Melatonin Receptor Research Articles

Melatonin alleviates early brain injury by inhibiting the NRF2-mediated ferroptosis pathway after subarachnoid hemorrhage

Ferroptosis is a novel form of cell death that plays a critical role in the pathological and physiological processes of early brain injury following subarachnoid hemorrhage. Melatonin, as the most potent endogenous antioxidant, has shown strong protective effects against pathological changes following subarachnoid hemorrhage, but its impact on ferroptosis induced by subarachnoid hemorrhage remains unexplored. In our study, we established a subarachnoid hemorrhage model in male SD rats. We found that subarachnoid hemorrhage induced changes in ferroptosis-related indicators such as lipid peroxidation and iron metabolism, while intraperitoneal injection of melatonin (40 mg/kg) effectively ameliorated these changes to a certain degree. Moreover, in a subset of rats with subarachnoid hemorrhage who received pre-treatment via intravenous injection of the melatonin receptor antagonist Luzindole (1 mg/kg) and 4P-PDOT (1 mg/kg), we found that the protective effect of melatonin against subarachnoid hemorrhage includes inhibition of lipid peroxidation and reduction of iron accumulation depended on melatonin receptor 1B (MT2). Furthermore, our study demonstrated that melatonin inhibited neuronal ferroptosis by activating the NRF2 signaling pathway, as evidenced by in vivo inhibition of NRF2. In summary, melatonin acts through MT2 and activates NRF2 and downstream genes such as HO-1/NQO1 to inhibit ferroptosis in subarachnoid hemorrhage-induced neuronal injury, thereby improving neurological function in rats. These results suggest that melatonin is a promising therapeutic target for subarachnoid hemorrhage.

Melatonin receptor, GhCAND2-D5 motivated responding to NaCl signaling in cotton

As a receptor for plant melatonin, CAND2/PMTR plays an important role in melatonin signaling. Most of the CANDs are membrane proteins and play indispensable roles in signal transduction. In this study, the CANDs from four cotton species were characterized, and the phylogenetic relationships, expression patterns, stress responses of cotton CANDs were analyzed by bioinformatics. Through the analysis of phylogenetic and protein structure, it was found that the CANDs in clade Ⅱ might function as cotton melatonin receptors, and most of the GhCANDs in clade Ⅱ were induced by melatonin. A putative cotton melatonin receptor, GhCAND2-D5, was functionally probed by gene silencing. The plants with silenced expression of this gene exhibited decreased salt tolerance. Protein interaction prediction identified that GhCAND2-D5 interacted with several membrane proteins and played an important role in melatonin signaling. This study provided a theoretical reference for further investigation of melatonin signaling in cotton.

Association of MTNR1A and GDF9 gene allelles with the reproductive performance, response to oestrus induction treatments and prolificacy, in improved and non-improved local indigenous sheep breeds.

Sheep farming plays a crucial role for Mediterranean countries, wherefrom a plethora of dairy products is produced. Yet, numerous indigenous sheep breeds in temperate latitudes such as the Mediterranean present a serious drawback that milk production is impaired by the seasonality of reproduction. Towards the efforts for reduction of this phenomenon, the purpose of this study was to evaluate and compare different oestrus synchronization treatments, as well as to associate two genes alleles', namely the MTNR1A and the GDF9, with the response to those treatments. Three indigenous breeds were investigated (Florina, Chios and Karagouniko sheep) and inside each breed three different oestrus synchronization treatments were applied (A: intravaginal sponges, B: GNRH use and C: male effect). In group A, Florina ewes expressed oestrus at 90% in July and fecundity was 85%. Karagouniko and Chios ewes exhibited an oestrus expression of 100% with fecundity rates at 95% and 99%, respectively. In group B, Florina ewes expressed oestrus at 60% with fecundity at 57%, Karagouniko ewes expressed oestrus at 65% with fecundity at 54%, whereas Chios breed animals expressed oestrus at 87% with fecundity rate at 85%. In group C, 68% of the Florina breed expressed oestrus 20-25 days post ram induction, whereas this proportion was 84% and 94%, for Karagouniko and Chios breed, respectively. For the molecular analysis, partial segments of the two genes were sequenced and analysed, whereas alleles were scored based on the detected SNPs. All frequencies of the four detected SNPs in MTNR1A gene were statistically and significantly different in ewes that expressed oestrus in comparison with ewes that did not express oestrus in Florina and Karagouniko breeds concerning all treatments. Two SNP's were detected in GDF9 gene, G1 and FecG , from which, only the FecG mutation exhibited statistically significant difference in twins and triplets than in singles in Florina and Karagouniko breeds.

