Melatonin regulates mitochondrial function to alleviate ferroptosis through the MT2/Akt signaling pathway in swine testicular cells.

Increasing evidence has shown that many environmental and toxic factors can cause testicular damage, leading to testicular ferroptosis and subsequent male reproductive disorders. Melatonin is a major hormone and plays an vital role in regulating male reproduction. However, there is a lack of research on whether Mel can alleviate testicular cell ferroptosis and its specific mechanism. In this study, the results indicated that Mel could enhance the viability of swine testis cells undergoing ferroptosis, reduce LDH enzyme release, increase mitochondrial membrane potential, and affect the expression of ferroptosis biomarkers. Furthermore, we found that melatonin depended on melatonin receptor 1B to exert these functions. Detection of MMP and ferroptosis biomarker protein expression confirmed that MT2 acted through the downstream Akt signaling pathway. Moreover, inhibition of the Akt signaling pathway can eliminate the protective effect of melatonin on ferroptosis, inhibit AMPK phosphorylation, reduce the expression of mitochondrial gated channel (VDAC2/3), and affect mitochondrial DNA transcription and ATP content. These results suggest that melatonin exerts a beneficial effect on mitochondrial function to mitigate ferroptosis through the MT2/Akt signaling pathway in ST cells.

Effect of melatonin supplementation on cardiometabolic risk factors, oxidative stress and hormonal profile in PCOS patients: a systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: To investigate whether melatonin supplementation can enhance cardiometabolic risk factors, reduce oxidative stress, and improve hormonal and pregnancy-related factors in patients with PCOS. METHODS: We conducted a systematic search of PubMed/Medline, Scopus, and the Cochrane Library for articles published in English from inception to March 2023. We included randomized controlled trials (RCTs) on the use of melatonin for patients with polycystic ovary syndrome (PCOS). We performed a meta-analysis using a random-effects model and calculated the standardized mean differences (SMDs) and 95% confidence intervals (CIs). RESULTS: Six studies met the inclusion criteria. The result of meta-analysis indicated that melatonin intake significantly increase TAC levels (SMD: 0.87, 95% CI: 0.46, 1.28, I2 = 00.00%) and has no effect on FBS, insulin, HOMA-IR, TC, TG, HDL, LDL, MDA, hs-CRP, mFG, SHBG, total testosterone, and pregnancy rate in patients with PCOS compare to controls. The included trials did not report any adverse events. CONCLUSION: Melatonin is a potential antioxidant that may prevent damage from oxidative stress in patients with PCOS. However, the clear effect of melatonin supplementation on cardiometabolic risk factors, hormonal outcomes, and pregnancy-related outcomes needs to be evaluated further in large populations and long-term RCTs.

In vitro cytoprotective and in vivo anti-oral mucositis effects of melatonin and its derivatives.

According to our preliminary study, melatonin and its N-amide derivatives (N-(2-(1-4-bromobenzoyl-5-methoxy-1H-indol-3-yl)ethyl)acetamide (BBM) and 4-bromo-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)benzamide (EBM)) inhibited the marker of acute inflammation in tests in vitro and in vivo. The anti-inflammatory agent is intended for the prevention and treatment of chemotherapy-induced toxicity. In this study aimed to evaluate the effect of melatonin and its derivatives on mechanisms related to chemotherapy-induced oral mucositis by in vitro ROS and 5-FU-induced human keratinocyte cells as well as in vivo oral mucositis model. In in vitro H2O2-induced HaCaT cells, BBM had the highest level of protection (34.57%) at a concentration 50 µM, followed by EBM (26.41%), and melatonin (7.9%). BBM also protected cells against 5-FU-induced to 37.69-27.25% at 12.5-100 µM while EBM was 36.93-29.33% and melatonin was 22.5-11.39%. In in vivo 5-FU-induced oral mucositis in mice, melatonin, BBM, and EBM gel formulations protected tissue damage from 5-FU similar to the standard compound, benzydamine. Moreover, the weight of mice and food consumption recovered more quickly in the BBM group. These findings suggested that it was possible to develop BBM and EBM as new therapeutic agents for the treatment of oral mucositis.

