Melatonin Receptor Research Articles

Recent advances in predicting, preventing, and managing postoperative delirium.

Postoperative delirium (POD) is a major public health problem associated with poor patient outcomes such as increased hospital lengths of stay, loss of functional independence, and higher mortality. Depending on the study, the reported incidence ranges from 5% to 65%, with the highest incidence in hip and cardiac surgery. Anesthesiologists should be familiar with the predisposing and precipitating factors of POD, particularly screening for preoperative cognitive impairment and frailty syndrome. Screening tools, for example, the Mini-Mental State Exam, Mini-Cog, 4 A's test for delirium screening, and Montreal Cognitive Assessment, can be used to assess for cognitive impairment and the Clinical Frailty Scale to assess for frailty syndrome. The Hospital Elder Life Program is the standard prevention protocol that is tried and tested in reducing the incidence of POD. Prehabilitation, lung protective strategies, pharmacologic agents such as ramelteon, a melatonin receptor agonist, glucocorticoids, dexmedetomidine, and non-pharmacologic agents, such as noise reduction strategies and the encouragement of nocturnal sleep, have all led to a decrease in the incidence of POD and are being studied for their efficacy. However, the data are inconclusive to date. Intraoperatively, preventing hypotension and blood pressure swings, ensuring adequate pain control and anesthetic depth, and using age-adjusted minimum alveolar concentration (MAC) titration reduce the incidence of POD. The incidence of POD using regional or general anesthesia is similar. In this narrative review, we will discuss the current understanding of the predictors, pathophysiology, prevention, and management of POD and identify areas of further research.

Melatonin improves oxidative state and lactate metabolism in rodent Sertoli cells

Antioxidant actions of melatonin and its impact on testicular function and fertility have already been described. Considering that Sertoli cells contribute to provide structural support and nutrition to germ cells, we evaluated the effect of melatonin on oxidative state and lactate metabolism in the immature murine TM4 cell line and in immature hamster Sertoli cells.A prooxidant stimulus applied to rodent Sertoli cells expressing MT1/MT2 receptors, increased lipid peroxidation whereas decreased antioxidant enzymes (superoxide dismutase 1, catalase, peroxiredoxin 1) expression and catalase activity. These changes were prevented by melatonin. Furthermore, melatonin stimulated lactate dehydrogenase (LDH) expression/activity via melatonin receptors, and increased intracellular lactate production in rodent Sertoli cells.Interestingly, oral melatonin supplementation in infertile men positively regulated LDHA testicular mRNA expression.Overall, our work provides insights into the potential benefits of melatonin on Sertoli cells contributing to testicular development and the future establishment of a sustainable spermatogenesis.

Highly-Sensitive In Vitro Bioassays for FSH, TSH, PTH, Kp, and OT in Addition to LH in Mouse Leydig Tumor Cell.

We demonstrate here that highly sensitive in vitro bioassays for FSH, TSH, and PTH can be set up in mouse Leydig Tumor Cells (mLTC), in addition to the normal LH/CG bioassay, after they were transfected with expression vectors encoding the corresponding Gs Protein-Coupled Receptors (GsPCR), such as FSHR, TSHR, or PTHR. Although the β2 adrenergic receptor is also a GsPCR, its expression in mLTC led to a significant but very low cAMP response compared to those observed with FSH, TSH, or PTH. Similarly, after transfection of the GiPCR MT1 melatonin receptor, we did not observe any inhibitory effect by melatonin of the LH or hCG stimulation. Interestingly, after transfection of mLTC with the human kisspeptin receptor (hKpR), which is a GqPCR, we observed a dose-dependent synergy of 10-12-10-7 M kisspeptin variants with a fixed concentration of 0.3 nM LH or hCG. Without any exogenous receptor transfection, a 2 h preincubation with OT or AVP led to a dose-dependent cAMP response to a fixed dose of LH or hCG. Therefore, highly sensitive in vitro bioassays for various hormones and other GPCR ligands can be set up in mLTC to measure circulating concentrations in only 3-10 µL of blood or other body fluids. Nevertheless, the development of an LHRKO mLTC cell line will be mandatory to obtain strict specificity for these bioassays to eliminate potential cross-reaction with LH or CG.

