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1.
Int J Mol Sci ; 25(16)2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39201396

RESUMO

Melatonin, noted for its anti-cancer properties in various malignancies, including cutaneous melanoma, shows promise in Uveal melanoma (UM) treatment. This study aimed to evaluate melatonin receptor expression in primary UM and its association with UM-related mortality and prognostic factors. Immunohistochemical analysis of 47 primary UM tissues showed low expression of melatonin receptor 1A (MTNR1A) and melatonin receptor 1B (MTNR1B), with MTNR1A significantly higher in patients who succumbed to UM. Analysis of TCGA data from 80 UM patients revealed RNA expression for MTNR1A, retinoic acid-related orphan receptor alpha (RORα), and N-ribosyldihydronicotinamide:quinone oxidoreductase (NQO2), but not MTNR1B or G protein-coupled receptor 50 (GPR50). Higher MTNR1A RNA levels were observed in patients with a BRCA1 Associated Protein 1 (BAP1) mutation, and higher NQO2 RNA levels were noted in patients with the epithelioid tumor cell type. However, Kaplan-Meier analysis did not show distinct survival probabilities based on receptor expression. This study concludes that UM clinical samples express melatonin receptors, suggesting a potential mechanism for melatonin's anti-cancer effects. Despite finding higher MTNR1A expression in patients who died of UM, no survival differences were observed.


Assuntos
Melanoma , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares , Receptor MT1 de Melatonina , Ubiquitina Tiolesterase , Neoplasias Uveais , Humanos , Neoplasias Uveais/metabolismo , Neoplasias Uveais/genética , Neoplasias Uveais/patologia , Neoplasias Uveais/mortalidade , Melanoma/metabolismo , Melanoma/genética , Melanoma/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Receptor MT1 de Melatonina/metabolismo , Receptor MT1 de Melatonina/genética , Idoso , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Ubiquitina Tiolesterase/metabolismo , Ubiquitina Tiolesterase/genética , Receptor MT2 de Melatonina/metabolismo , Receptor MT2 de Melatonina/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Prognóstico , Adulto , Idoso de 80 Anos ou mais , Mutação , Melatonina/metabolismo , Estimativa de Kaplan-Meier
2.
J Pineal Res ; 76(5): e13000, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39101387

RESUMO

Limited research has reported the association between MTNR1B gene polymorphisms and ischemic stroke (IS), and there is insufficient evidence on whether adopting a healthy lifestyle can mitigate genetic risks in this context. This study aimed to investigate the associations between MTNR1B gene variants (rs10830963 and rs1387153) and IS, examining the potential effect of gene-lifestyle interactions on IS risk. Conducted in northern China, this family-based cohort study involved 5116 initially IS-free subjects. Genotype data for rs10830963 and rs1387153 in MTNR1B were collected. Eight modifiable lifestyle factors, including body mass index (BMI), smoking, alcohol consumption, dietary habits, physical activity, sedentary time, sleep duration, and chronotype, were considered in calculating healthy lifestyle scores. Multilevel Cox models were used to examine the associations between MTNR1B variants and IS. Participants carrying the rs10830963-G and rs1387153-T alleles exhibited an elevated IS risk. Each additional rs10830963-G allele and rs1387153-T allele increased the IS risk by 36% (HR = 1.36, 95% CI, 1.12-1.65) and 32% (HR = 1.32, 95% CI, 1.09-1.60), respectively. Participants were stratified into low, medium, and high healthy lifestyle score groups (1537, 2188, and 1391 participants, respectively). Genetic-lifestyle interactions were observed for rs10830963 and rs1387153 (p for interaction < 0.001). Notably, as the healthy lifestyle score increased, the effect of MTNR1B gene variants on IS risk diminished (p for trend < 0.001). This study underscores the association between the MTNR1B gene and IS, emphasizing that adherence to a healthy lifestyle can mitigate the genetic predisposition to IS.


Assuntos
Estilo de Vida Saudável , AVC Isquêmico , Receptor MT2 de Melatonina , Humanos , Receptor MT2 de Melatonina/genética , Masculino , Feminino , Pessoa de Meia-Idade , China/epidemiologia , AVC Isquêmico/genética , AVC Isquêmico/epidemiologia , Estudos de Coortes , Polimorfismo de Nucleotídeo Único , Predisposição Genética para Doença , Adulto , Idoso
3.
Pharmacol Res ; 206: 107290, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38960012

