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1.
Int J Mol Sci ; 22(3)2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33540815

RESUMO

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin's effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.


Assuntos
Transtorno do Espectro Autista/complicações , Melatonina/farmacocinética , Transtornos Intrínsecos do Sono/tratamento farmacológico , Administração Oral , Adulto , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/psicologia , Disponibilidade Biológica , Criança , Pré-Escolar , Ritmo Circadiano , Preparações de Ação Retardada , Suplementos Nutricionais , Feminino , Humanos , Injeções Intravenosas , Masculino , Melatonina/administração & dosagem , Melatonina/análogos & derivados , Melatonina/fisiologia , Melatonina/uso terapêutico , Melatonina/urina , Receptores de Melatonina/fisiologia , Saliva/química , Estações do Ano , Serotonina/metabolismo , Transtornos Intrínsecos do Sono/etiologia , Transtornos Intrínsecos do Sono/fisiopatologia , Latência do Sono/efeitos dos fármacos , Transtornos do Comportamento Social/tratamento farmacológico , Transtornos do Comportamento Social/etiologia , Triptofano/metabolismo
2.
Sr Care Pharm ; 36(2): 83-91, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33509331

RESUMO

OBJECTIVE: The purpose of this systematic review is to evaluate the available evidence for safety and efficacy of over-the-counter (OTC) sleep aids used for the treatment of insomnia in older people.
DATA SOURCES: PubMed, EBSCO, and International Pharmaceutical Abstracts.
STUDY SELECTION: Five studies were included that involved humans 65 years of age and older being evaluated on OTC sleep aids in the outpatient setting.
DATA EXTRACTION: Data extraction from each study included primary and secondary efficacy endpoints, such as differences in the mean total sleep time, sleep latency, sleep efficiency, and number of awakenings, along with safety endpoints, such as psychomotor ability, cognitive ability, and adverse effect profiles. Both subjective and objective measures of changes in sleep and adverse effects were included.
DATA SYNTHESIS: Diphenhydramine had a statistically significant increase in sedation and decrease in number of awakenings but was not shown to be any less or more safe than compared products. Despite lacking safety issues, valerian was found to have no effect on subjective or objective sleep outcomes. Overall, melatonin had the most evidence and was found to have a statistically significant positive impact on sleep measures without safety issues.
CONCLUSION: Diphenhydramine and melatonin appear to be efficacious in improving some sleep measures while causing minimal adverse effects. However, there are very few studies that examine the use of over-the-counter sleep aids in those 65 years of age and older with primary insomnia. Additional studies are needed in this population.


Assuntos
Difenidramina/administração & dosagem , Hipnóticos e Sedativos/administração & dosagem , Melatonina/administração & dosagem , Medicamentos sem Prescrição , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Transtornos do Sono-Vigília/tratamento farmacológico , Sono/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Difenidramina/efeitos adversos , Humanos , Hipnóticos e Sedativos/efeitos adversos , Melatonina/efeitos adversos , Valeriana
3.
Int J Mol Sci ; 21(24)2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33339403

RESUMO

The gilthead seabream larval rearing in continuous light is common in most Mediterranean hatcheries to stimulate larval length growth and increase food consumption. Several studies have shown that continuous light affects larval development and increases the prevalence of skeletal deformities. Melatonin is a crucial pineal neurohormone that displays daily secretion patterns, stimulates cell proliferation and embryonic development in Atlantic salmon and zebrafish, and improves osseointegration in mice and humans. However, no studies have examined the effects of orally supplemented melatonin on skeletal deformities in Sparus aurata larvae. We administered exogenous melatonin to gilthead seabream larvae via enriched rotifers and nauplii of Artemia. Exogenous melatonin induced bone deformities and stimulated parathyroid hormone-related protein-coding gene (PTHrP) mRNA expression. In addition to the melatonin-induced PTHrP high expression level, the recorded non coordinated function of skeletal muscle and bone during growth can be the fountainhead of bone deformities. Both myosin light chain 2 (mlc2) and bone gamma-carboxyglutamate protein-coding gene (bglap) expression levels were significantly affected by melatonin administration in an inverse dose-response manner during the exogenous melatonin administration. This is the first study to report the effect of inducing melatonin bone deformities on Sparus aurata larvae reared under ordinary hatchery conditions.


Assuntos
Desenvolvimento Ósseo/efeitos dos fármacos , Osso e Ossos/anormalidades , Melatonina/toxicidade , Dourada/anormalidades , Animais , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Suplementos Nutricionais , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Larva/efeitos dos fármacos , Larva/metabolismo , Melatonina/administração & dosagem , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/metabolismo , Cadeias Leves de Miosina/genética , Cadeias Leves de Miosina/metabolismo , Osteocalcina/genética , Osteocalcina/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/genética , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Dourada/crescimento & desenvolvimento
4.
Trials ; 21(1): 882, 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33106171

