Current Insights and Future Directions in the Treatment of Heart Failure with Preserved Ejection Fraction.

Heart failure is a clinical syndrome associated with poor quality of life, substantial healthcare resource utilization, and premature mortality, in large part related to high rates of hospitalizations. The clinical manifestations of heart failure are similar regardless of the ejection fraction. Unlike heart failure with reduced ejection fraction, there are few therapeutic options for treating heart failure with preserved ejection fraction. Molecular therapies that have shown reduced mortality and morbidity in heart failure with reduced ejection have not been proven to be effective for patients with heart failure and preserved ejection fraction. The study of pathophysiological processes involved in the production of heart failure with preserved ejection fraction is the basis for identifying new therapeutic means. In this narrative review, we intend to synthesize the existing therapeutic means, but also those under research (metabolic and microRNA therapy) for the treatment of heart failure with preserved ejection fraction.

Papel de las alteraciones del sueño durante la gestación en la programación del feto para el desarrollo de obesidad y enfermedades crónicas degenerativas.

Sleep disturbances are common in the third trimester of pregnancy and generate changes in the secretion of melatonin in pregnant women who sleep less than eight hours or have sleep disturbances, which promote various physiological changes in the mother that in turn result in low birth weight (LBW) in the fetus. LBW is associated with a phenomenon known as "metabolic programming," in which the fetus is subjected to a stressful situation that results in irreversible metabolic alterations that predispose it to the development of obesity in adulthood.

En el tercer trimestre del embarazo son frecuentes las alteraciones del sueño, las cuales generan cambios en la secreción de melatonina en mujeres gestantes que duermen menos de ocho horas o presentan alteraciones de sueño, promoviendo diversos cambios fisiológicos en la madre, que a su vez derivan en bajo peso al nacimiento (BPN) en el producto. El bajo peso al nacimiento está asociado con un fenómeno conocido como "programación metabólica", en la que el feto es sometido a estrés que tiene como resultado alteraciones metabólicas irreversibles que lo predisponen al desarrollo de obesidad en la edad adulta.

Effects of melatonin on the acute inflammatory response associated with endoscopic retrograde cholangiopancreatography: A randomized, double-blind, placebo-controlled trial. / Efectos de la melatonina en la respuesta inflamatoria aguda asociada con la colangiopancreatografía retrógrada endoscópica: un ensayo clínico aleatorizado, doble ciego y controlado con placebo.

INTRODUCTION: Endoscopic retrograde cholangiopancreatography (ERCP) is associated with an acute inflammatory response and melatonin has a variety of immunomodulatory and antioxidant effects studied experimentally in pancreatobiliary pathology. AIMS: The aim of our study was to evaluate the effects of peri-procedural administration of melatonin on the inflammatory response and lipid peroxidation associated with ERCP. METHODS: In this proof-of-concept clinical trial, 37 patients with a high probability of choledocholithiasis were randomized to receive peri-procedure (ERCP) melatonin or placebo. We measured the serum concentration of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), lipid peroxidation, amylase, and liver function tests 24h before and after the procedure. RESULTS: We found no pre-procedure or post-procedure differences between the melatonin group or the placebo group (P>.05) in the serum concentrations of TNF-alpha (melatonin: 153.8 vs. 149.4ng/m; placebo: 103.5 vs. 107.3ng/ml), IL-6 (melatonin: 131.8 vs. 133.3ng/ml; placebo: 177.8 vs. 197.8ng/ml), or VEGF (melatonin: 157.3 vs. 157.8pg/ml; placebo: 97.3 vs. 97.8pg/ml), or in relation to lipid peroxidation (melatonin: 39.2 vs. 72.3µg/ml; placebo: 66.4 vs. 90.5µg/ml). After ERCP, a significant decrease in the AST, ALT, and total bilirubin levels was found only in the melatonin group (P<.05). The administration of melatonin was safe and tolerable. CONCLUSIONS: Melatonin is safe and tolerable in patients undergoing ERCP, but it does not appear to affect inflammatory cytokine concentrations or lipid peroxidation.

[Properties of milk in sleep induction]. / Propiedades de la leche en la inducción del sueño.

Introduction: Sleep induction and its quality are issues of growing concern because its deterioration affects a large number of people and poses a risk to their well-being and quality of life and long-term health. There are several factors involved in the problem, but nutrition is one of them and in particular milk consumption has often been linked to sleep habits, sometimes as a promoter and sometimes as an inhibitor. The purpose of this review is to examine the matter further. On reaching the brain, tryptophan is the basis for the synthesis of serotonin and melatonin, which improve the induction and quality of sleep. But there is competition between tryptophan and other long-chain neutral amino acids (LNAA) (valine, leucine, isoleucine, tyrosine and phenylalanine) to cross the blood-brain barrier and reach the brain. In this sense, milk proteins with a high tryptophan content and the highest ratio between tryptophan and LNAA are very useful in promoting sleep. Moreover, milk also provides various micronutrients that help in the transformation of tryptophan into serotonin and melatonin, as well as antioxidant components, anti-inflammatory and bioactive peptides, and recent studies indicate that it favorably modulates the composition of the intestinal microbiota. Studies show that increasing milk consumption, up to the recommended intake and within a correct diet, favors the achievement and maintenance of quality sleep.

