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Journal of Clinical Sleep Medicine :... Feb 2017Melatonin is an important neurohormone, which mediates circadian rhythms and the sleep cycle. As such, it is a popular and readily available supplement for the treatment...
STUDY OBJECTIVES
Melatonin is an important neurohormone, which mediates circadian rhythms and the sleep cycle. As such, it is a popular and readily available supplement for the treatment and prevention of sleep-related disorders including insomnia and jet lag. This study quantified melatonin in 30 commercial supplements, comprising different brands and forms and screened supplements for the presence of serotonin.
METHODS
A total of 31 supplements were analyzed by ultraperformance liquid chromatography with electrochemical detection for quantification of melatonin and serotonin. Presence of serotonin was confirmed through analysis by ultraperformance liquid chromatography with mass spectrometry detection.
RESULTS
Melatonin content was found to range from -83% to +478% of the labelled content. Additionally, lot-to-lot variable within a particular product varied by as much as 465%. This variability did not appear to be correlated with manufacturer or product type. Furthermore, serotonin (5-hydroxytryptamine), a related indoleamine and controlled substance used in the treatment of several neurological disorders, was identified in eight of the supplements at levels of 1 to 75 μg.
CONCLUSIONS
Melatonin content did not meet label within a 10% margin of the label claim in more than 71% of supplements and an additional 26% were found to contain serotonin. It is important that clinicians and patients have confidence in the quality of supplements used in the treatment of sleep disorders. To address this, manufacturers require increased controls to ensure melatonin supplements meet both their label claim, and also are free from contaminants, such as serotonin.
COMMENTARY
A commentary on this article appears in this issue on page 163.
Topics: Biological Products; Chromatography, Liquid; Dietary Supplements; Electrochemical Techniques; Mass Spectrometry; Melatonin; Serotonin
PubMed: 27855744
DOI: 10.5664/jcsm.6462 -
Journal of Pineal Research Oct 2022The oncostatic effects of melatonin correlate with increased reactive oxygen species (ROS) levels, but how melatonin induces this ROS generation is unknown. In the...
The oncostatic effects of melatonin correlate with increased reactive oxygen species (ROS) levels, but how melatonin induces this ROS generation is unknown. In the present study, we aimed to elucidate the two seemingly opposing actions of melatonin regarding its relationship with free radicals. We analyzed the effects of melatonin on head and neck squamous cell carcinoma cell lines (Cal-27 and SCC-9), which were treated with 0.5 or 1 mM melatonin. We further examined the potential effects of melatonin to induce ROS and apoptosis in Cal-27 xenograft mice. Here we report that melatonin mediates apoptosis in head and neck cancer by driving mitochondrial reverse electron transport (RET) to induce ROS production. Melatonin-induced changes in tumoral metabolism led to increased mitochondrial activity, which, in turn, induced ROS-dependent mitochondrial uncoupling. Interestingly, mitochondrial complex inhibitors, including rotenone, abolished the ROS elevation indicating that melatonin increased ROS generation via RET. Melatonin also increased membrane potential and CoQ H /CoQ ratio to elevate mitochondrial ROS production, which are essential conditions for RET. We found that genetic manipulation of cancer cells with alternative oxidase, which transfers electrons from QH to oxygen, inhibited melatonin-induced ROS generation, and apoptosis. RET restored the melatonin-induced oncostatic effect, highlighting the importance of RET as the site of ROS production. These results illustrate that RET and ROS production are crucial factors in melatonin's effects in cancer cells and establish the dual effect of melatonin in protecting normal cells and inducing apoptosis in cancer cells.
Topics: Animals; Apoptosis; Electron Transport; Head and Neck Neoplasms; Humans; Melatonin; Mice; Reactive Oxygen Species
PubMed: 35986493
DOI: 10.1111/jpi.12824 -
Frontiers in Endocrinology 2022Previous studies have revealed that melatonin could play a role in anti-osteoporosis and promoting osteogenesis. However, the effects of melatonin treatment on...
