TY - JOUR AU - Balla, Helga AU - Borsodi, Kinga AU - Őrsy, Petra AU - Horváth, Béla András AU - Molnár, Péter József AU - Lénárt, Ádám AU - Kosztelnik, Mónika AU - Ruisanchez, Éva AU - Wess, Jürgen AU - Offermanns, Stefan AU - Nyirády, Péter AU - Benyó, Zoltán TI - Intracellular signaling pathways of muscarinic acetylcholine receptor-mediated detrusor muscle contractions JF - AMERICAN JOURNAL OF PHYSIOLOGY: RENAL PHYSIOLOGY J2 - AM J PHYSIOL RENAL VL - 325 PY - 2023 IS - 5 SP - F618 EP - F628 PG - 11 SN - 1931-857X DO - 10.1152/ajprenal.00261.2022 UR - https://m2.mtmt.hu/api/publication/34148693 ID - 34148693 LA - English DB - MTMT ER - TY - GEN AU - Hricisák, László AU - Polycarpou, A AU - Iring, András AU - Safar, D AU - Ruisanchez, Éva AU - Horváth, Béla András AU - Sándor, Péter AU - Benyó, Zoltán TI - A NITROGÉN-MONOXID SZEREPE A REGIONÁLIS AGYKÉRGI VÉRÁRAMLÁS SZABÁLYOZÁSÁBAN FÉLOLDALI ARTERIA CAROTIS ELZÁRÁS UTÁN PY - 2017 PG - 1 UR - https://m2.mtmt.hu/api/publication/3243370 ID - 3243370 LA - Hungarian DB - MTMT ER - TY - JOUR AU - Polycarpou, A AU - Hricisák, László AU - Iring, András AU - Safar, D AU - Ruisanchez, Éva AU - Horváth, Béla András AU - Sándor, Péter AU - Benyó, Zoltán TI - Adaptation of the Cerebrocortical Circulation to Carotid Artery Occlusion Involves Blood Flow Redistribution between Cortical Regions and is Independent of eNOS JF - AMERICAN JOURNAL OF PHYSIOLOGY: HEART AND CIRCULATORY PHYSIOLOGY J2 - AM J PHYSIOL HEART C VL - 311 PY - 2016 IS - 4 SP - H972 EP - H980 SN - 0363-6135 DO - 10.1152/ajpheart.00197.2016 UR - https://m2.mtmt.hu/api/publication/3100748 ID - 3100748 N1 - Institute of Clinical Experimental Research, Semmelweis University, Budapest, Hungary Max Planck Institute for Heart and Lung Research, Department of Pharmacology, Bad Nauheim, Germany Cited By :10 Export Date: 13 January 2024 CODEN: AJPPD Correspondence Address: Benyó, Z.; Institute of Clinical Experimental Research, Tű u. 37-47, Hungary; email: benyo.zoltan@med.semmelweis-univ.hu AB - Cerebral circulation is secured by feed-forward and feed-back control pathways to maintain and eventually reestablish the optimal oxygen and nutrient supply of neurons in case of disturbances of the cardiovascular system. Using the high temporal and spatial resolution of laser-speckle imaging we aimed to analyze the pattern of cerebrocortical blood flow (CoBF) changes after unilateral (left) carotid artery occlusion (CAO) in anesthetized mice in order to evaluate the contribution of macrovascular (Willis circle) vs. pial collateral vessels as well as that of endothelial nitric oxide synthase (eNOS) to the cerebrovascular adaptation to CAO. In wild-type mice CoBF reduction in the left temporal cortex started immediately after CAO, reaching its maximum (-26%) at 5-10 s. Thereafter, CoBF recovered close to the pre-occlusion level within 30 s indicating the activation of feed-back pathway(s). Interestingly, the frontoparietal cerebrocortical regions also showed CoBF reduction in the left (-17-19%) but not in the right hemisphere, although these brain areas receive their blood supply from the common azygos anterior cerebral artery in mice. In eNOS-deficient animals the acute CoBF reduction after CAO was unaltered, and the recovery was even accelerated as compared to controls. These results indicate that (i) the Willis circle alone is not sufficient to provide an immediate compensation for the loss of one carotid artery, (ii) pial collaterals