Browsing by Author "Ghanshyam Upadhyay"

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Effects of cypermethrin on monoamine transporters, xenobiotic metabolizing enzymes and lipid peroxidation in the rat nigrostriatal system
(2010) Manindra Nath Tiwari; Anand Kumar Singh; Israr Ahmad; Ghanshyam Upadhyay; Dhirendra Singh; Devendra Kumar Patel; Chetna Singh; Om Prakash; Mahendra Pratap Singh
Long-term exposure to cypermethrin induces the nigrostriatal dopaminergic neurodegeneration in adult rats and its pre-exposure in the critical periods of brain development enhances the susceptibility during adulthood. Monoamine transporters, xenobiotic metabolizing enzymes and oxidative stress play critical roles in the nigrostriatal dopaminergic neurodegeneration. The study was undertaken to investigate the effects of cypermethrin on DAT, VMAT 2, CYP2E1, GST Ya, GST Yc and GSTA4-4 expressions, CYP2E1 and GST activities and lipid peroxidation in the nigrostriatal system of adult rats with/without post-natal exposure to cypermethrin. Cypermethrin reduced VMAT 2 and increased CYP2E1 expressions without causing significant change in DAT. Although GSTA4-4 mRNA expression and lipid peroxidation were increased, no significant changes were observed in GST Ya and GST Yc expressions and total GST activity. The results obtained demonstrate that long-term exposure to cypermethrin modulates VMAT 2, CYP2E1, GSTA4-4 expressions and lipid peroxidation, which could contribute to the nigrostriatal dopaminergic neurodegeneration. © 2010 Informa UK, Ltd.
Involvement of multiple molecular events in pyrogallol-induced hepatotoxicity and silymarin-mediated protection: Evidence from gene expression profiles
(2010) Ghanshyam Upadhyay; Manindra Nath Tiwari; Om Prakash; Anurag Jyoti; Rishi Shanker; Mahendra Pratap Singh
In this study, the involvement of various molecular events in pyrogallol-mediated hepatotoxicity was deciphered by differential mRNA transcription profiles of control and pyrogallol treated mice liver. The modulatory effects of silymarin on pyrogallol-induced differentially expressed transcripts were also looked into. Swiss albino mice were treated with or without pyrogallol. In some set of experiments, mice were also treated with silymarin 2. h prior to pyrogallol. Total RNA was isolated from liver and polyadenylated RNA was reverse-transcribed into Cye 3 or Cye 5 labelled cDNA. Equal amounts of labelled cDNA from two different groups were mixed and hybridized with mouse 15. k array. The hybridized arrays were scanned, analyzed and the expression level of each transcript was calculated. The differential expression was validated by quantitative real time polymerase chain reaction. Comparative transcription pattern showed an alteration in the expression of 183 transcripts (150 up-regulated and 33 down-regulated) associated with oxidative stress, cell cycle, cytoskeletal network, cell-cell adhesion, extra-cellular matrix, inflammation, apoptosis, cell-signaling and intermediary metabolism in pyrogallol-exposed liver and silymarin pre-treatment modulated the expression of many of these transcripts. Results obtained thus suggest that pyrogallol induces multiple molecular events leading to hepatotoxicity and silymarin effectively counteracts pyrogallol-mediated alterations. © 2010 Elsevier Ltd.
Long term exposure to cypermethrin induces nigrostriatal dopaminergic neurodegeneration in adult rats: Postnatal exposure enhances the susceptibility during adulthood
(2012) Anand Kumar Singh; Manindra Nath Tiwari; Ghanshyam Upadhyay; Devendra Kumar Patel; Dhirendra Singh; Om Prakash; Mahendra Pratap Singh
The study aimed to investigate the effects of cypermethrin on biochemical, histopathological, and motor behavioral indices of the nigrostriatal dopaminergic system in adult rats treated with or without cypermethrin (1/10 adult dose) during postnatal days 5-19. Spontaneous locomotor activity (SLA) and rotarod tests were performed to assess motor behavior. Levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum, and tyrosine hydroxylase (TH) immunoreactivity and 4',6-diamidino-2-phenylindole (DAPI)/Fluoro-Jade B staining in the substantia nigra were measured to assess dopaminergic neurodegeneration. Postnatal treated animals did not exhibit significant changes in any measured parameters. The significant reduction in the time of stay on rotarod, spontaneous locomotor activity, dopamine, 3,4-dihydroxyphenylacetic acid, and tyrosine hydroxylase immunoreactivity while an increase in homovanillic acid level and Fluoro-Jade B-positive cells were observed in cypermethrin treated adult rats. These changes were more pronounced in the animals treated with cypermethrin during postnatal days followed by adulthood compared with adulthood alone. The results obtained thus demonstrate that exposure to cypermethrin during adulthood induces dopaminergic neurodegeneration in rats and postnatal exposure enhances the susceptibility of animals to dopaminergic neurodegeneration if rechallenged during adulthood. © 2012 Elsevier Inc.
