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1.
Life Sci ; 246: 117431, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32061868

RESUMO

Melatonin is an endogenous indoleamine hormone involved in various physiological processes. However, the mechanism of melatonin in mediating Leydig cells function has not been fully explained. In this study, we investigated the mechanism through which melatonin inhibits apoptosis in mouse Leydig cells by activating the retinoic acid-related orphan nuclear receptor (ROR) α/p53 signaling pathway. We confirmed the expression and localization of RORα in mouse Leydig cells using immunofluorescence. After treatment with 10 ng/mL melatonin for 36 h, RORα mRNA and protein levels were significantly increased (P < 0.01). TUNEL and flow cytometry showed that melatonin significantly decreased the TUNEL-positive cell ratio and apoptosis rate (P < 0.05). Moreover, melatonin decreased BAX expression and increased BCL-2 expression (P < 0.05). However, the RORα inhibitor SR1001 reversed the inhibitory effects of melatonin on apoptosis (P < 0.05). Additionally, analysis of p53 expression showed that melatonin inhibited p53 mRNA and protein expression (P < 0.05), whereas SR1001 reversed these effects. p53 reversed the anti-apoptotic process involving RORα-mediated melatonin in mouse Leydig cells. Collectively, our findings suggested that melatonin inhibited apoptosis via the RORα/p53 pathway.


Assuntos
Apoptose/efeitos dos fármacos , Células Intersticiais do Testículo/efeitos dos fármacos , Melatonina/farmacologia , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo , Animais , Células Intersticiais do Testículo/metabolismo , Masculino , Camundongos
2.
Cell Physiol Biochem ; 54(1): 142-159, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32028545

RESUMO

BACKGROUND/AIMS: It is well established that oxidative stress and inflammation are common pathogenic features of retinal degenerative diseases. ITH12674 is a novel compound that induces the transcription factor Nrf2; in so doing, the molecule exhibits anti-inflammatory, and antioxidant properties, and affords neuroprotection in rat cortical neurons subjected to oxidative stress. We here tested the hypothesis that ITH12674 could slow the retinal degeneration that causes blindness in rd10 mice, a model of retinitis pigmentosa. METHODS: Animals were intraperitoneally treated with 1 or 10 mg/Kg ITH12674 or placebo from P16 to P30. At P30, retinal functionality and visual acuity were analyzed by electroretinography and optomotor test. By immunohistochemistry we quantified the photoreceptor rows and analyzed their morphology and connectivity. Oxidative stress and inflammatory state was studied by Western blot, and microglia reactivity was monitored by flow cytometry. The blood-brain barrier permeation of ITH12674 was evaluated using a PAMPA-BBB assay. RESULTS: In rd10 mice treated with 10 mg/Kg of the compound, the following changes were observed (with respect to placebo): (i) a decrease of vision loss with higher scotopic a- and b-waves; (ii) increased visual acuity; (iii) preservation of cone photoreceptors morphology, as well as their synaptic connectivity; (iv) reduced expression of TNF-α and NF-κB; (v) increased expression of p38 MAPK and Atg12-Atg5 complex; and (vi) decreased CD11c, MHC class II and CD169 positive cell populations. CONCLUSION: These data support the view that a Nrf2 inducer compound may arise as a new therapeutic strategy to combat retinal neurodegeneration. At present, we are chemically optimising compound ITH12674 with the focus on improving its neuroprotective potential in retinal neurodegenerative diseases.


Assuntos
Isotiocianatos/uso terapêutico , Melatonina/análogos & derivados , Fator 2 Relacionado a NF-E2/agonistas , Retinite Pigmentosa/tratamento farmacológico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Modelos Animais de Doenças , Eletrorretinografia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Isotiocianatos/química , Isotiocianatos/farmacologia , Masculino , Melatonina/química , Melatonina/farmacologia , Melatonina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Células Fotorreceptoras/efeitos dos fármacos , Células Fotorreceptoras/patologia , Retina/efeitos dos fármacos , Retina/metabolismo , Retinite Pigmentosa/metabolismo , Retinite Pigmentosa/patologia , Fator de Necrose Tumoral alfa/metabolismo , Acuidade Visual/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
Life Sci ; 248: 117455, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32088216