The Photoperiod-Driven Cyclical Secretion of Pineal Melatonin Regulates Seasonal Reproduction in Geese (Anser cygnoides).

The photoperiod is the predominant environmental factor that governs seasonal reproduction in animals; however, the underlying molecular regulatory mechanism has yet to be fully elucidated. Herein, Yangzhou geese (Anser cygnoides) were selected at the spring equinox (SE), summer solstice (SS), autumn equinox (AE), and winter solstice (WS), and the regulation of seasonal reproduction via the light-driven cyclical secretion of pineal melatonin was investigated. We show that there were seasonal variations in the laying rate and GSI, while the ovarian area decreased 1.5-fold from the SS to the AE. Moreover, not only did the weight and volume of the pineal gland increase with a shortened photoperiod, but the secretory activity was also enhanced. Notably, tissue distribution further revealed seasonal oscillations in melatonin receptors (Mtnrs) in the pineal gland and the hypothalamus-pituitary-gonadal (HPG) axis. The immunohistochemical staining indicated higher Mtnr levels due to the shortened photoperiod. Furthermore, the upregulation of aralkylamine N-acetyltransferase (Aanat) was observed from the SS to the AE, concurrently resulting in a downregulation of the gonadotrophin-releasing hormone (GnRH) and gonadotropins (GtHs). This trend was also evident in the secretion of hormones. These data indicate that melatonin secretion during specific seasons is indicative of alterations in the photoperiod, thereby allowing for insight into the neuroendocrine regulation of reproduction via an intrinsic molecular depiction of external photoperiodic variations.

Blockade of Melatonin Receptors Abolishes Its Antiarrhythmic Effect and Slows Ventricular Conduction in Rat Hearts.

Melatonin has been reported to cause myocardial electrophysiological changes and prevent ventricular tachycardia or fibrillation (VT/VF) in ischemia and reperfusion. We sought to identify electrophysiological targets responsible for the melatonin antiarrhythmic action and to explore whether melatonin receptor-dependent pathways or its antioxidative properties are essential for these effects. Ischemia was induced in anesthetized rats given a placebo, melatonin, and/or luzindole (MT1/MT2 melatonin receptor blocker), and epicardial mapping with reperfusion VT/VFs assessment was performed. The oxidative stress assessment and Western blotting analysis were performed in the explanted hearts. Transmembrane potentials and ionic currents were recorded in cardiomyocytes with melatonin and/or luzindole application. Melatonin reduced reperfusion VT/VF incidence associated with local activation time in logistic regression analysis. Melatonin prevented ischemia-related conduction slowing and did not change the total connexin43 (Cx43) level or oxidative stress markers, but it increased the content of a phosphorylated Cx43 variant (P-Cx43368). Luzindole abolished the melatonin antiarrhythmic effect, slowed conduction, decreased total Cx43, protein kinase Cε and P-Cx43368 levels, and the IK1 current, and caused resting membrane potential (RMP) depolarization. Neither melatonin nor luzindole modified INa current. Thus, the antiarrhythmic effect of melatonin was mediated by the receptor-dependent enhancement of impulse conduction, which was associated with Cx43 phosphorylation and maintaining the RMP level.

