Polymorphisms in genes of melatonin biosynthesis and signaling support the light-at-night hypothesis for breast cancer.

Light-at-night triggers the decline of pineal gland melatonin biosynthesis and secretion and is an IARC-classified probable breast-cancer risk factor. We applied a large-scale molecular epidemiology approach to shed light on the putative role of melatonin in breast cancer. We investigated associations between breast-cancer risk and polymorphisms at genes of melatonin biosynthesis/signaling using a study population of 44,405 women from the Breast Cancer Association Consortium (22,992 cases, 21,413 population-based controls). Genotype data of 97 candidate single nucleotide polymorphisms (SNPs) at 18 defined gene regions were investigated for breast-cancer risk effects. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CI) by logistic regression for the main-effect analysis as well as stratified analyses by estrogen- and progesterone-receptor (ER, PR) status. SNP-SNP interactions were analyzed via a two-step procedure based on logic regression. The Bayesian false-discovery probability (BFDP) was used for all analyses to account for multiple testing. Noteworthy associations (BFDP < 0.8) included 10 linked SNPs in tryptophan hydroxylase 2 (TPH2) (e.g. rs1386492: OR = 1.07, 95% CI 1.02-1.12), and a SNP in the mitogen-activated protein kinase 8 (MAPK8) (rs10857561: OR = 1.11, 95% CI 1.04-1.18). The SNP-SNP interaction analysis revealed noteworthy interaction terms with TPH2- and MAPK-related SNPs (e.g. rs1386483R ∧ rs1473473D ∧ rs3729931D: OR = 1.20, 95% CI 1.09-1.32). In line with the light-at-night hypothesis that links shift work with elevated breast-cancer risks our results point to SNPs in TPH2 and MAPK-genes that may impact the intricate network of circadian regulation.

The Relationship between Clock Genes, Sirtuin 1, and Mitochondrial Activity in Head and Neck Squamous Cell Cancer: Effects of Melatonin Treatment.

The circadian clock is a regulatory system, with a periodicity of approximately 24 h, which generates rhythmic changes in many physiological processes, including mitochondrial activity. Increasing evidence links chronodisruption with aberrant functionality in clock gene expression, resulting in multiple diseases such as cancer. Melatonin, whose production and secretion oscillates according to the light-dark cycle, is the principal regulator of clock gene expression. In addition, the oncostatic effects of melatonin correlate with an increase in mitochondrial activity. However, the direct links between circadian clock gene expression, mitochondrial activity, and the antiproliferative effects of melatonin in cancers, including head and neck squamous cell carcinoma (HNSCC), remain largely unknown. In this study, we analyzed the effects of melatonin on HNSCC cell lines (Cal-27 and SCC9), which were treated with 500 and 1000 µM melatonin. We found that the antiproliferative effect of melatonin is not mediated by the Bmal1 clock gene. Additionally, high doses of melatonin were observed to result in resynchronization of oscillatory circadian rhythm genes (Per2 and Sirt1). Surprisingly, the resynchronizing effect of melatonin on Per2 and Sirt1 did not produce alterations in the oscillation of mitochondrial respiratory activity. These results increase our understanding of the possible antiproliferative mechanisms in melatonin in the treatment of head and neck squamous cell carcinoma and suggest that its antiproliferative effects are independent of clock genes but are directly related to mitochondrial activity.

Light at night: effect on the daily clock, learning, memory, cognition, and expression of transcripts in different brain regions of rat.