RESUMO

AIMS: Idiopathic scoliosis is a common deformity of the spine that has an especially high incidence rate in adolescents. Some studies have demonstrated a close relationship between idiopathic scoliosis and melatonin deficiency. Our team's previous research showed that melatonin can inhibit the proliferation of osteoblasts, but the mechanism remains unclear. This study aimed to determine the mechanism by which melatonin inhibits the proliferation of osteoblasts. MAIN METHODS: Cell viability experiment, DNA fragment detection and alkaline phosphatase (ALP) activity assays were performed to determine the effects of melatonin on the proliferation, apoptosis and differentiation of osteoblasts. We used immunofluorescence to detect the expression of STIM1 in melatonin-treated osteoblasts. STIM1 interference was achieved using a specific siRNA, and a TRPC inhibitor was used to block the influx of Ca2+. The mRNA expression was determined by RT-qPCR, and protein levels were measured by Western blot. KEY FINDINGS: In this study, we found that melatonin inhibited the proliferation, differentiation and apoptosis of osteoblasts in a concentration-dependent manner. Additional studies showed that melatonin elevated cytosolic calcium levels by upregulation of STIM1, leading to osteoblast apoptosis via the mitochondrial pathway. Finally, we demonstrated that the STIM1-mediated increase in cytosolic calcium levels induced apoptosis through the ERK pathway. SIGNIFICANCE: Melatonin induces mitochondrial apoptosis in osteoblasts by regulating the STIM1/cytosolic calcium elevation/ERK pathway. These basic findings provide a basis for further clinical studies on melatonin as a drug therapeutic for idiopathic scoliosis.


Assuntos
Antioxidantes/farmacologia , Cálcio/metabolismo , Sistema de Sinalização das MAP Quinases , Melatonina/farmacologia , Osteoblastos/efeitos dos fármacos , Molécula 1 de Interação Estromal/genética , Fosfatase Alcalina/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica , Transporte de Íons/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Osteoblastos/citologia , Osteoblastos/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Molécula 1 de Interação Estromal/agonistas , Molécula 1 de Interação Estromal/antagonistas & inibidores , Molécula 1 de Interação Estromal/metabolismo , Canais de Cátion TRPC/antagonistas & inibidores , Canais de Cátion TRPC/genética , Canais de Cátion TRPC/metabolismo
4.
Life Sci ; 248: 117468, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32105705

RESUMO

AIMS: Treatment with 5-fluorouracil (5-FU) can cause impairment to adult hippocampal neurogenesis, resulting in cognitive deficits. As melatonin has been shown to enhance memory and hippocampal neurogenesis in animal models, this research investigated the neuroprotective effects of melatonin against spatial memory and hippocampal neurogenesis impairment in 5-fluorouracil (5-FU)-treated rats. MATERIALS AND METHODS: Four-Five weeks old male Spraque-Dawley rats weighing between 180 and 200 g were used. Animals were maintained under standard laboratory conditions with 25 °C and 12 h light/dark cycle. Animal were administered intravenous (i.v.) injections of 5-FU (25 mg/kg) 5 times every 3 days starting on day 9 of the experiment. The rats were divided into preventive, recovery, and throughout groups and co-treated with melatonin (8 mg/kg, i.p.) once daily (at 7.00 pm) for 21 days prior to, after, and throughout 5-FU treatment, respectively. Spatial memory was assessed using a novel object location (NOL) test. Hippocampal neurogenesis was then examined using Ki67, bromodeoxyuridine (BrdU), and doublecortin (DCX) immunohistochemistry staining. KEY FINDINGS: Melatonin administration was able to both protect the subjects from and reverse spatial memory deficits. 5-FU was also found to reduce the generation of hippocampal newborn neurons. However, co-treatment with melatonin ameliorated the reductions in neurogenesis caused by 5-FU. SIGNIFICANCE: These findings suggest that melatonin administration was able to ameliorate the 5-FU-induced spatial memory deficits associated with neurogenesis. The present work will be valuable for patients who suffer memory deficits from 5-FU chemotherapy.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Fluoruracila/antagonistas & inibidores , Melatonina/farmacologia , Transtornos da Memória/tratamento farmacológico , Neurogênese/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Memória Espacial/efeitos dos fármacos , Animais , Antimetabólitos/efeitos adversos , Biomarcadores/metabolismo , Proliferação de Células/efeitos dos fármacos , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Giro Denteado/patologia , Esquema de Medicação , Fluoruracila/efeitos adversos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Injeções Intravenosas , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Neurogênese/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Ratos , Ratos Sprague-Dawley , Memória Espacial/fisiologia
5.
Life Sci ; 242: 116931, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31618610