RESUMO

OBJECTIVES: We will evaluate the efficacy and safety of Melatonin, compared to the standard therapeutic regimen on clinical symptoms and serum inflammatory parameters in patients with confirmed COVID-19, who are moderately ill. TRIAL DESIGN: This is a single-center, randomized, double-blind, placebo-controlled clinical trial with a parallel-group design conducted at Shahid Mohammadi Hospital, Bandar Abbas, Iran. PARTICIPANTS: All patients admitted to Severe Acute Respiratory Syndrome Departments of Shahid Mohammadi Hospital, Bandar Abbas, Iran will be screened for the following criteria. INCLUSION CRITERIA: 1. Age ≥20 years 2. Confirmed SARS-CoV-2 diagnosis (positive polymerase chain reaction). 3. Moderate COVID-19 pneumonia (via computed tomography and or X-ray imaging), requiring hospitalization. 4. Hospitalized ≤48 hours. 5. Signing informed consent and willingness of the participant to accept randomization to any assigned treatment arm. EXCLUSION CRITERIA: 1. Underlying diseases, including chronic hypertension, diabetes mellitus, seizure, depression, chronic hepatitis, cirrhosis, and cholestatic liver diseases. 2. Severe and critical COVID-19 pneumonia. 3. Use of warfarin, corticosteroids, hormonal drugs, alcohol, other antiviral and investigational medicines, and illegal drugs (during the last 30 days). 4. History of known allergy to Melatonin. 5. Pregnancy and breastfeeding. INTERVENTION AND COMPARATOR: Intervention group: The standard treatment regimen for COVID-19, according to the Iranian Ministry of Health and Medical Education's protocol, along with Melatonin capsules at a dose of 50 mg daily for a period of seven days. CONTROL GROUP: The standard therapeutic regimen for COVID-19 along with Melatonin-like placebo capsules at a dose of one capsule daily for a period of seven days. Both Melatonin and placebo capsules were prepared at the Faculty of Pharmacy and Pharmaceutical Sciences, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. MAIN OUTCOMES: The primary outcomes are the recovery rate of clinical symptoms and oxygen saturation as well as improvement of serum inflammatory parameters, including C-reactive protein, tumor necrosis factor-alpha (TNF-ɑ), interleukin-1ß (IL-1ß), and IL-6 within seven days of randomization. The secondary outcomes are the time to improve clinical and paraclinical features along with the incidence of serious adverse drug reactions within seven days of randomization. RANDOMIZATION: Included patients will be allocated to one of the study arms using block randomization in a 1:1 ratio (each block consists of 10 patients). This randomization method ensures a balanced allocation between the arms during the study. A web-based system will generate random numbers for the allocation sequence and concealment of participants. Each number relates to one of the study arms. BLINDING (MASKING): All study participants, clinicians, nurses, research coordinators, and those analyzing the data are blinded to the group assignment. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): A total of 60 patients randomized into two groups (30 in each group). TRIAL STATUS: The trial protocol is Version 1.0, August 14, 2020. Recruitment began August 22, 2020, and is anticipated to be completed by November 30, 2020. TRIAL REGISTRATION: The trial protocol has been registered in the Iranian Registry of Clinical Trials (IRCT). The registration number is " IRCT20200506047323N5 ". The registration date was 14 August 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting the dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
Betacoronavirus/efeitos dos fármacos , Depressores do Sistema Nervoso Central/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Melatonina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Adulto , Betacoronavirus/genética , Biomarcadores/sangue , Estudos de Casos e Controles , Depressores do Sistema Nervoso Central/administração & dosagem , Depressores do Sistema Nervoso Central/efeitos adversos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Método Duplo-Cego , Hospitalização , Humanos , Irã (Geográfico)/epidemiologia , Melatonina/administração & dosagem , Melatonina/efeitos adversos , Oxigênio/sangue , Pandemias , Placebos/administração & dosagem , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Segurança , Fatores de Tempo , Resultado do Tratamento
5.
Biomolecules ; 10(9)2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32825327

RESUMO

There is a growing consensus that the antioxidant and anti-inflammatory properties of melatonin are of great importance in preserving the body functions and homeostasis, with great impact in the peripartum period and adult life. Melatonin promotes adaptation through allostasis and stands out as an endogenous, dietary, and therapeutic molecule with important health benefits. The anti-inflammatory and antioxidant effects of melatonin are intertwined and are exerted throughout pregnancy and later during development and aging. Melatonin supplementation during pregnancy can reduce ischemia-induced oxidative damage in the fetal brain, increase offspring survival in inflammatory states, and reduce blood pressure in the adult offspring. In adulthood, disturbances in melatonin production negatively impact the progression of cardiovascular risk factors and promote cardiovascular and neurodegenerative diseases. The most studied cardiovascular effects of melatonin are linked to hypertension and myocardial ischemia/reperfusion injury, while the most promising ones are linked to regaining control of metabolic syndrome components. In addition, there might be an emerging role for melatonin as an adjuvant in treating coronavirus disease 2019 (COVID 19). The present review summarizes and comments on important data regarding the roles exerted by melatonin in homeostasis and oxidative stress and inflammation related pathologies.


Assuntos
Adjuvantes Farmacêuticos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Melatonina/administração & dosagem , Melatonina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Adjuvantes Farmacêuticos/administração & dosagem , Adjuvantes Farmacêuticos/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Homeostase/efeitos dos fármacos , Humanos , Melatonina/farmacologia , Pandemias
6.
J Pineal Res ; 69(3): e12683, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32770854

RESUMO

The pharmacological properties of melatonin are well known. However, there is noticeable the lack of clinical trials that confirm the efficacy, security, absence of side effects in the short and long term, and the effective doses of melatonin. This point is especially important in diseases with high morbidity and mortality including COVID-19. There is not treatment for COVID-19, and several anti-inflammatory and antiviral molecules are being tested, and different vaccines are in preparation. Although the SARS-CoV-2 pandemic is apparently improving, it is expected new resurges next fall. Thus, looking for an effective treatment of COVID-19 is mandatory. Melatonin has significant anti-inflammatory, antioxidant, and mitochondrial protective effects, and its efficacy has been demonstrated in multiple experimental models of disease and in a clinical trial in sepsis. Because COVID-19 courses with a severe septic response, multiple reviews proposing melatonin as a treatment for COVID-19 have been published. Nevertheless, there is a lack of experimental and clinical data on the use of melatonin on SARS-CoV-2 infection. Accordingly, we designed a clinical trial with an injectable formulation of melatonin for intravenous perfusion in ICU patients suffering from COVID-19 that has been just approved by the Spanish Agency of Medicines and Medical Devices (AEMPS). The trial will allow by the first time understand the doses and efficacy of melatonin against COVID-19.


