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Melatonin: A Versatile Protector against Oxidative DNA Damage

Annia Galano, Dun-Xian Tan, Russel Reiter

Molecules · 2018 · Review · CC BY

doi:10.3390/molecules23030530

Abstract

Oxidative damage to DNA has important implications for human health and has been identified as a key factor in the onset and development of numerous diseases. Thus, it is evident that preventing DNA from oxidative damage is crucial for humans and for any living organism. Melatonin is an astonishingly versatile molecule in this context. It can offer both direct and indirect protection against a wide variety of damaging agents and through multiple pathways, which may (or may not) take place simultaneously. They include direct antioxidative protection, which is mediated by melatonin’s free radical scavenging activity, and also indirect ways of action. The latter include, at least: (i) inhibition of metal-induced DNA damage; (ii) protection against non-radical triggers of oxidative DNA damage; (iii) continuous protection after being metabolized; (iv) activation of antioxidative enzymes; (v) inhibition of pro-oxidative enzymes; and (vi) boosting of the DNA repair machinery. The rather unique capability of melatonin to exhibit multiple neutralizing actions against diverse threatening factors, together with its low toxicity and its ability to cross biological barriers, are all significant to its efficiency for preventing oxidative damage to DNA.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 20, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Oxidative damage (OD) to DNA may compromise the genomic integrity and, consequently, it has important implications for human health. In fact, OD has been identified as a key factor in the onset and development of numerous diseases. Thus, it is evident that preventing DNA from OD is crucial for humans and for any living organism. OD to DNA increases to unhealthy levels as a consequence of oxidative stress (OS), which is a chemical stress arising from the imbalance between the production and consumption of oxidants. Among such oxidants, free radicals (FR) seem to be particularly relevant, and there is a wide variety of them in living systems. At the same time, there are multiple endogenous and exogenous factors that contribute to elevate the levels of FR. Some examples are ischemia, infections, physical or mental stress, aging, pollution, radiation, heavy alcohol consumption, cigarette smoke, the intake of certain drugs, etc. It is then logical that antioxidants that are efficient FR scavengers are potential candidates to reduce OD to DNA.

There is abundant evidence on the antioxidant protection exerted by melatonin (N-acetyl-5-methoxytryptamine) and related compounds. Such protective effects can involve diverse routes including free radical scavenging, but also the deactivation of other oxidants and the inhibition of metal-induced lipid peroxidation. The data gathered so far on the antioxidant activity of melatonin is so convincing that it has led to the hypothesis that one of the main functions of melatonin in living organisms is to protect them from OD. Indeed, it has been found that low levels of endogenous melatonin in humans may lead to high levels of oxidative DNA damage.

In addition, melatonin metabolites also have antioxidant effects, which maintains protection against oxidants after melatonin is metabolized. This combined action has been proposed as one of the reason why melatonin is highly effective as an antioxidant and capable of providing long-term protection against OS. It has also been proposed that melatonin and its metabolites work in a “task-division” way, with some of them acting mainly as FR scavengers, while others act as metal chelating agents and inhibitors of the hydroxyl radical (•OH) production.

Based on the above mentioned facts, melatonin protects DNA from oxidation through different mechanisms, including its chemical antioxidant effects. Here, the data published to date regarding this particular action, and other possible protective mechanisms, are reviewed. In addition, some relevant aspects of OD to DNA are also discussed.

2.1. Induction by Free Radicals.

Free radicals can damage DNA directly or indirectly. The direct damage often involves hydrogen atom transfer (HAT), radical adduct formation (RAF), or single electron transfer (SET) routes. The indirect damage arises from the action of the electrophilic species yielded when FR react with biomolecules such as lipids, proteins, and other cellular components. For example, the peroxidation of polyunsaturated fatty acids produces a variety of aldehydes that can lead to the formation of DNA adducts.

Regarding direct routes, it has been proposed that the •OH is responsible for the most common oxidative damage to DNA. This is probably because •OH is the most reactive and electrophilic of the reactive oxygen species (ROS). The •OH can be produced by ultraviolet and ionizing radiations or from other radicals arising from enzymatic reactions. However, the main intracellular sources of •OH probably are the Fenton reaction and the metal catalyzed Haber-Weiss recombination (MC-HWR). Although there are several metal ions that, because of their redox properties, may be involved in such processes, only the chemical reactions with iron and copper are used next to illustrate them. The Fenton reaction involves the reduced forms of the metal ions:

The first step of the MC-HWR is: while the second step corresponds to the Fenton reaction.

Since the metal oxidized forms, Fe(III) and Cu(II), are their most abundant and stable oxidative state, the first step of the MC-HWR is more important in biological systems than the direct Fenton reaction. In other words, the reduction process -Fe(III) to Fe(II) or Cu(II) to Cu(I)- is the crucial step to the •OH production. Thus, if the formation of Fe(II) or Cu(I) is inhibited so is •OH production through the Fenton reaction, and therefore the •OH-related oxidative damage. This is an important aspect of the •OH production via the MC-HWR, because chelating agents able of decreasing the viability of Fe(III) and Cu(II) reduction reactions are expected to be effective in preventing, or inhibiting, oxidative damage to DNA.

From a chemical point of view, the direct reaction between •OH and DNA is a multifaceted process. Due to the high reactivity of this radical, and its consequent low selectivity, such reaction can yield a myriad of products. One of the possible reaction channels is the SET, yielding a radical cation, which is expected to involve mainly guanosine sites. This is because guanosine is the most easily oxidized of the nucleic acid bases, with a reduction potential of 1.29 V vs NHE. The fact that guanosine has the lowest ionization potential among the DNA components explains why it is the main sink for hole transfer in double-stranded DNA. The radical cation generated by SET can readily deprotonate (Scheme 1), under physiological conditions, yielding carbon-centered radicals in the deoxyribose unit, which are involved in one of the most important types of DNA damage (strand scissions). Such carbon-centered radicals can also be directly produced by HAT from the sugar sites to •OH. Addition of this radical to 2′-deoxyguanosine (2dG) yields adducts on different C sites in the imidazole ring (Scheme 1). In turn, the 8-OH-dG adduct can further evolve. It may yield 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG), due to one-electron oxidation, or 2,6-diamino-4-hydroxy-5-formamidopyrimidine 2′-deoxynucleoside (Fapy-dG) by cleavage of the C8-N9 bond plus one-electron reduction.

The 8-oxo-dG is one of the most abundant DNA lesions, and it considered as a biomarker of oxidative stress. It has been estimated that up to 100,000 8-oxo-dG lesions can occur daily in DNA per cell. The reduction potential of 8-oxo-dG is even lower (0.74 V vs. NHE) than that of guanosine. Therefore, it can be further oxidized by a large variety of oxidants, yielding the corresponding radical cation, which can be transformed into the 5-hydroxy-substituted derivative of 8-oxo-dG (5-OH-8-oxo-dG) by hydration, deprotonation and another SET reaction (Scheme 1). This species can also be oxidized, yielding 2′-deoxynucleoside (dGh), spiroiminodihydantoin 2′-deoxynucleoside (dSp), and/or other products. The relative abundance of such products would be influenced by the reacting species and by environmental factors. However, under physiological conditions dGh and dSp are both expected to be formed.

It seems worthwhile mentioning that, albeit they are not reviewed here, other nucleosides are also susceptible to be damaged by •OH and other free radicals. The chemical routes involved in such processes are similar to those described here for 2dG. In addition, oxidants such as FR, can produce not only single but multiple lesions to a DNA molecule, which may lead to the formation of cross-linked products.

2.2. Other Causes

In addition to the previously discussed metal-induced damage, which can be attributed at least partially to the production of •OH radicals, there are other possible factors that may contribute to DNA lesions. Some halogen compounds such as HOCl and HOBr, which are produced as a response to inflammation, can cause structural modifications to DNA. In fact, one of the products yielded by such processes, 5-chloro-2′-deoxycytidine, is considered a biomarker of chronic inflammation. Nitric oxide (•NO) and superoxide radical anion (O2−•) are also produced as a consequence of immune responses to inflammation. Albeit they do not directly damage DNA, their reaction yields peroxynitrite (ONOO−), which reacts with DNA. Guanine residues seems to be the main target of ONOO−, since its reaction with these residues is significantly faster than those involving other nucleosides, and its reactions with 8-oxo-dG is even more favorable than with the parent molecule.

Some by-products of lipid peroxidation also induce damaged to DNA. For example, aldehydes produced in this process can react with DNA, by RAF, yielding different products. In turn, they can lead to DNA interstrand cross-links. Other chemicals that can damage DNA are 17β-estradiol, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, d-aminolevulinic acid, thioacetamide, bisphenol A, methyl methanesulfonate and the amyloid beta peptide. In addition, there are other factors that represent a risk to DNA integrity such as radiation, ischemia/reperfusion, intracerebral hemorrhage and aging.

2.3. Consequences for Human Health

DNA damage has serious, and sometimes life-threatening, consequences to human health (Figure 1). In fact the evidence gathered so far, in this regard, is so abundant that it is not possible to review it all here. Thus, only some will be mentioned as illustrative examples of the highly deleterious effects that structural modifications to DNA imposes to human health. In particular OS-induced DNA damage has been associated with a wide variety of diseases.

It has been proposed that this kind of damage may play a key role in carcinogenesis induced by chronic inflammation. Elevated levels of OS and/or DNA damage have been found in cases of human breast, prostate, colorectal, gastric, lung and ovarian cancer; as well as in leukemia, melanoma and lymphoma patients. The relationship between oxidative DNA damage and cancer arises, at least partially, from the fact that DNA lesions that are not detected during replication, such as 8-oxo-dG, can lead to mutations. In addition, agents increasing oxidative DNA damage usually enhance the risk of cancer development, while diets rich in fruits and vegetables (which contain abundant antioxidants) decrease both oxidative DNA damage and cancer incidence. Three main mechanisms have been proposed to contribute to DNA damage, by environmental agents, leading to carcinogenesis. They are: (i) oxidative DNA damage, involving the production of 8-oxo-dG; (ii) the formation of lipid peroxide-derived DNA adducts; and (iii) the methylation of cytosine by free radicals.

OS-induced DNA damage has also been identified as an important contributing factor to neurodegeneration. It initiates a series of events that promote neuronal loss, following central nervous system (CNS) injuries. Increased nuclear and mitochondrial DNA oxidation have been observed in Alzheimer’s disease (AD), arising from the attack of reactive oxygen species (ROS) to DNA bases and from the impairment of DNA repair mechanisms. Amyloid beta-induced oxidative DNA damage also contributes to the development and progression of this disease. Elevated levels of mitochondrial DNA oxidation products have been found in cases of mild cognitive impairment and initial stages of AD, which has led to the suggestion that oxidative damage to DNA is an early event in AD. Levels of 8-OH-dG in the cerebrospinal fluid (CSF), higher than in control groups, have been found not only in patients with AD but also in patients with Parkinson’s disease. The same trend was found for sporadic amyotrophic lateral sclerosis, and the 8-OH-dG in the CSF was positively correlated with the illness duration. However, in the particular case of PD, it has been proposed that while the levels of 8-OH-dG might be used as an “early-stage marker”, the disease progression might be characterized by a decrease of such levels in the CSF.

Oxidative DNA damage also seems to be involved in the development of cardiovascular diseases. This kind of damage was found to be higher in coronary artery disease patients than in healthy subjects and to be potentiated by metabolic syndrome, which causes an increase in OS. In addition continuous flow left ventricular assist devices implanted in heart failure patients were found to lead to elevated OS and DNA damage in blood leukocytes, and also to malfunction in DNA repair pathways. The 8-OH-dG levels were found to be elevated in the serum and myocardium of patients with heart failure, compared to those in control subjects.

There are many other health disorders that have been related to high OS and OS-induced DNA damage. One of them is the Wilson’s disease, which is characterized by a copper accumulation, and the consequent increase in ROS production. Others are inflammatory bowel disease (including both ulcerative colitis and Crohn’s disease), diabetes and its complications, acquired immunodeficiency syndrome, Huntington’s disease, rheumatoid arthritis, and chronic obstructive pulmonary disease, just to mention a few.

3. Antioxidant Protection

Shielding biomolecules in general, and DNA in particular, from oxidative damage can be achieved in different ways that, depending on the moment at which they take place, might be roughly classified as prevention or repairing strategies. Antioxidant prevention involves deactivating free radicals (or other oxidants) or inhibiting their formation, thus they do not reach biological targets. In addition, DNA repair should occur before replication to maintain genomic integrity and a healthy status. Enzymatic DNA repair plays an essential role in the defense mechanisms of living organisms, albeit in some particular cases it can also involve chemical pathways.

Melatonin is produced by the pineal gland, although it also is found in several extra-pineal organs. It is best known for its regulatory role in circadian and seasonal rhythms. However, there is increasing evidence on its many other biological functions. Some examples are its anti-inflammatory and immune-enhancing properties, its homeostatic role in the mitochondrion and in maintaining the fluidity of biological membranes. In addition, melatonin has well-documented antioxidant capacity. As mentioned in the Introduction section, it has been proposed that one of the main functions of melatonin in living organisms is to protect them from OD. Melatonin has also been classified as a mitochondria targeted antioxidant, acting as a “firewall” against FR. We certainly agree with those statements. Since melatonin is a highly versatile molecule that plays diverse roles in living organisms, it might be difficult to establish (beyond any doubt) the relative importance of its many functions. However, its antioxidant protection is definitively a very important one.

Melatonin has protective effects against OD to DNA, and also beneficial effects regarding many of the previously mentioned diseases. Since elevated ROS levels are among the major causes of DNA damage, the protection exerted by melatonin has been largely attributed to its antioxidant capacity (AOC). Melatonin’s AOC can be exerted not only directly, i.e., through its FR scavenging activity, but also indirectly (Figure 2), for example through its metabolites, by stimulation of antioxidative enzymes or by modulating DNA repair pathways.

Some of the melatonin’s features make it particularly efficient for exerting AOC protection, since they are in line with those expected in ideal antioxidants. One of them is its amphiphilicity, which allows melatonin to readily cross physiological barriers. Therefore, it can provide on-site protection to DNA, against locally generated FR. Another important feature of melatonin is its low toxicity, over a wide dose range. There is a large number of studies, in both animals and humans, indicating that short-term use of melatonin is safe, even in massive doses, while long-term administration may induce only mild (if any) adverse effects, comparable to placebo treatment. The only significant short-term side effect reported after oral ingestion of ≤5 mg of melatonin by normal healthy adults was sleepiness. Similar doses (administered as prolonged-release melatonin preparations) were found to be efficient and safe for the treatment of insomnia in children and adolescents with autism spectrum disorder. Several in vivo studies on animals, involving high doses of melatonin showed that chances of acute and/or chronic toxicity of melatonin is extremely low. In addition, oral doses of melatonin (up to 1 g daily), taken by human volunteers, resulted in no negative side effects. In fact, there are no reports that exogenous melatonin causes any serious adverse effects. Thus, the general agreement that melatonin has minimal toxicity over a very wide dose range seems to be well justified. This allows considering supplementary intakes of this compound, to increase its level beyond those arising from endogenous production, thus boosting its capability to protect biomolecules in general, and DNA in particular, from OD. More information on the safety of melatonin and its clinical utility can be found elsewhere.

3.1. Free radical Scavenging Activity

Melatonin is capable of efficiently scavenging a wide variety of free radicals. Some of them are •OH, alkoxy radicals (RO•), peroxy radicals (ROO•), and •NO. It also scavenges other, non-radical, oxidants such as hydrogen peroxide (H2O2), singlet oxygen (1O2) and ONOO−. The relationship between these actions, and the protection exerted by melatonin against oxidative damage to DNA has been well documented.

Several reaction mechanisms have been investigated regarding the chemical protection exerted by melatonin through its free radical scavenging activity, including SET, HAT and RAF. It has been proposed that the relative importance of such mechanisms, as well as that of the different reaction sites, is influenced by the reacting FR. For example for FR of moderate reactivity, such as ROO•, the main reaction pathways are HAT from site 4 and RAF at site 6 (Scheme 2). However when R has a high electrophilic character (for example CCl3OO•) the SET pathway contributes to a significant extent to the FR scavenging activity of melatonin. On the other hand, if the reacting FR is •OH (which is more reactive than ROO•) the number of reaction paths involved in melatonin’s scavenging activity increases. In this case HAT occurs from sites C1, C3, C4, C6 and C7; and RAF at sites C5 to C12. Therefore, reaction with •OH would yield a wide variety of products.

