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Reproductive Toxicology (Elmsford, N.Y.) Mar 2024This review summarizes data related to the potential importance of the ubiquitously functioning antioxidant, melatonin, in resisting oxidative stress and protecting... (Review)
Review
This review summarizes data related to the potential importance of the ubiquitously functioning antioxidant, melatonin, in resisting oxidative stress and protecting against common pathophysiological disorders that accompany implantation, gestation and fetal development. Melatonin from the maternal pineal gland, but also trophoblasts in the placenta, perhaps in the mitochondria, produce this molecule as a hedge against impairment of the uteroplacental unit. We also discuss the role of circadian disruption on reproductive disorders of pregnancy. The common disorders of pregnancy, i.e., stillborn fetus, recurrent fetal loss, preeclampsia, fetal growth retardation, premature delivery, and fetal teratology are all conditions in which elevated oxidative stress plays a role and experimental supplementation with melatonin has been shown to reduce the frequency or severity of these conditions. Moreover, circadian disruption often occurs during pregnancy and has a negative impact on fetal health; conversely, melatonin has circadian rhythm synchronizing actions to overcome the consequences of chronodisruption which often appear postnatally. In view of the extensive findings supporting the ability of melatonin, an endogenously-produced and non-toxic molecule, to protect against experimental placental, fetal, and maternal pathologies, it should be given serious consideration as a supplement to forestall the disorders of pregnancy. Until recently, the collective idea was that melatonin supplements should be avoided during pregnancy. The data summarized herein suggests otherwise. The current findings coupled with the evidence, published elsewhere, showing that melatonin is highly protective of the fertilized oocyte from oxidative damage argues in favor of its use for improving pregnancy outcome generally.
Topics: Pregnancy; Female; Humans; Melatonin; Placenta; Pregnancy Outcome; Antioxidants; Fetus
PubMed: 38185312
DOI: 10.1016/j.reprotox.2024.108534 -
Biomedicine & Pharmacotherapy =... May 2024Melatonin is a highly conserved molecule produced in the human pineal gland as a hormone. It is known for its essential biological effects, such as antioxidant activity,... (Review)
Review
Melatonin is a highly conserved molecule produced in the human pineal gland as a hormone. It is known for its essential biological effects, such as antioxidant activity, circadian rhythm regulator, and immunomodulatory effects. The gut is one of the primary known sources of melatonin. The gut microbiota helps produce melatonin from tryptophan, and melatonin has been shown to have a beneficial effect on gut barrier function and microbial population. Dysbiosis of the intestinal microbiota is associated with bacterial imbalance and decreased beneficial microbial metabolites, including melatonin. In this way, low melatonin levels may be related to several human diseases. Melatonin has shown both preventive and therapeutic effects against various conditions, including neurological diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. This review was aimed to discuss the role of melatonin in the body, and to describe the possible relationship between gut microbiota and melatonin production, as well as the potential therapeutic effects of melatonin on neurological diseases.
Topics: Melatonin; Humans; Gastrointestinal Microbiome; Nervous System Diseases; Animals; Dysbiosis
PubMed: 38518598
DOI: 10.1016/j.biopha.2024.116487 -
Theriogenology Aug 2023Understanding the aging mechanism of the male reproductive system and developing anti-aging interventions are essential for preventing age-related male infertility. The...
