KARS Mutations Impair Brain Myelination by Inducing Oligodendrocyte Deficiency: One Potential Mechanism and Improvement by Melatonin.

It is very crucial to investigate key molecules that are involved in myelination to gain an understanding of brain development and injury. We have reported for the first time that pathogenic variants p.R477H and p.P505S in KARS, which encodes lysyl-tRNA synthetase (LysRS), cause leukoencephalopathy with progressive cognitive impairment in humans. The role and action mechanisms of KARS in brain myelination during development are unknown. Here, we first generated Kars knock-in mouse models through the CRISPR-Cas9 system. Kars knock-in mice displayed significant cognitive deficits. These mice also showed significantly reduced myelin density and content, as well as significantly decreased myelin thickness during development. In addition, Kars mutations significantly induced oligodendrocyte differentiation arrest and reduction in the brain white matter of mice. Mechanically, oligodendrocytes' significantly imbalanced expression of differentiation regulators and increased capase-3-mediated apoptosis were observed in the brain white matter of Kars knock-in mice. Furthermore, Kars mutations significantly reduced the aminoacylation and steady-state level of mitochondrial tRNALys and decreased the protein expression of subunits of oxidative phosphorylation complexes in the brain white matter. Kars knock-in mice showed decreased activity of complex IV and significantly reduced ATP production and increased reactive oxygen species in the brain white matter. Significantly increased percentages of abnormal mitochondria and mitochondrion area were observed in the oligodendrocytes of Kars knock-in mouse brain. Finally, melatonin (a mitochondrion protectant) significantly attenuated mitochondrion and oligodendrocyte deficiency in the brain white matter of KarsR504H/P532S mice. The mice treated with melatonin also showed significantly restored myelination and cognitive function. Our study first establishes Kars knock-in mammal models of leukoencephalopathy and cognitive impairment and indicates important roles of KARS in the regulation of mitochondria, oligodendrocyte differentiation and survival, and myelination during brain development and application prospects of melatonin in KARS (or even aaRS)-related diseases.

Effect of melatonin supplementation on body composition and blood pressure in adults: A systematic review and Dose-Response meta-analysis of randomized controlled trial.

Background: Several randomized controlled trials (RCTs) have explored the impact of melatonin on body composition and blood pressure (BP). However, the findings from these studies remain a topic of debate. This systematic review and meta-analysis of RCTs sought to evaluate the effects of melatonin consumption on body composition (body weight (BW), body mass index (BMI), waist circumference (WC), hip circumference (HC)) and asleep/daytime BP (systolic blood pressure (SBP) and diastolic blood pressure (DBP)) in adults. Methods: In order to identify eligible RCTs, a systematic literature search was carried out up to June 2024 in PubMed, Embase, Scopus, and Web of Science without any language restrictions. The I2 statistic was used to perform heterogeneity tests on the selected studies. After evaluating random effects models based on heterogeneity tests, the weighted mean differences (WMD) with a 95 % confidence interval (CI) were calculated using pooled data. Results: Overall, 28 studies (n = 1,543 participants) met our inclusion criteria. A pooled analysis of studies demonstrated that melatonin consumption led to a significant reduction in HC (WMD: 1.21 cm; 95 % CI: 1.94 to -0.49; P = 0.001), and daytime DBP (WMD: 1.40 mmHg; 95 % CI: 2.46 to -0.34; P = 0.009) in comparison with the control group. However, no substantial effects were observed on BW, BMI, WC, and SBP compared to the control group. Conclusion: The current meta-analysis of RCTs shows that treatment with melatonin reduces HC and daytime DBP levels in adults. However, further well-designed RCTs with large sample sizes and long durations are necessary to determine the effect of this supplement on body composition and BP.

Attenuation of brown adipocyte whitening in high-fat diet-induced obese rats: Effects of melatonin and ß-hydroxybutyrate on Cidea, Fsp27 and MT1 expression.