In addition, melatonin derivatives have been designed to increase its antioxidative protection via SET. Such a design was rationalized considering that the electron-rich aromatic ring promotes the redox behavior of melatonin, in particular as an electron donor. Therefore, introducing groups that stabilizes the indole ring, by increasing electron delocalization, might contribute to an improved antioxidant activity. Some of the melatonin derivatives designed that way resulted to be, in fact, better direct antioxidants than the parent molecule.

The role of the FR scavenging activity of melatonin on its protective effects against OD to DNA has been well documented. Liang et al. have recently shown that melatonin protects somatic cell nuclear transfer porcine embryos from OS-induced DNA damage. It was proposed that such protection involves the quenching of the FR arising from exposure to hydrogen peroxide (H2O2). In these experiments melatonin decreased the amounts of intracellular ROS, at the same time that it elevated the intracellular glutathione (GSH) levels, thus preventing H2O2-induced mitochondrial dysfunction.

Erenberk et al. investigated the effects of melatonin in preventing the DNA damage associated to the consumption of phenytoin sodium (PHT-Na). This is a drug used against epileptic seizures, and also as a prophylactic treatment in traumatic brain injury, which leads to the formation of ROS and the consequent DNA damage. It was found that melatonin (and/or its metabolites) attenuates the genotoxic effects of PHT-Na, and that it can reverse the DNA damage induced by this compound. This can be directly associated with the ROS scavenging activity of melatonin, and led the authors to proposed melatonin as an add-on antioxidant in the treatment of patients needing PHT-Na.

It has been proposed that melatonin may prevent the DNA damage caused by hyperglycemic conditions, by scavenging the excess of ROS derived from it. It was found that the administration of 10 mg/kg melatonin over six weeks has beneficial effects for diabetic rats. Such a treatment decreased OS parameters such as % tail DNA and mean tail moment. There is also evidence that melatonin has protective effects against the genotoxicity induced by cyclophosphamide, which is a medical drug used in chemotherapy and to suppress the immune system. Albeit, the exact mechanism of such protection has not been fully elucidated, it was attributed to the antioxidant and FR scavenging capabilities of melatonin.

There are other studies showing that OS-induced DNA damage in human spermatozoa is inhibited by melatonin. Espino et al. demonstrated that melatonin is capable of protecting ejaculated human spermatozoa against apoptosis caused by OD. In this case, in vitro samples treated with melatonin exhibited higher percentage of motile, progressive motile and rapid cells, as well as reduced number of nonviable spermatozoa, compared with the control; at the same time that •NO levels were significantly decreased. Bejarano et al. found that melatonin supplementation, for 90 days, resulted in an increased total antioxidant capacity in the seminal fluid and in a reduction of OD to sperm DNA. This is in line with other reports on the potential role of melatonin as a spermatozoa protector. The beneficial effects of melatonin on sperm quality have been attributed to its role in inhibiting increased ROS levels, which are related to teratozoospermia, sperm malformations and instability of sperm DNA.

There is also evidence that melatonin inhibits OS-induced DNA damage in mammalian oocytes. It has been recently reported that melatonin significantly decreased intracellular ROS levels, and the associated DNA damage, in aged bovine oocytes. Melatonin was found to reduce ROS levels, and to inhibit 8-oxo-dG production in mice oocytes; thus protecting DNA from OD-induced mutation.

UV radiation (UVR) is known to induce serious structural and functional alterations in human skin. ROS have been identified as key species in UVR-mediated photo-damage to skin, due to their potential to induce DNA oxidation, which yields 8-OH-dG and leads to carcinogenesis. It has been found that pre-incubation with melatonin significantly reduces the amounts of 8-OH-dG positive cells and prevents antioxidative enzyme gene and protein suppression. Based on this findings it was proposed that melatonin plays a crucial role protecting DNA against UVR-induced OD in human skin. It was hypothesized that the radical scavenging activity of melatonin is responsible for reducing ROS levels, albeit indirect ways of action may be involved, i.e., antioxidative enzymes (protected by melatonin) may also contribute to ROS reduction.

The 8-OH-dG lesions in DNA are also induced by microcystin, a liver-specific toxin synthesized by Microcystis aeruginosa. This can be ameliorated by melatonin in a concentration-dependent manner. To that purpose, melatonin (IC50 = 0.55 μM) was found to be significantly more effective than vitamin C or vitamin E (IC50 = 31.4, and 36.8 μM, respectively). It was proposed that melatonin’s protection against microcystin toxicity is caused, at least in part, by its direct •OH scavenging activity. This radical, together with other ROS, has also been held responsible for the l-cysteine-induced mitochondrial DNA (mtDNA) damage in mice brain. Melatonin was able to completely prevent such damage, which was attributed to its capability of scavenging •OH. Similar results were obtained, and similar conclusions drawn, for other chemical agents (kainic acid and potassium cyanide) that induce oxidative damage to mtDNA. Moreover, melatonin prevents the damage induced by cyanide, kainate, glutathione/Fe3+/O2 or H2O2/Fe2+ to calf thymus DNA. Based on these findings, together with the knowledge that melatonin is an excellent •OH scavenger, it was proposed that this radical may play a crucial role in the DNA damage induced by those chemicals.

Oxidative DNA damage can arise as a consequence of many other factors. Phosphine (PH3) is a widely used pesticide that was found to induce, both in vitro and in vivo, brain DNA oxidation in rats, yielding 8-OH-dG. The capability of melatonin to prevent such a damage was explained based on its FR scavenging activity. Naphthalene is another toxic agent. Its toxicity involves enhanced production of FR and DNA fragmentation, among other effects, which lead to cytoxicity. It has been found that two hours pre-treatment of cultured cells with melatonin significantly inhibits naphthalene’s cytoxicity.

Exposure to microwave (MW) radiation, in vivo, was found to cause DNA single- and double-strand breaks in brain cells; while melatonin treatment (immediately before or after exposure) was found to prevent this damage. This protection was attributed to the FR scavenging activity of melatonin. It has been reported that hyperoxia is another event that leads to increased ROS levels. Exposing bovine cerebral endothelial cells to 95 or 100% oxygen resulted in DNA fragmentation and cell death. Melatonin was found capable of preventing that outcome, in a dose-dependent way, which was explained based on its ROS scavenging activity.

Based on the evidence presented in this section, it can be stated that melatonin is a versatile FR scavenger, capable of deactivating a wide variety of these toxic agents. Such capability has been proven to have beneficial effects regarding OD-induced DNA damage. In particular there is ample evidence showing its role in reducing 8-OH-dG levels, and derived lesions.

There are some related aspects that still need investigation regarding the protective effects of melatonin against OD induced by chemical agents in general, and FR in particular. The possible chemical mechanisms implicated in the capability of melatonin to protect biomolecules against non-radical ROS, as well on reactive nitrogen species (RNS) and reactive sulfur species (RSS) is one of them. As mentioned before, the reacting FR (or oxidant in general) may influence the chemical route contributing the most to the scavenging activity of chemical antioxidants. Understanding such routes in detail is crucial to design adequate strategies to counteract the toxicity of chemical oxidants, and also to know the intermediate products yield in the process. The latter is important in the context of OD because there is a chance that such intermediates are reactive enough to damage some biological targets. That possibility certainly deserves detailed investigations.

3.2. Inhibiting Metal-induced Oxidation

As above mentioned, chelation is a chemical means of inhibiting metal-induced oxidation. This particular process is directly involved in the •OH-inactivating ligand (OIL) behavior of antioxidants. The protection exerted by OIL species against •OH-induced OD may involve two different ways of action: sequestering metal ions from reductants, i.e., inhibiting the reduction of metal ions thus their reduced forms are not available for Fenton-like reactions; ordeactivating •OH after being produced via Fenton-like reactions. In this case the •OH radicals are still formed, but they are rapidly scavenged by the organic ligands in the metal chelates.

sequestering metal ions from reductants, i.e., inhibiting the reduction of metal ions thus their reduced forms are not available for Fenton-like reactions; or

deactivating •OH after being produced via Fenton-like reactions. In this case the •OH radicals are still formed, but they are rapidly scavenged by the organic ligands in the metal chelates.

To the best of our knowledge, mechanistic insights regarding the OIL behavior of melatonin have been reported only for its role as OIL-(i), when the redox metal is copper. The most likely complex was identified (Scheme 3A) and proved to inhibit oxidation induced by Cu(II)-ascorbate mixtures, as well as the first step of the MC-HWR. Based on the high reactivity of free melatonin towards •OH (described in Section 3.1) it might be anticipated that this molecule can also be efficient as an OIL-(ii) antioxidant (Scheme 3B). However, further investigations on this subject are still needed.

It is known that melatonin is capable of chelating several metal ions including iron, copper, aluminum, lead, cadmium, and zinc. By binding these metals, melatonin retards Fenton reactions, preventing •OH generation. Moreover, melatonin protects DNA against OD induced by Fenton reagents. It over-performs, in this capacity, other antioxidants such as resveratrol, ascorbic acid, and lipoic acid. There is also evidence that melatonin is capable of significantly decreasing the amounts of FR yielded by the interactions of Fe(II), Cu(II), Al(III), Zn(II), and Mn(II) with the amyloid-beta peptide. It has even been suggested that the antioxidant and neuro-protective activities of melatonin may involve removing toxic metals from the central nervous system.

In the particular case of iron (Fe), it has been demonstrated that melatonin’s complexes involve Fe(III), although not Fe(II). This finding led to the proposal that Melatonin removes free Fe(III) from biological environments, thus preventing its reduction to Fe(II), and the associated production of FR. In the presence of iron, d-aminolevulinic acid generates ROS, via Fe-catalyzed oxidation, which leads to the formation of 8-OH-dG lesions. Melatonin inhibits the formation of such lesions, in calf thymus DNA, in a dose-dependent manner. To that purpose, melatonin was found to be more efficient than mannitol and Trolox. The inhibitory effects of melatonin on oxidative DNA damage induced by ferric nitrilotriacetate (Fe-NTA), in the rat kidney, have also been investigated. It was found that pre-treatment with melatonin prevents such damage, significantly reducing the levels of 8-OD-dG. It was inferred that the toxicity of Fe-NTA arises from the production of ROS, and that melatonin protection is a consequence of its FR scavenging activity and other antioxidative processes induced by this compound. The DNA strand breaks caused by the exposure of rat lymphocytes to iron ions and 50 Hz magnetic field, simultaneously, was found to be inhibited by melatonin. Such inhibition takes place in a dose-dependent manner, with melatonin 0.5 mM and 1.0 mM leading to 50% and 100% inhibition, respectively.

Copper (Cu) is also an active metal in the context of MC-HWR and/or Fenton reactions. It has been demonstrated that DNA damage caused by mixtures of Cu(II) + H2O2, at pH 7.4, is greater than that derived from Fe(III) + H2O2, under the same conditions. It was also found that the damage increases in the presence of ascorbic acid. This can be attributed to the fact that at pH 7.4 the ascorbate anion is the most abundant form of ascorbic acid; thus it can act as a reductant for both Cu(II) and Fe(III). In other words ascorbate promotes de formation of •OH via Fenton reaction. This seems to be confirmed by the finding that 8-OH-dG is the main product yielded in both cases. In addition, the DNA damage was inhibited by metal chelating agents but not by FR scavengers. Therefore, it seems that under the above mentioned conditions the inhibition of OD to DNA is mediated by OIL-(i) behavior, rather than by direct AOC. This is in line with recent theoretical predictions that the oxidative damage induced by copper can be successfully inhibited by melatonin, through its chelating capability. There is also experimental evidence that melatonin protects against copper-mediated FR damage.

Chromium (Cr) may exist in diverse oxidation states. The Cr(VI)/Cr(V) pair has been reported to mediate Fenton-like reactions, producing ROS that ultimately lead to DNA damage. Melatonin was found to protect DNA from strand break injuries caused by Cr (VI). Cr(III) can also induce oxidative damage to DNA. In fact it has been reported that Cr(III) is more reactive than Cr(VI) towards DNA, under in vitro conditions. There is abundant evidence that Cr(III)-induced 8-OH-dG lesions can be inhibited by melatonin and other antioxidants. However, melatonin was found to be more efficient for that purpose than ascorbate, Trolox, resveratrol, xanthurenic acid and lipoic acid. Moreover, melatonin significantly increases the protective effects of ascorbate and lipoic acid against Cr-induced oxidative damage to DNA. The formation of 8-OH-dG has been attributed to Cr(III)-mediated Fenton-type reaction yielding •OH. Thus, the protective effects of melatonin in this context have been proposed as promising for reducing the incidence of Cr-related cancers. It has been suggested that the protective effects of melatonin against oxidative damage to DNA induced by chromium can be exerted by (i) scavenging •OH, (ii) directly detoxifying H2O2, and/or (iii) metal chelation.

Lead (Pb) genotoxicity has been attributed to the increase of ROS levels and to the inhibition of DNA repair. The first one is two-fold, at least, and includes direct ROS production as well as depletion of the cellular antioxidant pool. Melatonin was found to significantly attenuate, in vivo, the effects of Pb on DNA repair in rat lymphocytes, albeit its efficiency depends on the administered Pb dose. In addition, it can be inferred that the melatonin’s protection against Pb-induced toxicity is mainly related to its ability of scavenging ROS, since it had only minor effects on the GSH levels.

It has been reported that Ni(II) can induce DNA damage acting as a catalyst for the Fenton reaction, or by disrupting DNA repair systems. Exposure to nickel causes the production of mitochondrial 8-OH-dG and reduces mtDNA content and transcript levels. These damaging effects have been associated with Ni-induced neurotoxicity, and are attenuated by melatonin. This led to the suggestion that melatonin may have pharmacological potential in protecting mtDNA against the adverse effects of nickel in the nervous system.

Cobalt (Co) is also a threat to DNA integrity. This metal can cause DNA-protein cross-linking and disruption of the DNA repair system. In addition, it has been proposed that OS may be involved in the Co-induced cytotoxicity and genotoxicity. In the same work, it was found that melatonin lowers tail DNA % and olive tail moment in rat kidney cells exposed to Co nanoparticles. The protective effects of melatonin in this case were attributed to its capability of lowering ROS levels. Considering that Co-induced FR production seems to be influenced by metal chelation and that melatonin can chelate this metal, Romero et al. proposed metal chelation as an alternative route to explain the protection exerted by melatonin against Co toxicity.

The toxicity of mercury (Hg) involves a wide variety of mechanisms, some of which are relevant in the context of this review. Hg has been reported to significantly increase ROS levels and OS, to deplete GSH levels, to damage DNA and to cause failure in the DNA repair machinery. In particular, Hg-induced genotoxic effects are believed to be mediated by its oxidant behavior, which can lead to DNA damage involving both the purine-pyrimidine bases and the deoxyribose units. It has been recently demonstrated that melatonin and vitamin E can both inhibit the Hg-induced genotoxicity, and that their protective effects are potentiated when simultaneously administered. This finding seems to support the hypothesis that melatonin’s protection against the toxic effects of Hg is mediated by its antioxidant capacity.

Exposure to arsenic (As) has been reported to cause oxidative DNA damage, as evidenced by the formation of 8-oxo-dG lesions, strand breaks, DNA-protein crosslinks and abnormal DNA methylation, as well as impairment of the DNA repair system. DNA damage induced by arsenite are mediated by ROS, which is in line with observations of depleted GSH levels and the protection provided by antioxidants. Melatonin was found to protect human blood cells, in vitro, against the DNA damage induced by As, which was attributed to the antioxidant potential of melatonin. In addition, it has been reported that methylated As can occur in vivo and lead to DNA oxidation, which is prevented by melatonin and other antioxidants. This finding led to the conclusion that the indirect genotoxic effects of As are mediated by ROS.