Previous studies have revealed that melatonin could play a role in anti-osteoporosis and promoting osteogenesis. However, the effects of melatonin treatment on osteoporotic bone defect and the mechanism underlying the effects of melatonin on angiogenesis are still unclear. Our study was aimed to investigate the potential effects of melatonin on angiogenesis and osteoporotic bone defect. Bone marrow mesenchymal stem cells (BMSCs) were isolated from the femur and tibia of rats. The BMSC osteogenic ability was assessed using alkaline phosphatase (ALP) staining, alizarin red S staining, qRT-PCR, western blot, and immunofluorescence. BMSC-mediated angiogenic potentials were determined using qRT-PCR, western blot, enzyme-linked immunosorbent assay, immunofluorescence, scratch wound assay, transwell migration assay, and tube formation assay. Ovariectomized (OVX) rats with tibia defect were used to establish an osteoporotic bone defect model and then treated with melatonin. The effects of melatonin treatment on osteoporotic bone defect in OVX rats were analyzed using micro-CT, histology, sequential fluorescent labeling, and biomechanical test. Our study showed that melatonin promoted both osteogenesis and angiogenesis . BMSCs treated with melatonin indicated higher expression levels of osteogenesis-related markers [ALP, osteocalcin (OCN), runt-related transcription factor 2, and osterix] and angiogenesis-related markers [vascular endothelial growth factor (VEGF), angiopoietin-2, and angiopoietin-4] compared to the untreated group. Significantly, melatonin was not able to facilitate human umbilical vein endothelial cell angiogenesis directly, but it possessed the ability to promote BMSC-mediated angiogenesis by upregulating the VEGF levels. In addition, we further found that melatonin treatment increased bone mineralization and formation around the tibia defect in OVX rats compared with the control group. Immunohistochemical staining indicated higher expression levels of osteogenesis-related marker (OCN) and angiogenesis-related markers (VEGF and CD31) in the melatonin-treated OVX rats. Then, it showed that melatonin treatment also increased the bone strength of tibia defect in OVX rats, with increased ultimate load and stiffness, as performed by three-point bending test. In conclusion, our study demonstrated that melatonin could promote BMSC-mediated angiogenesis and promote osteogenesis-angiogenesis coupling. We further found that melatonin could accelerate osteoporotic bone repair by promoting osteogenesis and angiogenesis in OVX rats. These findings may provide evidence for the potential application of melatonin in osteoporotic bone defect.
Topics: Animals; Cell Differentiation; Melatonin; Osteogenesis; Osteoporosis; Rats; Vascular Endothelial Growth Factor A
PubMed: 35273570
DOI: 10.3389/fendo.2022.826660 -
Redox Biology Feb 2022In mammalian ovaries, oocytes are physically coupled to somatic granulosa cells, and this coupling is crucial for the growth and development of competent oocytes as it...
In mammalian ovaries, oocytes are physically coupled to somatic granulosa cells, and this coupling is crucial for the growth and development of competent oocytes as it mediates the transfer of metabolic support molecules. However, aging-mediated dysregulation in communication between the oocytes and granulosa cells affects the oocyte quality. In the present study, we examined the defected germline-soma communication and reduced mRNA levels encoding key structural components of transzonal projections (TZPs) in maternally aged oocytes. Oral administration of melatonin to aged mice substantially increased TZPs and maintained the cumulus cells-oocyte communication, which played a central role in the production of adequate oocyte ATP levels and reducing the accumulation of reactive oxygen species (ROS), apoptosis, DNA damage, endoplasmic reticulum (ER) stress and spindle/chromosomal defects. This beneficial effect of melatonin was inhibited by carbenoxolone (CBX), a gap junctional uncoupler, which disrupts bidirectional communications between oocyte and somatic cells. Simultaneously, melatonin significantly increased the mRNA and protein levels corresponding to genes associated with TZPs and prevented TZP retraction in in vitro-cultured cumulus-oocyte complex (COCs). Furthermore, we infused melatonin and CBX into the COCs in vitro culture system and monitored the levels of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH) in cumulus cells and oocytes. Notably, COCs treated with melatonin demonstrated improved NADPH and GSH levels. Of note, CBX was capable of reducing NADPH and GSH levels, aggravated the ROS accumulation and ER stress. Collectively, our data demonstrate the role of melatonin in preventing age-associated germline-soma communication defects, aiding the relay of antioxidant metabolic molecules for the maintenance of oocyte quality from cumulus cells, which have important potential for improving deficient phenotypes of maternally aged oocytes and the treatment of woman infertility.
Topics: Animals; Antioxidants; Cell Communication; Cumulus Cells; Female; Melatonin; Mice; Oocytes
PubMed: 34929573
DOI: 10.1016/j.redox.2021.102215 -
Frontiers in Immunology 2022Microglial activation and melatonin protection have been reported in diabetic retinopathy (DR). Whether melatonin could regulate microglia to protect the inner...