The Efficacy of Ramelteon to Prevent Postoperative Delirium After General Anesthesia in the Elderly: A Double-Blind, Randomized, Placebo-Controlled Trial

Postoperative delirium is common and serious in elderly patients. Several drugs have been proposed as potential prophylactic agents for postoperative delirium. Studies on melatonin receptor agonists showed heterogeneity in age, cognitive function, anesthesia, surgery, interventions, methodologies for assessing outcomes, and results. Our objective was to examine the effect of ramelteon to prevent postoperative delirium in elderly patients, including those with dementia. A stratified, double-blind, randomized, placebo-controlled trial (UMIN000028436, jRCTs031180054). Tertiary medical center. Patients aged older than or equal to 65 years undergoing elective surgery under general anesthesia. Ramelteon (8 mg orally) or placebo (lactose) for six nights (the preoperative night and five consecutive nights from postoperative day 1 to 5) at around 9 P.M. Patients were screened for postoperative delirium using the Confusion Assessment Method for the Intensive Care Unit twice daily until the sixth postoperative day. Patients with positive results were referred to a consultant psychiatrist to establish the diagnosis of delirium. A total of 108 patients were randomly assigned to receive ramelteon (n=55) or placebo (n=53). Most of the patients' characteristics were reasonably well-balanced between the two groups. The stratified log-rank test showed no significant difference in preventing postoperative delirium between ramelteon and placebo (χ2=0.30, degrees of freedom=1, p=0.60). The Cox proportional hazard ratio for ramelteon compared to placebo was 1.40 (95% confidence interval: 0.40-4.85, χ2 for likelihood ratio test=0.29, degrees of freedom=1, p=0.60). There was no significant difference in the incidence of postoperative delirium between ramelteon and placebo after general anesthesia in elderly patients.

Myocardial Infarction Susceptibility and the MTNR1B Polymorphisms.

Melatonin is a circadian hormone with antioxidant properties that protects against myocardial ischemia-reperfusion injury. Genetic variations of the melatonin receptor 1B gene (MTNR1B) play an important role in the development of type 2 diabetes, a risk factor for cardiovascular diseases. Accordingly, MTNR1B polymorphisms are crucial in numerous disorders of the cardiovascular system. Therefore, the aim of the present study was to investigate a possible association of MTNR1B polymorphisms with chronotype and susceptibility to myocardial infarction. The present case-control study included 199 patients with myocardial infarction (MI) (57% men) and 198 control participants (52% men) without previous cardiovascular diseases who underwent genotyping for the MTNR1B polymorphisms rs10830963, rs1387153, and rs4753426 from peripheral blood samples. Chronotype was determined using the Morningness-Eveningness Questionnaire (MEQ). As estimated by the chi-square test, no significant association was found in the distribution of alleles and genotypes between myocardial infarction patients and controls. In addition, there was no association between MTNR1B polymorphisms and chronotype in MI patients. As some previous studies have shown, the present negative results do not exclude the role of the MTNR1B polymorphisms studied in the development of myocardial infarction. Rather, they may indicate that MTNR1B polymorphisms are a minor risk factor for myocardial infarction.

Melatonin regulates the periodic growth of secondary hair follicles through the nuclear receptor RORα.

Cashmere is the fine bottom hair produced by the secondary hair follicles of the skin. This hair is economically important. Previous studies by our research group have shown that exogenous melatonin (MT) can regulate the periodic growth of secondary hair follicles, induce the secondary development of villi, and alter the expression of some genes related to hair follicle development. Few studies on the regulation of villus growth by MT binding receptors have been published. In this study, MT was implanted subcutaneously behind the ear of Inner Mongolia cashmere goats. RT-qPCR, in situ hybridization, Western blot analysis, immunofluorescence and RNAi techniques were used to investigate the receptors and functions of MT in regulating the development of secondary hair follicles in Inner Mongolia cashmere goats. The results showed that MT binds to the nuclear receptor RORα on dermal papilla stimulates hair follicle development and promotes villus growth. The RORα mRNA expression in the skin of Inner Mongolia cashmere goats was periodic and showed a trend of first increasing and then decreasing. The expression began to increase in February, peaked in April, and reached the lowest level in May. RORα significantly affected the mRNA expression of β-catenin gene, a key gene in hair follicle development, in the presence of MT. It will lay a solid molecular foundation for further research on the regulation mechanism between MT receptor and villus growth and development and to achieve artificial regulation of villus growth time and yield to improve the effect of villus production.

