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1.
Molecules ; 27(14)2022 Jul 07.
Artículo en Inglés | MEDLINE | ID: mdl-35889222

RESUMEN

Ovarian cancer (OC) is the most lethal gynecologic malignancy, and melatonin has shown various antitumor properties. Herein, we investigated the influence of melatonin therapy on energy metabolism and mitochondrial integrity in SKOV-3 cells and tested whether its effects depended on MT1 receptor activation. SKOV-3 cells were exposed to different melatonin concentrations, and experimental groups were divided as to the presence of MT1 receptors (melatonin groups) or receptor absence by RNAi silencing (siRNA MT1+melatonin). Intracellular melatonin levels increased after treatment with melatonin independent of the MT1. The mitochondrial membrane potential of SKOV-3 cells decreased in the group treated with the highest melatonin concentration. Melatonin reduced cellular glucose consumption, while MT1 knockdown increased its consumption. Interconversion of lactate to pyruvate increased after treatment with melatonin and was remarkable in siRNA MT1 groups. Moreover, lactate dehydrogenase activity decreased with melatonin and increased after MT1 silencing at all concentrations. The UCSC XenaBrowser tool showed a positive correlation between the human ASMTL gene and the ATP synthase genes, succinate dehydrogenase gene (SDHD), and pyruvate dehydrogenase genes (PDHA and PDHB). We conclude that melatonin changes the glycolytic phenotype and mitochondrial integrity of SKOV-3 cells independent of the MT1 receptor, thus decreasing the survival advantage of OC cells.


Asunto(s)
Melatonina , Neoplasias Ováricas , Receptor de Melatonina MT1 , Carcinoma Epitelial de Ovario , Femenino , Humanos , Melatonina/metabolismo , Melatonina/farmacología , Potencial de la Membrana Mitocondrial , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Piruvatos , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Receptor de Melatonina MT1/genética , Receptor de Melatonina MT1/metabolismo
2.
J Mol Med (Berl) ; 99(2): 289-301, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33392634

RESUMEN

Primary brain tumors remain among the deadliest of all cancers. Glioma grade IV (glioblastoma), the most common and malignant type of brain cancer, is associated with a 5-year survival rate of < 5%. Melatonin has been widely reported as an anticancer molecule, and we have recently demonstrated that the ability of gliomas to synthesize and accumulate this indolamine in the surrounding microenvironment negatively correlates with tumor malignancy. However, our understanding of the specific effects mediated through the activation of melatonin membrane receptors remains limited. Thus, here we investigated the specific roles of MT1 and MT2 in gliomas and medulloblastomas. Using the MT2 antagonist DH97, we showed that MT1 activation has a negative impact on the proliferation of human glioma and medulloblastoma cell lines, while MT2 activation has an opposite effect. Accordingly, gliomas have a decreased mRNA expression of MT1 (also known as MTNR1A) and an increased mRNA expression of MT2 (also known as MTNR1B) compared to the normal brain cortex. The MT1/MT2 expression ratio negatively correlates with the expression of cell cycle-related genes and is a positive prognostic factor in gliomas. Notably, we showed that functional selective drugs that simultaneously activate MT1 and inhibit MT2 exert robust anti-tumor effects in vitro and in vivo, downregulating the expression of cell cycle and energy metabolism genes in glioma stem-like cells. Overall, we provided the first evidence regarding the differential roles of MT1 and MT2 in brain tumor progression, highlighting their relevance as druggable targets. KEY MESSAGES: • MT1 impairs while MT2 promotes the proliferation of glioma and medulloblastoma cell lines. • Gliomas have a decreased expression of MT1 and an increased expression of MT2 compared to normal brain cortex. • Tumors with a high MT1/MT2 expression ratio have significantly better survival rates. • Functional selective drugs that simultaneously activate MT1 and inhibit MT2 downregulate the expression of cell cycle and energy metabolism genes in glioma stem-like cells and exert robust anti-tumor effects in vivo.


