Protective Effect Of Melatonin Research Articles

Melatonin lessens the susceptibility to atrial fibrillation in sleep deprivation by ameliorating Ca2+ mishandling in response to mitochondrial oxidative stress.

The antiarrhythmic effect of melatonin(MLT) has been demonstrated in several studies; however, this hypothesis has recently been contested. Our research seeks to determine if exogenous MLT supplementation can reduce atrial fibrillation (AF) susceptibility due to sleep deprivation (SD) by addressing Ca2+ mishandling and atrial mitochondrial oxidative stress. Adult rats received daily MLT or vehicle injections and were exposed to a modified water tank. We evaluated MLT's impact on AF susceptibility by analyzing atrial electrical and structural changes, calcium handling, and oxidative stress markers. Techniques used included electrophysiological recording, echocardiography, optical mapping, histopathology, and molecular assays to understand MLT's protective effects against sleep deprivation-induced AF. Our findings indicate that MLT treatment effectively mitigates SD-induced AF, safeguards against atrial structural alterations, diminishes mitochondrial oxidative stress and normalizes calcium dynamics. Notably, MLT corrected calcium transient duration (CaD), action potential duration (APD), and conduction heterogeneity, shortened calcium transient refractoriness, and improved arrhythmogenic atrial alternans and spatially discordant alternans, thereby lowering the arrhythmogenic potential of the atria during sleep deprivation. In terms of mechanisms, MLT prevents SD-induced activation of ROS/CaMKII in atrial cardiomyocytes, reversing calcium transient refractoriness and inhibiting arrhythmogenic alternans. MLT significantly decreases the susceptibility to SD-induced AF by ameliorating mitochondrial oxidative stress and Ca2+ mishandling. These findings suggest a potential therapeutic application of MLT as an antiarrhythmic intervention for SD-related AF and underscore the need for further investigation, including clinical studies, to validate these mechanisms.

The Protective Effects of Melatonin on Hainan Black Goats Under Heat Stress: Understanding Its Actions and Mechanisms.

As the global climate changes, high temperatures will cause heat stress, which significantly affects the productive efficiency of livestock. Currently, there is a lack of efficient methods to use in targeting this issue. In this study, we report that melatonin supplementation may represent an alternative method to reduce the negative impact of heat stress on livestock, particularly in Hainan black goats. Our results show that melatonin treatment increased the average daily gain of Hainan black goats that were exposed to constantly high temperatures for two months compared to controls. Our mechanistic exploration revealed that melatonin treatment not only reduced the oxidative stress and inflammatory reaction caused by heat stress but also improved goats' metabolic capacity, promoting their growth and development. More importantly, for the first time, we observed that melatonin treatment modified the abundance of the intestinal microflora, altering the metabolism of the goats, which further improved their tolerance to constant heat stress.

Protective Effects of Melatonin on Kidney Function Against Contrast Media-Induced Kidney Damage in Patients With Chronic Kidney Disease: A Prospective, Randomized, Double-Blinded, Placebo-Controlled Trial.

Patients with chronic kidney disease (CKD) are at increased risk of acute kidney injury following exposure to contrast media. We evaluated the effect of melatonin, a potent antioxidant, as a protective strategy against contrast-induced acute kidney injury (CI-AKI), with a focus on molecular mechanisms. We randomized patients with an eGFR < 60 mL/min/1.73 m2 undergoing coronary angiography (CAG) into melatonin (10 mg twice daily) or placebo groups. Treatment started 48 h before CAG and continued for a total of 6 days. Peripheral blood mononuclear cells (PBMCs) were collected at baseline, at the time of CAG, and at 6, 24, 48, 72 h, and Day 30 post-procedure. The primary outcome was the incidence of CI-AKI; secondary outcomes included kidney function, oxidative stress, mitochondrial function, and cell death pathways. Forty patients were randomized into either the treatment or placebo group. All subsequent analyses were conducted on an as-treat basis. The incidence of CI-AKI was significantly lower in the melatonin group compared to the placebo group (25% vs. 60%, p = 0.025). The melatonin group showed a significantly smaller percentage change in plasma neutrophil gelatinase-associated lipocalin (NGAL)at all time points. In the PBMC study, cellular oxidative stress was significantly reduced in the melatonin group at each time point, and mitochondrial oxidative stress was lower at 48-72 h. Mitochondrial respiration improved significantly, and both necrosis and necroptosis were reduced at 24 h. Melatonin administration effectively reduced the incidence of CI-AKI in CKD patients undergoing CAG. This protective effect was associated with decreased oxidative stress, enhanced mitochondrial function, and reduced cell death, suggesting melatonin as a promising preventive strategy for CI-AKI. Trial Registration: TCTR20210123004.