The rapid increase in urbanization is altering the natural composition of the day-night light ratio. The light/dark cycle regulates animal learning, memory, and mood swings. A study was conducted to examine the effect of different quantity and quality of light at night on the daily clock, learning, memory, cognition, and expression of transcripts in key learning centers. Treatment was similar for experiments one to three. Rats were exposed for 30 days to 12 h light and 12 h dark with a night light of 2 lx (dLAN group), 250 lx (LL), or without night light (LD). In experiment one, after 28 days, blood samples were collected and 2 days later, animals were exposed to constant darkness. In experiment two, after 30 days of treatment, animals were subjected to various tests involving learning, memory, and cognition. In experiment three, after 30 days of treatment, animals were sampled, and transcript levels of brain-derived neurotrophic factor, tyrosine kinase, Growth-Associated Protein 43, Neurogranin, microRNA-132, cAMP Response Element-Binding Protein, Glycogen synthase kinase-3ß, and Tumor necrosis factor α were measured in hippocampus, thalamus, and cortex tissues. In experiment four, animals were exposed to night light of 0.019 W/m2 but of either red (640 nm), green (540 nm), or blue (450 nm) wavelength for 30 days, and similar tests were performed as mentioned in experiment 2. While in experiment five, after 30 days of respective wavelength treatments, all animals were sampled for gene expression studies. Our results show that exposure to dLAN and LL affects the daily clock as reflected by altered melatonin secretion and locomotor activity, compromises the learning, memory, and cognitive ability, and alterations in the expression levels of transcripts in the hypothalamus, cortex, and thalamus. The effect is night light intensity dependent. Further, blue light at night has less drastic effects than green and red light. These results could be of the potential use of framing the policies for the use of light at night.

Clock 3111 T/C and Period3 VNTR gene polymorphisms and proteins, and melatonin levels in women with infertility.

PURPOSE: One of the causes of infertility is circadian rhythm disorders. This study aimed to investigate Clock 3111 T/C and Period3 VNTR (variable number tandem repeat) gene polymorphisms and these gene proteins, some biochemical parameters, and circadian rhythm hormones in infertile women. METHODS: Thirty-five infertile women and thirty-one healthy fertile women were included. Blood samples were taken in the mid-luteal phase. DNAs obtained from peripheral blood were analyzed using polymerase chain reaction-restriction fragment length polymorphism methods. Follicle-stimulating hormone, LH (luteinizing hormone), estradiol, prolactin, free triiodothyronine, fT4 (free thyroxine), thyroid-stimulating hormone, testosterone, cortisol, progesterone, prolactin, ferritin, vitamin B12, and folate levels in serum samples were determined by the electrochemiluminescence immunoassay method. Melatonin, Clock, and Period3 protein levels were determined with ELISA kits. RESULTS: There was a significant difference in the frequency of Period3 DD (Per34/4) genotype between the groups. The Clock protein level of the infertile group was higher than the fertile group. Clock protein levels of the fertile group were positively correlated with estradiol levels and negatively correlated with LH, prolactin, and fT4 levels. PER3 protein levels of the infertile group were negatively correlated with LH levels. Melatonin levels of the fertile group were positively correlated with progesterone levels and negatively correlated with cortisol levels. Melatonin levels of the infertile group were positively correlated with LH levels and negatively correlated with cortisol levels. CONCLUSION: Per34/4 genotype may be an independent risk factor in infertile women. Different correlation results found in fertile and infertile women can form the basis for future studies.

Gene expression profile associated with Asmt knockout-induced depression-like behaviors and exercise effects in mouse hypothalamus.

Sleep disorder caused by abnormal circadian rhythm is one of the main symptoms and risk factors of depression. As a known hormone regulating circadian rhythms, melatonin (MT) is also namely N-acetyl-5-methoxytryptamine. N-acetylserotonin methyltransferase (Asmt) is the key rate-limiting enzyme of MT synthesis and has been reportedly associated with depression. Although 50-90% of patients with depression have sleep disorders, there are no effective treatment ways in the clinic. Exercise can regulate circadian rhythm and play an important role in depression treatment. In the present study, we showed that Asmt knockout induced depression-like behaviors, which were ameliorated by swimming exercise. Moreover, swimming exercise increased serum levels of MT and 5-hydroxytryptamine (5-HT) in Asmt knockout mice. In addition, the microarray data identified 10 differentially expressed genes (DEGs) in KO mice compared with WT mice and 29 DEGs in KO mice after swimming exercise. Among the DEGs, the direction and magnitude of change in epidermal growth factor receptor pathway substrate 8-like 1 (Eps8l1) and phospholipase C-ß 2 (Plcb2) were confirmed by qRT-PCR partly. Subsequent bioinformatic analysis showed that these DEGs were enriched significantly in the p53 signaling pathway, long-term depression and estrogen signaling pathway. In the protein-protein interaction (PPI) networks, membrane palmitoylated protein 1 (Mpp1) and p53-induced death domain protein 1 (Pidd1) were hub genes to participate in the pathological mechanisms of depression and exercise intervention. These findings may provide new targets for the treatment of depression.

