Therapeutic Potential of Melatonin Counteracting Chemotherapy-Induced Toxicity in Breast Cancer Patients: A Systematic Review.

The purpose of this systematic review is to provide an overview of the existing knowledge on the therapeutic potential of melatonin to counteract the undesirable effects of chemotherapy in breast cancer patients. To this aim, we summarized and critically reviewed preclinical- and clinical-related evidence according to the PRISMA guidelines. Additionally, we developed an extrapolation of melatonin doses in animal studies to the human equivalent doses (HEDs) for randomized clinical trials (RCTs) with breast cancer patients. For the revision, 341 primary records were screened, which were reduced to 8 selected RCTs that met the inclusion criteria. We assembled the evidence drawn from these studies by analyzing the remaining gaps and treatment efficacy and suggested future translational research and clinical trials. Overall, the selected RCTs allow us to conclude that melatonin combined with standard chemotherapy lines would derive, at least, a better quality of life for breast cancer patients. Moreover, regular doses of 20 mg/day seemed to increase partial response and 1-year survival rates. Accordingly, this systematic review leads us to draw attention to the need for more RCTs to provide a comprehensive view of the promising actions of melatonin in breast cancer and, given the safety profile of this molecule, adequate translational doses should be established in further RCTs.

Potential of melatonin to reverse epigenetic aberrations in oral cancer: new findings.

It is now an accepted principle that epigenetic alterations cause cellular dyshomeostasis and functional changes, both of which are essential for the initiation and completion of the tumor cycle. Oral carcinogenesis is no exception in this regard, as most of the tumors in the different subsites of the oral cavity arise from the cross-reaction between (epi)genetic inheritance and the huge challenge of environmental stressors. Currently, the biochemical machinery is put at the service of the tumor program, halting the cell cycle, triggering uncontrolled proliferation, driving angiogenesis and resistance to apoptosis, until the archetypes of the tumor phenotype are reached. Melatonin has the ability to dynamically affect the epigenetic code. It has become accepted that melatonin can reverse (epi)genetic aberrations present in oral and other cancers, suggesting the possibility of enhancing the oncostatic capacity of standard multimodal treatments by incorporating this indolamine as an adjuvant. First steps in this direction confirm the potential of melatonin as a countermeasure to mitigate the detrimental side effects of conventional first-line radiochemotherapy. This single effect could produce synergies of extraordinary clinical importance, allowing doses to be increased and treatments not to be interrupted, ultimately improving patients' quality of life and prognosis. Motivated by the urgency of improving the medical management of oral cancer, many authors advocate moving from in vitro and preclinical research, where the bulk of melatonin cancer research is concentrated, to systematic randomized clinical trials on large cohorts. Recognizing the challenge to improve the clinical management of cancer, our motivation is to encourage comprehensive and robust research to reveal the clinical potential of melatonin in oral cancer control. To improve the outcome and quality of life of patients with oral cancer, here we provide the latest evidence of the oncolytic activity that melatonin can achieve by manipulating epigenetic patterns in oronasopharyngeal tissue.

The Coronavirus Disease 2019 (COVID-19): Key Emphasis on Melatonin Safety and Therapeutic Efficacy.

Viral infections constitute a tectonic convulsion in the normophysiology of the hosts. The current coronavirus disease 2019 (COVID-19) pandemic is not an exception, and therefore the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, like any other invading microbe, enacts a generalized immune response once the virus contacts the body. Melatonin is a systemic dealer that does not overlook any homeostasis disturbance, which consequently brings into play its cooperative triad, antioxidant, anti-inflammatory, and immune-stimulant backbone, to stop the infective cycle of SARS-CoV-2 or any other endogenous or exogenous threat. In COVID-19, the corporal propagation of SARS-CoV-2 involves an exacerbated oxidative activity and therefore the overproduction of great amounts of reactive oxygen and nitrogen species (RONS). The endorsement of melatonin as a possible protective agent against the current pandemic is indirectly supported by its widely demonstrated beneficial role in preclinical and clinical studies of other respiratory diseases. In addition, focusing the therapeutic action on strengthening the host protection responses in critical phases of the infective cycle makes it likely that multi-tasking melatonin will provide multi-protection, maintaining its efficacy against the virus variants that are already emerging and will emerge as long as SARS-CoV-2 continues to circulate among us.

