Clinical Application of Melatonin in the Treatment of Cardiovascular Diseases: Current Evidence and New Insights into the Cardioprotective and Cardiotherapeutic Properties.

Cardiovascular diseases (CVDs) are the leading global cause of mortality and disability, tending to happen in younger individuals in developed countries. Despite improvements in medical treatments, the therapy and long-term prognosis of CVDs such as myocardial ischemia-reperfusion, atherosclerosis, heart failure, cardiac hypertrophy and remodeling, cardiomyopathy, coronary artery disease, myocardial infarction, and other CVDs threatening human life are not satisfactory enough. Therefore, many researchers are attempting to identify novel potential therapeutic methods for the treatment of CVDs. Melatonin is an anti-inflammatory and antioxidant agent with a wide range of therapeutic properties. Recently, several investigations have been carried out to evaluate its effectiveness and efficiency in CVDs therapy, focusing on mechanistic pathways. Herein, this review aims to summarize current findings of melatonin treatment for CVDs.

Therapeutic application of nutraceuticals in diabetic nephropathy: Current evidence and future implications.

Diabetes mellitus (DM) is a common metabolic disease which may cause several complications, such as diabetic nephropathy (DN). The routine medical treatments used for DM are not effective enough and have many undesirable side effects. Moreover, the global increased prevalence of DM makes researchers try to explore potential complementary or alternative treatments. Nutraceuticals, as natural products with pharmaceutical agents, have a wide range of therapeutic properties in various pathologic conditions such as DN. However, the exact underlying mechanisms have not been fully understood. The purpose of this review is to summarize recent findings on the effect of nutraceuticals on DN.

The Effects of Vitamin D3 and Melatonin Combination on Pentylenetetrazole- induced Seizures in Mice.

BACKGROUND: Epileptic seizures are associated with the overproduction of free radicals in the brain leading to neuronal cell death. Therefore, reduction of oxidative stress may inhibit seizure- induced neuronal cell damage. The current study evaluated the effects of Vit D3 and melatonin and their combination on pentylenetetrazol (PTZ)-induced tonic-clonic seizures in mice. METHODS: Animals were divided into six groups. Group I was administered with normal saline (0.5 ml, intraperitoneally (i.p.)) on the 15th day of the experiment. Group II was injected with PTZ (60 mg/kg dissolved in 0.5 ml normal saline, i.p) on the 15th day. Groups III-IV were treated with diazepam (4 mg/kg/day), Vit D3 (6000 IU/kg/day), melatonin (20 mg/kg/day), and Vit D3 (6000 IU/kg/day)/melatonin (20 mg/kg/day), respectively, and were then injected with PTZ (60 mg/kg) on the 15th day of the experiment. Immediately after the injection of PTZ on the 15th day, mice were observed for a 30-min period to measure seizure latency and duration. For determination of oxidative stress markers, malondialdehyde (MDA) level and superoxide dismutase (SOD) activity were measured in mouse brains. RESULTS: Treatment with Vit D3, melatonin, and Vit D3/melatonin significantly increased seizure latency and decreased seizure duration. The brain level of MDA was lower, and SOD activity was greater than in the PTZ group. Mice treated with Vit D3/melatonin had lower seizure duration than other treated groups. CONCLUSIONS: The combination of Vit D3 and melatonin may reduce seizure frequency in epileptic patients; this effect may result from various mechanisms, including inhibition of oxidative stress.

Anti-convulsive Effect of Thiamine and Melatonin Combination in Mice: Involvement of Oxidative Stress.

BACKGROUND: Epilepsy, the second most frequent neurological disease, is a chronic disorder with a high lifetime prevalence. Therefore, various studies are needed to find new effective therapeutic agents to treat seizures or prevent their complications. In this study, we investigated the effects of thiamine, melatonin and their combination on pentylenetetrazol (PTZ)-induced tonic-clonic seizures in mice. METHODS: Male mice were randomly divided into six groups, including control, seizure control, diazepam, melatonin, thiamine and melatonin, and thiamine combination groups. Drugs were given orally in drinking water for 14 days. On the 15th day, the seizure was induced (except the control group) by intraperitoneal injection of PTZ. In all groups, the time between the injection and the start of the seizure (latency), and also the length of the seizure attack (duration), were measured in a 30-minute period. After measuring the latency and duration in all groups, mice were killed by CO2 Box and their brains were dissected to be analyzed for malondialdehyde (MDA) level as a marker of oxidative stress. RESULTS: The seizure duration was significantly lower in the groups of melatonin, thiamine and thiamine and melatonin combination compared to the seizure control group. The latency times in these groups were significantly greater than in the seizure control group. Moreover, MDA concentrations were lower in these groups compared to the seizure control group. CONCLUSION: Thiamine, melatonin and their combination can decrease the duration time of seizure and increase the latency period, which may result from inhibition of oxidative stress in the brain.

Melatonin and morphine: potential beneficial effects of co-use.