Introducción: La inducción del sueño y su calidad son temas de preocupación creciente porque su deterioro afecta a un número elevado de personas y supone un riesgo en su bienestar y calidad de vida y en la salud a largo plazo. Hay diversos factores implicados en el problema, pero la nutrición es uno de ellos y, en concreto, el consumo de leche se ha relacionado frecuentemente con los hábitos de sueño, a veces como factor promotor y otras como inhibidor. Profundizar en el tema es el objeto de la presente revisión. El triptófano, al llegar al cerebro, es la base para la síntesis de serotonina y melatonina, que mejoran la inducción y la calidad del sueño. Pero hay una competencia entre el triptófano y otros aminoácidos neutros de cadena larga (ANCL) (valina, leucina, isoleucina, tirosina y fenilalanina) para cruzar la barrera hematoencefálica y llegar al cerebro. En este sentido, las proteínas de la leche, con elevado contenido en triptófano y la relación más elevada entre triptófano y ANCL, son muy útiles en la promoción del sueño. Por otra parte, la leche también aporta diversos micronutrientes que ayudan en la transformación del triptófano en serotonina y melatonina, así como componentes antioxidantes, antiinflamatorios y péptidos bioactivos, y estudios recientes indican que modula favorablemente la composición de la microbiota intestinal. Los estudios realizados ponen de relieve que aumentar el consumo de leche, hasta el aporte aconsejado y dentro de una alimentación correcta, favorece el conseguir y mantener un sueño de calidad.

Therapeutic effects of melatonin in long-term exposure to 2100MHz radiofrequency radiation on rat sperm characteristics.

INTRODUCTION: Radiofrequency electromagnetic fields (RF-EMFs) are one of the risk factors for male reproductive health and melatonin can be an ideal candidate for therapeutic development against RF-induced male fertility problems due to its antioxidant properties. The possible therapeutic role of melatonin in the destructive effects of 2100MHz RF radiation on rat sperm characteristics is investigated in the present study. METHODS: Wistar albino rats were divided into four groups and the experiment continued for ninety consecutive days; Control, Melatonin (10mg/kg, subcutaneously), RF (2100MHz, thirty minutes per day, whole-body), and RF+Melatonin groups. Left caudal epididymis and ductus deferens tissues were placed in sperm wash solution (at 37°C) and dissected. The sperms were counted and stained. Measurements of the perinuclear ring of the manchette and posterior portion of the nucleus (ARC) were performed and the sperms were examined at an ultrastructural level. All of the parameters were evaluated statistically. RESULTS: The percentages of abnormal sperm morphology were significantly increased with RF exposure, while the total sperm count was significantly decreased. RF exposure also showed harmful effects on acrosome, axoneme, mitochondrial sheath, and outer dense fibers at the ultrastructural level. The number of total sperms, sperms with normal morphology increased, and ultrastructural appearance returned to normal by melatonin administration. DISCUSSION: The data showed that melatonin may be a beneficial therapeutic agent for long-term exposure of 2100MHz RF radiation-related reproductive impairments.

Midazolam reduction with pre-operative melatonin in abdominal hysterectomy: double-blind randomized clinical trial.

INTRODUCTION: Midazolam is a benzodiazepine used for sedation, however, can cause respiratory depression and increases morbidity in patients. Melatonin is an effective alternative to manage anxiety in the perioperative period and could help to reduce the use of benzodiazepines during surgery. The aim of this clinical trial was to determine the efficacy of pre-operative sedation with a single-dose melatonin to reduce intraoperative use of midazolam in women under total abdominal hysterectomy (TAH). MATERIALS AND METHODS: This is a double-blind randomized clinical trial conducted in women over 25 years, scheduled for TAH, with American Society of Anesthesiologists Grade I or II. Each patient was randomly assigned to receive 5 mg of melatonin prolonged-release oral capsules or placebo. Midazolam use for anesthetic management was the decision of the treating anesthesiologist and sedation status was determined using the observer's assessment of alertness/sedation scale. RESULTS: In patients receiving melatonin, the use of midazolam during surgery was less than in patients receiving placebo. In addition, melatonin produces sedation 30 min after administration, the sedative effect was maintained at 60- and 90-min. Furthermore, hospital stay was shorter in patients who received melatonin (p = 0.006). CONCLUSION: Melatonin is effective for reduces intraoperative midazolam consumption and hospital stay in women undergoing TAH.

INTRODUCCIÓN: El midazolam es una benzodiazepina utilizada para la sedación, sin embargo, puede causar depresión respiratoria y aumentar la morbilidad en los pacientes. La melatonina es una alternativa eficaz para controlar la ansiedad en el período perioperatorio y podría ayudar a reducir el uso de benzodiazepinas durante la cirugía. El objetivo de este ensayo clínico fue determinar la eficacia de la sedación preoperatoria con una dosis única de melatonina para reducir el uso intraoperatorio de midazolam en mujeres sometidas a histerectomía abdominal total (HTA). MATERIAL Y MÉTODOS: Se trata de un ensayo clínico aleatorizado doble ciego realizado en mujeres mayores de 25 años, programadas para TAH, con American Society of Anesthesiologists Grado I o II. Cada paciente fue asignado al azar para recibir 5 mg de cápsulas orales de liberación prolongada de melatonina o placebo. El uso de midazolam para el manejo anestésico fue decisión del anestesiólogo tratante y el estado de sedación se determinó mediante la escala OAA/S. RESULTADOS: En las pacientes que recibieron melatonina, el uso de midazolam durante la cirugía fue menor que en las pacientes que recibieron placebo. Además, la melatonina produce sedación 30 min después de la administración, el efecto sedante se mantuvo a los 60 y 90 min. Además, la estancia hospitalaria fue más corta en los pacientes que recibieron melatonina (p = 0.006). CONCLUSIÓN: La melatonina es eficaz para reducir el consumo de midazolam intraoperatorio y la estancia hospitalaria en mujeres sometidas a HTA.