A novel signaling transduction pathway of melatonin on lactose synthesis in cows via melatonin receptor 1 (MT1) and prolactin receptor (PRLR).

In the current study, we explored the relationship between melatonin and lactose synthesis in in vivo and in vitro conditions. We found that long-term melatonin feeding to the dairy cows significantly reduced the milk lactose content in a dose dependent manner. This lactose reduction was not associated with a negative energy balance, since melatonin treatment did not alter the fat, glucose, or protein metabolisms of the cows. To identify the potential molecular mechanisms, the cow's mammary epithelial cells were cultured for gene expression analysis. The results showed that the effect of melatonin on lactose reduction was mediated by its receptor MT1. MT1 activation downregulated the mRNA expression of the prolactin receptor gene (PRLR), which then suppressed the gene expression of SLC35B1. SLC35B1 is a galactose transporter and is responsible for the transportation of galactose to Golgi apparatus for lactose synthesis. Its suppression reduced the lactose synthesis and the milk lactose content. The discovery of this signal transduction pathway of melatonin on lactose synthesis provides a novel aspect of melatonin's effect on carbohydrate metabolism in cows and maybe also in other mammals, including humans.

Regulation of Adipose-Derived Stem Cell Activity by Melatonin Receptors in Terms of Viability and Osteogenic Differentiation.

Melatonin is a hormone secreted mainly by the pineal gland and acts through the Mel1A and Mel1B receptors. Among other actions, melatonin significantly increases osteogenesis during bone regeneration. Human adipose-derived mesenchymal stem cells (ADSCs) are also known to have the potential to differentiate into osteoblast-like cells; however, inefficient culturing due to the loss of properties over time or low cell survival rates on scaffolds is a limitation. Improving the process of ADSC expansion in vitro is crucial for its further successful use in bone regeneration. This study aimed to assess the effect of melatonin on ADSC characteristics, including osteogenicity. We assessed ADSC viability at different melatonin concentrations as well as the effect on its receptor inhibitors (luzindole or 4-P-PDOT). Moreover, we analyzed the ADSC phenotype, apoptosis, cell cycle, and expression of MTNR1A and MTNR1B receptors, and its potential for osteogenic differentiation. We found that ADSCs treated with melatonin at a concentration of 100 µM had a higher viability compared to those treated at higher melatonin concentrations. Melatonin did not change the phenotype of ADSCs or induce apoptosis and it promoted the activity of some osteogenesis-related genes. We concluded that melatonin is safe, non-toxic to normal ADSCs in vitro, and can be used in regenerative medicine at low doses (100 μM) to improve cell viability without negatively affecting the osteogenic potential of these cells.

