Melatonin-treated Group Research Articles

Melatonin ameliorates inflammation and improves outcomes of ischemia/reperfusion injury in patients undergoing coronary artery bypass grafting surgery: a randomized placebo-controlled study.

To investigate the protective role of high dose melatonin concerning myocardial I/R injury and inflammation in patients undergoing on-pump coronary artery bypass grafting (CABG) surgery by evaluating IR/inflammatory biomarkers and clinical outcomes. This was a prospective; randomized; single-blinded placebo-controlled study conducted at cardio-thoracic surgery department of the Academy of the Cardiovascular and Thoracic Surgery, Ain Shams University. Eligible patients were randomly allocated to; melatonin-treated group (MTG) or placebo-treated group (PTG). The MTG (n = 17) received 60mg/day melatonin capsules daily starting 5 days before surgery in addition to the standard of care. PTG (n = 17) received placebo also 5 days before surgery plus standard of care. The levels of nuclear factor kappa beta (NF-κb) (primary outcome), tumor necrosis factor (TNF-α), cardiac troponins I, and IL-6 levels were all assessed for both groups at five time points: baseline before melatonin or placebo administration (T0), before cross-clamp application(T1), 5min after cross-clamp removal(T2), 6h after cross-clamp removal(T3) and 24h after cross-clamp removal(T4). Blood pressure was assessed at baseline, pre-operative and 24-hours post-operative. The Quality of recovery-40 score (QOR-40) was assessed for both groups on day 4 after surgery. TNF-α levels decreased in the MTG at T1(p = 0.034) versus PTG. At T2(p = 0.005), and T3(p = 0.04), TNF-α significantly increased in PTG versus MTG. Troponins significantly increased in PTG at T3 (p = 0.04) versus MTG. NF-κB levels declined at T1 (p = 0.013) and T2 (p = 0.0001) in MTG compared to PTG. IL-6 significantly increased in PTG versus MTG at T3 (p = 0.04). The QOR-40 score significantly decreased in MTG versus PTG. MTG had statistically significant decrease in DBP compared to the placebo group (p = 0.024). MTG had a statistically significant shorter intubation time than did the placebo group (p = 0.03). Melatonin 60mg was well-tolerated without any reported side effects. Our findings suggested that melatonin could ameliorate myocardial I/R injury after on-pump CABG and that this outcome was essentially correlated to its antiapoptotic and anti-inflammatory effects. Trial registration: ClinicalTrials.gov registration number NCT05552586, 9/2022.

Efficacy of melatonin for prolonged disorders of consciousness: a double-blind, randomized clinical trial

BackgroundSleep is essential for the recovery of patients with disorders of consciousness (DoC). However, few approaches targeting sleep were applied. Melatonin has been shown to enhance sleep efficiency with virtually no side effects. This study explored melatonin’s benefits for patients with prolonged DoC, as well as the underlying mechanisms involved.MethodsA cohort of 46 patients with prolonged DoC were randomly assigned to either the melatonin treatment group or the placebo group. Assessments were conducted using the Coma Recovery Scale-Revised (CRS-R), electroencephalography (EEG), and polysomnography (PSG) before and after the intervention, with follow-up CRS-R evaluations performed 6 months post-treatment.ResultsCompared to the placebo, melatonin demonstrated a significant improvement in CRS-R scores after a 2-week period in patients with unresponsive wakefulness syndrome (UWS) (Fgroup*time = 6.86, P = 0.032; Fgroup = 4.03, P = 0.045) and this improvement was particularly pronounced in visual scores (Fgroup*time = 7.03, P = 0.030; Fgroup = 4.90, P = 0.027). Moreover, patients with UWS who received melatonin exhibited a higher relative spectral density of the alpha band in the frontal lobe compared to those who received placebo (Ftime-mel = 4.55, P = 0.033) and benefited for their prognosis after 6 months (Pseudo R2 = 0.370, F = 12.03, P = 0.034).ConclusionsOverall, melatonin intervention seems to have a better response in UWS patients with preserved sleep cycles. These positive effects may not be solely attributed to improvements in the patients’ sleep quality.Trail registrationClinicalTrials.gov: NCT05285124.

Melatonin induces white-to-beige adipocyte transdifferentiation through melatonin receptor 1-mediated direct browning and indirect M2 polarization.

