Effects of 12 Weeks of Daily Melatonin Administration on Inflammatory Markers and Adipose Tissue Mass of Rats under Hypoestrogenism.

Background and Objectives: The hormonal state of hypoestrogenism is associated with the accumulation of white adipose tissue, which can induce an increase in pro-inflammatory markers, leading to progressive health complications. Melatonin can act on adipose tissue mass, promoting its reduction and influencing inflammation, reducing IL-6 and releasing IL-10, pro- and anti-inflammatory markers, respectively. However, the role of melatonin regarding such parameters under the context of hypoestrogenism remains unknown. The aim of this study was to determine the effect of 12 weeks of hypoestrogenism and melatonin on white adipose tissue mass and circulating levels of IL-6, IL-10, TGF-ß-1, and leukotriene C4 (LTC4). Materials and Methods: The animals (Wistar rats with sixteen weeks of age at the beginning of the experiment) under hypoestrogenism were submitted to the surgical technique of bilateral ovariectomy. The animals received melatonin (10 mg·kg-1) or vehicles by orogastric gavage every day for 12 weeks and administration occurred systematically 1 h after the beginning of the dark period. White adipose tissue (perigonadal, peritoneal, and subcutaneous) was collected for mass recording, while blood was collected for the serum determination of IL-6, IL-10, TGF-ß-1, and LTC4. Results: Hypoestrogenism increased the perigonadal and subcutaneous mass and IL-6 levels. Melatonin kept hypoestrogenic animals in physiological conditions similar to the control group and increased thymus tissue mass. Conclusions: Hypoestrogenism appears to have a negative impact on white adipose tissue mass and IL-6 and although melatonin commonly exerts a significant effect in preventing these changes, this study did not have a sufficiently negative impact caused by hypoestrogenism for melatonin to promote certain benefits.

Exogenous melatonin prolongs raspberry postharvest life quality by increasing some antioxidant and enzyme activity and phytochemical contents.

There is a growing trend towards enhancing the post-harvest shelf life and maintaining the nutritional quality of horticultural products using eco-friendly methods. Raspberries are valued for their diverse array of phenolic compounds, which are key contributors to their health-promoting properties. However, raspberries are prone to a relatively short post-harvest lifespan. The present study aimed to investigate the effect of exogenous melatonin (MEL; 0, 0.001, 0.01, and 0.1 mM) on decay control and shelf-life extension. The results demonstrated that MEL treatment significantly reduced the fruit decay rate (P ≤ 0.01). Based on the findings, MEL treatment significantly increased titratable acidity (TA), total phenolics content (TPC), total flavonoid content (TFC), and total anthocyanin content (TAC). Furthermore, the MEL-treated samples showed increased levels of rutin and quercetin content, as well as antioxidant activity as measured by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reduction activity potential (FRAP). Additionally, the samples exhibited higher levels of phenylalanine ammonia-lyase (PAL) and catalase (CAT) enzymes compared to the control samples. Moreover, the levels of pH, total soluble solids (TSS), and IC50 were decreased in the MEL-treated samples (P ≤ 0.01). The highest amount of TA (0.619 g/100 ml juice), rutin (16.722 µg/ml juice) and quercetin (1.467 µg/ml juice), and PAL activity (225.696 nm/g FW/min) was observed at 0.001 mM treatment, while, the highest amount of TAC (227.235 mg Cy-g/100 ml juice) at a concentration of 0.01 mM and CAT (0.696 u/g FW) and TAL activities (9.553 nm/100 g FW) at a concentration of 0.1 mM were obtained. Considering the lack of significant differences in the effects of melatonin concentrations and the low dose of 0.001 mM, this concentration is recommended for further research. The hierarchical cluster analysis (HCA) and principal component analysis (PCA) divided the treatments into three groups based on their characteristics. Based on the Pearson correlation between TPC, TFC, TAC, and TAA, a positive correlation was observed with antioxidant (DPPH and FRAP) and enzyme (PAL and CAT) activities. The results of this study have identified melatonin as an eco-friendly compound that enhances the shelf life of raspberry fruits by improving phenolic compounds, as well as antioxidant and enzyme activities.

Effect of preharvest melatonin applications at dusk on quality and bioactive compounds content of early sweet cherries.