Melatonin in sleep disorders.

Melatonin is the main hormone involved in the control of the sleep-wake cycle. It is easily synthesisable and can be administered orally, which has led to interest in its use as a treatment for insomnia. Moreover, as production of the hormone decreases with age, in inverse correlation with the frequency of poor sleep quality, it has been suggested that melatonin deficit is at least partly responsible for sleep disorders. Treating this age-related deficit would therefore appear to be a natural way of restoring sleep quality, which is lost as patients age. However, despite the undeniable theoretical appeal of this approach to insomnia, little scientific evidence is available that supports any benefit of this substitutive therapy. Furthermore, the most suitable dose ranges and pharmaceutical preparations for melatonin administration are yet to be clearly defined. This review addresses the physiology of melatonin, the different pharmaceutical preparations, and data on its clinical usefulness.

A comparative study of melatonin and immunomodulatory therapy with interferon beta and glatiramer acetate in a mouse model of multiple sclerosis. / Estudio comparativo de melatonina contra los tratamientos inmunomoduladores (interferón beta y acetato de glatirámero) en un modelo murino de esclerosis múltiple.

INTRODUCTION: Multiple sclerosis (MS) is a chronic, demyelinating, autoimmune disease of the central nervous system causing neuroinflammation. Experimental autoimmune encephalitis (EAE) is a model of the disease. MS is classically treated with interferon beta (IFN-ß) and glatiramer acetate (GA). Melatonin (MLT) has been reported to modulate immune system responses. The aim of the present study is to analyse the effects of MLT administration in comparison with the first-line treatments for MS (IFN-ß and GA). METHODS: EAE was induced in male Sprague-Dawley rats; the animals subsequently received either IFN-ß, GA, or MLT. Cerebrospinal fluid (CSF) samples were analysed by multiplex assay to determine the levels of proinflammatory cytokines. The neurological evaluation of EAE was also recorded. RESULTS: All immunised animals developed EAE. We evaluated the first relapse-remission cycle, observing that IFN-ß and GA had better results than MLT in the clinical evaluation. Neither EAE nor any of the treatments administered modified CSF IL-1ß and IL-12p70 concentrations. However, IFN-ß and MLT did decrease CSF TNF-α concentrations. CONCLUSIONS: Further studies are needed to evaluate the molecular mechanisms involved in the behaviour of MLT in EAE, and to quantify other cytokines in different biological media in order for MLT to be considered an anti-inflammatory agent capable of regulating MS.

Familiar Dermatologic Drugs as Therapies for COVID-19. / Fármacos de uso frecuente en dermatología como terapia para COVID-19.

Researchers the world over are working to find the treatments needed to reduce the negative effects of coronavirus disease 2019 (COVID-19) and improve the current prognosis of patients. Several drugs that are often used in dermatology are among the potentially useful treatments: ivermectin, antiandrogenic agents, melatonin, and the antimalarial drugs chloroquine and hydroxychloroquine. These and other agents, some of which have proven controversial, are being scrutinized by the scientific community. We briefly review the aforementioned dermatologic drugs and describe the most recent findings relevant to their use against COVID-19.

Melatonin ameliorates the drug induced nephrotoxicity: Molecular insights.

BACKGROUND: Drug-induced nephrotoxicity is a frequent adverse event that can lead to acute or chronic kidney disease and increase the healthcare expenditure. It has high morbidity and mortality incidence in 40-70% of renal injuries and accounts for 66% cases of renal failure in elderly population. OBJECTIVE: Amelioration of drug-induced nephrotoxicity has been long soughed to improve the effectiveness of therapeutic drugs. This study was conducted to review the melatonin potential to prevent the pathogenesis of nephrotoxicity induced by important nephrotoxic drugs. METHODS: We analyzed the relevant studies indexed in Pubmed, Medline, Scielo and Web of science to explain the molecular improvements following melatonin co-administration with special attention to oxidative stress, inflammation and apoptosis as key players of drug-induced nephrotoxicity. RESULTS: A robust consensus among researchers of these studies suggested that melatonin efficiently eradicate the chain reaction of free radical production and induced the endogenous antioxidant enzymes which attenuate the lipid peroxidation of cellular membranes and subcellular oxidative stress in drug-induced nephrotoxicity. This agreement was further supported by the melatonin role in disintegration of inflammatory process through inhibition of principle pro-inflammatory or apoptotic cytokines such as TNF-α and NF-κB. These studies highlighted that alleviation of drug-induced renal toxicity is a function of melatonin potential to down regulate the cellular inflammatory and oxidative injury process and to stimulate the cellular repair or defensive mechanisms. CONCLUSION: The comprehensive nephroprotection and safer profile suggests the melatonin to be a useful adjunct to improve the safety of nephrotoxic drugs.

