Eduardo Esteban-Zubero

Melatonin as a Potent and Inducible Endogenous Antioxidant: Synthesis and Metabolism

Melatonin is a tryptophan-derived molecule with pleiotropic activities. It is present in almost all or all organisms. Its synthetic pathway depends on the species in which it is measured. For example, the tryptophan to melatonin pathway differs in plants and animals. It is speculated that the melatonin synthetic machinery in eukaryotes was inherited from bacteria as a result of endosymbiosis. However, melatonin’s synthetic mechanisms in microorganisms are currently unknown. Melatonin metabolism is highly complex with these enzymatic processes having evolved from cytochrome C. In addition to its enzymatic degradation, melatonin is metabolized via pseudoenzymatic and free radical interactive processes. The metabolic products of these processes overlap and it is often difficult to determine which process is dominant. However, under oxidative stress, the free radical interactive pathway may be featured over the others. Because of the complexity of the melatonin degradative processes, it is expected that additional novel melatonin metabolites will be identified in future investigations. The original and primary function of melatonin in early life forms such as in unicellular organisms was as a free radical scavenger and antioxidant. During evolution, melatonin was selected as a signaling molecule to transduce the environmental photoperiodic information into an endocrine message in multicellular organisms and for other purposes as well. As an antioxidant, melatonin exhibits several unique features which differ from the classic antioxidants. These include its cascade reaction with free radicals and its capacity to be induced under moderate oxidative stress. These features make melatonin a potent endogenously-occurring antioxidant that protects organisms from catastrophic oxidative stress.

Melatonin’s role in preventing toxin-related and sepsis-mediated hepatic damage: A review

The liver is a central organ in detoxifying molecules and would otherwise cause molecular damage throughout the organism. Numerous toxic agents including aflatoxin, heavy metals, nicotine, carbon tetrachloride, thioacetamide, and toxins derived during septic processes, generate reactive oxygen species followed by molecular damage to lipids, proteins and DNA, which culminates in hepatic cell death. As a result, the identification of protective agents capable of ameliorating the damage at the cellular level is an urgent need. Melatonin is a powerful endogenous antioxidant produced by the pineal gland and a variety of other organs and many studies confirm its benefits against oxidative stress including lipid peroxidation, protein mutilation and molecular degeneration in various organs, including the liver. Recent studies confirm the benefits of melatonin in reducing the cellular damage generated as a result of the metabolism of toxic agents. These protective effects are apparent when melatonin is given as a sole therapy or in conjunction with other potentially protective agents. This review summarizes the published reports that document melatonins ability to protect hepatocytes from molecular damage due to a wide variety of substances (aflatoxin, heavy metals, nicotine, carbon tetrachloride, chemotherapeutics, and endotoxins involved in the septic process), and explains the potential mechanisms by which melatonin provides these benefits. Melatonin is an endogenously-produced molecule which has a very high safety profile that should find utility as a protective molecule against a host of agents that are known to cause molecular mutilation at the level of the liver.

Melatonin's role as a co-adjuvant treatment in colonic diseases: A review.

Abstract Melatonin is produced in the pineal gland as well as many other organs, including the enterochromaffin cells of the digestive mucosa. Melatonin is a powerful antioxidant that resists oxidative stress due to its capacity to directly scavenge reactive species, to modulate the antioxidant defense system by increasing the activities of antioxidant enzymes, and to stimulate the innate immune response through its direct and indirect actions. In addition, the dysregulation of the circadian system is observed to be related with alterations in colonic motility and cell disruptions due to the modifications of clock genes expression. In the gastrointestinal tract, the activities of melatonin are mediated by melatonin receptors (MT2), serotonin (5‐HT), and cholecystokinin B (CCK2) receptors and via receptor‐independent processes. The levels of melatonin in the gastrointestinal tract exceed by 10–100 times the blood concentrations. Also, there is an estimated 400 times more melatonin in the gut than in the pineal gland. Gut melatonin secretion is suggested to be influenced by the food intake. Low dose melatonin treatment accelerates intestinal transit time whereas high doses may decrease gut motility. Melatonin has been studied as a co‐adjuvant treatment in several gastrointestinal diseases including irritable bowel syndrome (IBS), constipation‐predominant IBS (IBS‐C), diarrhea‐predominant IBS (IBS‐D), Crohns disease, ulcerative colitis, and necrotizing enterocolitis. The purpose of this review is to provide information regarding the potential benefits of melatonin as a co‐adjuvant treatment in gastrointestinal diseases, especially IBS, Crohns disease, ulcerative colitis, and necrotizing enterocolitis.

Potential benefits of melatonin in organ transplantation: a review

Organ transplantation is a useful therapeutic tool for patients with end-stage organ failure; however, graft rejection is a major obstacle in terms of a successful treatment. Rejection is usually a consequence of a complex immunological and nonimmunological antigen-independent cascade of events, including free radical-mediated ischemia-reperfusion injury (IRI). To reduce the frequency of this outcome, continuing improvements in the efficacy of antirejection drugs are a top priority to enhance the long-term survival of transplant recipients. Melatonin (N-acetyl-5-methoxytryptamine) is a powerful antioxidant and ant-inflammatory agent synthesized from the essential amino acid l-tryptophan; it is produced by the pineal gland as well as by many other organs including ovary, testes, bone marrow, gut, placenta, and liver. Melatonin has proven to be a potentially useful therapeutic tool in the reduction of graft rejection. Its benefits are based on its direct actions as a free radical scavenger as well as its indirect antioxidative actions in the stimulation of the cellular antioxidant defense system. Moreover, it has significant anti-inflammatory activity. Melatonin has been found to improve the beneficial effects of preservation fluids when they are enriched with the indoleamine. This article reviews the experimental evidence that melatonin is useful in reducing graft failure, especially in cardiac, bone, otolaryngology, ovarian, testicular, lung, pancreas, kidney, and liver transplantation.