Previous studies have shown that melatonin induces adipocyte browning in vivo. However, the underlying mechanisms of melatonin action at the cellular level remain elusive. In this study, we investigated the mechanisms underlying melatonin-induced browning in 3T3-L1 adipocytes and RAW 264.7 macrophages. Melatonin caused the transdifferentiation of fully differentiated white adipocytes into beige adipocytes, which involves the activation of melatonin receptor 1, followed by increased phosphorylation of p38 MAPK and Akt. Both luzindole (LZ), a non-selective melatonin receptor antagonist, and selective melatonin receptor 1 knockdown attenuated the browning effects of melatonin. Melatonin also induced M2 polarization in RAW 264.7, involving the melatonin receptor 1-Src-STAT3/STAT6 phosphorylation signaling cascade. Melatonin-treated M2-conditioned medium (CM) contained increased levels of catecholamine (CA) and induced beige adipocytes when treated with differentiated 3T3-L1 white adipocytes. In vivo oral administration of melatonin to high-fat diet (HFD)-induced obese (DIO) mice reduced body weight, accompanied by increased expression of uncoupling protein-1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in subcutaneous adipose tissues. Moreover, arginase-1 (Arg1) and mannose receptor C type-1 (MRC1) levels were markedly higher in the melatonin-treated groups, suggesting that melatonin induces adipose browning and M2 polarization in vivo. Collectively, melatonin-induced adipocyte browning appeared to be reflected by the sum of melatonin receptor 1-activated direct browning effects and indirect M2 polarization-mediated effects.

Melatonin mitigates vincristine-induced peripheral neuropathy by inhibiting TNF-α/astrocytes/microglial cells activation in the spinal cord of rats, while preserving vincristine's chemotherapeutic efficacy in lymphoma cells

Vincristine (VCR), an anti-tubulin chemotherapy agent, is known to cause peripheral and central nerve damage, inducing severe chemotherapy-induced peripheral neuropathy (CIPN). Although melatonin has been recently recognized for its potential anti-neuropathic effects, its efficacy in countering VCR-induced neuropathy remains unclear. This study examines the neuroprotective potential of melatonin against VCR-induced neuropathy using a rat model. Neuropathic pain was induced through 10 VCR injections (0.1 mg/kg/day i.p.), administered in two five-day cycles with a two-day break. Melatonin treatment started two days before VCR administration and continued daily throughout the experiment. Rats were assigned to five groups: control, VCR, and three melatonin-treated groups receiving VCR with melatonin (5, 10, or 20 mg/kg/day i.p.). We assessed mechanical (von-Frey and Randall-Selitto tests) and thermal (hot-plate and tail-flick tests) hyperalgesia, motor coordination (rotarod test), and sciatic nerve conduction velocity (NCV). Changes in body weight, spinal cord histopathology (H&E), and proinflammatory markers (TNF-α, IL-1β, and IL-6), reactive astrocytes (GFAP) and microglial cells (IBA-1) were also assessed, as well as spinal cord degeneration (Nissl stain) and demyelination (LFB stain and MBP). Finally, the effect of melatonin on the cytotoxic activity of VCR against EL4 lymphoma cells was assessed using an MTT assay. Our results indicated that melatonin coadministration with VCR preserved spinal cord architecture, elevated nociceptive thresholds, improved motor coordination, enhanced NCV, and maintained normal body weight gain. Melatonin also reduced inflammation, decreased reactive astrocytes and microglia, and prevented neurodegeneration and demyelination in the spinal cord. Importantly, melatonin did not affect VCR's cytotoxic activity in cancer cells.

Melatonin can mitigate H2O2-induced atrophy and promote muscle fiber hypertrophy in morphological level in mouse myoblast cell line

Objective: It is known that oxidative stress is the main factor in the formation of disuse muscle atrophy which is the most common type of muscle atrophy. The utilization of antioxidants as supplements, particularly the category known as mitochondrial targeting antioxidants (MTA), such as melatonin, have demonstrated significant potential as an advanced therapeutic approach. In this study, we aimed to investigate the effect of melatonin application on the cellular morphology of the C2C12 cell line. Materials and Methods: In our experiment, we induced oxidative stress using hydrogen peroxide (H2O2) to create a model of skeletal muscle atrophy. We established four distinct groups of C2C12 cells, all exposed to the same conditions. These groups included Control (C), Melatonin (M), H2O2 (H), and Melatonin + H2O2 (MH). The aim was to examine morphological features, specifically myotube diameters, to assess atrophy. Results: The analysis revealed significant differences in diameters among the groups (p < 0.05). The melatonin treatment group not only showed a mitigation of diameter change due to atrophy but also exhibited a significant increase in diameter. Conclusion: The results suggest that H2O2 induces muscle atrophy, and melatonin plays a dual role in maintaining muscle health, protecting against atrophy and promoting hypertrophy, particularly at the morphological level. However, additional research is needed to figure out the details of underlying mechanisms.