Understanding the aging mechanism of the male reproductive system and developing anti-aging interventions are essential for preventing age-related male infertility. The pineal hormone melatonin has been effectively used as an antioxidant and anti-apoptotic molecule in various cells and tissues. However, the effects of melatonin on d-galactose (D-gal)-induced aging have not been studied with regards to testicular function. Thus, we investigated whether melatonin suppresses the dysfunction of male reproductive function induced by D-gal treatment. The mice were divided into the following four groups receiving treatments for six weeks: phosphate-buffered saline (PBS) group, d-galactose (200 mg/kg) group, melatonin (20 mg/kg) group, and d-galactose (200 mg/kg)+ melatonin (20 mg/kg) group. At six weeks of treatments, sperm parameters, body and testes weight, gene and protein expression of germ cell and spermatozoa marker were analyzed. Our results showed that melatonin suppressed the decrease in body weight, sperm vitality, motility, and gene expression levels of spermatozoa markers such as Protamine 1, PGK2, Camk4, TP1, and Crem in the testis of D-gal-induced aging models. However, the gene expression levels of the pre-meiotic and meiotic markers in the testes did not change in the D-gal-injected model. The injection of D-gal impaired the decreased expression of steroidogenic enzyme genes, such as HSD3b1, Cyp17a1, and Cyp11a1, but melatonin inhibited the decrease in the expression of these genes. In addition, protein levels of spermatozoa and germ cell markers were evaluated by immunostaining and immunoblotting. Consistent with the qPCR results, PGK2 protein levels were decreased by d-galactose treatment. A decrease in PGK2 protein levels by D-gal was inhibited by melatonin treatment. In conclusion, melatonin administration improves testicular function with age.
Topics: Male; Mice; Animals; Melatonin; Galactose; Semen; Aging; Testis; Disease Models, Animal
PubMed: 37224707
DOI: 10.1016/j.theriogenology.2023.05.001 -
Immunopharmacology and Immunotoxicology Dec 2023Rapidly growing evidence suggests that immune cells play a key role in determining tumor progression. Tumor cells are surrounded by a microenvironment composed of... (Review)
Review
OBJECTIVES
Rapidly growing evidence suggests that immune cells play a key role in determining tumor progression. Tumor cells are surrounded by a microenvironment composed of different cell populations including immune cells. The cross talk between tumor cells and the neighboring microenvironment is an important factor to take into account while designing tumor therapies. Despite significant advances in immunotherapy strategies, a relatively small proportion of patients have successfully responded to them. Therefore, the search for safe and efficient drugs, which could be used alongside conventional therapies to boost the immune system against tumors, is an ongoing need. In the present work, the modulatory effects of melatonin on different components of tumor immune microenvironment are reviewed.
METHODS
A thorough literature review was performed in PubMed, Scopus, and Web of Science databases. All published papers in English on tumor immune microenvironment and the relevant modulatory effects of melatonin were scrutinized.
RESULTS
Melatonin modulates macrophage polarization and prevents M2 induction. Moreover, it prevents the conversion of fibroblasts into cancer-associated fibroblasts (CAFs) and prevents cancer cell stemness. In addition, it can affect the payload composition of tumor-derived exosomes (TEXs) and their secretion levels to favor a more effective anti-tumor immune response. Melatonin is a safe molecule that affects almost all components of the tumor immune microenvironment and prevents them from being negatively affected by the tumor.
CONCLUSION
Based on the effects of melatonin on normal cells, tumor cells and microenvironment components, it could be an efficient compound to be used in combination with conventional immune-targeted therapies to increase their efficacy.