The melatonin agonist ramelteon attenuates bleomycin-induced lung fibrosis by suppressing the NLRP3/TGF-Β1/HMGB1 signaling pathway

PurposeThe possible effects of ramelteon, a melatonin receptor agonist on bleomycin-induced lung fibrosis were analyzed via transforming growth factor β1 (TGF-β1), the high mobility group box 1 (HMGB1) and Nod-like receptor pyrin domain-containing 3 (NLRP3) which are related to the fibrosis process. Materials and methodsBleomycin (0.1 ​mL of 5 ​mg/kg) was administered by intratracheal instillation to induce pulmonary fibrosis (PF). Starting 24 ​h after bleomycin administration, a single dose of ramelteon was administered by oral gavage to the healthy groups, i.e. PF ​+ ​RM2 (pulmonary fibrosis model with bleomycin ​+ ​ramelteon at 2 ​mg/kg) and PF ​+ ​RM4 (pulmonary fibrosis model with bleomycin ​+ ​ramelteon at 4 ​mg/kg) at 2 and 4 ​mg/kg doses, respectively. Real-time polymerase chain reaction (real-time PCR) analyses, histopathological, and immunohistochemical staining were performed on lung tissues. Lung tomography images of the rats were also examined. ResultsThe levels of TGF-β1, HMGB1, NLRP3, and interleukin 1 beta (IL-1β) mRNA expressions increased as a result of PF and subsequently decreased with both ramelteon doses (p ​< ​0.0001). Both doses of ramelteon partially ameliorated the reduction in the peribronchovascular thickening, ground-glass appearances, and reticulations, and the loss of lung volume. ConclusionsThe severity of fibrosis decreased with ramelteon application. These effects of ramelteon may be associated with NLRP3 inflammation cascade.

Efficacy and moderators of prevention and treatment of delirium with melatonin receptor agonists: A systematic review and meta-analysis of randomized controlled trials

ObjectiveDelirium is a complex and heterogeneous condition that significantly affects patient outcome. This study aimed to conduct a systematic review and meta-analysis to investigate the effects of melatonin and melatonin receptor agonists (MRAs) on delirium prevention and treatment. MethodRandomized controlled studies, using MRAs as an intervention and placebo as a control were included. We conducted meta-analyses with random-effects model and trial sequential analysis. ResultsA total of 33 studies involving 4850 participants were included. The meta-analysis revealed a significant preventive effect of MRAs on delirium (risk ratio = 0.65, p < 0.01), while no significant therapeutic effect was observed. Additionally, MRAs were associated with a significant reduction in mortality rate (risk ratio = 0.90, p = 0.02) in delirium prevention studies. Furthermore, subgroup analyses revealed that assessment scales and the frequency of delirium detection may be significant moderators of the delirium-preventive efficacy of MRAs. ConclusionThis study provides evidence of the potential effects of MRAs in preventing delirium and reducing mortality. Further research is required to elucidate the therapeutic potential of MRAs for delirium and identify specific patient populations that may benefit from this agent.

The Preventive Effect of Melatonin on Radiation-Induced Oral Mucositis.

Melatonin exerts various physiological effects through melatonin receptors and their ability to scavenge free radicals. Radiotherapy is a common treatment for head and neck tumors, but stomatitis, a side effect affecting irradiated oral mucosa, can impact treatment outcomes. This study investigated the preventive effect of melatonin, a potent free radical scavenger, on radiation-induced oral mucositis. Mice were irradiated with 15 Gy of X-ray radiation to the head and neck, and the oral mucosa was histologically compared between a melatonin-administered group and a control group. The results showed that radiation-induced oral mucositis was suppressed in mice administered melatonin before and after irradiation. It was suggested that the mechanism involved the inhibition of apoptosis and the inhibition of DNA damage. From these findings, we confirmed that melatonin has a protective effect against radiation-induced oral mucositis.

Melatonin, a natural antioxidant therapy in spinal cord injury.