Protective Role of Melatonin Against Abamectin-Induced Biochemical, Immunohistochemical, and Ultrastructural Alterations in the Testicular Tissues of Rats.

Abamectin is one of the most widely used pesticides due to its strong insecticidal and anthelmintic activities. Melatonin is a neurohormone with potent antioxidant, anti-apoptotic, and anti-inflammatory effects. This study aimed to investigate the potential ameliorative effects of melatonin against abamectin-induced testicular toxicity in rats. Twenty-four rats were divided into four groups: control group (1 mL/kg/day corn oil), melatonin-treated group (10 mg/kg/day), abamectin-treated group (0.5 mg/kg/day), and melatonin plus abamectin-treated group. Test substances were administered via oral gavage once daily for 28 days. While MDA and 8-OHdG levels increased in the testicular tissue of rats treated with abamectin, SOD, CAT, GPx, and GST enzyme activities decreased significantly. While interleukin-17 levels, TNF-α, and caspase3 expression increased in the testicular tissue, acetylcholinesterase activity decreased. At the same time, serum gonadotropins (luteinizing and follicle-stimulating hormones) and testosterone levels decreased. Light microscope examinations of testicular tissues revealed severe histopathological changes, such as atrophic hyalinized seminiferous tubules, basement membrane irregularity, degeneration, spermatogenic cell loss, and necrosis. Electron microscopy examinations revealed large vacuoles in Sertoli and spermatogenic cells, swelling and vacuolization in mitochondria, lysosomal structures, and increased pyknotic nuclei. In contrast, melatonin supplementation significantly ameliorated abamectin-induced testicular toxicity in rats through antioxidant, antiapoptotic, and anti-inflammatory mechanisms.

Effects of red-light irradiation and melatonininjection on the antioxidant capacity and occurrence of apoptosis in abalones (Haliotis discus hannai) subjected to thermal stress

High ocean temperatures caused by global warming induce oxidative stress in aquatic organisms. Melatonin treatment and irradiation using red light-emitting diodes (LEDs) have been reported to reduce oxidative stress in a few aquatic organisms. However, the effects of red LED irradiation and melatonin injection on the antioxidant capacity and degree of apoptosis in abalones, which are nocturnal organisms, have not yet been reported. In this study, we compared the expression levels of antioxidant enzymes, total antioxidant capacity, and the degree of apoptosis in abalones subjected to red LED irradiation and melatonin treatment. The results revealed that at high water temperatures (25 °C), the mRNA expression levels of the superoxide dismutase (SOD) and glutathione peroxidase (GPx) genes and the antioxidant activity of SOD decreased in abalones in the red-LED irradiated and melatonin-treated groups compared with those in abalones in the control group. Although high water temperatures induced DNA damage in the abalone samples, the degree of apoptosis was lower in the red-LED irradiated and melatonin-treated groups than in the control group. Overall, the abalones in the melatonin-treated and red-LED irradiated groups showed reduced oxidative stress and increased antioxidant enzyme levels under thermal stress compared with those in the control group. Therefore, red LED irradiation is a promising alternative to melatonin treatment, which is difficult to administer continuously for a long time, for protecting abalones from oxidative stress.

Melatonin and mesenchymal stem cells co-administration alleviates chronic obstructive pulmonary disease via modulation of angiogenesis at the vascular-alveolar unit

Chronic obstructive pulmonary disease (COPD) is considered a severe disease mitigating lung physiological functions with high mortality outcomes, insufficient therapy, and pathophysiology pathways which is still not fully understood. Mesenchymal stem cells (MSCs) derived from bone marrow play an important role in improving the function of organs suffering inflammation, oxidative stress, and immune reaction. It might also play a role in regenerative medicine, but that is still questionable. Additionally, Melatonin with its known antioxidative and anti-inflammatory impact is attracting attention nowadays as a useful treatment. We hypothesized that Melatonin may augment the effect of MSCs at the level of angiogenesis in COPD. In our study, the COPD model was established using cigarette smoking and lipopolysaccharide. The COPD rats were divided into four groups: COPD group, Melatonin-treated group, MSC-treated group, and combined treated group (Melatonin–MSCs). We found that COPD was accompanied by deterioration of pulmonary function tests in response to expiratory parameter affection more than inspiratory ones. This was associated with increased Hypoxia inducible factor-1α expression and vascular endothelial growth factor level. Consequently, there was increased CD31 expression indicating increased angiogenesis with massive enlargement of airspaces and thinning of alveolar septa with decreased mean radial alveolar count, in addition to, inflammatory cell infiltration and disruption of the bronchiolar epithelial wall with loss of cilia and blood vessel wall thickening. These findings were improved significantly when Melatonin and bone marrow-derived MSCs were used as a combined treatment proving the hypothesized target that Melatonin might augment MSCs aiming at vascular changes.