RESUMO

The placenta, as a "transit station" between mother and fetus, has functions delivering nutrients, excreting metabolic wastes and secreting hormones. A healthy placenta is essential for fetal growth and development while the melatonergic system seems to play a critical physiological role in this organ since melatonin, its synthetic enzymes and receptors are present in the placenta. In current study, Mtnr1a and Mtnr1b knockout mice were constructed to explore the potential roles of melatonergic system played on the placental function and intrauterine growth retardation (IUGR). The result showed that Mtnr1a knockout had little effect on placental function while Mtnr1b knockout reduced placental efficiency and increased IUGR. Considering the extremely high incidence of IURG in sows, the pregnant sows were treated with melatonin. This treatment reduced the incidence of IUGR. All the evidence suggests that the intact melatonergic system in placenta is required for its function. Mechanistical studies uncovered that Mtnr1b knockout increased placental oxidative stress and apoptosis but reduced the angiogenesis. The RNA sequencing combined with histochemistry study identified the reduced angiogenesis and placental vascular density in Mtnr1b knockout mice. These alterations were mediated by the disrupted STAT3/VEGFR2/PI3K/AKT pathway, i.e., Mtnr1b knockout reduced the phosphorylation of STAT3 which is the promotor of VEGFR2. The downregulated VEGFR2 and its downstream elements of PI3K and AKT expressions, then, jeopardizes the angiogenesis and placental development.


Assuntos
Retardo do Crescimento Fetal , Melatonina , Camundongos Knockout , Neovascularização Fisiológica , Placenta , Receptor MT2 de Melatonina , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Animais , Feminino , Gravidez , Placenta/metabolismo , Placenta/irrigação sanguínea , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Melatonina/farmacologia , Receptor MT2 de Melatonina/genética , Receptor MT2 de Melatonina/metabolismo , Camundongos , Receptor MT1 de Melatonina/genética , Receptor MT1 de Melatonina/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Apoptose , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Suínos , Angiogênese
4.
Beijing Da Xue Xue Bao Yi Xue Ban ; 56(3): 375-383, 2024 Jun 18.
Artigo em Chinês | MEDLINE | ID: mdl-38864120

RESUMO

OBJECTIVE: To explore the effects of short-term particulate matter (PM) exposure and the melatonin receptor 1B (MTNR1B) gene on triglyceride-glucose (TyG) index utilizing data from Fang-shan Family-based Ischemic Stroke Study in China (FISSIC). METHODS: Probands and their relatives from 9 rural areas in Fangshan District, Beijing, were included in the study. PM data were obtained from fixed monitoring stations of the National Air Pollution Monitoring System. TyG index was calculated by fasting triglyceride and glucose concentrations. The associations of short-term PM exposure and rs10830963 polymorphism of the MTNR1B gene with the TyG index were assessed using mixed linear models, in which covariates such as age, sex, and lifestyles were adjusted for. Gene-environment inter-action analysis was furtherly performed using the maximum likelihood methods to explore the potential effect modifier role of rs10830963 polymorphism in the association of PM with TyG index. RESULTS: A total of 4 395 participants from 2 084 families were included in the study, and the mean age of the study participants was (58.98±8.68) years, with 53. 90% females. The results of association analyses showed that for every 10 µg/m3 increase in PM2.5 concentration, TyG index increased by 0.017 (95%CI: 0.007-0.027), while for per 10 µg/m3 increment in PM10, TyG index increased by 0.010 (95%CI: 0.003-0.017). And the associations all had lagged effects. In addition, there was a positive association between the rs10830963 polymorphism and the TyG index. For per increase in risk allele G, TyG index was elevated by 0.040 (95%CI: 0.004-0.076). The TyG index was 0.079 (95%CI: 0.005-0.152) higher in carriers of the GG genotype compared with carriers of the CC genotype. The interaction of rs10830963 polymorphism with PM exposure had not been found to be statistically significant in the present study. CONCLUSION: Short-term exposure to PM2.5 and PM10 were associated with higher TyG index. The G allele of rs10830963 polymorphism in the MTNR1B gene was associated with the elevated TyG index.


Assuntos
Material Particulado , Receptor MT2 de Melatonina , Triglicerídeos , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Receptor MT2 de Melatonina/genética , Triglicerídeos/sangue , Glicemia , Exposição Ambiental/efeitos adversos , Poluentes Atmosféricos , Interação Gene-Ambiente , China , Polimorfismo de Nucleotídeo Único , AVC Isquêmico/genética , AVC Isquêmico/sangue , Genótipo , Poluição do Ar/efeitos adversos
5.
Int J Biol Sci ; 20(7): 2491-2506, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38725850

RESUMO

Colon inflammation is characterized by disturbances in the intestinal microbiota and inflammation. Melatonin (Mel) can improve colon inflammation. However, the underlying mechanism remains unclear. Recent studies suggest that m6A methylation modification may play an important role in inflammatory responses. This study aimed to explore the effects of melatonin and LPS-mediated m6A methylation on colon inflammation. Our study found that melatonin inhibits M1 macrophages, activates M2 macrophages, inhibit the secretion of pro-inflammatory factors, maintain colon homeostasis and improves colon inflammation through MTNR1B. In addition, the increased methylation level of m6A is associated with the occurrence of colon inflammation, and melatonin can also reduce the level of colon methylation to improve colon inflammation. Among them, the main methylated protein METTL3 can be inhibited by melatonin through MTNR1B. In a word, melatonin regulates m6A methylation by improving abnormal METTL3 protein level to reshape the microflora and activate macrophages to improve colon inflammation, mainly through MTNR1B.