Assuntos
Antioxidantes/administração & dosagem , Infecções por Coronavirus/tratamento farmacológico , Melatonina/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Betacoronavirus , Humanos , Infusões Intravenosas , Pandemias
7.
Trials ; 21(1): 699, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32758298

RESUMO

OBJECTIVES: • Primary objective: to evaluate the effect of intravenous melatonin (IVM) on mortality in adult patients admitted to the intensive care unit (ICU) with COVID-19. • Secondary objectives: ◦ To evaluate the effect of IVM on ICU length of stay. ◦ To evaluate the effect of IVM on the length of mechanical ventilation (MV). ◦ To evaluate if the use of IVM is associated with an increase in the number of ventilator-free days. ◦ To evaluate if the use of IVM is associated with a reduced number of failing organs as determined by the sequential organ failure assessment (SOFA) scale. ◦ To evaluate if the use of IVM is associated with a reduction of the frequency and severity of COVID-19-associated thromboembolic phenomena. ◦ To evaluate if the use of IVM is associated with a decreased systemic inflammatory response assessed by plasma levels of ferritin, D-dimer, C-reactive protein, procalcitonin and interleukin-6. ◦ To evaluate if the use of IVM is associated with an improvement in hematologic parameters. ◦ To evaluate if the use of IVM is associated with an improvement in biochemical parameters. ◦ To evaluate if the use of IVM is associated with an improvement in blood gas analysis parameters. ◦ To evaluate adverse events during the 28 day study period. TRIAL DESIGN: Phase II, single center, double-blind, placebo-controlled randomized trial with a two-arm parallel group design and 2:1 allocation ratio. PARTICIPANTS: Only critically ill adult patients that fulfill all of the inclusion criteria and none of the exclusion criteria will be included. The study will be conducted in a mixed ICU of a publicly funded tertiary referral center in Madrid, Spain with a 30-bed capacity and 1100 admissions per year. • Inclusion criteria: ◦ Patient, family member or legal guardian has provided written Informed Consent. ◦ Age ε 18 years. ◦ Confirmed SARS-CoV-2 infection with compatible symptoms AND a positive RT-PCR. ◦ Admission to the ICU with acute hypoxemic respiratory failure attributed to SARS-CoV-2 infection. ◦ ICU length of stay of less than 7 days prior to randomization with or without MV and without signs of improvement in respiratory failure (MURRAY score at randomization greater or equal to the MURRAY score at ICU admission). • Exclusion criteria: ◦ Participant in a different COVID-19 study in which the study drug is under clinical development and hasn't been previously authorized for commercialization. ◦ Liver enzymes > 5 times the upper normal range. ◦ Chronic kidney disease with GFR < 30 mL/min/1.73 m2 (stage 4 or greater) or need for hemodialysis. ◦ Pregnancy. A pregnancy test will be performed on every woman younger than 55 years of age prior to inclusion. ◦ Terminal surgical or medical illness. ◦ Autoimmune disease. ◦ Any patient condition that can prevent the study procedures to be carried out at the treating physician's judgement. INTERVENTION AND COMPARATOR: All patients will receive standard-of-care treatment according to the current institutional protocols. In addition, patients will be randomized in a 2:1 ratio to receive: • Experimental group (12 patients): 7 days of 5 mg per Kg of actual body weight per day of intravenous melatonin every 6 hours. Maximum daily dose 500 mg per day. • Control group (6 patients): 7 days of 5 mg per Kg of actual body weight per day of intravenous identically-looking placebo every 6 hours. After 3 days of treatment, 3 intensive care physicians will evaluate the participant and decide whether or not to complete the treatment based on their clinical assessment: • If objective or subjective signs of improvement or no worsening of the general clinical condition, respiratory failure, inflammatory state or multi-organ failure are observed, the participant will continue the treatment until completion. • If an adverse effect or clinical impairment is observed that is objectively or subjectively attributable to the study drug the treatment will be stopped. MAIN OUTCOME: Mortality in each study group represented in frequency and time-to-event at day 28 after randomization RANDOMIZATION: The randomization sequence was created using SAS version 9.4 statistical software (programmed and validated macros) with a 2:1 allocation. No randomization seed was pre-specified. The randomization seed was generated using the time on the computer where the program was executed. BLINDING (MASKING): Participants, caregivers and study groups will be blinded to arm allocation. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): A total of 18 patients will be randomized in this trial: 12 to the experimental arm and 6 to the control arm. TRIAL STATUS: Protocol version 2.0, June 5th 2020. Trial status: recruitment not started. The first patient is expected to be recruited in October 2020. The last patient is anticipated to be recruited in August 2021. TRIAL REGISTRATION: EU Clinical Trials Register. Date of trial registration: 10 July 2020. URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001808-42/ES FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Melatonina/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Administração Intravenosa , Método Duplo-Cego , Humanos , Unidades de Terapia Intensiva , Tempo de Internação , Melatonina/efeitos adversos , Pandemias
8.
J Cancer Res Clin Oncol ; 146(8): 1893-1922, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32583237

RESUMO

PURPOSE: Melatonin is an amphipathic indolamine molecule ubiquitously present in all organisms ranging from cyanobacteria to humans. The pineal gland is the site of melatonin synthesis and secretion under the influence of the retinohypothalamic tract. Some extrapineal tissues (skin, lens, gastrointestinal tract, testis, ovary, lymphocytes, and astrocytes) also enable to produce melatonin. Physiologically, melatonin regulates various functions like circadian rhythm, sleep-wake cycle, gonadal activity, redox homeostasis, neuroprotection, immune-modulation, and anticancer effects in the body. Inappropriate melatonin secretion advances the aging process, tumorigenesis, visceral adiposity, etc. METHODS: For the preparation of this review, I had reviewed the literature on the multidimensional activities of melatonin from the NCBI website database PubMed, Springer Nature, Science Direct (Elsevier), Wiley Online ResearchGate, and Google Scholar databases to search relevant articles. Specifically, I focused on the roles and mechanisms of action of melatonin in cancer prevention. RESULTS: The actions of melatonin are primarily mediated by G-protein coupled MT1 and MT2 receptors; however, several intracellular protein and nuclear receptors can modulate the activity. Normal levels of the melatonin protect the cells from adverse effects including carcinogenesis. Therapeutically, melatonin has chronomedicinal value; it also shows a remarkable anticancer property. The oncostatic action of melatonin is multidimensional, associated with the advancement of apoptosis, the arrest of the cell cycle, inhibition of metastasis, and antioxidant activity. CONCLUSION: The present review has emphasized the mechanism of the anti-neoplastic activity of melatonin that increases the possibilities of the new approaches in cancer therapy.