Anti-inflammatory effect of melatonin therapy in sepsis

Background The biggest cause of illness and death in children across the globe is sepsis. Melatonin, which is an endogenous lipophilic indoleamine that is primarily made from serotonin inside the pineal gland, has been shown in clinical research to be useful as an adjuvant treatment in septic newborns, improving outcomes and reducing complications, because of its strong antioxidant and immunological activities. Aim The goal of the present study is to evaluate the anti-inflammatory effects of melatonin as an additional treatment to antibiotics in children with sepsis, on laboratory markers and inflammatory cytokines: interleukin 6 (IL-6) and IL-8 as well as to study its impact on the outcome of these children. Patients and methods Our research is a prospective randomized controlled double-blinded trial from February 2017 to February 2018 at Mansoura University Children’s Hospital. This was accomplished by examining 30 children who were diagnosed with sepsis according to the Third International Consensus Definitions for Sepsis and Septic Shock. The study’s subjects were divided into two groups: group A (cases group) 15 children with sepsis in which antibiotics as well as a total oral dosage of 20 mg melatonin were given. Group B (control group) 15 matched septic children who received antibiotics as well as a cumulative oral dosage of 20 mg of a placebo. Results The research showed that melatonin administration as an adjuvant treatment was associated with a significant decrease in the C-reactive protein after treatment in group A than in group B (P=0.031). While there was a statistically insignificant decrease in white blood cells and an increase in hemoglobin as well as in platelets. Furthermore, serum IL-6 and IL-8 levels were significantly lower in the melatonin receiving group when matched with the control group 72 h after treatment (P=<0.001, 0.021, respectively). Melatonin administration improved the outcome in melatonin-treated group better than the control group (P=0.01). Conclusion Melatonin can be used as an adjuvant treatment for children with sepsis as it significantly reduced the C-reactive protein, serum IL-6, and IL-8 levels as well as it improves the outcome of sepsis in these children.

Impact of melatonin administration on sperm quality, steroid hormone levels, and testicular blood flow parameters in small ruminants: A meta-analysis.

The impact of exogenous melatonin on the sperm quality of small ruminants is controversial. Therefore, this study aimed to synthesize previous findings on the influence of melatonin injection on sperm quality, steroid hormones, and testicular blood flow in small ruminants. Thirty studies were analyzed by computing the raw mean difference (RMD) as the effect size between the control and melatonin treatment groups, using the inverse of the variance for the random-effect model of the method of moments by DerSimonian and Laird. We assessed heterogeneity among studies using Q test. I2 statistic was used to classify the observed heterogeneity. We used Egger's regression method to indicate publication bias. Melatonin injection (p < 0.05) affected sperm concentration (RMD = 0.42 × 109/mL), morphology (RMD = 2.82%), viability (RMD = 2.83%), acrosome integrity (RMD = 4.26%), and DNA integrity (RMD = 1.09%). Total motility (RMD = 5.62%), progressive motility (RMD = 7.90%), acrosome integrity (RMD = 8.68%), and DNA integrity (RMD = 2.01%) of post-thawed semen in the melatonin-treated group were also increased (p < 0.05). Similarly, treatment with melatonin (p < 0.05) enhanced total motility (RMD = 5.78%), progressive motility (RMD = 5.28%), curvilinear velocity (RMD = 4.09 μm/s), straight-line velocity (RMD = 5.61 μm/s), and average path velocity (RMD = 4.94 μm/s). Testosterone (RMD = 1.02 ng/mL) and estradiol 17-ß levels (RMD = 0.84 pg/mL) were elevated (p < 0.05) in the melatonin-injected group. Melatonin implantation ameliorated testicular blood flow, as indicated by a significant reduction (p < 0.05) in the resistive index (RMD = 0.11) and pulsatility index (RMD = -0.15). Melatonin administration can increase the reproductive performance of small male ruminants.