Assuntos
Adenosina , Lipopolissacarídeos , Macrófagos , Melatonina , Melatonina/farmacologia , Melatonina/metabolismo , Animais , Camundongos , Adenosina/metabolismo , Adenosina/análogos & derivados , Adenosina/farmacologia , Metilação/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Metiltransferases/metabolismo , Metiltransferases/genética , Inflamação/metabolismo , Colo/metabolismo , Colo/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Colite/induzido quimicamente , Colite/metabolismo , Receptor MT2 de Melatonina/metabolismo , Receptor MT2 de Melatonina/genética , Células RAW 264.7
6.
Theriogenology ; 225: 98-106, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38801791

RESUMO

Goat bucks are seasonal breeders that show variation in sperm quality, endogenous melatonin (MLT), and presumably in the expression of MLT receptors on the sperm throughout the year, which may modify sperm freezability. The aim of this study was to determine whether sperm freezability is associated with (i) endogenous melatonin levels in seminal plasma and (ii) the expression of sperm plasma membrane melatonin receptors (MT1, MT2). To evaluate this, spermatozoa from seven Saanen goat bucks were cryopreserved throughout the year in Mexico using a standard freezing protocol. Seminal plasma MLT concentrations were determined by ELISA and the expression and localization of MT1 and MT2 were detected by immunocytochemistry and confirmed by western blotting. The recovery rate of progressive motility after thawing was higher in spring than autumn and winter; in contrast, the F pattern (CTC assay) was higher in winter than in the other seasons. A proportional increase in the AR pattern (CTC assay) was smaller in winter than in the other seasons and the proportion of sperm showing high plasma membrane fluidity was higher in spring than in summer and autumn. The seminal plasma MLT concentrations showed no significant interseasonal differences. The MT1 receptor was immunolocalised at the apical region of the sperm head, while MT2 was mainly localised in the neck. The relative expression of MLT receptors showed significant differences between summer and winter for all bands, except at 75 kDa of MT2. In conclusion, there was an association between the relative expression of MT1 and MT2 receptors throughout the year and sperm freezability in goat bucks in México. Post-thaw sperm quality is enhanced in semen samples collected during breeding season.


Assuntos
Criopreservação , Cabras , Melatonina , Estações do Ano , Preservação do Sêmen , Sêmen , Espermatozoides , Animais , Masculino , Melatonina/metabolismo , Melatonina/sangue , Cabras/fisiologia , Cabras/metabolismo , Sêmen/química , Sêmen/metabolismo , Espermatozoides/metabolismo , Espermatozoides/fisiologia , Preservação do Sêmen/veterinária , Criopreservação/veterinária , Receptor MT1 de Melatonina/metabolismo , Receptor MT1 de Melatonina/genética , Receptor MT2 de Melatonina/metabolismo , Receptor MT2 de Melatonina/genética , Análise do Sêmen/veterinária , Receptores de Melatonina/metabolismo
7.
J Pineal Res ; 76(3): e12955, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38606787

RESUMO

Identifying the target cells of a hormone is a key step in understanding its function. Once the molecular nature of the receptors for a hormone has been established, researchers can use several techniques to detect these receptors. Here I will review the different tools used over the years to localize melatonin receptors and the problems associated with each of these techniques. The radioligand 2-[125I] iodomelatonin was the first tool to allow localization of melatonin receptors on tissue sections. Once the MT1 and MT2 receptors were cloned, in situ hybridization could be used to detect the messenger RNA for these receptors. The deduced amino acid sequences for MT1 and MT2 receptors allowed the production of peptide immunogens to generate antibodies against the MT1 and MT2 receptors. Finally, transgenic reporters driven by the promoter elements of the MT1 and MT2 genes have been used to map the expression of MT1 and MT2 in the brain and the retina. Several issues have complicated the localization of melatonin receptors and the characterization of melatonin target cells over the last three decades. Melatonin receptors are expressed at low levels, leading to sensitivity issues for their detection. The second problem are specificity issues with antibodies directed against the MT1 and MT2 melatonin receptors. These receptors are G protein-coupled receptors and many antibodies directed against such receptors have been shown to present similar problems concerning their specificity. Despite these specificity problems which start to be seriously addressed by recent studies, antibodies will be important tools in the future to identify and phenotype melatonin target cells. However, we will have to be more stringent than previously when establishing their specificity. The results obtained by these antibodies will have to be confronted and be coherent with results obtained by other techniques.


