Antioxidant enzymes form the first line of defense against free radicals in organisms. Their regulation depends mainly on the oxidant status of the cell, given that oxidants are their principal modulators. However, other factors have been reported to increase antioxidant enzyme activity and/or gene expression. During the last decade, the antioxidant melatonin has been shown to possess genomic actions, regulating the expression of several genes. Melatonin also influences both antioxidant enzyme activity and cellular mRNA levels for these enzymes. In the present report, we review the studies which document the influence of melatonin on the activity and expression of the antioxidative enzymes glutathione peroxidase, superoxide dismutases and catalase both under physiological and under conditions of elevated oxidative stress. We also analyze the possible mechanisms by which melatonin regulates these enzymes.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1600-079X.2003.00092.x

Regulation of antioxidant enzymes: a significant role for melatonin.

Melatonin is uncommonly effective in reducing oxidative stress under a remarkably large number of circumstances. It achieves this action via a variety of means: direct detoxification of reactive oxygen and reactive nitrogen species and indirectly by stimulating antioxidant enzymes while suppressing the activity of pro-oxidant enzymes. In addition to these well-described actions, melatonin also reportedly chelates transition metals, which are involved in the Fenton/Haber-Weiss reactions; in doing so, melatonin reduces the formation of the devastatingly toxic hydroxyl radical resulting in the reduction of oxidative stress. Melatonin's ubiquitous but unequal intracellular distribution, including its high concentrations in mitochondria, likely aid in its capacity to resist oxidative stress and cellular apoptosis. There is credible evidence to suggest that melatonin should be classified as a mitochondria-targeted antioxidant. Melatonin's capacity to prevent oxidative damage and the associated physiological debilitation is well documented in numerous experimental ischemia/reperfusion (hypoxia/reoxygenation) studies especially in the brain (stroke) and in the heart (heart attack). Melatonin, via its antiradical mechanisms, also reduces the toxicity of noxious prescription drugs and of methamphetamine, a drug of abuse. Experimental findings also indicate that melatonin renders treatment-resistant cancers sensitive to various therapeutic agents and may be useful, due to its multiple antioxidant actions, in especially delaying and perhaps treating a variety of age-related diseases and dehumanizing conditions. Melatonin has been effectively used to combat oxidative stress, inflammation and cellular apoptosis and to restore tissue function in a number of human trials; its efficacy supports its more extensive use in a wider variety of human studies. The uncommonly high-safety profile of melatonin also bolsters this conclusion. It is the current feeling of the authors that, in view of the widely diverse beneficial functions that have been reported for melatonin, these may be merely epiphenomena of the more fundamental, yet-to-be identified basic action(s) of this ancient molecule.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jpi.12360

Melatonin as an antioxidant: under promises but over delivers.

In aerobic organisms, oxygen is essential for efficient energy production but paradoxically, produces chronic toxic stress in cells. Diverse protective systems must exist to enable adaptation to oxidative environments. Oxidative stress (OS) results when production of reactive oxidative species (ROS) exceeds the capacity of cellular antioxidant defenses to remove these toxic species. Epidemiological and clinical studies have linked environmental factors such as diet and lifestyle to cancer, diabetes, atherosclerosis, and neurodegenerative disorders. All of these conditions, as well as the aging process, are associated with OS due to elevation of ROS or insufficient ROS detoxification. Many environmental pollutants engage signaling pathways that are activated in response to OS. The same sequences of events are also associated with the etiology and early pathology of many chronic diseases. Investigations of oxidative responses in different in vivo models suggest that, in complex organisms such as mammals, organs and tissues contain distinct antioxidant systems, and this may form the basis for differential susceptibility to environmental toxic agents Thus, understanding the pathways leading to the induction of antioxidant responses will enable development of strategies to protect against oxidative damage. We shall review evidence of organ-specific antioxidant responses elicited by environmental pollutants in humans and animal models.

The role of antioxidants and antioxidant-related enzymes in protective responses to environmentally induced oxidative stress

Background: Resveratrol is a natural compound suggested to have beneficial health effects. However, people are consuming resveratrol for this reason without having the adequate scientific evidence for its effects in humans. Therefore, scientific valid recommendations concerning the human intake of resveratrol based on available published scientific data are necessary. Such recommendations were formulated after the Resveratrol 2010 conference, held in September 2010 in Helsingor, Denmark. Methodology: Literature search in databases as PubMed and ISI Web of Science in combination with manual search was used to answer the following five questions: 1 Can resveratrol be recommended in the prevention or treatment of human diseases?; 2 Are there observed ‘‘side effects’’ caused by the intake of resveratrol in humans?; 3 What is the relevant dose of resveratrol?; 4 What valid data are available regarding an effect in various species of experimental animals?; 5 Which relevant (overall) mechanisms of action of resveratrol have been documented? Conclusions/Significance: The overall conclusion is that the published evidence is not sufficiently strong to justify a recommendation for the administration of resveratrol to humans, beyond the dose which can be obtained from dietary sources. On the other hand, animal data are promising in prevention of various cancer types, coronary heart diseases and diabetes which strongly indicate the need for human clinical trials. Finally, we suggest directions for future research in resveratrol regarding its mechanism of action and its safety and toxicology in human subjects.