Melatonin role preventing steatohepatitis and improving liver transplantation results

Liver steatosis is a prevalent process that is induced due to alcoholic or non-alcoholic intake. During the course of these diseases, the generation of reactive oxygen species, followed by molecular damage to lipids, protein and DMA occurs generating organ cell death. Transplantation is the last-resort treatment for the end stage of both acute and chronic hepatic diseases, but its success depends on ability to control ischemia–reperfusion injury, preservation fluids used, and graft quality. Melatonin is a powerful endogenous antioxidant produced by the pineal gland and a variety of other because of its efficacy in organs; melatonin has been investigated to improve the outcome of organ transplantation by reducing ischemia–reperfusion injury and due to its synergic effect with organ preservation fluids. Moreover, this indolamine also prevent liver steatosis. That is important because this disease may evolve leading to an organ transplantation. This review summarizes the observations related to melatonin beneficial actions in organ transplantation and ischemic–reperfusion models.

Transient headache and neurological deficits with cerebrospinal fluid lymphocytosis (Handl Syndrome): A case report

The syndrome of headache with neurologic deficits and cerebrospinal fluid lymphocytosis (HaNDL) is a rare entity. This disease has been related with migrainous headaches. It is a benign disorder, self-limited, and characterized by fluctuating neurological symptoms and cerebrospinal fluid (CSF) lymphocytosis. A small proportion of patients develop intracranial hypertension as a consequence of the illness. Confusional state may be also observed. We describe a case of a 29 years old man with acute onset of headache, dysthermia sensation, vomits, aphasia, and difficulty to perform daily activities such as unlocking the mobile phone. Blood tests as well as computed tomography (CT) and magnetic resonance imaging (MRI) were normal. Cerebroespinal fluid analysis revealed a lymphocytic pleocytosis (47 cells/μl, 100% lymphocytes). Electroencephalogram showed moderate slow rhythm in the left hemisphere, with frontotemporal predominance, and without epileptiform activity. With the diagnosis of HaNDL syndrome the patient was accepted in the Department of Neurology and discharged asymptomatic without treatment. Correspondence to: Eduardo Esteban Zubero, Emergency Department of Hospital San Pedro-26006, Logroño, Spain, Tel: +34654123994; Email: eezubero@gmail.com

Diagnosis Bias and its Revelance During the Diagnosis Process

Diagnosis bias occurs when the diagnosis is not intentionally delayed (the physician do not have the sufficient information available), after an error, or missed to evaluate some information provided (it may occurs due to it could be the first time that the physician try to diagnose the pathology). It may be clasified in cognitive errors, with different subtypes (including cognitive biases, heuristic, diagnostic anchoring, player’s fallacty, satisfaction bias, confirmation bias, outcome bias, retrospective distortion, and overconfidence), and affective influences. Both of them may occur in the two different diagnostics models: Model 1, based on an intuitive and automatic process that requires little cognitive ability; and model 2, a reflexive and analytical process that requires great cognitive ability. However, in the clinical practice, a mix of them is generally used. Diagnosis bias are important because it has been estimated an error rate in a range from 0.6% to 12%. In addition, the adverse effects generated by diagnostic errors have been estimated to range from 6.9% to 17%. The purpouse of this review is to improve the knowledge about diagnosis bias, the awareness of them, and provide adequate ways to avoid them.

Determination of plasma lactate in the emergency department for the early detection of tissue hypoperfusion in septic patients

Objective: To determine the validity of plasma lactate in the emergency department for the early detection of tissue hypoperfusion in septic patients. Materials and methods: Longitudinal descriptive study. Non probabilistic sampling for convenience. Plasma lactate levels were determined in patients admitted to the emergency department with systemic inflammatory response data and clinical suspicion or documented infection. Follow‐up was seven days. Complications were considered if the patients presented septic shock, severe sepsis, entry to intensive care or death. Results: Ninety patients were included. The mean age was 57.4 ± 20.31. Fifty five percent (n = 49) were women. 25% (n = 22) of the patients showed complications. Plasma lactate levels were 1.55 mmol/L in uncomplicated patients and 3.72 mmol/L for complicated patients (p < 0.001). The area under the ROC curve was 0.72 (95% CI, 0.575–0.829). The cutoff point that best described the relationship with the probability of complications was that set at 4.2 mmol/L. The variables studied that showed a significant association with the probability of complications were edema (p = 0.004), and infections of the respiratory tract (p = 0.037). A model that included lactate levels, using as adjustment variables edema and the presence of low respiratory tract infection explained between 0.234 and 0.349 of the dependent variant, correctly classifying 80% of the cases. Conclusion: Plasma lactate is useful in emergency departments as a predictive test for the early detection of patients with tissue hypoperfusion that evolve to severe sepsis, septic shock or death.