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Biomolecular Concepts Sep 2017The benefits of breastfeeding over formula feed are widely appreciated. However, for many mothers breastfeeding is not possible, highlighting the need for a significant... (Review)
Review
The benefits of breastfeeding over formula feed are widely appreciated. However, for many mothers breastfeeding is not possible, highlighting the need for a significant improvement in the contents of formula feed. In this article, the overlooked role of melatonin and the melatonergic pathways in breast milk and in the regulation of wider breast milk components are reviewed. There is a growing appreciation that the benefits of breastfeeding are mediated by its effects in the infant gut, with consequences for the development of the gut-brain axis and the immune system. The melatonergic pathways are intimately associated with highly researched processes in the gut, gut microbiome and gut-brain axis. As the melatonergic pathways are dependent on the levels of serotonin availability as a necessary precursor, decreased melatonin is linked to depression and depression-associated disorders. The association of breastfeeding and the gut-brain axis with a host of medical conditions may be mediated by their regulation of processes that modulate depression susceptibility. The biological underpinnings of depression include increased levels of pro-inflammatory cytokines, oxidative stress, kynurenine pathway activity and dysregulation of the hypothalamic-pituitary adrenal axis, all of which can decrease melatonergic pathway activity. The inclusion of the melatonergic pathways in the biological interactions of breast milk and gut development has significant theoretical and treatment implications, as well as being important to the prevention of a host of infant-, child- and adult-onset medical conditions.
Topics: Breast Feeding; Child Development; Gastrointestinal Microbiome; Humans; Infant; Melatonin; Metabolic Networks and Pathways; Milk, Human
PubMed: 28723608
DOI: 10.1515/bmc-2017-0009 -
International Journal of Molecular... Apr 2021The beneficial properties of the pineal hormone, melatonin, as a neuroprotective and cardioprotective agent, have been previously identified. Furthermore, melatonin... (Review)
Review
The beneficial properties of the pineal hormone, melatonin, as a neuroprotective and cardioprotective agent, have been previously identified. Furthermore, melatonin plays essential roles in biological rhythms resynchronization, sleep initiation/maintenance and metabolic, ocular, rheumatological diseases. In addition to these functions, melatonin is known to exert immunomodulation, anti‑inflammatory and anti‑oxidative effects. Due to these properties, coupled with its non‑toxic nature, melatonin has been suggested to limit viral infections; however, melatonin cannot be classified as a viricidal drug. In addition, the recent increase in the number of clinical trials on melatonin's role, as an adjuvant treatment for COVID‑19, has resurged the interest of the scientific community in this hormone. The present short review aimed to improve the understanding of the antiviral/anti‑COVID‑19 profile of melatonin and the clinical trials that have recently been conducted, with respect to its co‑administration in treating individuals with COVID‑19.
Topics: Animals; Humans; Melatonin; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33576451
DOI: 10.3892/ijmm.2021.4880 -
Biomedicine & Pharmacotherapy =... May 2021Melatonin is a key intracellular neuroimmune-endocrine regulator and coordinator of multiple complex and interrelated biological processes. The main functions of... (Review)
Review
Melatonin is a key intracellular neuroimmune-endocrine regulator and coordinator of multiple complex and interrelated biological processes. The main functions of melatonin include the regulation of neuroendocrine and antioxidant system activity, blood pressure, rhythms of the sleep-wake cycle, the retardation of ageing processes, as well as reseting and optimizing mitochondria and thereby the cells of the immune system. Melatonin and its agonists have therefore been mooted as a treatment option across a wide array of medical disorders. This article reviews the role of melatonin in the regulation of respiratory system functions under normal and pathological conditions. Melatonin can normalize the structural and functional organization of damaged lung tissues, by a number of mechanisms, including the regulation of signaling molecules, oxidant status, lipid raft function, optimized mitochondrial function and reseting of the immune response over the circadian rhythm. Consequently, melatonin has potential clinical utility for bronchial asthma, chronic obstructive pulmonary disease, lung cancer, lung vascular diseases, as well as pulmonary and viral infections. The integration of melatonin's effects with the alpha 7 nicotinic receptor and the aryl hydrocarbon receptor in the regulation of mitochondrial function are proposed as a wider framework for understanding the role of melatonin across a wide array of diverse pulmonary disorders.