Assuntos
Melatonina/metabolismo , Melatonina/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Progressão da Doença , Humanos , Melatonina/administração & dosagem , Neoplasias/metabolismo , Neoplasias/patologia , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/metabolismo
9.
Rev Assoc Med Bras (1992) ; 66(3): 353-358, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32520157

RESUMO

OBJECTIVE: Melatonin has anti-inflammatory and antioxidant properties that can influence tissue growth and apoptosis. This aspect may influence the success of organ transplantation. To evaluate the relationship between melatonin and organ transplantation. METHODS: A systematic review was performed in PubMed databases using the search terms: "melatonin physiology" or "melatonin therapy" and "transplant pharmacology" or "transplant physiology" or "transplant therapy" or "Transplant therapy". Experiments on the organs of the reproductive system were not included. After analysis, five articles were selected after reading the title and abstract of 50 manuscripts. The works were divided into two aspects: a) analysis of the influence of the organ transplantation procedure on melatonin production; b) action of melatonin on organ transplantation. RESULTS: The cardiac transplantation surgical procedure, immunosuppression, and graft did not influence melatonin secretion in rodents, but there was a significant reduction of melatonin in the renal transplantation procedure in patients with renal insufficiency. Melatonin administration in experimental models decreased rejection and improved transplant success. CONCLUSION: Studies show that melatonin can reduce organ and species dependence, and the use of melatonin decreases graft rejection.


Assuntos
Antioxidantes/administração & dosagem , Rejeição de Enxerto/prevenção & controle , Melatonina/administração & dosagem , Transplante de Órgãos , Animais , Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Coração , Humanos , Imunossupressão , Transplante de Rim , Melatonina/fisiologia , Ratos
10.
Trials ; 21(1): 466, 2020 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-32493475

RESUMO

OBJECTIVES: Primary objective: to evaluate the efficacy of melatonin as a prophylactic treatment on prevention of symptomatic SARS-CoV-2 infection among healthcare workers at high risk of SARS-CoV-2 exposure. Secondary objectives: To evaluate the efficacy of melatonin as a prophylactic treatment on prevention of asymptomatic SARS-CoV-2 infection.To evaluate the efficacy of melatonin to prevent the development of severe COVID-19 in the participants enrolled in this study who develop SARS-CoV-2 infection along the trial.To evaluate the duration of COVID-19 symptoms in participants receiving melatonin before the infection.To evaluate seroconversion timing post-symptom onset. Exploratory objectives:To compare severity of COVID-19 between men and women.To evaluate the influence of sleep and diet on prevention from SARS-CoV-2 infection.To evaluate the effect of melatonin on the incidence and characteristics of lymphopenia and increase of inflammatory cytokines related to COVID-19. TRIAL DESIGN: This is a two-arm parallel randomised double-blind controlled trial to evaluate the efficacy of melatonin versus placebo in the prophylaxis of coronavirus disease 2019 among healthcare workers. PARTICIPANTS: Inclusion Criteria: Male or female participants ≥ 18 and ≤ 80 years of age.Healthcare workers from the public and private Spanish hospital network at risk of SARS-CoV 2 infection.Not having a previous COVID19 diagnosis.Understanding the purpose of the trial and not having taken any pre-exposure prophylaxis (PrEP) including HIV PrEP from March 1st 2020 until study enrolment.Having a negative SARS-CoV 2 reverse-transcription PCR (RT-PCR) result or a negative serologic rapid test (IgM/IgG) result before randomization.Premenopausal women must have a negative urinary pregnancy test in the 7 days before starting the trial treatment.Premenopausal women and males with premenopausal couples must commit to using a high efficiency anticonceptive method. EXCLUSION CRITERIA: HIV infection.Active hepatitis B infection.Renal failure (CrCl < 60 mL/min/1.73 m2) or need for hemodialysis.Osteoporosis.Myasthenia gravis.Pre-existent maculopathy.Retinitis pigmentosa.Bradycardia (less than 50 bpm).Weight less than 40 Kg.Participant with any immunosuppressive condition or hematological disease.Treatment with drugs that may prolong QT in the last month before randomization for more than 7 days including: azithromycin, chlorpromazine, cisapride, clarithromycin, domperidone, droperidol, erythromycin, halofantrine, haloperidol, lumefantrine, mefloquine, methadone, pentamidine, procainamide, quinidine, quinine, sotalol, sparfloxacin, thioridazine, amiodarone.Hereditary intolerance to galactose, Lapp lactase deficiency or glucose or galactose malabsorption.Treatment with fluvoxamine.Treatment with benzodiazepines or benzodiazepine analogues such as zolpidem, zopiclone or zaleplon.Pregnancy.Breastfeeding.History of potentially immune derived diseases such as: lupus, Crohn's disease, ulcerative colitis, vasculitis or rheumatoid arthritis.Insulin-dependent diabetes mellitus.Known history of hypersensitivity to the study drug or any of its components.Patients that should not be included in the study at the judgment of the research team. Participants will be recruited from the following eight hospitals in Madrid, Spain: Hospital Universitario La Paz, Hospital Ramón y Cajal, Hospital Infanta Sofía, Hospital 12 de Octubre, Hospital Clínico San Carlos, Hospital Central de la defensa Gómez Ulla,Hospital de La Princesa and Hospital Infanta Leonor. INTERVENTION AND COMPARATOR: Experimental: Melatonin (Circadin®, Exeltis Healthcare, Spain): 2 mg of melatonin orally before bedtime for 12 weeks. Comparator: Identical looking placebo (Laboratorios Liconsa, Spain) orally before bedtime for 12 weeks. MAIN OUTCOMES: Number of SARS-CoV-2 (COVID-19) symptomatic infections confirmed by polymerase chain reaction (PCR) test or serologic test or according to each centre diagnosis protocol. Primary outcome will be measured until the end of treatment for each participant (until the date of the last dose taken by each patient). RANDOMISATION: Patients who meet all inclusion and no exclusion criteria will be randomised, stratified by centres, sex and age (<50 and ≥ 50 years old). The randomisation sequence was created using SAS version 9.4 statistical software (procedure 'PROC PLAN') with a 1:1 allocation. No randomisation seed was specified. The randomisation seed was generated taking the hour of the computer where the program was executed. Randomization will be done centrally through the electronic system RedCAP® in order to conceal the sequence until interventions are assigned BLINDING (MASKING): Participants, caregivers, and those assessing the outcomes are blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 450 participants are planned to be enrolled in this clinical trial, 225 in the experimental arm and 225 in the placebo arm. TRIAL STATUS: Protocol version 3.0, 17th of April 2020. Recruitment ongoing. First participant was recruited on the 21st of April 2020. The final participant is anticipated to be recruited on the 31st of May 2020. As of May 18th, 2020, a total of 312 participants have been enrolled (154 at Hospital La Paz, 85 at Hospital Infanta Sofía and 73 at Hospital 12 de Octubre). TRIAL REGISTRATION: EU Clinical Trials Register: 2020-001530-35; Date of trial registration: 13th of April 2020; https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001530-35/ES FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
Antivirais/administração & dosagem , Betacoronavirus/efeitos dos fármacos , Transmissão de Doença Infecciosa do Paciente para o Profissional/prevenção & controle , Melatonina/administração & dosagem , Exposição Ocupacional/efeitos adversos , Saúde do Trabalhador , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , Antivirais/efeitos adversos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Quimioprevenção , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Melatonina/efeitos adversos , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Soroconversão , Espanha , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
11.
Int. j. morphol ; 38(3): 737-746, June 2020. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1098314