RESUMO

AIMS: With the improvement of the survival rates in children acute lymphoblastic leukemia (ALL), some children ALL survivors show impaired cognitive function. Methotrexate (MTX), an essential component in ALL treatment, has been reported to be related to neurologic sequelae and to increased oxidative stress through its interactions with enzymes in the folate pathway. Asymmetric dimethylarginine (ADMA) is the main endogenous inhibitor of nitric oxide synthase, and increased ADMA may result from increased oxidants. Melatonin is an antioxidant; however, its role in MTX neuropathy is not well studied. We developed a rat model mimicking child ALL treatment to explore peripheral and central homocysteine and ADMA regulation after MTX and found potential treatment choice. MAIN METHODS: Preweaning male Sprague-Dawley rats were used in this study. Experiment 1 evaluated spatial performance in rats with intrathecal (IT) MTX, intraperitoneal (IP) MTX, or combined IT and IP MTX, protocols mimicking ALL treatment in children. Experiment 2 focused on rats with combined IT and IP MTX, evaluating spatial performance and plasma and dorsal hippocampal homocysteine and ADMA levels, their regulation, and the protective effect of melatonin. KEY FINDINGS: Combined IT and IP MTX treatment caused in spatial deficits in developing rats, and melatonin restored the spatial performance. Alterations in peripheral and central homocysteine and ADMA concentrations and their regulation were found and could be alleviated by melatonin treatment. SIGNIFICANCES: Combined IP and IT MTX treatment caused spatial deficits in developing rats. Melatonin could restore spatial performance through alleviating the effects on the imbalance of oxidative stress.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Arginina/análogos & derivados , Hipocampo/química , Hiper-Homocisteinemia/induzido quimicamente , Melatonina/farmacologia , Metotrexato/efeitos adversos , Comportamento Espacial/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Arginina/análise , Arginina/sangue , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Metotrexato/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley
6.
J Biochem Mol Toxicol ; 34(2): e22430, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31833155

RESUMO

The aim of this study was to investigate the effect of melatonin (MT) and its metabolite N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK) on Alzheimer-like learning and memory impairment in rats intracerebroventricularly injected with streptozotocin (STZ). The results showed that the escape latency of the STZ group was longer than that of the control (CON), MT, and AFMK groups. Increased levels of hyperphosphorylated tau, neurofilament proteins, and malondialdehyde and decreased superoxide dismutase levels were observed in the brains of the rats from the STZ group compared with the brains of the rats from the CON, MT, AFMK high and low group. These results suggest that exogenous MT and AFMK can improve memory impairment and downregulate AD-like hyperphosphorylation induced by STZ, most likely through their antioxidation function. Meanwhile, we found that an equal dose of AFMK had a stronger effect than that of MT. Our results indicate that MT and its metabolite AFMK represent novel treatment strategies for Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/uso terapêutico , Cinuramina/análogos & derivados , Melatonina/uso terapêutico , Memória Espacial/efeitos dos fármacos , Doença de Alzheimer/induzido quimicamente , Animais , Antioxidantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Glutationa Peroxidase/metabolismo , Cinuramina/farmacologia , Cinuramina/uso terapêutico , Masculino , Malondialdeído/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Melatonina/farmacologia , Proteínas de Neurofilamentos/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/efeitos adversos , Estreptozocina/farmacologia , Superóxido Dismutase/metabolismo , Proteínas tau/metabolismo
7.
Environ Pollut ; 256: 113374, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31672358

