Substantial 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 the Laboratory of Cardiovascular Physiology and Tissue Injury (LCPTI) to understand the cellular and molecular mechanisms of the complex interplay of oxidative/nitrative stress, inflammation, lipid signaling (for example endocannabinoid signaling) and cell death pathways (e.g. poly(ADP)-ribose polymerase) in tissue injury, and to identify new therapeutic targets using clinically relevant animal models of disease (e.g., ischemia reperfusion injury, cardiomyopathies/heart failure, nephropathies, cardiovascular aging, and alcohol induced cardiovascular, liver and kidney injury and neuroinflammation). 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 (CB2R) exerts anti-inflammatory effects and attenuates oxidative/nitrative stress in models of liver, cardiovascular and renal injury. Recently, in collaboration with Drs. Mario Van der Stelt and others we characterized all commonly used CB2 agonists. These studies revealed important off target effects for many of the CB2 ligands previously used and biased signaling. In collaboration with Dr. Gertsch we identified Pepcan-12 (RVD-hemopressin) as a CB2R positive allosteric modulator constitutively secreted by adrenals and in liver upon tissue damage. -Caryophyllene (BCP) is a plant-derived FDA approved food additive with anti-inflammatory properties. Some of its beneficial effects in vivo are reported to involve activation of cannabinoid CB2 receptors that are predominantly expressed in immune cells. Recently we evaluated the translational potential of BCP using a well-established model of chronic and binge alcohol-induced liver injury. We have investigated the effects of BCP on liver injury induced by chronic plus binge alcohol feeding in mice in vivo by using biochemical assays, real-time PCR and histology analyses. We found that chronic treatment with BCP alleviated the chronic and binge alcohol-induced liver injury and inflammation by attenuating the pro-inflammatory phenotypic M1 switch of Kupffer cells and by decreasing the expression of vascular adhesion molecules intercellular adhesion molecule 1, E-Selectin and P-Selectin, as well as the neutrophil infiltration. BCP also beneficially influenced hepatic metabolic dysregulation (steatosis, protein hyperacetylation and PPAR- signalling). These protective effects of BCP against alcohol-induced liver injury were attenuated in CB2 receptor knockout mice, indicating that the beneficial effects of this natural product in liver injury involve activation of these receptors. Following acute or chronic administration, BCP was detectable both in the serum and liver tissue homogenates but not in the brain. Our forthcoming 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, Van der Stelt, Mechoulam and Kunos) in various models of liver disease, cardiomyopathy and nephropathy. Role of oxidative/nitrosative stress, inflammation, metabolic reprograming in ethanol-induced liver injury. Poly(ADP-ribose) polymerases (PARP) are the most abundant nuclear enzymes. The PARP inhibitor olaparib (Lynparza) is a recently FDA-approved therapy for cancer. Recently we have demonstrated that PARP is overactivated in livers of subjects with alcoholic liver disease and that pharmacological inhibition of this enzyme with 3 different PARP inhibitors, including olaparib, attenuates high fat or alcohol induced liver injury, abnormal metabolic alteration, fat accumulation, inflammation and/or fibrosis in preclinical models of liver disease. These results suggest that PARP inhibition is a promising therapeutic strategy in the treatment of alcoholic and non-alcoholic liver diseases. Our collaborative studies with Dr. Persidsky have demonstrated that PARP inhibition in leukocytes diminished inflammation via effects on integrins/cytoskeleton and protected the blood-brain barrier. In collaboration with Dr. Gao we have showed that aging aggravated alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression and that inflammation was independent of steatosis in a murine model of steatohepatitis. In collaboration with Dr. Kunos we characterized non-brain-penetrant, hybrid cannabinoid CB1R inverse agonist/inducible nitric oxide synthase (iNOS) inhibitors for the treatment of liver fibrosis. Our impending collaborative studies with Drs. George Kunos and Bin Gao 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.
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