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Frontiers in Cell and Developmental... 2023Spinal cord injury (SCI) is a sudden onset of disruption to the spinal neural tissue, leading to loss of motor control and sensory function of the body. Oxidative stress... (Review)
Review
Spinal cord injury (SCI) is a sudden onset of disruption to the spinal neural tissue, leading to loss of motor control and sensory function of the body. Oxidative stress is considered a hallmark in SCI followed by a series of events, including inflammation and cellular apoptosis. Melatonin was originally discovered as a hormone produced by the pineal gland. The subcellular localization of melatonin has been identified in mitochondria, exhibiting specific onsite protection to excess mitochondrial reactive oxygen species and working as an antioxidant in diseases. The recent discovery regarding the molecular basis of ligand selectivity for melatonin receptors and the constant efforts on finding synthetic melatonin alternatives have drawn researchers' attention back to melatonin. This review outlines the application of melatonin in SCI, including 1) the relationship between the melatonin rhythm and SCI in clinic; 2) the neuroprotective role of melatonin in experimental traumatic and ischemia/reperfusion SCI, i.e., exhibiting anti-oxidative, anti-inflammatory, and anti-apoptosis effects, facilitating the integrity of the blood-spinal cord barrier, ameliorating edema, preventing neural death, reducing scar formation, and promoting axon regeneration and neuroplasticity; 3) protecting gut microbiota and peripheral organs; 4) synergizing with drugs, rehabilitation training, stem cell therapy, and biomedical material engineering; and 5) the potential side effects. This comprehensive review provides new insights on melatonin as a natural antioxidant therapy in facilitating rehabilitation in SCI.
PubMed: 37691830
DOI: 10.3389/fcell.2023.1218553 -
Nutrients Oct 2022Endometriosis is defined as the development of endometrial glands and stroma outside the uterine cavity. Pathophysiology of this disease includes abnormal hormone... (Review)
Review
Endometriosis is defined as the development of endometrial glands and stroma outside the uterine cavity. Pathophysiology of this disease includes abnormal hormone profiles, cell survival, migration, invasion, angiogenesis, oxidative stress, immunology, and inflammation. Melatonin is a neuroendocrine hormone that is synthesized and released primarily at night from the mammalian pineal gland. Increasing evidence has revealed that melatonin can be synthesized and secreted from multiple extra-pineal tissues where it regulates immune response, inflammation, and angiogenesis locally. Melatonin receptors are expressed in the uterus, and the therapeutic effects of melatonin on endometriosis and other reproductive disorders have been reported. In this review, key information related to the metabolism of melatonin and its biological effects is summarized. Furthermore, the latest in vitro and in vivo findings are highlighted to evaluate the pleiotropic functions of melatonin, as well as to summarize its physiological and pathological effects and treatment potential in endometriosis. Moreover, the pharmacological and therapeutic benefits derived from the administration of exogenous melatonin on reproductive system-related disease are discussed to support the potential of melatonin supplements toward the development of endometriosis. More clinical trials are needed to confirm its therapeutic effects and safety.
Topics: Animals; Endometriosis; Female; Humans; Inflammation; Mammals; Melatonin; Pineal Gland; Receptors, Melatonin
PubMed: 36235740
DOI: 10.3390/nu14194087 -
Comparative Biochemistry and... May 2023The transcriptional regulation of innate immune function across annual life history states (LHS) remains obscure in avian migrants. We, therefore, investigated this in a...
The transcriptional regulation of innate immune function across annual life history states (LHS) remains obscure in avian migrants. We, therefore, investigated this in a migratory passerine songbird, redheaded bunting (Emberiza bruniceps), which exhibits long-distance vernal migration from India to Central Asia. We exposed the birds (N = 10) to differential photoperiodic conditions to induce a non-migratory (NM), pre-migratory (PM), migratory (MIG), and refractory (REF) state, and performed gene expression assays of melatonin receptors (MEL1A and MEL1B), and innate immunity-linked genes (IL1B, IL6, TLR4, and NFKB) in spleen and blood. We found a significant reduction in splenic mass and volume, and a parallel increase in fat accumulation, and testicular growth in birds under migratory state. The gene expression assay revealed an upregulation of MEL1A and MEL1B mRNA levels in both the tissues in MIG. Additionally, we found a nocturnal increase of splenic IL1B expression, and IL1B, IL6, and TLR4 expression in the blood. The mRNA expression of melatonin receptors and proinflammatory cytokine showed a positive correlation. These results suggest that melatonin relays the photoperiodic signal to peripheral immune organs, which shows LHS-dependent changes in mRNA expression of immune genes.
