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Experimental Gerontology Nov 2023The intricate interplay between gut microbiota and the host is pivotal in maintaining homeostasis and health. Dietary tryptophan (TRP) metabolism initiates a cascade of... (Review)
Review
The intricate interplay between gut microbiota and the host is pivotal in maintaining homeostasis and health. Dietary tryptophan (TRP) metabolism initiates a cascade of essential endogenous metabolites, including kynurenine, kynurenic acid, serotonin, and melatonin, as well as microbiota-derived Trp metabolites like tryptamine, indole propionic acid (IPA), and other indole derivatives. Notably, tryptamine and IPA, among the indole metabolites, exert crucial roles in modulating immune, metabolic, and neuronal responses at both local and distant sites. Additionally, these metabolites demonstrate potent antioxidant and anti-inflammatory activities. The levels of microbiota-derived TRP metabolites are intricately linked to the gut microbiota's health, which, in turn, can be influenced by age-related changes. This review aims to comprehensively summarize the cellular and molecular impacts of tryptamine and IPA on health and aging-related complications. Furthermore, we explore the levels of tryptamine and IPA and their corresponding bacteria in select diseased conditions, shedding light on their potential significance as biomarkers and therapeutic targets.
Topics: Tryptophan; Microbiota; Kynurenine; Indoles; Melatonin
PubMed: 37898179
DOI: 10.1016/j.exger.2023.112319 -
International Journal of Molecular... May 2024Melatonin is ubiquitously present in all animals and plants, where it exerts a variety of physiological activities thanks to its antioxidant properties and its key role... (Review)
Review
Melatonin is ubiquitously present in all animals and plants, where it exerts a variety of physiological activities thanks to its antioxidant properties and its key role as the first messenger of extracellular signaling functions. Most of the clinical studies on melatonin refer to its widespread oral use as a dietary supplement to improve sleep. A far smaller number of articles describe the clinical applications of topical melatonin to treat or prevent skin disorders by exploiting its antioxidant and anti-inflammatory activities. This review focuses on the clinical studies in which melatonin was applied on the skin as a photoprotective, anti-aging, or hair growth-promoting agent. The methodologies and results of such studies are discussed to provide an overall picture of the state of the art in this intriguing field of research. The clinical studies in which melatonin was applied on the skin before exposure to radiation (UV, sunlight, and high-energy beams) were all characterized by an appropriate design (randomized, double-blind, and placebo-controlled) and strongly support its clinical efficacy in preventing or reducing skin damage such as dermatitis, erythema, and sunburn. Most of the studies examined in this review do not provide a clear demonstration of the efficacy of topical melatonin as a skin anti-aging or as a hair growth-promoting agent owing to limitations in their design and/or to the use of melatonin combined with extra active ingredients, except for one trial that suggests a possible beneficial role of melatonin in treating some forms of alopecia in women. Further research efforts are required to reach definitive conclusions concerning the actual benefits of topical melatonin to counteract skin aging and hair loss.
Topics: Melatonin; Humans; Administration, Topical; Antioxidants; Animals; Skin Aging; Clinical Studies as Topic; Skin; Skin Diseases
PubMed: 38791203
DOI: 10.3390/ijms25105167 -
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 -
International Journal of Molecular... May 2024While primarily produced in the pineal gland, melatonin's influence goes beyond its well-known role in regulating sleep, nighttime metabolism, and circadian rhythms, in... (Review)
Review
While primarily produced in the pineal gland, melatonin's influence goes beyond its well-known role in regulating sleep, nighttime metabolism, and circadian rhythms, in the field of chronobiology. A plethora of new data demonstrates melatonin to be a very powerful molecule, being a potent ROS/RNS scavenger with anti-inflammatory, immunoregulatory, and oncostatic properties. Melatonin and its metabolites exert multiple beneficial effects in cutaneous and systemic aging. This review is focused on the neuroprotective role of melatonin during aging. Melatonin has an anti-aging capacity, retarding the rate of healthy brain aging and the development of age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, etc. Melatonin, as well as its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), can reduce oxidative brain damage by shielding mitochondria from dysfunction during the aging process. Melatonin could also be implicated in the treatment of neurodegenerative conditions, by modifying their characteristic low-grade neuroinflammation. It can either prevent the initiation of inflammatory responses or attenuate the ongoing inflammation. Drawing on the current knowledge, this review discusses the potential benefits of melatonin supplementation in preventing and managing cognitive impairment and neurodegenerative diseases.