RESUMO

This study aimed to evaluate changes in beige adipocytes at different times of melatonin administration, in the morning (ZT01) or in the evening (ZT11), at 30 mg/kg daily by gavage for 7 weeks or continuously with drinking water in the term of high-calorie diet-induced obesity (HCD). Melatonin received at ZT11 or with drinking water resulted in an increased area of the browning zone in the subcutaneous white adipose tissue (sWAT), even in rats with HCD (compared with Control or HCD, respectively). The beige adipocyte and lipid droplet area after melatonin use were reduced compared to those with HCD and Control, in all administration modes (group ZT01 showed smaller changes compared to ZT11 or with drinking water groups). The fibrosis level decreased and significantly differed in HCD ZT01, HCD ZT11, and HCD water compared to that in HCD; moreover, the lowest value determined in HCD water, reached the control parameters. Furthermore, the IL-1b and IL-8 level was decreased in the HCD groups under melatonin treatment at ZT11 or with drinking water compared to that in HCD. The obtained results suggest that melatonin promotes sWAT browning in rats with diet-induced obesity and influences morphological signs of normal rats depending on the time of administration. Different functional activity of beige adipocytes was observed after melatonin was used depending on the time of administration, resulting in heat production and lipolysis (the relative mass of visceral fat was likewise diminished). More rapid browning was observed when melatonin treatment was performed at 1 h before lights-off (ZT11) or continuously via drinking water. Melatonin acted on beige adipocytes of obese rats through changing some parameters such as the area of adipocytes and lipid drops, the number of lipid drops, the relative area browning of sWAT, and the level of tissue fibrosis.


Este estudio tuvo como objetivo evaluar los cambios en los adipocitos beige en diferentes momentos de la administración de melatonina, en la mañana (ZT01) o por la noche (ZT11). Se administraron 30 mg/kg diariamente por sonda durante 7 semanas o continuamente con agua potable durante el periodo de obesidad inducida por una dieta alta en calorías (HCD). La melatonina recibida en ZT11 o con agua potable resultó en un aumento de área dorada en tejido adiposo blanco subcutáneo (sWAT), incluso en ratas con HCD (en comparación con Control o HCD, respectivamente). El área de gotas de lípidos y adipocitos de color beige después del uso de melatonina se redujo en comparación con aquellos con HCD y Control, en todos los modos de administración (el grupo ZT01 mostró cambios más pequeños en comparación con ZT11 o con grupos de agua potable). El nivel de fibrosis disminuyó y difirió significativamente en HCD ZT01, HCD ZT11 y agua HCD, en comparación con el HCD; además, el valor más bajo determinado en agua HCD alcanzó los parámetros de control. Además, el nivel de IL-1b e IL-8 disminuyó en los grupos HCD bajo tratamiento con melatonina en ZT11 o con agua potable en comparación con el de HCD. Los resultados obtenidos sugieren que la melatonina promueve el dorado sWAT en ratas con obesidad inducida por la dieta e influye en los signos morfológicos de las ratas normales dependiendo del momento de la administración. Se observó una actividad funcional diferente de los adipocitos de color beige después de usar melatonina dependiendo del tiempo de administración, dando como resultado la producción de calor y lipólisis (la masa relativa de grasa visceral también disminuyó). Se observó un ennegrecimiento más rápido cuando el tratamiento con melatonina se realizó 1 h antes de apagar las luces (ZT11) o de forma continua en grupos de agua potable. La melatonina actuó en los adipocitos beige de ratas obesas al cambiar algunos parámetros, como el área de adipocitos y gotas de lípidos, el número de gotas de lípidos, el área relativa de ennegrecimiento de sWAT y el nivel de fibrosis tisular.


Assuntos
Animais , Masculino , Ratos , Adipócitos Bege/efeitos dos fármacos , Melatonina/administração & dosagem , Obesidade , Fatores de Tempo , Fibrose , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/patologia , Interleucina-8/efeitos dos fármacos , Dieta , Interleucina-1beta/efeitos dos fármacos
12.
Int Rev Immunol ; 39(4): 153-162, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32347747

RESUMO

The current COVID-19 pandemic is one of the most devastating events in recent history. The virus causes relatively minor damage to young, healthy populations, imposing life-threatening danger to the elderly and people with diseases of chronic inflammation. Therefore, if we could reduce the risk for vulnerable populations, it would make the COVID-19 pandemic more similar to other typical outbreaks. Children don't suffer from COVID-19 as much as their grandparents and have a much higher melatonin level. Bats are nocturnal animals possessing high levels of melatonin, which may contribute to their high anti-viral resistance. Viruses induce an explosion of inflammatory cytokines and reactive oxygen species, and melatonin is the best natural antioxidant that is lost with age. The programmed cell death coronaviruses cause, which can result in significant lung damage, is also inhibited by melatonin. Coronavirus causes inflammation in the lungs which requires inflammasome activity. Melatonin blocks these inflammasomes. General immunity is impaired by anxiety and sleep deprivation. Melatonin improves sleep habits, reduces anxiety and stimulates immunity. Fibrosis may be the most dangerous complication after COVID-19. Melatonin is known to prevent fibrosis. Mechanical ventilation may be necessary but yet imposes risks due to oxidative stress, which can be reduced by melatonin. Thus, by using the safe over-the-counter drug melatonin, we may be immediately able to prevent the development of severe disease symptoms in coronavirus patients, reduce the severity of their symptoms, and/or reduce the immuno-pathology of coronavirus infection on patients' health after the active phase of the infection is over.


