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BACKGROUND: Ovarian cancer is a highly aggressive disease that is frequently diagnosed in advanced stages. Melatonin, with its numerous antitumor properties, holds great promise in cancer treatment. Herein, we investigated the effects of melatonin on apoptosis, cell migration, and kinase levels in human ovarian carcinoma SKOV-3 cells and determined whether these effects are mediated by the activation of the MT1 receptor. METHODS: SKOV-3 cells were exposed to different concentrations of melatonin based on the presence of MT1 receptor, and we also performed specific silencing of the melatonin receptor gene MTNR1A. RESULTS: Our findings revealed that melatonin reduced cell viability as shown by the MTT assay, and flow cytometry analysis showed increased rates of apoptosis and necrosis in all melatonin-treated cells. Melatonin significantly decreased the migratory and invasive capacities of the cells. Propidium iodide labeling indicated that melatonin induced cell cycle arrest by reducing DNA content in the S and G2/M phases in SKOV-3 cells. Additionally, the levels of AKT, ERK1/2, JNK, CREB, p70S6K, STAT3/5, and p38 MAP kinase involved in cell survival, proliferation, motility, and stress responses were depressed by melatonin and further reduced after MT1 knockdown. These molecules were found to be associated with lower overall survival in ovarian cancer patients. CONCLUSIONS: Melatonin had obvious oncostatic actions on ovarian cancer cells, and MT1 receptor knockdown intensified its antitumor effect. The inhibition of the MT1 receptor resulted in a substantial reduction in the migratory and invasive capacities of the cells, suggesting its potential as a therapeutic target for the treatment of ovarian cancer.
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Melatonin is a hormone secreted by the pineal gland, it can be associated with circadian rhythms, aging and neuroprotection. Melatonin levels are decreased in sporadic Alzheimer's disease (sAD) patients, which suggests a relationship between the melatonergic system and sAD. Melatonin may reduce inflammation, oxidative stress, TAU protein hyperphosphorylation, and the formation of ß-amyloid (Aß) aggregates. Therefore, the objective of this work was to investigate the impact of treatment with 10 mg/kg of melatonin (i.p) in the animal model of sAD induced by the intracerebroventricular (ICV) infusion of 3 mg/kg of streptozotocin (STZ). ICV-STZ causes changes in the brain of rats similar to those found in patients with sAD. These changes include; progressive memory decline, the formation of neurofibrillary tangles, senile plaques, disturbances in glucose metabolism, insulin resistance and even reactive astrogliosis characterized by the upregulation of glucose levels and glial fibrillary acidic protein (GFAP). The results show that ICV-STZ caused short-term spatial memory impairment in rats after 30 days of STZ infusion without locomotor impairment which was evaluated on day 27 post-injury. Furthermore, we observed that a prolonged 30-day treatment with melatonin can improve the cognitive impairment of animals in the Y-maze test, but not in the object location test. Finally, we demonstrated that animals receiving ICV-STZ have high levels of Aß and GFAP in the hippocampus and that treatment with melatonin reduces Aß levels but does not reduce GFAP levels, concluding that melatonin may be useful to control the progression of amyloid pathology in the brain.
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BACKGROUND: Agomelatine is a melatoninergic antidepressant approved to treat the major depressive disorder. Agomelatine exerts its behavioural, pharmacological, and physiological effects through the activation of MT1 and MT2 melatonin receptors and the blockade of 5-HT2B and 5-HT2C serotonin receptors. Some studies have reported that the activation of the MT1 and MT2 melatonin receptors decreased cocaine-induced locomotor activity and cocaine self-administration. These findings from another study showed that agomelatine decreased alcohol consumption. This study aimed to evaluate the effects of agomelatine administration on cocaine-induced behavioural (cocaine-induced locomotor activity and cocaine-induced locomotor sensitisation) and neurochemical (dopamine levels) effects. METHODS: Male Wistar rats (250-280 g) received cocaine (10 mg/kg) during the induction and expression of locomotor sensitisation. Agomelatine (10 mg/kg) was administered 30 minutes before cocaine. After each treatment, locomotor activity was recorded for 30 minutes. Dopamine levels were determined in the ventral striatum, the prefrontal cortex (PFC), and the ventral tegmental area (VTA) by high-performance liquid chromatographic (HPLC) in animals treated with agomelatine and cocaine. Luzindole (30 mg/kg) was administered to block the agomelatine effect. RESULTS: In this study, we found that agomelatine decreased cocaine-induced locomotor activity and the induction and expression of locomotor sensitisation. In addition, agomelatine decreased cocaine-induced dopamine levels. Luzindole blocked the agomelatine-induced decrease in the expression of locomotor sensitisation in rats. CONCLUSION: Our results suggest (1) that agomelatine showed efficacy in decreasing cocaine psychostimulant effects and (2) that agomelatine can be a useful therapeutic agent to reduce cocaine abuse.
