Therapeutic Efficacy Of Melatonin Research Articles

Melatonin improves stroke by inhibiting autophagy-dependent ferroptosis mediated by NCOA4 binding to FTH1

Ischemic stroke is a disease associated with high morbidity and disability rates; however, its pathogenesis remains elusive, and treatment options are limited. Ferroptosis, an iron-dependent form of cell death, represents a novel avenue for investigation. The objective of this study was to explore the role of melatonin in MCAO-induced ferroptosis and elucidate its underlying molecular mechanism. To simulate brain damage and neuronal injury caused by ischemic stroke, we established a mouse model of MCAO and an HT-22 cell model of OGD/R. The therapeutic efficacy of melatonin was assessed through measurements of infarct size, brain edema, and neurological scores. Additionally, qRT-PCR, WB analysis, and Co-IP assays were employed to investigate the impact of melatonin on ferroptosis markers such as NCOA4 and FTH1 expression levels. Confocal microscopy was utilized to confirm the colocalization between ferritin and lysosomes. Furthermore, we constructed a SIRT6 siRNA model to validate the regulatory effect exerted by SIRT6 on NCOA4 as well as their binding interaction. The present study provides initial evidence that melatonin possesses the ability to mitigate neuronal damage induced by MCAO and OGD/R. Assessment of markers for oxidative damage and ferroptosis revealed that melatonin effectively inhibits intracellular Fe2+ levels, thereby suppressing ferroptosis. Additionally, our findings demonstrate that melatonin modulates the interaction between FTH1 and NCOA4 via SIRT6, influencing ferritin autophagy without affecting cellular macroautophagy. These findings provide reliable data support for the promotion and application of melatonin in clinical practice.

Melatonin Improves Glucose Homeostasis and Insulin Sensitivity by Mitigating Inflammation and Activating AMPK Signaling in a Mouse Model of Sleep Fragmentation.

Sleep fragmentation (SF) can increase inflammation and production of reactive oxygen species (ROS), leading to metabolic dysfunction. SF is associated with inflammation of adipose tissue and insulin resistance. Several studies have suggested that melatonin may have beneficial metabolic effects due to activating AMP-activated protein kinase (AMPK). However, it is unclear whether melatonin affects the AMPK signaling pathway in SF-induced metabolic dysfunction. Therefore, we hypothesize that SF induces metabolic impairment and inflammation in white adipose tissue (WAT), as well as altered intracellular homeostasis. We further hypothesize that these conditions could be improved by melatonin treatment. We conducted an experiment using adult male C57BL/6 mice, which were divided into three groups: control, SF, and SF with melatonin treatment (SF+Mel). The SF mice were housed in SF chambers, while the SF+Mel mice received daily oral melatonin. After 12 weeks, glucose tolerance tests, insulin tolerance tests, adipose tissue inflammation tests, and AMPK assessments were performed. The SF mice showed increased weight gain, impaired glucose regulation, inflammation, and decreased AMPK in WAT compared to the controls. Melatonin significantly improved these outcomes by mitigating SF-induced metabolic dysfunction, inflammation, and AMPK downregulation in adipose tissue. The therapeutic efficacy of melatonin against cardiometabolic impairments in SF may be due to its ability to restore adipose tissue homeostatic pathways.

Melatonin-Derived Carbon Dots with Free Radical Scavenging Property for Effective Periodontitis Treatment via the Nrf2/HO-1 Pathway.