Melatonin-mediated corrective changes in gut microbiota of experimentally chronodisrupted C57BL/6J mice

ABSTRACT Chronic consumption of a high-calorie diet coupled with an altered sleep-wake cycle causes disruption of circadian clock that can impact the gut microbiome leading to metabolic syndrome and associated diseases. Herein, we investigate the effects of a high fat high fructose diet (H) alone or in combination with photoperiodic shifts induced chronodisruption (CD) on gut microbiota of C57BL/6J male mice. Further, the merits of daily evening intraperitoneal administration of melatonin in restoring gut microbiota are studied herein. Experimental groups viz. H, CD and HCD mice recorded higher levels of serum pro-inflammatory cytokines (TNF-α and IL-6) and lower levels of the anti-inflammatory cytokine, IL-10. These findings correlate with a concomitant increase in the transcripts of TLR4, TNF-α, and IL-6 in small intestine of the said groups. A decrement in mRNA levels of Ocln, ZO-1 and Vdr in these groups implied towards an altered gut permeability. These results were in agreement with the observed decrement in percentage abundance of total gut microflora and Firmicutes: Bacteroidetes (F/B) ratio. Melatonin administration accounted for lower-level inflammation (serum and gut) along with an improvement in gut permeability markers. The total abundance of gut microflora and F/B ratio showed an improvement in all the melatonin-treated groups and the same is the highlight of this study. Taken together, our study is the first to report perturbations in gut microbiota resulting due to a combination of photoperiodic shifts induced CD and a high fat high calorie diet-induced lifestyle disorder. Further, melatonin-mediated rejuvenation of gut microbiome provides prima facie evidence of its role in improving gut dysbiosis that needs a detailed scrutiny.

Effects of melatonin against experimentally induced apical periodontitis in rats.

Apical periodontitis is an inflammatory condition resulting from microbial invasion in the root canal system, causing periapical tissue destruction and bone resorption. This study investigated melatonin's effects, known for its antioxidant and anti-inflammatory properties, on experimentally induced apical periodontitis in rats. Three groups of rats were studied: control, apical periodontitis and apical periodontitis with melatonin treatment. Proinflammatory cytokines and enzyme levels in blood serum were measured, and micro-CT analysis assessed bone resorption. Results showed significantly elevated cytokines and enzyme levels in the apical periodontitis group compared to the control. However, in the melatonin-treated group, these levels were significantly reduced (p < 0.01-0.001). Micro-CT analysis indicated decreased periapical resorption cavity volume and surface area with melatonin treatment. This suggests that systemic melatonin administration can mitigate inflammation and reduce bone resorption in experimentally induced apical periodontitis in rats, potentially holding promise for human endodontic disease treatment pending further research.

Effect of melatonin on reproductive function in propylthiouracil induced hypothyroidism in adult male rats.

Thyroid hormones are essential for regulating metabolism, reproduction, and growth. Hypothyroidism is connected with lower sperm count and motility, leading to male infertility. Oxidative stress is likely to be linked to this interaction. Melatonin, being known as an oxidative scavenger, may offer a feasible treatment method for reproductive dysfunction accompanying hypothyroidism in adult male rats. The purpose of this investigation was to determine the mechanism by which melatonin treatment affected spermatogenic and steroidogenic function in an experimental model-induced hypothyroidism in adult male rats. Twenty-one male albino adult rats weighing between 150 and 210 g were used in this experiment. Rats were split into three groups and studied for 11 weeks. The control euthyroid group, in which rats received 0.9% Sodium Chloride (NaCl) solution by intraperitoneal injection [solvent for 6-propyl 2-thouracil (PTU)], 6 days/week for 8 weeks; the PTU-induced hypothyroid group, in which chemical thyroidectomy was induced by intraperitoneal injection of PTU at a dose of 10 mg/kg body weight, 6 days/week for 8 weeks; and the melatonin-treated hypothyroid group, which received 3 mg/kg melatonin intraperitoneally daily for 21 days plasma free Triiodothyronine (T3), free Thyroxin (T4), thyroid stimulating hormone (TSH), free testosterone, Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH) and prolactin were measured. Also, semen analysis, testicular tissue malondialdehyde (MDA), and tumor necrosis factor-α (TNF-α) were accessed. The results indicated that melatonin significantly increased sperm viability and motility compared to the untreated PTU-induced hypothyroid group (p<0.001). Testicular MDA and TNF-α showed a significant decrease in the melatonin-treated hypothyroid group compared with the PTU-induced hypothyroid group (p<0.05). In addition, plasma testosterone levels were significantly increased, accompanied by a significant reduction of plasma prolactin levels compared to the untreated hypothyroid group (p<0.05 for both). Based on the study findings, melatonin could mitigate gonadal dysfunction induced by hypothyroidism by improving several components of semen analysis, such as sperm motility and sperm viability, as well as by enhancing testosterone production focusing on oxidative and inflammatory stress as the underlying mechanisms.