Microglial activation and melatonin protection have been reported in diabetic retinopathy (DR). Whether melatonin could regulate microglia to protect the inner blood-retinal barrier (iBRB) remains unknown. In this study, the role of microglia in iBRB breakdown and the mechanisms of melatonin's regulation on microglia were explored. In diabetic rat retinas, activated microglia proliferated and migrated from the inner retina to the outer retina, accompanied by the obvious morphological changes. Meanwhile, significant leakage of albumin was evidenced at the site of close interaction between activated microglia and the damaged pericytes and endothelial cells. , inflammation-related cytokines, such as tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), interleukin (IL)-1β, and arginase-1 (Arg-1), were increased significantly in CoCl-treated BV2 cells. The supernatant derived from CoCl-treated BV2 cells significantly decreased the cell viability and disrupted the junctional proteins in both pericytes and endothelial cells, resulting in severe leakage. Melatonin suppressed the microglial overactivation, i.e., decreasing the cell number and promoting its anti-inflammatory properties in diabetic rat retinas. Moreover, the leakage of iBRB was alleviated and the pericyte coverage was restored after melatonin treatment. , when treated with melatonin in CoCl-treated BV2 cells, the inflammatory factors were decreased, while the anti-inflammatory factors were increased, further reducing the pericyte loss and increasing the tight junctions. Melatonin deactivated microglia inhibition of PI3K/Akt/Stat3/NF-κB signaling pathways, thus maintaining the integrity of iBRB. The present data support a causal role for activated microglia in iBRB breakdown and highlight the therapeutic potential of melatonin in the treatment of DR by regulating microglia.
Topics: Animals; Blood-Retinal Barrier; Diabetes Mellitus; Diabetic Retinopathy; Endothelial Cells; Melatonin; Microglia; NF-kappa B; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; STAT3 Transcription Factor; Signal Transduction
PubMed: 35371022
DOI: 10.3389/fimmu.2022.831660 -
Molecules (Basel, Switzerland) Feb 2018Melatonin is a natural indoleamine produced by the pineal gland that has many functions, including regulation of the circadian rhythm. Many studies have reported the... (Review)
Review
Melatonin is a natural indoleamine produced by the pineal gland that has many functions, including regulation of the circadian rhythm. Many studies have reported the anticancer effect of melatonin against a myriad of cancer types. Cancer hallmarks include sustained proliferation, evading growth suppressors, metastasis, replicative immortality, angiogenesis, resisting cell death, altered cellular energetics, and immune evasion. Melatonin anticancer activity is mediated by interfering with various cancer hallmarks. This review summarizes the anticancer role of melatonin in each cancer hallmark. The studies discussed in this review should serve as a solid foundation for researchers and physicians to support basic and clinical studies on melatonin as a promising anticancer agent.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Cell Transformation, Neoplastic; Disease Progression; Genomic Instability; Humans; Melatonin; Metabolic Networks and Pathways; Neoplasms; Neovascularization, Pathologic; Signal Transduction; Tumor Escape
PubMed: 29495398
DOI: 10.3390/molecules23030518 -
Advanced Science (Weinheim,... Sep 2023Periodontitis is a chronic infectious disease caused by bacterial irritation. As an essential component of the host immunity, macrophages are highly plastic and play a...
Periodontitis is a chronic infectious disease caused by bacterial irritation. As an essential component of the host immunity, macrophages are highly plastic and play a crucial role in inflammatory response. An appropriate and timely transition from proinflammatory (M1) to anti-inflammatory (M2) macrophages is indispensable for treating periodontitis. As M2 macrophage-derived exosomes (M2-exos) can actively target inflammatory sites and modulate immune microenvironments, M2-exos can effectively treat periodontitis. Excessive endoplasmic reticulum stress (ER stress) and unfolded protein response (UPR) are highly destructive pathological characteristics during inflammatory periodontal bone loss. Although melatonin has antioxidant and anti-inflammatory effects, studies focusing on melatonin ER stress modulation remain limited. This study fabricates engineered M2-exos loading with melatonin (Mel@M2-exos) for treating periodontitis. As a result, M2-exos drive an appropriate and timely macrophage reprogramming from M1 to M2 type, which resolves chronic inflammation and accelerated periodontal healing. Melatonin released from Mel@M2-exos rescues the osteogenic and cementogenic differentiation capacity in inflammatory human periodontal ligament cells (hPDLCs) by reducing excessive ER stress and UPR. Injectable gelatin methacryloyl (GelMA) hydrogels with sustained-release Mel@M2-exos accelerate periodontal bone regeneration in rats with ligation-induced periodontitis. Taken together, melatonin engineering M2 macrophage-derived exosomes are promising candidates for inflammatory periodontal tissue regeneration.