Melatonin Improves Turbot Oocyte Meiotic Maturation and Antioxidant Capacity, Inhibits Apoptosis-Related Genes mRNAs In Vitro.

High-quality eggs are essential for the sustainability of commercial aquaculture production. Melatonin is a potent candidate for regulating the growth and maturation of oocytes. Therefore, research on the effect of melatonin on marine fish oocytes in vitro has been conducted. The present study successfully established a culture system of turbot (Scophthalmus maximus) oocytes in vitro and investigated the effect of melatonin on oocyte meiotic maturation, antioxidant capacity, and the expression of apoptosis-related genes. The cultures showed that turbot Scophthalmus maximus late-vitellogenic denuded oocytes, with diameters of 0.5-0.7 mm, had a low spontaneous maturation rate and exhibited a sensitive response to 17α, 20β-dihydroxyprogesterone (DHP) treatment in vitro. Melatonin increased by four times the rate of oocyte germinal vesicle breakdown (GVBD) in a concentration- and time-dependent manner. The mRNA of melatonin receptor 1 (mtnr1) was significantly upregulated in the oocyte and follicle after treatment with melatonin (4.3 × 10-9 M) for 24 h in vitro, whereas melatonin receptor 2 (mtnr2) and melatonin receptor 3 (mtnr3) remained unchanged. In addition, melatonin significantly increased the activities of catalase, glutathione peroxidase, and superoxide dismutase, as well as the levels of glutathione, while decreasing the levels of malondialdehyde and reactive oxygen species (ROS) levels in turbot oocytes and follicles cultures in vitro. p53, caspase3, and bax mRNAs were significantly downregulated in oocytes and follicles, whereas bcl2 mRNAs were significantly upregulated. In conclusion, the use of turbot late-vitellogenesis oocytes (0.5-0.7 mm) is suitable for establishing a culture system in vitro. Melatonin promotes oocyte meiotic maturation and antioxidative capacity and inhibits apoptosis via the p53-bax-bcl2 and caspase-dependent pathways, which have important potential to improve the maturation and quality of oocytes.

Exogenous melatonin ameliorates steroid-induced osteonecrosis of the femoral head by modulating ferroptosis through GDF15-mediated signaling

BackgroundFerroptosis is an iron-related form of programmed cell death. Accumulating evidence has identified the pathogenic role of ferroptosis in multiple orthopedic disorders. However, the relationship between ferroptosis and SONFH is still unclear. In addition, despite being a common disease in orthopedics, there is still no effective treatment for SONFH. Therefore, clarifying the pathogenic mechanism of SONFH and investigating pharmacologic inhibitors from approved clinical drugs for SONFH is an effective strategy for clinical translation. Melatonin (MT), an endocrine hormone that has become a popular dietary supplement because of its excellent antioxidation, was supplemented from an external source to treat glucocorticoid-induced damage in this study.MethodsMethylprednisolone, a commonly used glucocorticoid in the clinic, was selected to simulate glucocorticoid-induced injury in the current study. Ferroptosis was observed through the detection of ferroptosis-associated genes, lipid peroxidation and mitochondrial function. Bioinformatics analysis was performed to explore the mechanism of SONFH. In addition, a melatonin receptor antagonist and shGDF15 were applied to block the therapeutic effect of MT to further confirm the mechanism. Finally, cell experiments and the SONFH rat model were used to detect the therapeutic effects of MT.ResultsMT alleviated bone loss in SONFH rats by maintaining BMSC activity through suppression of ferroptosis. The results are further verified by the melatonin MT2 receptor antagonist that can block the therapeutic effects of MT. In addition, bioinformatic analysis and subsequent experiments confirmed that growth differentiation factor 15 (GDF15), a stress response cytokine, was downregulated in the process of SONFH. On the contrary, MT treatment increased the expression of GDF15 in bone marrow mesenchymal stem cells. Lastly, rescue experiments performed with shGDF15 confirmed that GDF15 plays a key role in the therapeutic effects of melatonin.ConclusionsWe proposed that MT attenuated SONFH by inhibiting ferroptosis through the regulation of GDF15, and supplementation with exogenous MT might be a promising method for the treatment of SONFH.Graphical