Topics: Melatonin; Humans; Brain; Aging; Animals; Neurodegenerative Diseases; Neuroprotection; Neuroprotective Agents; Oxidative Stress; Kynuramine
PubMed: 38791160
DOI: 10.3390/ijms25105122 -
Drug Design, Development and Therapy 2023Epidemiological studies have indicated that lung injury is a frequent complication of sepsis. Mitophagy is vital to multiple pathological processes and diseases;...
BACKGROUND
Epidemiological studies have indicated that lung injury is a frequent complication of sepsis. Mitophagy is vital to multiple pathological processes and diseases; however, its influence on sepsis-induced acute lung injury remains elusive. Melatonin has multiple antioxidant action and anti-inflammatory effects, including regulating mitophagy and inflammatory cytokine expression. Whereas, little is known about the affection of melatonin and mitophagy on CLP-induced ALI.
METHODS
The in vivo effect of melatonin on OPTN-mediated mitophagy was studied by CLP-induced ALI in a mouse model using C57BL/6 followed by treatment with vehicle and melatonin (30 mg/kg/d, intraperitoneal injection). ALI was assayed by lung wet /dry ratio, hematoxylin and eosin staining, and immunohistochemical staining. Signaling pathway changes were subsequently determined by Western blotting and immunofluorescence staining. The effects of melatonin on STAT3 activation and TNF-α production were detected by Western blotting, PCR, and immunohistochemical staining.
RESULTS
Our results indicated that OPTN, mitophagy adaptors were significantly repressed in CLP-induced ALI, accompanied by overactivation of mitophagy and inflammation. At the same time, we found that melatonin treatment alleviated ALI caused by CLP, and the effect was highly correlated with OPTN-related mitophagy. Furthermore, we demonstrated that OPTN-related mitophagy, which was normalized by melatonin, blocked STAT3 involved epithelial barrier and inflammation in vivo.
CONCLUSION
Overall, our results confirm that mitophagy is adjusted by melatonin in the CLP-induced ALI. Moreover, manipulation of mitophagy through melatonin could be a possible treatment to reduce sepsis-associated lung injury.
Topics: Mice; Animals; Mice, Inbred C57BL; Melatonin; Mitophagy; Acute Lung Injury; Sepsis; Inflammation
PubMed: 37719362
DOI: 10.2147/DDDT.S423264 -
Biomedicine & Pharmacotherapy =... Oct 2023Septic cardiomyopathy (SCM) is a common complication of sepsis contributing to high mortality rates. Its pathophysiology involves complex factors, including inflammatory... (Review)
Review
Septic cardiomyopathy (SCM) is a common complication of sepsis contributing to high mortality rates. Its pathophysiology involves complex factors, including inflammatory cytokines, mitochondrial dysfunction, oxidative stress, and immune dysregulation. Despite extensive research, no effective pharmacological agent has been established for sepsis-induced cardiomyopathy. Melatonin, a hormone with diverse functions in the body, has emerged as a potential agent for SCM through its anti-oxidant, anti-inflammatory, anti-apoptotic, and cardioprotective roles. Through various molecular levels of its mechanism of action, it counterattacks the adverse event of sepsis. Experimental studies have mentioned that melatonin protects against many cardiovascular diseases and exerts preventive effects on SCM. Moreover, melatonin has been investigated in combination with other drugs such as antibiotics, resveratrol, and anti-oxidants showing synergistic effects in reducing inflammation, anti-oxidant, and improving cardiac function. While preclinical studies have demonstrated positive results, clinical trials are required to establish the optimal dosage, route of administration, and treatment duration for melatonin in SCM. Its safety profile, low toxicity, and natural occurrence in the human body provide a favorable basis for its clinical use. This review aims to provide an overview of the current evidence of the use of melatonin in sepsis-induced cardiomyopathy (SICM). Melatonin appears to be promising as a possible treatment for sepsis-induced cardiomyopathy and demands further investigation.