The effect of exogenous melatonin administration before superovulation on embryo yield in Assaf ewes.

The aim of this study was to determine the effect of exogenous melatonin administration on transferable embryos by increasing total antioxidant status before superovulation in Assaf ewes. Selected ewes were randomly divided into two equal groups: melatonin (n = 9) and control (n = 9). In the melatonin group, a melatonin implant (18 mg melatonin, Regulin®, Ceva, Turkey) was placed under the skin of the ear 7 days prior to insertion of the progesterone-containing sponge. In the control group, a physiological saline solution was injected under the skin of the ear on the same day. The same superovulation protocol was used in both groups. In addition, blood samples for determination of Glutathione peroxidase, superoxide dismutase, total antioxidant status and total oxidant status concentrations were collected on five different days, including the day of melatonin implant placement (Day-7), vaginal sponge insertion (Day 0), vaginal sponge removal (Day 11), mating (Day 12-13) and uterine flushing (Day 19). Embryos were collected by laparotomy on the 7th day after mating. Uterine flushing taken into petri dishes were scanned under a stereomicroscope, and the quality and developmental stages of the embryos were recorded. In the study, total corpus luteum count and total cell count were found to be higher in the control group than in the melatonin group (p < .05). When the results were evaluated in terms of oxidative stress index, a negative correlation was found between the total number of corpus luteum, number of cells obtained, count of transferable embryos and number of Grade 1 embryos on Day 0. There was also a positive correlation oxidative stress index and the number of unfertilized oocytes on Day-7. As a result, exogenous melatonin administration prior to superovulation during the breeding season is thought to have a negative effect on embryo yield and quality. Therefore, the use of exogenous melatonin in MOET studies during the breeding season is recommended to be investigated in new studies.

Insufficient Plasma Melatonin and Its Association With Neuropsychiatric Impairments in Patients With T2DM.

Purpose: Type 2 diabetes mellitus (T2DM) is associated with multiple neuropsychiatric impairments, including cognitive dysfunction, and melatonin (MLT) plays a crucial role in maintaining normal neuropsychiatric functions. This study is aimed at investigating the change in plasma MLT levels and its association with neuropsychiatric impairments in T2DM patients. Methods: One hundred twenty-six T2DM patients were recruited, and their demographics and clinical data were collected. Apart from the plasma glycated hemoglobin (HbA1c) levels and other routine metabolic indicators, the plasma concentrations of MLT, C-reactive protein (CRP), Interleukin 6 (IL-6), soluble myeloid triggered receptor 1 (sTREM 1), and receptor 2 (sTREM 2) were measured. Moreover, the executive function and depressive tendency were evaluated via the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) and the Epidemiological Research Center Depression Scale (CES-D), respectively. Result: Compared with the low HbA1c group, the T2DM patients in the high HbA1c group presented lower plasma MLT levels but higher plasma concentrations of inflammatory biomarker levels, together with higher scores in the BRIEF-A and CES-D scales. Moreover, results of the Pearson correlation test showed that the plasma MLT levels were negatively correlated with the BRIEF-A and CES-D scores, as well as plasma concentrations of HbA1c and inflammatory indications, indicating that MLT may mediate their neuroinflammation and neuropsychiatric impairments. Furthermore, the ROC curve results indicated that plasma MLT levels have a predictive effect on executive impairment and depressive status in T2DM patients. Conclusion: MLT levels decreased in patients with T2DM and were associated with neuropsychiatric impairments and inflammatory status, and MLT might be developed as a therapeutic agent and predictive indicator for T2DM-associated executive impairment and depression status.

Melatonin Protects Against Colistin-Induced Intestinal Inflammation and Microbiota Dysbiosis.

