Partha Mukhopadhyay

National Institute on Alcohol Abuse and Alcoholism, Maryland, United States

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Publications (75)362.65 Total impact

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    ABSTRACT: Poly (ADP-ribose) polymerase 1 (PARP-1) is a constitutive enzyme, the major isoform of PARP family, which is involved in the regulation of DNA repair, cell death, metabolism, and inflammatory responses. Pharmacological inhibitors of PARP provide significant therapeutic benefits in various preclinical disease models associated with tissue injury and inflammation. However, our understanding the role of PARP activation in the pathophysiology of liver inflammation and fibrosis is limited. In this study we have investigated the role of PARP-1 in the liver inflammation and fibrosis using acute and chronic models of CCl4 -induced liver injury and fibrosis, a model of bile duct ligation (BDL)-induced hepatic fibrosis in vivo, and isolated liver-derived cells ex vivo. Pharmacological inhibition of PARP with structurally distinct inhibitors or genetic deletion of PARP-1 markedly attenuated CCl4 -induced hepatic cell death, inflammation, and fibrosis. Interestingly, the chronic CCl4 -induced liver injury was also characterized by mitochondrial dysfunction and dysregulation of numerous genes involved in metabolism. Most of these pathological changes were attenuated by PARP inhibitors. PARP inhibition not only prevented CCl4 -induced chronic liver inflammation and fibrosis, but was also able to reverse these pathological processes. PARP inhibitors also attenuated the development of BDL-induced hepatic fibrosis in mice. In liver biopsies of subjects with alcoholic or hepatitis B-induced cirrhosis, increased nitrative stress and PARP activation was noted. These results, taken together, suggest that the reactive oxygen/nitrogen species-PARP pathway plays a pathogenetic role in the development of liver inflammation, metabolism and fibrosis. Several PARP inhibitors are currently in clinical trials for oncological indications. The current results indicate that liver inflammation and liver fibrosis may be additional clinical indications where PARP inhibition may be of translational potential.
    Hepatology 10/2013; · 12.00 Impact Factor
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    Dataset: cvp369supp
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    ABSTRACT: BACKGROUND & AIMS: The endocannabinoid and eicosanoid lipid signaling pathways have important roles in inflammatory syndromes. Monoacylglycerol lipase (MAGL) links these pathways, hydrolyzing the endocannabinoid 2-arachidonoylglycerol to generate the arachidonic acid precursor pool for prostaglandin production. We investigated whether blocking MAGL protects against inflammation and damage from hepatic ischemia/reperfusion (I/R) and other insults. METHODS: We analyzed the effects of hepatic I/R in mice given the selective MAGL inhibitor JZL184, in Mgll-/-mice, FAAH-/- mice, and in Cnr1(-/-)and Cnr2(-/-)mice, which have disruptions in the cannabinoid receptors 1 and 2 (CB(1/2)). Liver tissues were collected and analyzed, along with cultured hepatocytes and Kupffer cells. We measured endocannabinoids, eicosanoids, and markers of inflammation, oxidative stress, and cell death using molecular biology, biochemistry, and mass spectrometry analyses. RESULTS: Wild-type mice given JZL184 and Mgll-/- mice were protected from hepatic I/R injury by a mechanism that involved increased endocannabinoid signaling via CB(2) and reduced production of eicosanoids in the liver. JZL184 suppressed the inflammation and oxidative stress that mediate hepatic I/R injury. Hepatocytes were the major source of hepatic MAGL activity and endocannabinoid and eicosanoid production. JZL184 also protected from induction of liver injury by D-(+)-galactosamine and lipopolysaccharides or CCl(4). CONCLUSIONS: MAGL promotes hepatic injury via endocannabinoid and eicosanoid signaling; blockade of this pathway protects mice from liver injury. MAGL inhibitors might be developed to treat for conditions that expose the liver to oxidative stress and inflammatory damage.