Topics: Humans; Melatonin; Antioxidants; Cardiomyopathies; Cardiovascular Diseases; Sepsis
PubMed: 37619482
DOI: 10.1016/j.biopha.2023.115305 -
Progress in Neuro-psychopharmacology &... Aug 2023Ferroptosis is a type of regulated cell death that is dependent on iron and reactive oxygen species (ROS). Melatonin (N-acetyl-5-methoxytryptamine) reduces...
Ferroptosis is a type of regulated cell death that is dependent on iron and reactive oxygen species (ROS). Melatonin (N-acetyl-5-methoxytryptamine) reduces hypoxic-ischemic brain damage via mechanisms that involve free radical scavenging. How melatonin regulates radiation-induced ferroptosis of hippocampal neurons is yet to be elucidated. In this study, the mouse hippocampal neuronal cell line HT-22 was treated with 20μM melatonin before being stimulated with a combination of irradiation and 100 μM FeCl. Furthermore, in vivo experiments were performed in mice treated with melatonin via intraperitoneal injection, which was followed by radiation exposure. A series of functional assays, including CCK-8, DCFH-DA kit, flow cytometry, TUNEL staining, iron estimations, and transmission electron microscopy, were performed on cells as well as hippocampal tissues. The interactions between PKM2 and NRF2 proteins were detected using a coimmunoprecipitation (Co-IP) assay. Moreover, chromatin immunoprecipitation (ChIP), a luciferase reporter assay, and an electrophoretic mobility shift assay (EMSA) were performed to explore the mechanism by which PKM2 regulates the NRF2/GPX4 signaling pathway. The spatial memory of mice was evaluated using the Morris Water Maze test. Hematoxylin-eosin and Nissl staining were performed for histological examination. The results revealed that melatonin protected HT-22 neuronal cells from radiation-induced ferroptosis, as inferred from increased cell viability, decreased ROS production, reduced number of apoptotic cells, and less cristae, higher electron density in mitochondria. In addition, melatonin induced PKM2 nuclear transference, while PKM2 inhibition reversed the effects of melatonin. Further experiments demonstrated that PKM2 bound to and induced the nuclear translocation of NRF2, which regulated GPX4 transcription. Ferroptosis enhanced by PKM2 inhibition was also converted by NRF2 overexpression. In vivo experiments indicated that melatonin alleviated radiation-induced neurological dysfunction and injury in mice. In conclusion, melatonin suppressed ferroptosis to decrease radiation-induced hippocampal neuronal injury by activating the PKM2/NRF2/GPX4 signaling pathway.
Topics: Animals; Mice; Ferroptosis; Melatonin; NF-E2-Related Factor 2; Reactive Oxygen Species; Signal Transduction; Neurons; Hashimoto Disease; Hippocampus; Iron
PubMed: 37100272
DOI: 10.1016/j.pnpbp.2023.110777 -
Cell Chemical Biology Aug 2023The presence of signaling-competent G protein-coupled receptors in intracellular compartments is increasingly recognized. Recently, the presence of G protein-coupled...
The presence of signaling-competent G protein-coupled receptors in intracellular compartments is increasingly recognized. Recently, the presence of G protein-coupled melatonin MT receptors in mitochondria has been revealed, in addition to the plasma membrane. Melatonin is highly cell permeant, activating plasma membrane and mitochondrial receptors equally. Here, we present MCS-1145, a melatonin derivative bearing a triphenylphosphonium cation for specific mitochondrial targeting and a photocleavable o-nitrobenzyl group releasing melatonin upon illumination. MCS-1145 displayed low affinity for MT and MT but spontaneously accumulated in mitochondria, where it was resistant to washout. Uncaged MCS-1145 and exogenous melatonin recruited β-arrestin 2 to MT in mitochondria and inhibited oxygen consumption in mitochondria isolated from HEK293 cells only when expressing MT and from mouse cerebellum of WT mice but not from MT-knockout mice. Overall, we developed the first mitochondria-targeted photoactivatable melatonin ligand and demonstrate that melatonin inhibits mitochondrial respiration through mitochondrial MT receptors.