RESUMO

Melatonin is a hormone which is generated from pineal gland, and it is responsible for the regulation of wake-sleep cycle. Melatonin is a well-known antioxidant and free radical scavenger to protect against multiple type of tissue damage. While ochratoxin A (OTA) is a mycotoxin found widely in contaminated food and foodstuffs, which causes nephrotoxicity, hepatotoxicity, immunotoxicity, and reproductive damage in humans and animals. In present study we report the toxicity of OTA on porcine oocyte quality and the protective effects of melatonin on OTA-exposed oocytes. Using transcriptome analysis our results show that OTA exposure alters the expression of multiple genes in oocytes, indicating its effect on oocyte maturation. The cellular changes following OTA treatment are examined, and the results show that OTA adversely affects oocyte polar body extrusion, which is confirmed by the delay of Cdc2-mediated cell cycle progression. OTA exposure also disrupts meiotic spindle formation, which is confirmed by altered phosphorylated MAPK expression. RNA-seq screening and further fluorescence staining results show that OTA induces aberrant mitochondria distribution and oxidative phosphorylation defects, which then causes oxidative stress, followed by early apoptosis and autophagy. Treatment with melatonin significantly ameliorates oxidative stress and apoptosis, which further protects cell cycle and spindle formation in OTA-exposed oocytes. Collectively, these results show the protective effects of melatonin against defects induced by OTA during porcine meiotic oocyte maturation.


Assuntos
Apoptose/efeitos dos fármacos , Melatonina/farmacologia , Ocratoxinas/toxicidade , Oócitos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Suínos , Animais , Antioxidantes/metabolismo , Autofagia/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Feminino , Humanos , Oócitos/metabolismo , Oócitos/patologia
8.
Eur J Med Chem ; 185: 111847, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31727472

RESUMO

Melatonin is a natural hormone primarily released by the pineal gland that regulates the sleep-wake cycles. The diverse biological applications of melatonin, together with the need to develop new melatoninergic ligands, have stimulated the preparation of a wide range of melatonin derivatives. Here, all the synthetic approaches to indole-based melatonin analogues as well as their biological applications are reviewed. The modifications which have been performed on the melatonin's indole ring and the effects of these modifications on the biological activities have been analysed, detailing the binding affinity of the derivatives for melatonin receptors.


Assuntos
Indóis/farmacologia , Melatonina/farmacologia , Receptores de Melatonina/agonistas , Animais , Relação Dose-Resposta a Droga , Humanos , Indóis/química , Ligantes , Melatonina/análogos & derivados , Melatonina/química , Estrutura Molecular , Relação Estrutura-Atividade
9.
Food Chem ; 303: 125385, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31442899

RESUMO

In this study, the mechanism activated by melatonin treatment at 100 µM for maintaining nutraceutical properties in pomegranate fruits during storage at 4 °C for 120 days was investigated. Our results showed that the higher G6PDH and 6PGDH activities in pomegranate fruits treated with melatonin may be responsible for sufficient supply of intracellular NADPH. Also, higher AA and GSH accumulation in pomegranate fruits treated with melatonin may ascribe to higher APX and GR activities coincided with lower AAO activity. In addition, pomegranate fruits treated with melatonin exhibited significantly higher PAL activity resulting in higher phenols and anthocyanins accumulation as well as higher DPPH scavenging capacity. Additionally, higher AOX gene expression in pomegranate fruits treated with melatonin may be beneficial for ROS scavenging molecules accumulation. Therefore, maintaining nutraceutical properties of pomegranate fruits treated with melatonin may ascribe to sufficient intracellular NADPH supply by promoting G6PDH and 6PGDH activities during cold storage.


Assuntos
Antocianinas/análise , Conservação de Alimentos , Lythraceae/efeitos dos fármacos , Melatonina/farmacologia , Suplementos Nutricionais/análise , Frutas/química , Frutas/efeitos dos fármacos , Lythraceae/química
10.
Food Chem ; 307: 125562, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31648174

RESUMO

The effect of postharvest melatonin treatment on sulforaphane production of fresh-cut broccoli at 4℃ during storage was investigated in this study. Florets treated with 100 µM melatonin exhibited higher contents of total glucosinolates and sulforaphane. Glucoraphanin content was significantly increased after melatonin treatment, and which was explained by gene analysis. Expressions of glucoraphanin biosynthesis genes including Elong, CYP83A1, MYB28, UGT74B1 and FMOGS-OX1 were up-regulated while AOP2 was obviously decreased by melatonin treatment, leading to a higher glucoraphanin accumulation. In addition, application of melatonin enhanced the myrosinase activity and the expression level of MYO, benefiting the formation of sulforaphane. This study demonstrates that melatonin treatment positively affected the glucoraphanin-sulforaphane system in postharvest fresh-cut broccoli.