The protection against metal-catalyzed molecular damage provided by melatonin has been recently, and comprehensively, reviewed. It was proposed that the mechanism involved in the protection exerted by melatonin, in this context, is manifold and involves metal chelation, direct free radical scavenging and promotion of the activity and expression of antioxidant enzymes. It was suggested that the low toxicity of this compound and its ability to easily cross cellular membranes are contributing factors to the efficiency of melatonin for counteracting metal-induced damage to biological molecules, including DNA.

Regardless of the action mechanism, it can be stated that melatonin protects biomolecules in general, and DNA in particular, against metal-induced OD. However, more investigations on the chemical routes involved in such protection are still needed. In particular, mechanistic insights on the OIL-(i) and OIL-(ii) behavior of melatonin would be of great interest. In addition, the relative importance of the possible mechanisms, depending on the involved metal, would be relevant. From a chemical point of view OIL behavior may –arguably- be the most evident way of protecting biomolecules against metal-induced OD. However, metals can lead to OD by routes other than Fenton-like reactions. Such a possibility also deserves further investigation.

3.3. Counteracting the Effects of Other OD Triggers

In addition to FR and active redox metals there are other factors that can trigger OD to DNA. A few examples including some chemicals (Scheme 4), and other threatening factors are presented next.

It has been reported that exposure to formaldehyde increases the levels of DNA damage. This compound causes raised levels of ROS and depletion of GSH, among other effects, which ultimately induce morphological changes in tissues. Melatonin can significantly ameliorate formaldehyde’s toxicity. This protection likely involves reduction of ROS levels and DNA damage (in particular 8-OH-dG lesions), a balance of the oxidant/antioxidant status and an inhibition of neutrophil infiltration.

17β-Estradiol (E2) has been reported to produce DNA damage, which is reflected in the 8-oxo-dG levels. Thus the toxic effects of this compound might be mediated by OD. Melatonin prevents such a damage in hamster kidneys, which led to the proposal that melatonin is a likely protector from the E2-induced carcinogenesis.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a precursor of 1-methyl-4-phenyl-pyridine ion (MPP+). The MPTP/MPP+ pair has known neurotoxic effects and may induce Parkinson's disease. It has been shown that this pair causes OD to mtDNA, as indicated by the presence of 8-oxo-dG that, as previously mentioned, is considered as a biomarker of this kind of damage. In the same study it was demonstrated that melatonin can offer protection against the cell death induced by MPTP/MPP+. The protective effects of melatonin, in this context, were attributed to its capability of inhibiting generation of mitochondrial oxygen FR and preventing mitochondrial membrane potential collapse.

It has been found that potassium bromate (KBrO3) induces oxidative DNA damage in the kidney of rats. After treatment with this chemical, the levels of 8-oxo-dG in renal genomic DNA increased by more than 100%. This effect was partially inhibited by melatonin, which was explained by its antioxidant activity.

Exposure to hypochlorous acid (HOCl) can cause DNA strand breaks and modified nucleotides (including oxidation of pyrimidine bases and chlorination of cytosine) in human respiratory tract epithelial cells. Such DNA damage is thought to be involved in HOCl cytotoxicity, together with protein damage manifested as carbonyl formation and oxidation of thiol groups. Melatonin was found to protect cells from the molecular damage caused by HOCl exposure, diminishing its cytotoxic effects.

Overproduction and accumulation of d-aminolevulinic acid (dALA) can lead to DNA damage and, eventually, to carcinogenesis. Toxic levels of dALA arise as a consequence of acute intermittent porphyria, hereditary tyrosinemia, lead poisoning, and photodynamic therapy. The damaging effects of dALA to DNA have been measured based on the production of 8-OH-dG sites in rat lung and spleen homogenates. Melatonin treatment was found to completely inhibit the increase in 8-OH-dG levels caused by dALA. The hazard posed by dALA to DNA integrity was associated to the formation of ROS. Thus the protective effects of melatonin may arise from its antioxidant activity.

Thioacetamide induces DNA fragmentation and depletion of GSH levels, among many other effects, leading to hepatic fibrogenesis. Melatonin was found to inhibit such effects by decreasing OS levels and DNA damage, at the same time that it provided some additional benefits.

Currently it is well known that the amyloid beta peptide (βAP) is involved in the Alzheimer’s disease. In fact, it is considered the main neuropathologic marker of this disease. It has been found that exposure to βAP resulted in significant OD to mtDNA, while addition of melatonin prevents the damage in human neuroblastoma cells. Moreover, it was proposed that melatonin may be better than other antioxidants for treating the Alzheimer’s disease. This proposal was based on some additional appealing properties of melatonin, such as its low toxicity, its ability to cross biological barriers, and its inhibitory effects in βAP aggregation.

Melatonin has also been found to prevent radiation-induced damage to DNA. For example, it has been proven to reduce DNA fragmentation in the testes of rats exposed to microwaves, by reducing OS levels. Melatonin inhibits strand breaks in human cells exposed to X-ray radiation. Pre-treatment with melatonin also prevents DNA strand breakage in rat brain and 8-OH-dG lesions in rat liver, exposed to ionizing radiation (1000 and 800 cGy, respectively).

Some health disorders may lead to DNA damage as well. Ischemia/reperfusion induces increased levels of 8-OH-dG and thiobarbituric acid reactive substances, which are byproducts of lipid peroxidation. Pre-treatment with melatonin significantly prevents the formation of both markers. There is additional evidence supporting the protective effects exerted by melatonin against ischemia/reperfusion-induced OD to DNA.

Intracerebral hemorrhage (ICH) significantly increases OS, leading to DNA damage involving the formation of 8-OH-dG sites, apurinic/apyrimidinic abasic sites and depletion of DNA repair. It has been recently demonstrated that melatonin treatment alleviates ICH-induced DNA damage. It was proposed that the protective effects of melatonin in this context is multifaceted, impacting apoptosis, inflammation, OS levels, DNA damage, brain edema, and mitocondrial membrane permeability. The results from that work led to the suggestion that melatonin is a promising candidate in the treatment of mitochondrial dysfunction and ICH-induced disabilities.

In addition, it has been suggested that the administration of physiological doses of melatonin may help to prevent age-related oxidative DNA damage in the brain. Such a proposal was made based on the finding that increased levels of serum melatonin significantly decrease the 8-OH-dG content and the 8-OH-dG/dG ratios in the brain of adult mice.

Based on the data presented in this section, it can be stated that melatonin is a versatile protector against OD to DNA, since it prevents the damage caused by a wide variety of factors that may threaten DNA’s integrity. However, most of the information gathered so far account for the overall effects of melatonin. On the contrary, little information is currently available on the chemistry associated to the protection provided by melatonin against the toxic effects of chemical species other than FR. Based on the structures of the compounds shown in Scheme 4, it is likely that the mechanisms involved in both the damage and the melatonin protection would strongly depend on the toxic agent. Properly elucidating such reaction mechanisms is an important step in the way of fully understanding chemical induced OD and antioxidant protection.

3.4. Metabolic Derivatives

Many of the beneficial effects of chemical antioxidants are lost after being metabolized. This is not the case for melatonin, which maintains its protection against OD after being transformed by metabolism or oxidative conditions. There is compelling evidence that melatonin’s metabolites (Scheme 5) are capable of offering protection against oxidative insults.

N-Acetylserotonin (NAS) is not only the direct precursor of melatonin, in the tryptophan pathway, but it can also be reversibly formed from melatonin through demethylation. It has been reported that NAS has neuro-protective effects as well as antioxidant and anti-aging activities. NAS can efficiently protect DNA from the OD caused by H2O2 and Cr(III) and also from UV-induced damage. It also inhibits Cu-induced oxidation.

N1-Acetyl-N2-formyl-5-methoxykynuramine (AFMK) is a product of melatonin oxidation, which can involve both enzymatic and non-enzymatic processes. AFMK has an excellent ability as a •OH scavenger. It protects against high energy radiation and reduces oxidative DNA damage and lipid peroxidation, preventing neuronal cell injuries caused by H2O2. AFMK inhibits the OS induced by Cu(II)-ascorbate mixtures, via Cu(II) chelation. It also protects DNA from UV-induced damage and from the oxidation caused by Fenton reagents or derived from exposure to mixtures of 5-aminolevulinic acid + Fe(II).

N1-Acetyl-5-methoxykynuramine (AMK) is formed by deformylation of AFMK. There are several reports showing that AMK is a good and versatile free radical scavenger. It was found to be capable of deactivating a wide diversity of ROS, RNS and other oxidants. There is evidence that AMK also reduces Cr(III)-induced 8-OH-dG lesions in isolated calf thymus DNA.

Cyclic 3-hydroxymelatonin (c3OHM) is believed to be a non-enzymatic product of melatonin, which is yielded from the reactions of melatonin with oxidants, particularly •OH. Albeit it was once thought to be a biomarker of OS, currently c3OHM is known to be not an end-product, which can be further metabolized into AFM and AMK. It is also known that such a transformation is mediated by FR. c3OHM efficiently scavenges •OH, ABTS•+ (2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid)) and peroxyl radicals. It is also capable of chelating Cu(II), preventing its reduction and the consequent •OH production through Fenton-like reactions. This theoretical prediction is supported by experimental evidence demonstrating that c3OHM inhibits oxidative DNA damage and 8-OH-dG lesions, induced by Fenton reagents, under in vitro conditions.

6-Hydroxymelatonin (6OHM) has been identified as a major melatonin metabolite in the human skin. It is also a product yielded by the reaction of melatonin with •OH, in Fenton-type generating systems and by the UV-induced metabolism of melatonin in keratinocytes and cell-free systems. It has been reported that 6OHM can reduce neurotoxicity induced by quinolinic-acid, due to its capability of scavenging 1O2 and O2•−. It also lowers Fe(II)-induced neurotoxicity and inhibits the OD induced by this metal, UV radiation, thiobarbituric acid and cyanide. In addition, it has been proposed to inhibit OS induced by Cu(II)-ascorbate mixtures and •OH production. 6OHM also protects DNA damage induced by Fenton reagents and UV radiation. The latter is believed to take place by enhancing the DNA repair in exposed melanocytes.

4-Hydroxymelatonin (4OHM) and 2-hydroxymelatonin (2OHM) are generated during the UV-induced metabolism of melatonin. In addition, they can be produced during the oxidation of melatonin through chemical routes. For example, 2OHM is formed due to the reactions of melatonin with hypochlorous acid, oxoferryl hemoglobin and •OH. The latter also produces 4OHM. To the best of our knowledge, there are no previous studies indicating whether, or not, 2OHM and 4OHM can play a protective role against OS-induced damage to DNA. The information regarding their antioxidant capacity is also very scarce. It has been recently proposed, based on theoretical calculations, that 4OHM may play an important role on the protective effects of melatonin against OS. On the contrary, the effects of 2OHM in this context were predicted to be only minor. The antioxidant activity of these two compounds, as well as their potential role in protecting biomolecules against OD certainly deserves further investigation.

AFMK, AMK, c3OHM, 6OHM, 4OHM and 2OHM are all products yielded by the oxidation of melatonin. Since most of them also have antioxidant properties, the protection exerted by melatonin against OD is a continuous process in which multiple oxidative offenders can be deactivated. Moreover, part of the antioxidant protection exerted by melatonin may be attributed to its metabolites. In this regard melatonin is a particularly virtuous molecule. Most of the antioxidants, when metabolized, are transformed into species that do not necessarily offer protection against OD. Melatonin, on the other hand, is one of the few known antioxidants that does not loose AOC during metabolism.

3.5. Other Protection Mechanisms

This aspect would be only briefly addressed here since it is not within the main focus of this review. However, it seems important to emphasize the fact that there are several mechanisms (other than those more extensively reviewed here) that may significantly contribute to the indirect antioxidant activity of melatonin. A few examples of the evidence gathered so far, regarding some of them, are provided here.

3.5.1. Activating Antioxidative Enzymes

The protective effects of melatonin against radiation-induced DNA damage has been partially attributed to its indirect antioxidant activity. It has been proposed that its protection against UV-induced damage to human skin involves preventing the depletion of the antioxidative enzymes catalase, glutathione peroxidase and superoxide dismutase (SOD).

The fact that melatonin lowers the neurotoxic effects induced by 6-hydroxydopamine has been attributed to both its free radical scavenging activity and its role in adjusting the activity of Mn-SOD and Cu/Zn SOD. As in many other works, mentioned here, it seems that in this case the antioxidative protection exerted by melatonin involves multiple ways of action.

Exposure to bisphenol A can lead to DNA damage, which is believed to be mediated by increased OS levels and is accompanied by depletion of SOD activity. The capability of melatonin to prevent such alterations may then be attributed to both its direct antioxidant activity and its involvement in activating SOD. The role of melatonin in preventing OD and modulating SOD has also been related to the protective effects of this molecule against DNA damage induced by carbon-ion beam irradiation.

There is also evidence that melatonin and its metabolites (6OHM, AFMK and NAS) protect melanocytes from UVB-induced DNA damage and OS through activation of nuclear erythroid 2-related factor 2 (Nrf2) and its target enzymes. Induction of Nrf2 has also been associated with the effects of melatonin in reducing oxidative and nitrosative DNA damage. In fact, numerous investigations have shown that melatonin activates phase-2 antioxidative enzymes, via the Nrf2 pathway, including heme oxygenase-1 (HO-1), γ-glutamylcysteine synthetase (γ-GSC), nicotinamide adenine dinucleotide phosphate (NADPH): quinone dehydrogenase-1 (NQO1) and SOD.

There are many other reports in the literature documenting the role that antioxidant enzymes play in the protective effects exhibited by melatonin against OD. In addition, it seems that melatonin concentrations influence the relative importance of direct FR scavenging versus indirect actions involving activation of enzymatic pathways. Apparently, high concentrations (~1 mmol) favors the first, while low concentrations (~100 nm) promotes the enzymatic removal of ROS.

3.5.2. Inhibiting Pro-oxidative Enzymes

It has been reported that the activity of xanthine oxidase (XO), an enzyme that generates ROS, increases after exposure to MW radiation. At the same time, melatonin has protective effects against DNA fragmentation, induced by this kind of radiation. Thus, the beneficial effects of melatonin in this context has been attributed, at least partially, to the capability of melatonin for lowering the OS produced by XO. It is not clear, though, if in this case melatonin acts only as a ROS scavenger or if it actually inhibits XO activity. However, in a different study conducted on kidney tissue after ischemia and reperfusion, it was proposed that melatonin neutralizes the products of the XO + O2 reaction, rather than directly suppressing the XO activity. Therefore, it seems likely that the protection offered by melatonin against MW radiation is also mediated by its capability of scavenging ROS.

The protective effect of melatonin against Opisthorchis viverrini-induced oxidative and nitrosative stress and liver injury were investigated in hamsters. It was found that the formation of DNA lesions, namely 8-oxo-dG and 8-nitroguanine, is inhibited by melatonin. This protection was attributed to the inhibitory effects of melatonin on the mtRNA expression of oxidant generating genes, including inducible nitric oxide synthase, nuclear factor-kappa B and cyclooxygenase-2. Although, at the same time melatonin seems to increase the expression of antioxidant genes Nrf2 and Mn-SOD.

3.5.3. Boosting DNA Repair Machinery

It has been reported that pre-treatment with melatonin (100 mg/kg) protects rats exposed to whole-body X-ray radiation by modulating 8-oxoguanine glycosylase1 (Ogg1), apurinic/apyrimidinic endonuclease (Apex1) and X-ray repair cross-complementing group 1 (Xrcc1) gene expression in peripheral blood cells. These genes are among the most important ones for dealing with FR-induced DNA damage, in the base excision repair (BER) pathway. Ogg1 is involved in the removal of 8-oxo-dG DNA lesions, Apex1 mediates the repair of abasic sites and Xrcc1 is required for repairing strand breaks. Thus the finding that melatonin modulate these genes has a direct impact on reducing DNA damage. Moreover, based on the finding that melatonin may increase the normal tissue tolerance to radiation, by enhancing DNA repair, it was proposed that this molecule might be used to downgrade radiation toxicity in patients undergoing cancer radiotherapy.

Also relevant for cancer patients are the finding that melatonin reduces the DNA damage induced by cyclophosphamide, which is an anti-tumor agent currently used in clinical practice. The protective effect of melatonin in this case was attributed to its capacity to up-regulate the XPF expression, which is involved in the DNA nucleotide excision repair machinery. In view of that, melatonin administration was proposed as a co-treatment during chemotherapy.