Asunto(s)
Neoplasias Encefálicas , Glioma , Receptor de Melatonina MT1 , Receptor de Melatonina MT2 , Animales , Encéfalo/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Femenino , Glioma/genética , Glioma/metabolismo , Glioma/mortalidad , Glioma/patología , Humanos , Estimación de Kaplan-Meier , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Receptor de Melatonina MT1/genética , Receptor de Melatonina MT1/metabolismo , Receptor de Melatonina MT2/genética , Receptor de Melatonina MT2/metabolismo
3.
Trop Anim Health Prod ; 52(5): 2549-2557, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32445158

RESUMEN

In mammals, many melatonin biological functions are mediated through its interaction with the membrane receptors MT1 and MT2. We have previously reported their presence in ram spermatozoa from males located in temperate climates, but there is no information on their presence in spermatozoa from rams in areas with an equatorial photoperiod (12L:12D). Thus, we have investigated the existence and cellular distribution of melatonin receptors in spermatozoa from three sheep breeds in Colombia (Colombian Creole, Hampshire, and Romney Marsh) during dry and rainy seasons, using indirect immunofluorescence and western blot. Our results indicated the presence of melatonin receptors in spermatozoa from these rams, and that their distribution differs from that previously found in spermatozoa from rams in temperate climates. Moreover, two new immunotypes of MT2 were identified: type N, with staining only in the neck, and type E with a band of immunofluorescence in the upper part of the post-acrosome and the apical edge. Likewise, differences between breeds and climate seasons were detected for both receptors. However, densitometry analysis of western blot bands only revealed differences between seasons in the Creole rams for MT1 and the Romney Marsh rams for MT2, whereas differences between breeds were only detected for MT2. It could be inferred that melatonin receptors in rams subjected to an equatorial photoperiod might be more closely related to sperm quality than seasonal control. Therefore, the presence of these receptors suggests that melatonin could be a useful tool to increase the fertility of rams located in tropical or equatorial climates.


Asunto(s)
Receptor de Melatonina MT1/metabolismo , Receptor de Melatonina MT2/metabolismo , Ovinos/fisiología , Animales , Regulación de la Expresión Génica/fisiología , Masculino , Melatonina/fisiología , Fotoperiodo , Receptor de Melatonina MT1/genética , Receptor de Melatonina MT2/genética , Estaciones del Año , Espermatozoides
4.
Brain Res ; 1692: 1-8, 2018 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-29702086

RESUMEN

Melatonin, a powerful antioxidant, participates in the regulation of important physiological and pathological processes. We investigated the actions of melatonin on neuronal excitability of intact dorsal root ganglions (DRG) from rats using intracellular recording techniques in current clamps. Melatonin blocked the generation of action potentials in a concentration-dependent manner. Bath applied melatonin (1.0-1000.0 nM) hyperpolarized the resting membrane potential, and increased the input resistance and rheobase. Melatonin also altered the active electrophysiological properties of the action potential, amplitude and maximum descendant inclination, in a statistically significant way. In order to provide evidence on the mechanism of action of melatonin in the DRG, quantitative PCR (qPCR) was performed. Analyses were performed for melatonin membrane receptors, MT1 and MT2, and it was observed that the DRG expresses MT1 receptors. In addition, we noted that the melatonin-induced effects were blocked in the presence of luzindole, a melatonin receptor antagonist. The minimal effective concentrations of melatonin (10.0 nM) and the blockade of effects caused by luzindole suggest that the effects of melatonin are hormonal, and are induced when it binds to MT1 receptors.


Asunto(s)
Antioxidantes/farmacología , Ganglios Espinales/citología , Melatonina/farmacología , Potenciales de la Membrana/efectos de los fármacos , Neuronas/efectos de los fármacos , Animales , Estimulación Eléctrica , Expresión Génica/efectos de los fármacos , Masculino , Neuronas/clasificación , Técnicas de Placa-Clamp , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptor de Melatonina MT1/genética , Receptor de Melatonina MT1/metabolismo , Receptor de Melatonina MT2/genética , Receptor de Melatonina MT2/metabolismo , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo
5.
J Chem Neuroanat ; 81: 10-17, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28159659

RESUMEN

Melatonin is involved in the temporal organization of several physiological and behavioral events, controlled by hypothalamic nuclei, like sleep, feeding, reproduction and metabolic modulation and acts through two types of high-affinity G protein-coupled membrane receptors: MT1 and MT2. This study aimed to investigate the expression of MT1 and MT2 receptors proteins in four hypothalamic nuclei, i.e., SCN, supraoptic (SON), paraventricular (PVN) and anteroventral periventricular nuclei (AVPV), of the diurnal primate Sapajus apella using immunohistochemistry. Since these areas are involved in the expression of biological rhythms, they are candidates to have variations in their neurochemistry, so the MT1 and MT2 expression has been analyzed at a point in light and another in the dark phase. Both receptors were found to have day/night differences in the four hypothalamic nuclei with an apparent inverse expression in the SCN compared with the other areas. These differences could be related to the idea that the individual should be prepared to respond by different ways to melatonin signal within the several processes and can contribute to the efficacy of melatonin ligands or melatonin in therapies.