Colistin is renowned as a last-resort antibiotic due to the emergence of multidrug-resistant pathogens. However, its potential toxicity significantly hampers its clinical utilization. Melatonin, chemically known as N-acetyl-5-hydroxytryptamine, is an endogenous hormone produced by the pineal gland and possesses diverse biological functions. However, the protective role of melatonin in alleviating antibiotic-induced intestinal inflammation remains unknown. Herein, we reveal that colistin stimulation markedly elevates intestinal inflammatory levels and compromises the gut barrier. In contrast, pretreatment with melatonin safeguards mice against intestinal inflammation and mucosal damage. Microbial diversity analysis indicates that melatonin supplementation prevents a reduction in the abundance of Erysipelotrichales and Bifidobacteriales, as well as an increase in Desulfovibrionales abundance, following colistin exposure. Remarkably, short-chain fatty acids (SCFAs) analysis shows that propanoic acid contributes to the protective effect of melatonin on colistin-induced intestinal inflammation. Furthermore, the protection effects of melatonin and propanoic acid on LPS-induced cellular inflammation in RAW 264.7 cells are confirmed. Mechanistic investigations suggest that intervention with melatonin and propanoic acid can repress the activation of the TLR4 signal and its downstream NF-κB and MAPK signaling pathways, thereby mitigating the toxic effects of colistin. Our work highlights the unappreciated role of melatonin in preventing the potential detrimental effects of colistin on intestinal health and suggests a combined therapeutic strategy to effectively manage intestinal infectious diseases.

Mitigating Ni and Cu ecotoxicity in the ecological restoration material and ornamental Primula forbesii Franch. with exogenous 24-epibrassinolide and melatonin.

Nickel (Ni) and copper (Cu) contamination have become major threats to plant survival worldwide. 24-epibrassinolide (24-EBR) and melatonin (MT) have emerged as valuable treatments to alleviate heavy metal-induced phytotoxicity. However, plants have not fully demonstrated the potential mechanisms by which these two hormones act under Ni and Cu stress. Herein, this study investigated the impact of individual and combined application of 24-EBR and MT on the growth and physiological traits of Primula forbesii Franch. subjected to stress (200 µmol L-1 Ni and Cu). The experiments compared the effects of different mitigation treatments on heavy metal (HM) stress and the scientific basis and practical reference for using these exogenous substances to improve HM resistance of P. forbesii in polluted environments. Nickel and Cu stress significantly hindered leaf photosynthesis and nutrient uptake, reducing plant growth and gas exchange. However, 24-EBR, MT, and 24-EBR + MT treatments alleviated the growth inhibition caused by Ni and Cu stress, improved the growth indexes of P. forbesii, and increased the gas exchange parameters. Exogenous MT effectively alleviated Ni stress, and 24-EBR + MT significantly alleviated the toxic effects of Cu stress. Unlike HM stress, MT and 24-EBR + MT activated the antioxidant enzyme activity (by increasing superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT)), significantly reduced reactive oxygen species (ROS) accumulation, and regulated ascorbate and glutathione cycle (AsA-GSH) efficiency. Besides, the treatments enhanced the ability of P. forbesii to accumulate HMs, shielding plants from harm. These findings conclusively illustrate the capability of 24-EBR and MT to significantly bolster the tolerance of P. forbesii to Ni and Cu stress.

Melatonin Ameliorates Atherosclerotic Plaque Vulnerability by Regulating PPARδ-Associated Smooth Muscle Cell Phenotypic Switching.