Assuntos
Encéfalo , Receptor MT1 de Melatonina , Receptor MT2 de Melatonina , Sequência de Aminoácidos , Encéfalo/metabolismo , Melatonina/metabolismo , Receptor MT1 de Melatonina/genética , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/genética , Receptor MT2 de Melatonina/metabolismo
8.
Clin Lab ; 70(1)2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38213225

RESUMO

BACKGROUND: Disrupted circadian rhythm has been linked to the pathogenesis of type 2 diabetes mellitus (T2DM). Single nucleotide polymorphisms (SNPs) in melatonin receptors (MTNR), MTNR 1A rs2119882 (T>C) and MTNR 1B rs10830963 (C>G) may interfere with the normal function of melatonin and increase the risk of T2DM. This study investigated the prevalence of MTNR 1A rs2119882 (T>C) and MTNR 1B rs10830963 (C>G) SNPs and tested their association with T2DM in Saudi Arabian population. METHODS: A total of 459 Saudi Arabian participants from Jazan Province, Saudi Arabia, were selected and included 227 T2DM patients and 232 control subjects. DNA was extracted from all participants and genotyped for rs2119882 and rs10830963 SNPs using TaqMan technology. Genotype frequencies were determined for both SNPs, and logistic regression was fitted to test the association with T2DM. RESULTS: No association was found between MTNR 1A rs2119882 (T>C) SNP and T2DM (odds ratio (OR) = 0.69; 95% confidence interval (CI) = 0.44 - 1.08; p-value = 0.111). However, the MTNR 1B rs10830963 (C>G) SNP was significantly associated with T2DM (OR = 1.73; 95% CI = 1.18 - 2.55; p-value = 0.0065). Co-inheritance of the MTNR 1B rs10830963 G allele and MTNR 1A rs2119882 T allele further increased the risk of T2DM (OR = 2.80; 95% CI = 1.71 - 4.57; p-value < 0.0001). CONCLUSIONS: The minor G allele of the MTNR 1B rs10830963 SNP was significantly associated with T2DM in our population. This association further intensified with the presence of the T allele in MTNR 1A rs2119882 locus. This study sheds light on the importance of melatonin receptor polymorphisms as genetic candidates for the development of T2DM in Saudi Arabia.


Assuntos
Diabetes Mellitus Tipo 2 , Humanos , Arábia Saudita/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Receptor MT2 de Melatonina/genética , Genótipo , Polimorfismo de Nucleotídeo Único , Predisposição Genética para Doença/genética
9.
Int J Mol Sci ; 25(2)2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38255808

RESUMO

Pregnancy is a highly intricate and delicate process, where inflammation during early stages may lead to pregnancy loss or defective implantation. Melatonin, primarily produced by the pineal gland, exerts several pharmacological effects. N6-methyladenosine (m6A) is the most prevalent mRNA modification in eukaryotes. This study aimed to investigate the association between melatonin and m6A during pregnancy and elucidate the underlying protective mechanism of melatonin. Melatonin was found to alleviate lipopolysaccharide (LPS)-induced reductions in the number of implantation sites. Additionally, it mitigated the activation of inflammation, autophagy, and apoptosis pathways, thereby protecting the pregnancy process in mice. The study also revealed that melatonin regulates uterine m6A methylation levels and counteracts abnormal changes in m6A modification of various genes following LPS stimulation. Furthermore, melatonin was shown to regulate m6A methylation through melatonin receptor 1B (MTNR1B) and subsequently modulate inflammation, autophagy, and apoptosis through m6A. In conclusion, our study demonstrates that melatonin protects pregnancy by influencing inflammation, autophagy, and apoptosis pathways in an m6A-dependent manner via MTNR1B. These findings provide valuable insights into the mechanisms underlying melatonin's protective effects during pregnancy and may have implications for potential therapeutic strategies in managing pregnancy-related complications.