Assuntos
Antioxidantes/administração & dosagem , Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Melatonina/administração & dosagem , Medicamentos sem Prescrição/administração & dosagem , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Fatores Etários , Idoso , Envelhecimento/imunologia , Animais , Betacoronavirus/patogenicidade , Quirópteros/imunologia , Quirópteros/virologia , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Humanos , Fotoperíodo , Pneumonia Viral/imunologia , Pneumonia Viral/virologia
13.
Poult Sci ; 99(4): 2185-2195, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32241504

RESUMO

The signal pathway of target of rapamycin (TOR) plays an important role in regulating cell growth and proliferation, follicular development, and ovulation. Melatonin (N-acetyl-5-methoxytryptamine) (MT) is involved in the regulation of many physiological functions in animals. Recent studies have shown that MT affects the number and the degree of maturation of follicles in the ovary, but there are few studies concerning its mechanism. Therefore, the aim of this study was to investigate the mechanism of TOR signal pathway in the regulation of ovarian function by MT in aging laying hens. In the present study, a total of 60 hens (70-week-old) were randomly divided into 2 groups: control group and melatonin group (M). Melatonin was administered intraperitoneally at a dose of 20 mg/kg/D for 28 D in the M group. The results showed that MT significantly increased the levels of the antioxidant enzymes superoxide dismutase and total antioxidant capacity (P < 0.01) as well as levels of immunoglobulin (IgA, IgG, and IgM) (P < 0.05) and the reproductive hormones estradiol and luteinizing hormone (P < 0.01) in the plasma and also increased the numbers of middle white follicles and small white follicles (P < 0.05) and decreased the level of reactive oxygen species in plasma (P < 0.01) in laying hens. There were higher expression levels in MT receptor A (P < 0.05), melatonin receptor B (P < 0.01), and tuberous sclerosis complex 2 (P < 0.01). Activation of TOR, 4E binding protein-l (4E-BP1), and ribosomal protein 6 kinase (P < 0.01) was found in the M. The levels of mTOR and p-mTOR protein were increased in the M (P < 0.05). The mTORC1-dependent 4E-BP1 and p-4E-BP1 were increased in the M (P < 0.05). This study indicated that MT may enhance follicle growth by increasing levels of antioxidant enzymes and reproductive hormones and by activating the mTOR and downstream components in aging laying hens.


Assuntos
Antioxidantes/farmacologia , Galinhas/fisiologia , Melatonina/farmacologia , Folículo Ovariano/crescimento & desenvolvimento , Ovário/fisiologia , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Antioxidantes/administração & dosagem , Proteínas Aviárias/metabolismo , Feminino , Injeções Intraperitoneais/veterinária , Melatonina/administração & dosagem , Folículo Ovariano/efeitos dos fármacos , Ovário/efeitos dos fármacos , Distribuição Aleatória
14.
Int J Nanomedicine ; 15: 1321-1333, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32161461

RESUMO

Introduction: Currently, the unsatisfactory treatment of cardiac hypertrophy is due to the unbridled myocardial fibrosis. Melatonin has been demonstrated to ameliorate cardiac hypertrophy and its accompanied fibrosis in previous studies. But it is not clinically appealing due to its short-lasting time against the hostile microenvironment when administered orally. Methods: Herein, to address this, poly (lactide) polycarboxybetaine (PLGA-COOH) accompanied by cardiac homing peptide (CHP) and superparamagnetic iron oxide nanoparticles (SPIONs) were used to establish a novel drug delivery and transportation strategy for melatonin via a facile two-step emulsion method. This study characterized these nanoparticles (CHP-mel@SPIONs) and tested their delivery to the hypertrophied heart and their effect on myocardial hypertrophy and fibrosis in an animal model of pressure overload-induced cardiac hypertrophy. Results: The engineered magnetic nanoparticles of CHP-mel@SPIONs were spherical (diameter = 221 ± 13 nm) and had a negative zeta potential of -19.18 ± 3.27 mV. The CHP-mel@SPIONs displayed excellent drug encapsulation capacities of SPIONs (75.27 ± 3.1%) and melatonin (77.69 ± 6.04%) separately, and their magnetic properties were characterized by constructing magnetic hysteresis curves and exhibited no remnant magnetization or coercivity. The animal experiments showed that compared with mel@SPIONs, CHP-mel@SPIONs accumulated more in the heart, especially in the presence of an external magnetic field, with in vivo echocardiography and RT-PCR and histological assessments confirming the amelioration of the myocardial hypertrophy and fibrosis with low drug doses. Conclusion: This simple biocompatible dual-targeting nanoagent may be a potential candidate for the guided clinical therapy of heart disease.


Assuntos
Cardiomegalia/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas de Magnetita/química , Melatonina/administração & dosagem , Miocárdio/patologia , Animais , Cardiomegalia/patologia , Modelos Animais de Doenças , Óxido Ferroso-Férrico/química , Fibrose , Coração/efeitos dos fármacos , Campos Magnéticos , Melatonina/farmacologia , Nanoestruturas , Peptídeos/química , Pressão , Ratos Sprague-Dawley
15.
Toxicol Appl Pharmacol ; 392: 114933, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32112789

RESUMO

There is a lack of effective therapies for stroke patients; its treatment is even more difficult considering the unexpected onset of the disease. In the last decade, melatonin has emerged as a promising neuroprotective agent which is able to cross the blood-brain-barrier (BBB) and with a low toxicity profile. The aim of this systematic review was to summarize and critically review clinical and pre-clinical evidence related to melatonin's effectiveness as a stroke treatment. Together with a comparative dose extrapolation with those used in the selected randomized controlled trials (RCTs), and based on these data to discuss whether the administered doses correlate with those advisable in human patients. To address this purpose, we performed a systematic review of the available literature. A total of 529 records were screened with the selecting of six full articles containing RCTs that met the inclusion/exclusion criteria. The evidence drawn from these six reports was analyzed to identify remaining gaps, treatment efficacy, and to suggest future directions. The primary outcome reported was the reduction of the oxidative response; the secondary outcome was the increase of the survival rate of the patients in the intervention groups. Calculations derived from animal studies revealed that the translational doses to humans were substantially higher than those employed in the RCTs. The findings of this systematic review revealed that there are insufficient RCTs to prove melatonin's value in stroke patients. Nevertheless, the evidence is promising, and further clinical research may support the benefits of melatonin in stroke patients, if the adequate dose is administered.


