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Pal Pacher - One of the best experts on this subject based on the ideXlab platform.
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Cannabinoid 2 Receptor activation ameliorates hepatorenal syndrome
Free Radical Biology and Medicine, 2020Co-Authors: Eszter Trojnar, Partha Mukhopadhyay, Gyorgy Hasko, Katalin Erdelyi, Csaba Matyas, Suxian Zhao, Janos Paloczi, Zoltan Varga, Pal PacherAbstract:Abstract Study rationale Hepatorenal syndrome (HRS) is a life-threatening complication of end-stage liver disease characterized by the rapid decline of kidney function. Herein, we explored the therapeutic potential of targeting the Cannabinoid-2 Receptor (CB2-R) utilizing a commonly used mouse model of liver fibrosis and hepatorenal syndrome (HRS), induced by bile duct ligation (BDL). Methods Gene expression analysis, histological evaluation, determination of serum levels of renal injury-biomarkers were used to characterize the BDL-induced organ injury; laser speckle analysis to measure microcirculation in the kidneys. Key results We found that liver injury triggered marked inflammation and oxidative stress in the kidneys of BDL-operated mice. We detected pronounced histopathological alterations with tubular injury paralleled with increased inflammation, oxidative/nitrative stress and fibrotic remodeling both in hepatic and renal tissues as well as endothelial activation and markedly impaired renal microcirculation. This was accompanied by increased CB2-R expression in both the liver and the kidney tissues of diseased animals. A selective CB2-R agonist, HU-910, markedly decreased numerous markers of inflammation, oxidative stress and fibrosis both in the liver and in the kidneys. HU-910 also attenuated markers of kidney injury and improved the impaired renal microcirculation in BDL-operated mice. Conclusions Our results suggest that oxidative stress, inflammation and microvascular dysfunction are key events in the pathogenesis of BDL-associated renal failure. Furthermore, we demonstrate that targeting the CB2-R by selective agonists may represent a promising new avenue to treat HRS by attenuating tissue and vascular inflammation, oxidative stress, fibrosis and consequent microcirculatory dysfunction in the kidneys.
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β caryophyllene ameliorates cisplatin induced nephrotoxicity in a Cannabinoid 2 Receptor dependent manner
Free Radical Biology and Medicine, 2012Co-Authors: Bela Horvath, Partha Mukhopadhyay, Vivek Patel, Malek Kechrid, Galin Tanchian, David A Wink, Jurg Gertsch, Pal PacherAbstract:(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.
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Cannabinoid 2 Receptor limits inflammation oxidative nitrosative stress and cell death in nephropathy
Free Radical Biology and Medicine, 2010Co-Authors: Partha Mukhopadhyay, Mohanraj Rajesh, Hao Pan, Vivek Patel, Bani Mukhopadhyay, Sandor Batkai, Bin Gao, Gyorgy Hasko, Pal PacherAbstract:Abstract Cisplatin is an important chemotherapeutic agent; however, its nephrotoxicity limits its clinical use. Enhanced inflammatory response and oxidative/nitrosative stress seem to play a key role in the development of cisplatin-induced nephropathy. Activation of Cannabinoid-2 (CB 2 ) Receptors with selective agonists exerts anti-inflammatory and tissue-protective effects in various disease models. We have investigated the role of CB 2 Receptors in cisplatin-induced nephrotoxicity using the selective CB 2 Receptor agonist HU-308 and CB 2 knockout mice. Cisplatin significantly increased inflammation (leukocyte infiltration, CXCL1/2, MCP-1, TNFα, and IL-1β levels) and expression of adhesion molecule ICAM-1 and superoxide-generating enzymes NOX2, NOX4, and NOX1 and enhanced ROS generation, iNOS expression, nitrotyrosine formation, and apoptotic and poly(ADP-ribose) polymerase-dependent cell death in the kidneys of mice, associated with marked histopathological damage and impaired renal function (elevated serum BUN and creatinine levels) 3 days after the administration of the drug. CB 2 agonist attenuated the cisplatin-induced inflammatory response, oxidative/nitrosative stress, and cell death in the kidney and improved renal function, whereas CB 2 knockouts developed enhanced inflammation and tissue injury. Thus, the endoCannabinoid system, through CB 2 Receptors, protects against cisplatin-induced kidney damage by attenuating inflammation and oxidative/nitrosative stress, and selective CB 2 agonists may represent a promising novel approach to preventing this devastating complication of chemotherapy.