Assuntos
Brassica/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas , Glucosinolatos/metabolismo , Imidoésteres/metabolismo , Isotiocianatos/metabolismo , Melatonina/farmacologia , Brassica/genética , Brassica/metabolismo , Manipulação de Alimentos , Redes e Vias Metabólicas/genética
11.
J Food Sci ; 85(1): 5-13, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31856339

RESUMO

Sleep is an essential biological phenomenon, being a physiological and behavioral process necessary for quality of life. Melatonin is a circadian hormone produced at night by the pineal gland, regulated by the light/dark cycle, under the control of the suprachiasmatic nucleus. Melatonin is an indoleamine, synthesized from the essential amino acid tryptophan via serotonin. Melatonin is also found in plants, where it helps fight oxidative stress. To present a systematic review on the ability of food sources of melatonin to promote healthy sleep. A literature search was performed on the PubMed, Scopus, and ScienceDirect databases, including only randomized, placebo-controlled trials published in English between 2005 and 2019. The methodological quality of the trials was assessed by the Jadad scale. Of the 25 eligible articles, eight met the inclusion criteria. They addressed the intake of milk or cherry juice in children, adults, and elderly subjects and evaluated sleep quality by questionnaires, sleep diary, actigraphy, or polysomnography. The analysis of the studies presented limitations, including lack of homogeneity of treatment dosage and duration. Nonetheless, the results indicated that the consumption of milk and sour cherries, sources of melatonin, may improve sleep quality in humans. These results pointed out to the potential suitability of food sources of melatonin as adjuvants in the prevention and treatment of sleep disorders. Further studies are necessary to better ascertain the aspects relevant to their use.


Assuntos
Suplementos Nutricionais/análise , Melatonina/análise , Transtornos do Sono-Vigília/tratamento farmacológico , Sono , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Melatonina/farmacologia , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Sono/efeitos dos fármacos , Transtornos do Sono-Vigília/metabolismo , Transtornos do Sono-Vigília/fisiopatologia , Adulto Jovem
12.
Life Sci ; 242: 117191, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31863775

RESUMO

Melatonin is an indole neuroendocrine hormone that is mainly secreted by the pineal gland to regulate circadian rhythm, antioxidation, and immune regulation. Melatonin plays an important role in T cell-mediated immune responses against cancer, infections, and the development of many autoimmune diseases. The aim of this study was to investigate the immunomodulatory effects of melatonin on T/B cell activation in pinealectomy mice. The improved pinealectomy procedure for mice presented in this study is a good animal model to be used in follow-up studies on melatonin. After pinealectomy, the tissue removed was identified as the pineal body using HE staining. The effects of melatonin supplementation on T cell activation and activation-related changes to the MAPK/NF-κ B pathways were analyzed by flow cytometry and real-time PCR. We found that expression levels of Th1, Th2 and Th17-related cytokines in peripheral blood were lower in mice that had undergone pinealectomy, compared with normal mice. After melatonin supplementation, cytokine levels rapidly increased within a short period of time, which resulted in the gradual recovery of cytokine expression levels. Moreover, activation of T/B cells in mice was weakened and decreased after pineal gland removal. Melatonin was found to inhibit the expression of TLR3, p38, JNK, and MAPK/NF-κ B within a short period (2 weeks) of melatonin replenishment. This inhibition gradually weakened with time, since the degree of inhibition is negatively related with the dosage of melatonin. In conclusion, melatonin may regulate the activation of T/B cells, playing a critical role in the regulation of immune balance.


Assuntos
Linfócitos B/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Melatonina/farmacologia , Pinealectomia , Linfócitos T/efeitos dos fármacos , Animais , Citocinas/metabolismo , Citometria de Fluxo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Glândula Pineal/anatomia & histologia , Reação em Cadeia da Polimerase em Tempo Real
13.
Life Sci ; 239: 117036, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31697951

