Melatonin Research

Melatonin, an ancient ally against pancreatic disorders

2024-12-27T19:46:37-07:00

Melatonin is mainly produced in the pineal gland of mammals with a circadian rhythm. It has also been synthesized in different organs and tissues including the gastrointestinal tract. Additionally, melatonin is widely present in plants and foodstuff. In addition to its effects on the sleep-wake cycle and reproductive regulation in photoperiodic animals, melatonin regulates a wide variety of cellular processes, participating in the control of antioxidant defenses, immune response, energy metabolism, cell growth and proliferation, having beneficial effects on most of the tissues and organs, including the pancreas.

Here, we have reviewed the recent findings related to the effects of melatonin on the physiology of the exocrine pancreas. Of major relevance, the effects of the indoleamine on pathological processes such as cancer, inflammation, diabetes, and fibrosis are also reviewed. Not less important, its effects on normal/healthy cells of the pancreas to modulate normal physiological functions are discussed.

Potential therapeutic intervention of melatonin against COVID-19: A comparative pharmacokinetic study

2024-12-27T19:46:38-07:00

Melatonin synthesis is primarily regulated by environmental light-dark cycle and is well known for its biological rhythm regulation and its potent antioxidant and anti-inflammatory properties across species. The present investigation focuses on the potential actions of melatonin as a therapeutic agent against COVID-19 and these actions are compared with other commonly used pharmacological agents of this kind including methylprednisolone, doxycycline, oseltamivir, and remdesivir. The comprehensive comparisons of pharmacokinetic profiles include their absorption, distribution, metabolism, and excretion (ADME) properties. The further in-depth analyses on their target identification, functional enrichment are performed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, construction of protein-protein interaction (PPI) networks, and molecular docking. These analyses elucidate the potential correlation of melatonin with critical hub targets implicated in COVID-19 pathogenesis. The results from pharmacokinetics indicates that melatonin has the higher bioavailability than the other tested drugs due to its low molecular weight, lipophilicity, lack of P-glycoprotein (P-gp) along with inhibitory action on cytochrome P450 1A2 (CYP1A2). GO and enriched KEGG analyses suggests that melatonin-mediated modulation of COVID-19 pathogenesis likely targets the AGE-RAGE pathway, HIF-1α signaling, and apoptosis. Furthermore, PPI network analysis also shows that melatonin has the highest nodes and edges, as well as the greatest average node degree score and highest common potential targets with the genes associated with the development of COVID-19. Notably, molecular docking study demonstrates the substantial interactions of melatonin with principal hub targets TP53, AKT1, IL6, TNF, IL1B, BCL2, EGFR, STAT3, CASP3, and NFKB1. Hence, melatonin has several significant pharmacokinetic advantages compared to selected therapeutic agents which may appear to modulate multiple facets of COVID-19 pathology. Based on the significant pharmacokinetic advantages of melatonin over the commonly used other drugs, the substantial clinical studies are necessary to establish its methods of application as a potential therapeutic against SARS-CoV-2 in the near future.

Current state of the natural melatonin: the phytomelatonin market

2024-12-27T19:46:37-07:00

Melatonin is a dietary supplement substance widely distributed in the global market and its therapeutic use has been significantly expanded from its original use to target the jet-lag. In this report, we have discussed the current situation of the natural melatonin market, an “alternative melatonin” to chemically synthesized melatonin, with exclusive characteristics and possibilities, to focus on a more selective, eco-friendly market that orients its consumption to natural and healthy products. The different possibilities obtained melatonin from genetically modified organisms to phytomelatonin which are extracted from algae/microalgae or medicinal plants are discussed.

Melatonin-induced brassinosteroid biosynthesis enhances seed size, senescence tolerance, and salt stress susceptibility in transgenic rice plants overexpressing an archaeal serotonin N-acetyltransferase

2024-12-27T19:46:38-07:00

Serotonin N-acetyltransferase (SNAT) is the penultimate enzyme catalyzing serotonin into N-acetylserotonin in the melatonin biosynthetic pathway. Recently, an archaeal SNAT from Thermoplasma volcanium (TvSNAT) was cloned and rice lines with its ectopic overexpression (TvSNAT-OE) exhibited higher melatonin levels and generated larger seeds than those of the wild type (WT). In this study, we hypothesized that the increased seed size in TvSNAT-OE rice line might be linked to enhanced brassinosteroid (BR) synthesis since melatonin level is positively associated with BR production. In rice seedlings, roots were shorter and the lamina angle was larger in TvSNAT-OE lines than those in the WT. Also, the second leaves of seedlings were longer in the TvSNAT-OE lines than that in the WT, supporting BR elevation in the TvSNAT-OE lines. In parallel with these phenotypic features, BR levels were higher in the TvSNAT-OE lines than that in the WT. Increased BR levels were associated with enhanced expression of DWARF4 and BZR1, the key genes for BR biosynthesis and signaling, in the TvSNAT-OE lines compared with the WT. Consequently, the TvSNAT-OE lines showed delayed senescence, but were more susceptible to salt stress than the WT due to enhanced BR levels.