Transcriptome Analysis Reveals the Mechanism by Which Exogenous Melatonin Treatment Delays Leaf Senescence of Postharvest Chinese Kale (Brassica oleracea var. alboglabra).

Melatonin, a pleiotropic small molecule, is employed in horticultural crops to delay senescence and preserve postharvest quality. In this study, 100 µM melatonin treatment delayed a decline in the color difference index h* and a*, maintaining the content of chlorophyll and carotenoids, thereby delaying the yellowing and senescence of Chinese kale. Transcriptome analysis unequivocally validates melatonin's efficacy in delaying leaf senescence in postharvest Chinese kale stored at 20 °C. Following a three-day storage period, the melatonin treatment group exhibited 1637 differentially expressed genes (DEGs) compared to the control group. DEG analysis elucidated that melatonin-induced antisenescence primarily governs phenylpropanoid biosynthesis, lipid metabolism, plant signal transduction, and calcium signal transduction. Melatonin treatment up-regulated core enzyme genes associated with general phenylpropanoid biosynthesis, flavonoid biosynthesis, and the α-linolenic acid biosynthesis pathway. It influenced the redirection of lignin metabolic flux, suppressed jasmonic acid and abscisic acid signal transduction, and concurrently stimulated auxin signal transduction. Additionally, melatonin treatment down-regulated RBOH expression and up-regulated genes encoding CaM, thereby influencing calcium signal transduction. This study underscores melatonin as a promising approach for delaying leaf senescence and provides insights into the mechanism of melatonin-mediated antisenescence in postharvest Chinese kale.

Improving behavioral deficits induced by perinatal ethanol and stress exposure in adolescent male rat progeny via maternal melatonin treatment.

Early-life stressful situations and binge drinking have been thus far acknowledged as two burdensome conditions that potentially give rise to negative outcomes and then synergistically affect brain development. In this context, the hippocampus, with the greatest number of glucocorticoid receptors (GCRs) in the brain, is responsible for regulating negative responses to stress. Prolonged glucocorticoid (GC) exposure can accordingly cause oxidative stress (OS), leading to cognitive and emotional dysfunction. Against this background, melatonin, as a powerful antioxidant and hypothalamus-pituitary-adrenal (HPA) axis regulator, was administered in this study to ameliorate cognitive impairments induced by perinatal ethanol and stress exposure in adolescent male rat progeny. Wistar rat dams were exposed to ethanol (4 g/kg) and melatonin (10 mg/kg) from gestational day (GD) 6 to postnatal day (PND) 14 and then limited nesting material (LNS) from PND0 to PND14 individually or in combination. Maternal behavior was then investigated in mothers. Afterward, the plasma corticosterone (CORT) concentration, the OS marker, the corticotropin-releasing hormone receptor type 1 (CRHR1) expression, and the GCR and brain-derived neurotrophic factor (BDNF) levels were measured in the male pups. Moreover, behavioral tasks, including the elevated plus maze (EPM), the Morris water maze (MWM), the novel object recognition (NORT), and the object-location memory (OLM) tests were completed and assessed. The quantity and quality of maternal care significantly decreased in the mothers with dual exposure to ethanol and stress. The plasma CORT concentration in the progeny also dropped in the Ethanol + LNS group, but the risk-taking behavior elevated significantly. The ethanol and stress exposure further revealed a significant fall in the GCR and CRHR1 expression levels, compared with stress alone. The results of learning and memory tasks also indicated a significant reduction in spatial learning and memory among animals exposed to ethanol and stress. The BDNF mRNA levels correspondingly increased in the Ethanol + LNS group, compared with LNS alone. In the presence of ethanol and stress, the superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities correspondingly declined. On the other hand, the malondialdehyde (MDA) levels augmented in the hippocampus of the animals with ethanol and LNS dual exposure, as compared with the control group. Melatonin treatment (MT) thus improved nursing behaviors in dams, prevented OS, enhanced the CRHR1 and GCR expression, and reduced the BDNF levels to the similar ones in the control group. The animals in the Ethanol + LNS + MT group ultimately showed an ameliorated performance at behavioral tasks, including the memory and risk-taking behavior. It was concluded that MT could prevent stress response and memory impairments arising from dual exposure to ethanol and stress by inhibiting OS.