Melatonin and Pathological Cell Interactions: Mitochondrial Glucose Processing in Cancer Cells.

Melatonin is synthesized in the pineal gland at night. Since melatonin is produced in the mitochondria of all other cells in a non-circadian manner, the amount synthesized by the pineal gland is less than 5% of the total. Melatonin produced in mitochondria influences glucose metabolism in all cells. Many pathological cells adopt aerobic glycolysis (Warburg effect) in which pyruvate is excluded from the mitochondria and remains in the cytosol where it is metabolized to lactate. The entrance of pyruvate into the mitochondria of healthy cells allows it to be irreversibly decarboxylated by pyruvate dehydrogenase (PDH) to acetyl coenzyme A (acetyl-CoA). The exclusion of pyruvate from the mitochondria in pathological cells prevents the generation of acetyl-CoA from pyruvate. This is relevant to mitochondrial melatonin production, as acetyl-CoA is a required co-substrate/co-factor for melatonin synthesis. When PDH is inhibited during aerobic glycolysis or during intracellular hypoxia, the deficiency of acetyl-CoA likely prevents mitochondrial melatonin synthesis. When cells experiencing aerobic glycolysis or hypoxia with a diminished level of acetyl-CoA are supplemented with melatonin or receive it from another endogenous source (pineal-derived), pathological cells convert to a more normal phenotype and support the transport of pyruvate into the mitochondria, thereby re-establishing a healthier mitochondrial metabolic physiology.

Transcriptomics analysis of genes induced by melatonin related to glucosinolates synthesis in broccoli hairy roots.

Glucoraphanin (GRA) is found in the seeds and vegetative organs of broccoli (Brassica oleracea L. var. italica Planch) as the precursor of anti-carcinogen sulforaphane (SF). The yield of GRA obtained from these materials is weak and the cost is high. In recent years, the production of plant secondary metabolites by large-scale hairy roots culture in vitro has succeeded in some species. Melatonin (MT) is a natural hormone which existed in numerous organisms. Studies have demonstrated that MT can improve the synthesis of secondary metabolites in plants. At present, it has not been reported that MT regulates the biosynthesis of glucoraphanin in broccoli hairy roots. In this study, the broccoli hairy roots that grew for 20 d were respectively treated by 500 µM MT for 0, 6, 12, 20 and 32. To explore the reason of changes in secondary metabolites and reveal the biosynthetic pathway of glucoraphanin at transcriptional level. Compared with 0 h, the yield of GRA under other treatments was increased, and the overall trend was firstly increased and then decreased. The total yield of GRA reached the highest at 12 h, which was 1.22-fold of 0 h. Then, the genome of broccoli as the reference, a total of 13234 differentially expressed genes (DEGs) were identified in broccoli hairy roots under treatment with 500 µM MT for 0, 6, 12, 20 and 32 h, respectively. Among these DEGs, 6266 (47.35%) were upregulated and 6968 (52.65%) were downregulated. It was found that the pathway of 'Glucosinolates biosynthesis (ko00966)' was enriched in the 16th place by Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of the upregulated DEGs. The expression of key genes in the GRA biosynthesis pathway was upregulated at all time points, and a deduced GRA biosynthesis pathway map was constructed for reference.

Melatonin and neuroblastoma: a novel therapeutic approach.

Neuroblastoma is a deadly and serious malignancy among children. Although many developments have been occurred for the treatment of this disease, the rate of mortality is still high. Therefore, it is necessary to search for novel complementary and alternative therapies. Melatonin, a hormone secreted from pineal gland, is a multifunctional agent having anticancer potentials. Recently, several investigations have been conducted indicating melatonin effects against neuroblastoma. In this paper, we summarize current evidence on anti-neuroblastoma effects of melatonin based on cellular pathways.

FGF19/FGFR4 signaling axis confines and switches the role of melatonin in head and neck cancer metastasis.