attenuate the ischemia of the temporal cortex ipsilateral to CAO at the expense of the blood supply of the frontoparietal region, and (iii) eNOS, surprisingly, does not play an important role in this CoBF redistribution. LA - English DB - MTMT ER - TY - JOUR AU - Mukhopadhyay, P AU - Rajesh, M AU - Cao, Z AU - Horváth, Béla András AU - Park, O AU - Wang, H AU - Erdélyi, Katalin AU - Holovac, E AU - Wang, Y AU - Liaudet, L AU - Hamdaoui, N AU - Lafdil, F AU - Haskó, György AU - Szabo, C AU - Boulares, AH AU - Gao, B AU - Pacher, Pál TI - Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis JF - HEPATOLOGY J2 - HEPATOLOGY VL - 59 PY - 2014 IS - 5 SP - 1998 EP - 2009 PG - 12 SN - 0270-9139 DO - 10.1002/hep.26763 UR - https://m2.mtmt.hu/api/publication/2431460 ID - 2431460 N1 - Funding Agency and Grant Number: NIH/NIAAA; NIH [P50GM060338, HL072889] Funding text: Supported by the Intramural Program of the NIH/NIAAA to PP and BG. CS and AHB were supported by a grant from the NIH P50GM060338 and HL072889. AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Iring, András AU - Ruisanchez, Éva AU - Leszl-Ishiguro, Mirjam AU - Horváth, Béla András AU - Benkő, Rita AU - Lacza, Zsombor AU - Járai, Zoltán AU - Sándor, Péter AU - Di Marzo, V AU - Pacher, Pál AU - Benyó, Zoltán TI - Role of endocannabinoids and cannabinoid-1 receptors in cerebrocortical blood flow regulation JF - PLOS ONE J2 - PLOS ONE VL - 8 PY - 2013 IS - 1 PG - 11 SN - 1932-6203 DO - 10.1371/journal.pone.0053390 UR - https://m2.mtmt.hu/api/publication/2181946 ID - 2181946 N1 - Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, Budapest, Hungary Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, United States Department of Cardiology, St. Imre Teaching Hospital, Budapest, Hungary Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Naples, Italy National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States Cited By :22 Export Date: 1 February 2024 Correspondence Address: Benyó, Z.; Institute of Human Physiology and Clinical Experimental Research, , Budapest, Hungary; email: benyo.zoltan@med.semmelweis-univ.hu Chemicals/CAS: 1 (2,4 dichlorophenyl) 5 (4 iodophenyl) 4 methyl n (1 piperidyl) 1h pyrazole 3 carboxamide, 183232-66-8; n (4 hydroxyphenyl)arachidonamide, 183718-77-6, 198022-70-7; AM 251; Arachidonic Acids; Endocannabinoids; N-(4-hydroxyphenyl)arachidonylamide; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1 Funding details: National Institute on Alcohol Abuse and Alcoholism, NIAAA, ZIAAA000375 AB - BACKGROUND: Endocannabinoids are among the most intensively studied lipid mediators of cardiovascular functions. In the present study the effects of decreased and increased activity of the endocannabinoid system (achieved by cannabinoid-1 (CB1) receptor blockade and inhibition of cannabinoid reuptake, respectively) on the systemic and cerebral circulation were analyzed under steady-state physiological conditions and during hypoxia and hypercapnia (H/H). METHODOLOGY/PRINCIPAL FINDINGS: In anesthetized spontaneously ventilating rats the CB1-receptor antagonist/inverse agonist AM-251 (10 mg/kg, i.v.) failed to influence blood pressure (BP), cerebrocortical blood flow (CoBF, measured by laser-Doppler flowmetry) or arterial blood gas levels. In contrast, the putative cannabinoid reuptake inhibitor AM-404 (10 mg/kg, i.v.) induced triphasic responses, some of which could be blocked by AM-251. Hypertension during phase I was resistant to AM-251, whereas