Pre-treatment with melatonin was reported to increase DNA repair capacity in breast and colon cancer cells exposed to the mutagen methyl methanesulfonate. In the same study the genome-wide gene expression was examined and it was found that melatonin leads to altered expression of many of the investigated genes. This led to the suggestion that melatonin may enhance DNA repair capacity by affecting several key genes involved in DNA damage responsive pathways.

The effects of melatonin on DNA double-strand breaks caused by ionizing radiation were investigated using 108 male Wistar rats. The results from this investigation showed that the administration of melatonin (100 mg/kg), 8 and 24 h before exposure, significantly promotes DNA repair in non-homologous end joining pathways by increasing the expression of genes Ku70 and Xrcc4.

It is very interesting, in this context, that melatonin was found to reduce the time of DNA repair by one-half, although it does not seem to increase the activity of the base-excision repair glycosylases. It was then proposed that the melatonin’s ability to accelerate the DNA repair might involve other routes including: (i) chemical inactivation of H2O2; (ii) stimulation of DNA repair pathways other than BER; and/or (iii) interaction with BER-related enzymes other than glycosylases, or with their cofactors.

There is another interesting proposal regarding the relationship between melatonin’s anticancer activity and its role preserving DNA integrity. Santoro et al. proposed that melatonin-induced enhancement of the DNA repair machinery might (i) prevent carcinogenesis in healthy individuals; (ii) inhibit mutations in pre-cancerous lesions; (iii) reduce the risk that cancer cells mutate into more aggressive phenotypes; and (iv) limit the side effects of anticancer therapy in healthy tissues.

The role of melatonin in modulating DNA damage response and repair pathways has been recently, and thoroughly, reviewed. Thus the interested reader is referred to that work for further details on this topic.

4. Concluding Remarks

The beneficial effects of melatonin as an antioxidant have been profusely documented in the literature. In the particular case of its protection against oxidative DNA damage, the evidence gathered so far clearly indicates that melatonin is an astonishingly versatile molecule in this context. It can offer both direct and indirect protection against a wide variety of damaging agents and through multiple pathways, which may (or may not) take place simultaneously.

The direct antioxidative protection of melatonin is evidenced by its efficiency for scavenging free radicals, which are frequent triggers of oxidative damage to DNA. Melatonin has been proven to deactive several of these species including hydroxyl, alkoxy and peroxy radicals. Melatonin can also deactive non-radical reactive oxygen, and nitrogen, species. Such protection is evidenced by the melatonin effects in reducing 8-OH-dG, and associated DNA lesions.

The indirect antioxidative protection of melatonin involves many ways of action. It can protect DNA against metal-induced damage. Such protection seems to be quite general, since melatonin has been proven to inhibit the deleterious effects of a wide variety of metals including Fe, Cu, Cr, Pb, Ni, Co, Hg and As. Such protection itself may involve different mechanisms. One of them is mediated by the chelating capabilities of melatonin, which leads to the prevention of Fenton-related •OH generation.

There is also evidence supporting the protective effects of melatonin against other triggers of oxidative DNA damage. They include chemical agents such as formaldehyde, 17β-estradiol, the MPTP/MPP+ pair, potassium bromate, D-aminolevulinic acid and thioacetamide; as well as radiation and some health disorders.

In addition, melatonin’s metabolites (including AFMK, AMK, c3OHM, 6OHM and 4OHM) also have antioxidant properties. Thus, the protection exerted by melatonin against oxidative damage to DNA is a continuous, and virtuous, process in which multiple oxidative offenders can be deactivated. Moreover, part of the antioxidant protection exerted by melatonin may be attributed to its metabolites

Other indirect pathways contributing to melatonin’s protective effects against oxidative damage to DNA involve activating antioxidative enzymes, inhibiting pro-oxidative enzymes and boosting the DNA repair machinery. The rather unique capability of melatonin to exhibit multiple ways of actions, against diverse threatening factors, together with its low toxicity and its ability to cross biological barriers, are all significant to its efficiency for preventing oxidative damage to DNA.

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    Guenther A.L., Schmidt S.I., Laatsch H., Fotso S., Ness H., Ressmeyer A.R., Poeggeler B., Hardeland R. Reactions of the melatonin metabolite AMK (N1-acetyl-5-methoxykynuramine) with reactive nitrogen species: Formation of novel compounds, 3-acetamidomethyl-6-methoxycinnolinone and 3-nitro-AMK. J. Pineal Res. 2005;39:251-260.

    Not in our library10.1111/j.1600-079x.2005.00242.x

  36. 36.

    Hardeland R., Backhaus C., Fadavi A. Reactions of the NO redox forms NO+, •NO and HNO (protonated NO-) with the melatonin metabolite N1-acetyl-5-methoxykynuramine. J. Pineal Res. 2007;43:382-388.

    Not in our library10.1111/j.1600-079x.2007.00489.x

  37. 37.

    Tan D.X., Chen L.D., Poeggeler B., Manchester L.C., Reiter R.J. Melatonin: a potent, endogenous hydroxyl radical scavenger. Endocr. J. 1993;1:57-60.

    Not in our library

  38. 38.

    Matuszak Z., Bilska M.A., Reszkat K.J., Chignell C.F., Bilski P. Interaction of Singlet Molecular Oxygen with Melatonin and Related Indoles. Photochem. Photobiol. 2003;78:449-455.

    Not in our library10.1562/0031-8655(2003)078<0449:iosmow>2.0.co;2

  39. 39.

    Behrends A., Hardeland R., Ness H., Grube S., Poeggeler B., Haldar C. Photocatalytic actions of the pesticide metabolite 2-hydroxyquinoxaline: Destruction of antioxidant vitamins and biogenic amines-Implications of organic redox cycling. Redox Rep. 2004;9:279-288.

    Not in our library10.1179/135100004225006759

  40. 40.

    Kuesel J.T., Hardeland R., Pfoertner H., Aeckerle N. Reactions of the melatonin metabolite N1-acetyl-5-methoxykynuramine with carbamoyl phosphate and related compounds. J. Pineal Res. 2010;48:47-54.

    Not in our library10.1111/j.1600-079x.2009.00723.x

  41. 41.

    Mayo J.C., Tan D.X., Sainz R.M., Natarajan M., Lopez-Burillo S., Reiter R.J. Protection against oxidative protein damage induced by metal-catalyzed reaction or alkylperoxyl radicals: Comparative effects of melatonin and other antioxidants. Biochim. Biophys. Acta. 2003;1620:139-150.

    Not in our library10.1016/s0304-4165(02)00527-5

  42. 42.

    Park S., Lee D.E., Jang H., Byeon Y., Kim Y.S., Back K. Melatonin-rich transgenic rice plants exhibit resistance to herbicide-induced oxidative stress. J. Pineal Res. 2013;54:258-263.

    Not in our library10.1111/j.1600-079x.2012.01029.x

  43. 43.

    Maharaj D.S., Limson J.L., Daya S. 6-Hydroxymelatonin converts Fe (III) to Fe (II) and reduces iron-induced lipid peroxidation. Life Sci. 2003;72:1367-1375.

    Not in our library10.1016/s0024-3205(02)02405-0

  44. 44.

    Maharaj D.S., Maharaj H., Daya S., Glass B.D. Melatonin and 6-hydroxymelatonin protect against iron-induced neurotoxicity. J. Neurochem. 2006;96:78-81.

    Not in our library10.1111/j.1471-4159.2005.03532.x

  45. 45.

    García J.J., Reiter R.J., Karbownik M., Calvo J.R., Ortiz G.G., Tan D.X., Martínez-Ballarín E., Acua-Castroviejo D. N-Acetylserotonin suppresses hepatic microsomal membrane rigidity associated with lipid peroxidation. Eur. J. Pharmacol. 2001;428:169-175.

    Not in our library10.1016/s0014-2999(01)01342-5

  46. 46.

    Parmar P., Limson J., Nyokong T., Daya S. Melatonin protects against copper-mediated free radical damage. J. Pineal Res. 2002;32:237-242.

    Not in our library10.1034/j.1600-079x.2002.01859.x

  47. 47.

    Seeger H., Mueck A.O., Lippert T.H. Effect of melatonin and metabolites on copper-mediated oxidation of low density lipoprotein. Br. J. Clin. Pharmacol. 1997;44:283-284.

    Not in our library10.1046/j.1365-2125.1997.00648.x

  48. 48.

    Gozzo A., Lesieur D., Duriez P., Fruchart J.C., Teissier E. Structure-activity relationships in a series of melatonin analogues with the low-density lipoprotein oxidation model. Free Radic. Biol. Med. 1999;26:1538-1543.

    Not in our library10.1016/s0891-5849(99)00020-9

  49. 49.

    Tan D.X., Hardeland R., Manchester L.C., Paredes S.D., Korkmaz A., Sainz R.M., Mayo J.C., Fuentes-Broto L., Reiter R.J. The changing biological roles of melatonin during evolution: From an antioxidant to signals of darkness, sexual selection and fitness. Biol. Rev. Camb. Philos. Soc. 2010;85:607-623.

    Not in our library10.1111/j.1469-185x.2009.00118.x

  50. 50.
    Endogenous melatonin and oxidatively damaged guanine in DNA · 2009
    Not checked
  51. 51.

    Rosen J., Than N.N., Koch D., Poeggeler B., Laatsch H., Hardeland R. Interactions of melatonin and its metabolites with the ABTS cation radical: Extension of the radical scavenger cascade and formation of a novel class of oxidation products, C2-substituted 3-indolinones. J. Pineal Res. 2006;41:374-381.

    Not in our library10.1111/j.1600-079x.2006.00379.x

  52. 52.

    Tan D.X., Manchester L.C., Terron M.P., Flores L.J., Reiter R.J. One molecule, many derivatives: A never-ending interaction of melatonin with reactive oxygen and nitrogen species? J. Pineal Res. 2007;42:28-42.

    Not in our library10.1111/j.1600-079x.2006.00407.x

  53. 53.

    Yu Y., Cui Y., Niedernhofer L.J., Wang Y. Occurrence, Biological Consequences, and Human Health Relevance of Oxidative Stress-Induced DNA Damage. Chem. Res. Toxicol. 2016;29:2008-2039.

    Not in our library10.1021/acs.chemrestox.6b00265

  54. 54.

    Wiseman H., Halliwell B. Damage to DNA by reactive oxygen and nitrogen species: Role in inflammatory disease and progression to cancer. Biochem. J. 1996;313:17-29.

    Not in our library10.1042/bj3130017

  55. 55.

    Minko I.G., Kozekov I.D., Harris T.M., Rizzo C.J., Lloyd R.S., Stone M.P. Chemistry and biology of DNA containing 1,N2-deoxyguanosine adducts of the α,β-unsaturated aldehydes acrolein, crotonaldehyde, and 4-hydroxynonenal. Chem. Res. Toxicol. 2009;22:759-778.

    Not in our library10.1021/tx9000489

  56. 56.

    Chatgilialoglu C., D’Angelantonio M., Guerra M., Kaloudis P., Mulazzani Q.G. A reevaluation of the ambident reactivity of the guanine moiety towards hydroxyl radicals. Angew. Chem. Int. Ed. Engl. 2009;48:2214-2217.

    Not in our library10.1002/anie.200805372

  57. 57.

    Candeias L.P., Steenken S. Reaction of HO• with guanine derivatives in aqueous solution: Formation of two different redox-active OH-adduct radicals and their unimolecular transformation reactions. Properties of G(-H)•. Chem. Eur. J. 2000;6:475-484.

    Not in our library10.1002/(sici)1521-3765(20000204)6:3<475::aid-chem475>3.0.co;2-e

  58. 58.

    Pryor W.A. Why is the hydroxyl radical the only radical that commonly adds to DNA? Hypothesis: It has a rare combination of high electrophilicity, high thermochemical reactivity, and a mode of production that can occur near DNA. Free Radic. Biol. Med. 1988;4:219-223.

    Not in our library10.1016/0891-5849(88)90043-3

  59. 59.

    Galano A., Alvarez-Idaboy J.R. Guanosine + OH radical reaction in aqueous solution: A reinterpretation of the UV-vis data based on thermodynamic and kinetic calculations. Org. Lett. 2009;11:5114-5117.

    Not in our library10.1021/ol901862h

  60. 60.

    Steenken S., Jovanovic S.V. How easily oxidizable is DNA? One-electron reduction potentials of adenosine and guanosine radicals in aqueous solution. J. Am. Chem. Soc. 1997;119:617-618.

    Not in our library10.1021/ja962255b

  61. 61.

    Cadet J., Douki T., Ravanat J.-L. Oxidatively generated damage to the guanine moiety of DNA: Mechanistic aspects and formation in cells. Acc. Chem. Res. 2008;41:1075-1083.

    Not in our library10.1021/ar700245e

  62. 62.

    Galano A., Alvarez-Idaboy J.R. On the evolution of one-electron-oxidized deoxyguanosine in damaged DNA under physiological conditions: A DFT and ONIOM study on proton transfer and equilibrium. Phys. Chem. Chem. Phys. 2012;14:12476-12484.

    Not in our library10.1039/c2cp40799j

  63. 63.

    Balasubramanian B., Pogozelski W.K., Tullius T.D. DNA strand breaking by the hydroxyl radical is governed by the accessible surface areas of the hydrogen atoms of the DNA backbone. Proc. Natl. Acad. Sci. USA. 1998;95:9738-9743.

    Not in our library10.1073/pnas.95.17.9738

  64. 64.

    Malone M.E., Cullis P.M., Symons M.C.R., Parker A.W. Biphotonic photoionization of cytosine and its derivatives with UV radiation at 248 nm: An EPR study in low-temperature perchlorate glasses. J. Phys. Chem. 1995;99:9299-9308.

    Not in our library10.1021/j100022a052

  65. 65.

    Tronche C., Goodman B.K., Greenberg M.M. DNA damage induced via independent generation of the radical resulting from formal hydrogen atom abstraction from the C1′-position of a nucleotide. Chem. Biol. 1998;5:263-271.

    Not in our library10.1016/s1074-5521(98)90619-6

  66. 66.

    Pogozelski W.K., Tullius T.D. Oxidative Strand Scission of Nucleic Acids: Routes Initiated by Hydrogen Abstraction from the Sugar Moiety. Chem. Rev. 1998;98:1089-1108.

    Not in our library10.1021/cr960437i

  67. 67.

    Dedon P.C. The Chemical Toxicology of 2-Deoxyribose Oxidation in DNA. Chem. Res. Toxicol. 2007;21:206-219.

    Not in our library10.1021/tx700283c

  68. 68.

    Li M., Diao L., Liao X., Kou L., Lu W. DFT study on addition reaction mechanism of guanine-cytosine base pair with OH radical. J. Phys. Org. Chem. 2015;28:437-444.

    Not in our library10.1002/poc.3434

  69. 69.

    Valavanidis A., Vlachogianni T., Fiotakis C. 8-Hydroxy-2′-deoxyguanosine (8-OHdG): A critical biomarker of oxidative stress and carcinogenesis. J. Environ. Sci. Health C Environ. Carcinog. Ecotoxicol. Rev. 2009;27:120-139.

    Not in our library10.1080/10590500902885684

  70. 70.

    Roszkowski K., Jozwicki W., Blaszczyk P., Mucha-Malecka A., Siomek A. Oxidative damage DNA: 8-oxogua and 8-oxodG as molecular markers of cancer. Med. Sci. Monit. 2011;17:CR329-CR333.

    Not in our library10.12659/msm.881805

  71. 71.

    Steenken S., Jovanovic S.V., Bietti M., Bernhard K. The trap depth (in DNA) of 8-oxo-7,8-dihydro-2′deoxyguanosine as derived from electron-transfer equilibria in aqueous solution. J. Am. Chem. Soc. 2000;122:2373-2374.

    Not in our library10.1021/ja993508e

  72. 72.

    Cui L., Ye W., Prestwich E.G., Wishnok J.S., Taghizadeh K., Dedon P.C., Tannenbaum S.R. Comparative analysis of four oxidized guanine lesions from reactions of DNA with peroxynitrite, singlet oxygen, and γ-radiation. Chem. Res. Toxicol. 2013;26:195-202.