/pdf/what-is-new-for-an-old-molecule-systematic-review-and-36e7gs43t0.pdf

What Is New for an Old Molecule? Systematic Review and Recommendations on the Use of Resveratrol

Melatonin (N-acetyl-5-methoxytryptamine) is a molecule with a very wide phylogenetic distribution from plants to man. In vertebrates, melatonin was initially thought to be exclusively of pineal origin recent studies have shown, however, that melatonin synthesis may occur in a variety of cells and organs. The concentration of melatonin within body fluids and subcellular compartments varies widely, with blood levels of the indole being lower than those at many other sites. Thus, when defining what constitutes a physiological level of melatonin, it must be defined relative to a specific compartment. Melatonin has been shown to have a variety of functions, and research in the last decade has proven the indole to be both a direct free radical scavenger and indirect antioxidant. Because of these actions, and possibly others that remain to be defined, melatonin has been shown to reduce the toxicity and increase the efficacy of a large number of drugs whose side effects are well documented. Herein, we summarize the beneficial effects of melatonin when combined with the following drugs: doxorubicin, cisplatin, epirubicin, cytarabine, bleomycin, gentamicin, ciclosporin, indometacin, acetylsalicylic acid, ranitidine, omeprazole, isoniazid, iron and erythropoietin, phenobarbital, carbamazepine, haloperidol, caposide-50, morphine, cyclophosphamide and L-cysteine. While the majority of these studies were conducted using animals, a number of the investigations also used man. Considering the low toxicity of melatonin and its ability to reduce the side effects and increase the efficacy of these drugs, its use as a combination therapy with these agents seems important and worthy of pursuit.

https://onlinelibrary.wiley.com/doi/pdf/10.1211/002235702760345374

Melatonin: reducing the toxicity and increasing the efficacy of drugs.

Regarding the mechanisms of methotrexate (MTX) hepatotoxicity and nephrotoxicity, several hypotheses have been put forward, among which oxidative stress (including depletion of glutathione) is likely. This investigation elucidates the role of free radicals in MTX-induced toxicity and the protection by melatonin. Wistar albino rats were injected with MTX intraperitoneally. Following a single dose of MTX (20 mg/kg), either saline (MTX group) or melatonin (10 mg/kg, MTX + Mel group) was administered for 5 days. In other rats, physiologic saline (control group) or melatonin (10 mg/kg, Mel group) was injected for 5 days, following a single injection of saline. On the sixth day, rats were killed to obtain blood, liver, and kidney tissue samples. Malondialdehyde (MDA), an end product of lipid peroxidation, and glutathione (GSH), a key antioxidant, levels were evaluated in blood and tissue homogenates. Reactive oxygen metabolite-induced inflammatory changes in kidney and liver tissues were evaluated by measuring myeloperoxidase (MPO) activity, an index of neutrophil infiltration. MTX administration resulted in increased MDA levels and MPO activity and decreased GSH levels in the blood, liver, and kidney whereas melatonin reversed these effects. When melatonin was administered alone, no significant changes in biochemical parameters were noted. In conclusion, the present study suggests that melatonin may be of therapeutic benefit when used with MTX.

Melatonin prevents methotrexate-induced hepatorenal oxidative injury in rats.

Melatonin and N-acetylcysteine have beneficial effects during hepatic ischemia and reperfusion.

Taurine protects against methotrexate-induced toxicity and inhibits leukocyte death.

Acute renal failure is a major complication of gentamicin (GEN), which is widely used in the treatment of gram-negative infections. A large body of in vitro and in vivo evidence indicates that reactive oxygen metabolites (or free radicals) are important mediators of gentamicin nephrotoxicity. In this study we investigated the role of free radicals in gentamicin-induced nephrotoxicity and whether melatonin, a potent antioxidant could prevent it. For this purpose female Sprague-Dawley rats were given intraperitoneally either gentamicin sulphate (40 mg/kg), melatonin (10 mg/kg), gentamicin plus melatonin or vehicle (control) twice daily for 14 days. The rats were decapitated on the 15th day and kidneys were removed. Blood urea nitrogen (BUN) and creatinine levels were measured in the blood and malondialdehyde (MDA) and glutathione (GSH) levels, protein oxidation (PO) and myeloperoxidase (MPO) activity were determined in the renal tissue. Gentamicin was observed to cause a severe nephrotoxicity which was evidenced by an elevation of BUN and creatinine levels. The significant decrease in GSH and increases in MDA levels, PO and MPO activity indicated that GEN-induced tissue injury was mediated through oxidative reactions. On the other hand simultaneous melatonin administration protected kidney tissue against the oxidative damage and the nephrotoxic effect caused by GEN treatment.

A. Özer Şehirli

Papers

Melatonin prevents methotrexate-induced hepatorenal oxidative injury in rats.

Melatonin and N-acetylcysteine have beneficial effects during hepatic ischemia and reperfusion.

Taurine protects against methotrexate-induced toxicity and inhibits leukocyte death.

Melatonin protects against gentamicin-induced nephrotoxicity in rats.

Resveratrol alleviates bleomycin-induced lung injury in rats