RETRACTION: Protective Effect of Melatonin in a Non-Septic Shock Model Induced by Zymosan in the Rat.

S. Cuzzocrea, B. Zingarelli, G. Costantino, and A. R. Caputi, "Protective Effect of Melatonin in a Non-Septic Shock Model Induced by Zymosan in the Rat," Journal of Pineal Research 25, no. 1 (1998): 24-33, https://doi.org/10.1111/j.1600-079X.1998.tb00382.x. The above article, published online on 30 January 2007 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Gianluca Tosini; and John Wiley & Sons Ltd. The retraction has been agreed due to concerns raised by third parties on the data presented in the article. Specifically, there is evidence of image duplication between Figures 6A and 6C, indicating that the same biological sample has been utilized to represent two distinct experimental conditions. The article is retracted as the editors have lost trust in the accuracy and integrity of the overall body of data presented in the article and consider its conclusions invalid.

Melatonin Protects Against Cocaine-Induced Blood-Brain Barrier Dysfunction and Cognitive Impairment by Regulating miR-320a-Dependent GLUT1 Expression.

Cocaine abuse has been strongly linked to blood-brain barrier (BBB) dysfunction, though the exact mechanism by which cocaine disrupts the BBB remains unclear. In this study, we found that cocaine treatment reduces the expression of glucose transporter 1 (GLUT1) in brain microvascular endothelial cells, a key factor in cocaine-induced brain glucose uptake, BBB leakage, and cognitive impairment. Mechanistically, our results show that cocaine upregulates miR-320a, which in turn suppresses GLUT1 expression via the beta 2-adrenergic receptor (ADRB2). Notably, the administration of adeno-associated viruses encoding full-length GLUT1 or miR-320a inhibitors to the brain microvascular endothelium significantly mitigated cocaine-induced BBB leakage and cognitive deficits. Additionally, we discovered that melatonin, a well-known neuroprotective hormone, alleviates cocaine-induced BBB disruption and cognitive impairment. This protective effect of melatonin was mediated through the upregulation of miR-320a-dependent GLUT1 expression in brain endothelial cells via MT1 receptor-mediated inhibition of the cAMP/PKA/CREB signaling pathway. In conclusion, our findings demonstrate that cocaine downregulates brain microvascular GLUT1, leading to BBB dysfunction, and highlight melatonin as a potential therapeutic agent for treating cocaine-related complications.

Melatonin Alleviates Albumin-Induced Tubular Cell Injury by Activating Clock-Controlled Nuclear Enriched Abundant Transcript 1-Mediated Proliferation.