Topics: Animals; Humans; Mice; Receptor, Melatonin, MT1; Melatonin; HEK293 Cells; Receptors, G-Protein-Coupled; Mitochondria; Respiration
PubMed: 37572668
DOI: 10.1016/j.chembiol.2023.07.009 -
Ecotoxicology and Environmental Safety Dec 2023Fine particulate matter (PM2.5) is a source of pollution worldwide, that causes inflammation and liver fibrosis. Melatonin, as the predominant hormone secreted by the...
OBJECTIVE
Fine particulate matter (PM2.5) is a source of pollution worldwide, that causes inflammation and liver fibrosis. Melatonin, as the predominant hormone secreted by the pineal gland, can inhibit PM2.5-induced lung injury by activating nuclear factor erythroid 2-related factor 2 (Nrf2) to inhibit ferroptosis. However, the possible role of melatonin in PM2.5-induced liver damage remains unclear.
EXPERIMENTAL APPROACH
In vitro, the effects of melatonin on PM2.5-induced oxidative stress and LX-2 cell activation were examined. In vivo, a PM2.5-induced inflammation and liver fibrosis mouse model was used to evaluate the hepatoprotective effect of melatonin.
RESULTS
In vitro, melatonin induced the expression of Nrf2 and its downstream genes and inhibited PM2.5-induced reactive oxygen species (ROS) production and mitochondrial damage. Melatonin also ameliorated the PM2.5-induced oxidative stress and fibrogenic marker upregulation. However, the antifibrotic effect of melatonin was abolished in siNrf2-treated LX-2 cells. In vivo, we observed mitochondrial abnormalities and mitochondrial fragmentation, which were accompanied by increased PTEN-induced kinase 1 (PINK1) and Parkin expression, in PM2.5-treated mouse hepatocytes. These changes were partially reversed by melatonin. In addition, melatonin activated the Nrf2 signaling pathway and protected against PM2.5-induced oxidative stress. Furthermore, melatonin alleviated inflammation and liver fibrosis. Moreover, Nrf2-KO mice exhibited more severe inflammation and liver fibrosis after PM2.5 exposure than wild-type mice, and the protective effect of melatonin on PM2.5- treated Nrf2-KO mice was greatly compromised.
CONCLUSION
These data suggest that melatonin effectively inhibits PM2.5-induced liver fibrosis by activating Nrf2 and inhibiting ROS-mediated mitophagy and inflammation.
Topics: Animals; Mice; Inflammation; Liver Cirrhosis; Melatonin; Mitophagy; NF-E2-Related Factor 2; Particulate Matter; Reactive Oxygen Species
PubMed: 37992643
DOI: 10.1016/j.ecoenv.2023.115717 -
Reproductive Biomedicine Online Mar 2024Many women undergoing IVF take supplements during treatment. The purpose of this review was to systematically review these nutritional supplements. The therapies studied... (Review)
Review
Many women undergoing IVF take supplements during treatment. The purpose of this review was to systematically review these nutritional supplements. The therapies studied are dehydroepiandrosterone (DHEA), melatonin, co-enzyme Q10 (CoQ1O), carnitine, selenium, vitamin D, myo-inositol, omega-3, Chinese herbs and dietary interventions. A literature search up to May 2023 was undertaken. The data suggest that a simple nutritional approach would be to adopt a Mediterranean diet. With regards to supplements to treat a potential poor ovarian response to ovarian stimulation, starting DHEA and COQ-10 before cycle commencement is better than control therapies. Furthermore, medication with CoQ10 may have some merit, although it is unclear whether its place is for older women, for those with a poor response to ovarian stimulation or for poor embryonic development. There appears a benefit for some IVF outcomes for the use of melatonin, although it is unclear what group of patients would derive the benefit and the appropriate dosing regimen. For women with polycystic ovary syndrome, there may be a benefit to the use of myo-inositol, although again the dosing regimen is unclear. Furthermore, the place of vitamin D supplementation has yet to be clarified, and supplementation with omega-3 free fatty acids may lead to improvements in clinical and embryological IVF outcomes.
Topics: Pregnancy; Humans; Female; Aged; Melatonin; Fertilization in Vitro; Dietary Supplements; Inositol; Vitamin D; Dehydroepiandrosterone; Ovulation Induction
PubMed: 38184959
DOI: 10.1016/j.rbmo.2023.103770