Morphine is a potent analgesic agent used to control acute or chronic pain. Chronic administration of morphine results in analgesic tolerance, hyperalgesia, and other side effects including dependence, addiction, respiratory depression, and constipation, which limit its clinical usage. Therefore, identifying the new analgesics with fewer side effects which could increase the effect of morphine and reduce its side effects is crucial. Melatonin, a multifunctional molecule produced in the body, is known to play an important role in pain regulation. The strong anti-inflammatory effect of melatonin is suggested to be involved in the attenuation of the pain associated with inflammation. Melatonin also increases the anti-nociceptive actions of opioids, such as morphine, and reverses their tolerance through regulating several cellular signaling pathways. In this review, published articles evaluating the effect of the co-consumption of melatonin and morphine in different conditions were investigated. Our results show that melatonin has pain-killing properties when administered alone or in combination with other anti-nociceptive drugs. Melatonin decreases morphine consumption in different pathologies. Furthermore, attenuation of morphine intake can be accompanied by reduction of morphine-associated side-effects, including physical dependence, morphine tolerance, and morphine-related hyperalgesia. Therefore, it is reasonable to believe that the combination of melatonin with morphine could reduce morphine-induced tolerance and hyperalgesia, which may result from anti-inflammatory and antioxidant properties of melatonin. Overall, we underscore that, to further ameliorate patients' life quality and control their pain in various pathological conditions, melatonin deserves to be used with morphine by anesthesiologists in clinical practice.

Melatonin: new insights on its therapeutic properties in diabetic complications.

Diabetes and diabetic complications are considered as leading causes of both morbidity and mortality in the world. Unfortunately, routine medical treatments used for affected patients possess undesirable side effects, including kidney and liver damages as well as gastrointestinal adverse reactions. Therefore, exploring the novel therapeutic strategies for diabetic patients is a crucial issue. It has been recently shown that melatonin, as main product of the pineal gland, despite its various pharmacological features including anticancer, anti-aging, antioxidant and anti-inflammatory effects, exerts anti-diabetic properties through regulating various cellular mechanisms. The aim of the present review is to describe potential roles of melatonin in the treatment of diabetes and its complications.

Comparative phenotypic characterization of human colostrum and breast milk-derived stem cells.

There is a diverse population of stem cells in human breast milk that can be employed for therapeutic purposes as a reservoir of cells. The current study mainly aimed to determine the nature markers expressing on stem cells. For this aim, the expression of embryonic stem cell markers, as well as the expression of endothelial, mesenchymal, neural, and hematopoietic markers were evaluated by the flow cytometry analysis in fresh colostrum, breast milk, and cultured colostrum samples. The results showed that the embryonic (OCT4, SOX2, HLA-DR), hematopoietic (CD33, CD45, CD117), neural (CD133, Nestin), and mesenchymal (CD44, SCA1) stem cell markers present in colostrum had higher expression in comparison with their counterpart markers in fresh breast milk. The expression markers of stem cells in colostrum following a 2-week culture period were significantly increased compared with their counterpart markers in colostrum before the culture process. In the culture of breastmilk, cells were not observed adherent cells and colonies. Our findings form flow cytometry and cell culture suggest that the lactation stage could be one of the factors influencing the stem cell population and, consequently, the cultivation of breastmilk cells. The present study indicates that colostrum is a tremendous source of stem cells that could be applied in cell-based research.

Diabetic retinopathy pathogenesis and the ameliorating effects of melatonin; involvement of autophagy, inflammation and oxidative stress.

Diabetic retinopathy (DR), a microvascular complication of diabetes mellitus (DM), remains as one of the major causes of vision loss worldwide. The release of pro-inflammatory cytokines and the adhesion of leukocytes to retinal capillaries are initial events in DR development. Inflammation, ER stress, oxidative stress and autophagy are major causative factors involved in the pathogenesis of DR. Diabetes associated hyperglycemia leads to mitochondrial electron transport chain dysfunction culminating in a rise in ROS generation. Since mitochondria are the major source of ROS production, oxidative stress induced by mitochondrial dysfunction also contributes to the development of diabetic retinopathy. Autophagy increases in the retina of diabetic patients and is regulated by ER stress, oxidative stress and inflammation-related pathways. Autophagy functions as a double-edged sword in DR. Under mild stress, autophagic activity can lead to cell survival while during severe stress, dysregulated autophagy results in massive cell death and may have a role in initiation and exacerbation of DR. Melatonin and its metabolites play protective roles against inflammation, ER stress and oxidative stress due to their direct free radical scavenger activities and indirect antioxidant activity via the stimulation antioxidant enzymes including glutathione reductase, glutathione peroxidase, superoxide dismutase and catalase. Melatonin also acts as a cell survival agent by modulating autophagy in various cell types and under different conditions through amelioration of oxidative stress, ER stress and inflammation. Herein, we review the possible effects of melatonin on diabetic retinopathy, focusing on its ability to regulate autophagy processes.