Topics: Humans; Melatonin; Neoplasms; Fibroblasts; Cancer-Associated Fibroblasts; Immunotherapy; Tumor Microenvironment
PubMed: 37489565
DOI: 10.1080/08923973.2023.2239489 -
Journal of Sleep Research Dec 2023Insomnia is a common disorder and cognitive behavioural therapy for insomnia (CBT-I) is recommended as first-line treatment. However, CBT-I is not widely distributed and... (Review)
Review
Insomnia is a common disorder and cognitive behavioural therapy for insomnia (CBT-I) is recommended as first-line treatment. However, CBT-I is not widely distributed and infrequently available while medication is not indicated for long-term use. To close this evident gap in supply, alternative treatments could be utilised. High-quality research on this topic is scarce, and there is currently no comprehensive publication on the effectiveness of alternative treatments. To address this pressing question, we systematically summarised the existing research on alternative treatments for insomnia. A comprehensive search of systematic reviews and (network) meta-analyses of randomised controlled trials investigating the efficacy of alternative treatments compared to waiting-list control or placebo in adults with insomnia disorder with or without comorbidities was conducted in PubMed, MEDLINE, PsycInfo, and PsycArticles on December 6, 2022, yielding 391 records. Finally, 15 eligible studies were included. Evidence on acupuncture, exogenous melatonin, mind-body interventions and exercise, repetitive transcranial magnetic stimulation (rTMS), valerian, and light exposure was found. Acupuncture, rTMS and mind-body exercises significantly improved sleep quality and insomnia severity but effects on objectively assessed outcomes were inconclusive. Melatonin led to a reduction in both self-reported and objectively assessed sleep onset latency. Light exposure and valerian did not significantly improve sleep outcomes. Overall, the quality of studies was rated as low. Results indicate that alternative treatments are effective mostly on subjective outcomes. However, evidence on the efficacy of some intervention types is sparse and there is a need for high-quality original studies. Future research could investigate whether combining different alternative treatment aspects with CBT-I improves individual treatment.
Topics: Adult; Humans; Cognitive Behavioral Therapy; Melatonin; Sleep; Sleep Initiation and Maintenance Disorders; Systematic Reviews as Topic; Meta-Analysis as Topic; Randomized Controlled Trials as Topic
PubMed: 37527850
DOI: 10.1111/jsr.13979 -
International Immunopharmacology Dec 2023Melatonin is known to have protective effects in aging, neurodegenerative disorders and mitochondria-related diseases, while there is a poor understanding of the effects...
BACKGROUND
Melatonin is known to have protective effects in aging, neurodegenerative disorders and mitochondria-related diseases, while there is a poor understanding of the effects of melatonin treatment on mitophagy in neonatal cognitive dysfunction after repeated sevoflurane exposures. This study explores the protective effects of melatonin on mitophagy and cognition in developing rats exposed to sevoflurane.
METHODS
Postnatal day six (P6) neonatal rats were exposed to 3 % sevoflurane for 2 h daily from P6 to P8. In the intervention groups, rats received 3-Methyladenine (3-MA) intracerebroventricularly from P6 to P8 and melatonin intraperitoneally from P6 to P8 following water drinking once daily from P21 to P41, respectively. Behavioral tests, including open field (OF), novel object recognition (NOR), and fear conditioning (FC) tests, were performed to assess cognitive function during young adulthood. In another experiment, rat brains were harvested for biochemical, histopathological, and electron microscopy studies.
RESULTS
Rats exposed to sevoflurane showed disordered mitophagy and mitochondrial dysfunction as revealed by increased mitophagy marker proteins (microtubule-associated protein 1 light chain 3 (LC3) II/I, and parkin), decreased autophagy marker protein (sequestosome 1 (P62/SQSTM1)), electron transport chain (ETC) proteins and ATP levels. Immunofluorescent staining of LC3 was co-localized mostly with a neuronal marker and microglial marker but was not co-localized with a marker for astrocytes in rats exposed to sevoflurane. These rats had poorer performance in the NOR and FC tests than control rats during young adulthood. Melatonin treatment reversed the abnormal expression of mitophagy proteins, mitochondrial energy metabolism, the activity of microglia, and impaired cognition. These ameliorations were blocked by an autophagy inhibitor, 3-MA, except for the activation of microglia.
CONCLUSION
We have demonstrated that melatonin inhibits microglial activation by enhancing mitophagy and finally significantly reduces sevoflurane-induced deficits in cognition in neonatal rats. These results suggest that melatonin might be beneficial if considered when the anesthesia must be administered at a very young age.