Agomelatine inhibits platelet aggregation through melatonin receptor-dependent and independent mechanisms

AimsMelatonin is known to inhibit platelet aggregation induced by arachidonic acid (AA). In the present study we investigated whether agomelatine (Ago), an antidepressant with agonist activity at melatonin receptor 1 (MT1) and MT2 could reduce platelets aggregation and adhesion. Main methodsHuman platelets from healthy donors were used to test the in vitro effects of Ago in the presence of different platelet activators. We performed aggregation and adhesion assays, thromboxane B2 (TxB2), cAMP and cGMP measurements, intra-platelet calcium registration and flow cytometry assays. Key findingsOur data revealed that different concentrations of Ago reduced AA- and collagen-induced human platelet aggregation in vitro. Ago also reduced AA-induced increase in thromboxane B2 (TxB2) production, intracellular calcium levels and P-selectin expression at plasma membrane. The effects of Ago in AA-activated platelets were likely dependent on MT1 as they were blocked by luzindole (a MT1/MT2 antagonist) and mimicked by the MT1 agonist UCM871 in a luzindole-sensitive manner. The MT2 agonist UCM924 was also able to inhibit platelet aggregation, but this response was not affected by luzindole. On the other hand, although UCM871 and UCM924 reduced collagen-induced platelet aggregation and adhesion, inhibition of collagen-induced platelet aggregation by Ago was not mediated by melatonin receptors because it was not affected by luzindole. SignificanceThe present data show that Ago suppresses human platelet aggregation and suggest that this antidepressant may have the potential to prevent atherothrombotic ischemic events by reducing thrombus formation and vessel occlusion.

Pistacia vera Extract Potentiates the Effect of Melatonin on Human Melatonin MT1 and MT2 Receptors with Functional Selectivity.

Melatonin is a tryptophan derivative synthesized in plants and animals. In humans, melatonin acts on melatonin MT1 and MT2 receptors belonging to the G protein-coupled receptor (GPCR) family. Synthetic melatonin receptor agonists are prescribed for insomnia and depressive and circadian-related disorders. Here, we tested 25 commercial plant extracts, reported to have beneficial properties in sleep disorders and anxiety, using cellular assays (2─[125I]iodomelatonin binding, cAMP inhibition, ERK1/2 activation and β-arrestin2 recruitment) in mock-transfected and HEK293 cells expressing MT1 or MT2. Various melatonin receptor-dependent and -independent effects were observed. Extract 18 (Ex18) from Pistacia vera dried fruits stood out with very potent effects in melatonin receptor expressing cells. The high content of endogenous melatonin in Ex18 (5.28 ± 0.46 mg/g extract) is consistent with this observation. Ex18 contains an additional active principle that potentiates the effect of melatonin on Gi protein-dependent pathways but not on β-arrestin2 recruitment. Further active principles potentiating exogenous melatonin were detected in several extracts. In conclusion, we identified plant extracts with various effects in GPCR-based binding and signalling assays and identified high melatonin levels and a melatonin-potentiating activity in Pistacia vera dried fruit extracts that might be of therapeutic potential.

Melatonin Receptor 1B and Corticosteroid Receptor Polymorphisms in Infertile Women with Implantation Failure and Miscarriages.