BACKGROUND: There is no consensus about the effective dosages of melatonin in cancer management, thus, it is imperative to fully understand the dose-dependent responsiveness of cancer cells to melatonin and the underlying mechanisms. METHODS: Head and neck squamous cell carcinoma (HNSCC) cells with or without melatonin treatment were used as a research platform. Gene depletion was achieved by short hairpin RNA, small interfering RNA, and CRISPR/Cas9. Molecular changes and regulations were assessed by Western blotting, quantitative RT-PCR (qRT-PCR), immunohistochemistry, and chromatin Immunoprecipitation coupled with qPCR (ChIP-qPCR). The therapeutic efficacy of FGF19/FGFR4 inhibition in melatonin-mediated tumor growth and metastasis was evaluated in orthotopic tongue tumor mice. RESULTS: The effect of melatonin on controlling cell motility and metastasis varies in HNSCC cells, which is dose-dependent. Mechanistically, high-dose melatonin facilitates the upregulation of FGF19 expression through activating endoplasmic stress (ER)-associated protein kinase RNA-like endoplasmic reticulum kinase (PERK)-Eukaryotic initiation factor 2 alpha (eIF2α)-activating transcription factor 4 (ATF4) pathway, which in turn promotes FGFR4-Vimentin invasive signaling and attenuates the role of melatonin in repressing metastasis. Intriguingly, following long-term exposure to high-dose melatonin, epithelial HNSCC cells revert the process towards mesenchymal transition and turn more aggressive, which is enabled by FGF19/FGFR4 upregulation and alleviated by genetic depletion of the FGF19 and FGFR4 genes or the treatment of FGFR4 inhibitor H3B-6527. CONCLUSIONS: Our study gains novel mechanistic insights into melatonin-mediated modulation of FGF19/FGFR4 signaling in HNSCC, demonstrating that activating this molecular node confines the role of melatonin in suppressing metastasis and even triggers the switch of its function from anti-metastasis to metastasis promotion. The blockade of FGF19/FGFR4 signaling would have great potential in improving the efficacy of melatonin supplements in cancer treatment.

Melatonin Represses Oil and Anthocyanin Accumulation in Seeds.

Previous studies have clearly demonstrated that the putative phytohormone melatonin functions directly in many aspects of plant growth and development. In Arabidopsis (Arabidopsis thaliana), the role of melatonin in seed oil and anthocyanin accumulation, and corresponding underlying mechanisms, remain unclear. Here, we found that serotonin N-acetyltransferase1 (SNAT1) and caffeic acid O-methyltransferase (COMT) genes were ubiquitously and highly expressed and essential for melatonin biosynthesis in Arabidopsis developing seeds. We demonstrated that blocking endogenous melatonin biosynthesis by knocking out SNAT1 and/or COMT significantly increased oil and anthocyanin content of mature seeds. In contrast, enhancement of melatonin signaling by exogenous application of melatonin led to a significant decrease in levels of seed oil and anthocyanins. Further gene expression analysis through RNA sequencing and reverse-transcription quantitative PCR demonstrated that the expression of a series of important genes involved in fatty acid and anthocyanin accumulation was significantly altered in snat1-1 comt-1 developing seeds during seed maturation. We also discovered that SNAT1 and COMT significantly regulated the accumulation of both mucilage and proanthocyanidins in mature seeds. These results not only help us understand the function of melatonin and provide valuable insights into the complicated regulatory network controlling oil and anthocyanin accumulation in seeds, but also divulge promising gene targets for improvement of both oil and flavonoids in seeds of oil-producing crops and plants.

Melatonin: An atypical hormone with major functions in the regulation of angiogenesis.

Melatonin (N-acetyl-5-methoxytryptamine), a pleotropic molecule with a wide distribution, has received considerable attention in recent years, mostly because of its various major effects on tissues or cells since it has both receptor-dependent and receptor-independent actions over a wide range of concentrations. These biological and physiological functions of melatonin include regulation of circadian rhythms by modulating the expression of core oscillator genes, scavenging the reactive oxygen species and reactive nitrogen species, modulating the immune system and inflammatory response, and exerting cytoprotective and antiapoptotic effects. Given the multiple critical roles of melatonin, dysregulation of its production or any disruption in signaling through its receptors may have contributed in the development of a wide range of disorders including type 2 diabetes, aging, immune-mediated diseases, hypertension, and cancer. Herein, we focus on the modulatory effects of melatonin on angiogenesis and its implications as a therapeutic strategy in cancer and related diseases.