    Gastroenterology 01/2013; · 12.82 Impact Factor
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    ABSTRACT: Treatment with trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of Human Epidermal Growth Factor Receptor 2 (HER2), very successfully improves outcomes for women with HER2-positive breast cancer. However, trastuzumab treatment was recently linked to potentially irreversible serious cardiotoxicity, the mechanisms of which are largely elusive. This study reports that trastuzumab significantly alters the expression of myocardial genes essential for DNA repair, cardiac and mitochondrial functions, which is associated with impaired left ventricular performance in mice coupled with significant ultrastructural alterations in cardiomyocytes revealed by electron microscopy. Furthermore, trastuzumab treatment also promotes oxidative stress and apoptosis in myocardium of mice, and elevates serum levels of cardiac troponin-I (cTnI) and cardiac myosin light chain-1 (cMLC1). The elevated serum levels of cMLC1 in mice treated with trastuzumab highlights the potential that cMLC1 could be a useful biomarker for trastuzumab-induced cardiotoxicity.
    PLoS ONE 01/2013; 8(11):e79543. · 3.53 Impact Factor
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    ABSTRACT: Endogenous glucocorticoids are essential for mobilizing energy resources, restraining inflammatory responses and coordinating behavior to an immune challenge. Impaired glucocorticoid receptor (GR) function has been associated with impaired metabolic processes, enhanced inflammation and exaggerated sickness and depressive-like behaviors. To discern the molecular mechanisms underlying GR regulation of physiologic and behavioral responses to a systemic immune challenge, GR(dim) mice, in which absent GR dimerization leads to impaired GR-DNA-binding-dependent mechanisms but intact GR protein-protein interactions, were administered low-dose lipopolysaccharide (LPS). GR(dim)-LPS mice exhibited elevated and prolonged levels of plasma corticosterone (CORT), interleukin (IL)-6 and IL-10 (but not plasma tumor necrosis factor-α (TNFα)), enhanced early expression of brain TNFα, IL-1β and IL-6 mRNA levels, and impaired later central TNFα mRNA expression. Exaggerated sickness behavior (lethargy, piloerection, ptosis) in the GR(dim)-LPS mice was associated with increased early brain proinflammatory cytokine expression and late plasma CORT levels, but decreased late brain TNFα expression. GR(dim)-LPS mice also exhibited sustained locomotor impairment in the open field, body weight loss and metabolic alterations measured by indirect calorimetry, as well as impaired thermoregulation. Taken together, these data indicate that GR dimerization-dependent DNA-binding mechanisms differentially regulate systemic and central cytokine expression in a cytokine- and time-specific manner, and are essential for the proper regulation and recovery of multiple physiologic responses to low-dose endotoxin. Moreover, these results support the concept that GR protein-protein interactions are not sufficient for glucocorticoids to exert their full anti-inflammatory effects and suggest that glucocorticoid responses limited to GR monomer-mediated transcriptional effects could predispose individuals to prolonged behavioral and metabolic sequelae of an enhanced inflammatory state.Molecular Psychiatry advance online publication, 23 October 2012; doi:10.1038/mp.2012.131.
    Molecular Psychiatry 10/2012; · 15.15 Impact Factor
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    ABSTRACT: Mitochondrial reactive oxygen species generation has been implicated in the pathophysiology of ischemia-reperfusion (I/R) injury; however, its exact role and its spatial-temporal relationship with inflammation are elusive. Herein we explore the spatial-temporal relationship of oxidative/nitrative stress and inflammatory response during the course of hepatic I/R and the possible therapeutic potential of mitochondrial-targeted antioxidants, using a mouse model of segmental hepatic ischemia-reperfusion injury. Hepatic I/R was characterized by early (at 2 h of reperfusion) mitochondrial injury, decreased complex I activity, increased oxidant generation in the liver or liver mitochondria, and profound hepatocellular injury/dysfunction with acute proinflammatory response (TNF-α, MIP-1α/CCL3, MIP-2/CXCL2) without inflammatory cell infiltration, followed by marked neutrophil infiltration and a more pronounced secondary wave of oxidative/nitrative stress in the liver (starting from 6 h of reperfusion and peaking at 24 h). Mitochondrially targeted antioxidants, MitoQ or Mito-CP, dose-dependently attenuated I/R-induced liver dysfunction, the early and delayed oxidative and nitrative stress response (HNE/carbonyl adducts, malondialdehyde, 8-OHdG, and 3-nitrotyrosine formation), and mitochondrial and histopathological injury/dysfunction, as well as delayed inflammatory cell infiltration and cell death. Mitochondrially generated oxidants play a central role in triggering the deleterious cascade of events associated with hepatic I/R, which may be targeted by novel antioxidants for therapeutic advantage.