AIM: To investigate the effects of ß-hydroxybutyrate (BHB) and melatonin on brown adipose tissue (BAT) plasticity in rats fed a high-fat diet (HFD). METHODS: We employed a 7-week experimental design for a study on 30 male Sprague-Dawley rats divided into five groups: (1) a control-diet fed group; (2) a high-fat diet (HFD)-fed group; (3) a group that received an HFD and a BHB solution in their drinking water; (4) a group that received an HFD with 10 mg/kg/day melatonin in their drinking water; and (5) a group that received an HFD and were also treated with the combination of BHB and melatonin. Following the treatment period, biochemical indices, gene expression levels of key thermogenic markers (including uncoupling protein 1 [UCP1], PR domain containing 16 [PRDM16], Cidea, fat-specific protein 27 [Fsp27], and metallothionein 1 [MT1]), and stereological assessments of BAT were evaluated. RESULTS: Treatment with BHB and melatonin significantly boosted blood ketone levels, improved lipid profiles, and reduced weight gain from an HFD. It also downregulated genes linked to WAT, namely, Cidea and Fsp27, and upregulated key BAT markers, including UCP1, PRDM16 and peroxisome proliferator-activated receptor-gamma coactivator-1-alpha. Additionally, the co-treatment increased MT1 receptor expression and enhanced the structural density of BAT. CONCLUSION: The combined oral administration of BHB and melatonin successfully prevented the whitening of BAT in obese rats fed an HFD, indicating its potential as a therapeutic strategy for obesity-related BAT dysfunction. The synergistic effects of this treatment underscore the potential of a combined approach to address BAT dysfunction in obesity.

12-week melatonin supplementation improved dynamic postural stability and walking performance in persons living with multiple sclerosis: A randomized controlled trial.

BACKGROUND: Persons with multiple sclerosis (PwMS) suffer from sleep disturbances, fatigue and pain, which can be due, at least in part, to decreased levels of endogenous melatonin. These disorders could exacerbate postural instability, gait disorders and fall risk. Acute effects of exogenous melatonin on MS-related physical disorders have been studied but its long-term effects on these parameters have not been explored yet in PwMS. This study aimed to determine the impact of chronic melatonin intake on dynamic postural stability, walking performance and fall risk in PwMS. METHODS: This randomized placebo-controlled study included 27 PwMS who were assigned to either melatonin group (MG, n=15) or placebo group (PG, n=12) (3mg/night for 12 weeks). Dynamic postural balance (force platform), walking performance (locometer) and fall risk (Four Square Step Test) were evaluated pre- (T0) and post-intervention (T1). Sleep quality (Pittsburgh Sleep Quality Index (PSQI)), fatigue perception (Fatigue Severity Scale (FSS)), neuropathic pain (Neuropathic Pain Questionnaire 4 (DN4)) and quality of life (the International Multiple Sclerosis (MS)) quality of life questionnaire) were also assessed at T0 and T1. RESULTS: The center of pressure mean velocity decreased in MG compared with PG (22.98%, p=0.028) in the frontal plane. In MG, stride length and walking speed increased (18.09%, p=0.036; 9.65%, p=0.025, respectively) comparatively with PG. The PSQI (55.89%, p<0.001), FSS (32.38%, p=0.003) and DN4 (32.41%, p=0.035) scores decreased in MG compared with PG. CONCLUSION: Chronic melatonin ingestion can be recommended for managing MS-related gait disorders and dynamic postural imbalance. It had also anti-fatigue and analgesic effects as well as benefits on sleep quality in PwMS. CLINICAL REGISTRATION: This study was prospectively recorded in the Pan African Clinical Trial Registry database (PACTR202007465309582) (https://pactr.samrc.ac.za/.).

Melatonin-Nitric Oxide Crosstalk in Plants and the Prospects of NOMela as a Nitric Oxide Donor.

Melatonin regulates vital physiological processes in animals, such as the circadian cycle, sleep, locomotion, body temperature, food intake, and sexual and immune responses. In plants, melatonin modulates seed germination, longevity, circadian cycle, photoperiodicity, flowering, leaf senescence, postharvest fruit storage, and resistance against biotic and abiotic stresses. In plants, the effect of melatonin is mediated by various regulatory elements of the redox network, including RNS and ROS. Similarly, the radical gas NO mediates various physiological processes, like seed germination, flowering, leaf senescence, and stress responses. The biosynthesis of both melatonin and NO takes place in mitochondria and chloroplasts. Hence, both melatonin and nitric oxide are key signaling molecules governing their biological pathways independently. However, there are instances when these pathways cross each other and the two molecules interact with each other, resulting in the formation of N-nitrosomelatonin or NOMela, which is a nitrosated form of melatonin, discovered recently and with promising roles in plant development. The interaction between NO and melatonin is highly complex, and, although a handful of studies reporting these interactions have been published, the exact molecular mechanisms governing them and the prospects of NOMela as a NO donor have just started to be unraveled. Here, we review NO and melatonin production as well as RNS-melatonin interaction under normal and stressful conditions. Furthermore, for the first time, we provide highly sensitive, ozone-chemiluminescence-based comparative measurements of the nitric oxide content, as well as NO-release kinetics between NOMela and the commonly used NO donors CySNO and GSNO.