Topics: Animals; Receptors, Melatonin; Interleukin-6; Toll-Like Receptor 4; Photoperiod; Passeriformes; Songbirds; Melatonin; Seasons; RNA, Messenger; Animal Migration
PubMed: 36724811
DOI: 10.1016/j.cbpa.2023.111381 -
Veterinary Sciences Jun 2022Melatonin, a hormone produced by the mammalian pineal gland, influences various physiological activities, many of which are related to animal reproduction, including... (Review)
Review
Melatonin, a hormone produced by the mammalian pineal gland, influences various physiological activities, many of which are related to animal reproduction, including neuroendocrine function, rhythm regulation, seasonal behavior, gonadogenesis, gamete development and maturation, sexual maturation, and thermoregulation. Melatonin exerts beneficial actions mainly via binding with G-protein-coupled receptors (GPCR), termed MT1 and MT2. Melatonin receptors are crucial for mediating animal reproduction. This paper reviews the characteristics of melatonin receptors including MT1 and MT2, as well as their roles in mediating signal transduction and biological effects, with a focus on their function in animal reproduction. In addition, we briefly summarize the developments in pharmacological research regarding melatonin receptors as drug targets. It is expected that this review will provide a reference for further exploration and unveiling of melatonin receptor function in reproductive regulation.
PubMed: 35878326
DOI: 10.3390/vetsci9070309 -
Current Molecular Pharmacology 2021Melatonin, a neurohormone secreted from the pineal gland, circulates throughout the body and then mediates several physiological functions. The pharmacological effects... (Review)
Review
BACKGROUND
Melatonin, a neurohormone secreted from the pineal gland, circulates throughout the body and then mediates several physiological functions. The pharmacological effects of melatonin can be mediated through its direct antioxidant activity and receptor-dependent signaling.
OBJECTIVE
This article will mainly review receptor-dependent signaling. Human melatonin receptors include melatonin receptor type 1 (MT1) and melatonin receptor type 2 (MT2), which are widely distributed throughout the brain.
RESULT
Several lines of evidence have revealed the involvement of the melatonergic system in different neurodegenerative diseases. Alzheimer's disease pathology negatively affects the melatonergic system. Melatonin effectively inhibits β-amyloid (Aβ) synthesis and fibril formation. These effects are reversed by pharmacological melatonin receptor blockade. Reductions in MT1 and MT2 expression in the amygdala and substantia nigra pars compacta have been reported in Parkinson's disease patients. The protective roles of melatonin against ischemic insults via its receptors have also been demonstrated. Melatonin has been reported to enhance neurogenesis through MT2 activation in cerebral ischemic/reperfusion mice. The neurogenic effects of melatonin on mesenchymal stem cells are particularly mediated through MT2.
CONCLUSION
Understanding the roles of melatonin receptors in neuroprotection against diseases may lead to the development of specific analogs with specificity and potency greater than those of the original compound. These successfully developed compounds may serve as candidate preventive and disease-modifying agents in the future.
Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Animals; Biomarkers; Gene Expression Regulation; Humans; Hypoxia-Ischemia, Brain; Molecular Targeted Therapy; Myocytes, Cardiac; Neurodegenerative Diseases; Neuroprotection; Neuroprotective Agents; Parkinson Disease; Pharmaceutical Preparations; Receptors, Melatonin; Signal Transduction
PubMed: 32316905
DOI: 10.2174/1874467213666200421160835 -
Free Radical Biology & Medicine Nov 2023Ferroptosis is a novel form of cell death that plays a critical role in the pathological and physiological processes of early brain injury following subarachnoid...
Ferroptosis is a novel form of cell death that plays a critical role in the pathological and physiological processes of early brain injury following subarachnoid hemorrhage. Melatonin, as the most potent endogenous antioxidant, has shown strong protective effects against pathological changes following subarachnoid hemorrhage, but its impact on ferroptosis induced by subarachnoid hemorrhage remains unexplored. In our study, we established a subarachnoid hemorrhage model in male SD rats. We found that subarachnoid hemorrhage induced changes in ferroptosis-related indicators such as lipid peroxidation and iron metabolism, while intraperitoneal injection of melatonin (40 mg/kg) effectively ameliorated these changes to a certain degree. Moreover, in a subset of rats with subarachnoid hemorrhage who received pre-treatment via intravenous injection of the melatonin receptor antagonist Luzindole (1 mg/kg) and 4P-PDOT (1 mg/kg), we found that the protective effect of melatonin against subarachnoid hemorrhage includes inhibition of lipid peroxidation and reduction of iron accumulation depended on melatonin receptor 1B (MT2). Furthermore, our study demonstrated that melatonin inhibited neuronal ferroptosis by activating the NRF2 signaling pathway, as evidenced by in vivo inhibition of NRF2. In summary, melatonin acts through MT2 and activates NRF2 and downstream genes such as HO-1/NQO1 to inhibit ferroptosis in subarachnoid hemorrhage-induced neuronal injury, thereby improving neurological function in rats. These results suggest that melatonin is a promising therapeutic target for subarachnoid hemorrhage.