Asunto(s)
Ritmo Circadiano/fisiología , Núcleo Hipotalámico Paraventricular/metabolismo , Receptor de Melatonina MT1/biosíntesis , Receptor de Melatonina MT2/biosíntesis , Animales , Cebus , Expresión Génica , Masculino , Primates , Receptor de Melatonina MT1/genética , Receptor de Melatonina MT2/genética
6.
Oncol Rep ; 33(1): 311-9, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25384569

RESUMEN

Mammary neoplasias are the most common tumors observed in female dogs. Identification of these tumors is valuable in order to identify beneficial therapeutic agents as alternative treatments for this tumor type. Oral administration of melatonin appears to exert an oncostatic effect on mammary neoplasia and may have a possible mechanism of action through its interaction with estrogen receptors on epithelial cells. Hence, we analyzed the potential therapeutic value of melatonin in tumors that are estrogen-dependent or -independent, and established a relationship of its action with the expression of the melatonin receptors MT1 and MT2. Furthermore, we analyzed the rate of cell proliferation and apoptosis after treatment with melatonin. Cell cultures were performed using 10 canine mammary tumor fragments and were divided into estrogen receptor (ER)-positive and ER-negative tumors. The results showed that both ER-positive and ER-negative tumors had decreased cell viability and proliferation after treatment with melatonin (p<0.05), although treatment was more effective in the ER-positive tumors. Analysis of the relative expression of the MT1 and MT2 genes by quantitative PCR was performed and the data were compared with the expression of ER in 24 canine mammary tumors and the cellular response to melatonin in 10 samples. MT1 was overexpressed in ER-positive tumors (p<0.05), whereas MT2 was not expressed. Furthermore, melatonin treatment in ER-positive tumors showed an efficient oncostatic effect by inhibiting cell viability and proliferation and inducing apoptosis. These results suggest that melatonin decreased neoplastic mammary cell proliferation and viability and induced apoptosis, with greater efficacy in ER-positive tumors that have a high expression of melatonin receptor MT1. This is a strong evidence for the use of melatonin as a therapeutic agent for estrogen-dependent canine mammary tumors.


Asunto(s)
Antineoplásicos/farmacología , Enfermedades de los Perros/tratamiento farmacológico , Neoplasias Mamarias Animales/tratamiento farmacológico , Melatonina/farmacología , Animales , Apoptosis , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Enfermedades de los Perros/metabolismo , Perros , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Expresión Génica , Neoplasias Mamarias Animales/metabolismo , Cultivo Primario de Células , Receptor de Melatonina MT1/genética , Receptor de Melatonina MT1/metabolismo , Receptor de Melatonina MT2/genética , Receptor de Melatonina MT2/metabolismo , Células Tumorales Cultivadas
7.
Trop Anim Health Prod ; 46(2): 337-40, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24136157

RESUMEN

The main environmental factor that affects the regulation of reproductive seasonality is photoperiod through its effects on melatonin secretion. The melatonin receptor MTRN1A appears to be involved in regulating the reproductive seasonality and milk production in the period. The aim of this study was to identify polymorphisms in the MTRN1A gene and their possible associations with milk, fat and protein productions, fat and protein percentages, age at first calving, and first calving interval in buffaloes. Three genotypes (CC, CT, and TT) were identified by PCR-RFLP, and there was a significant association with protein percentage (P < 0.0001). Further studies are necessary to better understand the influence of melatonin gene and their receptors in the productive functions of buffaloes.