Periodontitis is a chronic inflammatory disease closely associated with reactive oxygen species (ROS) involvement. Eliminating ROS to control the periodontal microenvironment and alleviate the inflammatory response could potentially serve as an efficacious therapy for periodontitis. Melatonin (MT), renowned for its potent antioxidant and anti-inflammatory characteristics, is frequently employed as an ROS scavenger in inflammatory diseases. However, the therapeutic efficacy of MT remains unsatisfactory due to the low water solubility and poor bioavailability. Carbon dots have emerged as a promising and innovative nanomaterial with facile synthesis, environmental friendliness, and low cost. In this study, melatonin-derived carbon dots (MT-CDs) were successfully synthesized via the hydrothermal method. The MT-CDs have good water solubility and biocompatibility and feature excellent ROS-scavenging capacity without additional modification. The in vitro experiments proved that MT-CDs efficiently regulated intracellular ROS, which maintained mitochondrial homeostasis and suppressed the production of inflammatory mediators. Furthermore, findings from the mouse model of periodontitis indicated that MT-CDs significantly inhibited the deterioration of alveolar bone and reduced osteoclast activation and inflammation, thereby contributing to the regeneration of damaged tissue. In terms of the mechanism, MT-CDs may scavenge ROS, thereby preventing cellular damage and the production of inflammatory factors by regulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. The findings will offer a vital understanding of the advancement of secure and effective ROS-scavenging platforms for more biomedical applications.

Impairment of the melatonergic system in the pathophysiology of diabetic encephalopathy (review)

Objective: to analyze the scientific literature to identify the main pathophysiological mechanisms of melatonergic system disorders in the formation of diabetic encephalopathy and to highlight the possible therapeutic efficacy of melatonin (MLT). Review writing methodology. A total of 50 scientific papers were found using the Cochrane Library, PubMed, el_ibrary.ru, Medscape, and analyzed. Database search had been performed for papers published from2011 to 2023 using the keyword combination 'diabetesmellitus", "melatonergic system", "melatonin" and "diabetic encephalopathy". Conclusion. The pathophysiology of diabetic encephalopathy is not yet fully understood, and search is ongoing for novel mechanisms underlying its development, with melatonergic system dysfunction seen as a promising hypothetical mechanism. Oxidative stress, mitochondrial dysfunction, inflammation, disruption of the insulin signal transduction pathway and increased brain cell apoptosis may impair the production of MLT and trigger the melatonergic system dysfunction process. MLT is known for its marked neurotrophic effects, and its insufficiency may exacerbate cognitive impairment in diabetes mellitus.

Melatonin Reduces Aggravation of Renal Ischemia-Reperfusion Injury in Obese Rats by Maintaining Mitochondrial Homeostasis and Integrity through AMPK/PGC-1α/SIRT3/SOD2 Activation.

This study examined the potential benefits of melatonin against renal ischemia and reperfusion (IR) injury in obesity and explored the underlying mechanisms. Obesity was induced in Wistar rats by feeding a high-fat diet for 16 weeks. Three obese groups that underwent renal IR induction (30-min renal ischemia followed by 24-h reperfusion) were randomly assigned to receive melatonin at ischemic onset, reperfusion onset, or pretreatment for 4 weeks before IR induction. Groups of vehicle-treated obese and normal-diet-fed rats that underwent sham or IR induction were also included in the study. The results showed that renal functional and structural impairments after IR incidence were aggravated in obese rats compared to normal-diet-fed rats. The obese-IR rats also exhibited oxidative stress, mitochondrial dysfunction, apoptosis, and mitochondrial dynamics and mitophagy imbalances, which were all considerably improved upon melatonin treatment, irrespective of the treatment time. This study suggests the prophylactic and therapeutic efficacy of melatonin in IR-induced acute kidney injury (AKI) in obese individuals, which may improve the prognosis of AKI in these populations. The benefits of melatonin are likely mediated by the modification of various signaling molecules within the mitochondria that maintain mitochondrial redox balance and lead to the protection of mitochondrial homeostasis and integrity.

Therapeutic Efficacy of Melatonin in Patients with Coronavirus 2019: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