Spinal cord injury (SCI) is a sudden onset of disruption to the spinal neural tissue, leading to loss of motor control and sensory function of the body. Oxidative stress is considered a hallmark in SCI followed by a series of events, including inflammation and cellular apoptosis. Melatonin was originally discovered as a hormone produced by the pineal gland. The subcellular localization of melatonin has been identified in mitochondria, exhibiting specific onsite protection to excess mitochondrial reactive oxygen species and working as an antioxidant in diseases. The recent discovery regarding the molecular basis of ligand selectivity for melatonin receptors and the constant efforts on finding synthetic melatonin alternatives have drawn researchers' attention back to melatonin. This review outlines the application of melatonin in SCI, including 1) the relationship between the melatonin rhythm and SCI in clinic; 2) the neuroprotective role of melatonin in experimental traumatic and ischemia/reperfusion SCI, i.e., exhibiting anti-oxidative, anti-inflammatory, and anti-apoptosis effects, facilitating the integrity of the blood-spinal cord barrier, ameliorating edema, preventing neural death, reducing scar formation, and promoting axon regeneration and neuroplasticity; 3) protecting gut microbiota and peripheral organs; 4) synergizing with drugs, rehabilitation training, stem cell therapy, and biomedical material engineering; and 5) the potential side effects. This comprehensive review provides new insights on melatonin as a natural antioxidant therapy in facilitating rehabilitation in SCI.

The melatonin receptor agonist agomelatine protects against acute pancreatitis induced by cadmium by attenuating inflammation and oxidative stress and modulating Nrf2/HO-1 pathway

Pancreatitis is a serious effect of the heavy metal cadmium (Cd) and inflammation and oxidative stress (OS) are implicated in Cd-induced pancreatic injury. This study evaluated the effect of the melatonin receptor agonist agomelatine (AGM) on Cd-induced acute pancreatitis (AP), pointing to its modulatory effect on inflammation, OS, and Nrf2/HO-1 pathway. Rats were supplemented with AGM orally for 14 days and a single injection of cadmium chloride (CdCl2) on day 7. Cd increased serum amylase and lipase and caused pancreatic endocrine and exocrine tissue injury. Malondialdehyde (MDA), nitric oxide (NO) and myeloperoxidase (MPO) were elevated, nuclear factor (NF)-kB p65, inducible NO synthase (iNOS), interleukin (IL)-6, tumor necrosis factor (TNF)-α and CD40 were upregulated, and antioxidants were decreased in the pancreas of Cd-administered rats. AGM ameliorated serum amylase and lipase and pancreatic OS, NF-kB p65, CD40, pro-inflammatory mediators and caspase-3, prevented tissue injury and enhanced antioxidants. AGM downregulated Keap1 and enhanced Nrf2 and HO-1 in the pancreas of Cd-administered rats. In silico findings revealed the binding affinity of AGM with Keap1, HO-1, CD40L and caspase-3. In conclusion, AGM protected against AP induced by Cd by preventing inflammation, OS and apoptosis and modulating Nrf2/HO-1 pathway.

Design, Synthesis, In Silico Studies and In Vitro Evaluation of New Indole- and/or Donepezil-like Hybrids as Multitarget-Directed Agents for Alzheimer's Disease.

Alzheimer's disease (AD) is considered a complex neurodegenerative condition which warrants the development of multitargeted drugs to tackle the key pathogenetic mechanisms of the disease. In this study, two novel series of melatonin- and donepezil-based hybrid molecules with hydrazone (3a-r) or sulfonyl hydrazone (5a-l) fragments were designed, synthesized, and evaluated as multifunctional ligands against AD-related neurodegenerative mechanisms. Two lead compounds (3c and 3d) exhibited a well-balanced multifunctional profile, demonstrating intriguing acetylcholinesterase (AChE) inhibition, promising antioxidant activity assessed by DPPH, ABTS, and FRAP methods, as well as the inhibition of lipid peroxidation in the linoleic acid system. Compound 3n, possessing two indole scaffolds, showed the highest activity against butyrylcholinesterase (BChE) and a high selectivity index (SI = 47.34), as well as a pronounced protective effect in H2O2-induced oxidative stress in SH-SY5Y cells. Moreover, compounds 3c, 3d, and 3n showed low neurotoxicity against malignant neuroblastoma cell lines of human (SH-SY5Y) and murine (Neuro-2a) origin, as well as normal murine fibroblast cells (CCL-1) that indicate the in vitro biocompatibility of the experimental compounds. Furthermore, compounds 3c, 3d, and 3n were capable of penetrating the blood-brain barrier (BBB) in the experimental PAMPA-BBB study. The molecular docking showed that compound 3c could act as a ligand to both MT1 and MT2 receptors, as well as to AchE and BchE enzymes. Taken together, those results outline compounds 3c, 3d, and 3n as promising prototypes in the search of innovative compounds for the treatment of AD-associated neurodegeneration with oxidative stress. This study demonstrates that hydrazone derivatives with melatonin and donepezil are appropriate for further development of new AChE/BChE inhibitory agents.