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Cocaína , Transtorno Depressivo Maior , Ratos , Masculino , Animais , Cocaína/farmacologia , Dopamina/metabolismo , Ratos Wistar , Serotonina/metabolismo , Receptores de MelatoninaRESUMO
This study evaluated the protective effect of melatonin before cyclophosphamide administration on ovarian function and its potential mechanism in a mouse model. Two studies were performed. In the first, mice were pretreated with melatonin (10, 20, or 30 mg/kg body weight, i.p.) once daily for 3 days, followed by injection with a single dose of cyclophosphamide (200 mg/kg body weight, i.p.) 30 min after the last melatonin injection. The second study analyzed whether melatonin type 1 and/or 2 receptors mediate the effects of melatonin on the ovary through administration of non-selective MT1/MT2 antagonist (luzindole) or selective MT2 antagonist (4-PPDOT) before the treatment with melatonin plus cyclophosphamide. After treatment groups, the ovaries were harvested and destined to histology, immunohistochemistry, and fluorescence analyses. Lastly, we examined the p-PTEN, p-Akt, and p-FOXO3a participation in the protective effect of melatonin in cyclophosphamide-induced ovarian damage. Results demonstrated that pretreatment with 20 mg/kg melatonin before cyclophosphamide administration showed more morphologically normal follicles, attenuated primordial follicle loss, decreased growing follicle atresia and mitochondrial damage, and increased GSH concentrations. Furthermore, treatment with luzindole blocked the protective effects of melatonin against the damage caused by cyclophosphamide. Additionally, pretreatment with 20 mg/kg melatonin regulated the PTEN/Akt/FOXO3a signaling pathway components after cyclophosphamide treatment. In conclusion, pretreatment with 20 mg/kg melatonin prevented primordial follicle loss and reduced apoptosis and oxidative damage in the mouse ovary during experimental chemotherapy with cyclophosphamide. Furthermore, the MT1 receptor and PTEN/Akt/FOXO3a proteins mediated these cytoprotective effects.
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Melatonina , Animais , Peso Corporal , Ciclofosfamida/farmacologia , Feminino , Melatonina/farmacologia , Camundongos , Ovário/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
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.
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Neoplasias Encefálicas , Glioma , Receptor MT1 de Melatonina , Receptor MT2 de Melatonina , Animais , Encéfalo/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Feminino , Glioma/genética , Glioma/metabolismo , Glioma/mortalidade , Glioma/patologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Receptor MT1 de Melatonina/genética , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/genética , Receptor MT2 de Melatonina/metabolismoRESUMO
Melatonin is a hormone that produces behavioral, pharmacological, and physiological effects through the activation of MT1 and MT2 melatonin receptors. Melatonin receptors participate in the modulation of the reinforcing effects of cocaine. Some studies report that dosing of melatonin decreases cocaine-induced locomotor activity and cocaine self-administration and that luzindole, an MT1, and MT2 melatonin receptor antagonist, blocks the melatonin-dependent decrease in cocaine-induced locomotor activity. The objective of this study was to evaluate the effect of acute or chronic dosing of melatonin on the induction and expression of cocaine-induced locomotor sensitization and cocaine-CPP in rats. Male Wistar rats received cocaine during the induction and expression of locomotor sensitization. Melatonin was administered 30 min before cocaine. After each treatment, locomotor activity was recorded for 30 min. Additionally, dopamine levels were determined in the ventral striatum, the prefrontal cortex (PFc), and the ventral tegmental area (VTA) by HPLC in animals treated with melatonin and cocaine. Melatonin decreased cocaine-induced locomotor sensitization and intracellular dopamine levels, as well as cocaine-CPP. Luzindole blocked the melatonin-induced decrease in the expression of locomotor sensitization in rats. These data suggest that melatonin may be a useful therapeutic agent to reduce cocaine abuse; additionally, they suggest that MT1 and MT2 receptors could be therapeutic targets, useful for the treatment of drug abuse disorder.
