The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

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Nitric Oxide and Peroxynitrite in Health and Disease

Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

In recent years, there has been a great deal of attention toward the field of free radical chemistry. Free radicals reactive oxygen species and reactive nitrogen species are generated by our body by various endogenous systems, exposure to different physiochemical conditions or pathological states. A balance between free radicals and antioxidants is necessary for proper physiological function. If free radicals overwhelm the body's ability to regulate them, a condition known as oxidative stress ensues. Free radicals thus adversely alter lipids, proteins, and DNA and trigger a number of human diseases. Hence application of external source of antioxidants can assist in coping this oxidative stress. Synthetic antioxidants such as butylated hydroxytoluene and butylated hydroxyanisole have recently been reported to be dangerous for human health. Thus, the search for effective, nontoxic natural compounds with antioxidative activity has been intensified in recent years. The present review provides a brief overview on oxidative stress mediated cellular damages and role of dietary antioxidants as functional foods in the management of human diseases.

Free radicals, antioxidants and functional foods: Impact on human health

Phenolics are broadly distributed in the plant kingdom and are the most abundant secondary metabolites of plants. Plant polyphenols have drawn increasing attention due to their potent antioxidant properties and their marked effects in the prevention of various oxidative stress associated diseases such as cancer. In the last few years, the identification and development of phenolic compounds or extracts from different plants has become a major area of health- and medical-related research. This review provides an updated and comprehensive overview on phenolic extraction, purification, analysis and quantification as well as their antioxidant properties. Furthermore, the anticancer effects of phenolics in-vitro and in-vivo animal models are viewed, including recent human intervention studies. Finally, possible mechanisms of action involving antioxidant and pro-oxidant activity as well as interference with cellular functions are discussed.

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Plant phenolics: extraction, analysis and their antioxidant and anticancer properties.

Increasing evidence in both experimental and clinical studies suggests that oxidative stress plays a major role in the pathogenesis of both types of diabetes mellitus. Free radicals are formed disproportionately in diabetes by glucose oxidation, nonenzymatic glycation of proteins, and the subsequent oxidative degradation of glycated proteins. Abnormally high levels of free radicals and the simultaneous decline of antioxidant defense mechanisms can lead to damage of cellular organelles and enzymes, increased lipid peroxidation, and development of insulin resistance. These consequences of oxidative stress can promote the development of complications of diabetes mellitus. Changes in oxidative stress biomarkers, including superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, glutathione levels, vitamins, lipid peroxidation, nitrite concentration, nonenzymatic glycosylated proteins, and hyperglycemia in diabetes, and their consequences, are discussed in this review. In vivo studies of the effects of various conventional and alternative drugs on these biomarkers are surveyed. There is a need to continue to explore the relationship between free radicals, diabetes, and its complications, and to elucidate the mechanisms by which increased oxidative stress accelerates the development of diabetic complications, in an effort to expand treatment options.

Diabetes, oxidative stress, and antioxidants: a review

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.

Melatonin role preventing steatohepatitis and improving liver transplantation results

Obviously, the human diet has become progressively more divergent from those of our ancestors. This maladaptive change became apparent with the Industrial Revolution and has been accelerating in recent decades. In conjunction with this discordance between our ancient, genetically determined biology and the nutritional pattern, in contemporary Western populations, many of the so-called diseases of civilization such as cardiovascular diseases, cancer, and diabetes have emerged. Despite remarkable pharmacological and technological advances, the pandemic of civilization-related diseases continues. Because of this situation, in the last three decades, functional foods, officinal plants are becoming of progressive public and scientific interest and a variety of biologically active compounds have been found in plants. One of them is melatonin; a ubiquitous molecule in nature including most of the edible plants with a variety of health benefits. This

Melatonin; from pineal gland to healthy foods -

Radical and Reactive Intermediate-Scavenging Properties of Melatonin in Pure Chemical Systems

High mortality rates in severe progression of COVID-19 are predominantly caused by pulmonary failure due to high-grade airway inflammation. As investigations on the efficacy of melatonin in this disease are still in their beginning, it may be worth-while to recall the body of evidence on protective effects in other respiratory dysfunctions, which have been studied pre-clinically and clinically. In various diseases and corresponding animal models, melatonin has been shown to be protective, mainly because of its anti-inflammatory and antioxidant properties. This was documented in pathologies as different as allergic airway inflammation, toxicologically or radiation-induced acute lung injury, respiratory disorders such as COPD, obstructive sleep apnea, neonatal respiratory distress syndrome, bronchopulmonary dysplasia and asphyxia, impaired respiration in sepsis, idiopathic pulmonary fibrosis, and pulmonary hypertension. The prevailing outcome has been protection or amelioration by melatonin, in conjunction with reduced expression and release of proinflammatory cytokines, such as IL-1β, IL-2, IL-6, IL-8, and TNFα, which was often explained by interference with toll-like receptors, inhibition of NLRP3 inflammasome activation and suppression of NF-κB signaling. In several studies, these beneficial effects were partially related to the upregulation of sirtuin-1 (SIRT1) by melatonin. The body of knowledge on melatonin’s efficacy in respiratory diseases is encouraging for the use of this powerful agent in COVID-19.

https://www.melatonin-research.net/index.php/MR/article/download/84/603

Protection by melatonin in respiratory diseases: valuable information for the treatment of COVID-19

Melatonin as a natural occurring free radical scavenger and an inducer of antioxidant enzymes has been well documented in thousands of publications within the last decade. Melatonin is no longer exclusively classified as a neurohormone since melatonin has been identified in bacteria, fungi, algae and plants. Likewise, endogenously-produced melatonin is no longer the only source in the body since melatonin is also derived from the diet when vegetables, fruits, cereals, herbs, olive oil, wine or beer are consumed. One important characteristic of melatonin is its permeability into the brain. It readily passes through the blood-brain-barrier and accumulates in the central nervous system at substantially higher levels than exist in the blood. As a result, this molecule exhibits strong neuroprotective effects, especially under the conditions of elevated oxidative stress or intensive neural inflammation.

This volume contains review articles that summarize the newly-described actions of melatonin in the brain. The central nervous system of vertebrates, in addition to the pineal gland, produces melatonin at several sites including in astrocytes, other glia, some neurons and in the meninges. These novel findings point out new aspects regarding the physiological actions of melatonin in the brain.

The neuroprotective effects of melatonin have been tested in many different animal models. These include models of Parkinson’s disease, Alzheimer’s disease, stroke and chemical toxicities. The outcome of these studies provides highly promising evidence that melatonin will prove to be very important in reducing loss of neurons and glia under pathophysiological conditions. The results of clinical trials performed within the last half decade support this conclusion. Some of the major actions of melatonin are mediated at the mitochondrial level such as the action of free radical avoidance.

In addition to melatonin, it is now clear that metabolites of this indoleamine are also significant in executing some the effects initially thought to be exclusively a function of the parent molecule. These important metabolites include especially cyclic-3-hydroxymelatonin, AFMK and AMK. Melatonin as well as these previously-mentioned metabolites are found also in mitochondria, which may be a major site of melatonin’s actions.

These subjects are summarized in the chapters included in this volume. I am grateful to the authors of these contributions for conscientiously reviewing their respective literature in an objective manner.

Dun Xian Tan

Papers

Melatonin role preventing steatohepatitis and improving liver transplantation results

Melatonin; from pineal gland to healthy foods -

Radical and Reactive Intermediate-Scavenging Properties of Melatonin in Pure Chemical Systems

Protection by melatonin in respiratory diseases: valuable information for the treatment of COVID-19

Melatonin and brain.