Role of melatonin in mitigation of insulin resistance and ensuing diabetic cardiomyopathy.

Addressing insulin resistance or hyperinsulinemia might offer a viable treatment approach to stop the onset of diabetic cardiomyopathy, as these conditions independently predispose to the development of the disease, which is initially characterized by diastolic abnormalities. The development of diabetic cardiomyopathy appears to be driven mainly by insulin resistance or impaired insulin signalling and/or hyperinsulinemia. Oxidative stress, hypertrophy, fibrosis, cardiac diastolic dysfunction, and, ultimately, systolic heart failure are the outcomes of these pathophysiological alterations. Melatonin is a ubiquitous indoleamine, a widely distributed compound secreted mainly by the pineal gland, and serves a variety of purposes in almost every living creature. Melatonin is found to play a leading role by improving myocardial cell metabolism, decreasing vascular endothelial cell death, reversing micro-circulation disorders, reducing myocardial fibrosis, decreasing oxidative and endoplasmic reticulum stress, regulating cell autophagy and apoptosis, and enhancing mitochondrial function. This review highlights a relationship between insulin resistance and associated cardiomyopathy. It explores the potential therapeutic strategies offered by the neurohormone melatonin, an important antioxidant that plays a leading role in maintaining glucose homeostasis by influencing the glucose transporters independently and through its receptors. The vast distribution of melatonin receptors in the body, including beta cells of pancreatic islets, asserts the role of this indole molecule in maintaining glucose homeostasis. Melatonin controls the production of GLUT4 and/or the phosphorylation process of the receptor for insulin and its intracellular substrates, activating the insulin-signalling pathway through its G-protein-coupled membrane receptors.

Diethyl phthalate, a plasticizer, induces adipocyte inflammation and apoptosis in mice after long-term dietary administration.

The incidence of metabolic diseases is increasing alarmingly in recent times. Parallel to nutritional excess and sedentary lifestyle, the random usage of several endocrine disrupting chemicals including plasticizers is reported to be closely associated with metabolic diseases. Diethyl phthalate (DEP) is a widely used plasticizer in a host of consumer and daily care products. Adipose tissue plays a central role in energy storage and whole-body metabolism. The impairment of adipose function is critically implicated in the pathogenesis of insulin resistance, diabetes, and related metabolic diseases. Recently, exposure to certain phthalate esters has been linked to the development of obesity and diabetes, although there are contradictions and the mechanisms are not clearly understood. In an effort to ascertain the metabolic consequences of chronic phthalate exposure and the underlying mechanism, the present study was designed to examine the effects of long-term dietary consumption of DEP in adipocytes. DEP-treated mice were hyperglycemic but nonobese; their body weight initially increased which subsequently was reduced compared to control. DEP exposure at lower levels impaired adipogenesis by downregulating the key transcription factor, peroxisome proliferator-activated receptor γ and its downstream insulin-sensitizing adipokine, adiponectin, thereby severely compromising adipocyte function. The activation of master regulator nuclear factor κB led to rise in proinflammatory cytokines. We found that DEP triggered intrinsic apoptotic pathways through activated cytochrome c-Apaf1-caspase 9-caspase 3 axis in adipocytes. Taken together, our data revealed that chronic administration of dietary DEP could unleash adverse metabolic outcomes by initiating oxidative stress, inflammation, and apoptosis in the adipocytes, thus leading to adipose tissue dysfunction.

An integrated strategy to explore the potential role of melatonin against copper-induced adrenaline toxicity in rat cardiomyocytes: Insights into oxidative stress, inflammation, and apoptosis.