the concomitant CoBF-increase was attenuated. In contrast, hypotension during phase III was sensitive to AM-251, whereas the concomitant CoBF-decrease was not. Therefore, CoBF autoregulation appeared to shift towards higher BP levels after CB1-blockade. During phase II H/H developed due to respiratory depression, which could be inhibited by AM-251. Interestingly, however, the concomitant rise in CoBF remained unchanged after AM-251, indicating that CB1-blockade potentially enhanced the reactivity of the CoBF to H/H. In accordance with this hypothesis, AM-251 induced a significant enhancement of the CoBF responses during controlled stepwise H/H. CONCLUSION/SIGNIFICANCE: Under resting physiological conditions CB1-receptor mediated mechanisms appear to have limited influence on systemic or cerebral circulation. Enhancement of endocannabinoid levels, however, induces transient CB1-independent hypertension and sustained CB1-mediated hypotension. Furthermore, enhanced endocannabinoid activity results in respiratory depression in a CB1-dependent manner. Finally, our data indicate for the first time the involvement of the endocannabinoid system and CB1-receptors in the regulation of the cerebral circulation during H/H and also raise the possibility of their contribution to the autoregulation of CoBF. LA - English DB - MTMT ER - TY - CONF AU - Horváth, Béla András AU - Iring, András AU - Benyó, Balázs István AU - Hermán, P AU - Lenzsér, Gábor AU - Lacza, Zsombor AU - Sándor, Péter AU - Benyó, Zoltán TI - Low frequency pial arterial vasomotion and cerebrocortical blood flow oscillations in rodents. role of nitric oxide and thromboxane A2 TS - role of nitric oxide and thromboxane A2 T2 - SRBR Society for Research on Biological Rhythms 2012 PY - 2012 SP - 266 EP - 266 PG - 1 UR - https://m2.mtmt.hu/api/publication/2845095 ID - 2845095 LA - Hungarian DB - MTMT ER - TY - JOUR AU - Mukhopadhyay, Partha AU - Horváth, Béla András AU - Zsengeller, Zsuzsanna AU - Batkai, Sandor AU - Cao, Zongxian AU - Kechrid, Malek AU - Erdélyi, Katalin AU - Tanchian, Galin AU - Liaudet, Lucas AU - Stillman, Isaac E AU - Joseph, Joy AU - Kalyanaraman, Balaraman AU - Pacher, Pál TI - Mitochondrially Targeted Antioxidants Ameliorate Inflammatory Response and Tissue Injury Associated with Hepatic Ischemia-Reperfusion in Mice JF - FREE RADICAL BIOLOGY AND MEDICINE J2 - FREE RADICAL BIO MED VL - 53 PY - 2012 IS - Suppl. 2 SP - S113 EP - S113 SN - 0891-5849 DO - 10.1016/j.freeradbiomed.2012.10.276 UR - https://m2.mtmt.hu/api/publication/2204807 ID - 2204807 LA - English DB - MTMT ER - TY - JOUR AU - Mukhopadhyay, P AU - Horváth, Béla András AU - Zsengeller, Z AU - Zielonka, J AU - Tanchian, G AU - Holovac, E AU - Kechrid, M AU - Patel, V AU - Stillman, IE AU - Parikh, SM AU - Joseph, J AU - Kalyanaraman, B AU - Pacher, Pál TI - Mitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy JF - FREE RADICAL BIOLOGY AND MEDICINE J2 - FREE RADICAL BIO MED VL - 52 PY - 2012 IS - 2 SP - 497 EP - 506 PG - 10 SN - 0891-5849 DO - 10.1016/j.freeradbiomed.2011.11.001 UR - https://m2.mtmt.hu/api/publication/2199817 ID - 2199817 AB - 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. (C) 2011 Elsevier Inc. All rights reserved. LA - English DB - MTMT ER - TY - JOUR AU - Rajesh, M AU - Batkai, S AU - Kechrid, M AU - Mukhopadhyay, P AU - Lee, WS AU - Horváth, Béla András AU - Holovac, E AU - Cinar, R AU - Liaudet, L AU - Mackie, K AU - Haskó, György AU - Pacher, Pál