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Cannabinoid 2 Receptor limits inflammation oxidative nitrosative stress and cell death in nephropathy
Free Radical Biology and Medicine, 2010Co-Authors: Partha Mukhopadhyay, Mohanraj Rajesh, Hao Pan, Vivek Patel, Bani Mukhopadhyay, Sandor Batkai, Bin Gao, Gyorgy Hasko, Pal PacherAbstract:Cisplatin is an important chemotherapeutic agent; however, its nephrotoxicity limits its clinical use. Enhanced inflammatory response and oxidative/nitrosative stress seem to play a key role in the development of cisplatin-induced nephropathy. Activation of Cannabinoid-2 (CB(2)) Receptors with selective agonists exerts anti-inflammatory and tissue-protective effects in various disease models. We have investigated the role of CB(2) Receptors in cisplatin-induced nephrotoxicity using the selective CB(2) Receptor agonist HU-308 and CB(2) knockout mice. Cisplatin significantly increased inflammation (leukocyte infiltration, CXCL1/2, MCP-1, TNFalpha, and IL-1beta levels) and expression of adhesion molecule ICAM-1 and superoxide-generating enzymes NOX2, NOX4, and NOX1 and enhanced ROS generation, iNOS expression, nitrotyrosine formation, and apoptotic and poly(ADP-ribose) polymerase-dependent cell death in the kidneys of mice, associated with marked histopathological damage and impaired renal function (elevated serum BUN and creatinine levels) 3 days after the administration of the drug. CB(2) agonist attenuated the cisplatin-induced inflammatory response, oxidative/nitrosative stress, and cell death in the kidney and improved renal function, whereas CB(2) knockouts developed enhanced inflammation and tissue injury. Thus, the endoCannabinoid system, through CB(2) Receptors, protects against cisplatin-induced kidney damage by attenuating inflammation and oxidative/nitrosative stress, and selective CB(2) agonists may represent a promising novel approach to preventing this devastating complication of chemotherapy.
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pivotal advance Cannabinoid 2 Receptor agonist hu 308 protects against hepatic ischemia reperfusion injury by attenuating oxidative stress inflammatory response and apoptosis
Journal of Leukocyte Biology, 2007Co-Authors: Mohanraj Rajesh, Partha Mukhopadhyay, Hao Pan, Sandor Batkai, Bin Gao, Gyorgy Hasko, Douglas Oseihyiaman, Lucas Liaudet, Pal PacherAbstract:In this study, we have investigated the role of the Cannabinoid CB2 (CB2) Receptor in an in vivo mouse model of hepatic ischemia/reperfusion (I/R) injury. In addition, we have assessed the role of the CB2 Receptor in TNF-α-induced ICAM-1 and VCAM-1 expression in human liver sinusoidal endothelial cells (HLSECs) and in the adhesion of human neutrophils to HLSECs in vitro. The potent CB2 Receptor agonist HU-308, given prior to the induction of I/R, significantly attenuated the extent of liver damage (measured by serum alanine aminotransferase and lactate dehydrogenase) and decreased serum and tissue TNF-α, MIP-1α, and MIP-2 levels, tissue lipid peroxidation, neutrophil infiltration, DNA fragmentation, and caspase 3 activity. The protective effect of HU-308 against liver damage was also preserved when given right after the ischemic episode. HU-308 also attenuated the TNF-α-induced ICAM-1 and VCAM-1 expression in HLSECs, which expressed CB2 Receptors, and the adhesion of human neutrophils to HLSECs in vitro. These findings suggest that selective CB2 Receptor agonists may represent a novel, protective strategy against I/R injury by attenuating oxidative stress, inflammatory response, and apoptosis.
Partha Mukhopadhyay - One of the best experts on this subject based on the ideXlab platform.