A cross-sectional report on the use of high doses of melatonin in humans.

2024-12-27T19:46:37-07:00

The administration of melatonin in chronobiotic doses (≤10 mg daily) is a common procedure in clinics. In addition, research in animals has led to greater awareness on the potentiality of melatonin as an antioxidant, immunological and mitochondrial regulator and anti-inflammatory compound. Doses allometrically derived from animal studies correspond to 75 to 112.5 mg daily range for a 75 kg human adult. In view of the absence of toxicity of melatonin in phase 1 pharmacological studies with doses up to 100 mg in normal volunteers, we regularly use melatonin in this dose range to treat sleep disorders in aged patients to prevent age-related comorbidities. In an observational, analytical, retrospective, cross-sectional study of clinical history data from a closed population of patients taking melatonin in doses equal to or greater than 40 mg/day of melatonin for various sleep disorders, 80 patients (74.2 % female, mean age 74 years ± 9.26) were included. The indication of melatonin doses varied between 40 and 200 mg per day, with a mean of 76.56 mg ± 33.58 mg daily. The main reason for indication was complaints of disorders in falling asleep or maintaining sleep with melatonin doses varying depending on the comorbidities clinically detected. The 59 % of patients received treatment for more than 4 years. Laboratory variables related to liver function remain within the normal range after melatonin administration regardless of the dose employed. No relation was also found between melatonin dose and concomitant pharmacological treatment. The results advocate for the safe use of melatonin in higher doses than those commonly employed.

Differential effects of melatonin on adipose tissues under normoestrogenic and estrogen-deficient conditions in rats

2024-09-02T16:42:57-06:00

In post-menopause, oxidative stress due to the decline of natural antioxidants increases the susceptibility to metabolic syndromes (MetS). Estrogen and melatonin (MEL) share antioxidant properties; however, few studies have reported the impact of estrogen deficiency and MEL treatment on morphology, redox status, and antioxidant defense capacity of diverse adipose tissue (AT) subtypes. To investigate this issue, MEL was administered to ovariectomized (OVX) rats and sham-operated rats for 16 weeks (10 mg/kg). The adipocyte morphology, oxidative stress parameters and antioxidant enzyme activity were evaluated in the visceral retroperitoneal adipose tissue (rVAT), subcutaneous inguinal adipose tissue (iSAT) and brown adipose tissue (BAT). In OVX rats, MEL treatment suppressed rVAT hypertrophy and increased the prevalence of small adipocytes in iSAT, suggesting a better lipid distribution among ATs. MEL treatment increased glutathione reductase and glucose-6-phosphate dehydrogenase activity in iSAT; therefore, restored the glutathione level. In rVAT, MEL increased glutathione peroxidase and glutathione reductase activity. MEL minimized the risks for the development of metabolic abnormalities due to estrogen deficiency. However, under normoestrogenic condition, MEL decreased plasma estradiol levels and uterine mass, raising the concerning of its effect on reproductive functions.

Onset in late adolescence of schizophrenia: Could melatonin modulate this debut?

2024-09-02T16:42:57-06:00

Schizophrenia, one of the most serious and widespread mental disorders in the world, makes its debut often in late adolescence and early adulthood, which allows us to focus our attention on those brain areas that still retain plasticity during this period. Parvalbumin interneurons, GABAergic and inhibitory, in both cortical and hippocampal areas, maintain their plasticity and are particularly vulnerable to oxidative stress due to their high energy requirements. Evidence has shown that their damage favors the triggering of schizophrenia by altering the neurobehavioral development of individuals. These neurons have melatonin receptors of MT1 and MT2, and the cytoprotective role of melatonin has been reported on these neurons. However, the role of this indolamine played in adolescence in protecting parvalbumin interneurons, reducing their oxidative stress and/or preventing their disappearance, which could prevent the onset of schizophrenia, is not yet known. The importance of this activity and its implications on patient therapy require the urgent studies