Differentiation of T cells producing interleukin-17 (Th17) against the background of exogenous melatonin during pregnancy.

The population of T lymphocytes producing IL-17 (Th17) plays a dual role during pregnancy and its activity is tightly controlled during this period. One of the factors involved in this process may be the pineal hormone melatonin, which can effectively regulate this T cell population. Here we have shown that exogenous melatonin in pharmacological concentrations is able to enhance the differentiation of Th17 cells of pregnant women in vitro. The stimulatory effects of melatonin were limited to in the first trimester of pregnancy and were apparently mediated by both membrane and nuclear melatonin receptors. Since exogenous melatonin is currently considered as a promising drug in solving various problems associated with reproduction, it is necessary to take into account its immunoregulatory effects.

Melatonin Secretion in Regulating the Circadian Rhythms of Reproduction in Goose (Anser cygnoides)

Circadian rhythms affect the physiology and behavior of most organisms. The ovulation–laying cycle of poultry exhibits evident rhythmic patterns. However, the underlying biological mechanism has remained unclear. Herein, Yangzhou goose (Anser cygnoides) were selected at 6:00, 12:00, 18:00, and 24:00 (n = 6/timepoint) to investigate the regulation of circadian egg-laying through the light-driven melatonin secretion. Our study revealed that the laying rates displayed diurnal fluctuations, with a peak of 40% of eggs being laid between 4:00 and 7:00. The cosine analysis revealed that the expression of clock genes exhibited rhythmicities (p &lt; 0.05). Relevantly, melatonin secretion also displayed circadian rhythmicity and sharply decreases with increasing amount of light (p &lt; 0.001). The immunohistochemical analysis found that the melatonin receptor is highly expressed during the night period. Notably, tissue distribution analysis further revealed that the melatonin receptor genes showed a decreasing trend in the pineal gland and hypothalamic–pituitary–gonad (HPG) axis throughout the day. Concomitantly, the expression of reproduction-related genes at 12:00 was significantly higher than that at 24:00 (p &lt; 0.01). Taken together, these data suggested cyclical secretion of melatonin in response to photoperiod, which acts as a neuroendocrine transducer of circadian rhythm and the time preference of reproduction in domestic geese.

A Crosstalk Between Pineal and Major Extra-Pineal Sources of Melatonin and its Role in Ovarian Growth and Maturation in Fish

