Melatonin Research

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

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

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.

An insight into the importance of B vitamins and melatonin in the prevention of diabetes through modulation of the brain energy metabolism- a comprehensive review

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

Energy metabolism is the biochemical pathway of converting macronutrients (carbohydrates, protein, and fat) to cellular energy for the maintenance of cell homeostasis. The brain is an organ that consumes unproportional energy compared to its size. Glucose (glycogen, in storage form of glucose) is the principal source of brain energy. Impairment in brain energy metabolism results in neuronal loss and subsequent neurodegenerative diseases including AD, PD, amyotrophic lateral sclerosis, Huntington’s disease, etc. However, metabolic disorders such as chronic hyperglycemia, and insulin resistance are also linked with neuronal activity. Dysregulation in neuronal transmission is associated with oxidative stress and brain insulin resistance. Diabetes mellitus jeopardizes brain function through various mechanisms including glucose toxicity, BBB damage, neuroinflammation, and gliosis. B vitamins as antioxidants and neuroprotective agents, can improve brain glucose metabolism. Melatonin is a potent free radical scavenger and it can also modulate cellular cytokine levels and prevent insulin resistance. The neuroprotective and antihyperglycemic effects of melatonin improve the brain's antioxidant defense system, decrease brain NOS activity, and prevent glucose toxicity. Hence this review suggests a therapeutic use of a combination of melatonin and B vitamins to improve brain functioning disrupted by diabetes.

Effects of melatonin on the circadian functions of sleep-wake cycle, metabolism, hormonal regulation and immune activity: A recent review

2023-09-29T09:39:45-06:00

Rhythms following a period of approximately 24 hours are called circadian (from Latin circa diem, approximately one day) rhythms. These rhythms are observed in the activities of various vital body functions. Melatonin is considered as an important molecule participating in the formation of circadian rhythms of virtually all organisms. As a molecular regulator of the circadian clock, melatonin has various regulatory functions in both physiological and pathological conditions. Sleep-wake cycle depends on CSF melatonin levels, and melatonin also has a protective effect on the disrupted sleep-wake cycle in various pathological conditions. Melatonin ensures the proper function of vital metabolic pathways; therefore, it improves metabolism-related systems and protects them from damage. A bidirectional relationship between hormonal activity and melatonin ensures it having a healing effect on various reproductive disorders. Finally, melatonin can target inflammation pathways and various elements of immune system by changing their behavior and structure. In summary, melatonin has important effects on vital body functions mediated by its receptors, signaling pathways and clock genes, and has the capacity to protect and improve these functions under pathological conditions.

Tryptophan decarboxylase (TDC) in sweet pepper (Capsicum annuum L.): Gene expression analysis during fruit ripening and after nitric oxide exposure

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

Tryptophan decarboxylase (TDC) catalyzes the conversion of L-tryptophan (Trp) to tryptamine, a first step in the biosynthesis of serotonin and melatonin in plants. Pepper (Capsicum annuum L.) fruit, a globally popular horticultural product has great nutritional and economic values. In addition to that pepper fruit undergoes phenotypical changes during ripening, many other alterations also occur at the transcriptomic, proteomic, biochemical, and metabolic levels. However, little information is known on how many genes encoding for TDC in pepper plants and their expression levels during the ripening of sweet pepper fruit. In the current study, based on a data-mining approach on the pepper genome and transcriptome (RNA-seq), five putative CaTDC genes were identified. They are designated as 1 to 5 based on their localizations in chromosomes and also their previous biochemical data. Among them, CaTDC3 and CaTDC4 encode proteins with tryptophan decarboxylase activity; however, CaTDC1, CaTDC2 and CaTDC5 encode either tyrosine decarboxylase (TYDC) or aromatic aldehyde synthase (AAS), although CaTDC5 shares some degree TDC homology. Therefore, they are considered as the putative CaTDCs until their activity is corroborated. The CaTDC4 and putative CaTDC5 are expressed in pepper fruit. The time-course analysis of these genes during fruit ripening (green immature, breaking point, and red ripe) showed that they were differentially expressed, i.e., CaTDC4 was upregulated, and putative CaTDC5 was downregulated. CaTDC4 was positively modulated by two light-responsive elements, Box4 and TCT-motif, while CaTDC5 was influenced by GT1-motif and G-Box. The protein sequence analysis also allowed identifying the Trp-substrate-binding pocket which is a characteristic of the TDC proteins. Exogenous NO (a signaling molecule) treatment triggered the downregulation of CaTDC4 but not putative CaTDC5. These data provide a novel insight on the potential functions involved in the secondary metabolism of TDCs in fleshy fruits. In the identified three new CaTDC genes, two (CaTDC4 and CaTDC5) expressed in pepper fruits are modulated by exogenous NO treatment during ripening.

