Overwhelming evidence suggests that oxidative-nitrosative/nitrative stress and inflammation are involved in essentially all major pathological processes affecting humans, including those induced by excessive alcohol consumption. The research focus of SOSTI is to understand the cellular and molecular mechanisms underlying oxidative/nitrosative/nitrative stress, inflammation, and their downstream effector pathways using clinically relevant animal models of disease (e.g. ischemia reperfusion injury, cardiomyopathy/heart failure, nephropathy, liver injury), and to identify novel therapeutic targets against these pathologies. Interplay of oxidative/nitrative stress, inflammation with the endocannabinoid system (ES) in tissue injury and inflammation. We have been exploring the interplay of oxidative/nitrative stress, inflammation with the ES; an emerging very promising therapeutic target against various inflammatory and other diseases. Our prior studies provided evidence that the activation of cannabinoid 2 receptors (CB2) exerts anti-inflammatory effects and attenuates oxidative/nitrative stress in models of liver, cardiovascular and renal injury. Our recent and future studies have been directed towards the development and characterization of novel CB2 agonists with improved in vivo pharmacological profile, development of improved tools for CB2 detection in tissues/cells. In collaboration with investigators at Hoffmann-La Roche, Cecilia Hillard, Mario van der Stelt, AronLichtman, Mauro Maccarrone, Raphael Mechoulam and George Kunos we have been working on development of novel selective CB2 agonist, various radiolabels for autoradiography and PET imaging, as well as on better understanding the role of CB2 receptor function and signaling in various pathologies (e.g. neuroinflammation, kidney disease, among others). In collaboration with Dr. Kunos we also identified an important role overactive cannabinoid 1 receptor in podocytes in development and progression of type 2 diabetic nephropathy. In collaboration with Dr. Hamar we also described a new model of chronic kidney fibrosis and nephropathy in rats. Our future studies will also focus on the understanding of the mechanisms of the activation of the endocannabinoid system during tissue injury and on the further elucidation of the role of endocannabinoid system (particularly focusing on the endocannabinoid metabolizing enzymes and CB2 in collaboration with Drs. Cravatt, Mechoulam and Kunos) in various models of liver disease, cardiomyopathy and nephropathy. Our future collaborative studies with Drs. George Kunos, Bin Gao and Byoung-Joon Song will also explore the role of oxidative/nitrosative stress and ES in various other models of liver and metabolic disorders and fibrosis. The above mentioned studies may identify new pharmacological targets in various forms of tissue injury associated with increased inflammation, oxidative stress, and fibrosis. Cannabidiol (CBD) is a nonpsychotropic constituent of marijuana, which is well tolerated in humans, and has been evaluated in around 80 clinical trials for various indications. CBD exerts antioxidant and anti-inflammatory effects independent from classic CB1 and CB2. Previously we found that it protected against diabetic cardiomyopathy by antioxidant and anti-inflammatory mechanisms. Recently using a well-established model of doxorubicin (DOX)-induced cardiomyopathy, we discovered that CBD enhanced mitochondrial function and biogenesis. These results suggest that CBD may represent a novel cardioprotective strategy against DOX-induced cardiotoxicity, and the above-described effects on mitochondrial function and biogenesis may contribute to its beneficial properties described in numerous other models of tissue injury. Our collaborative studies with Dr. Liaudet we identified IL-1 as a crucial danger signal triggering acute myocardial inflammation during myocardial infarction and found that Toll-like receptor 5 deficiency exacerbates cardiac injury and inflammation induced by myocardial ischaemia-reperfusion in mice. Role of oxidative-nitrative stress, inflammation and apoptosis in ethanol-induced tissue-damage. Recently we described increased nitrative stress and PARP activation in liver biopsies of subjects with alcoholic or hepatitis B-induced cirrhosis and using mouse models we demonstrated beneficial effects of pharmacological inhibition of PARP with various structurally different inhibitors on development and progression of liver inflammation and fibrosis. Our ongoing collaborative studies with Dr. Gao are aimed to explore the mechanisms of these protective effects. Our results suggest that liver inflammation and liver fibrosis may be additional clinical indications where PARP inhibition may be of translational potential (they have recently been approved by FDA for various oncological indications). Chronic excessive drinking may promote development of cardiomyopathy and inflammation. Alcohol-mediated apoptosis of cardiomyocytes has been documented in experimental animals, and there is also evidence of skeletal muscle cell apoptosis in chronic heavy drinkers. The extent of apoptotic damage in the heart is similar in heavy drinkers and in patients with long-standing hypertension and is related to structural damage. Our recent ongoing studies are also focused on the understanding of the mechanisms of ethanol-induced oxidative/nitrative stress, inflammation and cell death in the cardiovascular system and also in the liver during pathological processes (e.g. associated with aging). We are also working on the development of a reproducible model of alcohol-induced cardiomyopathy in mice to study the mechanisms of its detrimental effects.
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