Assuntos
Melatonina/administração & dosagem , Melatonina/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Relação Dose-Resposta a Droga , Humanos
16.
Pediatrics ; 145(4)2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32217739

RESUMO

BACKGROUND: Approximately 25% of children with concussion have persistent postconcussive symptoms (PPCS) with resultant significant impacts on quality of life. Melatonin has significant neuroprotective properties, and promising preclinical data suggest its potential to improve outcomes after traumatic brain injury. We hypothesized that treatment with melatonin would result in a greater decrease in PPCS symptoms when compared with a placebo. METHODS: We conducted a randomized, double-blind trial of 3 or 10 mg of melatonin compared with a placebo (NCT01874847). We included youth (ages 8-18 years) with PPCS at 4 to 6 weeks after mild traumatic brain injury. Those with significant medical or psychiatric histories or a previous concussion within the last 3 months were excluded. The primary outcome was change in the total youth self-reported Post-Concussion Symptom Inventory score measured after 28 days of treatment. Secondary outcomes included change in health-related quality of life, cognition, and sleep. RESULTS: Ninety-nine children (mean age: 13.8 years; SD = 2.6 years; 58% girls) were randomly assigned. Symptoms improved over time with a median Post-Concussion Symptom Inventory change score of -21 (95% confidence interval [CI]: -16 to -27). There was no significant effect of melatonin when compared with a placebo in the intention-to-treat analysis (3 mg melatonin, -2 [95% CI: -13 to 6]; 10 mg melatonin, 4 [95% CI: -7 to 14]). No significant group differences in secondary outcomes were observed. Side effects were mild and similar to the placebo. CONCLUSIONS: Children with PPCS had significant impairment in their quality of life. Seventy-eight percent demonstrated significant recovery between 1 and 3 months postinjury. This clinical trial does not support the use of melatonin for the treatment of pediatric PPCS.


Assuntos
Melatonina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Síndrome Pós-Concussão/tratamento farmacológico , Adolescente , Concussão Encefálica/complicações , Criança , Cognição/efeitos dos fármacos , Intervalos de Confiança , Método Duplo-Cego , Feminino , Humanos , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Melatonina/administração & dosagem , Melatonina/efeitos adversos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/efeitos adversos , Síndrome Pós-Concussão/etiologia , Qualidade de Vida , Tamanho da Amostra , Sono/efeitos dos fármacos , Fatores de Tempo , Resultado do Tratamento
17.
Rev. Assoc. Med. Bras. (1992) ; 66(3): 353-358, Mar. 2020. tab, graf
Artigo em Inglês | LILACS, Sec. Est. Saúde SP | ID: biblio-1136204

RESUMO

SUMMARY Melatonin has anti-inflammatory and antioxidant properties that can influence tissue growth and apoptosis. This aspect may influence the success of organ transplantation. OBJECTIVE To evaluate the relationship between melatonin and organ transplantation. METHODS A systematic review was performed in PubMed databases using the search terms: "melatonin physiology" or "melatonin therapy" and "transplant pharmacology" or "transplant physiology" or "transplant therapy" or "Transplant therapy". Experiments on the organs of the reproductive system were not included. After analysis, five articles were selected after reading the title and abstract of 50 manuscripts. The works were divided into two aspects: a) analysis of the influence of the organ transplantation procedure on melatonin production; b) action of melatonin on organ transplantation. RESULTS The cardiac transplantation surgical procedure, immunosuppression, and graft did not influence melatonin secretion in rodents, but there was a significant reduction of melatonin in the renal transplantation procedure in patients with renal insufficiency. Melatonin administration in experimental models decreased rejection and improved transplant success. CONCLUSION Studies show that melatonin can reduce organ and species dependence, and the use of melatonin decreases graft rejection.


RESUMO A melatonina tem propriedades anti-inflamatórias e antioxidantes que podem influenciar o crescimento e a apoptose dos tecidos. Esse aspecto pode influenciar o sucesso do transplante de órgãos. OBJETIVO Avaliar a relação entre a melatonina e o transplante de órgãos. MÉTODO A revisão sistemática foi realizada nas bases de dados do PubMed, usando os termos de pesquisa: "fisiologia da melatonina" ou "terapêutica da melatonina" e "farmacologia do transplante" ou "fisiologia do transplante" ou "terapêutica do transplante" ou "terapia do transplante". Não foram incluídos os experimentos sobre os órgãos do sistema reprodutivo. Após análise, cinco artigos foram selecionados após a leitura do título e do resumo de 50 manuscritos. Os trabalhos foram divididos em duas vertentes: a) análise da influência do procedimento de transplante de órgão na produção de melatonina; b) ação da melatonina sobre o transplante de órgãos. RESULTADOS O procedimento cirúrgico do transplante cardíaco, a imunossupressão e o enxerto não influenciaram a secreção de melatonina em roedores, mas houve redução significante da melatonina nos casos do procedimento de transplante renal em pacientes com insuficiência renal. A ministração de melatonina em modelos experimentais diminuiu a rejeição e melhorou o sucesso de transplante. CONCLUSÃO Os estudos mostram que a melatonina pode reduzir a dependência da espécie e do órgão e que o emprego da melatonina diminui a rejeição do órgão.