Assuntos
Aborto Espontâneo , Adenina , Melatonina , Animais , Feminino , Camundongos , Gravidez , Adenina/análogos & derivados , Inflamação , Lipopolissacarídeos/toxicidade , Melatonina/farmacologia , Melatonina/uso terapêutico , Receptor MT2 de Melatonina/genética
10.
Gene ; 894: 148023, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38007162

RESUMO

AIM: To investigate the association of melatonin receptor 1B (MTNR1B) gene variations and pre-pregnancy body mass index (BMI) with gestational diabetes mellitus (GDM). MATERIALS AND METHOD: In this study, 1566 Chinese Han pregnant women were enrolled and multiple genetic models were used to evaluate the association between MTNR1B gene polymorphisms and the risk of GDM. The clinical value of pre-pregnancy BMI in predicting GDM was analyzed and evaluated using receiver operating characteristic (ROC) curves. Several methods of analysis were used to examine the impact of gene-gene and gene-BMI interactions on the incidence of GDM influence. RESULTS: For the MTNR1B gene, rs1387153 (C > T), rs10830962 (C > G), rs4753426 (T > C), and rs10830963 (C > G) are all risk mutations associated with the susceptibility of GDM. The ROC curve analysis indicated that the BMI demonstrated an area under the curve (AUC) of 0.595. Alongside, the sensitivity and specificity stood at 0.676 and 0.474 respectively. The maximum Joden index was found to be 0.150, with a corresponding critical BMI value of 20.5691 kg/m2. Interaction analysis revealed that gene-gene and gene-BMI interactions had no significant effect on GDM occurrence. CONCLUSION: MTNR1B genetic variations confers the risk to GDM in Chinese women. Furthermore, the high pre-pregnancy BMI (≥20.5691 kg/m2) significantly increases the risk of GDM in Chinese women.


Assuntos
Diabetes Gestacional , Gravidez , Feminino , Humanos , Diabetes Gestacional/genética , Índice de Massa Corporal , Genótipo , Polimorfismo de Nucleotídeo Único , Receptor MT2 de Melatonina/genética , China
11.
Diabetologia ; 67(3): 506-515, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38052941

RESUMO

AIMS/HYPOTHESIS: A type 2 diabetes-risk-increasing variant, MTNR1B (melatonin receptor 1B) rs10830963, regulates the circadian function and may influence the variability in metabolic responses to dietary carbohydrates. We investigated whether the effects of carbohydrate quantity and dietary glycaemic index (GI) on glycaemic response during OGTTs varied by the risk G allele of MTNR1B-rs10830963. METHODS: This study included participants (n=150) of a randomised crossover-controlled feeding trial of four diets with high/low GI levels and high/low carbohydrate content for 5 weeks. The MTNR1B-rs10830963 (C/G) variant was genotyped. Glucose response during 2 h OGTT was measured at baseline and the end of each diet intervention. RESULTS: Among the four study diets, carrying the risk G allele (CG/GG vs CC genotype) of MTNR1B-rs10830963 was associated with the largest AUC of glucose during 2 h OGTT after consuming a high-carbohydrate/high-GI diet (ß 134.32 [SE 45.69] mmol/l × min; p=0.004). The risk G-allele carriers showed greater increment of glucose during 0-60 min (ß 1.26 [0.47] mmol/l; p=0.008) or 0-90 min (ß 1.10 [0.50] mmol/l; p=0.028) after the high-carbohydrate/high-GI diet intervention, but not after consuming the other three diets. At high carbohydrate content, reducing GI levels decreased 60 min post-OGTT glucose (mean -0.67 [95% CI: -1.18, -0.17] mmol/l) and the increment of glucose during 0-60 min (mean -1.00 [95% CI: -1.67, -0.33] mmol/l) and 0-90 min, particularly in the risk G-allele carriers (pinteraction <0.05 for all). CONCLUSIONS/INTERPRETATION: Our study shows that carrying the risk G allele of MTNR1B-rs10830963 is associated with greater glycaemic responses after consuming a diet with high carbohydrates and high GI levels. Reducing GI in a high-carbohydrate diet may decrease post-OGTT glucose concentrations among the risk G-allele carriers.


Assuntos
Diabetes Mellitus Tipo 2 , Índice Glicêmico , Humanos , Glucose , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dieta , Genótipo , Receptor MT2 de Melatonina/genética , Carboidratos da Dieta
12.
Pharmacol Res ; 198: 106993, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37972722

RESUMO

The treatment of bipolar disorder (BD) still remains a challenge. Melatonin (MLT), acting through its two receptors MT1 and MT2, plays a key role in regulating circadian rhythms which are dysfunctional in BD. Using a translational approach, we examined the implication and potential of MT1 receptors in the pathophysiology and psychopharmacology of BD. We employed a murine model of the manic phase of BD (Clock mutant (ClockΔ19) mice) to study the activation of MT1 receptors by UCM871, a selective partial agonist, in behavioral pharmacology tests and in-vivo electrophysiology. We then performed a high-resolution Nuclear Magnetic Resonance study on isolated membranes to characterize the molecular mechanism of interaction of UCM871. Finally, in a cohort of BD patients, we investigated the link between clinical measures of BD and genetic variants located in the MT1 receptor and CLOCK genes. We demonstrated that: 1) UCM871 can revert behavioral and electrophysiological abnormalities of ClockΔ19 mice; 2) UCM871 promotes the activation state of MT1 receptors; 3) there is a significant association between the number of severe manic episodes and MLT levels, depending on the genetic configuration of the MT1 rs2165666 variant. Overall, this work lends support to the potentiality of MT1 receptors as target for the treatment of BD.