Impact of oral melatonin supplementation on urine and serum melatonin concentrations and quality-of-life measures in persons with relapsing multiple sclerosis.

INTRODUCTION: Melatonin is an antioxidant and anti-inflammatory agent that modulates the immune system by scavenging free radicals, reducing the upregulation of pro-inflammatory cytokines, and reducing transendothelial cell migration. Therefore, melatonin may play a role in regulating multiple sclerosis (MS) disease activity. However, little is known about how melatonin supplementation effects individuals with MS. OBJECTIVE: Determine if there was a dose-dependent elevation in urine and serum melatonin concentrations. Determine if melatonin supplementation had an impact on patient reported outcomes. METHODS: This was a randomized, dose-blinded exploratory study. Adults (age 18-65) with relapsing forms of multiple sclerosis (RMS) treated with a stable dose of oral disease modifying therapy for at least 6 months were randomized into melatonin 3 mg or 5 mg daily. Urinary and serum melatonin levels and modified fatigue impact scale (MFIS), multiple sclerosis impact scale (MSIS-29), and Pittsburgh sleep quality index (PSQI), patient determined disease steps (PDDS) and performance scales (PS) were measured at baseline, 3, 6, and 12 months. Urinary and serum melatonin analyses was performed to estimate mean concentrations and their differences between treatment arms over time by a repeated measures linear mixed model. The model included treatment, assessment time, and treatment × time interaction. RESULTS: Thirty patients, randomized 1:1, were analyzed in an intent to treat population. Twenty-three completed the study. The repeated measures linear mixed model analysis of all timepoints revealed higher melatonin concentrations in patients on 5 mg compared to 3 mg melatonin for both urinary 6-SMT (p = 0.03) and serum melatonin (p = 0.04). MFIS, MSIS-29, PSQI, and PDSS-PS scores did not significantly change from baseline to month 12. No significant differences in these measures were seen between the two doses. Five patients stopped melatonin (three on 5 mg and two on 3 mg) due to adverse events, including one patient who developed focal spongiotic dermatitis. One patient experienced three consecutive serious adverse events that were unrelated to melatonin supplementation. CONCLUSIONS: The 5 mg melatonin supplementation group had higher concentrations of urinary 6-SMT and serum melatonin compared to the 3 mg group over 12 months of treatment. There was a correlation between 6-SMT and serum melatonin concentrations. This suggests that measuring serum melatonin is a reliable alternative to measuring urinary 6-SMT. However, no differences in clinical benefit between the two dosage groups were demonstrated in the patient reported outcomes. TRIAL REGISTRATION NUMBER: NCT03498131.

Melatonin derivative 6a protects Caenorhabditis elegans from formaldehyde neurotoxicity via ADH5.

Formaldehyde (FA) is a carcinogen that is not only widespread in the environment, but is also produced endogenously by metabolic processes. In organisms, FA is converted to formic acid in a glutathione (GSH)-dependent manner by alcohol dehydrogenase 5 (ADH5). The abnormal accumulation of FA in the body can cause a variety of diseases, especially cognitive impairment leading to Alzheimer's disease (AD). In this study, melatonin derivative 6a (MD6a) markedly improved the survival and chemotactic performance of wild-type Caenorhabditis elegans exposed to high concentrations of FA. MD6a lowered FA levels in the nematodes by enhancing the release of covalently-bound GSH from S-hydroxymethyl-GSH in an adh-5-dependent manner. In addition, MD6a protected against mitochondrial dysfunction and cognitive impairment in beta-amyloid protein (Aß) transgenic nematodes by lowering endogenous FA levels and reducing Aß aggregation in an adh-5-dependent manner. Our findings suggest that MD6a detoxifies FA via ADH5 and protects against Aß toxicity by reducing endogenous FA levels in the C. elegans AD models. Thus, ADH5 might be a potential therapeutic target for FA toxicity and AD.