Assuntos
Humanos , Animais , Ratos , Transplante de Órgãos , Rejeição de Enxerto/prevenção & controle , Melatonina/administração & dosagem , Antioxidantes/administração & dosagem , Transplante de Coração , Imunossupressão , Transplante de Rim , Sobrevivência de Enxerto/efeitos dos fármacos , Melatonina/fisiologia
18.
Sci Rep ; 10(1): 2232, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-32042047

RESUMO

Microbial dysbiosis has long been postulated to be associated with the pathogenesis of inflammatory bowel disease (IBD). Although evidence supporting the anti-colitic effects of melatonin have been accumulating, it is not clear how melatonin affects the microbiota. Herein, we investigated the effects of melatonin on the microbiome in colitis and identified involvement of Toll-like receptor (TLR) 4 signalling in the effects. Melatonin improved dextran sulfate sodium (DSS)-induced colitis and reverted microbial dysbiosis in wild-type (WT) mice but not in TLR4 knockout (KO) mice. Induction of goblet cells was observed with melatonin administration, which was accompanied by suppression of Il1b and Il17a and induction of melatonin receptor and Reg3ß, an antimicrobial peptide (AMP) against Gram-negative bacteria. In vitro, melatonin treatment of HT-29 intestinal epithelial cells promotes mucin and wound healing and inhibits growth of Escherichia coli. Herein, we showed that melatonin significantly increases goblet cells, Reg3ß, and the ratio of Firmicutes to Bacteriodetes by suppressing Gram-negative bacteria through TLR4 signalling. Our study suggests that sensing of bacteria through TLR4 and regulation of bacteria through altered goblet cells and AMPs is involved in the anti-colitic effects of melatonin. Melatonin may have use in therapeutics for IBD.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Disbiose/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Células Caliciformes/efeitos dos fármacos , Melatonina/administração & dosagem , Receptor 4 Toll-Like/metabolismo , Animais , Bacteroidetes/efeitos dos fármacos , Bacteroidetes/imunologia , Bacteroidetes/isolamento & purificação , Diferenciação Celular/efeitos dos fármacos , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/imunologia , Colite Ulcerativa/microbiologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Disbiose/imunologia , Disbiose/microbiologia , Disbiose/patologia , Firmicutes/efeitos dos fármacos , Firmicutes/imunologia , Firmicutes/isolamento & purificação , Microbioma Gastrointestinal/imunologia , Células Caliciformes/imunologia , Células Caliciformes/microbiologia , Células Caliciformes/fisiologia , Células HT29 , Humanos , Masculino , Camundongos , Camundongos Knockout , Proteínas Associadas a Pancreatite/imunologia , Proteínas Associadas a Pancreatite/metabolismo , Receptores de Melatonina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/genética
19.
PLoS One ; 15(2): e0228943, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32040524

RESUMO

INTRODUCTION: Age-related hearing loss (ARHL) is a consequence of aging of the auditory system. The best known mechanism of cell death in ARHL is apoptosis due to increased production of reactive oxygen species. In this context, it is hypothesized that melatonin, owing to its high antioxidant potential and its action in the mitochondria, helps prevent or delay outer hair cell dysfunction (HCD). AIMS: To evaluate the effect of melatonin on the prevention of HCD dysfunction in the ARHL process in a susceptible murine C57BL/6J model. METHOD: C57BL/6J animals were divided into two groups: control (CG) and melatonin (MG). The CG received a saline and ethanol solution and the MG, melatonin (10 mg/kg/day). The solutions were offered daily (50 µl) orally over a 10-month period. Distortion Product Otoacoustic Emissions (DPOAE) measurements were conducted once a month. RESULTS: There was a decrease in DPOAE values in both groups over time and a differentiation between them from the 10th month of life onwards. At 10 months, the MG maintained higher DPOAE values than the CG at all frequencies tested. CONCLUSION: The use of melatonin has otoprotective effects on HCD in the ARHL process in the C57BL/6J model.


Assuntos
Melatonina/administração & dosagem , Presbiacusia/prevenção & controle , Administração Oral , Animais , Antioxidantes/administração & dosagem , Caderinas/genética , Modelos Animais de Doenças , Células Ciliadas Auditivas/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação de Sentido Incorreto , Emissões Otoacústicas Espontâneas/efeitos dos fármacos , Presbiacusia/genética , Presbiacusia/fisiopatologia
20.
Anatol J Cardiol ; 23(1): 19-27, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31911566

RESUMO

OBJECTIVE: Protective effects of ischemic postconditioning (PostC) decrease/disappear with age and chronic heart diseases. Similarly, low serum melatonin levels have been reported in the same risk groups. The aims of this study were to investigate the effects of melatonin on the protection of PostC in ischemia-reperfusion (I/R)-induced infarct size and roles of uncoupling protein (UCP) 3, irisin, and nuclear factor kappa B (NFkB) levels. METHODS: Rats were pinealectomized (Px) or sham operated (non-Px) 2 months before the I/R studies. The left main coronary artery was occluded for 30 min followed by 120 min reperfusion. PostC was induced with three cycles of R/I (10 s each) after ischemia. RESULTS: The infarct size was found to be significantly higher in Px rats (54.68±1.5%) than in the control group (35.1±2.5%). PostC and melatonin administrations to non-Px rats significantly reduced the infarct size. On the other hand, PostC did not create a significant effect in Px rats, but protection was provided when PostC was co-administrated with melatonin. While significant decreases were detected in the UCP3 levels, irisin and NFkB levels increased with I/R and Px. Treatment with PostC and melatonin in non-Px groups and their co-administration in Px groups were found to return all the genes close to normal levels. CONCLUSION: The physiological and pharmacological concentrations of melatonin may play a role in the protection of PostC. In cases when physiological melatonin is reduced, such as aging and heart diseases, this protection may decrease, and this effect may be restored by melatonin replacement. PostC and melatonin may regulate energy metabolism and inflammatory mediators and protect mitochondria by affecting the UCP3, irisin, and NFkB levels.


Assuntos
Pós-Condicionamento Isquêmico , Melatonina/uso terapêutico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Proteína Desacopladora 3/sangue , Animais , Modelos Animais de Doenças , Masculino , Melatonina/administração & dosagem , Traumatismo por Reperfusão Miocárdica/sangue , Ratos , Ratos Sprague-Dawley
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