Topics: Animals; Antioxidants; Humans; Melatonin; Mitochondria; Receptors, Aryl Hydrocarbon; Respiratory Tract Diseases; Signal Transduction; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 33761613
DOI: 10.1016/j.biopha.2021.111397 -
International Journal of Molecular... Sep 2019In this review we summarized the actual clinical data for a cardioprotective therapeutic role of melatonin, listed melatonin and its agonists in different stages of... (Review)
Review
In this review we summarized the actual clinical data for a cardioprotective therapeutic role of melatonin, listed melatonin and its agonists in different stages of development, and evaluated the melatonin cardiovascular target tractability and prediction using machine learning on ChEMBL. To date, most clinical trials investigating a cardioprotective therapeutic role of melatonin are in phase 2a. Selective melatonin receptor agonists Tasimelteon, Ramelteon, and combined melatonergic-serotonin Agomelatine, and other agonists with registered structures in CHEMBL were not yet investigated as cardioprotective or cardiovascular drugs. As drug-able for these therapeutic targets, melatonin receptor agonists have the benefit over melatonin of well-characterized pharmacologic profiles and extensive safety data. Recent reports of the X-ray crystal structures of MT1 and MT2 receptors shall lead to the development of highly selective melatonin receptor agonists. Predictive models using machine learning could help to identify cardiovascular targets for melatonin. Selecting ChEMBL scores > 4.5 in cardiovascular assays, and melatonin scores > 4, we obtained 284 records from 162 cardiovascular assays carried out with 80 molecules with predicted or measured melatonin activity. Melatonin activities (agonistic or antagonistic) found in these experimental cardiovascular assays and models include arrhythmias, coronary and large vessel contractility, and hypertension. Preclinical proof-of-concept and early clinical studies (phase 2a) suggest a cardioprotective benefit from melatonin in various heart diseases. However, larger phase 3 randomized interventional studies are necessary to establish melatonin and its agonists' actions as cardioprotective therapeutic agents.
Topics: Animals; Cardiotonic Agents; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Machine Learning; Melatonin; Proof of Concept Study; Translational Research, Biomedical
PubMed: 31491852
DOI: 10.3390/ijms20184342 -
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 -
Molecules (Basel, Switzerland) Jan 2022The unique ability to adapt and thrive in inhospitable, stressful tumor microenvironments (TME) also renders cancer cells resistant to traditional chemotherapeutic... (Review)
Review
The unique ability to adapt and thrive in inhospitable, stressful tumor microenvironments (TME) also renders cancer cells resistant to traditional chemotherapeutic treatments and/or novel pharmaceuticals. Cancer cells exhibit extensive metabolic alterations involving hypoxia, accelerated glycolysis, oxidative stress, and increased extracellular ATP that may activate ancient, conserved prion adaptive response strategies that exacerbate multidrug resistance (MDR) by exploiting cellular stress to increase cancer metastatic potential and stemness, balance proliferation and differentiation, and amplify resistance to apoptosis. The regulation of prions in MDR is further complicated by important, putative physiological functions of ligand-binding and signal transduction. Melatonin is capable of both enhancing physiological functions and inhibiting oncogenic properties of prion proteins. Through regulation of phase separation of the prion N-terminal domain which targets and interacts with lipid rafts, melatonin may prevent conformational changes that can result in aggregation and/or conversion to pathological, infectious isoforms. As a cancer therapy adjuvant, melatonin could modulate TME oxidative stress levels and hypoxia, reverse pH gradient changes, reduce lipid peroxidation, and protect lipid raft compositions to suppress prion-mediated, non-Mendelian, heritable, but often reversible epigenetic adaptations that facilitate cancer heterogeneity, stemness, metastasis, and drug resistance. This review examines some of the mechanisms that may balance physiological and pathological effects of prions and prion-like proteins achieved through the synergistic use of melatonin to ameliorate MDR, which remains a challenge in cancer treatment.