Utility of melatonin on brain injury, synaptic transmission, and energy metabolism in rats with sepsis.

Melatonin is a powerful endogenous antioxidant hormone. Its healing effects on energy balance and neuronal damage associated with oxidative metabolism disorders have been reported in pathologic conditions. We aimed to determinate the utility of melatonin on neuronal damage, synaptic transmission, and energy balance in the brain tissue of rats with sepsis induced with LPS. Rats was divided into four groups such as control, LPS (20 mg/kg i.p.), melatonin (10 mg/kg i.p. × 3), and LPS + Melatonin (LPS + Mel). After 6 h from the first injection, rats were decapitated, and also tissue and serum samples were taken. Lipid peroxidation and neuron-specific enolase (NSE) levels were determined from the serum in all group. High energy compounds, creatine, and creatine phosphate are measured by HPLC methods from the homogenized tissue. Counts of living neurons are marked with NeuN (neuronal nuclei), degenerated neurons are marked with S100-ß and synaptic vesicles transmission is analyzed with synaptophysin antibodies immunoreactivities. One-way ANOVA and post hoc Tukey tests were used to statistical analysis. In LPS group, AMP, ATP, creatine, and creatine phosphate levels were significantly decreased (p < 0.05), and also ADP levels were significantly increased compared with the other groups (p < 0.01). Living neurons counts were significantly decreased in LPS (p < 0.01), melatonin, and LPS + Melatonin (p < 0.05) groups compared with control. Degenerated neurons counts were increased in LPS group compared with control (p < 0.01) and also decreased in both of melatonin and LPS + Melatonin groups (p < 0.01). Synaptophysin immunoreactivity was decreased in LPS group compared with the other groups (p < 0.05). We observed that melatonin administration prevents neuronal damage, regulates energy metabolism, and protects synaptic vesicle proteins from sepsis-induced reduction.

Gamma-aminobutyric acid treatment promotes resistance against Sogatella furcifera in rice.

The Sogatella furcifera (Horváth) (Homoptera: Delphacidae) is a white-backed planthopper (WBPH) that causes "hopper burn" in rice, resulting in severe yield loss. Gamma-aminobutyric acid (GABA) is a well-known neurotransmitter that inhibits neurotransmission in insects by binding to specific receptors. In this study, we investigated the potential role of GABA in modulating rice resistance to WBPH and evaluated possible defense mechanisms. The experiment was conducted in green house in pots consist of four groups: control, GABA-treated, WBPH-infested, and WBPH-infested treated with GABA. Among the various tested concentration of GABA, 15 mM GABA was applied as a single treatment in water. The treatment was administered one week before WBPH infestation. The results revealed that 15 mM GABA treatment strongly increased WBPH resistance. A plate-based assay indicated that direct application of 15 mM GABA increased the mortality rate of WBPH and increased the damage recovery rate in rice plants. We found that GABA treatment increased the activation of antioxidant enzymes and reduced the reactive oxygen species content and malondialdehyde contents, and reduced the damage rate caused by WBPH. Interestingly, GABA-supplemented plants infested with WBPH exhibited increased phenylalanine ammonia-lyase and pathogenesis-related (PR) genes expression levels. GABA induced the accumulation of abscisic acid (ABA) and salicylic acid (SA) and enhanced the stomata closure and reduced leaf vessels to reduce water conductance during WBPH stress. Furthermore, we found that GABA application to the plant induced the expression of Jasmonic acid (JA) biosynthesis genes (LOX, AOS, AOC, and OPR) and melatonin biosynthesis-related genes (TDC, T5H, ASMT, and SNAT). Our study suggested that GABA increases resistance against WBPH infestation by regulating antioxidant defense system, TCA cycle regulation, phytohormonal signaling, and PR gene regulation.

Investigation of the therapeutic effect of melatonin on deltamethrin applied mouse primary hepatocyte culture.