Inflammation, oxidative stress, DNA damage response and epigenetic modifications interact behind the beneficial actions of melatonin on H. pylori-mediated gastric disorders

2023-06-26T05:35:19-06:00

Helicobacter pylori (H. pylori) infection is associated with several disorders of the gastrointestinal tract, including gastric cancer. Studies of ours and others suggest that H. pylori infection may affect melatonin synthesis in the gastric epithelial cells. On the other hand, melatonin ameliorates gastric disorders as shown in clinical trials and experimental studies. Moreover, melatonin not only suppresses the DNA-damaging reaction of diet-related mutagens that can initiate carcinogenesis in gastric mucosa, but also the oxidative DNA damage evoked by reactive oxygen and nitrogen species produced during H. pylori-related gastric inflammation. H. pylori infection is associated with several functional and organic gastric disorders, including gastritis, peptic ulcer disease and gastric cancer, but the precise mechanism behind this association is not known and many pathways can be involved. Some of beneficial effects of melatonin in the gastrointestinal tract are underlined by mechanisms that likely play a role in detrimental effects of H. pylori in the stomach. Therefore, melatonin may modulate these mechanisms resulting in ameliorating H. pylori-related symptoms. In this narrative review the role of inflammation, oxidative stress, DNA damage response and epigenetic modifications in H. pylori-associated gastric disorders will be discussed with an emphasis on gastric cancer. We also suggest that melatonin may have potential to inhibit H. pylori-mediated pathologies through its interaction with essential pathways as described herein. Overlapping mechanisms of H. pylori-associated pathogenesis and beneficial effects of melatonin justify further studies on the action of melatonin on gastric disorders associated with H. pylori infection, including clinical trials.

Effect of iron on rat serum melatonin levels under different light/dark cycle patterns

2023-06-26T05:35:20-06:00

Exposure to constant light or darkness for long periods has diverse effects on circadian physiology. Iron (Fe) overloading promotes oxidative stress and causes alterations in cellular structure and function in animals and humans. The aim of this study is to evaluate the interactions among serum melatonin (ML), photoperiod manipulation, and Fe overloading in rats. The results showed that constant darkness exposure for 15 days significantly increased serum ML levels (up to 22%) while the constant light exposure failed to reduce the serum ML level compared to the normal light/dark cycle treated rats. The lost serum ML level usually from the pineal gland under the long term of constant light exposure may be compensated by ML generated by other organs which adapted to the situation. Also, Fe overloading decreased ML production due to this molecule being consumed to scavenge the free radicals induced by the Fe overloading. In addition, we observed interactions among constant light or darkness exposure, Fe overloading and serum ML level. Overall, our results support the hypothesis of ML as scavenging molecule; it may be an effective therapeutic tool in iron-induced oxidative stress.

Melatonin is more effective on bone metabolism when given at early night than during the day in ovariectomized rats

2023-06-26T05:35:20-06:00

Melatonin has diverse effects, and has been reported to promote bone formation in addition to regulating the sleep–wake cycle. In the present study, we investigated the effects of melatonin on bone metabolism using ovariectomized (OVX) rats; a model of postmenopausal osteoporosis. Here, we focused on the differences in bone formation when melatonin was subcutaneous injected at day or early night. The OVX rats were injected with melatonin once daily (0.8 or 8 mg/head) between 11:00 to 14:00 or 18:00 to 19:30 for the day or early night, respectively, for six weeks. After completion of the injection, the femur and tibia in the OVX rats were dissected under general anesthesia and examined by quantitative computed tomography (pQCT) and histological analysis, respectively. Interestingly, the trabecular bone mineral density in the femur metaphysis of the OVX rats receiving 8 mg/head melatonin at early night was higher than those receiving melatonin during the day and they recovered to a similar level as the rats with sham treatment. In the diaphysis, the pQCT analysis results indicated that there was no significant difference in bone mineral density between the day and early night melatonin-injected OVX rats. Histological analysis of the secondary trabecular bone in the tibia of the OVX rats, revealed that the bone matrix area of the group receiving 8 mg/head melatonin at early night was higher compared with that of the day group and had a significant difference compared with OVX treatment rats. Taken together, the subcutaneous melatonin injection in OVX rats at early night was found to promote trabecular bone formation better than melatonin injection during the day. The timing of melatonin injection is a crucial factor when examining the influence of bone metabolism.