The efficacy of melatonin in the treatment of patients with coronavirus 2019 (COVID-19) is controversial. This review has summarized the evidence on the efficacy of oral melatonin compared to placebo in patients with mild to moderate COVID-19 infection. We searched four international online databases and all randomized clinical trials (RCTs) that investigated the effects of melatonin compared with the placebo on clinical outcomes, including mortality, discharge time, O2 saturation (SaO2), and c-reactive protein (CRP) levels in patients with COVID-19 infection, were included. The standard random-effects model with hybrid continuity correction was used to pool the risk ratio (RR), weighted mean difference (WMD), and the I2 index to assess the heterogeneity. A total of 272 patients from five RCTs were included. Our meta-analysis showed melatonin compared to placebo, decreased discharge time (WMD=-0.93 days; 95% confidence interval [CI]:-2.94 to 1.07, P=0.36; I2=56.78%) and the risk of mortality (RR=0.72; 95% CI:0.25 to 2.13, P=0.56; I2=0.0%) in COVID-19 patients. Melatonin intake compared to placebo significantly increased SaO2 (WMD=1.38%; 95% CI:0.09 to 2.68, P=0.04; I2=49.82%) and decreased the CRP levels (WMD=-7.24 mg/l; 95% CI:-11.28 to -3.21, P<0.001) in a sensitivity analysis. Our findings showed the efficacy of melatonin compared to placebo in patients with mild to moderate COVID-19 infection.

Dual role of melatonin as an anti-colitis and anti-extra intestinal alterations against acetic acid-induced colitis model in rats

The available ulcerative colitis drugs exhibit limited outcomes and adverse side effects. Therefore, our study aimed to investigate the therapeutic efficacy of melatonin in acetic acid (AA)-induced colitis to establish a possible treatment for colitis and its impacts on vital organs. Following colitis induction (2 ml 5% AA, rectally), rats were orally received melatonin (5 mg/kg) once per day for 6 days after colitis induction. Then, histopathological examination of colon, kidney, liver, and spleen was conducted, interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), myeloperoxidase (MPO), malondialdehyde (MDA), glutathione (GSH), and total antioxidant capacity (TAC) levels were assessed in colon tissue. Colitis induction in untreated rats caused necrotic effects in colon tissues, a significant increase in colonic IL-1β, TNF-α, MPO, and MDA levels, and a remarkable decrease in GSH and TAC levels in colon tissue in comparison to the control group. Meanwhile, melatonin treatment reversed these parameters by improving the microscopic and macroscopic colitis features and extra-intestinal (kidney, liver, and spleen) changes in all treated rats compared to the colitis control group. These results denote a reduction in colitis severity due to the anti-inflammatory and anti-oxidative effects of melatonin and its positive impact on the vital organs.

Effects of Melatonin on Diabetic Neuropathy and Retinopathy.

Diabetes mellitus (DM) leads to complications, the majority of which are nephropathy, retinopathy, and neuropathy. Redox imbalance and inflammation are important components of the pathophysiology of these complications. Many studies have been conducted to find a specific treatment for these neural complications, and some of them have investigated the therapeutic potential of melatonin (MEL), an anti-inflammatory agent and powerful antioxidant. In the present article, we review studies published over the past 21 years on the therapeutic efficacy of MEL in the treatment of DM-induced neural complications. Reports suggest that there is a real prospect of using MEL as an adjuvant treatment for hypoglycemic agents. However, analysis shows that there is a wide range of approaches regarding the doses used, duration of treatment, and treatment times in relation to the temporal course of DM. This wide range hinders an objective analysis of advances and prospective vision of the paths to be followed for the unequivocal establishment of parameters to be used in an eventual therapeutic validation of MEL in neural complications of DM.

Activation of p38/HSP27 pathway counters melatonin-induced inhibitory effect on proliferation of human gastric cancer cells

Overexpression of heat shock protein 27(HSP27) in gastric cancer is correlated with poor clinical prognosis. Melatonin, an endogenous hormone, shows promise in gastric cancer therapy. However, there is limited study on the biological activity of HSP27 in response to melatonin treatment. In this study, we show an anti-proliferative action of melatonin on human gastric cancer cell lines BGC-823 and MGC-803. Biochemically, the inhibitory effect of melatonin is accompanied by the upregulation of HSP27 phosphorylation level. Transfection of gastric cancer cells with HSP27-specific siRNA effectively reduces HSP27 phosphorylation and potentiated melatonin-induced inhibitory effect on cell proliferation. The reduction of cyclin D1 in melatonin-treated cells is also aggravated by HSP27 depletion. Moreover, melatonin stimulation increases p38 phosphorylation. Pretreatment with p38 inhibitor SB203580 not only remarkably suppresses melatonin-induced HSP27 phosphorylation, but also augment the inhibitory effect of melatonin on cyclin D1 expression as well as cell proliferation. Taken together, our study indicates the protective pathway of p38/HSP27 against melatonin-induced inhibitory effect on gastric cancer cell proliferation, suggesting that combined with p38/HSP27 pathway inhibitor, the therapeutic efficacy of melatonin on gastric cancer may be improved.