Vulnerable atherosclerotic plaque rupture, the leading cause of fatal atherothrombotic events, is associated with an increased risk of mortality worldwide. Peroxisome proliferator-activated receptor delta (PPARδ) has been shown to modulate vascular smooth muscle cell (SMC) phenotypic switching, and, hence, atherosclerotic plaque stability. Melatonin reportedly plays a beneficial role in cardiovascular diseases; however, the mechanisms underlying improvements in atherosclerotic plaque vulnerability remain unknown. In this study, we assessed the role of melatonin in regulating SMC phenotypic switching and its consequential contribution to the amelioration of atherosclerotic plaque vulnerability and explored the mechanisms underlying this process. We analyzed features of atherosclerotic plaque vulnerability and markers of SMC phenotypic transition in high-cholesterol diet (HCD)-fed apolipoprotein E knockout (ApoE-/-) mice and human aortic SMCs (HASMCs). Melatonin reduced atherosclerotic plaque size and necrotic core area while enhancing collagen content, fibrous cap thickness, and smooth muscle alpha-actin positive cell coverage on the plaque cap, which are all known phenotypic characteristics of vulnerable plaques. In atherosclerotic lesions, melatonin significantly decreased the synthetic SMC phenotype and KLF4 expression and increased the expression of PPARδ, but not PPARα and PPARγ, in HCD-fed ApoE-/- mice. These results were subsequently confirmed in the melatonin-treated HASMCs. Further analysis using PPARδ silencing and immunoprecipitation assays revealed that PPARδ plays a role in the melatonin-induced SMC phenotype switching from synthetic to contractile. Collectively, we provided the first evidence that melatonin mediates its protective effect against plaque destabilization by enhancing PPARδ-mediated SMC phenotypic switching, thereby indicating the potential of melatonin in treating atherosclerosis.

Gut microbiota-melatonin signaling axis in acute pancreatitis: Revealing the impact of gut health on pancreatic inflammation and disease severity in a case-control study.

Acute pancreatitis (AP), a severe inflammatory condition affecting the pancreas requires investigation into its predictors. Melatonin, a compound with anti-inflammatory and antioxidant properties, has shown promise in managing AP. Additionally, the gut microbiota, a community of microorganisms residing in the intestines has been linked to AP development. This study aims to explore the correlation between melatonin and gut microbiota in predicting AP severity. This study involved 199 participants, with 99 diagnosed with AP and 100 serving as healthy controls. The AP patients were categorized into 2 groups based on the severity of their condition: mild AP (MAP) and severe AP (SAP). Serum melatonin levels were measured on Days 1, 3, and 5 of hospitalization, and gut microbiota composition was examined via 16S rRNA gene sequencing. Other parameters were evaluated, such as the Acute Physiology and Chronic Health Evaluation (APACHE) score, Ranson, and Acute Gastrointestinal Injury (AGI) scores. Melatonin levels were significantly lower in subjects with severe AP compared those with mild AP (18.2 ng/mL vs 32.2 ng/mL, P = .001), and melatonin levels decreased significantly in patients with AP on Days 3 and 5. The study also revealed that individuals with AP exhibited a significantly altered gut microbiota composition compared to control individuals, with a lower Shannon index and higher Simpson index. The AUCs for Simpson index and F/B ratio were significantly higher than those for other biomarkers, indicating that these gut microbiota markers may also be useful for AP prediction. The study proposes that there is a relationship between melatonin levels and the dynamics of gut microbiota profiles in relation to the severity of AP. As a result, the severity of the disease can be assessed by assessing the levels of serum melatonin and gut microbiota profiles.

Co-delivery of Siape1 and Melatonin by 125I-loaded PSMA-targeted Nanoparticles for the Treatment of Prostate Cancer.

BACKGROUND: Both apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) inhibition and melatonin suppress prostate cancer (PCa) growth. OBJECTIVE: This study evaluated the therapeutic efficiency of self-assembled and prostate-specific membrane antigen (PSMA)-targeted nanocarrier loading 125I radioactive particles and encapsulating siRNA targeting APE1 (siAPE1) and melatonin for PCa. METHODS: The linear polyarginine R12 polypeptide was prepared using Fmoc-Arg-Pbf-OH. The PSMA-targeted polymer was synthesized by conjugating azide-modified R12 peptide to PSMA monoclonal antibody (mAb). Before experiments, the PSMA-R12 nanocarrier was installed with melatonin and siAPE1, which were subsequently labeled by 125I radioactive particles. In vitro biocompatibility and cytotoxicity of nanocomposites were examined in LNCaP cells and in vivo biodistribution and pharmacokinetics were determined using PCa tumor-bearing mice. RESULTS: PSMA-R12 nanocarrier was ~120 nm in size and was increased to ~150 nm by melatonin encapsulation. PSMA-R12 nanoparticles had efficient loading capacities of siAPE1, melatonin, and 125I particles. The co-delivery of melatonin and siAPE1 by PSMA-R12-125I showed synergistic effects on suppressing LNCaP cell proliferation and Bcl-2 expression and promoting cell apoptosis and caspase-3 expression. Pharmacokinetics analysis showed that Mel@PSMA-R12-125I particles had high uptake activity in the liver, spleen, kidney, intestine, and tumor, and were accumulated in the tumor sites within the first 8 h p.i., but was rapidly cleared from all the tested organs at 24 h p.i. Administration of nanoparticles to PCa tumors in vivo showed that Mel@PSMA-R12- 125I/siAPE1 had high efficiency in suppressing PCa tumor growth. CONCLUSION: The PSMA-targeted nanocarrier encapsulating siAPE1 and melatonin is a promising therapeutic strategy for PCa and can provide a theoretical basis for patent applications.