Txnrd3 knockout enhancement of lung injury induced by Ni exposure via the VEGF-VEGFR-2 axis and alleviation of this effect by melatonin.

Ni exposure leads to respiratory diseases in mice. Txnrd3 has been shown to have a protective effect on the body, but there is a paucity of empirical research focusing specifically on lung tissue. Melatonin possesses potent antioxidant, anti-inflammatory, and anti-fibrotic effects. By regulating inflammation-related factors, melatonin can activate the VEGF signaling pathway, ultimately alleviating lung injuries caused by Ni exposure. One hundred and sixty 8-week-old C57BL/6N mice, that were wild-type or Txnrd3-/- mice and 25-30g in weight, were randomly divided into eight groups, including the NC group, Ni group, melatonin-treated group, and Ni plus melatonin group. Ni (10mg/kg) was gavaged, and melatonin (2mg/kg) was administered for 21 days. Inflammatory cells were found in the bronchioles of Txnrd3-/- mice under Ni exposure. Ultrastructural examination revealed that the homozygous-Ni group had a high amount of collagen fibers. The antioxidant capacity studies also revealed that mice lungs underwent oxidative stress. The results of qRT-PCR and WB showed that Ni induced an inflammatory response, which was also aggravated in Txnrd3-/- mice. Melatonin can effectively reduce the above symptoms. In conclusion, Ni causes lung injury by activating the VEGF-VEGFR-2 pathway and Txnrd3 knockout aggravates injury after Ni exposure.

The effects of melatonin on the viability and osteogenic/odontogenic differentiation of human stem cells from the apical papilla.

An experimental study was conducted to examine whether melatonin influences osteogenic/odontogenic differentiation of human stem cells derived from the apical papilla (hSCAPs). In order to isolate hSCAPs, the undeveloped root of a third molar of a human tooth was used. Melatonin was administered to the experimental groups in an osteogenic medium. No treatment was administered to the control group. The methyl thiazolyl tetrazolium (MTT) assay was performed on days 1, 2, and 3 to assess cell viability (n = 8). A determination of odontogenic/osteogenic differentiation was accomplished using alkaline phosphatase (ALP) activity alizarin red staining (ARS) (n = 6), and the expression of osteogenic genes by real-time polymerase chain reaction (RT-PCR) (n = 3) on days 1, 2, and 7. Evaluation of the data was conducted using SPSS version 18. All experiments were conducted at least three times. The Mann Whitney U test, the ANOVA analysis, Tukey's test, and t-test was implemented to analyze the data(α = 0.05). After 24h, 48h, and 72h, No significant difference was observed between the control group and the melatonin treatment group in terms of viability of hSCAPs. (from 1 up to 10µg/ml) (P > 0.05). The assessment of ARS and ALP activity showed that melatonin treatment enhanced osteogenic differentiation of hSCAPs (P < 0.001). Melatonin treatment caused hSCAPs to show an increase of genes related to osteogenic/odontogenic differentiation. These genes included ALP, dentin sialophosphoprotein (DSPP), dentin matrix protein 1 (DMP-1), and bone sialoprotein (BSP) (P < 0.001). Melatonin treatment enhanced osteogenic/odontogenic differentiation of hSCAPs with a dose dependent effect on cell viability.

Response of exogenous melatonin on transcription and metabolism of soybean under drought stress.