    Free Radical Biology and Medicine 06/2012; 53(5):1123-38. · 5.27 Impact Factor
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    ABSTRACT: Cisplatin is a widely used antineoplastic agent. However, its major limitation is dose-dependent nephrotoxicity whose precise mechanism is poorly understood. Recent studies have suggested that mitochondrial dysfunction in tubular epithelium contributes to cisplatin-induced nephrotoxicity. Here the authors extend those findings by describing the role of an important electron transport chain enzyme, cytochrome c oxidase (COX). Immunohistochemistry for COX 1 protein demonstrated that, in response to cisplatin, expression was mostly maintained in focally damaged tubular epithelium. In contrast, COX enzyme activity in proximal tubules (by light microscopy) was decreased. Ultrastructural analysis of the cortex and outer stripe of the outer medulla showed decreased mitochondrial mass, disruption of cristae, and extensive mitochondrial swelling in proximal tubular epithelium. Functional electron microscopy showed that COX enzyme activity was decreased in the remaining mitochondria in the proximal tubules but maintained in distal tubules. In summary, cisplatin-induced nephrotoxicity is associated with structural and functional damage to the mitochondria. More broadly, using functional electron microscopy to measure mitochondrial enzyme activity may generate mechanistic insights across a spectrum of renal disorders.
    Journal of Histochemistry and Cytochemistry 04/2012; 60(7):521-9. · 2.26 Impact Factor
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    ABSTRACT: Endocannabinoids and cannabinoid 1 (CB(1)) receptors have been implicated in cardiac dysfunction, inflammation, and cell death associated with various forms of shock, heart failure, and atherosclerosis, in addition to their recognized role in the development of various cardiovascular risk factors in obesity/metabolic syndrome and diabetes. In this study, we explored the role of CB(1) receptors in myocardial dysfunction, inflammation, oxidative/nitrative stress, cell death, and interrelated signaling pathways, using a mouse model of type 1 diabetic cardiomyopathy. Diabetic cardiomyopathy was characterized by increased myocardial endocannabinoid anandamide levels, oxidative/nitrative stress, activation of p38/Jun NH(2)-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs), enhanced inflammation (tumor necrosis factor-α, interleukin-1β, cyclooxygenase 2, intracellular adhesion molecule 1, and vascular cell adhesion molecule 1), increased expression of CB(1), advanced glycation end product (AGE) and angiotensin II type 1 receptors (receptor for advanced glycation end product [RAGE], angiotensin II receptor type 1 [AT(1)R]), p47(phox) NADPH oxidase subunit, β-myosin heavy chain isozyme switch, accumulation of AGE, fibrosis, and decreased expression of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA2a). Pharmacological inhibition or genetic deletion of CB(1) receptors attenuated the diabetes-induced cardiac dysfunction and the above-mentioned pathological alterations. Activation of CB(1) receptors by endocannabinoids may play an important role in the pathogenesis of diabetic cardiomyopathy by facilitating MAPK activation, AT(1)R expression/signaling, AGE accumulation, oxidative/nitrative stress, inflammation, and fibrosis. Conversely, CB(1) receptor inhibition may be beneficial in the treatment of diabetic cardiovascular complications.