The pleiotropic and protective effects of melatonin have been demonstrated in a variety of animal models of renal injury. While coding RNAs regulated by melatonin in renal tissues are well identified, the functional involvement of long noncoding RNAs (lncRNAs) in melatonin signaling remains undefined. This study identified nuclear enriched abundant transcript 1 (NEAT1), a clock-controlled lncRNA that was upregulated by melatonin through the BMAL1/CLOCK heterodimer in renal tubular epithelial cells (TECs). Mechanistic studies showed that melatonin enhanced NEAT1 expression via increasing BMAL1 stability and thereby the enrichment of BMAL1 on NEAT1's promoter. Further studies have revealed that NEAT1 promotes the proliferation of TECs by increasing levels of H3K27ac and H3K4me1 at the promoter regions of the proliferation gene MKI67. Treatment of albumin-injured TECs with melatonin promoted proliferation by transactivating NEAT1 and restoring the expression levels of core clock genes and MKI67. Moreover, melatonin treatment ameliorated proteinuria, hypoalbuminemia, and fibrotic lesions, which was correlated with increased levels of core clock genes, H3K27ac, Mki67, and Neat1 in experimental MN kidneys. Melatonin mediates a novel regulatory axis, BMAL1-NEAT1-MKI67, in TEC proliferation, establishing potential therapeutic targets for MN and other renal diseases.

Melatonin Protects Against Mitochondrial Dyshomeostasis and Ovarian Damage Caused by Chronic Unpredictable Mild Stress Through the eIF2α-AFT4 Signaling Pathway in Mice.

Stress is an emotional state caused by an unexpected external environmental change or stimulus, and several experiments have demonstrated its negative impact on ovarian function, ultimately affecting reproductive ability. Melatonin (MT) has been shown to facilitate oocyte maturation and enhance ovarian function by regulating mitochondrial function. However, the specific effect and underlying molecular mechanisms of MT on stress-induced ovarian dysfunction remain largely unknown. In this study, we established a mouse model of chronic unpredictable mild stress (CUMS) to investigate its impact on ovarian function. Our findings revealed that CUMS led to premature ovarian insufficiency (POI) in mice, characterized by a reduction in follicle numbers and decreased levels of anti-Müllerian hormone (AMH) and bone morphogenetic protein 15 (BMP15). Furthermore, CUMS caused decreased expression of mitochondrial fission protein 1 (FIS1) and enhanced level of mitochondrial fusion protein optic atrophy 1(OPA1), mitofusin1(MFN1), as well as nucleus-encoded protein succinate dehydrogenase complex A (SDHA), reflecting mitochondrial dyshomeostasis. Additionally, CUMS resulted in excessive autophagy and apoptosis. However, MT reversed these effects and improved ovarian damage. Importantly, the protective effects of MT were mediated through the inhibition of the eIF2α-AFT4 pathway. Overall, this study provides valuable insights into the treatment of POI caused by CUMS.

Melatonin's protective effect against placental transfer of Methadone in mice: An experimental study.

Methadone is a substance widely used in the substitution treatment of opiate addiction in pregnancy. The placental transfer of methadone influences oxidative stress processes. Melatonin is a hormone with antioxidant activity. This study aimed to evaluate the protective effects of melatonin on oxidative stress induced by the transfer of transplacental methadone in mice. In this experimental study, 36 female mice (2 months old, 20 2 gr) were divided into 6 groups (n = 6/each) of control, methadone (0.3 mg/kg intraperitoneal, single dose) and melatonin (2, 4, and 6 mg/kg/day gavage) were administered 30 min before methadone, and one group received melatonin alone (0.6 mg/kg with single injection). Administration for 10 consecutive days of the pregnancy period was done. After baby mice were born, all neonatal mice were killed by beheading or sacrificing after anesthesia. The liver tissues were extracted. The samples were then sent for studying oxidative stress markers such as lipid peroxidation, glutathione, and protein carbonyl contents. Also, we have used the immunohistochemistry method for apoptotic markers such as: BAX, Bcl2, and Caspase3 for assaying apoptosis. This study has shown that methadone caused a significant decrease in glutathione concentration (p = 0.035). Also, we observed a significant increase in lipid peroxidation and protein carbonyl contents (p = 0.015, 0.025 respectively). However, melatonin treatment significantly inhibited oxidative stress markers (p = 0.025). Also, apoptosis assay has shown that melatonin could decrease BAX and Caspase 9 as apoptotic and increase Bcl2 as an antiapoptotic proteins (p = 0.015). Our findings have shown that melatonin has a protective effect against oxidative stress and apoptosis induced by the placental transfer of methadone via its antioxidant effects.