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Cannabinoid 2 Receptor activation ameliorates hepatorenal syndrome
Free Radical Biology and Medicine, 2020Co-Authors: Eszter Trojnar, Partha Mukhopadhyay, Gyorgy Hasko, Katalin Erdelyi, Csaba Matyas, Suxian Zhao, Janos Paloczi, Zoltan Varga, Pal PacherAbstract:Abstract Study rationale Hepatorenal syndrome (HRS) is a life-threatening complication of end-stage liver disease characterized by the rapid decline of kidney function. Herein, we explored the therapeutic potential of targeting the Cannabinoid-2 Receptor (CB2-R) utilizing a commonly used mouse model of liver fibrosis and hepatorenal syndrome (HRS), induced by bile duct ligation (BDL). Methods Gene expression analysis, histological evaluation, determination of serum levels of renal injury-biomarkers were used to characterize the BDL-induced organ injury; laser speckle analysis to measure microcirculation in the kidneys. Key results We found that liver injury triggered marked inflammation and oxidative stress in the kidneys of BDL-operated mice. We detected pronounced histopathological alterations with tubular injury paralleled with increased inflammation, oxidative/nitrative stress and fibrotic remodeling both in hepatic and renal tissues as well as endothelial activation and markedly impaired renal microcirculation. This was accompanied by increased CB2-R expression in both the liver and the kidney tissues of diseased animals. A selective CB2-R agonist, HU-910, markedly decreased numerous markers of inflammation, oxidative stress and fibrosis both in the liver and in the kidneys. HU-910 also attenuated markers of kidney injury and improved the impaired renal microcirculation in BDL-operated mice. Conclusions Our results suggest that oxidative stress, inflammation and microvascular dysfunction are key events in the pathogenesis of BDL-associated renal failure. Furthermore, we demonstrate that targeting the CB2-R by selective agonists may represent a promising new avenue to treat HRS by attenuating tissue and vascular inflammation, oxidative stress, fibrosis and consequent microcirculatory dysfunction in the kidneys.
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β caryophyllene ameliorates cisplatin induced nephrotoxicity in a Cannabinoid 2 Receptor dependent manner
Free Radical Biology and Medicine, 2012Co-Authors: Bela Horvath, Partha Mukhopadhyay, Vivek Patel, Malek Kechrid, Galin Tanchian, David A Wink, Jurg Gertsch, Pal PacherAbstract:(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.
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Cannabinoid 2 Receptor limits inflammation oxidative nitrosative stress and cell death in nephropathy
Free Radical Biology and Medicine, 2010Co-Authors: Partha Mukhopadhyay, Mohanraj Rajesh, Hao Pan, Vivek Patel, Bani Mukhopadhyay, Sandor Batkai, Bin Gao, Gyorgy Hasko, Pal PacherAbstract:Abstract Cisplatin is an important chemotherapeutic agent; however, its nephrotoxicity limits its clinical use. Enhanced inflammatory response and oxidative/nitrosative stress seem to play a key role in the development of cisplatin-induced nephropathy. Activation of Cannabinoid-2 (CB 2 ) Receptors with selective agonists exerts anti-inflammatory and tissue-protective effects in various disease models. We have investigated the role of CB 2 Receptors in cisplatin-induced nephrotoxicity using the selective CB 2 Receptor agonist HU-308 and CB 2 knockout mice. Cisplatin significantly increased inflammation (leukocyte infiltration, CXCL1/2, MCP-1, TNFα, and IL-1β levels) and expression of adhesion molecule ICAM-1 and superoxide-generating enzymes NOX2, NOX4, and NOX1 and enhanced ROS generation, iNOS expression, nitrotyrosine formation, and apoptotic and poly(ADP-ribose) polymerase-dependent cell death in the kidneys of mice, associated with marked histopathological damage and impaired renal function (elevated serum BUN and creatinine levels) 3 days after the administration of the drug. CB 2 agonist attenuated the cisplatin-induced inflammatory response, oxidative/nitrosative stress, and cell death in the kidney and improved renal function, whereas CB 2 knockouts developed enhanced inflammation and tissue injury. Thus, the endoCannabinoid system, through CB 2 Receptors, protects against cisplatin-induced kidney damage by attenuating inflammation and oxidative/nitrosative stress, and selective CB 2 agonists may represent a promising novel approach to preventing this devastating complication of chemotherapy.