Potential of Melatonin as Adjuvant Therapy of Oral Cancer in the Era of Epigenomics.

The wide variety of epigenetic controls available is rapidly expanding the knowledge of molecular biology even overflowing it. At the same time, it can illuminate unsuspected ways of understanding the etiology of cancer. New emerging therapeutic horizons, then, promise to overcome the current antitumor strategies need. The translational utility of this complexity is particularly welcome in oral cancer (OC), in which natural history is alarmingly disappointing due to the invasive and mutilating surgery, the high relapsing rate, the poor quality of life and the reduced survival after diagnosis. Melatonin activates protective receptor-dependent and receptor-independent processes that prevent tissue cancerisation and inhibit progressive tumor malignancy and metastasis. Related evidence has shown that melatonin pleiotropy encompasses gene expression regulation through all the three best-characterized epigenetic mechanisms: DNA methylation, chromatin modification, and non-coding RNA. OC has received less attention than other cancers despite prognosis is usually negative and there are no significant therapy improvements recorded in the past decade. However, a large research effort is being carried out to elucidate how melatonin´s machinery can prevent epigenetic insults that lead to cancer. In the light of recent findings, a comprehensive examination of biochemistry through which melatonin may reverse epigenetic aberrations in OC is an extraordinary opportunity to take a step forward in the clinical management of patients.

Melatonin: A hypothesis for Kawasaki disease treatment.

Kawasaki disease (KD) is the most common cause of acquired heart disease with unknown etiology among children in developed countries. Acute inflammation of the vasculature, genetic susceptibility and immunopathogenesis based on a transmittable and infectious origin, are the pathologic events involved in the early inflammatory etiology and progression of this disease. However, the exact causes of KD remain unknown. Current proposed recommendations include three therapy lines; firstly, an initial standard therapy with intravenous immunoglobulin (IVIG) followed by aspirin. Secondly, in cases of high risk of coronary lesions, the adjunctive therapy with corticosteroid is commonly considered. Thirdly, in KD patients refractory to the previous therapies, tumor necrosis factor (TNF-α) antagonists are being used to modulate pro-inflammatory cytokines. In view of this status quo, our starting hypothesis is that the ubiquitous and non-toxic neurohormone melatonin could be of critical importance in developing novel adjuvant therapies against KD, as it occurs with a plethora of other diseases. Considering its pleiotropic properties, particularly its antiinflammatory and immunoregulatory capacities, melatonin should be of great therapeutic interest for helping to control the main pathologic features of KD patients. In addition, this multifunctional indole has a safe pharmacological profile, enhancing the therapeutic activity of several drugs and reducing their possible side effects. Consequently, melatonins actions to manage KD need to be tested in further clinical studies.

Melatonin as a versatile molecule to design novel multitarget hybrids against neurodegeneration.

Melatonin is an indoleamine produced mainly in the pineal gland. The natural decline of melatonin levels with aging strongly contributes to the development of neurodegenerative disorders. Pleiotropic actions displayed by melatonin prevent several processes involved in neurodegeneration such as neuroinflammation, oxidative stress, excitotoxicity and/or apoptosis. This review focuses on a number of melatonin hybrids resulting from the juxtaposition of tacrine, berberine, tamoxifen, curcumin, N,N-dibenzyl(N-methyl)amine, among others, with potential therapeutic effects for the treatment of neurodegenerative diseases.

Listado de plantas medicinales comunes con actividad diurética / List of common medicinal plants with diuretic activity

Las plantas medicinales constituyen una fuente inagotable de sustancias activas, se destacan las de acción diurética por su empleo en la terapéutica de enfermedades importantes. Los estudios preclínicos necesarios para el conocimiento y efectividad de su empleo precisan de búsqueda de información que facilite el avance del compromiso investigativo en esta rama de la Medicina Natural. El objetivo consistió en elaborar un listado de plantas medicinales con actividad diurética de fácil localización y amplia distribución en el país, que informe su nombre común y taxonómico, caracteres generales y partes de la planta a utilizar. El trabajo se desarrolló en la Universidad de Ciencias Médicas de Ciego de Ávila, de enero a marzo del 2011 mediante un análisis documental que incluyó literatura especializada (Plantas medicinales, aromáticas o venenosas de Cuba) y publicaciones seriadas como la Revista Cubana de Plantas Medicinales. Se obtuvo un listado de 36 plantas medicinales con actividad diurética presentes en lugares de fácil acceso con amplia distribución en el país, en orden alfabético a partir de su nombre común. Además de, nomenclatura taxonómica, caracteres botánicos, localización, partes botánicas que se utilizan y, en algunos casos, la forma de preparación, además de información complementaria para su consulta por investigadores y especialistas (AU)