Asunto(s)
Búfalos/fisiología , Genotipo , Polimorfismo Genético , Receptor de Melatonina MT1/metabolismo , Reproducción/genética , Animales , Búfalos/genética , Femenino , Regulación de la Expresión Génica/fisiología , Lactancia/genética , Lactancia/fisiología , Fotoperiodo , Embarazo , Receptor de Melatonina MT1/genética , Reproducción/fisiología
8.
Reprod Domest Anim ; 48(6): 1025-33, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23981138

RESUMEN

The expression of melatonin type 1 (MT1) and FSH (FSHR) receptors in caprine ovaries and the effects of these hormones on the in vitro development of isolated pre-antral follicles were evaluated. Follicles (≤200 µm) were cultured for 12 days in α-MEM (control) or melatonin (100 or 1000 pg/ml) or sequential melatonin medium (100 pg/ml: from day 0 to day 6; 1000 pg/ml: from day 6 to day 12; experiment 1) and in control or sequential FSH (100 ng/ml from day 0 to day 6; 500 ng/ml from day 6 to day 12) or sequential melatonin or this latter plus sequential FSH (experiment 2). MT1 and FSHR expressions were observed in granulosa cells from secondary and antral follicles. The oocytes from primordial and primary follicles also express FSHR. Sequential melatonin increased the percentage of normal follicles and oocyte recovery compared with the control or melatonin (1000 pg/ml) at day 12. In experiment 2, all the treatments increased the normal follicles and growth compared with the control. In conclusion, this study demonstrated the presence of MT1 and FSHR in caprine ovaries. The addition of increased concentrations of melatonin (sequential medium) or FSH can be used to promote the in vitro development of caprine pre-antral follicles.


Asunto(s)
Cabras/fisiología , Ovario/metabolismo , Receptor de Melatonina MT1/metabolismo , Receptores de HFE/metabolismo , Técnicas de Cultivo de Tejidos/veterinaria , Animales , Femenino , Regulación de la Expresión Génica/fisiología , Melatonina/metabolismo , Folículo Ovárico , Receptor de Melatonina MT1/genética , Receptores de HFE/genética
9.
Int. j. morphol ; 30(2): 546-549, jun. 2012. ilus
Artículo en Español | LILACS | ID: lil-651827

RESUMEN

La melatonina es una hormona que regula los ciclos circadianos y muchos de los aspectos reproductivos de los mamíferos y es secretada por la glándula pineal en las horas de ausencia de luz. Esta hormona posee receptores de alta afinidad acoplados a proteínas de tipo G, denominados MT1. Un polimorfismo de la secuencia que codifica para estos receptores estaría involucrado en el control de la reproducción estacional de los ovinos. El propósito de este estudio busca determinar la presencia del polimorfismo del receptor MT1 en la oveja criolla Araucana, un ovino local en el que se ha registrado un corto anestro reproductivo. Para poder realizar este trabajo se utilizó la técnica denominada reacción en cadena de la polimerasa para polimorfismo en el tamaño de los fragmentos de restricción PCR-RFLP, para lo cual, se obtuvieron muestras de ADN genómico de 50 ovejas Araucanas, las cuales fueron digeridas con la endonucleasa de restricción Mnl1. Se logró identificar la presencia del polimorfismo del receptor MT1 en la oveja Araucana. Los genotipos se hallaron en una frecuencia de 68 por ciento para el genotipo +/+, 28 por ciento para el genotipo +/- y4 por ciento para el genotipo -/-. Este alto porcentaje de animales con genotipo +/+ podría explicar el corto anestro reproductivo que presenta esta raza.


Melatonin is a hormone that regulates circadian rhythms and many of the reproductive aspects of mammals and is secreted by the pineal gland during the hours of absence of light. This hormone has high affinity receptors coupled to G-like proteins, termed MT1. A polymorphism of the sequence coding for these receptors was involved in the control of seasonal reproduction in sheep. The purpose of this study was to determine the presence of MT1 receptor polymorphism in Araucana creole sheep, a local breed with a short reproductive anestrus. To carry out this work, we used a technique called polymerase chain reaction-restriction fragment lengh polymorphism PCR-RFLP, for which samples were obtained from genomic DNA of 50 Araucana sheep, which were digested with Mnl1 restriction endonuclease. It was possible to identify the presence of MT1 receptor polymorphism in Araucana sheep. The genotypes were found in a genotype frequency of 68 percent for genotype + / +, 28 percent for genotype + / - y4 percent for genotype - / -. This high percentage of animals with genotype + / + could explain the short reproductive anestrus featuring this breed.


