Melatonin protects against diclofenac induced oxidative stress mediated myocardial toxicity in rats: A mechanistic insight.

Diclofenac, a traditional non-steroidal anti-inflammatory drug, is commonly used for treating chronic pain and inflammation. Recently, a number of articles have highlighted the toxicities associated with diclofenac. The current study explores the molecular mechanism of diclofenac induced cardiac toxicity following oxidative stress. Diclofenac inhibits catalase, disrupts the redox balance in cardiac tissue, accelerates the monoamine oxidase induced hydroperoxide generation and eventually inhibits crucial mitochondrial enzyme, viz., aldehyde dehydrogenase, thereby causing myocardial injury. Melatonin, the pineal indoleamine with high antioxidative efficacy, is well known for its cardio-protective properties and its dietary consumption has profound impact on cardiac health. The present study demonstrates perhaps for the first time, that apart from ameliorating oxidative load in the cardiac tissue, melatonin also attenuates the inhibition of catalase and aldehyde dehydrogenase, and prevents stress mediated stimulation of monoamine oxidase. Moreover, favourable binding of diclofenac with melatonin may protect the myocardium from the deleterious effects of this drug. The results indicate toward a novel mechanism of protection by melatonin, having future therapeutic relevance.

Melatonin protects against ketorolac induced gastric mucosal toxic injuries through molecular mechanism associated with the modulation of Arylakylamine N-Acetyltransferase (AANAT) activity.

Ketorolac tromethamine (KT), is a widely used non-steroidal anti-inflammatory drug (NSAID) for treating moderate to severe pain. However, the use of KT has been restricted due to its highly toxic attributes that lead to severe gastric ulceration and bleeding. The protective effects of exogenous melatonin (MT) has been reported in conditions associated with gastro-intestinal disorders. This study aims at exploring the role of gastric endogenous MT level and it's metabolizing enzyme AANAT, at the onset of ketorolac mediated toxicities in the gastric mucosa. Gastric mucosal damage was induced in experimental rats by oral administration of graded doses of KT, where 50 mg/kg b.w. of KT was observed to incur maximum gastric lesions. However, gastric damages were found to be protected in rats, pre-treated with 60 mg/kg b.w. of MT. Post-sacrifice, mean ulcer index, oxidative status, total melatonin levels and enzyme activities associated with MT biosynthesis and catabolism were estimated. The results reveal that KT decreases AANAT activity with a concomitant decline in endogenous MT level which cumulatively aggravates gastric toxicity. Moreover, exogenous MT administration has been found to be protective in ameliorating this ulcerogenic process in rats, challenged with KT. Biochemical and histo-pathological observations revealed the reduction in oxidative stress level and replenishment of depleted gastric MT levels in MT pre-treated animals, which might be the causative factors in conferring protection to the gastric tissues and residing mitochondria. The results revealed a correlation between depleted gastric MT level and ulcer formation, which unveiled a novel ulcerogenic mechanism. This may bring forth future therapeutic relevance for treating patients suffering from KT mediated acute gastric toxicities.

Insights into the antioxidative mechanisms of melatonin in ameliorating chromium-induced oxidative stress-mediated hepatic and renal tissue injuries in male Wistar rats.

Chromium (Cr), a hazardous heavy metal, is toxic to human health and the environment. Severe detrimental effects of Cr on different physiological systems involve oxidative stress. In the current study, sodium dichromate di-hydrate was subcutaneously injected to male Wistar rats at a dose of 5 mg/kg b.w. and experimented up to 14 days to induce alterations in hepatic and renal tissues. Another group of rats was pre-treated with melatonin at three different doses (5, 10, and 20 mg/kg b.w.; orally) and 20 mg/kg b.w. dose was evidenced to provide maximal protection against Cr-induced alterations. The study demonstrated that melatonin efficiently preserved body weight, organ weight, intracellular antioxidant enzymes, and tissue morphology. Furthermore, melatonin was also found to protect organ damage markers, oxidative stress-biomarkers, activities of pro-oxidant enzymes, levels of reactive oxygen species (ROS), nitric oxide (NO), and collagen content through its antioxidative mechanisms. Moreover, melatonin effectively decreased tissue Cr content through its metal-chelating activity. Hence, the present study has established melatonin as a promising antioxidant for conserving the liver and kidney tissues from Cr-induced oxidative damage thereby strengthening the notion that this small indoleamine can act as a future therapeutic against Cr-induced oxidative stress-mediated tissue damage.