Protective effect of melatonin against radiobiological damage in the brain of rats exposed to low and high dose rate radiotherapy

This study aimed to investigate the radioprotective effect of melatonin (MLT) on brain damage in rats exposed to low and high dose rate radiotherapy. The dose rates of 10 MV photon beams used in the study were 600 MU/min and 2400 MU/min for low dose rate radiotherapy (LDR_RT) and high dose rate radiotherapy (HDR_RT), respectively. A total of 46 female Wistar albino rats aged between 8 and 12 weeks were divided in 6 groups. These groups were control, MLT, LDR_RT, HDR_RT, LDR_RT plus MLT and HDR_RT plus MLT, respectively. Rats in the radiation group received 16 Gy single dose whole body radiotherapy. Rats in the LDR_RT plus MLT and HDR_RT plus MLT groups received 10 mg/kg melatonin by intraperitoneal injection 15 min before radiotherapy. The rats were sacrificed 48 h after radiotherapy. Biochemical and histopathological methods analyzed radiation damage in rats. There was a statistically significant difference between the LDR_RT and HDR_RT radiation groups and the control group in terms of biochemical and histopathological parameters (p < 0.05). In the groups that received only LDR_RT and HDR_RT, the moderate neuro-degeneration scores were 1 and 4, respectively, while the moderate neuro-degeneration scores were 0 and 2 when MLT was applied to these groups. Superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) enzymes were decreased due to radiotherapy, whereas these enzymes were improved in MLT-treated groups. In conclusion, melatonin was found to be effective as a radioprotective agent in the prevention of brain damage caused by exposure to 10 MV photon radiation at dose rates of 600 MU/min and 2400 MU/min.

Significant Interaction between Melatonin and Titanium Bone Implants: Available Evidence and Future Research Directions.

The trend in the incidence rate of bone fractures has been upward and as a result, the burden associated with orthopedic fractures has increased significantly. Titanium (Ti) implants are considered a preferred method of managing long bone fractures. However, no benefit comes without some downside, and using Ti implants is associated with several complications. In this respect, it was observed that in bones, Ti can disrupt the bone healing process by disturbing the balance of osteoclast and osteoblast activation and also increasing the production of inflammatory cytokines. Melatonin is a widely-acting molecule that possesses strong anti-oxidant features. This molecule reinforces mineral density and improves bone formation processes. In this review, we focused on the protective effect of melatonin in mitigating the Ti-related complications.

Melatonin and resveratrol alleviate molecular and metabolic toxicity induced by Bisphenol A in endometrial organoids

Bisphenol A (BPA), a widespread environmental contaminant, poses concerns due to its disruptive effects on physiological functions of the uterine endometrium. In contrast, melatonin (MT) and Resveratrol (RSV) are under scrutiny for their potential protective roles against BPA-induced damage. For the efficacy and ethical concerns in the animal test, endometrial organoids, three-dimensional models mimicking endometrium, serve as crucial tools for unraveling the impact of environmental factors on reproductive health. This study aimed to comprehensively characterize the morphological, molecular and metabolic responses of porcine endometrial organoids to BPA and assess the potential protective effects of MT and RSV. Porcine uteri were prepared, digested with collagenase, mixed with Matrigel, and incubated at 38°C with 5 % CO2. Passaging involved dissociation through trypsin-EDTA treatment and subculturing. The culture medium was refreshed every 2–3 days. To investigate the environmental impact on reproductive health, endometrial organoids were treated with BPA (0.5 µM), MT (with/without BPA at 0.1 µM), and/or RSV (10 µM). Various molecular screening using gene expression, western blotting, immunofluorescence staining, and metabolites profiling were assessed the effects of BPA, MT, and RSV in terms of cell viability, morphology, reproductivity, and metabolism alteration in the endometrial organoids. As expected, BPA induced structural and molecular disruptions in organoids, affecting cytoskeletal proteins, Wnt/β-catenin signaling, and epithelial/mesenchymal markers. It triggered oxidative stress and apoptotic pathways, altered miRNA expression, and disrupted the endocannabinoid system. The level of glucose, galactose, and essential amino acids were increased or decreased by approximately 1.5–3 times in BPA-treated groups compared to the control groups (p-value < 0.05), indicating metabolic changes. Moreover, MT and RSV treated groups exhibited protective effects, mitigating BPA-induced disruptions across multiple pathways. For the first time, our study models endometrial organoids, advancing understanding of environmental impacts on reproductive health.