Pinealocytes of the pineal gland in vertebrates mainly synthesize melatonin (5-methoxy-N-acetyl-tryptamine). Moreover, melatonin is synthesized in several extra-pineal cells, including the photoreceptor cells of the retina, the cells of the gut, and the hepatocytes of the liver in different vertebrates, including fish species. One of the remarkable features of pineal and retinal melatonin is that it is produced rhythmically in synchronization with the environmental Light-Dark (LD) cycle, with a daily nighttime peak. However, the melatonin synthesis in tissue/cells from the extra-pineal and extra-retinal origin(s) may not always undergo photoperiod-regulated daily variations but is also dependent on the environmental food entrainment factors (in the gut), acting as the most reliable synchronizer(s) in its daily rhythm features. Moreover, the regulation of the liver and ovary (important for fish reproduction) is unclear. In this review, we attempt a comparative account of the nature and regulation of endogenous melatonin synthesis between a source like the pineal gland and many other nonpineal origins, which have gained serious attention in the last ten years. We also review the functions of melatonin in regulating fish ovarian growth and maturation. The physiological melatonin levels, manipulated either endogenously (by photoperiodic modulations) or exogenously (by injections or by feeds), have tremendous effects on reproductive events in fish at the age of its first maturity, as revealed in recent findings. Characterization and identification of the importance of pineal gland melatonin in the growth of the oocytes via the hypothalamic-pituitary-gonadal axis have been explored several years back. The identification of melatonin receptors about fourteen years back on the wall of developing oocyte spurt the breakthrough, which introduced the concept of direct control of melatonin on developing oocytes. Thus, this review gains uniqueness by addressing the latest developments recorded in the field of melatonin and fish reproduction, particularly in improving oocyte maturation. Nonetheless, an attempt has been made to underline approaches that need to be developed to apply the molecule in large-scale aquaculture.

Cognition damage due to disruption of cyclic adenosine monophosphate-related signaling pathway in melatonin receptor 2 knockout mice

Alzheimer&amp;rsquo;s disease (AD) was characterized by the presence of neurofibrillary tangles and senile plaques. Although melatonin plays an important role in AD, its mechanism is still unknown. In this study, we found obvious cognition damage in melatonin receptor 2 knockout mice (MT2KO) and double knockout mice (DKO), but not in melatonin receptor 1 knockout mice (MT1KO). To explore the mechanism in-depth, we attempted to determine the levels of metabolites and amyloid-&amp;beta; peptide (A&amp;beta;). A high level of Cho/tCr (choline/total creatine) was detected in MT2KO and MT1KO by nuclear magnetic resonance (NMR), while a high level of myo-inositol/total creatine (mI/tCr) was only detected in MT1KO. A higher ratio of A&amp;beta;42/40 was found in MT2KO, but not in MT1KO and DKO. We also found an abnormal increase of plaque detected by the A3981 antibody in MT2KO and DKO. Furthermore, a huge decrease of postsynapses was confirmed in MT2KO and DKO, but not MT1KO, accompanied by a low level of phosphorylated cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) at the site of serine 133 and a low activity of protein kinase A. Finally, the cAMP, cyclic guanosine monophosphate, and cAMP-regulated guanine nucleotide exchange factor (EPAC) were detected. We observed a significant decrease of cAMP and EPAC2 in MT2KO, but not MT1KO. Thus, we identified that cAMP-related signaling pathway was disturbed in MT2KO and was critical for normal cognitive function.

Toll-like Receptor 2-Melatonin Feedback Loop Regulates the Activation of Spinal NLRP3 Inflammasome in Morphine-Tolerant Rats.

Morphine is amongst the most effective analgesics available for the management of severe pain. However, prolonged morphine treatment leads to analgesic tolerance which limits its clinical usage. Previous studies have demonstrated that melatonin ameliorates morphine tolerance by reducing neuroinflammation. However, little is known about the relationship between Toll like receptor 2 (TLR2) and neuroinflammation in morphine tolerance. The aim of this study was to explore the role of TLR2 in morphine tolerance and its connections with melatonin and Nod-like receptor protein 3 (NLRP3) inflammasome. Sprague-Dawley rats were treated with morphine for 7 days and tail-flick latency test was performed to identify the induction of analgesic tolerance. The roles of TLR2 in microglia activation and morphine tolerance were assessed pharmacologically, and the possible interactions between melatonin, TLR2 and NLRP3 inflammasome were investigated. Morphine tolerance was accompanied by increased TLR2 expression and NLRP3 inflammasome activation in spinal cord. whereas melatonin level was down-regulated. Chronic melatonin administration resulted in a reduced TLR2 expression and NLRP3 inflammasome activation. Moreover, the analgesic effect of morphine was partially restored. Inhibition of TLR2 suppressed the microglia and NLRP3 inflammasome activation, as well as restored the spinal melatonin level while attenuated the development of morphine tolerance. Furthermore, the inhibition of microglia activation ameliorated morphine tolerance via inhibiting TLR2-NLRP3 inflammasome signaling in spinal cord. In this study, we directly demonstrate a TLR2-melatonin negative feedback loop regulating microglia and NLRP3 inflammasome activation during the development of morphine tolerance.