BACKGROUND: Early sweet cherries have a high economic impact on cherry growers but have poorer quality characteristics and shorter shelf-life than late cherries. Melatonin has been proposed as a biostimulant that regulates plant and fruit growth and increases fruit quality and shelf-life but, in general in fruit and vegetables, there is controversy about its effects. Therefore, this work aimed to evaluate the impact of exogenous preharvest melatonin applications at dusk on the quality and bioactive compounds of two early sweet cherry cultivars. RESULTS: The M3 and M5 (3 × 10-4 and 5 × 10-4 mol L-1 melatonin, respectively) treatments effectively enhanced the endogenous melatonin and hydroxycinnamic acid concentration, enhancing the functional properties of the fruit. Additionally, the M5 treatment enhanced skin colour and consumer acceptance of 'Samba' cherries, while the M3 treatment improved cherry size in 'Sandon Rose'. CONCLUSION: Preharvest melatonin applications at dusk could be included in the scheduled preharvest treatments for early cherry cultivars in order to improve the quality and to stimulate the functionality of the fruit. However, further studies are needed to adjust the concentration depending on the cultivar and the objective pursued. © 2023 Society of Chemical Industry.

Melatonin Potentiates Exercise-Induced Increases in Skeletal Muscle PGC-1α and Optimizes Glycogen Replenishment.

Compelling evidence has demonstrated the effect of melatonin on exhaustive exercise tolerance and its modulatory role in muscle energy substrates at the end of exercise. In line with this, PGC-1α and NRF-1 also seem to act on physical exercise tolerance and metabolic recovery after exercise. However, the literature still lacks reports on these proteins after exercise until exhaustion for animals treated with melatonin. Thus, the aim of the current study was to determine the effects of acute melatonin administration on muscle PGC-1α and NRF-1, and its modulatory role in glycogen and triglyceride contents in rats subjected to exhaustive swimming exercise at an intensity corresponding to the anaerobic lactacidemic threshold (iLAn). In a randomized controlled trial design, thirty-nine Wistar rats were allocated into four groups: control (CG = 10), rats treated with melatonin (MG = 9), rats submitted to exercise (EXG = 10), and rats treated with melatonin and submitted to exercise (MEXG = 10). Forty-eight hours after the graded exercise test, the animals received melatonin (10 mg/kg) or vehicles 30 min prior to time to exhaustion test in the iLAn (tlim). Three hours after tlim the animals were euthanized, followed by muscle collection for specific analyses: soleus muscles for immunofluorescence, gluteus maximus, red and white gastrocnemius for the assessment of glycogen and triglyceride contents, and liver for the measurement of glycogen content. Student t-test for independent samples, two-way ANOVA, and Newman keuls post hoc test were used. MEXG swam 120.3% more than animals treated with vehicle (EXG; p < 0.01). PGC-1α and NRF-1 were higher in MEXG with respect to the CG (p < 0.05); however, only PGC-1α was higher for MEXG when compared to EXG. Melatonin reduced the triglyceride content in gluteus maximus, red and white gastrocnemius (F = 6.66, F = 4.51, and F = 6.02, p < 0.05). The glycogen content in red gastrocnemius was higher in MEXG than in CG (p = 0.01), but not in EXG (p > 0.05). In conclusion, melatonin was found to enhance exercise tolerance, potentiate exercise-mediated increases in PGC-1α, decrease muscle triglyceride content and increase muscle glycogen 3 h after exhaustive exercise, rapidly providing a better cellular metabolic environment for future efforts.

Melatonin or L-arginine in semen extender mitigate reductions in quality of frozen-thawed sperm from heat-stressed rams.