The development of assisted reproductive techniques has significantly improved fertility chances in many women, but recurrent implantation failure (RIF) and miscarriages (RM) might preclude successful pregnancy. Alterations in the intrinsic secretory patterns of melatonin and cortisol influence reproduction in humans, and imperfection of receptor - dependent signaling may additionally compromise the hormonal effects. Therefore, the present study aims to investigate the influence of certain melatonin and cortisol receptor polymorphisms in infertile women. A total of 111 female infertile patients suffering from implantation failure and/or miscarriages were genotyped for MTNR1B rs1562444, MTNR1Brs10830962, GCCR rs41423247, and GCCR ER22/23EK variants. Additionally, 106 female volunteers were genotyped for the same polymorphisms. The allele and genotype distribution of the investigated polymorphisms did not differ between infertile women and the control group. Significantly more women with history of RIF have MTNR1B rs1562444 G-allele-containing genotypes in comparison to AA carriers (19.3% vs. 3.6%, p = 0.004). The minor allele of the ER22/23EK variant was more frequent in infertile patients with three or more unsuccessful implantation attempts than in other women (12.5% vs. 2.4%, p = 0.025). Melatonin receptor 1B polymorphisms might affect embryo implantation and early pregnancy loss, while their influence on late pregnancy complications needs further evaluation. The possible association between the cortisol receptor ER22/23EK variant and recurrent implantation failure might help to differentiate women who could benefit from corticosteroid treatment.

Association between single nucleotide polymorphisms in serotonin receptor 2A and melatonin receptor 1A genes and pain after root canal treatment.

This study aimed to investigate whether single nucleotide polymorphisms (SNPs) in the genes encoding 5-HTR2A (5-Hydroxytryptamine (serotonin) receptor 2A) and MTNR1A (melatonin receptor 1A) may contribute to postoperative pain perception after root canal treatment. We hypothesised that SNPs in HTR2A and MTNR1A genes were associated with postoperative pain after root canal treatment. This genetic cohort study enrolled patients with single-rooted teeth diagnosed with pulp necrosis and asymptomatic apical periodontitis before root canal treatment. Root canal treatment was performed in one session using a standardised protocol. Postoperative pain and tenderness were assessed using a visual analogue scale (recorded every day for seven days and on the 14th and 30th days after root canal treatment). Genomic DNA was extracted from saliva and used to genotype the SNPs in HTR2A (rs4941573 and rs6313) and MTNR1A (rs6553010, rs6847693, and rs13140012) using real-time polymerase chain reaction. Genotypes were compared using univariate and multivariate Poisson regression with generalised estimating equations (p<0.05). In total, 108 patients were enrolled in this study. The SNPs rs6553010 (MTNR1A), rs4941573, and rs6313 (HTR2A) were associated with an increased risk of developing pain after root canal treatment (p<0.05). This study suggests that SNPs in HTR2A and MTNR1A influence pain response after root canal treatment.

Melatonin enhances cell death and suppresses the metastatic capacity of ovarian cancer cells by attenuating the signaling of multiple kinases

BackgroundOvarian cancer is a highly aggressive disease that is frequently diagnosed in advanced stages. Melatonin, with its numerous antitumor properties, holds great promise in cancer treatment. Herein, we investigated the effects of melatonin on apoptosis, cell migration, and kinase levels in human ovarian carcinoma SKOV-3 cells and determined whether these effects are mediated by the activation of the MT1 receptor. MethodsSKOV-3 cells were exposed to different concentrations of melatonin based on the presence of MT1 receptor, and we also performed specific silencing of the melatonin receptor gene MTNR1A. ResultsOur findings revealed that melatonin reduced cell viability as shown by the MTT assay, and flow cytometry analysis showed increased rates of apoptosis and necrosis in all melatonin-treated cells. Melatonin significantly decreased the migratory and invasive capacities of the cells. Propidium iodide labeling indicated that melatonin induced cell cycle arrest by reducing DNA content in the S and G2/M phases in SKOV-3 cells. Additionally, the levels of AKT, ERK1/2, JNK, CREB, p70S6K, STAT3/5, and p38 MAP kinase involved in cell survival, proliferation, motility, and stress responses were depressed by melatonin and further reduced after MT1 knockdown. These molecules were found to be associated with lower overall survival in ovarian cancer patients. ConclusionsMelatonin had obvious oncostatic actions on ovarian cancer cells, and MT1 receptor knockdown intensified its antitumor effect. The inhibition of the MT1 receptor resulted in a substantial reduction in the migratory and invasive capacities of the cells, suggesting its potential as a therapeutic target for the treatment of ovarian cancer.