The investigation of relationship between serum melatonin levels with Beck Depression Inventory and Beck Scale for Suicidal Ideation in suicide patients.

OBJECTIVE: Melatonin plays a role in many biological and physiological events. There are studies in the literature relating melatonin levels to many psychiatric disorders such as schizophrenia, bipolar disorder, and major depressive disorder. We aimed to investigate the relationship between serum melatonin levels with the Beck Depression Inventory and the Beck Scale for Suicidal Ideation in suicide patients. METHODS: The study was conducted prospectively with volunteer patients aged 20-50 years who were admitted to the emergency department after a suicide attempt. The social and occupational status, educational levels, marital status, and stressor factors of patients were questioned. Beck Depression Inventory and Beck Scale for Suicidal Ideation were applied to each patient included in the study. Blood melatonin levels were evaluated using the enzyme-linked immunosorbent assay method. The data were analyzed with the SPSS 23.00 statistical program. Descriptive values were expressed by the number of cases (n), percentage (%), median (interquartile range), and mean±standard deviation. The Kolmogorov-Smirnov test was used to assess the distribution of continuous variables, and the Pearson or Spearman correlation test was used to assess the relationship between disease severity and melatonin level. A value of p<0.05 was considered statistically significant. RESULTS: No statistically significant correlation was found between melatonin level and the Beck Depression Inventory score (r=-0.098, p=0.44). However, a statistically weak, inverse, and significant correlation was discovered between melatonin levels and the Beck Scale for Suicidal Ideation score (r=-0.465, p=0.00). CONCLUSION: According to our results, it was determined that there was a significant negative relationship between melatonin level and the Beck Scale for Suicidal Ideation scoring.

Melatonin mitigated methotrexate-induced hepatotoxicity through interrelated biological processes.

BACKGROUND: Hepatotoxicity associated with methotrexate (MTX) is mainly due to disruption of redox balance and development of oxidative injury to hepatocytes. Melatonin (MLT) is a potent antioxidant and regulates wide range of biological functions, processes and utilized as adjuvant for number of medical applications. The current study investigated the mitigating effect of MLT on the MTX-induced hepatotoxicity. METHODS AND RESULTS: Adult male rats received MLT (25 mg/kg, orally) for seven days flowed by single injection of MTX (20 mg/kg, ip) then treat with MLT continued for additional 7 days. The present result showed MLT treatment mitigated histopathological changes in the liver that associated with normalization of ALT and AST activity as well as bilirubin, albumin and alfa-fetoprotein levels in serum of MLT + MTX-treated rat to comparable control level. MLT treatment significantly reduced MDA content and myeloperoxidase activity while enhanced the activity of superoxide dismutase, catalase and glutathione content in the liver indicating the empowerment of the antioxidant status. Amelioration of MLT-induced oxidative stress resulted in a reduction in the inflammatory response due to antioxidant restoration and inhibited apoptosis indicated by downregulation of caspase-3 expression. The replenishment of antioxidant content powers the defense system of the hepatocytes. As a result, apoptosis is reduced which might be due to the ability of MLT protect DNA integrity thus maintaining hepatocyte functions and structure. Consequently, liver histology was protected. CONCLUSIONS: In summary, MLT modulates liver function and structure by orchestrating linked processes, including redox balance, inflammatory response, suppression of caspase-3, and DNA damage.