Melatonin confers cadmium tolerance by modulating critical heavy metal chelators and transporters in radish plants.

Cadmium (Cd) is an environmental pollutant that causes health hazard to living organisms. Melatonin (MT) has emerged as a ubiquitous pleiotropic molecule capable of coordinating heavy metal (HM) stresses in plants. However, it remains unclear how melatonin mediates Cd homeostasis and detoxification at transcriptional and/or post-transcriptional levels in radish. Herein, the activities of five key antioxidant enzymes were increased, while root and shoot Cd contents were dramatically decreased by melatonin. A combined small RNA and transcriptome sequencing analysis showed that 14 differentially expressed microRNAs (DEMs) and 966 differentially expressed genes (DEGs) were shared between the Cd and Cd + MT conditions. In all, 23 and ten correlated miRNA-DEG pairs were identified in Con vs. Cd and Con vs. Cd + MT comparisons, respectively. Several DEGs encoding yellow stripe 1-like (YSL), heavy metal ATPases (HMA), and ATP-binding cassette (ABC) transporters were involved in Cd transportation and sequestration in radish. Root exposure to Cd2+ induced several specific signaling molecules, which consequently trigger some HM chelators, transporters, and antioxidants to achieve reactive oxygen species (ROS) scavenging and detoxification and eliminate Cd toxicity in radish plants. Notably, transgenic analysis revealed that overexpression of the RsMT1 (Metallothionein 1) gene could enhance Cd tolerance of tobacco plants, indicating that the exogenous melatonin confers Cd tolerance, which might be attributable to melatonin-mediated upregulation of RsMT1 gene in radish plants. These results could contribute to dissecting the molecular basis governing melatonin-mediated Cd stress response in plants and pave the way for high-efficient genetically engineering low-Cd-content cultivars in radish breeding programs.

Melatonin Accumulation in Sweet Cherry and Its Influence on Fruit Quality and Antioxidant Properties.

Although the effects of melatonin on plant abiotic and biotic stress resistance have been explored in recent decades, the accumulation of endogenous melatonin in plants and its influence on fruit quality remains unclear. In the present study, melatonin accumulation levels and the expression profiles of five synthesis genes were investigated during fruit and leaf development in sweet cherry (Prunus avium L.). Melatonin was strongly accumulated in young fruits and leaves, then decreased steadily with maturation. Transcript levels of PacTDC and PacSNAT were highly correlated with melatonin content in both fruit and leaves, indicating their importance in melatonin accumulation. Furthermore, application of 50 and 100 µmol·L-1 of melatonin to leaves had a greater influence on fruit quality than treatments applied to fruits, by significantly improving fruit weight, soluble solids content, and phenolic content including total phenols, flavanols, total anthocyanins, and ascorbic acid. Meanwhile, melatonin application promoted the antioxidant capacity of fruit assayed by 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azinobis (3-ethylben zothiazoline-6-sulfonic acid) (ABTS), and ferric reducing antioxidant power (FRAP). These results provide insights into the physiological and molecular mechanisms underlying melatonin metabolism of sweet cherry.

Daily and seasonal mitochondrial protection: Unraveling common possible mechanisms involving vitamin D and melatonin.

From an evolutionary point of view, vitamin D and melatonin appeared very early and share functions related to defense mechanisms. In the current clinical setting, vitamin D is exclusively associated with phosphocalcic metabolism. Meanwhile, melatonin has chronobiological effects and influences the sleep-wake cycle. Scientific evidence, however, has identified new actions of both molecules in different physiological and pathological settings. The biosynthetic pathways of vitamin D and melatonin are inversely related relative to sun exposure. A deficiency of these molecules has been associated with the pathogenesis of cardiovascular diseases, including arterial hypertension, neurodegenerative diseases, sleep disorders, kidney diseases, cancer, psychiatric disorders, bone diseases, metabolic syndrome, and diabetes, among others. During aging, the intake and cutaneous synthesis of vitamin D, as well as the endogenous synthesis of melatonin are remarkably depleted, therefore, producing a state characterized by an increase of oxidative stress, inflammation, and mitochondrial dysfunction. Both molecules are involved in the homeostatic functioning of the mitochondria. Given the presence of specific receptors in the organelle, the antagonism of the renin-angiotensin-aldosterone system (RAAS), the decrease of reactive species of oxygen (ROS), in conjunction with modifications in autophagy and apoptosis, anti-inflammatory properties inter alia, mitochondria emerge as the final common target for melatonin and vitamin D. The primary purpose of this review is to elucidate the common molecular mechanisms by which vitamin D and melatonin might share a synergistic effect in the protection of proper mitochondrial functioning.