Melatonina en trastornos del sueño: comparación de distintos productos y revisión bibliográfica / Melatonin in sleep disorders. comparison of different products and literature review

Introducción: los trastornos del sueño en Pediatría son un problema creciente. La melatonina es el producto de elección y es común recibir publicidad de múltiples productos que la contienen. En este texto se lleva a cabo un análisis comparativo de los mismos, examinando la evidencia científica más reciente, con el fin de determinar si está justificado o no su uso. Métodos: se ha realizado un estudio descriptivo de los productos que contenían melatonina comercializados en España, de venta en farmacias y dirigidos a la población pediátrica. Posteriormente, se ha llevado a cabo una revisión de documentos sobre el uso de melatonina en niños y sobre cada componente extra presente en los productos recogidos. Resultados: se analizaron 53 productos. La forma de administración mayoritaria fue en gotas o mililitros. La dosis recomendada habitual de melatonina fue de 1 mg al día. El componente añadido más frecuente registrado fue la vitamina B6, y melisa y pasiflora fueron las plantas más utilizadas. Ninguno de los productos estaba catalogado como fármaco por la Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) y tampoco se encontró en la publicidad de ninguno referencias bibliográficas. Conclusiones: aunque es conocida la eficacia de la melatonina en trastornos del sueño, actualmente no hay un consenso sobre su dosis eficaz en edad pediátrica. Las sustancias que más frecuentemente se asocian a melatonina cuentan con poca bibliografía que respalde sus resultados sobre el sueño, además de que para ellas tampoco existen, de momento, dosis estandarizadas para la población infantil. (AU)

Introduction: sleep disorders in paediatrics are a growing problem. Melatonin is the drug of choice and it is common to receive advertising for multiple products containing melatonin in primary care. In this paper, a comparative analysis of these products is carried out, examining the most recent scientific evidence, in order to determine whether their use is justified or not. Methods: a descriptive study was conducted on melatonin-containing products sold in pharmacies in Spain and aimed at the paediatric population. Subsequently, a systematic review of documents on the use of melatonin in children and on each extra component present in the products collected was carried out. Results: fifty-three products were analysed. The most common form of administration was drops or millilitres. The usual recommended dose of melatonin was 1 mg per day. The most frequently reported added component was vitamin B6, and lemon balm and passionflower were the most frequently used herbs. None of the products were specifically listed in the Spanish Agency for Medicines and Health Products, and no bibliographical references were found in the advertising of any of the products. Conclusions: although the efficacy of melatonin in sleep disorders is well known, there is currently no consensus on its effective dose in children. The substances most frequently associated with melatonin have little literature to support their results in sleep, and there are no standardised doses for them either, or doses lower than these are used due to a lack of studies in the paediatric population. (AU)

[Effect of melatonin on the daytime sleepiness side-effect of gabapentin in adults patients with neuropathic pain]. / Efeito da melatonina sobre o efeito colateral de sonolência diurna da gabapentina em pacientes adultos com dor neuropática.

BACKGROUND AND OBJECTIVES: Gabapentin is an antiepileptic drug. Widely used for the management of neuropathic pain. Although it is known to be well tolerated, somnolence and dizziness are the most frequent adverse effects. In this study, we aimed to evaluate the effect of melatonin on daytime sleepiness side effect of gabapentin, sleep quality and pain intensity of patients with neuropathic pain. METHODS: Patients suffering from "neuropathic pain" and planed to receive gabapentin therapy were randomly divided into two groups. Group 1 received melatonin 3mg and gabapentin 900mg orally, group 2 received matching placebo capsule and gabapentin 900mg. The Epworth Sleepiness Scale, the Pittsburgh sleep quality index for assessment of sleep quality and Verbal Rating Scale were completed at the 0th, 10th and 30th days of treatment. Additive analgesic drug requirements were recorded. RESULTS: Eighty patients were enrolled to the study; age, gender, ratio of additive analgesic consumption, baseline Epworth Sleepiness Scale, Pittsburg Sleep Quality index and Verbal Rating Scale scores were similar between the groups. Epworth Sleepiness Scale scores, Pittsburgh sleep quality index scores and Verbal Rating Scale scores in Group 1 were significantly lower than group 2 at the 10th day of treatment (p=0.002, p=0.003, p=0.002 respectively). At the 30th day of treatment, Epworth Sleepiness Scale scores and Verbal Rating Scale scores were significantly lower in Group 1 (p=0.002, p=0.008 respectively). However, Pittsburgh sleep quality index scores did not significantly differ between the groups (p=0.0566). CONCLUSIONS: Melatonin supplementation rapidly and significantly improved daytime sleepiness side-effect of gabapentin, however sleep quality of the patients with neuropathic pain was similar between groups.

Therapeutic potential of stem cell and melatonin on the reduction of CCl4-induced liver fibrosis in experimental mice model

Abstract Liver fibrosis is initial stage of any chronic liver disease and its end stage is develops into cirrhosis. Chronic liver diseases are a crucial global health issue and the cause of approximately 2 million deaths per year worldwide. Cirrhosis is currently the 11th most common cause of death globally. Mesenchymal stem cell (MSCs) treatment is the best way to treat acute and chronic liver disease. The aim of this study is to improve the therapeutic potential of MSCs combined with melatonin (MLT) to overcome CCl4-induced liver fibrosis and also investigate the individual impact of melatonin and MSCs against CCl4-induced liver impairment in animal model. Female BALB/c mice were used as CCL4-induced liver fibrotic animal model. Five groups of animal model were made; negative control, Positive control, CCl4+MSCs treated group, CCl4+MLT treated group and CCl4+MSCs+MLT treated group. Cultured MSCs from mice bone marrow were transplanted to CCl4-induced liver injured mice model, individually as well as together with melatonin. Two weeks after MSCs and MLT administration, all groups of mice were sacrificed for examination. Morphological and Histopathological results showed that combined therapy of MSCs+MLT showed substantial beneficial impact on CCl4-induced liver injured model, compared with MSCs and MLT individually. Biochemically, considerable reduction was observed in serum bilirubin and ALT levels of MLT+MSC treated mice, compared to other groups. PCR results shown down-regulation of Bax and up-regulation of Bcl-xl and Albumin, confirm a significant therapeutic effect of MSCs+MLT on CCI4-induced liver fibrosis. From the results, it is concluded that combined therapy of MSCs and MLT show strong therapeutic effect on CCL4-induced liver fibrosis, compared with MSCs and MLT individually.