Topics: Animals; Rats; Mitophagy; Melatonin; Sevoflurane; Autophagy; Cognition
PubMed: 37976600
DOI: 10.1016/j.intimp.2023.111210 -
European Journal of Medicinal Chemistry Dec 2023Melatonin, a neurohormone secreted by the pineal gland and regulated by the suprachiasmatic nucleus (SCN) of the hypothalamus, is synthesized and directly released into... (Review)
Review
Melatonin, a neurohormone secreted by the pineal gland and regulated by the suprachiasmatic nucleus (SCN) of the hypothalamus, is synthesized and directly released into the cerebrospinal fluid (CSF) of the third ventricle (3rdv), where it undergoes rapid absorption by surrounding tissues to exert its physiological function. The hippocampus, a vital structure in the limbic system adjacent to the ventricles, plays a pivotal role in emotional response and memory formation. Melatonin MT and MT receptors are G protein-coupled receptors (GPCRs) that primarily mediate melatonin's receptor-dependent effects. In comparison to the MT receptor, the widely expressed MT receptor is crucial for mediating melatonin's biological functions within the hippocampus. Specifically, MT receptor is implicated in hippocampal synaptic plasticity and memory processes, as well as neurogenesis and axogenesis. Numerous studies have demonstrated the involvement of MT receptors in the pathophysiology and pharmacology of Alzheimer's disease, depression, and epilepsy. This review focuses on the anatomical localization of MT receptor in the hippocampus, their physiological function in this region, and their signal transduction and pharmacological roles in neurological disorders. Additionally, we conducted a comprehensive review of MT receptor ligands used in psychopharmacology and other MT-selective ligands over recent years. Ultimately, we provide an outlook on future research for selective MT receptor drug candidates.
Topics: Humans; Melatonin; Hippocampus; Alzheimer Disease; Receptor, Melatonin, MT2; Receptor, Melatonin, MT1
PubMed: 37866336
DOI: 10.1016/j.ejmech.2023.115888 -
Biomedicine & Pharmacotherapy =... Nov 2023Head and neck squamous cell carcinoma present a high mortality rate. Melatonin has been shown to have oncostatic effects in different types of cancers. However,...
Intratumoral injection of melatonin enhances tumor regression in cell line-derived and patient-derived xenografts of head and neck cancer by increasing mitochondrial oxidative stress.
Head and neck squamous cell carcinoma present a high mortality rate. Melatonin has been shown to have oncostatic effects in different types of cancers. However, inconsistent results have been reported for in vivo applications. Consequently, an alternative administration route is needed to improve bioavailability and establish the optimal dosage of melatonin for cancer treatment. On the other hand, the use of patient-derived tumor models has transformed the field of drug research because they reflect the heterogeneity of patient tumor tissues. In the present study, we explore mechanisms for increasing melatonin bioavailability in tumors and investigate its potential as an adjuvant to improve the therapeutic efficacy of cisplatin in the setting of both xenotransplanted cell lines and primary human HNSCC. We analyzed the effect of two different formulations of melatonin administered subcutaneously or intratumorally in Cal-27 and SCC-9 xenografts and in patient-derived xenografts. Melatonin effects on tumor mitochondrial metabolism was also evaluated as well as melatonin actions on tumor cell migration. In contrast to the results obtained with the subcutaneous melatonin, intratumoral injection of melatonin drastically inhibited tumor progression in HNSCC-derived xenografts, as well as in patient-derived xenografts. Interestingly, intratumoral injection of melatonin potentiated CDDP effects, decreasing Cal-27 tumor growth. We demonstrated that melatonin increases ROS production and apoptosis in tumors, targeting mitochondria. Melatonin also reduces migration capacities and metastasis markers. These results illustrate the great clinical potential of intratumoral melatonin treatment and encourage a future clinical trial in cancer patients to establish a proper clinical melatonin treatment.