The Lhx4 homeobox transcript in the rat pineal gland: Adrenergic regulation and impact on transcripts encoding melatonin-synthesizing enzymes.

Homeobox genes generally encode transcription factors involved in regulating developmental processes. In the pineal gland, a brain structure devoted to nocturnal melatonin synthesis, a number of homeobox genes are also expressed postnatally; among these is the LIM homeobox 4 gene (Lhx4). We here report that Lhx4 is specifically expressed in the postnatal pineal gland of rats and humans. Circadian analyses revealed a fourfold rhythm in Lhx4 expression in the rat pineal gland, with rhythmic expression detectable from postnatal day 10. Pineal Lhx4 expression was confirmed to be positively driven by adrenergic signaling, as evidenced by in vivo modulation of Lhx4 expression by pharmacological (isoprenaline injection) and surgical (superior cervical ganglionectomy) interventions. In cultured pinealocytes, Lhx4 expression was upregulated by cyclic AMP, a second messenger of norepinephrine. By use of RNAscope technology, Lhx4 transcripts were found to be exclusively localized in melatonin-synthesizing pinealocytes. This prompted us to investigate the possible role of Lhx4 in regulation of melatonin-producing enzymes. By use of siRNA technology, we knocked down Lhx4 by 95% in cultured pinealocytes; this caused a reduction in transcripts encoding the melatonin-producing enzyme arylalkylamine N-acetyl transferase (Aanat). Screening the transcriptome of siRNA-treated pinealocytes by RNAseq revealed a significant impact of Lhx4 on the phototransduction pathway and on transcripts involved in development of the nervous system and photoreceptors. These data suggest that rhythmic expression of Lhx4 in the pineal gland is controlled via an adrenergic-cyclic AMP mechanism and that Lhx4 acts to promote nocturnal melatonin synthesis.

Therapeutic Opportunities in Colorectal Cancer: Focus on Melatonin Antioncogenic Action.

Colorectal cancer (CRC) influences individual health worldwide with high morbidity and mortality. Melatonin, which shows multiple physiological functions (e.g., circadian rhythm, immune modulation, and antioncogenic action), can be present in almost all organisms and found in various tissues including gastrointestinal tract. Notably, melatonin disruption is closely associated with the elevation of CRC incidence, indicating that melatonin is effective in suppressing CRC development and progression. Mechanistically, melatonin favors in activating apoptosis and colon cancer immunity, while reducing proliferation, autophagy, metastasis, and angiogenesis, thereby exerting its anticarcinogenic effects. This review highlights that melatonin can be an adjuvant therapy and be beneficial in treating patients suffering from CRC.

Night-shift work, circadian and melatonin pathway related genes and their interaction on breast cancer risk: evidence from a case-control study in Korean women.

Our purpose is to investigate the impact of circadian and melatonin pathway genes as well as their interactions with night-shift work (NSW) on breast cancer risk in Korean women. Information about NSW and other covariates was collected using a structured questionnaire and twenty-two polymorphisms in 11 genes were analyzed in a hospital-based case-control study with 941 cases of breast cancer and 959 controls. In analysis of the main effects of each single nucleotide polymorphisms(SNPs), variants in CLOCK rs11133373 was associated with breast cancer risk even after false discovery rate (FDR) correction (Odd Ratios (OR) = 1.38 (95% Confident Interval (CI) 1.14-1.69) in CG and CC compared to GG genotype. Analysis of MTNR1A rs2119882 demonstrated a decreased risk of breast cancer in CC compared to TT (p-FDR = 0.043). A correlation between NSW and breast cancer interaction was found in two loci. NSW increased risk of breast cancer in women who carried the heterozygote genotype of CRY2 rs2292912 (OR = 1.98, 95% CI = 1.14-3.44) or carried at least one minor allele of RORA rs1482057 (OR = 2.20, 95% CI = 1.10-4.37). Our study results support a putative role for several loci of circadian genes and genes of melatonin biosynthesis and their interaction, and the gene interactions with NSW in the development of breast cancer.