    Not in our library10.1021/tx300294d

  73. 73.

    Fleming A.M., Muller J.G., Ji I., Burrows C.J. Characterization of 2′-deoxyguanosine oxidation products observed in the Fenton-like system Cu(ii)/H2O2/reductant in nucleoside and oligodeoxynucleotide contexts. Org. Biomol. Chem. 2011;9:3338-3348.

    Not in our library10.1039/c1ob05112a

  74. 74.

    Suzuki T. Formation of spiroiminodihydantoin nucleoside from 8-oxo-7,8-dihydro-2′-deoxyguanosine by nitric oxide under aerobic conditions. Bioorg. Med. Chem. Lett. 2009;19:4944-4947.

    Not in our library10.1016/j.bmcl.2009.07.085

  75. 75.

    Niles J.C., Wishnok J.S., Tannenbaum S.R. Spiroiminodihydantoin and guanidinohydantoin are the dominant products of 8-oxoguanosine oxidation at low fluxes of peroxynitrite: Mechanistic studies with 18O. Chem. Res. Toxicol. 2004;17:1510-1519.

    Not in our library10.1021/tx0400048

  76. 76.

    Luo W., Muller J.G., Rachlin E.M., Burrows C.J. Characterization of hydantoin products from one-electron oxidation of 8-oxo-7,8-dihydroguanosine in a nucleoside model. Chem. Res. Toxicol. 2001;14:927-938.

    Not in our library10.1021/tx010072j

  77. 77.

    Dizdaroglu M., Kirkali G., Jaruga P. Formamidopyrimidines in DNA: Mechanisms of formation, repair, and biological effects. Free Radic. Biol. Med. 2008;45:1610-1621.

    Not in our library10.1016/j.freeradbiomed.2008.07.004

  78. 78.

    Dizdaroglu M., Jaruga P. Mechanisms of free radical-induced damage to DNA. Free Radic. Res. 2012;46:382-419.

    Not in our library10.3109/10715762.2011.653969

  79. 79.

    Wagner J.R., Cadet J. Oxidation reactions of cytosine DNA components by hydroxyl radical and one-electron oxidants in aerated aqueous solutions. Acc. Chem. Res. 2010;43:564-571.

    Not in our library10.1021/ar9002637

  80. 80.

    Box H.C., Budzinski E.E., Dawidzik J.B., Gobey J.S., Freund H.G. Free radical-induced tandem base damage in DNA oligomers. Free Radic. Biol. Med. 1997;23:1021-1030.

    Not in our library10.1016/s0891-5849(97)00166-4

  81. 81.

    Bellon S., Ravanat J.L., Gasparutto D., Cadet J. Cross-linked thymine-purine base tandem lesions: Synthesis, characterization, and measurement in γ-irradiated isolated DNA. Chem. Res. Toxicol. 2002;15:598-606.

    Not in our library10.1021/tx015594d

  82. 82.

    Zhang Q., Wang Y. Independent generation of 5-(2′-deoxycytidinyl)methyl radical and the formation of a novel cross-link lesion between 5-methylcytosine and guanine. J. Am. Chem. Soc. 2003;125:12795-12802.

    Not in our library10.1021/ja034866r

  83. 83.

    Zeng Y., Wang Y. UVB-induced formation of intrastrand cross-link products of DNA in MCF-7 cells treated with 5-bromo-2′-deoxyuridine. Biochemistry. 2007;46:8189-8195.

    Not in our library10.1021/bi700431q

  84. 84.

    Crean C., Uvaydov Y., Geacintov N.E., Shafirovich V. Oxidation of single-stranded oligonucleotides by carbonate radical anions: Generating intrastrand cross-links between guanine and thymine bases separated by cytosines. Nucleic Acids Res. 2008;36:742-755.

    Not in our library10.1093/nar/gkm1092

  85. 85.

    Uvaydov Y., Geacintov N.E., Shafirovich V. Generation of guanine-amino acid cross-links by a free radical combination mechanism. Phys. Chem. Chem. Phys. 2014;16:11729-11736.

    Not in our library10.1039/c4cp00675e

  86. 86.

    Leinisch F., Mariotti M., Rykaer M., Lopez-Alarcon C., Hägglund P., Davies M.J. Peroxyl radical- and photo-oxidation of glucose 6-phosphate dehydrogenase generates cross-links and functional changes via oxidation of tyrosine and tryptophan residues. Free Radic. Biol. Med. 2017;112:240-252.

    Not in our library10.1016/j.freeradbiomed.2017.07.025

  87. 87.

    Asahi T., Kondo H., Masuda M., Nishino H., Aratani Y., Naito Y., Yoshikawa T., Hisaka S., Kato Y., Osawa T. Chemical and immunochemical detection of 8-halogenated deoxyguanosines at early stage inflammation. J. Biol. Chem. 2010;285:9282-9291.

    Not in our library10.1074/jbc.m109.054213

  88. 88.

    Kang Jr J.I., Sowers L.C. Examination of hypochlorous acid-induced damage to cytosine residues in a CpG dinucleotide in DNA. Chem. Res. Toxicol. 2008;21:1211-1218.

    Not in our library10.1021/tx800037h

  89. 89.

    Kawai Y., Morinaga H., Kondo H., Miyoshi N., Nakamura Y., Uchida K., Osawa T. Endogenous formation of novel halogenated 2′-deoxycytidine: Hypohalous acid-mediated DNA modification at the site of inflammation. J. Biol. Chem. 2004;279:51241-51249.

    Not in our library10.1074/jbc.m408210200

  90. 90.

    Badouard C., Masuda M., Nishino H., Cadet J., Favier A., Ravanat J.L. Detection of chlorinated DNA and RNA nucleosides by HPLC coupled to tandem mass spectrometry as potential biomarkers of inflammation. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2005;827:26-31.

    Not in our library10.1016/j.jchromb.2005.03.025

  91. 91.

    Knutson C.G., Mangerich A., Zeng Y., Raczynski A.R., Liberman R.G., Kang P., Ye W., Prestwich E.G., Lu K., Wishnok J.S., et al. Chemical and cytokine features of innate immunity characterize serum and tissue profiles in inflammatory bowel disease. Proc. Natl. Acad. Sci. USA. 2013;110:E2332-E2341.

    Not in our library10.1073/pnas.1222669110

  92. 92.

    Lonkar P., Dedon P.C. Reactive species and DNA damage in chronic inflammation: Reconciling chemical mechanisms and biological fates. Int. J. Cancer. 2011;128:1999-2009.

    Not in our library10.1002/ijc.25815

  93. 93.

    Huie R.E., Padmaja S. The reaction of no with superoxide. Free Radic. Res. 1993;18:195-199.

    Not in our library10.3109/10715769309145868

  94. 94.

    Dedon P.C., Tannenbaum S.R. Reactive nitrogen species in the chemical biology of inflammation. Arch. Biochem. Biophys. 2004;423:12-22.

    Not in our library10.1016/j.abb.2003.12.017

  95. 95.

    Cantoni O., Guidarelli A. Peroxynitrite damages U937 cell DNA via the intermediate formation of mitochondrial oxidants. IUBMB Life. 2008;60:753-756.

    Not in our library10.1002/iub.116

  96. 96.

    Yu H., Venkatarangan L., Wishnok J.S., Tannenbaum S.R. Quantitation of four guanine oxidation products from reaction of DNA with varying doses of peroxynitrite. Chem. Res. Toxicol. 2005;18:1849-1857.

    Not in our library10.1021/tx050146h

  97. 97.

    Burney S., Niles J.C., Dedon P.C., Tannenbaum S.R. DNA damage in deoxynucleosides and oligonucleotides treated with peroxynitrite. Chem. Res. Toxicol. 1999;12:513-520.

    Not in our library10.1021/tx980254m

  98. 98.

    Blair I.A. DNA adducts with lipid peroxidation products. J. Biol. Chem. 2008;283:15545-15549.

    Not in our library10.1074/jbc.r700051200

  99. 99.

    Stonez M.P., Cho Y.J., Huang H., Kim H.Y., Kozekov I.D., Kozekova A., Wang H., Minko I.G., Lloyd R.S., Harris T.M., et al. Interstrand DNA cross-links induced by α,β-unsaturated aldehydes derived from lipid peroxidation and environmental sources. Acc. Chem. Res. 2008;41:793-804.

    Not in our library10.1021/ar700246x

  100. 100.

    Karbownik M., Reiter R.J., Cabrera J., Garcia J.J. Comparison of the protective effect of melatonin with other antioxidants in the hamster kidney model of estradiol-induced DNA damage. Mutat. Res. 2001;474:87-92.

    Not in our library10.1016/s0027-5107(00)00164-0

  101. 101.

    Chen L.J., Gao Y.Q., Li X.J., Shen D.H., Sun F.Y. Melatonin protects against MPTP/MPP+-induced mitochondrial DNA oxidative damage in vivo and in vitro. J. Pineal Res. 2005;39:34-42.

    Not in our library10.1111/j.1600-079x.2005.00209.x

  102. 102.

    Karbownik M., Tan D.X., Reiter R.J. Melatonin reduces the oxidation of nuclear DNA and membrane lipids induced by the carcinogen δ-aminolevulinic acid. Int. J. Cancer. 2000;88:7-11.

    Not in our library10.1002/1097-0215(20001001)88:1<7::aid-ijc2>3.0.co;2-t

  103. 103.

    Lebda M.A., Sadek K.M., Abouzed T.K., Tohamy H.G., El-Sayed Y.S. Melatonin mitigates thioacetamide-induced hepatic fibrosis via antioxidant activity and modulation of proinflammatory cytokines and fibrogenic genes. Life Sci. 2018;192:136-143.

    Not in our library10.1016/j.lfs.2017.11.036

  104. 104.

    Wu H.J., Liu C., Duan W.X., Xu S.C., He M.D., Chen C.H., Wang Y., Zhou Z., Yu Z.P., Zhang L., et al. Melatonin ameliorates bisphenol A-induced DNA damage in the germ cells of adult male rats. Mutat. Res. 2013;752:57-67.

    Not in our library10.1016/j.mrgentox.2013.01.005

  105. 105.

    Liu R., Fu A., Hoffman A.E., Zheng T., Zhu Y. Melatonin enhances DNA repair capacity possibly by affecting genes involved in DNA damage responsive pathways. BMC Cell Biol. 2013;14:1.

    Not in our library10.1186/1471-2121-14-1

  106. 106.

    Pappolla M.A., Chyan Y.J., Poeggeler B., Bozner P., Ghiso J., LeDoux S.P., Wilson G.L. Alzheimer β protein mediated oxidative damage of mitochondrial DNA: Prevention by melatonin. J. Pineal Res. 1999;27:226-229.

    Not in our library10.1111/j.1600-079x.1999.tb00619.x

  107. 107.

    Sokolovic D., Djordjevic B., Kocic G., Stoimenov T.J., Stanojkovic Z., Sokolovic D.M., Veljkovic A., Ristic G., Despotovic M., Milisavljevic D., et al. The effects of melatonin on oxidative stress parameters and DNA fragmentation in testicular tissue of rats exposed to microwave radiation. Adv. Clin. Exp. Med. 2015;24:429-436.

    Not in our library10.17219/acem/43888

  108. 108.

    Das B., Bennett P.V., Cutter N.C., Sutherland J.C., Sutherland B.M. Melatonin protects human cells from clustered DNA damages, killing and acquisition of soft agar growth induced by X-rays or 970 MeV/n Fe ions. Int. J. Radiat. Biol. 2011;87:545-555.

    Not in our library10.3109/09553002.2011.560993

  109. 109.

    Ündeǧer Ü., Giray B., Zorlu A.F., Öge K., Baçaran N. Protective effects of melatonin on the ionizing radiation induced DNA damage in the rat brain. Exp. Toxicol. Pathol. 2004;55:379-384.

    Not in our library10.1078/0940-2993-00332

  110. 110.

    Wakatsuki A., Okatani Y., Izumiya C., Ikenoue N. Melatonin protects against ischemia and reperfusion-induced oxidative lipid and DNA damage in fetal rat brain. J. Pineal Res. 1999;26:147-152.

    Not in our library10.1111/j.1600-079x.1999.tb00576.x

  111. 111.
    Melatonin Alleviates Intracerebral Hemorrhage-Induced Secondary Brain Injury in Rats via Suppressing Apoptosis, Inflammation, Oxidative Stress, DNA Damage, and Mitochondria Injury · 2017
    No notice
  112. 112.

    Morioka N., Okatani Y., Wakatsuki A. Melatonin protects against age-related DNA damage in the brains of female senescence-accelerated mice. J. Pineal Res. 1999;27:202-209.

    Not in our library10.1111/j.1600-079x.1999.tb00616.x

  113. 113.

    Evans M.D., Dizdaroglu M., Cooke M.S. Oxidative DNA damage and disease: Induction, repair and significance. Mutat. Res. 2004;567:1-61.

    Not in our library10.1016/j.mrrev.2003.11.001

  114. 114.

    Cooke M.S., Evans M.D., Dizdaroglu M., Lunec J. Oxidative DNA damage: Mechanisms, mutation, and disease. FASEB J. 2003;17:1195-1214.

    Not in our library10.1096/fj.02-0752rev

  115. 115.

    Kawanishi S., Ohnishi S., Ma N., Hiraku Y., Oikawa S., Murata M. Nitrative and oxidative DNA damage in infection-related carcinogenesis in relation to cancer stem cells. Genes Environ. 2016;38:26.

    Not in our library10.1186/s41021-016-0055-7

  116. 116.
    Role of Nitrative and Oxidative DNA Damage in Inflammation-Related Carcinogenesis · 2012
    No notice
  117. 117.

    Kryston T.B., Georgiev A.B., Pissis P., Georgakilas A.G. Role of oxidative stress and DNA damage in human carcinogenesis. Mutat. Res. 2011;711:193-201.

    Not in our library10.1016/j.mrfmmm.2010.12.016

  118. 118.

    Markkanen E. Not breathing is not an option: How to deal with oxidative DNA damage. DNA Repair. 2017;59:82-105.

    Not in our library10.1016/j.dnarep.2017.09.007

  119. 119.

    Talhaoui I., Matkarimov B.T., Tchenio T., Zharkov D.O., Saparbaev M.K. Aberrant base excision repair pathway of oxidatively damaged DNA: Implications for degenerative diseases. Free Radic. Biol. Med. 2017;107:266-277.

    Not in our library10.1016/j.freeradbiomed.2016.11.040

  120. 120.

    Kasprzak K.S. Oxidative DNA and protein damage in metal-induced toxicity and carcinogenesis. Free Radic. Biol. Med. 2002;32:958-967.

    Not in our library10.1016/s0891-5849(02)00809-2

  121. 121.

    Kasai H. What causes human cancer? Approaches from the chemistry of DNA damage. Genes Environ. 2016;38:19.

    Not in our library10.1186/s41021-016-0046-8

  122. 122.

    Smith J.A., Park S., Krause J.S., Banik N.L. Oxidative stress, DNA damage, and the telomeric complex as therapeutic targets in acute neurodegeneration. Neurochem. Int. 2013;62:764-775.

    Not in our library10.1016/j.neuint.2013.02.013

  123. 123.

    Santos R.X., Correia S.C., Zhu X., Lee H.G., Petersen R.B., Nunomura A., Smith M.A., Perry G., Moreira P.I. Nuclear and mitochondrial DNA oxidation in Alzheimer’s disease. Free Radic. Res. 2012;46:565-576.

    Not in our library10.3109/10715762.2011.648188

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    Mao P., Reddy P.H. Aging and amyloid beta-induced oxidative DNA damage and mitochondrial dysfunction in Alzheimer’s disease: Implications for early intervention and therapeutics. Biochim. Biophys. Acta. 2011;1812:1359-1370.

    Not in our library10.1016/j.bbadis.2011.08.005

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    Markesbery W.R., Lovell M.A. DNA oxidation in Alzheimer’s disease. Antioxid. Redox Signal. 2006;8:2039-2045.

    Not in our library10.1089/ars.2006.8.2039

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    Isobe C., Abe T., Terayama Y. Levels of reduced and oxidized coenzyme Q-10 and 8-hydroxy-2′-deoxyguanosine in the CSF of patients with Alzheimer’s disease demonstrate that mitochondrial oxidative damage and/or oxidative DNA damage contributes to the neurodegenerative process. J. Neurol. 2010;257:399-404.