Protective effect of melatonin against metabolic disorders and neuropsychiatric injuries in type 2 diabetes mellitus mice

BackgroundType 2 diabetes mellitus (T2DM) is a metabolic disease characterized by hyperglycemia and progressive cognitive dysfunction, and our clinical investigation revealed that the plasma concentration of melatonin (Mlt) decreased and was closely related to cognition in T2DM patients. However, although many studies have suggested that Mlt has a certain protective effect on glucose and lipid metabolism disorders and neuropsychiatric injury, the underlying mechanism of Mlt against T2DM-related metabolic and cognitive impairments remains unclear. PurposeThe aim of the present study was to investigate the therapeutic effect of Mlt on metabolic disorders and Alzheimer's disease (AD)-like neuropsychiatric injuries in T2DM mice and to explore the possible underlying molecular mechanism involved. MethodsA T2DM mouse model was established by a combination of a high-fat diet (HFD) and streptozotocin (STZ, 100 mg/kg, i.p.), and Mlt (5, 10 or 20 mg/kg) was intragastrically administered for six consecutive weeks. The serum levels of glycolipid metabolism indicators were measured, behavioral performance was tested, and the protein expression of key molecules involved in the regulation of synaptic plasticity, circadian rhythms, and neuroinflammation in the hippocampus was detected. Moreover, the fluorescence intensities of glial fibrillary acidic protein (GFAP), ionized calcium binding adapter molecule 1 (IBA-1), amyloid β-protein (Aβ) and phosphorylated Tau (p-Tau) in the hippocampus were also observed. ResultsTreatment with Mlt not only improved T2DM-related metabolic disorders, as indicated by increased serum concentrations of fasting blood glucose (FBG), glycosylated hemoglobin (HbAlc), insulin (INS), total cholesterol (TC) and triglyceride (TG), improved glucose tolerance and liver and pancreas function but also alleviated AD-like neuropsychiatric injuries in a HFD/STZ-induced mouse model, as indicated by decreased immobility time in the tail suspension test (TST) and forced swimming test (FST), increased preference indices of novel objects or novel arms in the novel object recognition test (NOR) and Y-maze test (Y-maze), and improved platform positioning capability in the Morris water maze (MWM) test. Moreover, treatment with Mlt also improved the hyperactivation of astrocytes and microglia in the hippocampus of mice, accompanied by reduced expression of interleukin 1β (IL-1β), interleukin 6 (IL-6), tumor necrosis factor (TNF-α), Aβ, and p-Tau and increased expression of brain-derived neurotrophic factor (BDNF), Synapsin I, Synaptotagmin I, melatonin receptor 1B (MT1B), brain muscle arnt-like protein 1 (Bmal1), circadian locomotor output cycles kaput (Clock), period 2 (Per2), and cryptochrome 2 (Cry2). ConclusionMlt alleviated T2DM-related metabolic disorders and AD-like neuropsychiatric injuries in a HFD/STZ-induced mouse model, possibly through a mechanism involving the regulation of glial activation and associated neuroinflammation and the balancing of synaptic plasticity and circadian rhythms in the hippocampus.