MicroRNA-92b-5p modulates melatonin-mediated osteogenic differentiation of bone marrow mesenchymal stem cells by targeting ICAM-1.

Osteoporosis is closely associated with the dysfunction of bone metabolism, which is caused by the imbalance between new bone formation and bone resorption. Osteogenic differentiation plays a vital role in maintaining the balance of bone microenvironment. The present study investigated whether melatonin participated in the osteogenic commitment of bone marrow mesenchymal stem cells (BMSCs) and further explored its underlying mechanisms. Our data showed that melatonin exhibited the capacity of regulating osteogenic differentiation of BMSCs, which was blocked by its membrane receptor inhibitor luzindole. Further study demonstrated that the expression of miR-92b-5p was up-regulated in BMSCs after administration of melatonin, and transfection of miR-92b-5p accelerated osteogenesis of BMSCs. In contrast, silence of miR-92b-5p inhibited the osteogenesis of BMSCs. The increase in osteoblast differentiation of BMSCs caused by melatonin was attenuated by miR-92b-5p AMO as well. Luciferase reporter assay, real-time qPCR analysis and western blot analysis confirmed that miR-92b-5p was involved in osteogenesis by directly targeting intracellular adhesion molecule-1 (ICAM-1). Melatonin improved the expression of miR-92b-5p, which could regulate the differentiation of BMSCs into osteoblasts by targeting ICAM-1. This study provided novel methods for treating osteoporosis.

Melatonin, a toll-like receptor inhibitor: Current status and future perspectives.

Toll-like receptors (TLRs) are crucial activators of inflammatory responses, they are considered immune receptors. TLRs are of fundamental importance in the pathophysiology of disorders related to inflammation including neurodegenerative diseases and cancer. Melatonin is a beneficial agent in the treatment of inflammatory and immune disorders. Melatonin is potent anti-inflammatory hormone that regulates various molecular pathways. Withal, limited studies have evaluated the inhibitory role of melatonin on TLRs. This review summarizes the current knowledge related to the effects of melatonin on TLRs in some common inflammatory and immunity disorders.

Responses of Transgenic Melatonin-Enriched Goats on LPS Stimulation and the Proteogenomic Profiles of Their PBMCs.

The anti-inflammatory activity of melatonin (MT) has been well documented; however, little is known regarding endogenously occurring MT in this respect, especially for large animals. In the current study, we created a MT-enriched animal model (goats) overexpressing the MT synthetase gene Aanat. The responses of these animals to lipopolysaccharide (LPS) stimulation were systematically studied. It was found that LPS treatment exacerbated the inflammatory response in wild-type (WT) goats and increased their temperature to 40 °C. In addition, their granulocyte counts were also significantly elevated. In contrast, these symptoms were not observed in transgenic goats with LPS treatment. The rescue study with MT injection into WT goats who were treated with LPS confirmed that the protective effects in transgenic goats against LPS were attributed to a high level of endogenously produced MT. The proteomic analysis in the peripheral blood mononuclear cells (PBMCs) isolated from the transgenic animals uncovered several potential mechanisms. MT suppressed the lysosome formation as well as its function by downregulation of the lysosome-associated genes Lysosome-associated membrane protein 2 (LAMP2), Insulin-like growth factor 2 receptor (IGF2R), and Arylsulfatase B (ARSB). A high level of MT enhanced the antioxidant capacity of these cells to reduce the cell apoptosis induced by the LPS. In addition, the results also uncovered previously unknown information that showed that MT may have protective effects on some human diseases, including tuberculosis, bladder cancer, and rheumatoid arthritis, by downregulation of these disease-associated genes. All these observations warranted further investigations.