Therapeutic efficacy of melatonin in reducing retinal damage in an experimental model of early type 2 diabetes in rats

Diabetic retinopathy (DR) is a leading cause of acquired blindness in adults, mostly affected by type 2 diabetes mellitus (T2DM). We have developed an experimental model of early T2DM in adult rats which mimics some features of human T2DM at its initial stages and provokes significant retinal alterations. The aim of this work was to analyze the effect of melatonin on retinal changes induced by the moderate metabolic derangement. For this purpose, adult male Wistar rats received a control diet or 30% sucrose in the drinking water. Three weeks after this treatment, animals were injected with vehicle or streptozotocin (STZ, 25mg/kg). One day or 3wk after vehicle or STZ injection, animals were subcutaneously implanted with a pellet of melatonin. Fasting and postprandial glycemia, and glucose, and insulin tolerance tests were analyzed. At 12wk of treatment, animals which received a sucrose-enriched diet and STZ showed significant differences in metabolic tests, as compared with control groups. Melatonin, which did not affect glucose metabolism in control or diabetic rats, prevented the decrease in the electroretinogram a-wave, b-wave, and oscillatory potential amplitude, and the increase in retinal lipid peroxidation, NOS activity, TNFα, Müller cells glial fibrillary acidic protein, and vascular endothelial growth factor levels. In addition, melatonin prevented the decrease in retinal catalase activity. These results indicate that melatonin protected the retina from the alterations observed in an experimental model of DR associated with type 2 diabetes.

Melatonin, Insomnia and the Use of Melatonergic Drugs

Due to inconsistency among reports on the therapeutic efficacy of melatonin, attention has been focused on the development of more potent melatonin analogues with prolonged effects. Melatonergic drugs, ramelteon and agomelatine have been effective in treating either sleep disorders or sleep disturbances associated with depressive disorders. MT 1 and MT 2 melatonergic receptor agonist, ramelteon, was found effective in increasing total sleep time and sleep efficiency, and in reducing sleep latency in patients with insomnia. No reduction in its efficacy was found even after 6-12 months of continuous use. The mechanism of sleep promoting action of ramelteon is entirely different from that of conventional hypnotics that are in use today. Ramelteon's use is not associated with any adverse effects even after six months to one year after its continuous usage. Another melatonergic drug, agomelatine, has also been found effective in improving sleep efficiency and quality, and this action of agomelatine is suggested to be one of the major mechanism by which agomelatine ameliorates depressive symptoms in patients with major depressive disorders and bipolar disorders.

Therapeutic potential of melatonin agonists

Melatonin, a hormone secreted by the pineal gland, has been successfully employed to improve sleep in both normal patients and insomniacs, and for the treatment of circadian rhythm sleep disorders. Melatonergic MT1 and MT2 receptors exist in high concentrations in the suprachiasmatic nucleus of the hypothalamus and have been shown to be instrumental for the sleep-promoting and circadian rhythm-regulating effects of melatonin. A lack of consistency among reports on the therapeutic efficacy of melatonin has been attributed to differences in melatonin’s bioavailability and the short half-life of the hormone. In view of the need for longer acting melatonergic agonists that improve sleep efficiency without causing drug abuse or dependency, ramelteon (Rozerem™, Takeda) was developed. Ramelteon, which acts via MT1/MT2 melatonergic agonism, has been found clinically effective for improving total sleep time and sleep efficiency in insomniacs. Agomelatine (Valdoxan™, Servier) is another MT1/MT2 melatonergic agonist that also displays antagonist activity at 5-HT2C serotonin receptors. Agomelatine has been found effective in treating depression and sleep disorders in patients with major depressive disorder. A slow-release preparation of melatonin (Circadin™, Neurim) has been shown to be effective in treating sleep disorders in the elderly population.