    Not in our library10.1007/s00415-009-5333-x

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    Isobe C., Abe T., Terayama Y. Levels of reduced and oxidized coenzymeQ-10 and 8-hydroxy-2′-deoxyguanosine in the cerebrospinal fluid of patients with living Parkinson’s disease demonstrate that mitochondrial oxidative damage and/or oxidative DNA damage contributes to the neurodegenerative process. Neurosci. Lett. 2010;469:159-163.

    Not in our library10.1016/j.neulet.2009.11.065

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    Gackowski D., Rozalski R., Siomek A., Dziaman T., Nicpon K., Klimarczyk M., Araszkiewicz A., Olinski R. Oxidative stress and oxidative DNA damage is characteristic for mixed Alzheimer disease/vascular dementia. J. Neurol. Sci. 2008;266:57-62.

    Not in our library10.1016/j.jns.2007.08.041

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    Murata T., Ohtsuka C., Terayama Y. Increased mitochondrial oxidative damage and oxidative DNA damage contributes to the neurodegenerative process in sporadic amyotrophic lateral sclerosis. Free Radic. Res. 2008;42:221-225.

    Not in our library10.1080/10715760701877262

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    Gmitterová K., Gawinecka J., Heinemann U., Valkovič P., Zerr I. DNA versus RNA oxidation in Parkinson’s disease: Which is more important? Neurosci. Lett. 2018;662:22-28.

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    Malik Q., Herbert K.E. Oxidative and non-oxidative DNA damage and cardiovascular disease. Free Radic. Res. 2012;46:554-564.

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    Satoh M., Ishikawa Y., Takahashi Y., Itoh T., Minami Y., Nakamura M. Association between oxidative DNA damage and telomere shortening in circulating endothelial progenitor cells obtained from metabolic syndrome patients with coronary artery disease. Atherosclerosis. 2008;198:347-353.

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    Mondal N.K., Sorensen E., Hiivala N., Feller E., Griffith B., Wu Z.J. Oxidative stress, DNA damage and repair in heart failure patients after implantation of continuous flow left ventricular assist devices. Int. J. Med. Sci. 2013;10:883-893.

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    Kono Y., Nakamura K., Kimura H., Nishii N., Watanabe A., Banba K., Miura A., Nagase S., Sakuragi S., Kusano K.F., et al. Elevated levels of oxidative DNA damage in serum and myocardium of patients with heart failure. Circ. J. 2006;70:1001-1005.

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    Yu Y., Guerrero C.R., Liu S., Amato N.J., Sharma Y., Gupta S., Wang Y. Comprehensive assessment of oxidatively induced modifications of DNA in a rat model of human Wilson’s disease. Mol. Cell. Proteom. 2016;15:810-817.

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    Mansouri A., Gaou I., Fromenty B., Berson A., Letteron P., Degott C., Erlinger S., Pessayre D. Premature oxidative aging of hepatic mitochondrial DNA in Wilson’s disease. Gastroenterology. 1997;113:599-605.

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    Pereira C., Coelho R., Grácio D., Dias C., Silva M., Peixoto A., Lopes P., Costa C., Teixeira J.P., Macedo G., et al. DNA damage and oxidative DNA damage in inflammatory bowel disease. J. Crohn’s Colitis. 2016;10:1316-1323.

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    Sohn J.J., Schetter A.J., Yfantis H.G., Ridnour L.A., Horikawa I., Khan M.A., Robles A.I., Hussain S.P., Goto A., Bowman E.D., et al. Macrophages, nitric oxide and microRNAs are associated with DNA damage response pathway and senescence in inflammatory bowel disease. PLoS ONE. 2012;7:e44156.

    Not in our library10.1371/journal.pone.0044156

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    Tatsch E., Bochi G.V., Piva S.J., De Carvalho J.A.M., Kober H., Torbitz V.D., Duarte T., Signor C., Coelho A.C., et al. Association between DNA strand breakage and oxidative, inflammatory and endothelial biomarkers in type 2 diabetes. Mutat. Res. 2012;732:16-20.

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    Liu X., Gan W., Zou Y., Yang B., Su Z., Deng J., Wang L., Cai J. Elevated levels of urinary markers of oxidative DNA and RNA damage in type 2 diabetes with complications. Oxid. Med. Cell. Longev. 2016;2016.

    Not in our library10.1155/2016/4323198

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    Tatsch E., Carvalho J.A., Hausen B.S., Bollick Y.S., Torbitz V.D., Duarte T., Scolari R., Duarte M.M.M.F., Londero S.W.K., Vaucher R.A., et al. Oxidative DNA damage is associated with inflammatory response, insulin resistance and microvascular complications in type 2 diabetes. Mutat. Res. 2015;782:17-22.

    Not in our library10.1016/j.mrfmmm.2015.10.003

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    Tabak O., Gelisgen R., Erman H., Erdenen F., Muderrisoglu C., Aral H., Uzun H. Oxidative lipid, protein, and DNA damage as oxidative stress markers in vascular complications of diabetes mellitus. Clin. Investig. Med. 2011;34:E163-E171.

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    Olinski R., Gackowski D., Foksinski M., Rozalski R., Roszkowski K., Jaruga P. Oxidative DNA damage: Assessment of the role in carcinogenesis, atherosclerosis, and acquired immunodeficiency syndrome. Free Radic. Biol. Med. 2002;33:192-200.

    Not in our library10.1016/s0891-5849(02)00878-x

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    Kolgiri V., Patil V.W., Nagar V. Correlation of total antioxidant status (TAS) with DNA damage in HIV/AIDS patients. Int. J. Pharm. Pharm. Sci. 2016;8:240-244.

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    De Luca G., Russo M.T., Degan P., Tiveron C., Zijno A., Meccia E., Ventura I., Mattei E., Nakabeppu Y., Crescenzi M., et al. A role for oxidized DNA precursors in Huntington’s disease-like striatal neurodegeneration. PLoS Genet. 2008;4:e1000266.

    Not in our library10.1371/journal.pgen.1000266

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    Ayala-Peña S. Role of oxidative DNA damage in mitochondrial dysfunction and Huntington’s disease pathogenesis. Free Radic. Biol. Med. 2013;62:102-110.

    Not in our library10.1016/j.freeradbiomed.2013.04.017

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    Seven A., Güzel S., Aslan M., Hamuryudan V. Lipid, protein, DNA oxidation and antioxidant status in rheumatoid arthritis. Clin. Biochem. 2008;41:538-543.

    Not in our library10.1016/j.clinbiochem.2008.01.029

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    Altindag O., Karakoc M., Kocyigit A., Celik H., Soran N. Increased DNA damage and oxidative stress in patients with rheumatoid arthritis. Clin. Biochem. 2007;40:167-171.

    Not in our library10.1016/j.clinbiochem.2006.10.006

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    Hajizadeh S., DeGroot J., TeKoppele J.M., Tarkowski A., Collins L.V. Extracellular mitochondrial DNA and oxidatively damaged DNA in synovial fluid of patients with rheumatoid arthritis. Arthritis Res. Ther. 2003;5:R234-240.

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    Neofytou E., Tzortzaki E.G., Chatziantoniou A., Siafakas N.M. DNA damage due to oxidative stress in chronic obstructive pulmonary disease (COPD). Int. J. Mol. Sci. 2012;13:16853-16864.

    Not in our library10.3390/ijms131216853

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    Galano A. Free radicals induced oxidative stress at a molecular level: The current status, challenges and perspectives of computational chemistry based protocols. J. Mex. Chem. Soc. 2015;59:231-262.

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    Alvarez-Idaboy J.R., Galano A. On the chemical repair of DNA radicals by glutathione: Hydrogen vs. electron transfer. J. Phys. Chem. B. 2012;116:9316-9325.

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    Wiechmann A.F., Sherry D.M. Role of melatonin and its receptors in the vertebrate retina. Int. Rev. Cell Mol. Biol. 2013;300:211-242.

    Not in our library10.1016/b978-0-12-405210-9.00006-0

  154. 154.

    Kim T.K., Kleszczynśki K., Janjetovic Z., Sweatman T., Lin Z., Li W., Reiter R.J., Fischer T.W., Slominski A.T. Metabolism of melatonin and biological activity of intermediates of melatoninergic pathway in human skin cells. FASEB J. 2013;27:2742-2755.

    Not in our library10.1096/fj.12-224691

  155. 155.

    Pinato L., da Silveira Cruz-Machado S., Franco D.G., Campos L.M.G., Cecon E., Fernandes P.A.C.M., Bittencourt J.C., Markus R.P. Selective protection of the cerebellum against intracerebroventricular LPS is mediated by local melatonin synthesis. Brain Struct. Funct. 2013;220:1-14.

    Not in our library10.1007/s00429-013-0686-4

  156. 156.

    Lahiri D.K., Ge Y.W., Sharman E.H., Bondy S.C. Age-related changes in serum melatonin in mice: Higher levels of combined melatonin and 6-hydroxymelatonin sulfate in the cerebral cortex than serum, heart, liver and kidney tissues. J. Pineal Res. 2004;36:217-223.

    Not in our library10.1111/j.1600-079x.2004.00120.x

  157. 157.

    Cruz M.H.C., Leal C.L.V., Cruz J.F., Tan D.X., Reiter R.J. Essential actions of melatonin in protecting the ovary from oxidative damage. Theriogenology. 2014;82:925-932.

    Not in our library10.1016/j.theriogenology.2014.07.011

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    Peschke E. Melatonin, endocrine pancreas and diabetes. J. Pineal Res. 2008;44:26-40.

    Not in our library10.1111/j.1600-079x.2007.00519.x

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    Acuna-Castroviejo D., Lowenstein P.R., Rosenstein R., Cardinali D.P. Diurnal variations of benzodiazepine binding in rat cerebral cortex: Disruption by pinealectomy. J. Pineal Res. 1986;3:101-109.

    Not in our library10.1111/j.1600-079x.1986.tb00732.x

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    Reiter R.J. The melatonin rhythm: both a clock and a calendar. Experientia. 1993;49:654-664.

    Not in our library10.1007/bf01923947

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    Reiter R.J. Circannual reproductive rhythms in mammals related to photoperiod and pineal function: A review. Chronobiologia. 1974;1:365-395.

    Not in our library

  162. 162.

    Reiter R.J., Tan D.X., Fuentes-Broto L. Melatonin: A multi-tasking molecule. Prog. Brain Res. 2010;181:127-151.

    Not in our library10.1016/s0079-6123(08)81008-4

  163. 163.

    Jung K.H., Hong S.W., Zheng H.M., Lee H.S., Lee H., Lee D.H., Lee S.Y., Hong S.S. Melatonin ameliorates cerulein-induced pancreatitis by the modulation of nuclear erythroid 2-related factor 2 and nuclear factor-kappaB in rats. J. Pineal Res. 2010;48:239-250.

    Not in our library10.1111/j.1600-079x.2010.00748.x

  164. 164.

    Chahbouni M., Escames G., Venegas C., Sevilla B., García J.A., López L.C., Muñoz-Hoyos A., Molina-Carballo A., Acuna-Castroviejo D. Melatonin treatment normalizes plasma pro-inflammatory cytokines and nitrosative/oxidative stress in patients suffering from Duchenne muscular dystrophy. J. Pineal Res. 2010;48:282-289.

    Not in our library10.1111/j.1600-079x.2010.00752.x

  165. 165.

    Carrillo-Vico A., Guerrero J.M., Lardone P.J., Reiter R.J. A review of the multiple actions of melatonin on the immune system. Endocrine. 2005;27:189-200.

    Not in our library10.1385/endo:27:2:189

  166. 166.

    Jou M.J., Peng T.I., Hsu L.F., Jou S.B., Reiter R.J., Yang C.M., Chiao C.C., Lin Y.F., Chen C.C. Visualization of melatonin’s multiple mitochondrial levels of protection against mitochondrial Ca2+-mediated permeability transition and beyond in rat brain astrocytes. J. Pineal Res. 2010;48:20-38.

    Not in our library10.1111/j.1600-079x.2009.00721.x

  167. 167.

    Paradies G., Petrosillo G., Paradies V., Reiter R.J., Ruggiero F.M. Melatonin, cardiolipin and mitochondrial bioenergetics in health and disease. J. Pineal Res. 2010;48:297-310.

    Not in our library10.1111/j.1600-079x.2010.00759.x

  168. 168.

    Milczarek R., Hallmann A., Sokołowska E., Kaletha K., Klimek J. Melatonin enhances antioxidant action of α-tocopherol and ascorbate against NADPH- and iron-dependent lipid peroxidation in human placental mitochondria. J. Pineal Res. 2010;49:149-155.

    Not in our library10.1111/j.1600-079x.2010.00779.x

  169. 169.

    García J.J., Lõpez-Pingarrõn L., Almeida-Souza P., Tres A., Escudero P., García-Gil F.A., Tan D.X., Reiter R.J., Ramírez J.M., et al. Protective effects of melatonin in reducing oxidative stress and in preserving the fluidity of biological membranes: A review. J. Pineal Res. 2014;56:225-237.

    Not in our library10.1111/jpi.12128

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    Reiter R.J., Rosales-Corral S., Tan D.X., Jou M.J., Galano A., Xu B. Melatonin as a mitochondria-targeted antioxidant: one of evolution’s best ideas. Cell. Mol. Life Sci. 2017;74:3863-3881.

    Not in our library10.1007/s00018-017-2609-7

  171. 171.

    Majidinia M., Sadeghpour A., Mehrzadi S., Reiter R.J., Khatami N., Yousefi B. Melatonin: A pleiotropic molecule that modulates DNA damage response and repair pathways. J. Pineal Res. 2017;63:e12416.

    Not in our library10.1111/jpi.12416

  172. 172.

    Galano A., Castañeda-Arriaga R., Pérez-González A., Tan D.X., Reiter R.J. Phenolic melatonin-related compounds: Their role as chemical protectors against oxidative stress. Molecules. 2016;21:1442.

    Not in our library10.3390/molecules21111442

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    Galano A., Tan D.-X., Reiter R.J. Melatonin and related compounds: chemical insights into their protective effects against oxidative stress. Curr. Org. Chem. 2016;21:1-19.

    Not in our library10.2174/1385272820666161024124058

  174. 174.

    Sliwinski T., Rozej W., Morawiec-Bajda A., Morawiec Z., Reiter R., Blasiak J. Protective action of melatonin against oxidative DNA damage-Chemical inactivation versus base-excision repair. Mutat. Res. 2007;634:220-227.

    Not in our library10.1016/j.mrgentox.2007.07.013

  175. 175.

    George A. The Role of Indoleamines in Reducing Free Radical Damage and Oxidative Stress: A Physicochemical Perspective. Indoleamines: Sources, Role in Biological Processes and Health Effects. 2015;1-41.

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    Reiter R.J., Tan D.X., Rosales-Corral S., Manchester L.C. The universal nature, unequal distribution and antioxidant functions of melatonin and its derivatives. Mini-Rev. Med. Chem. 2013;13:373-384.

    Not in our library10.2174/1389557511313030006

  177. 177.

    Hevia D., González-Menéndez P., Quiros-González I., Miar A., Rodríguez-García A., Tan D.X., Reiter R.J., Mayo J.C., Sainz R.M. Melatonin uptake through glucose transporters: A new target for melatonin inhibition of cancer. J. Pineal Res. 2015;58:234-250.

    Not in our library10.1111/jpi.12210

  178. 178.

    Andersen L.P.H., Gögenur I., Rosenberg J., Reiter R.J. The safety of melatonin in humans. Clin. Drug Investig. 2016;36:169-175.

    Not in our library10.1007/s40261-015-0368-5

  179. 179.

    Arendt J. Safety of melatonin in long-term use (?). J. Biol. Rhythms. 1997;12:673-681.

    Not in our library10.1177/074873049701200624

  180. 180.

    Gringras P., Nir T., Breddy J., Frydman-Marom A., Findling R.L. Efficacy and safety of pediatric prolonged-release melatonin for insomnia in children with autism spectrum disorder. J. Am. Acad. Child Adolesc. Psychiatry. 2017;56:948-957.