RESUMO

AIMS: Previous literature has shown that melatonin plays a critical role in protecting against cerebral ischemia/reperfusion (I/R) injury. Sirtuin3(SIRT3), as one member of the sirtuin family, protects against oxidative stress-related diseases. However, the association between melatonin and SIRT3 in cerebral I/R injury is not well understood. Our experiment was planned to investigate whether melatonin protects against cerebral I/R injury through SIRT3 activation. MAIN METHODS: We selected transient middle cerebral artery occlusion (tMCAO) mice as the model of cerebral I/R injury. Male C57/BL6 mice were pre-treated with or without a selective SIRT3 inhibitor and then subjected to tMCAO surgery. Melatonin (20 mg/kg) was given to mice by intraperitoneal injection after ischemia and before reperfusion. Then, we observed the changes in the SIRT3 and downstream relative proteins, infarction volume, neurological score, Nissl, H&E and TUNEL staining, and the expression of apoptosis proteins after tMCAO. KEY FINDINGS: Melatonin upregulated the expression of SIRT3 after tMCAO, and alleviated the neurological dysfunction and cell apoptosis through SIRT3 activation. SIGNIFICANCE: Our research proved that melatonin promoted SIRT3 expression after tMCAO and alleviated cerebral I/R injury by activating the SIRT3 signaling pathway. This study provides novel therapeutic targets and mechanisms for the treatment of ischemic stroke in the clinic, especially during cerebrovascular reperfusion.


Assuntos
Melatonina/farmacologia , Traumatismo por Reperfusão/metabolismo , Sirtuína 3/metabolismo , Animais , Apoptose/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Masculino , Melatonina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Sirtuína 3/fisiologia , Acidente Vascular Cerebral/tratamento farmacológico
14.
Life Sci ; 239: 117067, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31738882

RESUMO

AIMS: Both CpG oligodeoxynucleotide (CpG-ODN) and melatonin have been reported to induce Th1 response and contribute to allergic asthma resistance. Here, we aimed to reveal how they confer such effect as well as whether they crosstalk with each other. MAIN METHODS: Six-week-old Female C57BL/6 mice were challenged by OVA to induce allergic airway inflammation, and were treated with CpG-ODN, CpG-ODN plus Luzindole or melatonin respectively. Bronchoalveolar lavage fluid (BALF) cellularity was classified and counted by Wright's-Giemsa staining. HE and PAS staining were used to analyze airway inflammation. The levels of IL-4, IL-5, IL-13,GM-CSF and IFN-γ, as well as IL-1ß and IL-18 were analyzed by ELISA. Protein expressions of ASMT, AANAT, NLRP3, IL-1ß and caspase-1 in lung tissue were detected by Western blotting, expression of ASMT and AANAT were further observed by immunohistochemistry. KEY FINDINGS: We found that CpG-ODN considerably suppressed OVA-induced airway leukocytes infiltration, goblet cell hyperplasia and Th2 cytokines production. Furthermore, the resolution effect of CpG-ODN on OVA-induced allergic airway inflammation occurred in parallel with decreased-activation of NLRP3 inflammasome and increased biosynthesis of melatonin. Blocking the effect of endogenous melatonin by Luzindole abolished the suppressive effect of CpG-ODN on OVA-induced airway inflammation and activation of NLRP3 inflammasome, suggesting such effect was mediated by endogenous melatonin. Moreover, exogenous melatonin pronouncedly ameliorated airway inflammation and decreased the activation of NLRP3 inflammasome. SIGNIFICANCE: These results proven that CpG-ODN protects against allergic airway inflammation via suppressing the activation of NLRP3 inflammasome, and such effect may be resulted from the restored-production of melatonin.


Assuntos
Inflamassomos/efeitos dos fármacos , Melatonina/farmacologia , Oligodesoxirribonucleotídeos/farmacologia , Animais , Asma , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Feminino , Hipersensibilidade/metabolismo , Inflamassomos/metabolismo , Inflamassomos/fisiologia , Inflamação/metabolismo , Inflamação/prevenção & controle , Pulmão/metabolismo , Melatonina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Oligodesoxirribonucleotídeos/genética , Oligodesoxirribonucleotídeos/metabolismo , Células Th2 , Triptaminas/farmacologia
15.
Life Sci ; 239: 117046, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31730869