OBJECTIVE: In recent years, it has been known that the melatonin hormone, secreted from the pineal gland, possesses significant antioxidant activity. This study explores the therapeutic effect of melatonin on the deleterious effects of deltamethrin, a pyrethroid pesticide extensively used worldwide, including in Türkiye, on mouse liver cells. METHODS: Hepatocytes from Balb/C mice were isolated using a two-stage perfusion method, resulting in over 85% live hepatocytes. The isolated cells were cultured with different doses of deltamethrin (1 and 10 µM) and melatonin (100 µM) for 24 and 48 hours. At the conclusion of the culture period, hepatocytes were extracted at the 24th and 48th hours, and Malondialdehyde (MDA), Total Antioxidant Capacity (TAC), Total Oxidation Status (TOS), and DNA damages (8-hydroxy-2'-deoxyguanosine (8-OHdG)) were examined. RESULTS: While an increase in MDA, TOS, and DNA damage was observed in the deltamethrin-administered groups of hepatocytes, a decrease in TAC level was noted. It was determined that the applied deltamethrin had no effect on cell viability throughout the application period. CONCLUSION: Furthermore, it was observed that melatonin, when administered concurrently with deltamethrin, reduced the toxic effect of deltamethrin. This study suggests that melatonin has a protective effect against deltamethrin-induced damage in mouse hepatocyte cells.

A Complex Interplay Between Melatonin and RORß: RORß is Unlikely a Putative Receptor for Melatonin as Revealed by Biophysical Assays.

A nuclear retinoic acid receptor (RAR)-related orphan receptor ß (RORß) is strictly expressed in the brain, particularly in the pineal gland where melatonin is primarily synthesized and concentrated. The controversial issues regarding the direct interaction of melatonin toward ROR receptors have prompted us to investigate the potential melatonin binding sites on different ROR isoforms. We adopted computational and biophysical approaches to investigate the potential of melatonin as the ligand for RORs, in particular RORß. Herein, possible melatonin binding sites were predicted by molecular docking on human RORs. The results showed that melatonin might be able to bind within the ligand-binding domain (LBD) of all RORs, despite their difference in sequence homology. The predicted melatonin binding scores were comparable to binding energies with respect to those of melatonin interaction to the well-characterized membrane receptors, MT1 and MT2. Although the computational analyses suggested the binding potential of melatonin to the LBD of RORß, biophysical validation failed to confirm the binding. Melatonin was unable to alter the stability of human RORß as shown by the unaltered melting temperatures upon melatonin administration in differential scanning fluorometry (DSF). A thermodynamic isothermal titration calorimetry (ITC) profile showed that melatonin did not interact with human RORß in solutions, even in the presence of SRC-1 co-activator peptide. Although the direct interaction between the LBD of RORß could not be established, RORα and RORß gene expressions were increased upon 24 h treatment with µM-range melatonin. Our data, thus, support the studies that the nuclear effects of melatonin may not be directly mediated via its interaction with the RORß. These findings warrant further investigation on how melatonin interacts with ROR signaling and urge the melatonin research community for a paradigm shift in the direct interaction of melatonin toward RORs. The quest to identify nuclear receptors for melatonin in neuronal cells remains valid for the community to achieve.

Maintaining quality of postharvest green pepper fruit using melatonin by regulating membrane lipid metabolism and enhancing antioxidant capacity.

Green pepper quality often deteriorates during storage because of membrane lipid damage and oxidative stress. This study investigated the effects of exogenous melatonin (MT) on green pepper storage quality, membrane lipids, and antioxidant metabolism. The results showed that MT increased the activities of superoxide dismutase, catalase, ascorbate peroxidase, peroxidase, monodehydroascorbate reductase, and dehydroascorbate reductase in green peppers compared to the control group. It upregulated expression of multiple enzymes; reduced accumulation of reactive oxygen species such as dehydroascorbic acid, H2O2, and O2.-; and maintained high ascorbic acid, glutathione, coenzyme II, and nicotinamide adenine dinucleotide while reducing oxidized glutathione levels. In addition, MT decreased lipoxygenase and phospholipase D activities, downregulated ReLOX and RePLD expression, and delayed the degradation of phosphatidylcholine, phosphatidylethanolamine, and oleic, linoleic, and linolenic acids in green peppers. These results suggest that MT helps to improve the chilling injury and quality of green peppers and extends shelf life.