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Cannabinoid 2 Receptor limits inflammation oxidative nitrosative stress and cell death in nephropathy
Free Radical Biology and Medicine, 2010Co-Authors: Partha Mukhopadhyay, Mohanraj Rajesh, Hao Pan, Vivek Patel, Bani Mukhopadhyay, Sandor Batkai, Bin Gao, Gyorgy Hasko, Pal PacherAbstract:Cisplatin is an important chemotherapeutic agent; however, its nephrotoxicity limits its clinical use. Enhanced inflammatory response and oxidative/nitrosative stress seem to play a key role in the development of cisplatin-induced nephropathy. Activation of Cannabinoid-2 (CB(2)) Receptors with selective agonists exerts anti-inflammatory and tissue-protective effects in various disease models. We have investigated the role of CB(2) Receptors in cisplatin-induced nephrotoxicity using the selective CB(2) Receptor agonist HU-308 and CB(2) knockout mice. Cisplatin significantly increased inflammation (leukocyte infiltration, CXCL1/2, MCP-1, TNFalpha, and IL-1beta levels) and expression of adhesion molecule ICAM-1 and superoxide-generating enzymes NOX2, NOX4, and NOX1 and enhanced ROS generation, iNOS expression, nitrotyrosine formation, and apoptotic and poly(ADP-ribose) polymerase-dependent cell death in the kidneys of mice, associated with marked histopathological damage and impaired renal function (elevated serum BUN and creatinine levels) 3 days after the administration of the drug. CB(2) agonist attenuated the cisplatin-induced inflammatory response, oxidative/nitrosative stress, and cell death in the kidney and improved renal function, whereas CB(2) knockouts developed enhanced inflammation and tissue injury. Thus, the endoCannabinoid system, through CB(2) Receptors, protects against cisplatin-induced kidney damage by attenuating inflammation and oxidative/nitrosative stress, and selective CB(2) agonists may represent a promising novel approach to preventing this devastating complication of chemotherapy.
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pivotal advance Cannabinoid 2 Receptor agonist hu 308 protects against hepatic ischemia reperfusion injury by attenuating oxidative stress inflammatory response and apoptosis
Journal of Leukocyte Biology, 2007Co-Authors: Mohanraj Rajesh, Partha Mukhopadhyay, Hao Pan, Sandor Batkai, Bin Gao, Gyorgy Hasko, Douglas Oseihyiaman, Lucas Liaudet, Pal PacherAbstract:In this study, we have investigated the role of the Cannabinoid CB2 (CB2) Receptor in an in vivo mouse model of hepatic ischemia/reperfusion (I/R) injury. In addition, we have assessed the role of the CB2 Receptor in TNF-α-induced ICAM-1 and VCAM-1 expression in human liver sinusoidal endothelial cells (HLSECs) and in the adhesion of human neutrophils to HLSECs in vitro. The potent CB2 Receptor agonist HU-308, given prior to the induction of I/R, significantly attenuated the extent of liver damage (measured by serum alanine aminotransferase and lactate dehydrogenase) and decreased serum and tissue TNF-α, MIP-1α, and MIP-2 levels, tissue lipid peroxidation, neutrophil infiltration, DNA fragmentation, and caspase 3 activity. The protective effect of HU-308 against liver damage was also preserved when given right after the ischemic episode. HU-308 also attenuated the TNF-α-induced ICAM-1 and VCAM-1 expression in HLSECs, which expressed CB2 Receptors, and the adhesion of human neutrophils to HLSECs in vitro. These findings suggest that selective CB2 Receptor agonists may represent a novel, protective strategy against I/R injury by attenuating oxidative stress, inflammatory response, and apoptosis.
Hao Pan - One of the best experts on this subject based on the ideXlab platform.
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Cannabinoid 2 Receptor limits inflammation oxidative nitrosative stress and cell death in nephropathy
Free Radical Biology and Medicine, 2010Co-Authors: Partha Mukhopadhyay, Mohanraj Rajesh, Hao Pan, Vivek Patel, Bani Mukhopadhyay, Sandor Batkai, Bin Gao, Gyorgy Hasko, Pal PacherAbstract:Abstract Cisplatin is an important chemotherapeutic agent; however, its nephrotoxicity limits its clinical use. Enhanced inflammatory response and oxidative/nitrosative stress seem to play a key role in the development of cisplatin-induced nephropathy. Activation of Cannabinoid-2 (CB 2 ) Receptors with selective agonists exerts anti-inflammatory and tissue-protective effects in various disease models. We have investigated the role of CB 2 Receptors in cisplatin-induced nephrotoxicity using the selective CB 2 Receptor agonist HU-308 and CB 2 knockout mice. Cisplatin significantly increased inflammation (leukocyte infiltration, CXCL1/2, MCP-1, TNFα, and IL-1β levels) and expression of adhesion molecule ICAM-1 and superoxide-generating enzymes NOX2, NOX4, and NOX1 and enhanced ROS generation, iNOS expression, nitrotyrosine formation, and apoptotic and poly(ADP-ribose) polymerase-dependent cell death in the kidneys of mice, associated with marked histopathological damage and impaired renal function (elevated serum BUN and creatinine levels) 3 days after the administration of the drug. CB 2 agonist attenuated the cisplatin-induced inflammatory response, oxidative/nitrosative stress, and cell death in the kidney and improved renal function, whereas CB 2 knockouts developed enhanced inflammation and tissue injury. Thus, the endoCannabinoid system, through CB 2 Receptors, protects against cisplatin-induced kidney damage by attenuating inflammation and oxidative/nitrosative stress, and selective CB 2 agonists may represent a promising novel approach to preventing this devastating complication of chemotherapy.