Evaluating the Antidepressant-like Properties of Melatonin and Vitamin D3 Combination in Mice Subjected to Restraint Stress: Investigating the Involvement of Oxidative Stress

Background: Increased levels of oxidative stress are connected with depression. Due to the melatonin's antioxidant effects and Vitamin D3 (Vit D3)'s regulatory effect on the biosynthesis of neurotransmitters and neurotrophic factors, the present study investigated the possible protective effect of melatonin and Vit D3 combination on restraint stress-induced depression-like behaviors in mice. Methods: After being subjected to restraint stress, mice were divided into six groups using a randomization process. These groups included non-stressed and stressed vehicle-treated groups, as well as groups treated with Vit D3 (25 μg/kg/day), melatonin (10 mg/kg) or fluoxetine. A group also received a combination of both melatonin and Vit D3. The Forced Swimming Test (FST), and Open Field Test (OFT) were conducted to evaluate behavioural changes. The Malondialdehyde (MDA) level and Catalase (CAT), Superoxide Dismutase (SOD) activity, and ADP/ATP ratio were evaluated in the hippocampus of mice. Results: Restraint stress lengthened the immobility period in FST, while melatonin, Vit D3, and their combination all significantly reversed this impact. Co-administration of melatonin and Vit D3 was more effective than melatonin or Vit D3 administration alone at reducing immobility time. The exposure of mice to restraint stress has been linked to an elevation in the ADP/ATP ratio and oxidative stress in their hippocampus; however, these effects are reversed by the administration of melatonin and Vit D3 (10 mg/kg) alone or in combination. Melatonin and Vit D3 combination increased the hippocampus CAT activity compared with melatonin and Vit D3 alone. Conclusion: The current study's findings suggested that Vit D3 may enhance melatonin's potential as an antidepressant in FST.

Protective effect of melatonin against methamphetamine-induced attention deficits through miR-181/SIRT1 axis in the prefrontal cortex.

Methamphetamine (METH) is an addictive psychostimulant with deleterious effects on the central nervous system. Chronic use of METH in high doses impairs cognition, attention and executive functions, but the underlying mechanisms are still unclear. Sirtuin 1 (SIRT1) is a post-translational regulator that is downregulated following METH neurotoxicity. Melatonin is a neuroprotective hormone that enhances mitochondrial metabolism. Here, we evaluated the effect of melatonin on METH-induced attention deficits disorder and the involvement of the miR-181/SIRT1 axis in melatonin neuroprotection. METH at a dose of 5mg/kg was injected for 21 consecutive days. The animals were assigned to receive either melatonin or the vehicle after METH injections. Attention levels were evaluated with abject-based attention test. In the prefrontal cortex, the expression levels of miR-181a-5p, SIRT1, p53 and CCAR2, as well as the mtDNA copy numbers were evaluated using qRT-PCR and western blotting. The outcomes revealed that melatonin treatment following METH injections improved METH-induced attention deficits. METH toxicity can be associated with changes in the miR-181/SIRT1 axis, elevated levels of p53 and COXII, and decreased levels of mtDNA in the prefrontal cortex of adult rats. Interestingly, administration of melatonin can improve the expression of these molecules and reduces the toxic effects of METH. Melatonin ameliorated the neurotoxicity of METH in the prefrontal cortex and the miR-181/SIRT1 axis is involve in the protective effects of melatonin. However, melatonin can be potentially administrated to improve attention impairment in METH use disorders.

Melatonin suppresses atherosclerosis by ferroptosis inhibition via activating NRF2 pathway.