Resumo A fibrose hepática é a fase inicial de qualquer doença hepática crônica, e em sua fase final desenvolve-se para cirrose. As doenças hepáticas crônicas são uma questão de saúde global crucial e a causa de aproximadamente 2 milhões de mortes por ano em todo o mundo. A cirrose, hoje em dia, é a 11ª causa mais comum de morte globalmente. O tratamento da célula-tronco mesenquimal (MSCs) é uma maneira eletiva de tratar a doença hepática aguda e crônica. O objetivo deste estudo é melhorar o potencial terapêutico dos MSCs combinados com a melatonina (MLT) para superar a fibrose hepática induzida por CCl4 e também investigar o impacto individual da melatonina e MSCs contra o comprometimento do fígado induzido por CCl4 no modelo animal. Os ratos BALB / C fêmeas foram usados como modelo de animal fibrótico de fígado induzido por CCl4. Cinco grupos de modelo animal foram feitos: Controle Negativo, Controle Positivo, CCl4 + MSCs Tratados Grupo, Grupo Tratado CCl4 + MLT e Grupo Tratado CCl4 + MSCs + MLT. MSCs cultivados da medula óssea dos ratos foram transplantados para o modelo de camundongos de fígado induzido por CCl4, individualmente, bem como em conjunto com a melatonina. Duas semanas após a administração MSCs e MLT, todos os grupos de camundongos foram sacrificados para o exame. Os resultados morfológicos e histopatológicos mostraram que a terapia combinada do MSCs + MLT mostrou impacto benéfico substancial no modelo ferido no fígado induzido pelo CCl4, em comparação com o MSCs e o MLT individualmente. A redução bioquimicamente considerável foi observada em bilirrubina sérica e níveis ALT de ratinhos tratados com MLT + MSCs, em comparação com outros grupos. Os resultados de PCR mostraram regulação negativa do BAX e regulação positiva do BCL-XL e da albumina, confirmando um efeito terapêutico significativo do MSCs + MLT na fibrose hepática induzida por CCl4. Dos resultados, conclui-se que a terapia combinada de MSCs e MLT mostram um forte efeito terapêutico na fibrose hepática induzida por CCl4, em comparação com MSCs e MLT individualmente.

Therapeutic potential of stem cell and melatonin on the reduction of CCl4-induced liver fibrosis in experimental mice model / Potencial terapêutico de células-tronco e melatonina na redução da fibrose hepática induzida por CCl4 no modelo de ratos experimentais

Liver fibrosis is initial stage of any chronic liver disease and its end stage is develops into cirrhosis. Chronic liver diseases are a crucial global health issue and the cause of approximately 2 million deaths per year worldwide. Cirrhosis is currently the 11th most common cause of death globally. Mesenchymal stem cell (MSCs) treatment is the best way to treat acute and chronic liver disease. The aim of this study is to improve the therapeutic potential of MSCs combined with melatonin (MLT) to overcome CCl4-induced liver fibrosis and also investigate the individual impact of melatonin and MSCs against CCl4-induced liver impairment in animal model. Female BALB/c mice were used as CCL4-induced liver fibrotic animal model. Five groups of animal model were made; negative control, Positive control, CCl4+MSCs treated group, CCl4+MLT treated group and CCl4+MSCs+MLT treated group. Cultured MSCs from mice bone marrow were transplanted to CCl4-induced liver injured mice model, individually as well as together with melatonin. Two weeks after MSCs and MLT administration, all groups of mice were sacrificed for examination. Morphological and Histopathological results showed that combined therapy of MSCs+MLT showed substantial beneficial impact on CCl4-induced liver injured model, compared with MSCs and MLT individually. Biochemically, considerable reduction was observed in serum bilirubin and ALT levels of MLT+MSC treated mice, compared to other groups. PCR results shown down-regulation of Bax and up-regulation of Bcl-xl and Albumin, confirm a significant therapeutic effect of MSCs+MLT on CCI4-induced liver fibrosis. From the results, it is concluded that combined therapy of MSCs and MLT show strong therapeutic effect on CCL4-induced liver fibrosis, compared with MSCs and MLT individually.

A fibrose hepática é a fase inicial de qualquer doença hepática crônica, e em sua fase final desenvolve-se para cirrose. As doenças hepáticas crônicas são uma questão de saúde global crucial e a causa de aproximadamente 2 milhões de mortes por ano em todo o mundo. A cirrose, hoje em dia, é a 11ª causa mais comum de morte globalmente. O tratamento da célula-tronco mesenquimal (MSCs) é uma maneira eletiva de tratar a doença hepática aguda e crônica. O objetivo deste estudo é melhorar o potencial terapêutico dos MSCs combinados com a melatonina (MLT) para superar a fibrose hepática induzida por CCl4 e também investigar o impacto individual da melatonina e MSCs contra o comprometimento do fígado induzido por CCl4 no modelo animal. Os ratos BALB / C fêmeas foram usados ​​como modelo de animal fibrótico de fígado induzido por CCl4. Cinco grupos de modelo animal foram feitos: Controle Negativo, Controle Positivo, CCl4 + MSCs Tratados Grupo, Grupo Tratado CCl4 + MLT e Grupo Tratado CCl4 + MSCs + MLT. MSCs cultivados da medula óssea dos ratos foram transplantados para o modelo de camundongos de fígado induzido por CCl4, individualmente, bem como em conjunto com a melatonina. Duas semanas após a administração MSCs e MLT, todos os grupos de camundongos foram sacrificados para o exame. Os resultados morfológicos e histopatológicos mostraram que a terapia combinada do MSCs + MLT mostrou impacto benéfico substancial no modelo ferido no fígado induzido pelo CCl4, em comparação com o MSCs e o MLT individualmente. A redução bioquimicamente considerável foi observada em bilirrubina sérica e níveis ALT de ratinhos tratados com MLT + MSCs, em comparação com outros grupos. Os resultados de PCR mostraram regulação negativa do BAX e regulação positiva do BCL-XL e da albumina, confirmando um efeito terapêutico significativo do MSCs + MLT na fibrose hepática induzida por CCl4. Dos resultados, conclui-se que a terapia combinada de MSCs e MLT mostram um forte efeito terapêutico na fibrose hepática induzida por CCl4, em comparação com MSCs e MLT individualmente.