Assuntos
Transtorno Bipolar , Melatonina , Psicofarmacologia , Humanos , Camundongos , Animais , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Melatonina/uso terapêutico , Melatonina/farmacologia , Receptor MT1 de Melatonina/genética , Receptor MT2 de Melatonina/genética , Receptor MT2 de Melatonina/agonistas
13.
Public Health Genomics ; 26(1): 201-211, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37980891

RESUMO

BACKGROUND: Published data on the association between the MTNR1B rs1387153 polymorphism and gestational diabetes mellitus (GDM) risk are controversial. OBJECTIVE: A meta-analysis was performed to assess whether the polymorphism of MTNR1B rs1387153 is associated with GDM risk. METHOD: Medline, Embase, China National Knowledge Infrastructure, and Chinese Biomedicine Databases were searched to identify eligible studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for MTNR1B rs1387153 polymorphism and GDM were appropriately derived from fixed-effects or random effects models. RESULTS: A total of 8 studies were enrolled in this meta-analysis. The pooled analyses revealed that MTNR1B rs1387153 polymorphism significantly increased the risk of GDM in all models (allele contrast (C vs. T): OR, 0.78; 95% CI, 0.73-0.83; homozygote (CC vs. TT): OR, 0.61; 95% CI, 0.53-0.69; heterozygote (CT vs. TT): OR, 0.78; 95% CI, 0.69-0.89; dominant model (CC + CT vs. TT): OR, 0.71; 95% CI, 0.63-0.80; recessive model (CC vs. CT + TT): OR, 0.73; 95% CI, 0.67-0.81). Further subgroup analyses by ethnicity of participants yielded similar positive results. CONCLUSIONS: Present meta-analysis reveals that MTNR1B rs1387153 variant may serve as genetic biomarkers of GDM.


Assuntos
Diabetes Gestacional , Gravidez , Feminino , Humanos , Diabetes Gestacional/genética , Predisposição Genética para Doença , Polimorfismo Genético , Alelos , Homozigoto , Polimorfismo de Nucleotídeo Único , Receptor MT2 de Melatonina/genética
14.
J Pak Med Assoc ; 73(11): 2209-2213, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38013530

RESUMO

Objective: To assess the association of oxytocin receptor (rs53576) and melatonin hormone receptor 1B (rs1387153) gene single nucleotide polymorphisms with psychological symptoms in women with gestational diabetes mellitus. METHODS: The case-control study was conducted from May 1 to June 1, 2022, at the Department of Physiology, University of Karachi, in collaboration with the Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, and the Department of Obstetrics and Gynaecology, Jinnah Postgraduate Medical Centre, Karachi. Fifty gestational diabetic pregnant women and ninety healthy pregnant women were recruited. Sanger sequencing was performed to assess the genotypic frequency and polymorphic variation of all subjects. Perceived stress scale and diabetes-related distress scale were used to assess the stress levels. Data was analysed using SPSS 23. RESULTS: Of the 140 subjects, 90 (64.3%) were controls with mean age 24.96±4.35 years, and 50 (35.7%) were cases with mean age 28.78±5.25 (p<0.05). Mean body weight and mean gestational age were not significantly different between the groups (p>0.05). Melatonin hormone receptor 1B rs1387153 frequency was significantly different between the groups (p<0.05). Among the cases, a significant mean difference for regimen distress scores between AA and GG was observed for oxytocin receptor rs53576 (p=0.04). A significant mean difference in sum of PSS, diabetes-related stress, total diabetes- related stress and emotional distress was noted between CC and TT genotypes for melatonin hormone receptor 1B rs1387153 (p=0.001). Conclusion: MTNR1B rs1387153 genotypes were associated with perceived stress, diabetes-related stress, diabetic distress, and emotional burden, while OXTR rs53576 genotypes were associated with regimen distress in GDM women.


Assuntos
Diabetes Gestacional , Melatonina , Feminino , Gravidez , Humanos , Adulto Jovem , Adulto , Diabetes Gestacional/genética , Estudos de Casos e Controles , Receptores de Ocitocina/genética , Polimorfismo de Nucleotídeo Único , Genótipo , Estresse Psicológico/genética , Receptor MT2 de Melatonina/genética
15.
Int J Mol Sci ; 24(14)2023 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-37511203

RESUMO

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.