    Diabetes 03/2012; 61(3):716-27. · 7.90 Impact Factor
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    ABSTRACT: (E)-β-caryophyllene (BCP) is a natural sesquiterpene found in many essential oils of spice (best known for contributing to the spiciness of black pepper) and food plants with recognized anti-inflammatory properties. Recently it was shown that BCP is a natural agonist of endogenous cannabinoid 2 (CB(2)) receptors, which are expressed in immune cells and mediate anti-inflammatory effects. In this study we aimed to test the effects of BCP in a clinically relevant murine model of nephropathy (induced by the widely used antineoplastic drug cisplatin) in which the tubular injury is largely dependent on inflammation and oxidative/nitrative stress. β-caryophyllene dose-dependently ameliorated cisplatin-induced kidney dysfunction, morphological damage, and renal inflammatory response (chemokines MCP-1 and MIP-2, cytokines TNF-α and IL-1β, adhesion molecule ICAM-1, and neutrophil and macrophage infiltration). It also markedly mitigated oxidative/nitrative stress (NOX-2 and NOX-4 expression, 4-HNE and 3-NT content) and cell death. The protective effects of BCP against biochemical and histological markers of nephropathy were absent in CB(2) knockout mice. Thus, BCP may be an excellent therapeutic agent to prevent cisplatin-induced nephrotoxicity through a CB(2) receptor-dependent pathway. Given the excellent safety profile of BCP in humans it has tremendous therapeutic potential in a multitude of diseases associated with inflammation and oxidative stress.
    Free Radical Biology and Medicine 01/2012; 52(8):1325-33. · 5.27 Impact Factor
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    ABSTRACT: BACKGROUND AND PURPOSE Cannabinoid CB2 receptor activation has been reported to attenuate myocardial, cerebral and hepatic ischaemia‐reperfusion (I/R) injury.EXPERIMENTAL APPROACH We have investigated the effects of a novel CB2 receptor agonist ((1S,4R)‐2‐(2,6‐dimethoxy‐4‐(2‐methyloctan‐2‐yl)phenyl)‐7,7‐dimethylbicyclo[2.2.1]hept‐2‐en‐1‐yl)methanol (HU‐910) on liver injury induced by 1 h of ischaemia followed by 2, 6 or 24 h of reperfusion, using a well‐established mouse model of segmental hepatic I/R.KEY RESULTS Displacement of [3H]CP55940 by HU‐910 from specific binding sites in CHO cell membranes transfected with human CB2 or CB1 receptors (hCB1/2) yielded Ki values of 6 nM and 1.4 µM respectively. HU‐910 inhibited forskolin‐stimulated cyclic AMP production by hCB2 CHO cells (EC50= 162 nM) and yielded EC50 of 26.4 nM in [35S]GTPγS binding assays using hCB2 expressing CHO membranes. HU‐910 given before ischaemia significantly attenuated levels of I/R‐induced hepatic pro‐inflammatory chemokines (CCL3 and CXCL2), TNF‐α, inter‐cellular adhesion molecule‐1, neutrophil infiltration, oxidative stress and cell death. Some of the beneficial effect of HU‐910 also persisted when given at the beginning of the reperfusion or 1 h after the ischaemic episode. Furthermore, HU‐910 attenuated the bacterial endotoxin‐triggered TNF‐α production in isolated Kupffer cells and expression of adhesion molecules in primary human liver sinusoidal endothelial cells stimulated with TNF‐α. Pretreatment with a CB2 receptor antagonist attenuated the protective effects of HU‐910, while pretreatment with a CB1 antagonist tended to enhance them.CONCLUSION AND IMPLICATIONS HU‐910 is a potent CB2 receptor agonist which may exert protective effects in various diseases associated with inflammation and tissue injury.LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit . To view Part I of Cannabinoids in Biology and Medicine visit
    British Journal of Pharmacology 01/2012; 165(8). · 5.07 Impact Factor
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    Béla Horváth, Partha Mukhopadhyay, György Haskó, Pál Pacher
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    ABSTRACT: Oxidative stress and inflammation play critical roles in the development of diabetes and its complications. Recent studies provided compelling evidence that the newly discovered lipid signaling system (ie, the endocannabinoid system) may significantly influence reactive oxygen species production, inflammation, and subsequent tissue injury, in addition to its well-known metabolic effects and functions. The modulation of the activity of this system holds tremendous therapeutic potential in a wide range of diseases, ranging from cancer, pain, neurodegenerative, and cardiovascular diseases to obesity and metabolic syndrome, diabetes, and diabetic complications. This review focuses on the role of the endocannabinoid system in primary diabetes and its effects on various diabetic complications, such as diabetic cardiovascular dysfunction, nephropathy, retinopathy, and neuropathy, particularly highlighting the mechanisms beyond the metabolic consequences of the activation of the endocannabinoid system. The therapeutic potential of targeting the endocannabinoid system and certain plant-derived cannabinoids, such as cannabidiol and Δ9-tetrahydrocannabivarin, which are devoid of psychotropic effects and possess potent anti-inflammatory and/or antioxidant properties, in diabetes and diabetic complications is also discussed.
