Inhibition of Cardiac RIP3 Mitigates Early Reperfusion Injury and Calcium-Induced Mitochondrial Swelling without Altering Necroptotic Signalling

Receptor-interacting protein kinase 3 (RIP3) is a convergence point of multiple signalling pathways, including necroptosis, inflammation and oxidative stress; however, it is completely unknown whether it underlies acute myocardial ischemia/reperfusion (I/R) injury. Langendorff-perfused rat hearts subjected to 30 min ischemia followed by 10 min reperfusion exhibited compromised cardiac function which was not abrogated by pharmacological intervention of RIP3 inhibition. An immunoblotting analysis revealed that the detrimental effects of I/R were unlikely mediated by necroptotic cell death, since neither the canonical RIP3–MLKL pathway (mixed lineage kinase-like pseudokinase) nor the proposed non-canonical molecular axes involving CaMKIIδ–mPTP (calcium/calmodulin-dependent protein kinase IIδ–mitochondrial permeability transition pore), PGAM5–Drp1 (phosphoglycerate mutase 5–dynamin-related protein 1) and JNK–BNIP3 (c-Jun N-terminal kinase–BCL2-interacting protein 3) were activated. Similarly, we found no evidence of the involvement of NLRP3 inflammasome signalling (NOD-, LRR- and pyrin domain-containing protein 3) in such injury. RIP3 inhibition prevented the plasma membrane rupture and delayed mPTP opening which was associated with the modulation of xanthin oxidase (XO) and manganese superoxide dismutase (MnSOD). Taken together, this is the first study indicating that RIP3 regulates early reperfusion injury via oxidative stress- and mitochondrial activity-related effects, rather than cell loss due to necroptosis

Effect of hypercholesterolemia on myocardial function, ischemia-reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning

Hypercholesterolemia is considered to be a principle risk factor for cardiovascular disease, having direct negative effects on the myocardium itself, in addition to the development of atherosclerosis. Since hypercholesterolemia affects global cardiac gene expression profile, among many other factors, increased myocardial oxidative stress, mitochondrial dysfunction and inflammation trigger apoptosis and this may account for myocardial dysfunction and increased susceptibility of the myocardium to infarction. In addition, numerous experimental and clinical studies revealed that hyperlcholesterolemia may interfere with the cardioprotective potential of conditioning mechanisms. Although not fully elucidated, the underlying mechanisms for the lost cardioprotection in hypercholesterolemic animals have been reported to involve dysregulation of eNOS-cGMP, RISK, peroxynitrite-MMP2 signaling pathways, modulation of KATP channels and apoptotic pathways. In this review article, we summarize current knowledge on the effect of hypercholesterolemia on the non-ischemic and ischemic heart as well as on the cardioprotection induced by drugs or ischemic preconditioning (PC), postconditioning (PostC) and remote conditioning. We also summarize the effects of hypercholesterolemia on drug-induced cardioprotection, in the presence of hypercholesterolemia. Future perspectives concerning the mechanisms and the design of pre-clinical and clinical trials are highlighted

Environmental and Genetic Preconditioning for Long-Term Anoxia Responses Requires AMPK in Caenorhabditis elegans

Article on environmental and genetic preconditioning for long-term anoxia responses requires AMPK in Caenorhabditis elegans

EVALUATION OF EZENUS IN AN EXPERIMENTAL MODEL OF DIET-INDUCED ALCOHOLIC AND NON-ALCOHOLIC FATTY LIVER CONDITION IN RATS

Objective: Alcoholic and non-alcoholic fatty liver disease are found to affect more than 10% of the general population. Fatty liver condition in humans is directly correlated with psychosocial stress. Herbal formulations for the management of stress may present an alternative for the treatment of fatty liver disease. Ezenus is a polyherbal candy containing herbs that can ameliorate stress and consequent liver abnormality. The present study aimed to evaluate the effect of Ezenus in experimentally induced alcoholic and non-acloholic fatty liver condition.Methods: Two models were studied simultaneously, prophylactic and therapeutic. Prophylactic groups received Ezenus along with fatty diet whereas the therapeutic groups received Ezenus only after induction of alcoholic or non-alcoholic fatty liver condition. Biochemical parameters were estimated in the serum on Days 0, 45 and 90. Lipid biochemistry of liver and histopathology were performed after terminal necropsy.Results: Fatty liver condition was induced in rats within 45 days of fatty diet administration with or without alcohol. Results of the present study suggested that prophylactic administration of Ezenus prevented the development of fatty liver condition in rats to a certain extent. Therapeutic intervention with Ezenus after fatty diet intake for 45 days was able to prevent the deranging effects of fatty liver disease. This beneficial effect of Ezenus was attributed to the adaptogenic and antioxidant effects of the ingredients present in Ezenus.Conclusion: Based on the results of the study, it was concluded that long term treatment of Ezenus exhibits a preventive effect in fatty liver disease. It not only protects the liver from toxic insults to a certain extent but also has the capability of maintaining the normal liver function.Â