Amino acid metabolism is an important factor in regulating nitrogen source assimilation and source/sink transport in soybean. Melatonin can improve plant stress resistance, but whether it affects amino acid metabolism is not known. Therefore, this study investigated whether exogenous melatonin had an effect on amino acid metabolism of soybean under drought conditions and explored its relationship with yield. The treatments were normal water supply treatment (WW), drought stress treatment (D), drought stress and melatonin treatment group (D + M), sprayed with 100 μmol/L melatonin. The effects of melatonin on amino acid metabolism and grain filling were studied by physiological and omics experiments using Kangxian 9 (drought-sensitive variety) and Suinong 26 (drought-resistant variety) soybean cultivars. The results showed that drought stress decreased the activity of carbon and nitrogen metabolizing enzymes, which inhibited the accumulation of dry matter and protein, and decreased the yield. In the drought-sensitive soybean variety, glycoenzymes and amino acid synthetases synthetic genes were upregulated in melatonin-treated soybeans, hence carbon and nitrogen metabolism enzyme activity increased, increasing the carbohydrate and amino acid contents simultaneously. This resulted in higher dry matter and yield than drought-stressed soybean not treated with melatonin. In the drought-resistant variety, the grain weight per plant increased by 7.98% and 6.57% in 2020 and 2021, respectively, while it increased by 23.20% and 14.07% in the drought-sensitive variety during the respective years. In conclusion, melatonin treatment can enhance the activity of nitrogen and carbon metabolism and amino acid content by upregulating the expression of soybean metabolic pathway and related genes, thus increasing the yield of soybean under drought stress.

Melatonin attenuates monocrotaline-induced hepatic sinusoidal obstruction syndrome in rats via activation of Sirtuin-3.

Melatonin possesses potent hepatoprotective properties, but it remains to be elucidated whether melatonin has a therapeutic effect on monocrotaline (MCT)-induced hepatic sinusoidal obstruction syndrome (HSOS). In this study, male Sprague Dawley rats were intraperitoneally injected with melatonin or the same volume of vehicle at 0 and 24 h after MCT intragastric administration. Next, hematoxylin-eosin staining and electron microscopy were performed to evaluate the hepatic sinusoidal injury of rats. Endothelial cell marker RECA-1 was observed by immunohistochemistry. Hepatic oxidative stress was analyzed by detecting malondialdehyde, glutathione S-transferase, and reactive oxygen species. Assessment of liver function was carried out byanalysis of serum aspartate aminotransferase, alanine aminotransferase, total bilirubin, and albumin levels. Real-time polymerase chain reaction and Western blot analysis were used to identifyliver Sirtuin-3 (SIRT3) and active matrix metallopeptidase 9 (MMP-9) expression. Besides, liver sinusoidal endothelial cells (LSECs) were used for the in vitro functional verification experiment. Specifically, liver histology of the melatonin-treated groups showed that the pathological damages caused by MCT were significantly attenuated, total HSOS scores were decreased, and the elevation of serum hyaluronic acid observed in the model group was also reduced. Moreover, melatonin treatment also improved the survival of rats after partial hepatectomy. Administration of melatonin ameliorated MCT-induced LSECs injury, hepatic oxidative stress, and hepatic dysfunction. Furthermore, melatonin treatment increased SIRT3 expression while attenuating MMP-9 activity in liver tissues. Cell experiment also demonstrated that SIRT3 might mediate the protective effect of melatonin on LSECs. Collectively, our study provided the potential rationale for the application of melatonin for the prevention of MCT-induced HSOS.

Investigation of the anti-oxidative and anti-inflammatory effects of melatonin on experimental liver damage by radiation.

Radiotherapy is one of the inevitable treatment approaches for several types of cancer. We aimed to show the protective and therapeutic effects of daily use of melatonin on liver tissues subjected to a single dose of 10Gy (gamma-ray) total body radiation. Rats were divided into 6 groups, of which 10 were in each: control, sham, melatonin, radiation, radiation+melatonin, and melatonin+radiation. The rats received 10 Gy of external radiation throughout their entire bodies. The rats were given 10 mg/kg/day of melatonin intraperitoneally before or after radiation treatment, depending on the group. Histological methods, immunohistochemical analysis (Caspase-3, Sirtuin-1, α-SMA, NFΚB-p65), biochemical analysis by ELİSA (SOD, CAT, GSH-PX, MDA, TNF-α, TGF-β, PDGF, PGC-1α) and the Comet assay as a marker of DNA damage were applied to the liver tissues. Histopathological examinations showed structural changes in the liver tissue of the radiation group. Radiation treatment increased the immunoreactivity of Caspase-3, Sirtuin-1 and α-SMA, but these effects were relatively attenuated in the melatonin-treated groups. The melatonin+radiation group had statistically significant results close to those of the control group, in terms of Caspase-3, NFΚB-p65 and Sirtuin-1 immunoreactivity. In melatonin treated groups, hepatic biochemical markers, MDA, SOD, TNF-α, TGF-β levels, and DNA damage parameters were decreased. Administration of melatonin before and after radiation has beneficial effects, but using it before radiation may be more efficient. Accordingly, daily melatonin usage could mitigate ionizing radiation induced damage.