    American Journal Of Pathology 12/2011; 180(2):432-42. · 4.60 Impact Factor
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    ABSTRACT: Cisplatin is a widely used antineoplastic agent; however, its major limitation is the development of dose-dependent nephrotoxicity whose precise mechanisms are poorly understood. Here we show not only that mitochondrial dysfunction is a feature of cisplatin nephrotoxicity, but also that targeted delivery of superoxide dismutase mimetics to mitochondria largely prevents the renal effects of cisplatin. Cisplatin induced renal oxidative stress, deterioration of mitochondrial structure and function, an intense inflammatory response, histopathological injury, and renal dysfunction. A single systemic dose of mitochondrially targeted antioxidants, MitoQ or Mito-CP, dose-dependently prevented cisplatin-induced renal dysfunction. Mito-CP also prevented mitochondrial injury and dysfunction, renal inflammation, and tubular injury and apoptosis. Despite being broadly renoprotective against cisplatin, Mito-CP did not diminish cisplatin's antineoplastic effect in a human bladder cancer cell line. Our results highlight the central role of mitochondrially generated oxidants in the pathogenesis of cisplatin nephrotoxicity. Because similar compounds seem to be safe in humans, mitochondrially targeted antioxidants may represent a novel therapeutic approach against cisplatin nephrotoxicity.
    Free Radical Biology and Medicine 11/2011; 52(2):497-506. · 5.27 Impact Factor
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    ABSTRACT: Resveratrol, a constituent of red wine, and γ-tocotrienol, a constituent of palm oil are important for cardioprotection. Although microRNAs are known regulators for genes involved in cardiac remodelling, the regulatory pathway involving microRNA has not been studied so far. We explored the cardioprotection by resveratrol, longevinex and γ-tocotrienol in ischaemia/reperfusion(I/R) model of rat and determined miRNA profile from isolated RNA. Systemic analyses of miRNA array and theirs targets were determined using a number of computational approaches. Resveratrol and γ-tocotrienol, either alone or in combination, modulated the expression pattern of miRNAs close to the control level based on PCA analyses. Differential expression was observed in over 75 miRNAs, some of them, such as miR-21 and miR-20b (anti-angiogenic) were previously implicated in cardiac remodelling. The target genes for the highest differentially expressed miRNA include genes of various molecular functions such as TGFβ1-Smad3 signalling pathway, inflammation and their transcription factors, which may play key role in reducing I/R injury. Administration of antagomiR-20 attenuated I/R induced vascular endothelial growth factor and HIF1α level. All the interventions treated for 3 weeks lead to significant cardioprotection against ischaemia/reperfusion injury. A unique signature of miRNA profile is observed in control heart pretreated with resveratrol or γ-tocotrienol. We have determined specific group of miRNA in heart that have altered during IR injuries. Most of those altered microRNA expressions modulated close to their basal level in resveratrol or longevinex treated I/R rat. Interestingly, resveratrol and γ-tocotrienol resulted in synergestic action.