    Not in our library10.1016/j.jaac.2017.09.414

  181. 181.

    Vijayalaxmi, Meltz M.L., Reiter R.J., Herman T.S. Melatonin and protection from genetic damage in blood and bone marrow: Whole-body irradiation studies in mice. J. Pineal Res. 1999;27:221-225.

    Not in our library10.1111/j.1600-079x.1999.tb00618.x

  182. 182.

    Jahnke G., Marr M., Myers C., Wilson R., Travlos G., Price C. Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats. Toxicol. Sci. 1999;50:271-279.

    Not in our library10.1093/toxsci/50.2.271

  183. 183.

    Vijayalaxmi, Meltz M.L., Reiter R.J., Herman T.S., Kumar K S. Melatonin and protection from whole-body irradiation: Survival studies in mice. Mutat. Res. 1999;425:21-27.

    Not in our library10.1016/s0027-5107(98)00246-2

  184. 184.

    Kaya H., Delibas N., Serteser M., Ulukaya E., Özkaya O. The effect of melatonin on lipid peroxidation during radiotherapy in female rats. Strahlenther. Onkol. 1999;175:285-288.

    Not in our library10.1007/bf02743581

  185. 185.

    Nordlund J.J., Lerner A.B. The effects of oral melatonin on skin color and on the release of pituitary hormones. J. Clin. Endocrinol. Metab. 1977;45:768-774.

    Not in our library10.1210/jcem-45-4-768

  186. 186.

    Sharman E.H., Bondy S.C. Melatonin: A safe nutraceutical and clinical agent. Nutraceuticals. 2016;501-509.

    Not in our library10.1016/b978-0-12-802147-7.00036-x

  187. 187.

    Yoshida M., Fukuda A., Hara M., Terada A., Kitanaka Y., Owada S. Melatonin prevents the increase in hydroxyl radical-spin trap adduct formation caused by the addition of cisplatin in vitro. Life Sci. 2003;72:1773-1780.

    Not in our library10.1016/s0024-3205(02)02480-3

  188. 188.

    Reiter R.J., Acuña-Castroviejo D., Tan D.X., Burkhardt S. Free radical-mediated molecular damage: Mechanisms for the protective actions of melatonin in the central nervous system. Ann. N. Y. Acad. Sci. 2001;939:200-215.

    Not in our library10.1111/j.1749-6632.2001.tb03627.x

  189. 189.

    Escames G., Guerrero J.M., Reiter R.J., Garcia J.J., Munoz-Hoyos A., Ortiz G.G., Oh C.S. Melatonin and vitamin E limit nitric oxide-induced lipid peroxidation in rat brain homogenates. Neurosci. Lett. 1997;230:147-150.

    Not in our library10.1016/s0304-3940(97)00498-9

  190. 190.

    Siu A.W., Ortiz G.G., Benitez-King G., To C.H., Reiter R.J. Effect of melatonin on the nitric oxide treated retina. Br. J. Ophthalmol. 2004;88:1078-1081.

    Not in our library10.1136/bjo.2003.037879

  191. 191.

    Zavodnik I.B., Domanski A.V., Lapshina E.A., Bryszewska M., Reiter R.J. Melatonin directly scavenges free radicals generated in red blood cells and a cell-free system: Chemiluminescence measurements and theoretical calculations. Life Sci. 2006;79:391-400.

    Not in our library10.1016/j.lfs.2006.01.030

  192. 192.

    Tan D.X., Manchester L.C., Reiter R.J., Plummer B.F., Limson J., Weintraub S.T., Qi W. Melatonin directly scavenges hydrogen peroxide: A potentially new metabolic pathway of melatonin biotransformation. Free Radic. Biol. Med. 2000;29:1177-1185.

    Not in our library10.1016/s0891-5849(00)00435-4

  193. 193.

    Romero M.P., Osuna C., García-Pergañeda A., Carrillo-Vico A., Guerrero J.M. The pineal secretory product melatonin reduces hydrogen peroxide- induced DNA damage in U-937 cells. J. Pineal Res. 1999;26:227-235.

    Not in our library10.1111/j.1600-079x.1999.tb00588.x

  194. 194.

    Reiter R.J., Tan D.X., Osuna C., Gitto E. Actions of melatonin in the reduction of oxidative stress: A review. J. Biomed. Sci. 2000;7:444-458.

    Not in our library10.1007/bf02253360

  195. 195.

    Gurer-Orhan H., Suzen S. Melatonin, its metabolites and its synthetic analogs as multi-faceted compounds: Antioxidant, prooxidant and inhibitor of bioactivation reactions. Curr. Med. Chem. 2015;22:490-499.

    Not in our library10.2174/0929867321666141215095259

  196. 196.

    Suzen S. Melatonin and synthetic analogs as antioxidants. Curr. Drug Del. 2013;10:71-75.

    Not in our library10.2174/1567201811310010013

  197. 197.

    Ateş-Alagöz Z., Coban T., Suzen S. A comparative study: Evaluation of antioxidant activity of melatonin and some indole derivatives. Med. Chem. Res. 2005;14:169-179.

    Not in our library10.1007/s00044-005-0132-0

  198. 198.

    Suzen S., Bozkaya P., Coban T., Nebioǧlu D. Investigation of the in vitro antioxidant behaviour of some 2-phenylindole derivatives: Discussion on possible antioxidant mechanisms and comparison with melatonin. J. Enzyme Inhib. Med. Chem. 2006;21:405-411.

    Not in our library10.1080/14756360500381210

  199. 199.

    Shirinzadeh H., Eren B., Gurer-Orhan H., Suzen S., Özden S. Novel indole-based analogs of melatonin: Synthesis and in vitro antioxidant activity studies. Molecules. 2010;15:2187-2202.

    Not in our library10.3390/molecules15042187

  200. 200.

    Yilmaz A.D., Coban T., Suzen S. Synthesis and antioxidant activity evaluations of melatonin-based analogue indole-hydrazide/hydrazone derivatives. J. Enzyme Inhib. Med. Chem. 2012;27:428-436.

    Not in our library10.3109/14756366.2011.594048

  201. 201.

    Gürkök G., Coban T., Suzen S. Melatonin analogue new indole hydrazide/hydrazone derivatives with antioxidant behavior: Synthesis and structureactivity relationships. J. Enzyme Inhib. Med. Chem. 2009;24:506-515.

    Not in our library10.1080/14756360802218516

  202. 202.

    Suzen S., Cihaner S.S., Coban T. Synthesis and comparison of antioxidant properties of indole-based melatonin analogue indole amino acid derivatives. Chem. Biol. Drug Des. 2012;79:76-83.

    Not in our library10.1111/j.1747-0285.2011.01216.x

  203. 203.

    Liang S., Jin Y.X., Yuan B., Zhang J.B., Kim N.H. Melatonin enhances the developmental competence of porcine somatic cell nuclear transfer embryos by preventing DNA damage induced by oxidative stress. Sci. Rep. 2017;7:11114.

    Not in our library10.1038/s41598-017-11161-9

  204. 204.

    Erenberk U., Dundaroz R., Gok O., Uysal O., Agus S., Yuksel A., Yilmaz B., Kilic U. Melatonin attenuates phenytoin sodium-induced DNA damage. Drug Chem. Toxicol. 2014;37:233-239.

    Not in our library10.3109/01480545.2013.838777

  205. 205.

    Sekkin S., İpek E.D., Boyacioğlu M., Kum C., Karademir Ü., Yalinkilinç H.S., Ak M.O., Başaloğlu H. DNA protective and antioxidative effects of melatonin in streptozotocin-induced diabetic rats. Turkish J. Biol. 2015;39:932-940.

    Not in our library10.3906/biy-1507-55

  206. 206.

    Shokrzadeh M., Naghshvar F., Ahmadi A., Chabra A., Jeivad F. The potential ameliorative effects of melatonin against cyclophosphamide-induced DNA damage in murine bone marrow cells. Eur. Rev. Med. Pharmacol. Sci. 2014;18:605-611.

    Not in our library

  207. 207.

    Espino J., Bejarano I., Ortiz A., Lozano G.M., García J.F., Pariente J.A., Rodríguez A.B. Melatonin as a potential tool against oxidative damage and apoptosis in ejaculated human spermatozoa. Fertil. Steril. 2010;94:1915-1917.

    Not in our library10.1016/j.fertnstert.2009.12.082

  208. 208.

    Bejarano I., Monllor F., Marchena A.M., Ortiz A., Lozano G., Jiménez M.I., Gaspar P., García J.F., Pariente J.A., Rodríguez A.B., Espino J. Exogenous melatonin supplementation prevents oxidative stress-evoked DNA damage in human spermatozoa. J. Pineal Res. 2014;57:333-339.

    Not in our library10.1111/jpi.12172

  209. 209.
    Peripheral Reproductive Organ Health and Melatonin: Ready for Prime Time · 2013
    No notice
  210. 210.

    Vargas A., Bustos-Obregón E., Hartley R. Effects of hypoxia on epididymal sperm parameters and protective role of ibuprofen and melatonin. Biol. Res. 2011;44:161-167.

    Not in our library10.4067/s0716-97602011000200008

  211. 211.

    Liang S., Guo J., Choi J.W., Kim N.H., Cui X.S. Effect and possible mechanisms of melatonin treatment on the quality and developmental potential of aged bovine oocytes. Reprod. Fertil. Dev. 2017;29:1821-1831.

    Not in our library10.1071/rd16223

  212. 212.
    Mitochondria Synthesize Melatonin to Ameliorate Its Function and Improve Mice Oocyte’s Quality under in Vitro Conditions · 2016
    No notice
  213. 213.

    Kulms D., Zeise E., Pöppelmann B., Schwarz T. DNA damage, death receptor activation and reactive oxygen species contribute to ultraviolet radiation-induced apoptosis in an essential and independent way. Oncogene. 2002;21:5844-5851.

    Not in our library10.1038/sj.onc.1205743

  214. 214.

    Ahmed N.U., Ueda M., Nikaido O., Osawa T., Ichihashi M. High levels of 8-hydroxy-2′-deoxyguanosine appear in normal human epidermis after a single dose of ultraviolet radiation. Br. J. Dermatol. 1999;140:226-231.

    Not in our library10.1111/j.1365-2133.1999.02653.x

  215. 215.

    Fischer T.W., Kleszczyński K., Hardkop L.H., Kruse N., Zillikens D. Melatonin enhances antioxidative enzyme gene expression (CAT, GPx, SOD), prevents their UVR-induced depletion, and protects against the formation of DNA damage (8-hydroxy-2′-deoxyguanosine) in ex vivo human skin. J. Pineal Res. 2013;54:303-312.

    Not in our library10.1111/jpi.12018

  216. 216.

    Al-Jassabi S., Khalil A.M. Microcystin-induced 8-hydroxydeoxyguanosine in DNA and its reduction by melatonin, vitamin C, and vitamin e in mice. Biochemistry. 2006;71:1115-1119.

    Not in our library10.1134/s0006297906100099

  217. 217.

    Yamamoto H.A., Mohanan P.V. In vivo and in vitro effects of melatonin or ganglioside GT1B on l-cysteine-induced brain mitochondrial DNA damage in mice. Toxicol. Sci. 2003;73:416-422.

    Not in our library10.1093/toxsci/kfg089

  218. 218.

    Yamamoto H.A., Mohanan P.V. Ganglioside GT1B and melatonin inhibit brain mitochondrial DNA damage and seizures induced by kainic acid in mice. Brain Res. 2003;964:100-106.

    Not in our library10.1016/s0006-8993(02)04083-0

  219. 219.

    Mohanan P.V., Yamamoto H.A. Preventive effect of melatonin against brain mitochondria DNA damage, lipid peroxidation and seizures induced by kainic acid. Toxicol. Lett. 2002;129:99-105.

    Not in our library10.1016/s0378-4274(01)00475-1

  220. 220.

    Yamamoto H., Mohanan P.V. Melatonin attenuates brain mitochondria DNA damage induced by potassium cyanide in vivo and in vitro. Toxicology. 2002;179:29-36.

    Not in our library10.1016/s0300-483x(02)00244-5

  221. 221.

    Yamamoto H.A., Mohanan P.V. Preventive effect of melatonin against DNA damage induced by cyanide, kainate, glutathione/Fe3+/O2, or H2O2/Fe2+. J. Pineal Res. 2001;31:314-319.

    Not in our library10.1034/j.1600-079x.2001.310405.x

  222. 222.

    Hsu C.H., Chi B.C., Casida J.E. Melatonin reduces phosphine-induced lipid and DNA oxidation in vitro and in vivo in rat brain. J. Pineal Res. 2002;32:53-58.

    Not in our library10.1034/j.1600-079x.2002.10809.x

  223. 223.

    Bagchi M., Balmoori J., Ye X., Bagchi D., Ray S.D., Stohs S.J. Protective effect of melatonin on naphthalene-induced oxidative stress and DNA damage in cultured macrophage J774A.1 cells. Mol. Cell. Biochem. 2001;221:49-55.

    Not in our library10.1023/a:1010946517651

  224. 224.

    Lai H., Singh N.P. Melatonin and a spin-trap compound block radiofrequency electromagnetic radiation-induced DNA strand breaks in rat brain cells. Bioelectromagnetics. 1997;18:446-454.

    Not in our library10.1002/(sici)1521-186x(1997)18:6<446::aid-bem7>3.0.co;2-2

  225. 225.

    Shaikh A.Y., Xu J., Wu Y., He L., Hsu C.Y. Melatonin protects bovine cerebral endothelial cells from hyperoxia- induced DNA damage and death. Neurosci. Lett. 1997;229:193-197.

    Not in our library10.1016/s0304-3940(97)00307-8

  226. 226.

    Miche H., Brumas V., Berthon G. Copper(II) interactions with nonsteroidal antiinflammatory agents. II. Anthranilic acid as a potential OH-inactivating ligand. J. Inorg. Biochem. 1997;68:27-38.

    Not in our library10.1016/s0162-0134(97)00005-6

  227. 227.

    Gaubert S., Bouchaut M., Brumas V., Berthon G. Copper-ligand interactions and physiological free radical processes. Part 3. Influence of histidine, salicylic acid and anthranilic acid on copper-driven Fenton chemistry in vitro. Free Radic. Res. 2000;32:451-461.

    Not in our library10.1080/10715760000300451

  228. 228.

    Berthon G. Is copper pro- or anti-inflammatory? A reconciling view and a novel approach for the use of copper in the control of inflammation. Agents Actions. 1993;39:210-217.

    Not in our library10.1007/bf01998975

  229. 229.

    Limson J., Nyokong T., Daya S. The interaction of melatonin and its precursors with aluminium, cadmium, copper, iron, lead, and zinc: An adsorptive voltammetric study. J. Pineal Res. 1998;24:15-21.

    Not in our library10.1111/j.1600-079x.1998.tb00361.x

  230. 230.

    López-Burillo S., Tan D.X., Mayo J.C., Sainz R.M., Manchester L.C., Reiter R.J. Melatonin, xanthurenic acid, resveratrol, EGCG, vitamin C and α-lipoic acid differentially reduce oxidative DNA damage induced by Fenton reagents: A study of their individual and synergistic actions. J. Pineal Res. 2003;34:269-277.

    Not in our library10.1034/j.1600-079x.2003.00041.x

  231. 231.

    Zatta P., Tognon G., Carampin P. Melatonin prevents free radical formation due to the interaction between β-amyloid peptides and metal ions [Al(III), Zn(II), Cu(II), Mn(II), Fe(II)]. J. Pineal Res. 2003;35:98-103.

    Not in our library10.1034/j.1600-079x.2003.00058.x

  232. 232.

    Romero A., Ramos E., De Los Ríos C., Egea J., Del Pino J., Reiter R.J. A review of metal-catalyzed molecular damage: Protection by melatonin. J. Pineal Res. 2014;56:343-370.

    Not in our library10.1111/jpi.12132

  233. 233.

    Qi W., Reiter R.J., Tan D.X., Manchester L.C., Calvo J.R. Melatonin prevents δ-aminolevulinic acid-induced oxidative DNA damage in the presence of Fe2+. Mol. Cell. Biochem. 2001;218:87-92.

    Not in our library10.1023/a:1007225809674

  234. 234.