Asunto(s)
Animales , Femenino , Anestro/genética , Polimorfismo Genético , Receptor de Melatonina MT1/genética , Ovinos , Chile , Marcadores Genéticos , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Reproducción/genética
10.
Reprod Fertil Dev ; 23(3): 417-23, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21426859

RESUMEN

In the present study, we analysed the molecular mechanism(s) by which melatonin directly affects ovarian function in the mare. In Experiment 1, follicles and corpora lutea (CL) were collected from slaughterhouse ovaries and analysed for melatonin (MT(1)) receptor mRNA and protein. In Experiment 2, CL were collected from slaughterhouse ovaries and cultured in Dulbecco's modified Eagle's medium-F12 medium (control medium) supplemented with 50 ng mL(-1) equine chorionic gonadotrophin (eCG), 1 nM-1 µM melatonin, 1 µM forskolin or 1 µM luzindole. Explants were cultured for 3 h in the presence of these drugs. Conditioned media were analysed for progesterone production; luteal cells were analysed for cholesterol side-chain cleavage enzyme (P450scc), a steroidogenic enzyme that converts cholesterol into pregnenolone. Both MT(1) receptor mRNA and protein were expressed in follicles and CL. Melatonin inhibited both the eCG- and forskolin-stimulated production of progesterone, as well as the forskolin-stimulated expression of P450scc, in equine luteal cells and the effect was dose-dependent. The inhibitory effect of melatonin was blocked by luzindole, a non-selective melatonin MT(1) and MT(2) receptor antagonist. The data support the presence of functional melatonin receptors in luteal cells and a regulatory role for melatonin in the endocrine function of the equine CL.


Asunto(s)
Caballos/fisiología , Células Lúteas/efectos de los fármacos , Células Lúteas/metabolismo , Melatonina/farmacología , Folículo Ovárico/metabolismo , Progesterona/metabolismo , Receptor de Melatonina MT1/biosíntesis , Animales , Western Blotting/veterinaria , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/biosíntesis , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/metabolismo , Gonadotropina Coriónica/farmacología , Colforsina/farmacología , Femenino , Folículo Ovárico/citología , Folículo Ovárico/efectos de los fármacos , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Receptor de Melatonina MT1/antagonistas & inhibidores , Receptor de Melatonina MT1/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/veterinaria , Estadísticas no Paramétricas , Triptaminas/farmacología
11.
Endocrinology ; 152(5): 1891-900, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21363938

RESUMEN

The adrenal gland in the adult is a peripheral circadian clock involved in the coordination of energy intake and expenditure, required for adaptation to the external environment. During fetal life, a peripheral circadian clock is present in the nonhuman primate adrenal gland. Whether this extends to the fetal adrenal gland like the rat is unknown. Here we explored in vivo and in vitro whether the rat fetal adrenal is a peripheral circadian clock entrained by melatonin. We measured the 24-h changes in adrenal content of corticosterone and in the expression of clock genes Per-2 and Bmal-1 and of steroidogenic acute regulatory protein (StAR), Mt1 melatonin receptor, and early growth response protein 1 (Egr-1) expression. In culture, we explored whether oscillatory expression of these genes persisted during 48 h and the effect of a 4-h melatonin pulse on their expression. In vivo, the rat fetal adrenal gland showed circadian expression of Bmal-1 and Per-2 in antiphase (acrophases at 2200 and 1300 h, respectively) as well as of Mt1 and Egr-1. This was accompanied by circadian rhythms of corticosterone content and of StAR expression both peaking at 0600 h. The 24-h oscillatory expression of Bmal-1, Per-2, StAR, Mt1, and Egr-1 persisted during 48 h in culture; however, the antiphase between Per-2 and Bmal-1 was lost. The pulse of melatonin shifted the acrophases of all the genes studied and restored the antiphase between Per-2 and Bmal-1. Thus, in the rat, the fetal adrenal is a strong peripheral clock potentially amenable to regulation by maternal melatonin.