Our objective was to determine effects of melatonin or L-arginine on quality of frozen-thawed sperm from heat-stressed (HS) rams. Ten Dorset rams were randomly allocated to either scrotal neck insulation for 3.5 d or whole-body heating (28 °C and 30-34% RH for 8 h/d for 4 consecutive days). Semen was collected before HS then once weekly for 1-5 wk, extended (Steridyl CSS One Step ®), and divided into 5 aliquots: control (no additive) or 0.5- or 1-mM of melatonin or L-arginine. For total and progressive motility (CASA), there were effects of group (P = 0.023 and P = 0.008, respectively); for morphological abnormalities (eosin-nigrosin), effects of group (P = 0.01) and a group*week interaction (P = 0.03); and for acrosome integrity (FITC-PSA), effects of group (P = 0.046) and week (P = 0.001). All 4 treatments improved motility (~5-10% points), whereas 1 mM of either compound optimized abnormalities and acrosomal integrity (~7% and 12% points, respectively). For superoxide dismutase and catalase, there were effects of week (P = 0.01 and P = 0.045, respectively), with 1 mM of either additive yielding best results. For DNA fragmentation index (DFI%), there was an effect of week (P = 0.01), and a group*week interaction (P = 0.05), with all 4 treatments reducing DFI%. For total ROS%, there was an effect of week (P = 0.044) and a group*week interaction (P = 0.037), with 1 mM melatonin or L-arginine being best. The hypothesis that melatonin or L-arginine improve quality of frozen-thawed sperm from HS rams was supported; 1 mM of either gave best results, except 0.5 mM minimized DFI%.

Melatonin effects on sleep quality and outcomes of COVID-19 patients: An open-label, randomized, controlled trial.

This trial aims to evaluate the effectiveness of adding melatonin to the treatment protocol of hospitalized coronavirus disease 2019 (COVID-19) patients. This was an open-label, randomized controlled clinical trial in hospitalized COVID-19 patients. Patients were randomized into a treatment arm receiving melatonin plus standard care or a control arm receiving standard care alone. The trial's primary endpoint was sleep quality examined by the Leeds Sleep Evaluation Questionnaire (LSEQ). The trial's secondary endpoints were symptoms alleviation by Day 7, intensive care unit admission, 10-day mortality, white blood cell count, lymphocyte count, C-reactive protein status, and peripheral capillary oxygen saturation. Ninety-six patients were recruited and allocated to either the melatonin arm (n = 48) or control arm (n = 48). Baseline characteristics were similar across treatment arms. There was no significant difference in symptoms on Day 7. The mean of the LSEQ scores was significantly higher in the melatonin group (p < 0.001). There was no significant difference in laboratory data, except for blood oxygen saturation, which has improved significantly in the melatonin group compared with the control group (95.81% vs. 93.65% respectively, p = 0.003). This clinical trial study showed that the combination of oral melatonin tablets and standard treatment could substantially improve sleep quality and blood oxygen saturation in hospitalized COVID-19 patients.

Role of epigenetic regulation in myocardial ischemia/reperfusion injury.

Nowadays acute myocardial infarction (AMI) is a serious cardiovascular disease threatening the human life and health worldwide. The most effective treatment is to quickly restore coronary blood flow through revascularization. However, timely revascularization may lead to reperfusion injury, thereby reducing the clinical benefits of revascularization. At present, no effective treatment is available for myocardial ischemia/reperfusion injury. Emerging evidence indicates that epigenetic regulation is closely related to the pathogenesis of myocardial ischemia/reperfusion injury, indicating that epigenetics may serve as a novel therapeutic target to ameliorate or prevent ischemia/reperfusion injury. This review aimed to briefly summarize the role of histone modification, DNA methylation, noncoding RNAs, and N6-methyladenosine (m6A) methylation in myocardial ischemia/reperfusion injury, with a view to providing new methods and ideas for the research and treatment of myocardial ischemia/reperfusion injury.

Exogenous melatonin improves cotton (Gossypium hirsutum L.) pollen fertility under drought by regulating carbohydrate metabolism in male tissues.

Although exogenous melatonin can enhance the drought tolerance of plants, reports on the role of melatonin in drought tolerance in male reproductive organs are limited. To explore this, a pot experiment was conducted with cotton cultivar Yuzaomian 9110 to study the effects of exogenous melatonin (100, 200, and 1000 µM) on male fertility and related carbohydrate metabolism in anther under drought. Results showed that drought inhibited the translocation of carbon assimilates to anthers, however, melatonin application (100 and 200 µM) significantly improved the translocation of carbon assimilates to drought-stressed anthers. Drought reduced the deposition of starch, the hydrolysis of sucrose into hexoses, the generation of adenosine triphosphate (ATP) in anthers, restricting pollen viability and germination. Nevertheless, the appropriate melatonin concentrations (100 and 200 µM) increased the starch accumulation by enhancing ADP-glucose pyrophosphorylase and soluble starch synthases activities and accelerated the hydrolysis of sucrose by increasing sucrose synthase, acid and alkaline invertases activities in drought-stressed anthers. Appropriate melatonin concentrations (100 and 200 µM) also could help to generate more ATP for reproductive activities of drought-stressed anthers, finally increasing the pollen viability and germination of drought-stressed plants. These findings suggest that drought inhibited male fertility of cotton, but a precise melatonin application could regulate the carbohydrate balance of drought-stressed anthers to improve male fertility. This is the first report demonstrating the important role of exogenous melatonin in improving male fertility under drought conditions by regulating the carbohydrate metabolism in the male part of cotton.