Topics: Animals; Drug Resistance, Multiple; Humans; Lipid Peroxidation; Melatonin; Membrane Microdomains; Neoplasms; Prion Proteins; Prions; Signal Transduction; Tumor Microenvironment
PubMed: 35163973
DOI: 10.3390/molecules27030705 -
Hepatology (Baltimore, Md.) Apr 2022Melatonin reduces biliary damage and liver fibrosis in cholestatic models by interaction with melatonin receptors 1A (MT1) and 1B (MT2). MT1 and MT2 can form...
BACKGROUND AND AIMS
Melatonin reduces biliary damage and liver fibrosis in cholestatic models by interaction with melatonin receptors 1A (MT1) and 1B (MT2). MT1 and MT2 can form heterodimers and homodimers, but MT1 and MT2 can heterodimerize with the orphan receptor G protein-coupled receptor 50 (GPR50). MT1/GPR50 dimerization blocks melatonin binding, but MT2/GPR50 dimerization does not affect melatonin binding. GPR50 can dimerize with TGFβ receptor type I (TGFβRI) to activate this receptor. We aimed to determine the differential roles of MT1 and MT2 during cholestasis.
APPROACH AND RESULTS
Wild-type (WT), MT1 knockout (KO), MT2KO, and MT1/MT2 double KO (DKO) mice underwent sham or bile duct ligation (BDL); these mice were also treated with melatonin. BDL WT and multidrug resistance 2 KO (Mdr2 ) mice received mismatch, MT1, or MT2 Vivo-Morpholino. Biliary expression of MT1 and GPR50 increases in cholestatic rodents and human primary sclerosing cholangitis (PSC) samples. Loss of MT1 in BDL and Mdr2 mice ameliorated biliary and liver damage, whereas these parameters were enhanced following loss of MT2 and in DKO mice. Interestingly, melatonin treatment alleviated BDL-induced biliary and liver injury in BDL WT and BDL MT2KO mice but not in BDL MT1KO or BDL DKO mice, demonstrating melatonin's interaction with MT1. Loss of MT2 or DKO mice exhibited enhanced GPR50/TGFβR1 signaling, which was reduced by loss of MT1.
CONCLUSIONS
Melatonin ameliorates liver phenotypes through MT1, whereas down-regulation of MT2 promotes liver damage through GPR50/TGFβR1 activation. Blocking GPR50/TGFβR1 binding through modulation of melatonin signaling may be a therapeutic approach for PSC.
Topics: Animals; Cholestasis; Liver Cirrhosis; Melatonin; Mice; Mice, Knockout; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2
PubMed: 34743371
DOI: 10.1002/hep.32233 -
Cells Nov 2022Metabolic rewiring in glioblastoma (GBM) is linked to intra- and extracellular pH regulation. In this study, we sought to characterize the role of melatonin on...
Metabolic rewiring in glioblastoma (GBM) is linked to intra- and extracellular pH regulation. In this study, we sought to characterize the role of melatonin on intracellular pH modulation and metabolic consequences to identify the mechanisms of action underlying melatonin oncostatic effects on GBM tumor initiating cells. GBM tumor initiating cells were treated at different times with melatonin (1.5 and 3.0 mM). We analyzed melatonin's functional effects on GBM proliferation, cell cycle, viability, stemness, and chemo-radiosensitivity. We then assessed the effects of melatonin on GBM metabolism by analyzing the mitochondrial and glycolytic parameters. We also measured the intracellular and extracellular pH. Finally, we tested the effects of melatonin on a mouse subcutaneous xenograft model. We found that melatonin downregulated LDHA and MCT4, decreasing lactate production and inducing a decrease in intracellular pH that was associated with an increase in ROS and ATP depletion. These changes blocked cell cycle progression and induced cellular death and we observed similar results in vivo. Melatonin's cytotoxic effects on GBM were due, at least in part, to intracellular pH modulation, which has emerged as a newly identified mechanism, providing new insights into the oncostatic effect of melatonin on GBM.