EFFECT OF MELATONIN ON THE LEVEL OF CYTOKINES IN PREECLAMPSIA

Introduction. The literature reports a decrease in melatonin levels in preeclampsia, when the degree of decrease correlates with the severity of the process, as well as a decrease in the expression of melatonin receptors in the placental tissue in case of fetal growth restriction.Regarding changes in the cytokine profile in PE: there is evidence that the levels of proinflammatory cytokines, namely TNF-α and IL-6, increase in preeclampsia, while the concentrations of anti-inflammatory cytokines, namely IL-4 and IL-10, decrease. Melatonin, on the contrary, reduces the secretion of proinflammatory cytokines, in particular TNF-α, and increases the production of anti-inflammatory cytokines, namely IL-10. Therefore, normalization of melatonin levels may be a promising direction in the treatment of PE in pregnant women.Objective of the study. Assess the pathogenetic mechanisms of complications arising from a decrease in melatonin, and, in particular, find out more about the changes in melatonin, IL-6 and IL-10, determine the correlation between them.Material and research methodsThe study conducted at the Department of Pregnancy Pathology of the Chernivtsi Regional Perinatal Center, involved 32 women whose pregnancy was complicated by preeclampsia. The control group consisted of 33 women with uncomplicated pregnancies observed in the antenatal clinic of the Chernivtsi Regional Perinatal Center.The patient's informed consent form and the patient's examination card were approved by the Biomedical Ethics Committee of Bukovinian State Medical University (BSMU) of the Ministry of Health of Ukraine (Chernivtsi). The work was guided by the general provisions of the Declaration of Helsinki "Recommendations for Physicians for Biomedical Research Involving Human Subjects" (1964), the World Medical Association on Ethical Principles for Scientific Medical Research Involving Human Subjects (1964-2000), considering the requirements of Directive 2001/20/EC of the European Parliament and of the Council, ICH GCP, the Council of Europe Convention on Human Rights and Biomedicine (04.04.1997), Order of the Ministry of Health of Ukraine No. 690 of 23.09.2009.Statistical data were calculated using MedCalc software developed by MedCalc Software (Ostend, Belgium). The results were evaluated using the Mann-Whitney U-test for small groups. The P value of &lt;0.05 was considered valid. Correlation and regression statistical evaluations were also performed using the aforementioned software.R&amp;D «Preservation and restoration of reproductive health of women and girls in obstetric and gynecological pathology». State registration number: 0121U110020. Terms of execution: 01.2021–12.2025 yy.Research results. The level of melatonin in venous blood taken from women with diagnosed PE was significantly lower (p=0.029), as well as levels of placental growth factor PlGF (p&lt;0.0001), compared to healthy women. In our study we also found that the concentrations of both proinflammatory IL-6 and anti-inflammatory IL-10 were elevated in women with PE compared to women with uncomplicated pregnancies. We performed a prognostic assessment of the impact of the biochemical parameters we studied on the outcome of pregnancies in the examined patients. Melatonin, if present in the blood of a pregnant woman in a concentration higher than the threshold values we established (6.71 pg/ml), reduces the chances of clinical manifestations of severe preeclampsia with a high degree of reliability (p=0.00173). We assume that placental dysfunction in particular leads to impaired synthesis of the antioxidant melatonin, which causes disorders in the tissues of the mother, placenta and fetus and, as a result, provokes clinical manifestations of preeclampsia. The condition of the placenta also worsens the subclinical inflammatory process, as evidenced by an increase in IL-6 levels in patients with diagnosed preeclampsia; an increase in IL-10 in the study group, in our opinion, is a kind of compensatory reaction that prevents preterm labour. In women with pregnancies complicated by preeclampsia, melatonin is a prognostic criterion for delivery before 38 weeks of gestation, and this delivery is mainly associated with the progression of preeclampsia to its severe stage. In the group of patients with uncomplicated pregnancy, proinflammatory interleukin-6 is predictive of spontaneous onset of labour before 38 weeks of gestation. Placental growth factor PlGF was a predictor of the birth of children with a body weight of less than 3000 g in both study groups.Conclusions. Concentrations of melatonin and of placental growth factor in venous blood in women whose pregnancy was complicated by preeclampsia in the third trimester of pregnancy are significantly lower compared to uncomplicated pregnancies. On the other hand, the levels of proinflammatory IL-6 and anti-inflammatory IL-10 were significantly increased in the group of patients with diagnosed preeclampsia compared with normal pregnancy.