Melatonin reduces inflammatory response in human intestinal epithelial cells stimulated by interleukin-1ß.

Melatonin is the main secretory product of the pineal gland, and it is involved in the regulation of periodic events. A melatonin production independent of the photoperiod is typical of the gut. However, the local physiological role of melatonin at the intestinal tract is poorly characterized. In this study, we evaluated the anti-inflammatory activities of melatonin in an in vitro model of inflamed intestinal epithelium. To this purpose, we assessed different parameters usually associated with intestinal inflammation using IL-1ß-stimulated Caco-2 cells. Differentiated monolayers of Caco-2 cells were preincubated with melatonin (1 nmol/L-50 µmol/L) and then exposed to IL-1ß. After each treatment, different inflammatory mediators, DNA-breakage, and global DNA methylation status were assayed. To evaluate the involvement of melatonin membrane receptors, we also exposed differentiated monolayers to melatonin in the presence of luzindole, a MT1 and MT2 antagonist. Our results showed that melatonin, at concentrations similar to those obtained in the lumen gut after ingestion of dietary supplements for the treatment of sleep disorders, was able to attenuate the inflammatory response induced by IL-1ß. Anti-inflammatory effects were expressed as both a decrease of the levels of inflammatory mediators, including IL-6, IL-8, COX-2, and NO, and a reduced increase in paracellular permeability. Moreover, the protection was associated with a reduced NF-κB activation and a prevention of DNA demethylation. Conversely, luzindole did not reverse the melatonin inhibition of stimulated-IL-6 release. In conclusion, our findings suggest that melatonin, through a local action, can modulate inflammatory processes at the intestinal level, offering new opportunities for a multimodal management of IBD.

Proteomic analysis of melatonin-mediated osmotic tolerance by improving energy metabolism and autophagy in wheat (Triticum aestivum L.).

MAIN CONCLUSION: Melatonin-mediated osmotic tolerance was attributed to increased antioxidant capacity, energy metabolism, osmoregulation and autophagy in wheat (Triticum aestivum L.). Melatonin is known to play multiple roles in plant abiotic stress tolerance. However, its role in wheat has been rarely investigated. In this study, 25% polyethylene glycol 6000 (PEG 6000) was used to simulate osmotic stress, and wheat seeds and seedlings were treated with different concentrations of melatonin under PEG stress. Isobaric tag for relative and absolute quantification (iTRAQ)-based proteomic techniques were used to identify the differentially accumulated proteins from melatonin-treated and non-treated seedlings. Seeding priming with melatonin significantly increased the germination rate, coleoptile length, and primary root number of wheat under PEG stress, as well as the fresh weight, dry weight, and water content of wheat seedlings. Under PEG stress, melatonin significantly improved reactive oxygen species homeostasis, as revealed by lower H2O2 and O 2· content; and the expression of antioxidant enzymes at the transcription and translation levels was increased. Melatonin maintained seedling growth by improving photosynthetic rates and instantaneous and intrinsic water use efficiencies, as well as carbon fixation and starch synthesis at the protein level. Melatonin treatment significantly affected the expression of glycolytic proteins, including fructose-1,6-bisphosphate aldolase, hexokinase, glyceraldehyde-3-phosphate dehydrogenase, and enolase, and remarkably increased the expression of the nicotinamide adenine dinucleotide transporter and nicotinamide adenine dinucleotide binding protein, thereby indirectly modulating electron transport in the respiratory chain. This indicated that melatonin improved energy production in PEG-stressed seedlings. Further, melatonin played a regulatory role in autophagy, protease expression, and ubiquitin-mediated protein degradation by significantly upregulating rab-related protein, fused signal recognition particle receptor, aspartyl protease, serine protease, ubiquitin-fold modifier 1, and ubiquitin at the mRNA or protein level. These findings suggested that melatonin might activate a metabolic cascade related to autophagy under PEG stress in wheat seedlings.