Efficacy of melatonin in decreasing the incidence of delirium in critically ill adults: a randomized controlled trial / Eficácia da melatonina na redução da incidência de delirium em pacientes adultos graves: um ensaio clínico randomizado

ABSTRACT Objective: To determine whether enteral melatonin decreases the incidence of delirium in critically ill adults. Methods: In this randomized controlled trial, adults were admitted to the intensive care unit and received either usual standard care alone (Control Group) or in combination with 3mg of enteral melatonin once a day at 9 PM (Melatonin Group). Concealment of allocation was done by serially numbered opaque sealed envelopes. The intensivist assessing delirium and the investigator performing the data analysis were blinded to the group allocation. The primary outcome was the incidence of delirium within 24 hours of the intensive care unit stay. The secondary outcomes were the incidence of delirium on Days 3 and 7, intensive care unit mortality, length of intensive care unit stay, duration of mechanical ventilation and Glasgow outcome score (at discharge). Results: We included 108 patients in the final analysis, with 54 patients in each group. At 24 hours of intensive care unit stay, there was no difference in the incidence of delirium between Melatonin and Control Groups (29.6 versus 46.2%; RR = 0.6; 95%CI 0.38 - 1.05; p = 0.11). No secondary outcome showed a statistically significant difference. Conclusion: Enteral melatonin 3mg is not more effective at decreasing the incidence of delirium than standard care is in critically ill adults.

RESUMO Objetivo: Determinar se a melatonina enteral diminui a incidência de delirium em adultos em estado grave. Métodos: Neste estudo controlado e randomizado, os adultos foram admitidos à unidade de terapia intensiva e/ou receberam apenas o padrão de cuidado habitual (Grupo Controle) ou o tratamento combinado com 3mg de melatonina enteral uma vez ao dia às 21h (Grupo Melatonina). A ocultação da alocação foi feita por meio de envelopes selados opacos e numerados sequencialmente. O intensivista que avaliou o delirium e o pesquisador que realizou a análise dos dados foram cegados quanto à alocação do grupo. O desfecho primário foi a incidência de delirium dentro de 24 horas de internação na unidade de terapia intensiva. Os desfechos secundários foram a incidência de delirium nos dias 3 e 7, a mortalidade na unidade de terapia intensiva, a duração da internação na unidade de terapia intensiva, a duração da ventilação mecânica e o escore da escala de desfecho de Glasgow (na alta). Resultados: Foram incluídos 108 pacientes na análise final, com 54 sujeitos em cada grupo. Em 24 horas de internação na unidade de terapia intensiva, a incidência de delirium não foi diferente entre os Grupos Melatonina e Controle (29,6% versus 46,2%; RR = 0,6; IC95% 0,38 - 1,05; p = 0,11). Nenhum desfecho secundário apresentou diferenças estatisticamente significativas. Conclusão: Em adultos em estado grave, 3mg de melatonina enteral não foi mais eficaz que os cuidados padrão na redução da incidência de delirium.

Serum melatonin levels during the first seven days of severe sepsis diagnosis are associated with sepsis severity and mortality.

OBJECTIVE: Higher serum melatonin levels have previously been found in patients with severe sepsis who died within 30 days of diagnosis than in survivors. The objective of our study were to determine whether serum melatonin levels during the first seven days of severe sepsis diagnosis could be associated with sepsis severity and mortality. METHODS: Multicentre study in eight Spanish Intensive Care Units which enrolled 308 patients with severe sepsis. We determined serum levels of melatonin, malondialdehyde (as biomarker of lipid peroxidation) and tumor necrosis factor-alpha at days 1, 4 and 8 of severe sepsis diagnosis. The study's primary endpoint was 30-day mortality. RESULTS: A total of 103 patients had died and 205 survived at 30 days of severe sepsis diagnosis, with the non-survivors presenting higher serum melatonin levels at days 1 (p<0.001), 4 (p<0.001) and 8 (p<0.001) of severe sepsis diagnosis than the survivor patient group. The multiple logistic regression analysis found that serum melatonin levels at days 1, 4 and 8 of severe sepsis diagnosis (p<0.001, p=0.01 and p=0.001, respectively) were associated with mortality adjusted for age, serum lactic acid, SOFA score and diabetes mellitus. CONCLUSIONS: The novel and more interesting findings of our study were that serum melatonin levels during the first seven days of severe sepsis diagnosis are associated with sepsis severity and mortality.