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Cannabinoid 2 Receptor limits inflammation oxidative nitrosative stress and cell death in nephropathy
Free Radical Biology and Medicine, 2010Co-Authors: Partha Mukhopadhyay, Mohanraj Rajesh, Hao Pan, Vivek Patel, Bani Mukhopadhyay, Sandor Batkai, Bin Gao, Gyorgy Hasko, Pal PacherAbstract:Cisplatin is an important chemotherapeutic agent; however, its nephrotoxicity limits its clinical use. Enhanced inflammatory response and oxidative/nitrosative stress seem to play a key role in the development of cisplatin-induced nephropathy. Activation of Cannabinoid-2 (CB(2)) Receptors with selective agonists exerts anti-inflammatory and tissue-protective effects in various disease models. We have investigated the role of CB(2) Receptors in cisplatin-induced nephrotoxicity using the selective CB(2) Receptor agonist HU-308 and CB(2) knockout mice. Cisplatin significantly increased inflammation (leukocyte infiltration, CXCL1/2, MCP-1, TNFalpha, and IL-1beta levels) and expression of adhesion molecule ICAM-1 and superoxide-generating enzymes NOX2, NOX4, and NOX1 and enhanced ROS generation, iNOS expression, nitrotyrosine formation, and apoptotic and poly(ADP-ribose) polymerase-dependent cell death in the kidneys of mice, associated with marked histopathological damage and impaired renal function (elevated serum BUN and creatinine levels) 3 days after the administration of the drug. CB(2) agonist attenuated the cisplatin-induced inflammatory response, oxidative/nitrosative stress, and cell death in the kidney and improved renal function, whereas CB(2) knockouts developed enhanced inflammation and tissue injury. Thus, the endoCannabinoid system, through CB(2) Receptors, protects against cisplatin-induced kidney damage by attenuating inflammation and oxidative/nitrosative stress, and selective CB(2) agonists may represent a promising novel approach to preventing this devastating complication of chemotherapy.
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pivotal advance Cannabinoid 2 Receptor agonist hu 308 protects against hepatic ischemia reperfusion injury by attenuating oxidative stress inflammatory response and apoptosis
Journal of Leukocyte Biology, 2007Co-Authors: Mohanraj Rajesh, Partha Mukhopadhyay, Hao Pan, Sandor Batkai, Bin Gao, Gyorgy Hasko, Douglas Oseihyiaman, Lucas Liaudet, Pal PacherAbstract:In this study, we have investigated the role of the Cannabinoid CB2 (CB2) Receptor in an in vivo mouse model of hepatic ischemia/reperfusion (I/R) injury. In addition, we have assessed the role of the CB2 Receptor in TNF-α-induced ICAM-1 and VCAM-1 expression in human liver sinusoidal endothelial cells (HLSECs) and in the adhesion of human neutrophils to HLSECs in vitro. The potent CB2 Receptor agonist HU-308, given prior to the induction of I/R, significantly attenuated the extent of liver damage (measured by serum alanine aminotransferase and lactate dehydrogenase) and decreased serum and tissue TNF-α, MIP-1α, and MIP-2 levels, tissue lipid peroxidation, neutrophil infiltration, DNA fragmentation, and caspase 3 activity. The protective effect of HU-308 against liver damage was also preserved when given right after the ischemic episode. HU-308 also attenuated the TNF-α-induced ICAM-1 and VCAM-1 expression in HLSECs, which expressed CB2 Receptors, and the adhesion of human neutrophils to HLSECs in vitro. These findings suggest that selective CB2 Receptor agonists may represent a novel, protective strategy against I/R injury by attenuating oxidative stress, inflammatory response, and apoptosis.
Gyorgy Hasko - One of the best experts on this subject based on the ideXlab platform.