Topics: Rats; Male; Animals; Melatonin; Ferroptosis; NF-E2-Related Factor 2; Rats, Sprague-Dawley; Receptors, Melatonin; Subarachnoid Hemorrhage; Brain Injuries; Iron
PubMed: 37717795
DOI: 10.1016/j.freeradbiomed.2023.09.012 -
Aging Clinical and Experimental Research Nov 2023The prophylactic effect of exogenous melatonin and melatonin receptor agonists (MMRAs) on postoperative delirium (POD) in elderly patients remains controversial. (Meta-Analysis)
Meta-Analysis Review
Prophylactic effect of exogenous melatonin and melatonin receptor agonists on postoperative delirium in elderly patients: a systemic review and meta-analysis of randomized controlled trials.
BACKGROUND
The prophylactic effect of exogenous melatonin and melatonin receptor agonists (MMRAs) on postoperative delirium (POD) in elderly patients remains controversial.
OBJECTIVE
This study aimed to assess the prophylactic effect of MMRAs on POD by conducting a systemic review and meta-analysis of randomized controlled trials (RCTs).
METHODS
We systematically searched four electronic databases including PubMed, Web of Science, Cochrane Library, and Embase for the eligible studies up to February 28, 2023. The Cochrane risk of bias tool was used for assessing the risk of bias in the included RCTs. The occurrence of POD was the primary outcome. The quality of evidence was evaluated by Grading of Recommendations Assessment, Development, and Evaluation.
RESULTS
A total of 11 RCTs comprising patients (MMRA group: 777 patients and placebo group: 781 patients) were included. The results of the meta-analysis showed that the MMRA group had a lower occurrence of POD than the placebo group (risk ratio = 0.70, 95% confidence interval: 0.51-0.97, P < 0.05, I = 59%). The subgroup analysis showed that melatonin significantly reduced the occurrence of POD (moderate-quality evidence), whereas ramelteon and tryptophan had no significant impact (moderate-quality evidence).
CONCLUSION
Existing evidence suggested that perioperative use of melatonin can prevent POD in elderly patients.
Topics: Humans; Aged; Emergence Delirium; Melatonin; Receptors, Melatonin; Randomized Controlled Trials as Topic; Hypnotics and Sedatives
PubMed: 37776484
DOI: 10.1007/s40520-023-02564-y -
Human Reproduction (Oxford, England) Jul 2019Are melatonin receptors (melatonin receptor 1A (MR1A) and melatonin receptor 1B (MR1B)) expressed in human endometrium and endometriotic tissue, and does melatonin...
STUDY QUESTION
Are melatonin receptors (melatonin receptor 1A (MR1A) and melatonin receptor 1B (MR1B)) expressed in human endometrium and endometriotic tissue, and does melatonin affect endometrial cell proliferation?
SUMMARY ANSWER
Melatonin receptors are expressed in human eutopic endometrium, endometriomas and peritoneal lesions, although to different extents, and melatonin treatment attenuated estradiol-induced endometrial epithelial cell proliferation in culture.
WHAT IS KNOWN ALREADY
Melatonin decreased endometriotic lesion volume in a rat model of endometriosis. Melatonin treatment reduced pain scores in and analgesic use by women with endometriosis.
STUDY DESIGN, SIZE, DURATION
Basic science study using human endometrial tissue and an endometrial epithelial cell line.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Measurement of melatonin receptor expression (mRNA and protein) in women with surgically confirmed endometriosis (endometrioma (n = 20) or peritoneal lesion (n = 11) alone) and women without surgical evidence of endometriosis (control, n = 15). Collection of endometrial and endometriotic tissue samples, gynecologic history and demographic information. Quantification of estradiol (1.0 nM) and melatonin (0.1 nM-1.0 μM) ± estradiol-induced endometrial epithelial cell proliferation in cultures of endometrial epithelial cells (CRL-1671) following 24 and 48 hours of culture.
MAIN RESULTS AND THE ROLE OF CHANCE
MR1A and MR1B were localized by immunohistochemistry in glandular epithelial cells of endometrial biopsies from women with and without endometriosis. Both receptors were expressed in eutopic and ectopic endometrial tissue. mRNA expression of MR1A and MR1B was significantly greater in peritoneal lesions than in either endometriomas or eutopic endometrium. However, protein expression of MR1A was decreased in peritoneal lesions compared to control eutopic endometrium, whereas MR1B expression did not differ between the groups. Melatonin (0.1 nM-1.0 μM) treatment inhibited estradiol (1.0 nM)-induced endometrial epithelial cell proliferation at 48 hours but not 24 hours of culture.