Topics: Humans; Mice; Animals; Glioblastoma; Melatonin; Glycolysis; Cell Division; Hydrogen-Ion Concentration
PubMed: 36359862
DOI: 10.3390/cells11213467 -
The Journal of Investigative Dermatology Mar 2018Melatonin, an evolutionarily ancient derivative of serotonin with hormonal properties, is the main neuroendocrine secretory product of the pineal gland. Although... (Review)
Review
Melatonin, an evolutionarily ancient derivative of serotonin with hormonal properties, is the main neuroendocrine secretory product of the pineal gland. Although melatonin is best known to regulate circadian rhythmicity and lower vertebrate skin pigmentation, the full spectrum of functional activities of this free radical-scavenging molecule, which also induces/promotes complex antioxidative and DNA repair systems, includes immunomodulatory, thermoregulatory, and antitumor properties. Because this plethora of functional melatonin properties still awaits to be fully appreciated by dermatologists, the current review synthesizes the main features that render melatonin a promising candidate for the management of several dermatoses associated with substantial oxidative damage. We also review why melatonin promises to be useful in skin cancer prevention, skin photo- and radioprotection, and as an inducer of repair mechanisms that facilitate the recovery of human skin from environmental damage. The fact that human skin and hair follicles not only express functional melatonin receptors but also engage in substantial, extrapineal melatonin synthesis further encourages one to systematically explore how the skin's melatonin system can be therapeutically targeted in future clinical dermatology and enrolled for preventive medicine strategies.
Topics: Animals; Antineoplastic Agents; Hair Follicle; Humans; Melatonin; Radiation-Protective Agents; Receptors, Melatonin; Skin; Skin Neoplasms; Skin Pigmentation; Wound Healing
PubMed: 29428440
DOI: 10.1016/j.jid.2017.10.025 -
International Journal of Molecular... Feb 2019Salt stress is one of the most serious limiting factors in worldwide agricultural production, resulting in huge annual yield loss. Since 1995, melatonin... (Review)
Review
Salt stress is one of the most serious limiting factors in worldwide agricultural production, resulting in huge annual yield loss. Since 1995, melatonin (-acetyl-5-methoxytryptamine)-an ancient multi-functional molecule in eukaryotes and prokaryotes-has been extensively validated as a regulator of plant growth and development, as well as various stress responses, especially its crucial role in plant salt tolerance. Salt stress and exogenous melatonin lead to an increase in endogenous melatonin levels, partly via the phyto-melatonin receptor CAND2/PMTR1. Melatonin plays important roles, as a free radical scavenger and antioxidant, in the improvement of antioxidant systems under salt stress. These functions improve photosynthesis, ion homeostasis, and activate a series of downstream signals, such as hormones, nitric oxide (NO) and polyamine metabolism. Melatonin also regulates gene expression responses to salt stress. In this study, we review recent literature and summarize the regulatory roles and signaling networks involving melatonin in response to salt stress in plants. We also discuss genes and gene families involved in the melatonin-mediated salt stress tolerance.
Topics: Gene Expression Regulation, Plant; Genes, Plant; Melatonin; Metabolic Networks and Pathways; Multigene Family; Photosynthesis; Plant Development; Plant Growth Regulators; Plant Physiological Phenomena; Plants; Receptors, Melatonin; Salt Stress; Salt Tolerance; Signal Transduction; Stress, Physiological
PubMed: 30736409
DOI: 10.3390/ijms20030709