity of key antioxidant and redox enzymes along with oxidative stress were also normalized due to CG pre-treatment. Downstream effects like decreased mitochondrial swelling, inhibition in release of apoptotic proteins, prevention of mitochondrial depolarization along with reduction in oxidized NAD(P)H and increased mitochondrial electron flow further supported protective action of selected terpenes against nimesulide toxicity. Therefore CG, a combination of natural terpenes prevented nimesulide induced cellular damage and ensuing hepatotoxicity. © 2012 Singh et al.
Source Title: PLoS ONE
URI: https://scholarbank.nus.edu.sg/handle/10635/161990
ISSN: 19326203
DOI: 10.1371/journal.pone.0034200
Rights: Attribution 4.0 International
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