RESUMO

Aims; The present study was designed to ameliorate the integrated efficacy of exogenous melatonin and insulin on tissue biochemical, serological, histopathological architecture and receptor expression of melatonin (MT1, MT2) and insulin receptor (IR) expression against the hepatic injury in diabetic rats. Materials and Method; the rats were randomly allocated into nine different experimental groups. Diabetes was induced by streptozotocin (15 mg/kg) for 6 days. Rats having blood glucose level above 250 mg/dl were considered as diabetic. Animals euthanized after 4 weeks, blood and liver samples were collected to perform various biochemical, serological, histopathological and receptor expression of melatonin (MT1, MT2) and insulin receptor (IR). Key findings; Diabetic rats revealed significant increase in lipid peroxidation (LPO) of liver tissue, liver function tests (ALT, AST and ALP), increase in serum cholesterol, LDL, VLD, but decrease in HDL level. Further, diabetic rats exhibited significant decrement in antioxidative enzymatic system (GSH, SOD, CAT, GR, GPX, G6PDH and GST), total tissue protein and glycogen content. Histomicrograph of liver of diabetic rats resulted in vacuolization indicating cellular damages as well as upregulation in liver MT1, MT2 and IR protein expression. However, the combined therapy (Melatonin and insulin treatment) revealed significant recovery and restoration in biochemical, cellular architecture of liver cells and receptor expression pattern of MT1, MT2 and IR. Significance; It may establish a synergistic action of melatonin and insulin, which might be a novel evidence for clinicians to combat the hepatic complication along with controlling diabetes.


Assuntos
Insulina/metabolismo , Fígado/metabolismo , Melatonina/farmacologia , Animais , Antioxidantes/farmacologia , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Hepatócitos/metabolismo , Peroxidação de Lipídeos , Fígado/lesões , Testes de Função Hepática , Masculino , Melatonina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Receptor de Insulina/metabolismo
16.
Int J Mol Sci ; 20(19)2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31597233

RESUMO

When exposed to hostile environments such as radiation, physical injuries, chemicals, pollution, and microorganisms, the skin requires protective chemical molecules and pathways. Melatonin, a highly conserved ancient molecule, plays a crucial role in the maintenance of skin. As human skin has functional melatonin receptors and also acts as a complete system that is capable of producing and regulating melatonin synthesis, melatonin is a promising candidate for its maintenance and protection. Below, we review the studies of new metabolic pathways involved in the protective functions of melatonin in dermal cells. We also discuss the advantages of the topical use of melatonin for therapeutic purposes and skin protection. In our view, endogenous intracutaneous melatonin production, together with topically-applied exogenous melatonin and its metabolites, represent two of the most potent defense systems against external damage to the skin.


Assuntos
Melatonina/metabolismo , Melatonina/farmacologia , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologia , Pele/metabolismo , Administração Tópica , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Humanos , Melatonina/administração & dosagem , Redes e Vias Metabólicas , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/administração & dosagem , Pele/efeitos dos fármacos
17.
Pak J Pharm Sci ; 32(4): 1453-1459, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31608862

RESUMO

The present investigation aimed to study the possible antidiabetic and related antioxidant potentials of tannic acid and melatonin in streptozotocin (STZ) induced diabetes in rats. Four groups of rats received intraperitoneal one dose of 50mg/kg body weight STZ for the induction of diabetes. The first group served as diabetic control group and received the vehicle. Four days after induction of diabetes, the remaining three groups received glibenclamide (6mg/kg/day), tannic acid (1 g/kg/day) and melatonin (10 mg/kg/day) for two weeks. A fifth group served as vehicle control group. At the end of the experimental period, blood samples and liver samples were collected for the determination of diabetes correlated biomarkers. Treatment of diabetic rats with tannic acid or melatonin attenuated most of the changes associated with STZ induced diabetes. The present results evidenced the beneficial effects of tannic acid and melatonin in diabetes management.


Assuntos
Antioxidantes/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Melatonina/farmacologia , Taninos/farmacologia , Animais , Glicemia/metabolismo , Nefropatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/prevenção & controle , Glicogênio/metabolismo , Insulina/sangue , Resistência à Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/fisiologia , Testes de Função Renal , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Ratos Wistar
18.
Turk Neurosurg ; 29(6): 887-900, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31608966