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Transtornos Relacionados ao Uso de Cocaína , Cocaína , Melatonina , Animais , Cocaína/farmacologia , Masculino , Melatonina/farmacologia , Ratos , Ratos Wistar , Receptor MT2 de MelatoninaRESUMO
BACKGROUND: Breast cancer is a heterogeneous disease and is the leading cause of cancer-related deaths among women. Even after diagnosis, the prognosis cannot be concluded since patients can develop resistance to therapy, which favors tumor growth, invasion and metastasis. In recent years, research has focused on identifying significant markers that can be used to determine the prognosis. Melatonin can act through G protein- coupled MT1 receptor, which controls selected protein kinases, influences the levels of transcription factor phosphorylation, specific genes expression, proliferation, angiogenesis, cell differentiation, migration, and indirectly controls the transport of glucose in cancer cells. It is known that glucose enters the cells by glucose transporters, such as GLUT1 which shows wide tissue distribution and appears to be altered in human breast carcinoma. High GLUT1 expression is associated with increased malignant potential, invasiveness and poor prognosis in some cancers including breast cancer. OBJECTIVE: The aim of this study was to evaluate the expression of MT1 receptor and GLUT1 in breast tumors and correlate with molecular subtypes and prognostic characteristics. METHOD: Protein expression was performed by an immunohistochemical procedure with specific antibodies and positive and negative controls. RESULTS: We found that MT1 high expression was associated with good prognosis subtype (Luminal A), while GLUT1 high expression was related to poor prognosis subtype (triple-negative). In addition, we found high expression of MT1 in ER+ and the inverse in GLUT1 expression. GLUT1 is also highly expressed in tumor ≥20mm. CONCLUSION: These results indicate MT1 and GLUT1 as potential targets for breast cancer subtypes and prognosis.
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Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Transportador de Glucose Tipo 1/metabolismo , Receptor MT1 de Melatonina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Invasividade Neoplásica , PrognósticoRESUMO
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 (1.0-1000.0â¯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 (10.0â¯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.
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Antioxidantes/farmacologia , Gânglios Espinais/citologia , Melatonina/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Estimulação Elétrica , Expressão Gênica/efeitos dos fármacos , Masculino , Neurônios/classificação , Técnicas de Patch-Clamp , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptor MT1 de Melatonina/genética , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/genética , Receptor MT2 de Melatonina/metabolismo , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismoRESUMO
La movilización dentaria involucra una serie de cambios en los tejidos de soporte caracterizados por la activa remodelación de estos. La MT1-MMP o MMP-14 es una potente enzima proteolítica capaz de degradar colágeno tipo I, la principal molécula estructural del ligamento periodontal. La migración dentaria requiere de la degradación controlada del colágeno constituyente del ligamento periodontal. Sin embargo, no existen evidencias de la participación de MT1-MMP en la remodelación del tejido periodontal durante este proceso. En el presente estudio hemos analizado la expresión de MT1 -MMP y del marcador de actividad osteoclástica Fosfatasa Acida Tartrato Resistente (TRAP) en un modelo de migración dentaria en ratas. La migración dentaria fue activada mediante la inserción de una banda separadora entre los incisivos superiores. La expresión y distribución de TRAP y MT1-MMP fue evaluada a través de citoquímica e inmunohistoquímica a los días 1, 3, 5 y 7. La producción de TRAP fue identificada principalmente en osteoclastos ubicados en la zona de compresión del ligamento periodontal. La producción de MT1-MMP fue observada en fibroblastos de la zona de compresión del ligamento periodontal y osteoclastos ubicados en esta misma región. Nuestros resultados permiten proponer que tanto MT1 -MMP como TRAP participan en la remodelación de los tejidos de soporte periodontal durante la migración dentaria.
Tooth movement involves a series of changes of the supporting periodontal tissues characterized by the active connective tissue remodeling. MT1-MMP or MMP-14 belongs to the family of matrix metalloproteinases that are able to degrade type I collagen, the main molecule involved in periodontal attachment. Tooth migration requires the controlled degradation of periodontal ligament collagen fibers. However, evidences linking MT1 -MMP expression with periodontal tissue remodeling are lacking. In the present study, we have evaluated the expression of MT1-MMPand of the osteoclast marker Tartrate Resistant Acid Phosphatase (TRAP) in a model of tooth migration in rats. Tooth migration was induced after the insertion of a rubber band between the upper incisors. The distribution of TRAP and MT1 -MMP was evaluated by means of cytochemistry and immunohistochemistry respectively at days 1, 3, 5 and 7. TRAP production was identified in osteoclasts at the area of compression of the periodontal ligament. MT1-MMP distribution was observed in fibroblastsatthe compressed area of the periodontal ligament and also in osteoclasts of the same region. Our findings allow us to propose that MT1-MMP and TRAP take part of the tissue remodeling events observed during tooth movement.