Multiple actions of melatonin in reducing viral pathophysiologies

2024-09-02T16:42:57-06:00

Viral infections lead to significant morbidity and mortality while the effective therapeutic approaches are lacking. Melatonin (MEL) (N-acetyl-5-methoxytryptamine) is a pleiotropic molecule that has a variety of functions, including the antiviral properties. It is a potent antioxidant, anti-inflammatory agent, a stimulator of immune functions, and regulator of apoptosis. These effects support the use of MEL in viral infections, which are often associated with excessive inflammatory responses and elevated oxidative stress. The virus- and cytokine- storm-driven control of the pineal and mitochondrial melatonergic pathway regulates immune responses and increases gut dysbiosis, suppressing levels of the short-chain fatty acid, butyrate, and increasing circulating lipopolysaccharides, stimulating viral replication and host symptoms severity. MEL has a contrasting role in controlling the pathophysiological effects of various viruses due to its chronobiotic, antioxidant and anti-inflammatory actions. Several recent preclinical and clinical studies have documented a robust protective effect of MEL against viral infections, including COVID-19 and it has emerged as an excellent candidate for protection against an array of different viruses. This review summarizes available data on the beneficial effects of MEL on viral pathophysiological actions, and also discusses and highlights likely evidence-based therapeutic applications.

Transgenerational effects of maternal circadian melatonin deficiency and melatonin replacement in rats during pregnancy and lactation on the energy metabolism and thermoregulation in the offspring subjected to a high-fat diet

2024-09-02T16:42:57-06:00

Pineal melatonin participates in the control of numerous biological functions through its immediate effects, which result from its high presence in the systemic circulation during the dark phase of the circadian cycle or, through its prolonged effects, when its level is extremely low during the light phase. At pregnancy, maternal melatonin signals the external photoperiod to the fetus, highlighting its importance not only in synchronizing rhythms, but also in preparing the fetus to adapt the external environments. The fetus and newborns are exclusively dependent on maternal melatonin since their pineal melatonin production only occurs weeks after birth. Thus, maternal hypomelatoninemia stands out as an important factor capable of modulating the physiological systems of their descendants, demonstrating its transgenerational capacity. The present study evaluated the transgenerational influence of maternal melatonin deficiency and replacement during pregnancy on morphometric parameters, thermoregulation and energy metabolism of the offspring submitted to the normal and high-fat diets, respectively. For this, nulliparous Wistar rats at an age of 8 weeks were used and randomized into three groups: CTL (pregnant rats), PINX (pinealectomized pregnant rats), PINX + MEL (pinealectomized pregnant rats submitted to melatonin replacement). After birth, the pups were divided into three groups: (C) pups from control mothers, (P) pups from PINX mothers and (PM) pups from PINX + MEL mothers. One week after weaning, part of the animals was fed a high-fat diet (DH) and rest of them were fed a normal diet (ND) for 12 weeks. Subsequently, the animals were euthanized at ZTs 6 and 18. The results showed that maternal melatonin deficiency disrupted the energy metabolism of the offspring and melatonin replacement normalized the energy metabolism in the offspring submitted to the high-fat diet, enabling them to make functional adaptations such as reduced food consumption and greater thermoregulatory capacity, resulting in reduction in body weight gain white adipose tissue mass.

Cell polarization, migration and tissue repair: A promising field for future melatonin research

2024-09-02T16:42:57-06:00

Melatonin has been shown to support the repair of various tissue injuries. Wound healing is a complicated process that comprises several different cellular activities and regulation mechanisms, such as activation and programming of stem cells, interaction of different cell types, polarization of cells, especially concerning the alternative of pro- vs. anti-inflammatory behavior, migration of cells to the site of replacement, with guidance by other cells and modified extracellular matrix, as observed in the formation of biobridges. In most of these processes, melatonin acts as a decisive modulator, but details depend on tissue and cell types and have not been completely identified. Many aspects will require a considerable amount of work for understanding, in this context, the role of melatonin on a comprehensive basis. Moreover, the modulation of important cell properties has remained partially unknown or has only poorly considered in recent work. For instance, pro- or anti-inflammatory polarization of cells has been described in various cell types, not only in macrophages, in which melatonin is a major regulator, but also in microglia, in astrocytes and in neutrophils. Even in fibroblasts, polarization has been observed and concerns the alternative of inflammatory or fibrotic behavior. Notably, polarized cells that support healing in normal tissue seem to also protect tumors, whereas inflammatory phenotypes show antitumor activities. With regard to antitumor properties of melatonin, it seems necessary to clarify whether melatonin polarizes cells differently in the tumor microenvironment, compared to normal tissue, in which it promotes healing.