Melatonin (MLT), a conserved small indole compound, exhibits anti-inflammatory and antioxidant properties, contributing to its cardioprotective effects. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is associated with atherosclerosis disease risk, and is known as an atherosclerosis risk biomarker. This study aimed to investigate the impact of MLT on Lp-PLA2 expression in the atherosclerotic process and explore the underlying mechanisms involved. Invivo, ApoE-/- mice were fed a high-fat diet, with or without MLT administration, after which the plaque area and collagen content were assessed. Macrophages were pretreated with MLT combined with ox-LDL, and the levels of ferroptosis-related proteins, NRF2 activation, mitochondrial function, and oxidative stress were measured. MLT administration significantly attenuated atherosclerotic plaque progression, as evidenced by decreased plaque area and increased collagen. Compared with those in the high-fat diet (HD) group, the levels of glutathione peroxidase 4 (GPX4) and SLC7A11 (xCT, a cystine/glutamate transporter) in atherosclerotic root macrophages were significantly increased in the MLT group. Invitro, MLT activated the nuclear factor-E2-related Factor 2 (NRF2)/SLC7A11/GPX4 signaling pathway, enhancing antioxidant capacity while reducing lipid peroxidation and suppressing Lp-PLA2 expression in macrophages. Moreover, MLT reversed ox-LDL-induced ferroptosis, through the use of ferrostatin-1 (a ferroptosis inhibitor) and/or erastin (a ferroptosis activator). Furthermore, the protective effects of MLT on Lp-PLA2 expression, antioxidant capacity, lipid peroxidation, and ferroptosis were decreased in ML385 (a specific NRF2 inhibitor)-treated macrophages and in AAV-sh-NRF2 treated ApoE-/- mice. MLT suppresses Lp-PLA2 expression and atherosclerosis processes by inhibiting macrophage ferroptosis and partially activating the NRF2 pathway.

Cuproptosis is involved in decabromodiphenyl ether-induced ovarian dysfunction and the protective effect of melatonin

Decabromodiphenyl ether (BDE-209) has been universally detected in environmental media and animals, but its damage to ovarian function and mechanism is still unclear, and melatonin has been shown to improve mammalian ovarian function. This study aimed to investigate the toxic effects of BDE-209 on the ovary and tried to improve ovarian function with melatonin. Herein, BDE-209 was administered orally to female SD rats for 60 days. Enzyme-linked immunosorbent assay, HE staining, transcriptome analysis, qPCR and immunohistochemical staining were used to explore and verify the potential mechanism. We found that BDE-209 exposure had effects on the ovary, as shown by abnormal changes in the estrous cycle, hormone levels and ovarian reserve function in rats, while increasing the proportion of collagen fibres in ovarian tissue. In terms of mechanism, cuproptosis, a form of cell death, was identified to play a crucial role in BDE-209-induced ovarian dysfunction, with the phenotype manifested as copper salt accumulation in ovary, downregulation of glutathione pathway metabolism and copper transfer molecule (ATP7A/B), and upregulation of FDX1, lipoic acid pathway (LIAS, LIPT1), pyruvate dehydrogenase complex components (DLAT, PDHB, PDHA1), and copper transfer molecule (SLC31A1). Furthermore, possible interventions were explored. Notably, a supplement with melatonin has a repair effect on the damage to ovarian function by reversing the gene expression of cuproptosis-involved molecules. Overall, this study revealed that cuproptosis is involved in BDE-209-induced ovarian damage and the beneficial effect of melatonin on ovarian copper damage, providing evidence for the prevention and control of female reproductive damage induced by BDE-209.

Protective effect of melatonin on imidacloprid-induced pyroptosis and ferroptosis by mediating peptidoglycan in the gut of the common carp (Cyprinus carpio)

Imidacloprid (IMI) is a contaminant widespread in surface water, causing serious intestinal damage in the common carp. Melatonin (MT), an endogenous indoleamine hormone, plays a crucial role in mitigating pesticide-induced toxicity. Our previous research has demonstrated that MT effectively reduces the production of intestinal microbial-derived signal peptidoglycan (PGN) induced by IMI, thereby alleviating intestinal tight junction injuries in the common carp. In this study, we performed a transcriptomic analysis to explore the effect of MT on the IMI exposure-induced gut damage of the common carp. The results elucidated that the ferroptosis, mitogen-activated protein kinases (MAPKs), and nucleotide oligomerization domain (NOD)-like signaling pathways were significantly associated with IMI exposure and MT treatment. Meanwhile, the exposure to IMI resulted in the formation of pyroptotic bodies and distinct morphological features of ferroptosis, both mitigated with the addition of MT. Immunofluorescence double staining demonstrated that MT abolished the elevated expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and Gasdermin D (GSDMD) induced by IMI, as well as reduced expression of ferritin heavy chains (FTH) and glutathione peroxidase 4 (GPX4) in gut tissues. Subsequently, we found that the exposure to IMI or PGN enhanced the expression of toll-like receptors (TLR) 2 (a direct recognition receptor of PGN) triggering the P38MAPK signaling pathway, thereby aggravating the process of pyroptosis and ferroptosis of cell models. The addition of MT or SB203580 (a P38MAPK inhibitor) significantly reduced pyroptotic cells, and also decreased iron accumulation. Consequently, these results indicate that MT alleviates IMI-induced pyroptosis and ferroptosis in the gut of the common carp through the PGN/TLR2/P38MAPK pathway.