Acute melatonin administration enhances aerobic tolerance: an analysis of biochemical and hematological parameters

Aims: This study is aimed at testing the acute melatonin administration (oral; 6 mg) on aerobic tolerance at cycloergometer and analyzing the consequences on biochemical and hematological parameters. Methods: The maximal aerobic capacity intensity (iMAC) at cycloergometer of eleven male healthy men (24.18±3.92 years-old; 87.07±12.48 kg; 1.82±0.05 m; 26.18±3.63 kg/m2; and 16.28±5.77 % of fat) was individually determined and used to perform a time to exhaustion (tlim) trial of 30 minutes after melatonin or placebo administration. We observed 48-72h interval between tests, performed in a double-blind experiment design. In order to determine hematological and biochemical parameters we collected venous blood samples before and after tlim. Statistical significance was set at 5%. Results The intensity and the lactatemia corresponding to the maximal aerobic capacity were 120.88±18.78 W and 3.32±1.03 mmol.L-1, respectively. The tlim with placebo (33.94±15.26 min, confidence interval = 24.92 - 42.95) was significantly lower than the tlim with melatonin (41.94±17.22 min; CI = 31.76 - 52.12; p = 0.03; 19.06%; effect size = 0.49). All of the 21 analyzed blood physiological variables resulted in no significant variation after tlim when placebo was compared to melatonin, except for total sera cholesterol (lower after exercise with melatonin). Conclusion: Acute melatonin administration enhanced aerobic tolerance at iMAC in 19% at cycloergometer; however, the biochemical and hematological variables assessed were not significantly modulated.(AU)

Melatonin for Spinal Cord Injury in Animal Models: A Systematic Review and Network Meta-Analysis.

Spinal cord injury (SCI) leads to loss of function below the lesion and affects individuals worldwide. An increasing number of experimental studies support the effectiveness of melatonin (MT) for SCI. Our objectives were to investigate neurological recovery and anti-oxidant effects of MT in animal models of SCI, and to explore the appropriate dose. Published MT studies in SCI animal models described in six databases were searched. Two practiced investigators selected the studies, extracted the data, and independently evaluated the quality of the included studies. A meta-analysis evaluated the effect of MT in SCI and a network meta-analysis was performed to explore the appropriate MT dose for SCI models. Thirteen studies were analyzed, of which three were high quality. The results of the meta-analysis manifested that the behavioral evaluation (Basso, Beattie, and Bresnahan scales, n = 90, p = 0.003; motor function scores, n = 92, p = 0.004; Tarlov's criteria, n = 150, p = 0.002; inclined plane test, n = 150, p = 0.001) and biochemical outcomes (malondialdehyde, n = 121, p = 0.0010; glutathione levels, n = 64, p < 0.0001; and myeloperoxidase activity, n = 32, p < 0.00001) were improved, compared with the control group, after MT administration. A dose of 12.5 mg/kg was most effective in SCI rat models. Studies indicated that MT administration significantly improved neurological recuperation and anti-oxidant effects in rat models of SCI. The appropriate dose of MT was 12.5 mg/kg for SCI rat models. The majority of included studies were low quality; however, optimal MT treatment in SCI still requires high quality studies.

ALLEVIATION OF SALINITY STRESS ON Vicia faba L. PLANTS VIA SEED PRIMING WITH MELATONIN / Disminución del estrés salino en plantas de Vicia faba L. a través de la activación de las semillas con melatonina