Melatonin and the intervertebral disc: a potential intervention for lower back pain?

2024-08-20T10:35:52-06:00

Lower back pain is a common disability associated with aging that continues to carry a huge economic and health burden globally. Importantly, lower back pain is strongly associated with diseases involving intervertebral discs (IVDs), and many of the treatment options for the repair and maintenance of the IVDs are insufficient. Being a well-tolerated and endogenously produced molecule, melatonin is a suitable candidate for the treatment and prevention of a wide variety of skeletal conditions. In this review, we have evaluated current updates regarding melatonin’s activities in IVD degenerative disease and discuss multiple mechanisms related to its effects on inflammation, oxidative stress, autophagy and senescence that contribute towards its support of the IVDs as well as its benefits in the treatment of IVD disease.

The effects of endogenous melatonin on brain tissue oxidative stress induced by photoperiodic alterations and iron overloading in rats

2024-04-25T10:01:58-06:00

Melatonin is a potent endogenously occurring antioxidant with the pleiotropic activities to neurodegenerative diseases associated with brain oxidative damage. In this study, we examined the prolonged photoperiodic alterations and iron (Fe) overload on melatonin production and brain oxidative stress in rats. The result showed that the 15 days of constant light (CL) exposure did not low the melatonin production but the 15 days of constant darkness (CD) significantly increased serum melatonin level in rats. The Fe treatment in both CL and CD conditions significantly reduced endogenous melatonin levels and increased brain tissue lipid peroxidation. Fe as a toxic transition metal can induce Fenton reaction to generated hydroxyl radical which can damage the neuronal cell membrane and impair the brain antioxidant system. In the current study, we observed the imbalanced antioxidant defense alterations upon Fe treatment in rat brain including the increased levels of alpha-tocopherol (α-T) and total thiols and the reduced melatonin level and catalase (CAT) activity. We speculated that the reduced melatonin level caused by Fe was due to its consumption since melatonin served as a metal chelator and antioxidant. Understanding these aspects enhances knowledge of brain Fe metabolism and its role in neurodegenerative disorders as well as the potential protective effects of melatonin on this metal.

Melatonin as a promising agent alleviating endocrine deregulation and concurrent cardiovascular dysfunction: a review and future prospect

2024-04-25T10:01:58-06:00

Endocrine modulation of various growth and survival mechanisms is at the helm of cellular homeostasis and impaired endocrine balance may potentially galvanize cardiovascular health to go haywire. Melatonin, an effective antioxidant and multipotent hormone has preponderant influence on the activities of several endocrine factors including growth hormones, thyroid hormones, gastro-intestinal hormones, and those controlling reproductive and metabolic functions. Many of these hormones tightly regulate cardiovascular functions while the mammalian heart has its own endocrine machinery. Endocrine disruptions severely affect cardiovascular integrity and hormonal therapies may instigate adverse cardiac events. Therefore, this review focuses on the cardioprotective potential of melatonin concerning endocrine instability-mediated cardiovascular dysfunction. Melatonin has been reported to effectively counteract sympathetic overstimulation and also reduce the cardiotoxic attributes of catecholamines and their derivatives. Melatonin suppresses the pernicious cardiovascular manifestation of thyrotoxicosis and autoimmune thyroiditis, which is possibly attributed to its antioxidant property and regulation of iodothyronine-deiodinase activity. Interestingly, being a circadian synchronizer melatonin potentially preserves the diurnal pattern of insulin secretion and thereby improves glucose tolerance and cardiac GLUT-4 expression. Besides, melatonin modulates insulin signaling pathway by enhancing the activation of insulin receptor-associated tyrosine kinase, thus protecting the heart against diabetogenic outcomes. Further, melatonin has demonstrated its beneficial action against non-dipper hypertension by regulating the RAAS function. However, there is a plethora of unresolved research question that necessitates additional investigation into the potential therapeutic effect of melatonin in endocrine dysfunctions that emanates during various physiological and pathological states and may have potentially harmful cardiovascular implications.