The medicinal plants constitute an inexhaustible source of active substances; those of diuretic action stand out due to its employment in the therapeutics of important diseases. The necessary pre-clinical studies for knowledge and effectiveness of its use require search of information which facilitates the research commitment advance in this branch of the Natural Medicine. The purpose of this investigation consisted in elaborating a list of medicinal plants with diuretic activity that can be of easy location and wide distribution in the country, which informs its common and taxonomic name, general characters and parts of the plants to be used. The investigation work was developed in the Medical Sciences University of Ciego de Avila, from January to March 2011 by means of a documentary analysis which included specialized literature: “Cuba´s medicinal, aromatic or poisonous plants” and serials of the Cuban Magazine of Medicinal plants. It was obtained a list of 36 medicinal plants with diuretic activity, which are present in places of easy access with wide distribution in the country, in alphabetical order as per its common name. Besides the taxonomic nomenclature, botanical characters, location, botanical parts which are used and in some cases the form of preparation, in addition to complementary information for its consultation for researchers and specialists (AU)

Acute oral safety study of dairy fat rich in trans-10 C18:1 versus vaccenic plus conjugated linoleic acid in rats.

The acute oral toxicity of a trans-10 C18:1-rich milk fat (T10, 20% of total FA), and a trans-11 C18:1+cis-9 trans-11 C18:2-rich milk fat (T11-CLA, 14% and 4.8% of total FA, respectively) was studied in rats receiving a single oral dose of 2000 mg/kg body weight (BW). T10 and T11-CLA milk fats were well tolerated; no adverse effects or mortality were observed during the 2-week observation period. Two weeks following a single oral dose of 2000 mg/kg BW of T10 and T11-CLA milk fats there were no changes in haematological and serum chemistry parameters (excepting plasma lipid) organ weights, gross pathology or histopathology. In rats treated with T10 milk fat a significant increase of triglycerides was observed. In contrast, in rats treated with T11-CLA milk fat significantly decreased triglycerides were detected. It was concluded that dairy fats rich in T10 and T11-CLA have a low order of acute toxicity, the oral lethal dose (DL50) for male and female rats are in excess of 2000 mg/kg BW. Our results suggest that the T10 milk fat treatment tended to increase triglycerides concentrations, whereas the T11-CLA milk fat treatment tended to reduce it.

Acute and repeated dose (28 days) oral safety studies of an alkoxyglycerol extract from shark liver oil in rats.

Shark liver oil has been used for over 50 years as both a therapeutic and preventive agent. The active ingredients in shark liver oil have been found to be a group of ether-linked glycerols known as alkoxyglycerols. Despite its popularity, there is little published toxicology data on alkoxyglycerols. The toxicity of a supercritical fluid extract of shark liver oil (AKG-1 extract) has been evaluated in acute and repeated dose (28 days) oral toxicity studies in rats at doses of 200 and 100 times the maximum recommended dose by supplement manufacturers in humans, respectively. The AKG-1 extract administered in a single oral gavage dose of 2000 mg kg(-1) of body weight resulted in no adverse events or mortality. The AKG-1 extract administered as a daily dose of 1000 mg kg(-1) of body weight for 28 days by gavage resulted in no adverse effects or mortality. For both studies, no abnormal clinical signs, behavioral changes, body weight changes, or change in food and water consumption occurred. There were no changes in hematological and serum chemistry values, organ weights, or gross or histological characteristics. It is concluded that the AKG-1 extract is well tolerated in rats at an acute dose of 2000 mg kg(-1) and at a subchronic (28 days) dose of 1000 mg kg(-1).