Topics: Humans; Squamous Cell Carcinoma of Head and Neck; Melatonin; Carcinoma, Squamous Cell; Heterografts; Injections, Intralesional; Head and Neck Neoplasms; Cisplatin; Cell Line, Tumor; Oxidative Stress
PubMed: 37717534
DOI: 10.1016/j.biopha.2023.115518 -
Journal of Pineal Research Oct 2023Transarterial chemoembolization (TACE) has been widely used for hepatocellular carcinoma. Reducing hypoxia in the tumor microenvironment after TACE remains a challenge...
Transarterial chemoembolization (TACE) has been widely used for hepatocellular carcinoma. Reducing hypoxia in the tumor microenvironment after TACE remains a challenge as tumor progression is common in post-TACE patients due to the hypoxic tumor microenvironment. In this study, melatonin loaded on p(N-isopropyl-acrylamide-co-butyl methylacrylate) (PIB-M) was used for tumor embolism. Two types of human hepatoma cell lines were used to explore the mechanism by which melatonin prevents the growth and metastasis of cancer cells in vitro. A VX2 rabbit tumor model was used to evaluate the efficacy, mechanism, and safety of PIB-M in vivo. We found that under hypoxic condition, melatonin could inhibit tumor cell proliferation and migration by targeting hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (VEGF-A) in vitro. In vivo, PIB-M inhibited tumor growth and metastasis in rabbit VX2 tumors by promoting apoptosis of tumor cells and targeting related angiogenic proteins and vascular permeability proteins. A high concentration of melatonin in the PIB-M group could be maintained in tumor tissue for 72 h after embolization. The liver and kidney functions were most damaged on the first day but recovered to normal on the seventh day after embolization in the PIB-M group. This novel method may open avenues for reduction of tumor growth and metastasis after TACE and is efficacy and safety, which may be used for treatment for other solid tumors and clinical translation.
Topics: Animals; Humans; Rabbits; Carcinoma, Hepatocellular; Liver Neoplasms; Nanogels; Vascular Endothelial Growth Factor A; Melatonin; Chemoembolization, Therapeutic; Hypoxia; Tumor Microenvironment
PubMed: 37492880
DOI: 10.1111/jpi.12900 -
Advances in Medical Sciences Sep 2023Melatonin might be beneficial to coronavirus disease 2019 (COVID-19) patients in terms of both prevention and treatment. We investigated how melatonin affected various... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Melatonin might be beneficial to coronavirus disease 2019 (COVID-19) patients in terms of both prevention and treatment. We investigated how melatonin affected various clinical and laboratory results in COVID-19 patients.
METHODS
PubMed, Scopus, Cochrane Library and Web of Science databases were utilized for searching eligible articles fulfilling our inclusion criteria up to December 2022. We used random effect model in case of significant heterogeneity; in other cases, a fixed model was applied. RevMan was used for meta-analysis.
RESULTS
We included 11 studies in our review. Clinical improvement rate was found to be statistically significantly higher in patients taking melatonin than in the control group (OR: 5.09; 95% CI: 2.60-9.96, p < 0.001). Patients receiving melatonin showed a non-significant difference in mortality rate compared to the control group (OR: 0.37; 95% CI: 0.07-1.81, p = 0.22). However, in the randomized controlled trials subgroup, melatonin-treated patients showed significantly lower mortality than did the controls (OR: 0.17; 95% CI: 0.08-0.38, p < 0.001). CRP level was statistically significantly lower due to melatonin treatment (weighted mean difference [WMD] = -9.85; 95% CI: -18.54 to -1.16, p = 0.03). Length of hospital stay was statistically significantly shorter in patients taking melatonin compared to controls (WMD = -4.05; 95% CI: -5.39 to -2.7, p < 0.001).
CONCLUSION
Melatonin was found to have substantial effects on COVID-19 patients when used as adjuvant therapy, enhancing clinical improvement and decreasing time to recovery with a shorter length of hospital stay and a shorter duration of mechanical ventilation.
Topics: Humans; COVID-19; Melatonin; Length of Stay
PubMed: 37742478
DOI: 10.1016/j.advms.2023.09.007