Melatonin and viral infections: A review focusing on therapeutic effects and SARS-CoV-2

2024-04-25T10:01:58-06:00

Viral infections can cause serious diseases which lead to significant morbidity and mortality of patients. In most cases, effective therapeutic approaches are lacking. Melatonin (MEL), a multifunctional molecule produced in the pineal gland and many other organs, is known as a potent anti-inflammatory and antioxidant, a positive regulator of immune functions and a suppressor of apoptosis, with therapeutic effects in diverse diseases. These actions suggest the potential of MEL to treat viral infections. A variety of studies have shown that MEL supplementation is effective against a number of viral infections. Many of these reports have strongly suggested its use as an adjuvant or therapeutic agent. Notably, the efficacy of this molecule as a prophylactic or therapeutic weapon against COVID-19 has been demonstrated both in experimental conditions and in clinical trials, and it can reduce the severity and mortality of the patients. This review summarizes actions of MEL on viral infections and focuses on its therapeutic effects against COVID-19 and generally highlights MEL as an attractive therapy in other viral infections.

Physiological processes underpinning the ubiquitous benefits and interactions of melatonin, butyrate and green tea in neurodegenerative conditions

2024-04-25T10:01:58-06:00

There is a growing dissatisfaction at the lack of progress in treating neurodegenerative conditions, such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. No current pharmaceuticals have any significant impact on the pathophysiological changes occurring in such neurodegenerative conditions. More promising has been the utilization of nutraceuticals, a number of which show preventative and treatment benefits. This article reviews the beneficial effects of melatonin, sodium butyrate and epigallocatechin gallate (EGCG) in the management of the pathophysiological changes underpinning neurodegenerative conditions. It is proposed that all three nutraceuticals upregulate the tryptophan-melatonin pathway, which may be particularly important in astrocytes given astrocyte regulation of neuronal energy supply and antioxidants, including released melatonin. Alterations in the tryptophan-melatonin pathway are intimately intertwined with changes in the kynurenine pathway and its neuroregulatory products, including kynurenic acid and quinolinic acid. This article places these changes in the tryptophan-melatonin pathways within a novel circadian-systemic interaction, involving the regulation of the night-time rise in cortisol culminating in the morning cortisol awakening response that mediates effects via glucocorticoid receptor (GR) activation. The night-time and morning GR activation is suppressed by melatonin, gut microbiome derived butyrate and bcl2-associated athanogene (BAG)-1. As melatonin, butyrate and BAG-1 decrease over age, there is a heightened level of GR nuclear translocation with age at night and early morning. This is exemplified by the 10-fold decrease in pineal melatonin in people in their 9^th, versus 2^nd, decade of life. The ‘battle’ of melatonin/butyrate/EGCG versus cortisol/GR for influence on cellular function, microenvironment homeostasis and systemic system (immune) regulation at night and early morning shapes how the body and brain are prepared for the coming day and drives the emergence of aging associated neurodegenerative conditions. It is upon such processes that melatonin, butyrate and EGCG have their impacts.

Melatonin and cancer: Exploring gene networks and functional categories

2023-12-31T07:51:57-07:00

While melatonin is known for its multifaceted properties and its potential to combat cancer, there has been limited exploration of the cancer-melatonin interaction at the gene network level. One of the ways to better understand the molecular mechanisms of melatonin’s anti-cancer effects is to use text-mining strategies to extract relevant information that creates knowledge networks of entities and their associations. In this study, we mined gene-publication associations to search for genes most relevant to the terms of “melatonin” and “cancer”. A total of 152 genes were identified and ranked, among which 15 were kinase-related and three G-protein coupled receptor genes. The hub genes (STAT3, JUN, TP53, MAPK3, EP300, SRC, HSP90AA1, AKT1, ESR1, and IL6) were involved with several pathways in cancer. After examining the melatonin-treated cancers, we mapped 25 upregulated and 51 downregulated genes; these were strongly associated with cancer hallmarks such as resisting cell death, sustaining proliferative signaling, and inducing invasion and metastasis. Upregulated genes showed molecular functions including apoptotic protease activator, caspase activator, enzyme regulator, and protein binding, whereas the downregulated genes affected protein kinase activities, transcription factor binding, protein, enzyme, DNA, and promoter bindings. By connecting gene subsets, we detected a closer relationship among breast, hepatocellular, prostate, and oral cancers, in addition to neuroblastoma and osteosarcoma in terms of changes in melatonin-related signaling pathways. TCGA data were analyzed to understand the impact of gene signatures on survival of patients, and melatonin-downregulated genes were associated with longer survival of patients with glioblastoma, bladder, breast, colon, stomach, liver, lung, and ovarian carcinomas. These results provide a global view of gene interaction networks in melatonin-treated cancers and their functional value, opening new opportunities to consider melatonin for cancer therapy.