Melatonin-related dysfunction in chronic restraint stress triggers sleep disorders in mice.

Stress may trigger sleep disorders and are also risk factors for depression. The study explored the melatonin-related mechanisms of stress-associated sleep disorders on a mouse model of chronic stress by exploring the alteration in sleep architecture, melatonin, and related small molecule levels, transcription and expression of melatonin-related genes as well as proteins. Mice undergoing chronic restraint stress modeling for 28days showed body weight loss and reduced locomotor activity. Sleep fragmentation, circadian rhythm disorders, and insomnia exhibited in CRS-treated mice formed sleep disorders. Tryptophan and 5-hydroxytryptamine levels were increased in the hypothalamus, while melatonin level was decreased. The transcription and expression of melatonin receptors were reduced, and circadian rhythm related genes were altered. Expression of downstream effectors to melatonin receptors was also affected. These results identified sleep disorders in a mice model of chronic stress. The alteration of melatonin-related pathways was shown to trigger sleep disorders.

Melatonin-vorinostat hybrid ligands show higher histone deacetylase and cancer cell growth inhibition than vorinostat.

Anticancer drug conjugates are an emerging approach for future cancer treatment. Here, we report a series of hybrid ligands merging the neurohormone melatonin with the approved histone deacetylase (HDAC) inhibitor vorinostat, using melatonin's amide side chain (3a-e), its indolic nitrogen (5a-d), and its ether oxygen (7a-d) as attachment points. Several hybrid ligands showed higher potency thanvorinostat in both HDAC inhibition and cellular assays on different cultured cancer cell lines. In the most potent HDAC1 and HDAC6 inhibitors, 3e, 5c, and 7c, the hydroxamic acid moiety of vorinostat is linked to melatonin through a hexamethylene spacer. Hybrid ligands 5c and 7c were also found to be potent growth inhibitors of MCF-7, PC-3M-Luc, and HL-60 cancer cell lines. As these compounds showed only weak agonist activity at melatonin MT1 receptors, the findings indicate that their anticancer actions are driven by HDAC inhibition.

Melatonin modulates endometrial decidualization via NOTCH1-NRF2-FOXO1-GSH pathway†.

Melatonin is important for oocyte maturation, fertilization, early embryonic development, and embryo implantation, but less knowledge is available regarding its role in decidualization. The present study found that melatonin did not alter the proliferation of human endometrial stromal cells (ESCs), as well as cell cycle progress, but suppressed stromal differentiation after binding to the melatonin receptor 1B (MTNR1B), which was visualized in decidualizing ESCs. Further analysis evidenced that application of melatonin resulted in the diminishment for NOTCH1 and RBPJ expression. Supplementation of recombinant NOTCH1 protein (rNOTCH1) counteracted the impairment of stromal differentiation conferred by melatonin, while the addition of the NOTCH signaling pathway inhibitor DAPT aggravated the differentiation progress. Meanwhile, melatonin might restrain the expression and transcriptional activity of nuclear factor erythroid 2-related factor 2 (NRF2), whose blockage accelerated the fault of stromal differentiation under the context of melatonin, but this restraint was subsequently ameliorated by rNOTCH1. Forkhead box O 1 (FOXO1) was identified as a downstream target of melatonin in decidualization. Repression of NRF2 antagonized the retrieval of rNOTCH1 due to aberrant FOXO1 expression elicited by melatonin. Moreover, melatonin brought about the occurrence of oxidative stress accompanied by an obvious accumulation of intracellular reactive oxygen species and a significant reduction in glutathione (GSH) content, as well as enzymatic activities of glutathione peroxidase and glutathione reductase, whereas supplementation of rNOTCH1 improved the above-mentioned effects. Nevertheless, this improvement was disrupted by the blockage of NRF2 and FOXO1. Furthermore, addition of GSH rescued the defect of stromal differentiation by melatonin. Collectively, melatonin might impair endometrial decidualization by restraining the differentiation of ESCs dependent on NOTCH1-NRF2-FOXO1-GSH pathway after binding to the MTNR1B receptor.