Nigrostriatal proteomics of cypermethrin-induced dopaminergic neurodegeneration: Microglial activation-dependent and -independent regulations
(2011) Anand Kumar Singh; Manindra Nath Tiwari; Anubhuti Dixit; Ghanshyam Upadhyay; Devendra Kumar Patel; Dhirendra Singh; Om Prakash; Mahendra Pratap Singh
The study aimed to identify the differentially expressed nigrostriatal proteins in cypermethrin-induced neurodegeneration and to investigate the role of microglial activation therein. Proteomic approaches were used to identify the differentially expressed proteins. Microglial activation, tyrosine hydroxylase immunoreactivity (TH-IR), dopamine content, and neurobehavioral changes were measured according to the standard procedures. The expressions of a-internexin intermediate filament (α-IIF), ATP synthase D chain (ATP-SD), heat shock protein (Hsp)-70, truncated connexin-47, Hsp-60, mitogen-activated protein kinaseactivated kinase-5, nicotinamide adenine dinucleotide dehydrogenase 24k chain precursor, platelet-activating factor acetyl hydrolase 1b-α2 (PAF-AH 1b-α2), and synaptosomal-associated protein-25 (SNAP-25) were altered in the substantia nigra and nicotinamide adenine dinucleotide- specific isocitrate dehydrogenase, phosphatidylethanolamine-binding protein-1, prohibitin, protein disulfide isomerase-endoplasmic reticulum 60 protease, stathmin, and ubiquitin-conjugating enzyme in the striatum along with motor impairment, decreased dopamine and TH-IR, and increased microglial activation after cypermethrin exposure. Minocycline restored α-IIF, ATP-SD chain, truncated connexin-47, Hsp-60, PAF-AH 1b-α2, stathmin and SNAP-25 expressions, motor impairment, dopamine, TH-IR, and microglial activation. The results suggest that cypermethrin produces microglial activation-dependent and -independent changes in the expression patterns of the nigrostriatal proteins leading to dopaminergic neurodegeneration. © The Author 2011. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.
Pyrogallol-mediated toxicity and natural antioxidants: Triumphs and pitfalls of preclinical findings and their translational limitations
(2010) Ghanshyam Upadhyay; Satya Prakash Gupta; Om Prakash; Mahendra Pratap Singh
Pyrogallol, a potent anti-psoriatic drug, produces toxicity due to its ability to generate free radicals, besides its beneficial effects. Oxidative stress is implicated in pyrogallol-mediated toxicity in general and hepatotoxicity in particular. Naturally occurring antioxidants including, resveratrol and silymarin have been proposed as potential supplements to counteract pyrogallol-mediated toxicity, without reducing its efficacy. Due to increase in the popularity of natural antioxidants in combating pyrogallol-mediated toxicity, a literature-based survey was performed to assess their role in experimental studies and possible implications in real life situations. Although preclinical studies revealed the boons of naturally occurring antioxidants in attenuating/abolishing the undesirable effects of pyrogallol exposure, limited studies have been conducted to evaluate their role in clinics. In this review, an update on the recent development in assessing the potential of natural antioxidants in pyrogallol-mediated toxicity in preclinical interventions, triumphs and pitfalls of such investigations, their translational challenges and future possibilities are discussed. © 2009 Elsevier Ireland Ltd. All rights reserved.
Resveratrol modulates pyrogallol-induced changes in hepatic toxicity markers, xenobiotic metabolizing enzymes and oxidative stress
(2008) Ghanshyam Upadhyay; Anand Kumar Singh; Abhai Kumar; Om Prakash; Mahendra Pratap Singh
Previously, we reported that pyrogallol, an anti-psoriatic agent, causes hepatotoxicity in experimental animals and silymarin, an herbal antioxidant, reduces pyrogallol-induced changes [Upadhyay, G., Kumar, A., Singh, M.P., 2007. Effect of silymarin on pyrogallol- and rifampicin-induced hepatotoxicity in mouse. Eur. J. Pharmacol. 565, 190-201.]. The present study was undertaken to assess the effect of resveratrol against pyrogallol-induced changes in hepatic damage markers, xenobiotic metabolizing enzymes and oxidative stress. Swiss albino mice were treated intraperitoneally, daily with pyrogallol (40 mg/kg), for one to four weeks, along with respective controls. In some set of experiments, animals were pre-treated with resveratrol (10 mg/kg), 2 h prior to pyrogallol treatment, along with respective controls. Alanine aminotransaminase, aspartate aminotransaminase and bilirubin were measured in blood plasma and mRNA expression of cytochrome P-450 (CYP) 1A1, CYP1A2, CYP2E1, glutathione-S-transferase (GST)-ya and GST-yc, catalytic activity of CYP1A1, CYP1A2, CYP2E1, GST, glutathione reductase and glutathione peroxidase, lipid peroxidation and reduced glutathione (GSH) level were measured in liver. Resveratrol reduced pyrogallol-mediated increase in alanine aminotransaminase, aspartate aminotransaminase, bilirubin, lipid peroxidation and mRNA expression and catalytic activity of CYP2E1 and CYP1A2. Pyrogallol-mediated decrease in GST-ya and GST-yc expressions, GST, glutathione peroxidase and glutathione reductase activities and GSH content was significantly attenuated in resveratrol co-treated animals. CYP1A1 expression and catalytic activity were not altered significantly in any treated groups. The results demonstrate that resveratrol modulates pyrogallol-induced changes in hepatic toxicity markers, xenobiotic metabolizing enzymes and oxidative stress. © 2008 Elsevier B.V. All rights reserved.