RESUMO

AIM: To investigate the potential protective effects of melatonin on the chronic radiation emitted by third generation mobile phones on the brain. MATERIAL AND METHODS: A total of 24 male Wistar albino rats were divided into four equal groups. Throughout a 90-day experiment, no application was performed on the control group. The second group was exposed to 2100 MHz radiation for 30 minutes. Subcutaneous melatonin was injected into the third group. Subcutaneous melatonin injection was applied 40 minutes before radiation and then the fourth group was exposed to radiation for 30 minutes. At the end of the experiment, brain (cerebrum and cerebellum) tissues were taken from the subjects. Histochemical, immunohistochemical, ultrastructural and western blot analyses were applied. In addition to brain weight, Purkinje cells’ number, immunohistochemical H Score analyses and the results of the Western blot were examined statistically. RESULTS: With the application of radiation, neuronal edema, relatively-decreased numbers of neurons on hippocampal CA1 and CA3 regions, displacement of the Purkinje neurons and dark neurons findings were observed as a result of histochemical stainings. Radiation also activated the NMDA-receptor 2B/Calpain-1/Caspase-12 pathway, NMDA-receptor 2B and Calpain-1 with the findings being supported by western blot analyses. Pre-increased protein synthesis before apoptosis was identified by electron microscopy. CONCLUSION: Mobile phone radiation caused certain (ultra) structural changes on the brain and activated the NMDA-receptor 2B/ Calpain-1/Caspase-12 pathway; in addition, melatonin was found to be effective, but insufficient in demonstrating the protective effects.


Assuntos
Encéfalo/metabolismo , Calpaína/metabolismo , Caspase 12/metabolismo , Radiação Eletromagnética , Melatonina/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Encéfalo/efeitos dos fármacos , Encéfalo/efeitos da radiação , Calpaína/efeitos da radiação , Caspase 12/efeitos da radiação , Telefone Celular , Masculino , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/efeitos da radiação , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação
19.
Rev Assoc Med Bras (1992) ; 65(8): 1122-1127, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31531613

RESUMO

Melatonin is known for its effects on both the sleep and reproductive system of mammals. The latter has melatonin receptors type 1 and 2, which act to regulate, among other things, cyclic AMP. Notwithstanding all the literature data, there is still no sound knowledge or a clear understanding of the hormone's action on the physiology of ovarian follicular cells. OBJECTIVE To review and evaluate studies about melatonin action on the ovarian granulosa/theca interna cells from the literature. METHODS The systematic review was carried out according to the PRISMA recommendations. The MEDLINE and Cochrane primary databases were consulted with the use of specific terms. There was no limitation on language or publication year. RESULTS Seven papers about melatonin action on granulosa cells were selected. The following can be attributed to the hormone's effects: a) progesterone increase in culture medium; b) increased estrogen production; c) antagonistic action on estrogen; d) improvement in cell quality resulting in improved embryo and higher pregnancy rates; e) improved cell proliferation via MAPK; f) reduction of free radicals. Nevertheless, there are contrarian papers reporting a reduction in progesterone production. Melatonin interferes in sex steroid production, boosting progesterone output. Such action may help improve oocyte quality.


Assuntos
Melatonina/farmacologia , Oócitos/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Células Cultivadas , Feminino , Células da Granulosa/efeitos dos fármacos , Humanos , Oócitos/crescimento & desenvolvimento , Gravidez , Progesterona/antagonistas & inibidores , Células Tecais/efeitos dos fármacos
20.
J Pharm Pharmacol ; 71(11): 1695-1705, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31531878

RESUMO

OBJECTIVES: Alzheimer's disease (AD) is a neurodegenerative disorder with no cure. Limited treatment options available today do not offer solutions to slow or stop any of the suspected causes. The current medications used for the symptomatic treatment of AD include memantine and acetylcholine esterase inhibitors. Some studies suggest that melatonin could also be used in AD patients due to its sleep-improving properties. METHODS: In this study, we evaluated whether a combination of memantine with melatonin, administered for 32 days in drinking water, was more effective than either drug alone with respect to Aß aggregates, neuroinflammation and cognition in the double transgenic APP/PS1 (5xFAD) mouse model of AD. KEY FINDINGS: In this study, chronic administration of memantine with melatonin improved episodic memory in the object recognition test and reduced the number of amyloid aggregates and reactive microgliosis in the brains of 5xFAD mice. Although administration of memantine or melatonin alone also reduced the number of amyloid aggregates and inflammation in brain, this study shows a clear benefit of the drug combination, which had a significantly stronger effect in this amyloid-dominant mouse model of AD. CONCLUSION: Our data suggest considerable potential for the use of memantine with melatonin in patients with AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Encéfalo/efeitos dos fármacos , Melatonina/farmacologia , Memantina/farmacologia , Transtornos da Memória/tratamento farmacológico , Neurônios/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Inibidores da Colinesterase/farmacologia , Modelos Animais de Doenças , Combinação de Medicamentos , Feminino , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/metabolismo , Fragmentos de Peptídeos/farmacologia
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