Melatonin is an environmentally friendly-molecule with a potent free radical scavenger and antioxidant capacity. Two pot experiments were conducted during two successive winter seasons (2011/2012 and 2012/2013) at the wire-house of the National Research Centre, Dokki, Cairo, Egypt to study the potentiality of melatonin (100 mM and 500 mM) in alleviating the harmful effect of diluted seawater at a relatively low and high concentrations (3.85 dS/m and 7.69 dS/m, respectively) on the performance of faba bean plants. The results revealed that irrigation of faba bean plants with diluted seawater reduced growth parameters (plant height, leaves number/plant, fresh and dry weights of plant), relative water content (RWC), photosynthetic pigments (chlorophylls a, b and carotenoids), indole acetic acid, total carbohydrate, K+,Ca+2, as well as the ratios of K+/Na+ and Ca+2/Na+. Thiswasaccompanied by significant increases in phenolic content, compatible solutes (total soluble carbohydrate, free amino acids, proline), Na+ and Cl- relative to the control plants (untreated plants). On the other hand, melatonin treatments improved growth parameters, RWC, photosynthetic pigments, total carbohydrate, total phenolic content, indole acetic acid, K+,Ca+2 as well as K+/Na+ and Ca+2/Na+ ratios, either in the plants irrigated with tap water or with diluted seawater, as compared with corresponding controls. Meanwhile, melatonin treatments reduced the levels of compatible solutes, as well as Na+ and Cl- contents, relative to those of corresponding controls. Salinity stress and/ or melatonin treatments induced the production of new protein bands that did not occur in the control plants. Melatonin at 500 mM had a more pronounced effect in alleviating the adverse effects of the two salinity levels under study on the performance of faba bean plants than 100 mM melatonin.

La melatonina es una molécula ambientalmente amigable con una potente capacidad antioxidante y de trampa de radicales libres. Dos experimentos en materas fueron realizados en dos inviernos consecutivos (2011/2012 y 2012/2013) en instalaciones del Centro Nacional de Investigaciones, Dokki, Cairo, Egipto, para estudiar el potencial de la melatonina (100 mM and 500 mM) para disminuir los efectos nocivos del agua de mar diluida a concentraciones relativamente bajas y altas (3,85 dS/m and 7,69 dS/m, respectivamente). Los resultados mostraron que la irrigación de plantas de haba con agua de mar diluida reduce los parámetros de crecimiento (altura de la planta, número de hojas/planta, peso fresco y seco de la planta), el contenido relativo de agua (RWC), los pigmentos fotosintéticos (clorofilas a, b y carotenoides), el ácido indo lacético, los carbohidratos totales, K+, Ca+2, al igual que las relaciones K+/Na+ y Ca2+/Na+. Esto fue acompañado por un incremento significativo en el contenido de fenoles, solutos compatibles (carbohidratos solubles totales, aminoácidos libres, prolina), Na+ y Cl- en comparación con las plantas control (plantas no tratadas). De otro lado, los tratamientos con melatonina mejoraron los parámetros de crecimiento, RWC, los pigmentos fotosintéticos, carbohidratos totales, contenido fenólico total, ácido indo acético, K+,Ca+2 al igual que las relaciones K+/Na+ y Ca+2/Na+ , tanto en las plantas irrigadas con agua dulce de la llave como en las irrigadas con agua de mar diluida en comparación con los controles correspondientes. De otro lado, los tratamientos con melatonina redujeron los niveles de solutos compatibles, al igual que los contenidos de Na+ y Cl-, en comparación con los controles. El estrés por salinidad y/o los tratamientos con melatonina indujeron la producción de nuevas bandas de proteínas que no estuvieron presentes en las plantas control. El tratamiento de melatonina 500 mM tuvo un efecto más pronunciado que el tratamiento de 100 mM en disminuir los efectos adversos de los dos niveles de salinidad estudiados sobre el comportamiento de las plantas de haba.

Melatonin content of pepper and tomato fruits: effects of cultivar and solar radiation.

We evaluated the effect of cultivar and solar radiation on the melatonin content of Capsicum annuum (pepper) and Solanum lycopersicum (tomato) fruits. The melatonin content of red pepper fruits ranged from 31 to 93ngg(-1) (dry weight). The melatonin content of tomato ranged from 7.5 to 250ngg(-1) (dry weight). We also studied the effect of ripeness on melatonin content and identified one group of pepper cultivars in which the melatonin content increased as the fruit ripened and another in which it decreased as the fruit ripened. Under shade conditions, the melatonin content in most of tomato cultivars tended to increase (up to 135%), whereas that of most pepper cultivars decreased (to 64%). Overall, the results also demonstrated that the melatonin content of the fruits was not related to carbon fluxes from leaves.