Immunohistochemical evidence of melatonin protection on lung tissue during chemotherapy / Evidencia inmunohistoquímica de la protección de la melatonina en el tejido pulmonar durante la quimioterapia

SUMMARY: The present study investigated the possible protective effects of melatonin on Bleomycin, Cisplatin and etoposide (BEP) chemotherapy regimens using immunohistochemistry. Forty male Wistar rats were divided into four groups of ten as; group 1 as untreated control; group 2 as BEP group which received the three cycles of 21 days' regimen each of 0.5¥ dose levels ofBEP (bleomycin 0.75 mg/kg, etoposide 7.5 mg/kg and cisplatin 1.5 mg/kg). Rats in the group 3 (MEL group) received 10 mg/kg/day melatonin once daily. Group 4 received the melatonin (30 min before the BEP injections) and BEP as in groups 2. Proliferating cell nuclear antigen (PCNA) staining was used to detect cell proliferation and caspase-3, caspase-9 and Caspase-8 were detected to investigate apoptosis. PCNA immunostaining in alveolar epithelium, alveolar macrophages and bronchus was weak to moderate in BEP group. However, diffuse and strong caspase immunoreactions for caspase-3, caspase 8- and caspase-9 were detected in the bronchioles epithelium, vascular endothelium, alveolar luminal macrophages in the BEP group. PCNA and caspase immunoreactivities in MEL and Mel + BEP groups were close to the control one. The surface are in the BEP group was significantly reduced as compared to the control one ((P0.05). It can be concluded that BEP regimen can affects negatively on lung tissue and melatonin inhibits lung tissue injuries during BEP chemotherapy.

El presente estudio investigó los posibles efectos protectores de la melatonina en los regímenes de quimioterapia con bleomicina, etopósido y cisplatino (BEP) mediante inmunohistoquímica. Cuarenta ratas Wistar macho se dividieron en cuatro grupos de diez: grupo 1, control sin tratar; grupo 2, quimioterapia con una dosis de 0,5x de BEP (0,75 mg/kg de bleomicina, 7,5 mg/ kg de etopósido y 1,5 mg/kg de cisplatino) con tres ciclos de 21 días cada uno. Las ratas del grupo 3 (grupo MEL) recibieron 10 mg/kg/día de melatonina una vez al día. El grupo 4 (Mel + BEP) recibió melatonina (30 minutos antes de las inyecciones de BEP) y BEP, como en los grupos 2. Se usó la tinción del antígeno nuclear de células en proliferación (PCNA) para detectar la proliferación celular y, caspasa- 3, caspasa-9 y caspasa-8 para investigar apoptosis. La inmunotinción de PCNA en el epitelio alveolar, los macrófagos alveolares y los bronquios varió de débil a moderada en el grupo BEP. Sin embargo, se detectaron inmunorreacciones difusas y fuertes para caspasa-3, caspasa 8- y caspasa-9 en el epitelio de los bronquiolos, endotelio vascular y macrófagos luminales alveolares. Las inmunorreactividades de PCNA y caspasa en los grupos MEL y Mel + BEP fueron similares a las del control. El área de superficie en el grupo BEP se redujo significativamente en comparación con el control (P0,05). Se puede concluir que la quimioterapia con BEP puede afectar negativamente al tejido pulmonar y la melatonina inhibe las lesiones durante la quimioterapia.

Maternal obesity and its repercussions on melatonin and cortisol in breast milk and human colostrum

Introduction: scientific evidence has highlighted the role of chronobiological disruptions in promoting obesity through mechanisms involving important circadian rhythm hormones: melatonin and cortisol. These hormones are present in human colostrum and serve as crucial maternal and child protection mechanisms against obesity and childhood infections, owing to the intense interaction between mother and child during pregnancy and breastfeeding. Consequently, the melatonin and cortisol hormones present in human colostrum hold promise as potential candidates for yielding clinically applicable results and supporting future intervention strategies aimed at reducing obesity and neonatal infections. However, there is a scarcity of literature on this subject. Objective: the objective of this study is to to analyze the impact of maternal obesity on the levels and functions of melatonin and cortisol in colostrum and breast milk. Methods: a systematic review of the scientific literature was conducted following the recommendations outlined in the PRISMA protocol. Original articles published in English were searched in the PubMed, Medline, Lilacs, and Scopus databases. There were no restrictions on the publication year. Results: a total of 37 articles were identified from the searched databases. After removing duplicates and applying the inclusion and exclusion criteria, only five studies were relevant to the topic: two studies addressing melatonin and three studies analyzing cortisol. This review revealed that melatonin levels are elevated in the colostrum of obese women, and for this particular group, it has the potential to restore phagocyte activity and increase lymphocyte proliferation. Studies on cortisol have demonstrated that maternal obesity does not alter the levels of this hormone in breast milk. Conclusion: breastfeeding should be encouraged for all populations, and further original research should be conducted to elucidate the protective mechanisms of colostrum and breast milk.