Asunto(s)
Glándulas Suprarrenales/metabolismo , Relojes Circadianos/fisiología , Ritmo Circadiano/fisiología , Melatonina/sangre , Factores de Transcripción ARNTL/genética , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/embriología , Análisis de Varianza , Animales , Relojes Circadianos/genética , Corticosterona/sangre , Corticosterona/metabolismo , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Técnicas In Vitro , Masculino , Melatonina/farmacología , Proteínas Circadianas Period/genética , Fosfoproteínas/genética , Embarazo , Ratas , Ratas Sprague-Dawley , Receptor de Melatonina MT1/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo
12.
Endocrinology ; 149(3): 995-1003, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18039783

RESUMEN

We previously demonstrated that melatonin is involved in the regulation of adrenal glucocorticoid production in diurnal primates through activation of MT1 membrane-bound melatonin receptors. However, whether melatonin has a similar role in nocturnal rodents remains unclear. Using an integrative approach, here we show that the adult rat adrenal gland expresses a functional MT1 melatonin receptor in a rhythmic fashion. We found that: 1) expression of the cognate mRNA encoding for the MT1 membrane-bound melatonin receptor, displaying higher levels in the day/night transition (1800-2200 h); 2) expression of the predicted 37-kDa MT1 polypeptide in immunoblots from adrenals collected at 2200 h but not 1000 h; 3) no expression of the MT2 melatonin receptor mRNA and protein; 4) specific high-affinity 2-[(125)I]iodomelatonin binding in membrane fractions and frozen sections from adrenals collected at 2200 h but not 0800 h (dissociation constant = 14.22 +/- 1.23 pm; maximal binding capacity = 0.88 +/- 0.02 fmol/mg protein); and 5) in vitro clock time-dependent inhibition of ACTH-stimulated corticosterone production by 1-100 nm melatonin, which was reversed by 1 microm luzindole (a melatonin membrane receptor antagonist). Our findings indicate not only expression but also high amplitude diurnal variation of functional MT1 melatonin receptors in the rat adrenal gland. It is conceivable that plasma melatonin may play a role to fine-tune corticosterone production in nocturnal rodents, probably contributing to the down slope of the corticosterone rhythm.


Asunto(s)
Glándulas Suprarrenales/metabolismo , Ritmo Circadiano/fisiología , Receptor de Melatonina MT1/metabolismo , Glándulas Suprarrenales/efectos de los fármacos , Hormona Adrenocorticotrópica/farmacología , Animales , Corticosterona/metabolismo , Masculino , Melatonina/metabolismo , Melatonina/farmacología , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor de Melatonina MT1/genética , Receptor de Melatonina MT2/metabolismo
13.
Endocrinology ; 147(10): 4618-26, 2006 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16840546

RESUMEN

In the adult mammal the circadian system, which allows predictive adaptation to daily environmental changes, comprises peripheral oscillators in most tissues, commanded by the suprachiasmatic nucleus (SCN) of the hypothalamus. The external environment of the fetus is provided by its mother. In primates, maternal melatonin is a candidate to entrain fetal circadian rhythms, including the SCN rhythms of metabolic activity. We found in the 90% of gestation capuchin monkey fetus expression of the clock genes Bmal-1, Per-2, Cry-2, and Clock in the SCN, adrenal, pituitary, brown fat, and pineal. Bmal-1, Per-2, and the melatonin 1 receptor (MT1) showed a robust oscillatory expression in SCN and adrenal gland, whereas a circadian rhythm of dehydroepiandrosterone sulphate was found in plasma. Maternal melatonin suppression changed the expression of Bmal-1, Per-2, and MT1 in the fetal SCN. These effects were reversed by maternal melatonin replacement. In contrast, neither maternal melatonin suppression nor its replacement had effects on the expression of Per-2 and Bmal-1 or MT1 in the fetal adrenal gland or the circadian rhythm of fetal plasma dehydroepiandrosterone sulphate. Our data suggest that maternal melatonin is a Zeitgeber for the fetal SCN but probably not for the adrenal gland.


Asunto(s)
Feto/metabolismo , Regulación del Desarrollo de la Expresión Génica/fisiología , Melatonina/fisiología , Transactivadores/genética , Factores de Transcripción ARNTL , Glándulas Suprarrenales/fisiología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proteínas CLOCK , Cebus , Ritmo Circadiano/genética , Ritmo Circadiano/fisiología , ADN Complementario/biosíntesis , ADN Complementario/genética , Sulfato de Deshidroepiandrosterona/sangre , Femenino , Hidrocortisona/sangre , Proteínas Nucleares/genética , Embarazo , Receptor de Melatonina MT1/biosíntesis , Receptor de Melatonina MT1/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Núcleo Supraquiasmático/fisiología , Temperatura , Factores de Transcripción/genética
14.
Eur J Pharmacol ; 525(1-3): 24-31, 2005 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-16297382