LIMITATIONS, REASONS FOR CAUTION
Beneficial effects of melatonin seen in culture have yet to be comprehensively evaluated in women with endometriosis.
WIDER IMPLICATIONS OF THE FINDINGS
Our data suggest that melatonin may be useful as an adjunct to current endometriosis treatments.
STUDY FUNDING/COMPETING INTEREST(S)
This study was supported by the Canadian Institutes of Health Research (grant MOP142230 to W.G.F.). A.A.M. is supported by a resident research grant through the Physicians Services Incorporated Foundation. The authors have no conflicts of interest.
Topics: Adult; Case-Control Studies; Cell Line, Tumor; Cell Proliferation; Endometriosis; Endometrium; Female; Humans; Melatonin; Receptors, Melatonin
PubMed: 31211323
DOI: 10.1093/humrep/dez082 -
International Journal of Molecular... Nov 2022The concentration of melatonin is elevated during the night when patients mainly wear removable orthodontic appliances. Next to periodontal ligament fibroblasts and...
The concentration of melatonin is elevated during the night when patients mainly wear removable orthodontic appliances. Next to periodontal ligament fibroblasts and osteoblasts, macrophages react to mechanical strain with an increased expression of inflammatory mediators. Here, we investigated the impact of melatonin on RAW264.7 macrophages exposed to tensile or compressive strain occurring during orthodontic tooth movement in the periodontal ligament. Before exposure to mechanical strain for 4 h, macrophages were pre-incubated with different melatonin concentrations for 24 h, to determine the dependence of melatonin concentration. Afterwards, we performed experiments with and without mechanical strain, the most effective melatonin concentration (25 µM), and the melatonin receptor 2 (MT2) specific antagonist 4P-PDOT. The expression of inflammatory genes and proteins was investigated by RT-qPCR, ELISAs, and immunoblot. Both tensile and compressive strain increased the expression of the investigated inflammatory factors interleukin-1-beta, interleukin-6, tumor necrosis factor alpha, and prostaglandin endoperoxide synthase-2. This effect was inhibited by the addition of melatonin. Incubation with 4P-PDOT blocked this anti-inflammatory effect of melatonin. Melatonin had an anti-inflammatory effect on macrophages exposed to mechanical strain, independent of the type of mechanical strain. As inhibition was possible with 4P-PDOT, the MT2 receptor might be involved in the regulation of the observed effects.
Topics: Humans; Melatonin; Receptor, Melatonin, MT2; Macrophages; Anti-Inflammatory Agents
PubMed: 36362201
DOI: 10.3390/ijms232113397 -
Biochimica Et Biophysica Acta.... Jan 2024Hypertrophic scar (HS) is a fibrotic skin condition and characterized by abnormal proliferation of myofibroblasts and accumulation of extracellular matrix. Melatonin, an...
Hypertrophic scar (HS) is a fibrotic skin condition and characterized by abnormal proliferation of myofibroblasts and accumulation of extracellular matrix. Melatonin, an endogenous hormone, can alleviate fibrosis in multiple models of diseases. This study examined the effect of melatonin on fibrosis in primary fibroblasts from human HS (HSFs) and a rabbit ear model and potential mechanisms. Melatonin treatment significantly decreased the migration and contraction capacity, collagen and α-smooth muscle actin (α-SMA) production in HSFs. RNA-sequencing and bioinformatic analyses indicated that melatonin modulated the expression of genes involved in autophagy and oxidative stress. Mechanistically, melatonin treatment attenuated the AKT/mTOR activation through affecting the binding of MT2 receptor with PI3K to enhance autophagy, decreasing fibrogenic factor production in HSFs. Moreover, melatonin treatment inhibited HS formation in rabbit ears by enhancing autophagy. The anti-fibrotic effects of melatonin were abrogated by treatment with an autophagy inhibitor (3-methyladenine, 3-MA), an Akt activator (SC79), or an MT2 selective antagonist (4-phenyl-2propionamidotetralin, 4-P-PDOT). Therefore, melatonin may be a potential drug for prevention and treatment of HS.
Topics: Animals; Humans; Rabbits; Autophagy; Cicatrix, Hypertrophic; Fibroblasts; Fibrosis; Melatonin; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptor, Melatonin, MT2; TOR Serine-Threonine Kinases
PubMed: 37739092
DOI: 10.1016/j.bbadis.2023.166887