AIMS: Circumstantial anxiety as well as chronic stress may stimulate the release of stress hormones including catecholamines. Adrenaline toxicity has been implicated in many cardiovascular conditions. Considering previous literature that suggests the oxidative potential of the adrenaline-copper entity, we have investigated its potential nocuous role in isolated adult rat cardiomyocytes, the underlying molecular mechanism, and its possible protection by melatonin. MAIN METHODS: Given the mechanistic congruity of adrenaline-copper (AC) with the well-established H2O2-copper-ascorbate (HCA) system of free radical generation, we have used the latter as a representative model to study the cytotoxic nature of AC. We further investigated the cardioprotective efficacy of melatonin in both the stress models through scanning electron microscopy, immunofluorescence, flow cytometry, and western blot analysis. KEY FINDINGS: Results show that melatonin significantly protects AC-treated cardiomyocytes from ROS-mediated membrane damage, disruption of mitochondrial membrane potential, antioxidant imbalance, and distortion of cellular morphology. Melatonin protects cardiomyocytes from inflammation by downregulating pro-inflammatory mediators viz., COX-2, NF-κB, TNF-α, and upregulating anti-inflammatory IL-10. Melatonin significantly ameliorated cardiomyocyte apoptosis in AC and HCA-treated cells as evidenced by decreased BAX/BCL-2 ratio and subsequent suppression of caspase-9 and caspase-3 levels. The isothermal calorimetric study revealed that melatonin inhibits the binding of adrenaline bitartrate with copper in solution, which fairly explains the rescue potential of melatonin against AC-mediated toxicity in cardiomyocytes. SIGNIFICANCE: Findings suggest that the multipronged strategy of melatonin that includes its antioxidant, anti-inflammatory, anti-apoptotic, and overall cardioprotective ability may substantiate its potential therapeutic efficacy against adrenaline-copper-induced damage and death of adult rat cardiomyocytes.

Chronic dietary administration of lower levels of diethyl phthalate induces murine testicular germ cell inflammation and sperm pathologies: Involvement of oxidative stress.

The wide occurrence of male infertility is a matter of grave concern. One of the major causes being exposure to endocrine disrupting chemicals (EDCs) many of which are known reproductive toxicants but the molecular mechanisms of action remain much unexplored. Diethyl phthalate (DEP) is ubiquitous in the environment due to its extensive use as plasticizer in myriad consumer products. In the present study, we sought to find out whether chronic DEP exposure affects reproductive function in sexually mature adult male mice. For this, 8-week old Swiss albino mice were treated with DEP (1 mg and 10 mg kg-1 body weight day-1) in diet for three months, mirroring the relevant doses of human exposure, and various analyses were carried out in the testicular germ cells and epididymal spermatozoa. We found that altered testicular histoarchitecture was accompanied with disturbed prooxidant: antioxidant balance in the germ cells. Involvement of Nrf2-HO-1 pathway was crucial in this altered cellular redox state. Besides, NFκB mediated inflammatory response was triggered in the germ cells leading to enhanced levels of proinflammatory cytokines. DEP adversely affected sperm count, motility, viability and morphology. Numerous structural anomalies were found in DEP treated mice spermatozoa reflecting decline in sperm function. Our results revealed overactivation of PARP-1 and subsequent cleavage in spermatozoa with induction of apoptosis as a key mechanism in DEP mediated sperm pathology. Given the indiscriminate use of plasticizers and long term low level human exposure, the present study highlights the undesirable male reproductive outcomes following chronic DEP exposure.

Testicular germ cell apoptosis and sperm defects in mice upon long-term high fat diet feeding.

The growing prevalence of male infertility is a matter of serious concern. One of the putative causes being nutritional excess from continuous consumption of high fat diet (HFD) leading to insulin resistance albeit the specific relationship is not fully understood. Besides, there are many contradictions in the available literature on the subject. Therefore, we sought to characterize in detail the effects of HFD upon testicular function and sperm quality in mice with particular focus on isolated testicular germ cells and spermatozoa, respectively. In this study, we treated 8-week old male Swiss albino mice with HFD for the duration of 5 months; control animals were reared on standard diet. We observed HFD induced progressive deterioration of testicular histoarchitecture leading to disruption of seminiferous tubules, increased vacuolization, and partial to complete tubular atrophy. Time dependent adverse effects on sperm count, motility, and morphology were noticed. Interestingly, numerous anomalies were detectable in sperm head and tail structures reflecting loss of reproductive capacity due to HFD. Maximal tissue and sperm damage was conspicuous at the endpoint, prompting us to examine oxidative stress markers. Enhanced intracellular reactive oxygen species (ROS) generation, augmentation of prooxidant activities, and compromised testicular antioxidant defences clearly implied conditions of oxidative stress in long-term HFD treated mice. This was concomitant with the onset of abnormally enhanced testicular germ cell apoptosis involving the mitochondrial intrinsic pathway. Thus, our findings revealed that ROS mediated deregulation of testicular germ cell apoptosis is critical in male reproductive impairment due to diet induced obesity.