Assuntos
Diabetes Mellitus Tipo 2 , Infarto do Miocárdio , Receptor MT2 de Melatonina , Feminino , Humanos , Masculino , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Genótipo , Infarto do Miocárdio/genética , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Receptor MT2 de Melatonina/genética , Fatores de Risco
16.
BMC Genomics ; 24(1): 232, 2023 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-37138267

RESUMO

BACKGROUND: The purpose of this study is to investigate the association of rotating night shift work, CLOCK, MTNR1A, MTNR1B genes polymorphisms and their interactions with type 2 diabetes among steelworkers. METHODS: A case-control study was conducted in the Tangsteel company in Tangshan, China. The sample sizes of the case group and control group were 251 and 451, respectively. The logistic regression, log-linear model and generalized multifactor dimensionality (GMDR) method were used to investigate the interaction between circadian clock gene, melatonin receptor genes and rotating night shift work on type 2 diabetes among steelworkers. Relative excess risk due to interaction (RERI) and attributable proportions (AP) were used to evaluate additive interactions. RESULTS: Rotating night shift work, current shift status, duration of night shifts, and average frequency of night shifts were associated with an increased risk of type 2 diabetes after adjustment for confounders. Rs1387153 variants in MTNR1B was found to be associated with an increased risk of type 2 diabetes, which was not found between MTNR1A gene rs2119882 locus, CLOCK gene rs1801260 locus and the risk of type 2 diabetes. The association between rotating night shift work and risk of type 2 diabetes appeared to be modified by MTNR1B gene rs1387153 locus (RERI = 0.98, (95% CI, 0.40-1.55); AP = 0.60, (95% CI, 0.07-1.12)). The interaction between MTNR1A gene rs2119882 locus and CLOCK gene rs1801260 locus was associated with the risk of type 2 diabetes (RERI = 1.07, (95% CI, 0.23-1.91); AP = 0.77, (95% CI, 0.36-1.17)). The complex interaction of the MTNR1A-MTNR1B-CLOCK-rotating night shift work model based on the GMDR methods may increase the risk of type 2 diabetes (P = 0.011). CONCLUSIONS: Rotating night shift work and rs1387153 variants in MTNR1B were associated with an increased risk of type 2 diabetes among steelworkers. The complex interaction of MTNR1A-MTNR1B-CLOCK-rotating night shift work may increase the risk of type 2 diabetes.


Assuntos
Relógios Circadianos , Diabetes Mellitus Tipo 2 , Jornada de Trabalho em Turnos , Humanos , Estudos de Casos e Controles , Relógios Circadianos/genética , Ritmo Circadiano/genética , Diabetes Mellitus Tipo 2/genética , Polimorfismo Genético , Receptor MT1 de Melatonina/genética , Receptor MT2 de Melatonina/genética , Jornada de Trabalho em Turnos/efeitos adversos
17.
Int J Mol Sci ; 24(8)2023 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-37108290

RESUMO

In the current study, using Aanat and Mt2 KO mice, we observed that the preservation of the melatonergic system is essential for successful early pregnancy in mice. We identified that aralkylamine N-acetyltransferase (AANAT), melatonin receptor 1A (MT1), and melatonin receptor 1B (MT2) were all expressed in the uterus. Due to the relatively weak expression of MT1 compared to AANAT and MT2, this study focused on AANAT and MT2. Aanat and Mt2 KO significantly reduced the early implantation sites and the abnormal morphology of the endometrium of the uterus. Mechanistical analysis indicated that the melatonergic system is the key player in the induction of the normal nidatory estrogen (E2) response for endometrial receptivity and functions by activating the STAT signaling pathway. Its deficiency impaired the interactions between the endometrium, the placenta, and the embryo. The reduction in melatonin production caused by Aanat KO and the impairment of signal transduction caused by Mt2 KO reduced the uterine MMP-2 and MMP-9 activity, resulting in a hyperproliferative endometrial epithelium. In addition, melatonergic system deficiency also increased the local immunoinflammatory reaction with elevated local proinflammatory cytokines leading to early abortion in the Mt2 KO mice compared to the WT mice. We believe that the novel data obtained from the mice might apply to other animals including humans. Further investigation into the interaction between the melatonergic system and reproductive effects in different species would be worthwhile.