    Journal of Cellular and Molecular Medicine 11/2011; 16(10):2504-17. · 4.75 Impact Factor
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    ABSTRACT: Cisplatin is a commonly used chemotherapeutic drug, the clinical use of which is limited by the development of dose-dependent nephrotoxicity. Enhanced inflammatory response, oxidative stress, and cell death have been implicated in the development of cisplatin-induced nephropathy; however, the precise mechanisms are elusive. Overactivation of the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) by oxidative DNA damage under various pathological conditions promotes cell death and up-regulation of key proinflammatory pathways. In this study, using a well-established model of nephropathy, we have explored the role of PARP-1 in cisplatin-induced kidney injury. Genetic deletion or pharmacological inhibition of PARP-1 markedly attenuated the cisplatin-induced histopathological damage, impaired renal function (elevated serum BUN and creatinine levels), and enhanced inflammatory response (leukocyte infiltration; TNF-α, IL-1β, F4/80, adhesion molecules ICAM-1/VCAM-1 expression) and consequent oxidative/nitrative stress (4-HNE, 8-OHdG, and nitrotyrosine content; NOX2/NOX4 expression). PARP inhibition also facilitated the cisplatin-induced death of cancer cells. Thus, PARP activation plays an important role in cisplatin-induced kidney injury, and its pharmacological inhibition may represent a promising approach to preventing the cisplatin-induced nephropathy. This is particularly exciting because several PARP inhibitors alone or in combination with DNA-damaging anticancer agents show considerable promise in clinical trials for treatment of various malignancies (e.g., triple-negative breast cancer).
    Free Radical Biology and Medicine 08/2011; 51(9):1774-88. · 5.27 Impact Factor
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    ABSTRACT: Cisplatin (cis-diamminedichloroplatinum II, CIS) is a potent and widely used chemotherapeutic agent to treat various malignancies, but its therapeutic use is limited because of dose-dependent nephrotoxicity. Cell death and inflammation play a key role in the development and progression of CIS-induced nephropathy. Sulforaphane (SFN), a natural constituent of cruciferous vegetables such as broccoli, Brussels sprouts, etc., has been shown to exert various protective effects in models of tissue injury and cancer. In this study, we have investigated the role of prosurvival, cell death and inflammatory signaling pathways using a rodent model of CIS-induced nephropathy, and explored the effects of SFN on these processes. Cisplatin triggered marked activation of stress signaling pathways [p53, Jun N-terminal kinase (JNK), and p38-α mitogen-activated protein kinase (MAPK)] and promoted cell death in the kidneys (increased DNA fragmentation, caspases-3/7 activity, terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick-end labeling), associated with attenuation of various prosurvival signaling pathways [e.g., extracellular signal-regulated kinase (ERK) and p38-β MAPK]. Cisplatin also markedly enhanced inflammation in the kidneys [promoted NF-κB activation, increased expression of adhesion molecules ICAM and VCAM, enhanced tumor necrosis factor-α (TNF-α) levels and inflammatory cell infiltration]. These effects were significantly attenuated by pretreatment of rodents with SFN. Thus, the cisplatin-induced nephropathy is associated with activation of various cell death and proinflammatory pathways (p53, JNK, p38-α, TNF-α and NF-κB) and impairments of key prosurvival signaling mechanisms (ERK and p38-β). SFN is able to prevent the CIS-induced renal injury by modulating these pathways, providing a novel approach for preventing this devastating complication of chemotherapy.
    The Journal of nutritional biochemistry 06/2011; 23(5):494-500. · 4.29 Impact Factor

Publication Stats

3k Citations
362.65 Total Impact Points

Institutions

  • 2007–2013
    • National Institute on Alcohol Abuse and Alcoholism
      Maryland, United States
  • 2006–2013
    • National Institutes of Health
      • Laboratory of Physiologic Studies
      Bethesda, MD, United States
  • 2012
    • Beth Israel Deaconess Medical Center
      • Department of Pathology
      Boston, MA, United States
  • 2011
    • University of Georgia
      • College of Pharmacy
      Athens, GA, United States
    • National Eye Institute
      Maryland, United States
    • Virginia Commonwealth University
      • Department of Pharmacology and Toxicology
      Richmond, VA, United States
  • 2009
    • Zhejiang University
      • School of Medicine
      Hangzhou, Zhejiang Sheng, China
  • 2008–2009
    • New York Medical College
      • Department of Physiology
      New York City, NY, United States