TI - Cannabinoid 1 Receptor Promotes Cardiac Dysfunction, Oxidative Stress, Inflammation, and Fibrosis in Diabetic Cardiomyopathy JF - DIABETES J2 - DIABETES VL - 61 PY - 2012 IS - 3 SP - 716 EP - 727 PG - 12 SN - 0012-1797 DO - 10.2337/db11-0477 UR - https://m2.mtmt.hu/api/publication/2199816 ID - 2199816 N1 - Funding Agency and Grant Number: NIH/NIAAA; National Office for Research and Technology-Hungarian Scientific Research Fund-European [MB08-A80238]; Alexander von Humboldt Foundation; European Commission [FP7-CIG-294278] Funding text: This study was supported by the Intramural Research Program of NIH/NIAAA (to P.P.). B.H. was supported by an National Office for Research and Technology-Hungarian Scientific Research Fund-European Union 7th Framework fellowship (MB08-A80238). S.B. was supported by the Alexander von Humboldt Foundation and the European Commission (FP7-CIG-294278). AB - Endocannabinoids and cannabinoid 1 (CB1) 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 CB1 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 NH2-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs), enhanced inflammation (tumor necrosis factor-alpha, interleukin-1 beta, cyclooxygenase 2, intracellular adhesion molecule 1, and vascular cell adhesion molecule 1), increased expression of CB1, 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, beta-myosin heavy chain isozyme switch, accumulation of AGE, fibrosis, and decreased expression of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA2a). Pharmacological inhibition or genetic deletion of CB1 receptors attenuated the diabetes-induced cardiac dysfunction and the above-mentioned pathological alterations. Activation of CBI receptors by endo-cannabinoids 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, CB1 receptor inhibition may be beneficial in the treatment of diabetic cardiovascular complications. Diabetes 61:716-727, 2012 LA - English DB - MTMT ER - TY - JOUR AU - Horváth, Béla András AU - Magid, L AU - Mukhopadhyay, P AU - Batkai, S AU - Rajesh, M AU - Park, O AU - Tanchian, G AU - Gao, RY AU - Goodfellow, CE AU - Glass, M AU - Mechoulam, R AU - Pacher, Pál TI - A new cannabinoid CB2 receptor agonist HU-910 attenuates oxidative stress, inflammation and cell death associated with hepatic ischaemia/reperfusion injury JF - BRITISH JOURNAL OF PHARMACOLOGY J2 - BR J PHARMACOL VL - 165 PY - 2012 IS - 8 SP - 2462 EP - 2478 PG - 17 SN - 0007-1188 DO - 10.1111/j.1476-5381.2011.01381.x UR - https://m2.mtmt.hu/api/publication/2199812 ID - 2199812 N1 - Cited By :73 Export Date: 31 January 2021 CODEN: BJPCB AB - 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 [H-3]CP55940 by HU-910 from specific binding sites in CHO cell membranes transfected with human CB2 or CB1 receptors (hCB(1/2)) yielded K-i values of 6 nM and 1.4 mM respectively. HU-910 inhibited forskolin-stimulated cyclic AMP production by hCB(2) CHO cells (EC50 = 162 nM) and yielded EC50 of 26.4 nM in [S-35]GTP gamma S binding assays using hCB(2) expressing CHO membranes. HU-910 given before ischaemia significantly attenuated levels of I/R-induced hepatic proinflammatory chemokines (CCL3 and CXCL2), TNF-alpha, 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-alpha production in isolated Kupffer cells and expression of adhesion molecules in primary human liver sinusoidal endothelial cells stimulated with TNF-alpha. 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. LA - English DB - MTMT ER -