Protective effect of melatonin against oxygen-induced retinopathy: a study based on the HMGB1/NF-κB/NLRP3 axis

To study the protective effect of melatonin (Mel) against oxygen-induced retinopathy (OIR) in neonatal mice and the role of the HMGB1/NF-κB/NLRP3 axis. Neonatal C57BL/6J mice, aged 7 days, were randomly divided into a control group, a model group (OIR group), and a Mel treatment group (OIR+Mel group), with 9 mice in each group. The hyperoxia induction method was used to establish a model of OIR. Hematoxylin and eosin staining and retinal flat-mount preparation were used to observe retinal structure and neovascularization. Immunofluorescent staining was used to measure the expression of proteins and inflammatory factors associated with the HMGB1/NF-κB/NLRP3 axis and lymphocyte antigen 6G. Colorimetry was used to measure the activity of myeloperoxidase. The OIR group had destruction of retinal structure with a large perfusion-free area and neovascularization, while the OIR+Mel group had improvement in destruction of retinal structure with reductions in neovascularization and perfusion-free area. Compared with the control group, the OIR group had significant increases in the expression of proteins and inflammatory factors associated with the HMGB1/NF-κB/NLRP3 axis, the expression of lymphocyte antigen 6G, and the activity of myeloperoxidase (P<0.05). Compared with the OIR group, the OIR+Mel group had significant reductions in the above indices (P<0.05). Compared with the control group, the OIR group had significant reductions in the expression of melatonin receptors in the retina (P<0.05). Compared with the OIR group, the OIR+Mel group had significant increases in the expression of melatonin receptors (P<0.05). Mel can alleviate OIR-induced retinal damage in neonatal mice by inhibiting the HMGB1/NF-κB/NLRP3 axis and may exert an effect through the melatonin receptor pathway.

The Interaction of SRL-2 Peptide with LRP-1 Receptor and Identification of Breast Cancer Related Biomarkers: An In-silico Approach

Background: Breast cancer is a multifaceted disease characterized by genetic and epigenetic changes that lead to uncontrolled cell growth and metastasis. Early detection and treatment are crucial for managing diseases. Objectives: The objective of this study is to investigate the potential of chimeric peptides for drug delivery and to identify biomarkers associated with breast cancer. Recent studies have shown that the low-density lipoprotein receptor-related protein 1 (LRP-1) receptor has a significant impact on the development of breast cancer. In order to facilitate the identification of biomarkers, we have created a chimeric peptide that has been proven to bind successfully to the LRP-1 receptor. Methods: To identify biomarkers, we utilized advanced computational methods to conduct a meta-analysis of microarray data. Specifically, the g:Profiler and eXpression2Kinases (X2K) databases were utilized to identify gene ontologies and transcription factors. We then used the Human Protein Atlas to identify and assess crucial gene expressions. Results: Our results demonstrated that nucleolar and spindle-associated protein 1 (NUSAP1), melatonin receptor 1A (MELT), and cyclin-dependent kinase 1 (CDK1) are three hub genes that play pivotal roles in the pathogenesis of breast cancer. Conclusions: The research findings provide a deeper understanding of the molecular mechanisms involved in developing breast cancer. These findings have significant implications for developing novel therapies and diagnostics for this disease.