RESUMEN

Melatonin, the pineal gland hormone, modulates alpha-bungarotoxin sensitive nicotinic acetylcholine receptors in sympathetic nerve terminals, cerebellum and chick retina imposing a diurnal variation in functional responses [Markus, R.P., Zago, W.M., Carneiro, R.C., 1996. Melatonin modulation of presynaptic nicotinic acetylcholine receptors in the rat vas deferens. J. Pharmacol. Exp. Ther. 279, 18-22; Markus, R.P., Santos, J.M., Zago, W., Reno, L.A., 2003. Melatonin nocturnal surge modulates nicotinic receptors and nicotine-induced [3HI] glutamate release in rat cerebellum slices. J. Pharmacol. Exp. Ther. 305, 525-530; Sampaio, L.F.S., Hamassaki-Britto, D.E., Markus, R.P., 2005. Influence of melatonin on the development of functional nicotinic acetylcholine receptors in cultured chick retinal cells. Braz. J. Med. Biol. Res. 38, 603-613]. Here we show that in rat myotubes forskolin and melatonin reduced the number of nicotinic acetylcholine receptors expressed in plasma membrane. In addition, these cells expressed melatonin MT1 receptors, which are known to be coupled to G(i)-protein. However, the pharmacological profile of melatonin analogs regarding the reduction in cyclic AMP accumulation and number of nicotinic acetylcholine receptors did not point to a mechanism mediated by activation of G(i)-protein coupled receptors. On the other hand, calmidazolium, a classical inhibitor of calmodulin, reduced in a similar manner both effects. Considering that one isoform of adenylyl cyclase present in rat myotubes is regulated by Ca2+/calmodulin, we propose that melatonin modulates the number of nicotinic acetylcholine receptors via reduction in cyclic AMP accumulation.


Asunto(s)
Calmodulina/antagonistas & inhibidores , Melatonina/farmacología , Fibras Musculares Esqueléticas/efectos de los fármacos , Receptores Nicotínicos/efectos de los fármacos , Animales , Células Cultivadas , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Fibras Musculares Esqueléticas/metabolismo , ARN Mensajero/metabolismo , Ratas , Receptor de Melatonina MT1/genética , Receptor de Melatonina MT1/metabolismo , Receptor de Melatonina MT2/genética , Receptor de Melatonina MT2/metabolismo , Receptores Nicotínicos/metabolismo
15.
J Pineal Res ; 36(3): 204-11, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15009512

RESUMEN

Melatonin, a derivative of tryptophan that is present in all vertebrates, was first described in bovine pineal gland. It is known that melatonin is a highly conserved molecule, present also in unicellular organisms and plants. Several effects of melatonin have been described, including receptor- and non-receptor-mediated actions. Herein, we studied the effects of melatonin on in vitro and in vivo cell proliferation of Cloudman S-91 murine melanoma cells. We demonstrated that melatonin treatment significantly inhibits S-91 melanoma cell proliferation in vitro (EC50 = 10-7 m) as well as reduces tumor growth in vivo. We also demonstrated that melatonin directly increases the activity of the antioxidant enzymes catalase and glutathione peroxidase. These effects are most likely triggered through the direct intracellular action of melatonin, since the presence of receptors could not be demonstrated in this cell line. Expression of MT-1 melatonin receptor by stable transfection, mediated a dramatic antiproliferative melatonin effect (EC50 = 10-10 m) in S-91 cells. The expressed receptor is negatively coupled to the adenylyl cyclase/cyclic AMP signaling pathway via Gi protein. These results suggest that expression of the MT-1 melatonin receptor in melanoma cells is a potential alternative approach to specifically target cells in cancer therapeutic treatment.


Asunto(s)
Melanoma/tratamiento farmacológico , Melatonina/farmacología , Receptor de Melatonina MT1/metabolismo , Animales , Antineoplásicos/farmacología , Sitios de Unión , Catalasa/efectos de los fármacos , Catalasa/metabolismo , División Celular/efectos de los fármacos , Colforsina/farmacología , AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/efectos de los fármacos , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Glutatión Peroxidasa/efectos de los fármacos , Glutatión Peroxidasa/metabolismo , Masculino , Melanoma/metabolismo , Melanoma/patología , Ratones , Ratones Endogámicos DBA , Receptor de Melatonina MT1/efectos de los fármacos , Receptor de Melatonina MT1/genética , Transducción de Señal , Transfección , Células Tumorales Cultivadas
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