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Cannabinoid 2 Receptor activation ameliorates hepatorenal syndrome
Free Radical Biology and Medicine, 2020Co-Authors: Eszter Trojnar, Partha Mukhopadhyay, Gyorgy Hasko, Katalin Erdelyi, Csaba Matyas, Suxian Zhao, Janos Paloczi, Zoltan Varga, Pal PacherAbstract:Abstract Study rationale Hepatorenal syndrome (HRS) is a life-threatening complication of end-stage liver disease characterized by the rapid decline of kidney function. Herein, we explored the therapeutic potential of targeting the Cannabinoid-2 Receptor (CB2-R) utilizing a commonly used mouse model of liver fibrosis and hepatorenal syndrome (HRS), induced by bile duct ligation (BDL). Methods Gene expression analysis, histological evaluation, determination of serum levels of renal injury-biomarkers were used to characterize the BDL-induced organ injury; laser speckle analysis to measure microcirculation in the kidneys. Key results We found that liver injury triggered marked inflammation and oxidative stress in the kidneys of BDL-operated mice. We detected pronounced histopathological alterations with tubular injury paralleled with increased inflammation, oxidative/nitrative stress and fibrotic remodeling both in hepatic and renal tissues as well as endothelial activation and markedly impaired renal microcirculation. This was accompanied by increased CB2-R expression in both the liver and the kidney tissues of diseased animals. A selective CB2-R agonist, HU-910, markedly decreased numerous markers of inflammation, oxidative stress and fibrosis both in the liver and in the kidneys. HU-910 also attenuated markers of kidney injury and improved the impaired renal microcirculation in BDL-operated mice. Conclusions Our results suggest that oxidative stress, inflammation and microvascular dysfunction are key events in the pathogenesis of BDL-associated renal failure. Furthermore, we demonstrate that targeting the CB2-R by selective agonists may represent a promising new avenue to treat HRS by attenuating tissue and vascular inflammation, oxidative stress, fibrosis and consequent microcirculatory dysfunction in the kidneys.
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Cannabinoid 2 Receptor limits inflammation oxidative nitrosative stress and cell death in nephropathy
Free Radical Biology and Medicine, 2010Co-Authors: Partha Mukhopadhyay, Mohanraj Rajesh, Hao Pan, Vivek Patel, Bani Mukhopadhyay, Sandor Batkai, Bin Gao, Gyorgy Hasko, Pal PacherAbstract:Abstract Cisplatin is an important chemotherapeutic agent; however, its nephrotoxicity limits its clinical use. Enhanced inflammatory response and oxidative/nitrosative stress seem to play a key role in the development of cisplatin-induced nephropathy. Activation of Cannabinoid-2 (CB 2 ) Receptors with selective agonists exerts anti-inflammatory and tissue-protective effects in various disease models. We have investigated the role of CB 2 Receptors in cisplatin-induced nephrotoxicity using the selective CB 2 Receptor agonist HU-308 and CB 2 knockout mice. Cisplatin significantly increased inflammation (leukocyte infiltration, CXCL1/2, MCP-1, TNFα, and IL-1β levels) and expression of adhesion molecule ICAM-1 and superoxide-generating enzymes NOX2, NOX4, and NOX1 and enhanced ROS generation, iNOS expression, nitrotyrosine formation, and apoptotic and poly(ADP-ribose) polymerase-dependent cell death in the kidneys of mice, associated with marked histopathological damage and impaired renal function (elevated serum BUN and creatinine levels) 3 days after the administration of the drug. CB 2 agonist attenuated the cisplatin-induced inflammatory response, oxidative/nitrosative stress, and cell death in the kidney and improved renal function, whereas CB 2 knockouts developed enhanced inflammation and tissue injury. Thus, the endoCannabinoid system, through CB 2 Receptors, protects against cisplatin-induced kidney damage by attenuating inflammation and oxidative/nitrosative stress, and selective CB 2 agonists may represent a promising novel approach to preventing this devastating complication of chemotherapy.