Melatonin intervention to prevent nanomaterial exposure-induced damages: A systematic review and meta-analysis of in vitro and in vivo studies.

Given its antioxidant, anti-inflammatory, and antiapoptotic properties, melatonin (MEL), a health-caring food to improve sleep disorders, is hypothesized to protect against nanomaterial exposure-induced toxicity. However, the conclusion derived from different studies seemed inconsistent. A meta-analysis of all available preclinical studies was performed to examine the effects of MEL on nanomaterial-induced damages. Eighteen relevant studies were retrieved through searching five electronic databases up to December 2023. The meta-analysis showed that relative to control, MEL treatment significantly increased cell viability (standardized mean difference [SMD = 1.27]) and alleviated liver function (lowered AST [SMD = -3.89] and ALT [SMD = -5.89]), bone formation (enhanced BV/TV [SMD = 4.13] and lessened eroded bone surface [SMD = -5.40]), and brain nerve (inhibition of AChE activity [SMD = -3.60]) damages in animals. The protective mechanisms of MEL against damages caused by nanomaterial exposure were associated with its antiapoptotic (decreased Bax/Bcl-2 ratio [SMD = -4.50] and caspase-3 levels [dose <100 µM: SMD = -3.66]), antioxidant (decreased MDA [in vitro: SMD = -2.84; in vivo: SMD = -4.27]), and anti-inflammatory (downregulated TNF-α [in vitro: SMD = -5.41; in vivo: SMD = -3.21] and IL-6 [in vitro: SMD = -5.90; in vivo: SMD = -2.81]) capabilities. In conclusion, our study suggests that MEL should be supplemented to prevent damages in populations exposed to nanomaterials.

Antitumoral melatonin-loaded nanostructured lipid carriers.

Aim: Cancer constitutes the second leading cause of death worldwide, with conventional therapies limited by significant side effects. Melatonin (MEL), a natural compound with antitumoral properties, suffers from instability and low solubility. To overcome these issues, MEL was encapsulated into nanostructured lipid carriers (MEL-NLC) containing rosehip oil to enhance stability and boost its antitumoral activity. Methods: MEL-NLC were optimized by a design of experiments approach and characterized for their physicochemical properties. Stability and biopharmaceutical behavior were assessed, along with interaction studies and in vitro antitumoral efficacy against various cancer cell lines. Results: Optimized MEL-NLC exhibited desirable physicochemical characteristics, including small particle size and sustained MEL release, along with long-term stability. In vitro studies demonstrated that MEL-NLC selectively induced cytotoxicity in several cancer cell lines while sparing healthy cells. Conclusion: MEL-NLC represent a promising alternative for cancer, combining enhanced stability and targeted antitumoral activity, potentially overcoming the limitations of conventional treatments.

Despite current advances, cancer is the second cause of death worldwide, but conventional therapies have side effects and limited efficacy. Natural therapies are emerging as suitable alternatives and, among them, Melatonin is a well-known compound with antitumoral properties. However, it is degraded by light, decreasing its therapeutical activity. In order to effectively deliver Melatonin into cancer cells, it has been encapsulated into biodegradable nanoparticles containing rosehip oil, which may boost the antitumoral properties. These nanoparticles have been optimized, showing a small size and a high Melatonin encapsulation, sustained drug release and good stability. Furthermore, in vitro studies demonstrated antitumoral activity against several cancer cell lines, also showing a high internalization inside them. Moreover, studies conducted using chicken embryonated eggs, showed that nanoparticles were non-toxic, thus confirming its promising therapeutical applications.

Adrenergic Agonists Activate Transcriptional Activity in Immortalized Neuronal Cells From the Mouse Suprachiasmatic Nucleus.