Greater sensitivity of the circadian system of women to bright light, but not dim-to-moderate light.

Women typically sleep and wake earlier than men and have been shown to have earlier circadian timing relative to the light/dark cycle that synchronizes the clock. A potential mechanism for earlier timing in women is an altered response of the circadian system to evening light. We characterized individual-level dose-response curves for light-induced melatonin suppression using a within-subjects protocol. Fifty-six participants (29 women, 27 men; aged 18-30 years) were exposed to a range of light illuminances (10, 30, 50, 100, 200, 400, and 2000 lux) using melatonin suppression relative to a dim control (<1 lux) as a marker of light sensitivity. Women were free from hormonal contraception. To examine the potential influence of sex hormones, estradiol and progesterone was examined in women and testosterone was examined in a subset of men. Menstrual phase was monitored using self-reports and estradiol and progesterone levels. Women exhibited significantly greater melatonin suppression than men under the 400-lux and 2000-lux conditions, but not under lower light conditions (10-200 lux). Light sensitivity did not differ by menstrual phase, nor was it associated with levels of estradiol, progesterone, or testosterone, suggesting the sex differences in light sensitivity were not acutely driven by circulating levels of sex hormones. These results suggest that sex differences in circadian timing are not due to differences in the response to dim/moderate light exposures typically experienced in the evening. The finding of increased bright light sensitivity in women suggests that sex differences in circadian timing could plausibly instead be driven by a greater sensitivity to phase-advancing effects of bright morning light.

Sleep Deprivation Induces Gut Damage via Ferroptosis.

Sleep deprivation (SD) has been associated with a plethora of severe pathophysiological syndromes, including gut damage, which recently has been elucidated as an outcome of the accumulation of reactive oxygen species (ROS). However, the spatiotemporal analysis conducted in this study has intriguingly shown that specific events cause harmful damage to the gut, particularly to goblet cells, before the accumulation of lethal ROS. Transcriptomic and metabolomic analyses have identified significant enrichment of metabolites related to ferroptosis in mice suffering from SD. Further analysis revealed that melatonin could rescue the ferroptotic damage in mice by suppressing lipid peroxidation associated with ALOX15 signaling. ALOX15 knockout protected the mice from the serious damage caused by SD-associated ferroptosis. These findings suggest that melatonin and ferroptosis could be targets to prevent devastating gut damage in animals exposed to SD. To sum up, this study is the first report that proposes a noncanonical modulation in SD-induced gut damage via ferroptosis with a clearly elucidated mechanism and highlights the active role of melatonin as a potential target to maximally sustain the state during SD.

The Role of Piromelatine on Peripheral and Hippocampal Insulin Resistance in Rat Offspring Exposed to Chronic Maternal Stress.

Prenatal stress (PNS), which alters the hypothalamic-pituitary-adrenal axis function in the offspring, predisposes to insulin resistance (IR) in later life and is associated with numerous disorders, including cognitive and memory impairments. At present, our main goal is to assess the effects of chronic piromelatine (Pir) administration, a melatonin analogue, on PNS-provoked IR in the periphery and the hippocampus in male and female offspring. Pregnant Sprague-Dawley rats were exposed to chronic stress (one short-term stressor on a daily basis and one long-term stressor on a nightly basis) from the first gestation week until birth. Vehicle or Pir 20 mg/kg were administered intraperitoneally for 21 days. Plasma glucose, serum insulin levels, and the homeostasis model assessment of insulin resistance (HOMA-IR) were determined as markers of peripheral IR. For the hippocampal IR assessment, insulin receptors (IRs) and glucose transporter 4 (GLUT4) were examined. Prenatally stressed offspring of both sexes indicated enhanced plasma glucose and serum insulin concentrations, increased HOMA-IR, and decreased hippocampal GLUT4 only in male rats. The PNS-induced changes were corrected by chronic treatment with Pir. The present results suggest that the melatoninergic compound Pir exerts beneficial effects on altered glucose/insulin homeostasis in PNS-exposed offspring.