Introdução: evidências científicas enfatizam que disrupções cronobiológicas podem promover a obesidade por mecanismos envolvendo ação de importantes hormônios marcadores do ritmo circadiano: a melatonina e cortisol. Estes hormônios estão presentes no colostro humano e representam importante mecanismo de proteção materno infantil frente à obesidade e infecções infantis, devido à intensa interação entre mãe e filho durante a gravidez e amamentação. Assim, os hormônios melatonina e cortisol presentes no colostro humano representam promissores candidatos para fornecer resultados com capacidade de aplicação clínica e de embasamento de futuras estratégias de intervenção com enfoque na redução da obesidade e de infecções neonatais. Entretanto, são escassos os estudos na literatura sobre o tema. Objetivo: analisar as repercussões da obesidade materna sobre os níveis e as ações da melatonina e do cortisol no colostro e leite materno. Método: foi realizada uma revisão sistematizada da literatura científica seguindo as recomendações do protocolo Prisma. Foram pesquisados artigos originais, publicados em inglês, nas bases de dados PubMed, Medline, Lilacs e Scopus. Não houve restrição quanto ao ano de publicação. Resultados: foram identificados 37 artigos nas bases de dados pesquisados, 15 artigos foram excluídos por estarem duplicados, após aplicação do critério de inclusão e exclusão apenas 5 estudos tiveram relação ao tema, sendo 2 estudos abordando sobre melatonina e 3 pesquisas que analisaram o cortisol. Esta revisão mostrou que a melatonina está elevada em colostro de obesas e para este grupo ela possui potencial de restaurar atividade de fagócitos e de elevar a proliferação de linfócitos. Os estudos sobre o cortisol ilustraram que os níveis deste hormônio no leite materno não foram alterados pela obesidade materna. Conclusão: o aleitamento materno deve ser encorajado para todos os públicos, assim como mais pesquisas originais devem ser desenvolvidas para descrever os mecanismos protetores do colostro e leite materno

Serum levels of melatonin may contribute to the pathogenesis of heart failure in children with median age of 1 year.

OBJECTIVE: Melatonin has a protective role in adults with cardiovascular disease, but the effects of melatonin in children with cardiac dysfunction are not well understood. This study was designed to explore the variations in melatonin, myeloperoxidase, and caspase-3 levels in children suffering from heart failure. METHODS: Seventy-two pediatric patients with heart failure and twelve healthy children were enrolled in this study. A modified Ross scoring system was used to evaluate clinical cardiac function. Patients with a score of >2 points were included in the study and were divided into three groups according to severity of heart failure: mild (score: 3-6), moderate (score: 7-9), and severe (score: 10-12). Echocardiographic parameters, laboratory data, and serum levels of melatonin, myeloperoxidase, and caspase-3 were measured and analyzed in all patients. RESULTS: Compared with patients with mild and moderate heart failure, patients in the severe heart failure group had significantly decreased left ventricular ejection fraction (p<0.001), and significantly increased serum melatonin levels (p=0.013) and myeloperoxidase levels (p<0.001). Serum melatonin levels were positively correlated with serum caspase-3 levels (p<0.001). The optimal cutoff values of serum melatonin levels for the diagnosis of severe heart failure and primary cardiomyopathy in pediatric patients with heart failure were 54.14pg/mL and 32.88pg/mL, respectively. CONCLUSIONS: Serum melatonin and myeloperoxidase levels were increased in children with severe heart failure. It is likely that increasing melatonin levels may act as a compensatory mechanism in pediatric children with heart failure.

Propiedades de la leche en la inducción del sueño / Properties of milk in sleep induction

La inducción del sueño y su calidad son temas de preocupación creciente porque su deterioro afecta a un número elevado de personas y suponeun riesgo en su bienestar y calidad de vida y en la salud a largo plazo. Hay diversos factores implicados en el problema, pero la nutrición es unode ellos y, en concreto, el consumo de leche se ha relacionado frecuentemente con los hábitos de sueño, a veces como factor promotor y otrascomo inhibidor. Profundizar en el tema es el objeto de la presente revisión.El triptófano, al llegar al cerebro, es la base para la síntesis de serotonina y melatonina, que mejoran la inducción y la calidad del sueño. Pero hayuna competencia entre el triptófano y otros aminoácidos neutros de cadena larga (ANCL) (valina, leucina, isoleucina, tirosina y fenilalanina) paracruzar la barrera hematoencefálica y llegar al cerebro. En este sentido, las proteínas de la leche, con elevado contenido en triptófano y la relaciónmás elevada entre triptófano y ANCL, son muy útiles en la promoción del sueño. Por otra parte, la leche también aporta diversos micronutrientesque ayudan en la transformación del triptófano en serotonina y melatonina, así como componentes antioxidantes, antiinflamatorios y péptidosbioactivos, y estudios recientes indican que modula favorablemente la composición de la microbiota intestinal.Los estudios realizados ponen de relieve que aumentar el consumo de leche, hasta el aporte aconsejado y dentro de una alimentación correcta,favorece el conseguir y mantener un sueño de calidad. (AU)

Sleep induction and its quality are issues of growing concern because its deterioration affects a large number of people and poses a risk to theirwell-being and quality of life and long-term health. There are several factors involved in the problem, but nutrition is one of them and in particularmilk consumption has often been linked to sleep habits, sometimes as a promoter and sometimes as an inhibitor. The purpose of this review isto examine the matter further.On reaching the brain, tryptophan is the basis for the synthesis of serotonin and melatonin, which improve the induction and quality of sleep. Butthere is competition between tryptophan and other long-chain neutral amino acids (LNAA) (valine, leucine, isoleucine, tyrosine and phenylalanine)to cross the blood-brain barrier and reach the brain. In this sense, milk proteins with a high tryptophan content and the highest ratio betweentryptophan and LNAA are very useful in promoting sleep.Moreover, milk also provides various micronutrients that help in the transformation of tryptophan into serotonin and melatonin, as well as antioxidantcomponents, anti-inflammatory and bioactive peptides, and recent studies indicate that it favorably modulates the composition of the intestinalmicrobiota. Studies show that increasing milk consumption, up to the recommended intake and within a correct diet, favors the achievementand maintenance of quality sleep. (AU)