Protective Effects of Melatonin against Carcinogen-Induced Oxidative Damage in the Thyroid.

Melatonin, primarily synthesized in the pineal gland, plays a crucial role in regulating circadian rhythms and possesses significant antioxidative properties. By neutralizing free radicals and reducing oxidative stress, melatonin emerges as a promising agent for the prevention and therapy of many different disorders, including cancer. This paper reviews the relationship between the thyroid gland and melatonin, presenting experimental evidence on the protective effects of this indoleamine against oxidative damage to macromolecules in thyroid tissue caused by documented carcinogens (as classified by the International Agency for Research on Cancer, IARC) or caused by potential carcinogens. Furthermore, the possible influence on cancer therapy in humans and the overall well-being of cancer patients are discussed. The article highlights melatonin's essential role in maintaining thyroid health and its contribution to management strategies in patients with thyroid cancer and other thyroid diseases.

Protective effects of melatonin on AT1, ACE2, and Mas genes expression in induced diabetic aortic rats

Protective effects of melatonin on AT1, ACE2, and Mas genes expression in induced diabetic aortic rats

Melatonin modulates lipopolysaccharides-induced inflammatory response and maintains circadian rhythm associated with histone H3 acetylation in bovine mammary epithelial cells

Lipopolysaccharides (LPS) can disrupt the barrier function of mammary epithelial cells, leading to mastitis. The protective effects of melatonin (MT) have been demonstrated against various infections, but the underlying mechanism remains unclear in LPS-induced bovine mastitis. This study, therefore, aimed to investigate the modulatory effect of melatonin (MT) on LPS-induced inflammation in bovine mammary epithelial cells (BMECs), its influence on the disruption of circadian rhythms triggered by this inflammation, and the potential underlying molecular mechanisms. BMECs extracted from lactating cows underwent one of 4 treatments in triplicates for 12 h simultaneously: Control (CON), LPS (exposed to LPS at 1 μg/mL), MT (exposed to MT at 40 μmol/L), or LPS + MT (LMT, exposed to both LPS at 1 μg/mL and MT at 40 μmol/L). The flow cytometry results demonstrated that MT reduced the ratios of cells in the G0/G1 phase but increased those in the G2/M phase (P < 0.05). Additionally, MT inhibited p65 phosphorylation levels, leading to a decreased cellular inflammatory response (P < 0.05). Treatment with MT elevated the acetylation levels of histone H3 in BMECs compared to the LPS treatment (P < 0.05). The circadian rhythm analysis revealed a significant increase in the gene expression levels of BMAL1, PER1, CRY1, and CRY2 at the 12 h mark in LMT compared to the LPS treatment (P < 0.05). Additionally, this study assessed the fluctuations in clock-related genes PER2 and CLOCK over 24 h under various treatment conditions. The results demonstrated that BMECs exposed to LMT treatment exhibited a significant increase in the expression levels of CLOCK and PER2 genes from 4 to 24 h in comparison to the LPS treatment (P < 0.05). Moreover, cells in the LMT treatment displayed a more regular circadian rhythm cycle compared to those in the LPS treatment. Overall, the data suggest that MT could alleviate the inflammatory response in BMECs by upregulating histone H3 acetylation, thereby maintaining the physiological circadian rhythm of BMECs.