The role of melatonin receptor 1B gene (MTNR1B) in the susceptibility to depression and type 2 diabetes comorbidity

The role of melatonin receptor 1B gene (MTNR1B) in the susceptibility to depression and type 2 diabetes comorbidity

Polarization of Melatonin-Modulated Colostrum Macrophages in the Presence of Breast Tumor Cell Lines.

Human colostrum and milk contain diverse cells and soluble components that have the potential to act against tumors. In breast cancer, macrophages play a significant role in immune infiltration and contribute to the progression and spread of tumors. However, studies suggest that these cells can be reprogrammed to act as an antitumor immune response. This study aimed to evaluate the levels of melatonin and its receptors, MT1 (melatonin receptor 1) and MT2 (melatonin receptor 2), in colostrum and assess the differentiation and polarization of the colostrum macrophages modulated by melatonin in the presence of breast tumor cells. Colostrum samples were collected from 116 mothers and tested for their melatonin and receptor levels. The colostrum cells were treated with or without melatonin and then cultured for 24 h in the presence or absence of breast tumor cells. The results showed that melatonin treatment increased the expression of MT1 and MT2 in the colostrum cells. Furthermore, melatonin treatment increased the percentage of M1 macrophages and decreased the percentage of M2 macrophages. When the colostrum macrophages were cocultured with breast tumor cells, melatonin reduced the percentage of both macrophage phenotypes and the cytokines tumor necrosis factor-alpha (TNF-α) and interleukin 8 (IL-8). These data suggest that melatonin can regulate the inflammatory process via M1 macrophages in the tumor microenvironment and, simultaneously, the progression of M2 macrophages that favor tumorigenesis.

Mitochondria-targeted melatonin photorelease supports the presence of melatonin MT1 receptors in mitochondria inhibiting respiration

The presence of signaling-competent G protein-coupled receptors in intracellular compartments is increasingly recognized. Recently, the presence of Gi/o protein-coupled melatonin MT1 receptors in mitochondria has been revealed, in addition to the plasma membrane. Melatonin is highly cell permeant, activating plasma membrane and mitochondrial receptors equally. Here, we present MCS-1145, a melatonin derivative bearing a triphenylphosphonium cation for specific mitochondrial targeting and a photocleavable o-nitrobenzyl group releasing melatonin upon illumination. MCS-1145 displayed low affinity for MT1 and MT2 but spontaneously accumulated in mitochondria, where it was resistant to washout. Uncaged MCS-1145 and exogenous melatonin recruited β-arrestin 2 to MT1 in mitochondria and inhibited oxygen consumption in mitochondria isolated from HEK293 cells only when expressing MT1 and from mouse cerebellum of WT mice but not from MT1-knockout mice. Overall, we developed the first mitochondria-targeted photoactivatable melatonin ligand and demonstrate that melatonin inhibits mitochondrial respiration through mitochondrial MT1 receptors.