Topics: Rats; Humans; Animals; Melatonin; Exosomes; Periodontitis; Endoplasmic Reticulum Stress; Inflammation; Macrophages
PubMed: 37452425
DOI: 10.1002/advs.202302029 -
Frontiers in Immunology 2024Melatonin (N-acetyl-5-methoxytryptamine) is an indolamine hormone with many physiological and biological roles. Melatonin is an antioxidant, anti-inflammatory, free... (Review)
Review
Melatonin (N-acetyl-5-methoxytryptamine) is an indolamine hormone with many physiological and biological roles. Melatonin is an antioxidant, anti-inflammatory, free radical scavenger, circadian rhythm regulator, and sleep hormone. However, its most popular role is the ability to regulate sleep through the circadian rhythm. Interestingly, recent studies have shown that melatonin is an important and essential hormone during pregnancy, specifically in the placenta. This is primarily due to the placenta's ability to synthesize its own melatonin rather than depending on the pineal gland. During pregnancy, melatonin acts as an antioxidant and anti-inflammatory, which is necessary to ensure a stable environment for both the mother and the fetus. It is an essential antioxidant in the placenta because it reduces oxidative stress by constantly scavenging for free radicals, i.e., maintain the placenta's integrity. In a healthy pregnancy, the maternal immune system is constantly altered to accommodate the needs of the growing fetus, and melatonin acts as a key anti-inflammatory by regulating immune homeostasis during early and late gestation. This literature review aims to identify and summarize melatonin's role as a powerful antioxidant and anti-inflammatory that reduces oxidative stress and inflammation to maintain a favorable homeostatic environment in the placenta throughout gestation.
Topics: Pregnancy; Female; Humans; Melatonin; Antioxidants; Placenta; Free Radical Scavengers; Anti-Inflammatory Agents
PubMed: 38361952
DOI: 10.3389/fimmu.2024.1339304 -
International Journal of Molecular... Feb 2022Melatonin interacts with various types of stem cells, in multiple ways that comprise stimulation of proliferation, maintenance of stemness and self-renewal, protection... (Review)
Review
Melatonin interacts with various types of stem cells, in multiple ways that comprise stimulation of proliferation, maintenance of stemness and self-renewal, protection of survival, and programming toward functionally different cell lineages. These various properties are frequently intertwined but may not be always jointly present. Melatonin typically stimulates proliferation and transition to the mature cell type. For all sufficiently studied stem or progenitor cells, melatonin's signaling pathways leading to expression of respective morphogenetic factors are discussed. The focus of this article will be laid on the aspect of programming, particularly in pluripotent cells. This is especially but not exclusively the case in neural stem cells (NSCs) and mesenchymal stem cells (MSCs). Concerning developmental bifurcations, decisions are not exclusively made by melatonin alone. In MSCs, melatonin promotes adipogenesis in a Wnt (Wingless-Integration-1)-independent mode, but chondrogenesis and osteogenesis Wnt-dependently. Melatonin upregulates Wnt, but not in the adipogenic lineage. This decision seems to depend on microenvironment and epigenetic memory. The decision for chondrogenesis instead of osteogenesis, both being Wnt-dependent, seems to involve fibroblast growth factor receptor 3. Stem cell-specific differences in melatonin and Wnt receptors, and contributions of transcription factors and noncoding RNAs are outlined, as well as possibilities and the medical importance of re-programming for transdifferentiation.
Topics: Animals; Cell Differentiation; Cell Lineage; Cellular Reprogramming; Humans; Melatonin; Stem Cells
PubMed: 35216086
DOI: 10.3390/ijms23041971 -
Biomolecules Jun 2023Melatonin is a fascinating molecule that has captured the imagination of many scientists since its discovery in 1958. In recent times, the focus has changed from... (Review)
Review
Melatonin is a fascinating molecule that has captured the imagination of many scientists since its discovery in 1958. In recent times, the focus has changed from investigating its natural role as a transducer of biological time for physiological systems to hypothesized roles in virtually all clinical conditions. This goes along with the appearance of extensive literature claiming the (generally) positive benefits of high doses of melatonin in animal models and various clinical situations that would not be receptor-mediated. Based on the assumption that melatonin is safe, high doses have been administered to patients, including the elderly and children, in clinical trials. In this review, we critically review the corresponding literature, including the hypotheses that melatonin acts as a scavenger molecule, in particular in mitochondria, by trying not only to contextualize these interests but also by attempting to separate the wheat from the chaff (or the wishful thinking from the facts). We conclude that most claims remain hypotheses and that the experimental evidence used to promote them is limited and sometimes flawed. Our review will hopefully encourage clinical researchers to reflect on what melatonin can and cannot do and help move the field forward on a solid basis.
Topics: Animals; Melatonin; Mitochondria
PubMed: 37371523
DOI: 10.3390/biom13060943