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Cannabinoid 2 Receptor limits inflammation oxidative nitrosative stress and cell death in nephropathy
Free Radical Biology and Medicine, 2010Co-Authors: Partha Mukhopadhyay, Mohanraj Rajesh, Hao Pan, Vivek Patel, Bani Mukhopadhyay, Sandor Batkai, Bin Gao, Gyorgy Hasko, Pal PacherAbstract:Cisplatin is an important chemotherapeutic agent; however, its nephrotoxicity limits its clinical use. Enhanced inflammatory response and oxidative/nitrosative stress seem to play a key role in the development of cisplatin-induced nephropathy. Activation of Cannabinoid-2 (CB(2)) Receptors with selective agonists exerts anti-inflammatory and tissue-protective effects in various disease models. We have investigated the role of CB(2) Receptors in cisplatin-induced nephrotoxicity using the selective CB(2) Receptor agonist HU-308 and CB(2) knockout mice. Cisplatin significantly increased inflammation (leukocyte infiltration, CXCL1/2, MCP-1, TNFalpha, and IL-1beta levels) and expression of adhesion molecule ICAM-1 and superoxide-generating enzymes NOX2, NOX4, and NOX1 and enhanced ROS generation, iNOS expression, nitrotyrosine formation, and apoptotic and poly(ADP-ribose) polymerase-dependent cell death in the kidneys of mice, associated with marked histopathological damage and impaired renal function (elevated serum BUN and creatinine levels) 3 days after the administration of the drug. CB(2) agonist attenuated the cisplatin-induced inflammatory response, oxidative/nitrosative stress, and cell death in the kidney and improved renal function, whereas CB(2) knockouts developed enhanced inflammation and tissue injury. Thus, the endoCannabinoid system, through CB(2) Receptors, protects against cisplatin-induced kidney damage by attenuating inflammation and oxidative/nitrosative stress, and selective CB(2) agonists may represent a promising novel approach to preventing this devastating complication of chemotherapy.
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pivotal advance Cannabinoid 2 Receptor agonist hu 308 protects against hepatic ischemia reperfusion injury by attenuating oxidative stress inflammatory response and apoptosis
Journal of Leukocyte Biology, 2007Co-Authors: Mohanraj Rajesh, Partha Mukhopadhyay, Hao Pan, Sandor Batkai, Bin Gao, Gyorgy Hasko, Douglas Oseihyiaman, Lucas Liaudet, Pal PacherAbstract:In this study, we have investigated the role of the Cannabinoid CB2 (CB2) Receptor in an in vivo mouse model of hepatic ischemia/reperfusion (I/R) injury. In addition, we have assessed the role of the CB2 Receptor in TNF-α-induced ICAM-1 and VCAM-1 expression in human liver sinusoidal endothelial cells (HLSECs) and in the adhesion of human neutrophils to HLSECs in vitro. The potent CB2 Receptor agonist HU-308, given prior to the induction of I/R, significantly attenuated the extent of liver damage (measured by serum alanine aminotransferase and lactate dehydrogenase) and decreased serum and tissue TNF-α, MIP-1α, and MIP-2 levels, tissue lipid peroxidation, neutrophil infiltration, DNA fragmentation, and caspase 3 activity. The protective effect of HU-308 against liver damage was also preserved when given right after the ischemic episode. HU-308 also attenuated the TNF-α-induced ICAM-1 and VCAM-1 expression in HLSECs, which expressed CB2 Receptors, and the adhesion of human neutrophils to HLSECs in vitro. These findings suggest that selective CB2 Receptor agonists may represent a novel, protective strategy against I/R injury by attenuating oxidative stress, inflammatory response, and apoptosis.
Mohanraj Rajesh - One of the best experts on this subject based on the ideXlab platform.
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Cannabinoid 2 Receptor limits inflammation oxidative nitrosative stress and cell death in nephropathy
Free Radical Biology and Medicine, 2010Co-Authors: Partha Mukhopadhyay, Mohanraj Rajesh, Hao Pan, Vivek Patel, Bani Mukhopadhyay, Sandor Batkai, Bin Gao, Gyorgy Hasko, Pal PacherAbstract:Abstract Cisplatin is an important chemotherapeutic agent; however, its nephrotoxicity limits its clinical use. Enhanced inflammatory response and oxidative/nitrosative stress seem to play a key role in the development of cisplatin-induced nephropathy. Activation of Cannabinoid-2 (CB 2 ) Receptors with selective agonists exerts anti-inflammatory and tissue-protective effects in various disease models. We have investigated the role of CB 2 Receptors in cisplatin-induced nephrotoxicity using the selective CB 2 Receptor agonist HU-308 and CB 2 knockout mice. Cisplatin significantly increased inflammation (leukocyte infiltration, CXCL1/2, MCP-1, TNFα, and IL-1β levels) and expression of adhesion molecule ICAM-1 and superoxide-generating enzymes NOX2, NOX4, and NOX1 and enhanced ROS generation, iNOS expression, nitrotyrosine formation, and apoptotic and poly(ADP-ribose) polymerase-dependent cell death in the kidneys of mice, associated with marked histopathological damage and impaired renal function (elevated serum BUN and creatinine levels) 3 days after the administration of the drug. CB 2 agonist attenuated the cisplatin-induced inflammatory response, oxidative/nitrosative stress, and cell death in the kidney and improved renal function, whereas CB 2 knockouts developed enhanced inflammation and tissue injury. Thus, the endoCannabinoid system, through CB 2 Receptors, protects against cisplatin-induced kidney damage by attenuating inflammation and oxidative/nitrosative stress, and selective CB 2 agonists may represent a promising novel approach to preventing this devastating complication of chemotherapy.