Melatonin mediates intestinal barrier dysfunction and systemic inflammation in moderate-severe OSA patients.

BACKGROUND: Intestinal barrier dysfunction and systemic inflammation are common in obstructive sleep apnoea (OSA). We aimed to investigate the role of melatonin, an anti-inflammatory mediator, in mediating the relationships between OSA, intestinal barrier dysfunction and systemic inflammation. METHODS: Two hundred and thirty-five male participants who complained with sleep problems and underwent whole night polysomnography at our sleep centre between 2017 and 2018 were enrolled. Polysomnographic data, anthropometric measurements and biochemical indicators were collected. Serum melatonin, intestinal barrier function biomarker zonula occludens-1 (ZO-1) and inflammatory biomarkers C-reactive protein (CRP) with lipopolysaccharide (LPS) were detected. Spearman's correlation analysis assessed the correlations between sleep parameters, melatonin and biomarkers (ZO-1, LPS and CRP). Mediation analysis explored the effect of OSA on intestinal barrier dysfunction and systemic inflammation in moderate-severe OSA patients. RESULTS: As OSA severity increased, serum melatonin decreased, whereas ZO-1, LPS and CRP increased. Spearman's correlation analysis showed that serum melatonin was significantly negatively correlated with ZO-1 (r = -0.19, p < .05) and LPS (r = -0.20, p < .05) in the moderate-OSA group; serum melatonin was significantly negatively correlated with ZO-1 (r = -0.46, p < .01), LPS (r = -0.35, p < .01) and CPR (r = -0.30, p < .05) in the severe-OSA group. Mediation analyses showed melatonin explain 36.12% and 35.38% of the effect of apnoea-hypopnea index (AHI) on ZO-1 and LPS in moderate to severe OSA patients. CONCLUSIONS: Our study revealed that melatonin may be involved in mediating intestinal barrier dysfunction and systemic inflammation in moderate-to-severe OSA patients.

Investigating the role of obesity, circadian disturbances and lifestyle factors in people with schizophrenia and bipolar disorder: Study protocol for the SOMBER trial.

The aim of this study is to investigate circadian rhythms in independently living adults with obesity and mental disease, exploring the interplay between biological markers and lifestyle factors. Eighty participants divided equally into four groups; (i) people with obesity and schizophrenia; (ii) people with obesity and bipolar disorder; (iii) people with obesity without mental disease or sleep disorders, and (iv) people without obesity, mental disease or sleep disorders. Over two consecutive days, participants engage in repeated self-sampling of hair follicle and saliva; concurrently, data is collected on diet, body temperature, light exposure, sleep parameters, and physical activity by accelerometry. Hair follicles are analyzed for circadian gene expression, saliva samples for cortisol and melatonin concentrations. Circadian rhythms are investigated by cosinor analysis. The study employs a participant-tailored sampling schedule to minimize disruptions to daily routine and enhance ecological validity. The methodology aims to provide a comprehensive insight into the factors contributing to circadian disruptions in people with obesity, bipolar disorder and schizophrenia, potentially informing strategies for future management and mitigation. Trial registration: (ClinicalTrials.gov Identifier: NCT05413486).

Melatonin improves fertilization rate in assisted reproduction: Systematic review and meta-analysis.

BACKGROUND: Melatonin is a hormone produced by the pineal gland and it has antioxidant properties. AIM: This study aimed to evaluate the effects of melatonin on assisted reproductive technologies through a systematic review and a meta-analysis. MATERIALS AND METHODS: Search strategies were used in PubMed and in other databases covering the last 15 years. After screening for eligibility, 17 articles were selected for the systematic review. For the meta-analysis statistics, two groups were formed, the treatment group (with melatonin) and the control group (without melatonin) for various assisted reproduction outcomes. RESULTS: The main results were that no statistical differences were found concerning the clinical pregnancy outcome (p = 0.64), but there was a statistical difference with respect to Mature Oocytes (MII) (p = 0.001), antral follicle count (p = 0.0002), and the fertilization rate (p ≤ 0.0001). CONCLUSIONS: Melatonin had beneficial effects such as the improvement in the fertilization rate, although the authors did not obtain significance in the clinical pregnancy rate.