The suprachiasmatic nucleus of the hypothalamus (SCN) houses the central circadian oscillator of mammals. The main neurotransmitters produced in the SCN are γ-amino-butyric acid, arginine-vasopressin (AVP), vasoactive intestinal peptide (VIP), pituitary-derived adenylate cyclase-activating peptide (PACAP), prokineticin 2, neuromedin S, and gastrin-releasing peptide (GRP). Apart from these, catecholamines and their receptors were detected in the SCN as well. In this study, we confirmed the presence of ß-adrenergic receptors in SCN and a mouse SCN-derived immortalized cell line by immunohistochemical, immuno-cytochemical, and pharmacological techniques. We then characterized the effects of ß-adrenergic agonists and antagonists on cAMP-regulated element (CRE) signaling. Moreover, we investigated the interaction of ß-adrenergic signaling with substances influencing parallel signaling pathways. Our findings have potential implications on the role of stress (elevated adrenaline) on the biological clock and may explain some of the side effects of ß-blockers applied as anti-hypertensive drugs.

Arsenic-induced transition of thymic inflammation-to-fibrosis involves Stat3-Twist1 interaction: Melatonin to the rescue.

Groundwater arsenic is a notorious toxicant and exposure to environmentally relevant concentrations persists as a healthcare burden across the world. Arsenic has been reported to jeopardize the normal functioning of the immune system, but there are still gaps in the understanding of thymic T cell biology. Immunotoxic influence of arsenic in thymic integrity demands a potent restorative molecule. The objectives of this study were to examine key signaling cross-talks associated with arsenic-induced immune alterations in the thymus and propose melatonin as a potential candidate against immunological complications arising from arsenic exposure. Swiss albino mice were exposed to sodium arsenite (0.05 mg/L; in drinking water) and melatonin (IP:10 mg/kg BW) for 28 days. Melatonin successfully protected thymus from arsenic-mediated tissue degeneration and maintained immune homeostasis including T cell maturation and proliferation by mitigating oxidative stress through Nrf2 upregulation. Additionally, melatonin exerted ameliorative effect against arsenic-induced apoptosis and inflammation by inhibiting p53-mediated mitochondrial cell death pathway and NF-κB-p65/STAT3-mediated proinflammatory pathway, respectively. For the first time, we showed that arsenic-induced profibrotic changes were inhibited by melatonin through targeting of inflammation-associated EMT. Our findings clearly demonstrate that melatonin can be a viable and promising candidate in combating arsenic-induced immune toxicity with no collateral damage, making it an important research target.

Exploring effects of melatonin supplementation on insulin resistance: An updated systematic review of animal and human studies.

BACKGROUND: Insulin resistance (IR), defined as an impaired response to insulin stimulation of target tissues, is a substantial determinant of many metabolic disorders. This study aimed to update the findings of the previous systematic review evidence regarding the effect of melatonin on factors related to IR, including hyperinsulinemia, hyperglycemia, homeostasis model assessment of insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index (QUICKI). METHODS: We systematically reviewed the evidence on the impact of melatonin supplementation on IR indices, fasting insulin, and fasting plasma glucose. PubMed, ScienceDirect, SCOPUS, and Google Scholar databases were searched until March 2024. RESULTS: We identified 6114 potentially relevant articles during the search. Eighteen animal studies and 15 randomized clinical trials met the inclusion criteria. The results indicated that melatonin supplementation reduced fasting plasma glucose (FPG, 14 out of 29 studies), fasting insulin (22 out of 28 studies), HOMA-IR (28 out of 33 studies), and increased QUICKI (7 out of 7 studies). According to RCT studies, melatonin treatment at a dosage of 10 mg reduced HOMA-IR levels in individuals with various health conditions. CONCLUSION: According to most evidence, melatonin supplementation may decrease fasting insulin and HOMA-IR and increase QUICKI but may not affect FPG.

Melatonin modulates TLR4/MyD88/NF-κB signaling pathway to ameliorate cognitive impairment in sleep-deprived rats.