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Cannabinoid 2 Receptor limits inflammation oxidative nitrosative stress and cell death in nephropathy
Free Radical Biology and Medicine, 2010Co-Authors: Partha Mukhopadhyay, Mohanraj Rajesh, Hao Pan, Vivek Patel, Bani Mukhopadhyay, Sandor Batkai, Bin Gao, Gyorgy Hasko, Pal PacherAbstract:Cisplatin is an important chemotherapeutic agent; however, its nephrotoxicity limits its clinical use. Enhanced inflammatory response and oxidative/nitrosative stress seem to play a key role in the development of cisplatin-induced nephropathy. Activation of Cannabinoid-2 (CB(2)) Receptors with selective agonists exerts anti-inflammatory and tissue-protective effects in various disease models. We have investigated the role of CB(2) Receptors in cisplatin-induced nephrotoxicity using the selective CB(2) Receptor agonist HU-308 and CB(2) knockout mice. Cisplatin significantly increased inflammation (leukocyte infiltration, CXCL1/2, MCP-1, TNFalpha, and IL-1beta levels) and expression of adhesion molecule ICAM-1 and superoxide-generating enzymes NOX2, NOX4, and NOX1 and enhanced ROS generation, iNOS expression, nitrotyrosine formation, and apoptotic and poly(ADP-ribose) polymerase-dependent cell death in the kidneys of mice, associated with marked histopathological damage and impaired renal function (elevated serum BUN and creatinine levels) 3 days after the administration of the drug. CB(2) agonist attenuated the cisplatin-induced inflammatory response, oxidative/nitrosative stress, and cell death in the kidney and improved renal function, whereas CB(2) knockouts developed enhanced inflammation and tissue injury. Thus, the endoCannabinoid system, through CB(2) Receptors, protects against cisplatin-induced kidney damage by attenuating inflammation and oxidative/nitrosative stress, and selective CB(2) agonists may represent a promising novel approach to preventing this devastating complication of chemotherapy.
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pivotal advance Cannabinoid 2 Receptor agonist hu 308 protects against hepatic ischemia reperfusion injury by attenuating oxidative stress inflammatory response and apoptosis
Journal of Leukocyte Biology, 2007Co-Authors: Mohanraj Rajesh, Partha Mukhopadhyay, Hao Pan, Sandor Batkai, Bin Gao, Gyorgy Hasko, Douglas Oseihyiaman, Lucas Liaudet, Pal PacherAbstract:In this study, we have investigated the role of the Cannabinoid CB2 (CB2) Receptor in an in vivo mouse model of hepatic ischemia/reperfusion (I/R) injury. In addition, we have assessed the role of the CB2 Receptor in TNF-α-induced ICAM-1 and VCAM-1 expression in human liver sinusoidal endothelial cells (HLSECs) and in the adhesion of human neutrophils to HLSECs in vitro. The potent CB2 Receptor agonist HU-308, given prior to the induction of I/R, significantly attenuated the extent of liver damage (measured by serum alanine aminotransferase and lactate dehydrogenase) and decreased serum and tissue TNF-α, MIP-1α, and MIP-2 levels, tissue lipid peroxidation, neutrophil infiltration, DNA fragmentation, and caspase 3 activity. The protective effect of HU-308 against liver damage was also preserved when given right after the ischemic episode. HU-308 also attenuated the TNF-α-induced ICAM-1 and VCAM-1 expression in HLSECs, which expressed CB2 Receptors, and the adhesion of human neutrophils to HLSECs in vitro. These findings suggest that selective CB2 Receptor agonists may represent a novel, protective strategy against I/R injury by attenuating oxidative stress, inflammatory response, and apoptosis.