Oleic acid prevents erythrocyte death by preserving haemoglobin and erythrocyte membrane proteins.

Haemolysis of erythrocytes upon exposure to haemato-toxic phenylhydrazine (PHZ), makes it an experimental model of anaemia and a partial model of ß-thalassaemia, where oxidative stress (OS) was identified as principal causative factor. Oleic acid (OA) was evidenced to ameliorate such stress with antioxidative potential. Erythrocytes were incubated in vitro using 1 mM PHZ, 0.06 nM OA. Erythrocyte membrane protein densities and haemoglobin (Hb) status were examined. Any interaction of Hb with PHZ/OA was checked by calorimetric and spectroscopic analysis using pure molecules. Occurrence of erythrocyte apoptosis and involvement of free iron in all groups were evaluated. PHZ exposure to erythrocytes results in OS with subsequent apoptosis as evidenced from increased lipid peroxidation and translocation of phosphatidylserine in outer membrane. Preservations of erythrocyte cytoskeletal architecture and membrane bound enzyme activity were found in presence of OA. Moreover, both heme and globin of Hb was examined to be conserved by OA. Presence of OA, impeded apoptosis also, possibly by thwarting Hb breakdown followed by free iron release and consequent free radical generation. Additionally, direct sequential binding of OA with PHZ endorsed another protective mechanism of OA toward erythrocytes. OA affords protection to erythrocytes by conserving its major components and prevents haemolysis which project OA as a haemato-protective agent. Apart from combating PHZ toxicity, anti-apoptotic action of OA strongly suggests its usage in anaemia and ß-thalassaemia patients to curb irreversible erythrocyte breakdown. This research strongly recommends OA in pure form or from dietary sources as a therapeutic against haemolytic disorders.

Fused Furan Moieties from Enol-like Compounds and ß-Keto Sulfoxonium Ylides Involving sp2 C-H Activation and Concomitant Tandem C-O Annulation.

An efficient and fascinating protocol has been devised for the preparation of fused furan moieties involving a Rh(II) catalyzed one-pot C-H activation/concomitant tandem annulation process, employing an enolic compound and ß-keto sulfoxonium ylide as the reacting conjugates. The developed technique demands only Rh2(TFA)4 as the catalyst to proceed forward and is devoid of additional metallic or nonmetallic additives. The skeletal transformation of naphthoquinone fused furan to highly decorated naphthoquinone fused indolizines is a promising synthetic application.

Snf2h-mediated chromatin organization and histone H1 dynamics govern cerebellar morphogenesis and neural maturation.

Chromatin compaction mediates progenitor to post-mitotic cell transitions and modulates gene expression programs, yet the mechanisms are poorly defined. Snf2h and Snf2l are ATP-dependent chromatin remodelling proteins that assemble, reposition and space nucleosomes, and are robustly expressed in the brain. Here we show that mice conditionally inactivated for Snf2h in neural progenitors have reduced levels of histone H1 and H2A variants that compromise chromatin fluidity and transcriptional programs within the developing cerebellum. Disorganized chromatin limits Purkinje and granule neuron progenitor expansion, resulting in abnormal post-natal foliation, while deregulated transcriptional programs contribute to altered neural maturation, motor dysfunction and death. However, mice survive to young adulthood, in part from Snf2l compensation that restores Engrailed-1 expression. Similarly, Purkinje-specific Snf2h ablation affects chromatin ultrastructure and dendritic arborization, but alters cognitive skills rather than motor control. Our studies reveal that Snf2h controls chromatin organization and histone H1 dynamics for the establishment of gene expression programs underlying cerebellar morphogenesis and neural maturation.