Assuntos
Arilalquilamina N-Acetiltransferase , Receptor MT2 de Melatonina , Animais , Feminino , Humanos , Camundongos , Gravidez , Acetiltransferases/metabolismo , Arilalquilamina N-Acetiltransferase/genética , Arilalquilamina N-Acetiltransferase/metabolismo , Endométrio/metabolismo , Melatonina/farmacologia , Receptor MT1 de Melatonina/genética , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/genética , Receptor MT2 de Melatonina/metabolismo , Útero/metabolismo
18.
Nutrients ; 15(8)2023 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-37111205

RESUMO

Type 2 diabetes is associated with both dietary iron intake and single-nucleotide polymorphism (SNP) of intronic rs10830963 in melatonin receptor 1B (MTNR1B); however, it is unclear whether they interact. The aim of this study was to examine the associations between dietary iron intake, SNP of rs10830963, and glucose metabolism. Data were obtained from the Shanghai Diet and Health Survey (SDHS) during 2012-2018. Standardized questionnaires were carried out through face-to-face interviews. A 3-day 24 h dietary recall was used to evaluate dietary iron intake. Anthropometric and laboratory measurements were applied. Logistic regression and general line models were used to evaluate the association between dietary iron intake, SNP of the MTNR1B rs10830963, and glucose metabolism. In total, 2951 participants were included in this study. After adjusting for age, sex, region, years of education, physical activity level, intentional physical exercise, smoking status, alcohol use, and total energy, among G allele carriers, dietary iron intake was associated with a risk of elevated fasting glucose, higher fasting glucose, and higher HbA1c, while no significant results were observed among G allele non-carriers. The G allele of intronic rs10830963 in MTNR1B potentially exacerbated unfavorable glucose metabolism with the increasing dietary iron intake, and it was possibly a risk for glucose metabolism homeostasis in the Chinese population.


Assuntos
Diabetes Mellitus Tipo 2 , Polimorfismo de Nucleotídeo Único , Humanos , Ferro da Dieta , Diabetes Mellitus Tipo 2/metabolismo , Glicemia/metabolismo , Ferro , População do Leste Asiático , Receptor MT2 de Melatonina/genética , China , Jejum
19.
Nutrients ; 15(6)2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36986139

RESUMO

Night-shift work and sleep disorders are associated with type 2 diabetes (T2DM), and circadian rhythm disruption is intrinsically involved. Studies have identified several signaling pathways that separately link two melatonin receptors (MT1 and MT2) to insulin secretion and T2DM occurrence, but a comprehensive explanation of the molecular mechanism to elucidate the association between these receptors to T2DM, reasonably and precisely, has been lacking. This review thoroughly explicates the signaling system, which consists of four important pathways, linking melatonin receptors MT1 or MT2 to insulin secretion. Then, the association of the circadian rhythm with MTNR1B transcription is extensively expounded. Finally, a concrete molecular and evolutionary mechanism underlying the macroscopic association between the circadian rhythm and T2DM is established. This review provides new insights into the pathology, treatment, and prevention of T2DM.


Assuntos
Diabetes Mellitus Tipo 2 , Melatonina , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Receptor MT2 de Melatonina/genética , Receptor MT2 de Melatonina/metabolismo , Melatonina/metabolismo , Ritmo Circadiano , Secreção de Insulina
20.
Ann Med ; 55(1): 1262-1286, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-36974476

RESUMO

Disturbed circadian rhythms have been a risk factor for type 2 diabetes mellitus (T2DM). Melatonin is the major chronobiotic hormone regulating both circadian rhythm and glucose homeostasis. The rs10830963 (G allele) of the melatonin receptor 1B (MTNR1B) gene has the strongest genetic associations with T2DM according to several genome-wide association studies. The MTNR1B rs10830963 G allele is also associated with disturbed circadian phenotypes and altered melatonin secretion, both factors that can elevate the risk of diabetes. Furthermore, evolutionary studies implied the presence of selection pressure and ethnic diversity in MTNR1B, which was consistent with the "thrifty gene" hypothesis in T2DM. The rs10830963 G risk allele is associated with delayed melatonin secretion onset in dim-light and prolonged duration of peak melatonin. This delayed melatonin secretion may help human ancestors adapt to famine or food shortages during long nights and early mornings and avoid nocturnal hypoglycemia but confers susceptibility to T2DM due to adequate energy intake in modern society. We provide new insight into the role of MTNR1B variants in T2DM via disturbed circadian rhythms from the perspective of the "thrifty gene" hypothesis; these data indicate a novel target for the prevention and treatment of susceptible populations with the thrifty genotype.


Assuntos
Ritmo Circadiano , Diabetes Mellitus Tipo 2 , Melatonina , Receptor MT2 de Melatonina , Humanos , Glicemia/genética , Ritmo Circadiano/genética , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Receptor MT2 de Melatonina/genética
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