The therapeutic potential of melatonin against hepatotoxicity caused by obesity and NSAIDs: A comprehensive review

2023-12-31T07:51:56-07:00

The obesity and increased free fatty acid level are considered the etiology of hepatotoxicity leading to steatohepatitis and hepatic fibrosis. Obesity promotes inflammatory response and oxidative stress. Adipocytes secrete various proinflammatory cytokines including TNF-α, IL-1β, IL-6 and leptin to initiate a vicious cycle and cause further fat accumulation and weight gain. Specifically, to liver, the fat accumulation will cause non-alcoholic fatty liver disease (NAFLD), the most prevailing chronic liver ailment, if it is not properly treated, then it will cause severe outcomes including fatality. In addition, obesity also cause other inflammatory disorders including osteoarthritis of the knee, joint pain, etc. Non-steroidal anti-inflammatory drugs (NSAIDs) are most often used medicines for treatment of inflammation but their serious side effects are concerning. These include gastric mucosal damage, liver injury with elevated aminotransferase (AST/ALT) levels, hepatitis, jaundice and more fatal liver diseases. Melatonin, an antioxidant and anti-inflammatory molecule can be used to treat diverse kind of inflammatory diseases. It remarkably reduces the mRNA levels of pro-inflammatory cytokines of TNF-α, IL-6, IL-1β, etc. Melatonin and its metabolites retain the properties as an effective free radical scavenger and regulate various antioxidative and pro-oxidative enzymes. This molecule can potentially abate the ill effects of hepatotoxicity induced by both NSAIDs and obesity. Therefore, this review briefly summarizes the recent available knowledge on the protective effects of melatonin against various disorders involving weight gain and hepatotoxicity.

Melatonin and Covid-19: An opened Pandora's box and the hope for the time being

2023-12-31T07:51:57-07:00

The SARS-CoV-2 pandemic is a global health concern still ongoing. No single therapeutic intervention with high efficacy exists and virus mutations continue to improve immune evasion decreasing vaccine efficacy. Therefore, a therapy which instead targets severe symptoms of COVID-19 should be contemplated. Hyperinflammation, cytokine storm and oxidation are relevant in the evolution of COVID-19. Considering the anti-inflammatory, anti-oxidative and cytoprotective effects of melatonin (MEL) on viral infections, its potential links with COVID-19 should be researched. In addition, evidence suggests a viricidal action of MEL and an increase in the efficacy of SARS-CoV-2 vaccines. One of the neglected and excellent options for therapy is MEL. We strongly support and encourage the use of MEL as a therapy for COVID-19.

Olfactory neuronal precursors as a model to analyze the effects of melatonin in Alzheimer's disease.

2023-12-31T07:51:57-07:00

Alzheimer's disease (AD) is a multifactorial disorder of great importance affecting millions globally and its prevalence will triple in the following decades. Therefore, analysis and identification of substances which can effectively reduce the pathological process of this disease in different study models are crucial. Melatonin works as a multitasking substance and some of its activities could be used to target the neurodegenerative process of AD. These include, but not limited to, its potent antioxidant activity, regulation of sleep-wake rhythms (important for the consolidation of memory and cognition) and its action as a neurotrophic growth factor that promotes differentiation and neuronal proliferation. To evaluate the effects of melatonin at cellular level in AD, it is essential to have a study model that reflects the pathological process occurring in the CNS. In this, review we summarize the potential use of olfactory neuronal precursors derived from olfactory neuroepithelium directly obtained from patients for such purposes.

Nanocarriers for melatonin delivery

2023-12-31T07:51:57-07:00

More attention has been drawn to the drug delivery systems to achieve more precise and efficient treatment for patients with less doses of medicines. The use of nanoparticles for drug delivery system has emerged for this purpose. It can enhance the treatment efficiency by use of the drugs more selectively and precisely to deliver them to the targeted organs or tissues. Drug delivery systems can also help to reduce the side effects, especially for the chemotherapeutic agents that have severe toxicity. Melatonin (N-acetyl-5-methoxytriptamine) is a small indolamine molecule that is produced by most cells and can influence on circadian manner. Melatonin also has antiapoptotic and antioxidant actions depending on the microenvironment; these actions are enhanced when it is incorporated into nanocarriers. Although the therapeutic effects of melatonin are promising, to achieve its optimal results is required. Therefore, the use of nanocarriers of melatonin is of clinical interest. Different melatonin loaded nanocarriers such as lipid-based nanocarriers, hybrid nanocarriers, synthetic ones, etc. can be used to deliver melatonin more efficiently for prevention or treatment of various diseases. In this review, we summarize the treatment efficiency of melatonin when it is incorporated into different nanocarriers.