Sleep deprivation (SD) is commonplace in today's fast-paced society. SD is a severe public health problem globally since it may cause cognitive decline and even neurodegenerative disorders like Alzheimer's disease. Melatonin (MT) is a natural chemical secreted by the pineal gland with neuroprotective effects. The purpose of this study was to investigate the protective effect and mechanism of MT on chronic sleep deprivation-induced cognitive impairment. A 3-week modified multi-platform method was used to create the SD rat model. The Morris water maze test (MWM), Tissue staining (including Hematoxylin and Eosin (H & E) staining, Nissl staining, and immunofluorescence), Western blot, Enzyme-linked immunosorbent assay (ELISA), and Quantitative real-time polymerase chain reaction (qPCR) were used to investigate the protective effect and mechanism of MT in ameliorating cognitive impairment in SD rats. The results showed that MT (50 and 100 mg/kg) significantly improved cognitive function in rats, as evidenced by a shortening of escape latency and increased time of crossing the platform and time spent in the quadrant. Additionally, MT therapy alleviated hippocampus neurodegeneration and neuronal loss while lowering levels of pathogenic factors (LPS) and inflammatory indicators (IL-1ß, IL-6, TNF-α, iNOS, and COX2). Furthermore, MT treatment reversed the high expression of Aß42 and Iba1 as well as the low expression of ZO-1 and occludin, and inhibited the SD-induced TLR4/MyD88/NF-κB signaling pathway. In summary, MT ameliorated spatial recognition and learning memory dysfunction in SD rats by reducing neuroinflammation and increasing neuroprotection while inhibiting the TLR4/MyD88/NF-κB signaling pathway. Our study supports the use of MT as an alternate treatment for SD with cognitive impairment.

Melatonin Improves Oxidative Stress Injury in Retinopathy of Prematurity by Targeting miR-23a-3p/Nrf2.

PURPOSE: Melatonin has promising protective effects for retinopathy. However, its roles in retinopathy of prematurity (ROP) and the underlying mechanisms remain unknown. We aimed to explore its roles and mechanisms in a ROP model. METHODS: Hematoxylin and eosin staining were used to observe the morphology of the retina. Immunofluorescence was used to detect positive (Nrf2+ and VEGF+) cells. Immunohistochemistry was used to detect the level of nuclear expression of PCNA in retinal tissue. Transmission electron microscope (TEM) was used to observe the morphology and structure of pigment cells. qRT-PCR was used to assay the expression of miR-23a-3p, Nrf2, and HO-1. Western blotting was used to detect the expression of Nrf2, HO-1, ß-actin, and Lamin B1. RESULTS: Melatonin or miR-23a-3p antagomir treatment could ameliorate the Oxygen-induced pathological changes, increased the expression of Nrf2 and HO-1, SOD, and GSH-Px, and decreased the expression of VEGF, miR-23a-3p, MDA and the apoptosis in the ROP model. Further target prediction and luciferase reporter assays confirmed the targeted binding relationship between miR-23a-3p and Nrf2. CONCLUSION: Our study showed that melatonin could ameliorate H2O2-induced apoptosis and oxidative stress injury in RGC cells by mediating miR-23a-3p/Nrf2 signaling pathway, thereby improving retinal degeneration.

Exogenous Melatonin Enhances Cold Tolerance by Regulating the Expression of Photosynthetic Performance, Antioxidant System, and Related Genes in Cotton.

In China, cotton is a significant cash crop, and cold stress negatively impacts the crop's development, production, and quality formation. Recent studies have shown that melatonin (MT) can alleviate the damage to plants under cold stress and promote good growth and development. In this study, the morphological and physiological changes induced by exogenous melatonin pretreatment on 'Xinluzao 33' cotton seedlings under cold stress were examined to investigate its defensive effects. The results showed that 100 µM MT pretreatment improved the cold resistance of cotton most significantly. It also improved the wilting state of cotton under cold stress, greatly increased the photosynthetic rate (Pn), stomatal conductance (Gs), maximum photochemical efficiency (Fv/Fm), and photosynthetic performance index (PIabs) by 116.92%, 47.16%, 32.30%, and 50.22%, respectively, and mitigated the adverse effects of low-temperature. In addition, MT supplementation substantially reduced the accumulation of superoxide anion (O2•-) and hydrogen peroxide (H2O2) by 14.5% and 45.49%, respectively, in cold-stressed cotton leaves by modulating the antioxidant system, thereby mitigating oxidative damage. Furthermore, MT pretreatment increased the endogenous melatonin content (23.80%) and flavonoid content (21.44%) and considerably induced the expression of biosynthesis enzyme-related genes. The above results indicate that exogenous melatonin improves the low-temperature resistance of cotton seedlings by regulating photosynthetic performance, antioxidant enzyme activity, antioxidant content, endogenous melatonin and flavonoid content, and the expression levels of genes related to their synthesis.