Foliar-applied melatonin and titanium nanoparticles modulate cadmium (Cd) toxicity through minimizing Cd accumulation and optimizing physiological and biochemical properties in sage (Salvia officinalis L.).

Notwithstanding the fact that melatonin (MT) and titanium nanoparticles (Ti NPs) alone have been widely used recently to modulate cadmium (Cd) stress in plants, there is a gap in the comparative impacts of these materials on lowering Cd toxicity in sage plants. The objective of this study was to determine how foliar application of MT and Ti NPs affected the growth, Cd accumulation, photosynthesis, water content, lipid peroxidation, and essential oil (EO) quality and quantity of sage plants in Cd-contaminated soils. A factorial experiment was conducted using MT at 100 and 200 µM and Ti NPs at 50 and 100 mg L-1 topically, together with Cd toxicity at 10 and 20 mg Cd kg-1 soil. The results showed that Cd toxicity decreased plant growth and enhanced lipid peroxidation. The Cd stress at 20 mg kg-1 soil resulted in increases in Cd root (693%), Cd shoot (429%), electrolyte leakage (EL, 29%), malondialdehyde (MDA, 72%), shoot weight (31%), root weight (27%), chlorophyll (Chl) a + b (26%), relative water content (RWC, 23%), and EO yield (30%). The application of MT and Ti NPs controlled drought stress by reducing MDA and EL, enhancing plant weight, Chl, RWC, and EO production, and minimizing Cd accumulation in plant tissues. The predominant compounds in the EO were α-thujone, 1,8-cineole, ß-thujone, camphor, and α-humulene. MT and Ti NPs caused α-thujone to rise, whereas Cd stress caused it to fall. Based on heat map analysis, MDA was the trait that was most sensitive to treatments. In summary, the research emphasizes the possibility of MT and Ti NPs, particularly MT at 200 µM, to mitigate Cd toxicity in sage plants and enhance their biochemical reactions.

ß-Hydroxybutyrate and melatonin suppress maladaptive UPR, excessive autophagy and pyroptosis in Aß 1-42 and LPS-Induced SH-SY5Y cells.

BACKGROUND: Alzheimer's disease is a neurological disease characterized by the build-up of amyloid beta peptide (Aß) and lipopolysaccharide (LPS), which causes synapse dysfunction, cell death, and neuro-inflammation. A maladaptive unfolded protein response (UPR), excessive autophagy, and pyroptosis aggravate the disease. Melatonin (MEL) and hydroxybutyrate (BHB) have both shown promise in terms of decreasing Aß pathology. The goal of this study was to see how BHB and MEL affected the UPR, autophagy, and pyroptosis pathways in Aß1-42 and LPS-induced SH-SY5Y cells. MATERIALS AND METHODS: Human neuroblastoma SH-SY5Y cells were treated with BHB, MEL, or a combination of the two after being exposed to A ß1-42 and LPS. Cell viability was determined using the MTT test, and gene expression levels of UPR (ATF6, PERK, and CHOP), autophagy (Beclin-1, LC3II, P62, and Atg5), and pyroptosis-related markers (NLRP3, TXNIP, IL-1ß, and NFκB1) were determined using quantitative Real-Time PCR (qRT-PCR). For statistical analysis, one-way ANOVA was employed, followed by Tukey's post hoc test. RESULTS: BHB and MEL significantly increased SH-SY5Y cell viability in the presence of A ß1-42 and LPS. Both compounds inhibited the expression of maladaptive UPR and autophagy-related genes, as well as inflammatory and pyroptotic markers caused by Aß1-42 and LPS-induced SH-SY5Y cells. CONCLUSION: BHB and MEL rescue neurons in A ß1-42 and LPS-induced SH-SY5Y cells by reducing maladaptive UPR, excessive autophagy, and pyroptosis. More research is needed to fully comprehend the processes behind their beneficial effects and to discover their practical applications in the treatment of neurodegenerative disorders.