A novel study of melatonin diffusion in a 3D cell culture model

2023-06-26T05:35:20-06:00

Melatonin is now considered a major physiological regulator of many different functions including synchronization of circadian rhythms, antioxidant defense at different levels, immunomodulation, cell growth control, neuroprotector and anti-tumor agent. In addition to its membrane receptor-dependent actions, it has been classically assumed that its diffusion through lipid bilayers contribute to its intracellular actions, including direct and indirect free radical scavenging activities. While pineal gland is the major site of nocturnal production of the indolamine, skin is considered an important source of melatonin synthesis. Here, using a 3-D culture model of HaCaT cells in an artificial scaffold (epidermal equivalents), we have quantified diffusion of melatonin in these cells and compared it to 2-D or spheroid cultures. Diffusion in 3-D scaffold cultures was similar to that found in 2-D culture and proportion of intracellular melatonin was low. AFMK, a major oxidative metabolite of melatonin, was also found and quantified. Redox parameters including total ROS, superoxide or mitochondrial mass were also assayed. We also report the effect of melatonin on the cytoskeleton of normal human keratinocyte HaCaT cells. We propose HaCaT epidermal equivalents as an affordable, easy-to-use, 3-D cell culture tool to test diffusion rates of melatonin but also other similar small molecules. This 3-D models can also be studied at cellular and molecular level, including redox parameters, and can provide important information regarding molecules that can be topically added to skin. Similarly, mechanisms of transportation can also be approached with this methodology.

The dual-actions of melatonin as a potential oncostatic agent and a protector against chemotherapy-induced toxicity

2023-06-26T05:35:19-06:00

Cancer is one of the most complicated and arduous diseases, causing immense physical and emotional tribulations in the life of patients. Carcinogens can lead to genetic mutations and cancer progression either by directly binding to DNA covalently, forming cross-links, or indirectly via the generation of oxidative stress and/or by other recondite mechanisms. Despite being the most widely used treatment, chemotherapy has several adverse consequences, including acute and/or chronic toxicities. Numerous studies have demonstrated melatonin being a potential anticancer molecule with multiple activities including prevention of the initiation, promotion, and progression of cancer. In addition to its role as a potent antioxidant, melatonin exhibits its cytostatic effects by arresting the mutated cell in the G0/G1 phase, preventing epithelial-to-mesenchymal transition and inciting the immune battle against tumours, possibly by dampening MMP activities. Melatonin inhibits the MAP-K/ERK and p38 pathways and regulates NF-ĸB-mediated inflammatory responses. Melatonin exerts its anti-angiogenic activity by curbing VEGF levels, while its anti-estrogenic activity by inhibiting the cellular uptake of linoleic acid (LA). In addition, melatonin reduces the toxicities of the chemotherapy while improving its effectiveness in cancer treatment. The purpose of this review is to assemble the knowledge available on melatonin’s oncostatic role and its protective effects against chemotherapy-induced toxicities. Further studies are needed to investigate the adjunctive role of melatonin with chemotherapy in the clinical setting and to corroborate its effectiveness in cancer cure.

Effects of long-term exposure to light or darkness and return to normal light-dark cycle on serum melatonin levels in rats

2023-06-26T05:35:20-06:00

Increasing evidence suggests that the presence of constant light or darkness have diverse effects on circadian physiology. The aim of this study is to explore serum levels of melatonin upon return to a normal light-dark cycle (LDC) in rats exposed to constant light (LL) or darkness (DD). Results showed the different profiles of melatonin levels after exposure to LL or DD. Similarly, the restoration of the LDC (12L:12D) modified the endogenous melatonin levels. In the LL group, serum melatonin remained at levels similar to control values, and when normal LDC was restored, melatonin levels of the rats decreased but without significant difference compared to control. In the DD group, serum melatonin increased significantly (22%), and upon switching to normal LDC, serum melatonin level was significantly decreased compared to constant dark condition. Even 15 days later, a significant 76% drop in serum melatonin level was still observed in LDC condition. The results suggested that prolonged exposure to LL or DD, especially to DD, had profound effects on the serum melatonin. LL has little influence and this result can be explained by the potential compensation of extrapineal melatonin generated by other tissues and organs.

Research in Plant Melatonin: Original and Current Studies

2023-06-26T05:35:20-06:00

Melatonin from plants, also known as phytomelatonin, was discovered in 1995, and since then, affecting many areas of research related to plants. Thus, the number of publications on phytomelatonin has grown exponentially in recent years, especially in Plant Physiology and Plant Molecular studies. In this paper, we try to expose the great incidence that the detection of this neurohormone in plants is having, and its relevance in areas such as agronomy, genetics, human nutrition and food chemistry/technology, animal nutrition and other more specific fields of interest such as cosmetics and nutraceuticals.