CREB1 spatio-temporal dynamics within the rat pineal gland

2023-09-29T09:39:46-06:00

In the rat pineal gland (PG), cyclic AMP responsive element-binding protein 1 (CREB1) participates in the nocturnal melatonin synthesis that rhythmically modulates physiology and behavior. Phosphorylation of CREB1 is one of the key regulatory steps that drives pineal transcription. The spatio-temporal dynamics of CREB1 itself in the different PG cell types have not yet been documented. In this study we analyzed total CREB1 in the rat PG via Western blot and fluorescence immunohistochemistry followed by confocal laser-scanning microscopy and quantitative analysis. Total CREB1 levels remained constant in the PG throughout the light:dark cycle. The distribution pattern of nuclear CREB1 did vary among PG cell types. Pinealocytes emerged to have discrete CREB1 domains within their nucleoplasm that were especially distinct. The number, size, and location of CREB1 foci fluctuated among pinealocytes, within the same PG and among Zeitgeber times (ZTs). A significantly larger dispersion of CREB1-immunoreactive nuclear sites was found at night than during the day. However, the overall transcription activity was mostly conserved between the light and dark phases, as shown by the expression of a particular phosphorylated form of the RNA polymerase II (RNAPII-pSer⁵CTD). Suppression of the nocturnal norepinephrine pulse by chronic bilateral superior cervical ganglionectomy increased CREB1 dispersion in pinealocyte nuclei at early night, as compared to sham-derived cells. In addition, differences in CREB1 distribution were found between sham-operated and non-operated rats at ZT14. Together, these data suggest that in mature pinealocytes, nuclear CREB1 is subjected to a dynamic spatio-temporal distribution. Further studies are necessary to elucidate the underlying mechanisms and to understand the impact of CREB1 reorganization in the pineal transcriptome.

Melatonin modulates the in vitro angiogenesis of granulosa cells collected from women with marital infertility for IVF

2023-09-29T09:39:47-06:00

Melatonin concentration is several folds higher in the follicular fluid than that in blood suggesting an important role of this molecule on follicular physiology. However, the actions of melatonin on angiogenesis in granulosa cells are currently unknown. In this study, we have specifically investigated the potential effects of melatonin on the angiogenesis in granulosa cells from female individuals with marital infertility. Sixty patients who were submitted to the in vitrofertilization were included. The granulosa-luteal cells of these females were collected for cell culture. The cells were divided into four groups: a) vehicle (control); b) 0.1 µM melatonin; c) 1 µM melatonin; d) 10 µM melatonin treated groups, respectively. After a period of 10 days of culture, expression of genes involved in the angiogenesis signaling pathway were analyzed by Real-Time PCR and Western Blot assays. The results showed that the expressions of FGF1(fibroblast growth factor 1), IL1B (interleukin 1-beta), VEGFR-2(type 2 vascular-endothelial growth factor receptor), and TGFB1 (tumor growth factor 1- beta) were significantly upregulated in melatonin treated groups compared to the control. In contrast, the expressions of HIF-1A(hypoxia-inducing factor 1-alpha), FGF2 (fibroblastic growth factor 2), IGF-1(insulin-like growth factor 1), and VEGFA (vascular endothelial growth factor alpha) were significantly downregulated by melatonin compared to the control. The results suggest that melatonin modulates angiogenesis of granulosa cells from women with marital infertility. The underlining mechanism may relate to melatonin maintaining the homeostasis of VEGF, especially at a low dose of melatonin.

Why are aging and stress associated with dementia, cancer, and other diverse medical conditions? Role of pineal melatonin interactions with the HPA axis in mitochondrial regulation via BAG-1

2023-09-29T09:39:46-06:00

Pineal melatonin and the cortisol awakening response (CAR) are integral aspects of the circadian rhythm. Pineal melatonin release during sleep is proposed to optimize mitochondrial function and dampen any residual oxidant and inflammatory activity. Little is known about CAR, which is generally thought to prepare the body for the coming day, primarily through the activation of the glucocorticoid receptor (GR). Melatonin, like the gut microbiome-derived butyrate, suppresses GR nuclear translocation, indicating that pineal melatonin and night-time butyrate may interact to modulate CAR effects via the GR, including CAR priming of immune and glia cells that underpin the pathogenesis of most medical conditions. Cutting edge research shows that the GR can be chaperoned by bcl2-associated athanogene (BAG)-1 to mitochondria, where GR can have significant and diverse impacts on mitochondrial function. A number of lines of evidence indicate that melatonin indirectly increases BAG-1, including via epigenetic mechanisms, such as derepressing miR-138 inhibition of BAG-1. The dramatic decrease in pineal melatonin production over aging will therefore have significant impacts on GR nuclear translocation, but also possibly the levels of BAG-1 mediated mitochondrial translocation of the GR. This may have dramatic consequences for how CAR ‘prepares the body for the coming day’, via the differential consequence of GR location in the cytoplasm, nucleus or mitochondria, with differential effects in different cell types. The interactions of melatonin/butyrate/BAG-1/GR are especially important in the hypothalamus, where a maintained heightened melatonin concentration occurs over the night due to the direct release of pineal melatonin, via the pineal recess, into the third ventricle. The interaction of melatonin/butyrate/BAG-1/GR will have differential effects in different cell types, thereby altering the intercellular homeostatic interactions in a given microenvironment that will contribute to the pathogenesis of many aging-associated conditions, including neurodegenerative conditions and cancer. This reframes the nature of the circadian rhythm as well as how stress-associated hypothalamus-pituitary-adrenal (HPA) axis may modulate both the pathogenesis and course of diverse medical presentations. This has a number of research and treatment implications across a host of current medical conditions.

The preventive and protective role of melatonin in SARS-CoV-2 infection: a retrospective study

2023-09-29T09:39:47-06:00

This study has investigated the protective role of melatonin against SARS-CoV-2 infection. For this purpose, 62 adults were recruited who were in daily relatively high doses of melatonin intaking, with the particularity that they started taking it before the beginning of the COVID-19 pandemic and continued to present. A continuous validation process has been carried out with a series of questionnaires to identify the risk factors, whether they were contacts, were infected, if yes, the level of disease severity, need for treatment, hospitalization, etc. According to the dose of melatonin the individuals took/are taking, they were divided into two groups: a) those taking 20 mg (n = 27) and, b) those taking ≥ 40 mg (n = 32). For statistical analysis, the shi2 test and Fisher's exact test were used. The number of infected subjects with positive PCR was 7 (11.9%). Only one required medication, the rest had a very favorable clinical evolution, mild in three cases and asymptomatic in three others. While in their environment this percentage is 22.05% (chi2 = 2.928; p < 0.087). Melatonin offers a good safety profile, is well tolerated and can play an important role in the different levels of COVID-19 prevention.

The cardioprotective potential of melatonin on cardiac hypertrophy: A mechanistic overview

2023-09-29T09:39:46-06:00

Cardiac hypertrophy (CH) is an increment of muscle mass to maintain the heart regular operations. A physiological cardiac hypertrophy due to exercise or other normal physiological process is characterized by normal contractile function and structural framework of heart tissue. In contrast, pathological hypertrophy occurs in response to increased pressure or volume overload from several cardiovascular diseases including hypertension, valvular diseases, cardiac infarction and heart failure. It is of major concern as it is one of the leading causes of death worldwide. Despite much progress in this field there is a scope for understanding of the molecular mechanisms of this condition. In this review, various types of cardiac hypertrophy and their intricate physio-pathological mechanisms have been discussed. In addition, the genetic mutations in sarcomere genes and oxidative stress are also closely linked to hypertrophic cardiomyopathy. Although several drugs against cardiac hypertrophy have been used, it appears that melatonin, due to its high bioavailability and low side effects, is a better candidate than the conventional medicine for treatment of hypertrophic cardiomyopathy. Melatonin, a hormone and a potent antioxidant, is secreted mainly from the pineal gland, but it is also synthesized from different peripheral tissues including the heart. This molecule can regulate a myriad of cellular functions. It can protect against cardiac hypertrophy via reducing oxidative stress, elevating Cu-Mn SOD via controlling several cell signalling pathways of Akt/mTOR, ROR-α and NLRP3 cascades. Melatonin also mitigates cardiac hypertrophy by suppressing pro-inflammatory cytokines including TNF-α and TGF-β and cardiac hypertrophy markers like β-MHC, ANP, BNP, LDH. This review focuses on the molecular mechanisms of cardiac hypertrophy and the defensive role of melatonin on it. We propose melatoninas a propitious adjunct for the treatment of cardiac hypertrophy.