    Onuki J., Almeida E.A., Medeiros M.H.G., Di Mascio P. Inhibition of 5-aminolevulinic acid-induced DNA damage by melatonin, N1-acetyl-N2-formyl-5-methoxykynuramine, quercetin or resveratrol. J. Pineal Res. 2005;38:107-115.

    Not in our library10.1111/j.1600-079x.2004.00180.x

  235. 235.

    Qi W., Reiter R.J., Tan D.X., Manchester L.C., Kim S.J., Garcia J.J. Inhibitory effects of melatonin on ferric nitrilotriacetate-induced lipid peroxidation and oxidative DNA damage in the rat kidney. Toxicology. 1999;139:81-91.

    Not in our library10.1016/s0300-483x(99)00100-6

  236. 236.

    Jajte J., Zmyślony M., Palus J., Dziubałtowska E., Raikowska E. Protective effect of melatonin against in vitro iron ions and 7 mT 50 Hz magnetic field-induced DNA damage in rat lymphocytes. Mutat. Res. 2001;483:57-64.

    Not in our library10.1016/s0027-5107(01)00230-5

  237. 237.

    Aruoma O.I., Halliwell B., Gajewski E., Dizdaroglu M. Copper-ion-dependent damage to the bases in DNA in the presence of hydrogen peroxide. Biochem. J. 1991;273:601-604.

    Not in our library10.1042/bj2730601

  238. 238.

    Aiyar J., Berkovits H.J., Floyd R.A., Wetterhahn K.E. Reaction of chromium(VI) with hydrogen peroxide in the presence of glutathione: reactive intermediates and resulting DNA damage. Chem. Res. Toxicol. 1990;3:595-603.

    Not in our library10.1021/tx00018a016

  239. 239.

    Susa N., Ueno S., Furukawa Y., Ueda J., Sugiyama M. Potent protective effect of melatonin on chromium(VI)-induced DNA single-strand breaks, cytotoxicity, and lipid peroxidation in primary cultures of rat hepatocytes. Toxicol. Appl. Pharmacol. 1997;144:377-384.

    Not in our library10.1006/taap.1997.8151

  240. 240.

    Qi W., Reiter R.J., Tan D.X., Garcia J.J., Manchester L.C., Karbownik M., Calvo J.R. Chromium(III)-induced 8-hydroxydeoxyguanosine in DNA and its reduction by antioxidants: Comparative effects of melatonin, ascorbate, and vitamin E. Environ. Health Perspect. 2000;108:399-403.

    Not in our library10.1289/ehp.00108399

  241. 241.

    Cabrera J., Burkhardt S., Tan D.X., Manchester L.C., Karbownik M., Reiter R.J. Autoxidation and toxicant-induced oxidation of lipid and DNA in monkey liver: Reduction of molecular damage by melatonin. Pharmacol. Toxicol. 2001;89:225-230.

    Not in our library10.1034/j.1600-0773.2001.d01-152.x

  242. 242.

    Beyersmann D., Hartwig A. Carcinogenic metal compounds: Recent insight into molecular and cellular mechanisms. Arch. Toxicol. 2008;82:493-512.

    Not in our library10.1007/s00204-008-0313-y

  243. 243.

    Martínez-Alfaro M., Hernández-Cortés D., Wrobel K., Cruz-Jiménez G., Rivera-Leyva J.C., Piña-Zentella R.M., Cárabez Trejo A. Effect of melatonin administration on DNA damage and repair responses in lymphocytes of rats subchronically exposed to lead. Mutat. Res. 2012;742:37-42.

    Not in our library10.1016/j.mrgentox.2011.11.011

  244. 244.

    Xu S.C., He M.D., Lu Y.H., Li L., Zhong M., Zhang Y.W., Wang Y., Yu Z.P., Zhou Z. Nickel exposure induces oxidative damage to mitochondrial DNA in Neuro2a cells: The neuroprotective roles of melatonin. J. Pineal Res. 2011;51:426-433.

    Not in our library10.1111/j.1600-079x.2011.00906.x

  245. 245.

    Hengstler J.G., Bolm-Audorff U., Faldum A., Janssen K., Reifenrath M., Götte W., Jung D., Mayer-Popken O., Fuchs J., Gebhard S., et al. Occupational exposure to heavy metals: DNA damage induction and DNA repair inhibition prove co-exposures to cadmium, cobalt and lead as more dangerous than hitherto expected. Carcinogenesis. 2003;24:63-73.

    Not in our library10.1093/carcin/24.1.63

  246. 246.

    Wang G., Hazra T.K., Mitra S., Lee H.M., Englander E.W. Mitochondrial DNA damage and a hypoxic response are induced by CoCl2 in rat neuronal PC12 cells. Nucleic Acids Res. 2000;28:2135-2140.

    Not in our library10.1093/nar/28.10.2135

  247. 247.

    Liu Y., Yang X., Wang W., Wu X., Zhu H., Liu F. Melatonin counteracts cobalt nanoparticle-induced cytotoxicity and genotoxicity by deactivating reactive oxygen species-dependent mechanisms in the NRK cell line. Mol. Med. Report. 2017;16:4413-4420.

    Not in our library10.3892/mmr.2017.7309

  248. 248.

    Şener G., Şehirli A.Ö., Ayanoǧlu-Dülger G. Melatonin protects against mercury(II)-induced oxidative tissue damage in rats. Pharmacol. Toxicol. 2003;93:290-296.

    Not in our library10.1111/j.1600-0773.2003.pto930607.x

  249. 249.

    Purohit A.R., Rao M.V. Mitigative role of melatonin and α-tocopherol against mercury-induced genotoxicity. Drug Chem. Toxicol. 2014;37:221-226.

    Not in our library10.3109/01480545.2013.838774

  250. 250.

    Cebulska-Wasilewska A., Panek A., Zabiński Z., Moszczyński P., Au W.W. Occupational exposure to mercury vapour on genotoxicity and DNA repair. Mutat. Res. 2005;586:102-114.

    Not in our library10.1016/j.mrgentox.2005.06.009

  251. 251.

    Rao M.V., Sharma P.S.N. Protective effect of vitamin E against mercuric chloride reproductive toxicity in male mice. Reprod. Toxicol. 2001;15:705-712.

    Not in our library10.1016/s0890-6238(01)00183-6

  252. 252.

    Kim C.Y., Nakai K., Kameo S., Kurokawa N., Liu Z.M., Satoh H. Protective effect of melatonin on methylmercury-induced mortality in mice. Tohoku J. Exp. Med. 2000;191:241-246.

    Not in our library10.1620/tjem.191.241

  253. 253.

    Rossman T.G. Mechanism of arsenic carcinogenesis: An integrated approach. Mutat. Res. 2003;533:37-65.

    Not in our library10.1016/j.mrfmmm.2003.07.009

  254. 254.

    Pant H.H., Rao M.V. Evaluation of in vitro anti-genotoxic potential of melatonin against arsenic and fluoride in human blood cultures. Ecotoxicol. Environ. Saf. 2010;73:1333-1337.

    Not in our library10.1016/j.ecoenv.2010.05.004

  255. 255.

    Aydemir S., Akgun S.G., Beceren A., Yuksel M., Kumas M., Erdogan N., Sardas S., Omurtag G.Z. Melatonin ameliorates oxidative DNA damage and protects against formaldehyde-induced oxidative stress in rats. Int. J. Clin. Exp. Med. 2017;10:6250-6261.

    Not in our library

  256. 256.

    Hare D.J., Adlard P.A., Doble P.A., Finkelstein D.I. Metallobiology of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity. Metallomics. 2013;5:91-109.

    Not in our library10.1039/c2mt20164j

  257. 257.

    Nicotra A., Parvez S.H. Apoptotic molecules and MPTP-induced cell death. Neurotoxicol. Teratol. 2002;24:599-605.

    Not in our library10.1016/s0892-0362(02)00213-1

  258. 258.

    Przedborski S., Vila M. MPTP: A review of its mechanisms of neurotoxicity. Clin. Neurosci. Res. 2001;1:407-418.

    Not in our library10.1016/s1566-2772(01)00019-6

  259. 259.

    Cadenas S., Barja G. Resveratrol, melatonin, vitamin E, and PBN protect against renal oxidative DNA damage induced by the kidney carcinogen KBrO3. Free Radic. Biol. Med. 1999;26:1531-1537.

    Not in our library10.1016/s0891-5849(99)00019-2

  260. 260.

    Spencer J.P.E., Whiteman M., Jenner A., Halliwell B. Nitrite-induced deamination and hypochlorite-induced oxidation of DNA in intact human respiratory tract epithelial cells. Free Radic. Biol. Med. 2000;28:1039-1050.

    Not in our library10.1016/s0891-5849(00)00190-8

  261. 261.

    Zavodnik I.B., Lapshina E.A., Zavodnik L.B., Łabieniec M., Bryszewska M., Reiter R.J. Hypochlorous acid-induced oxidative stress in Chinese hamster B14 cells: Viability, DNA and protein damage and the protective action of melatonin. Mutat. Res. 2004;559:39-48.

    Not in our library10.1016/j.mrgentox.2003.12.009

  262. 262.

    Bozner P., Grishko V., LeDoux S.P., Wilson G.L., Chyan Y.C., Pappolla M.A. The amyloid 13 protein induces oxidative damage of mitochondrial DNA. J. Neuropathol. Exp. Neurol. 1997;56:1356-1362.

    Not in our library10.1097/00005072-199712000-00010

  263. 263.

    Rezapoor S., Shirazi A., Abbasi S., Bazzaz J., Izadi P., Rezaeejam H., Valizadeh M., Soleimani-Mohammadi F., Najafi M. Modulation of radiation-induced base excision repair pathway gene expression by melatonin. J. Med. Phys. 2017;42:245-250.

    Not in our library10.4103/jmp.jmp_9_17

  264. 264.

    Karbownik M., Reiter R.J., Qi W., Garcia J.J., Tan D.X., Manchester L.C., Vijayalaxmi. Protective effects of melatonin against oxidation of guanine bases in DNA and decreased microsomal membrane fluidity in rat liver induced by whole body ionizing radiation. Mol. Cell. Biochem. 2000;211:137-144.

    Not in our library10.1023/a:1007148530845

  265. 265.

    Sun C.K., Chen C.H., Chang C.L., Chiang H.J., Sung P.H., Chen K.H., Chen Y.L., Chen S.Y., Kao G.S., Chang H.W., et al. Melatonin treatment enhances therapeutic effects of exosomes against acute liver ischemia-reperfusion injury. Am. J. Transl. Res. 2017;9:1543-1560.

    Not in our library

  266. 266.

    Nagai R., Watanabe K., Wakatsuki A., Hamada F., Shinohara K., Hayashi Y., Imamura R., Fukaya T. Melatonin preserves fetal growth in rats by protecting against ischemia/reperfusion-induced oxidative/nitrosative mitochondrial damage in the placenta. J. Pineal Res. 2008;45:271-276.

    Not in our library10.1111/j.1600-079x.2008.00586.x

  267. 267.

    Cetin N., Suleyman H., Sener E., Demirci E., Gundogdu C., Akcay F. The prevention of ischemia/reperfusion induced oxidative damage by venous blood in rabbit kidneys monitored with biochemical, histopatological and immunohistochemical analysis. J. Physiol. Pharmacol. 2014;65:383-392.

    Not in our library

  268. 268.

    Chen H.H., Chen Y.T., Yang C.C., Chen K.H., Sung P.H., Chiang H.J., Chen C.H., Chua S., Chung S.Y., Chen Y.L., et al. Melatonin pretreatment enhances the therapeutic effects of exogenous mitochondria against hepatic ischemia–reperfusion injury in rats through suppression of mitochondrial permeability transition. J. Pineal Res. 2016;61:52-68.

    Not in our library10.1111/jpi.12326

  269. 269.

    Nakamura T., Keep R.F., Hua Y., Hoff J.T., Xi G. Oxidative DNA injury after experimental intracerebral hemorrhage. Brain Res. 2005;1039:30-36.

    Not in our library10.1016/j.brainres.2005.01.036

  270. 270.

    Young I.M., Leone R.M., Francis P., Stovell P., Silman R.E. Melatonin is metabolized to N-acetyl serotonin and 6-hydroxymelatonin in man. J. Clin. Endocrinol. Metab. 1985;60:114-119.

    Not in our library10.1210/jcem-60-1-114

  271. 271.

    Zhou H., Wang J., Jiang J., Stavrovskaya I.G., Li M., Li W., Wu Q., Zhang X., Luo C., Zhou S., et al. N-Acetyl-serotonin offers neuroprotection through inhibiting mitochondrial death pathways and autophagic activation in experimental models of ischemic injury. J. Neurosci. 2014;34:2967-2978.

    Not in our library10.1523/jneurosci.1948-13.2014

  272. 272.

    Bachurin S., Oxenkrug G.F., Lermontova N., Afanasiev A., Beznosko B., Vankin G., Shevtzova E., Mukhina T., Serkova T. N-Acetylserotonin, melatonin and their derivatives improve cognition and protect against β-amyloid-induced neurotoxicity. Ann. N. Y. Acad. Sci. 1999;890:155-166.

    Not in our library10.1111/j.1749-6632.1999.tb07990.x

  273. 273.

    Oxenkrug G., Requintina P., Bachurin S. Antioxidant and antiaging activity of N-acetylserotonin and melatonin in the in vivo models. Ann. N. Y. Acad. Sci. 2001;939:190-199.

    Not in our library10.1111/j.1749-6632.2001.tb03626.x

  274. 274.

    Qi W., Reiter R.J., Tan D.X., Manchester L.C., Siu A.W., Garcia J.J. Increased levels of oxidatively damaged DNA induced by chromium(III) and H2O2: Protection by melatonin and related molecules. J. Pineal Res. 2000;29:54-61.

    Not in our library10.1034/j.1600-079x.2000.290108.x

  275. 275.

    Jiang J., Yu S., Jiang Z., Liang C., Yu W., Li J., Du X., Wang H., Gao X., Wang X. N-Acetyl-serotonin protects HepG2 cells from oxidative stress injury induced by hydrogen peroxide. Oxid. Med. Cell. Longev. 2014;2014:310504.

    Not in our library10.1155/2014/310504

  276. 276.

    Reiter R.J., Mayo J.C., Tan D.X., Sainz R.M., Alatorre-Jimenez M., Qin L. Melatonin as an antioxidant: under promises but over delivers. J. Pineal Res. 2016;61:253-278.

    Not in our library10.1111/jpi.12360

  277. 277.
    Melatonin and its metabolites protect human melanocytes against UVB-induced damage: Involvement of NRF2-mediated pathways · 2017
    No notice
  278. 278.
    Local Melatoninergic System as the Protector of Skin Integrity · 2014
    No notice
  279. 279.

    Ximenes V.F., Padovan C.Z., Carvalho D.A., Fernandes J.R. Oxidation of melatonin by taurine chloramine. J. Pineal Res. 2010;49:115-122.

    Not in our library10.1111/j.1600-079x.2010.00772.x

  280. 280.

    De Oliveira Silva S., Ximenes V.F., Catalani L.H., Campa A. Myeloperoxidase-catalyzed oxidation of melatonin by activated neutrophils. Biochem. Biophys. Res. Commun. 2000;279:657-662.

    Not in our library10.1006/bbrc.2000.3993

  281. 281.

    Semak I., Korik E., Antonova M., Wortsman J., Slominski A. Metabolism of melatonin by cytochrome P450s in rat liver mitochondria and microsomes. J. Pineal Res. 2008;45:515-523.

    Not in our library10.1111/j.1600-079x.2008.00630.x

  282. 282.

    Horstman J.A., Wrona M.Z., Dryhurst G. Further insights into the reaction of melatonin with hydroxyl radical. Bioorg. Chem. 2002;30:371-382.

    Not in our library10.1016/s0045-2068(02)00511-4

  283. 283.

    Hardeland R., Poeggeler B., Niebergall R., Zelosko V. Oxidation of melatonin by carbonate radicals and chemiluminescence emitted during pyrrole ring cleavage. J. Pineal Res. 2003;34:17-25.

    Not in our library10.1034/j.1600-079x.2003.02941.x

  284. 284.

    De Almeida E.A., Martinez G.R., Klitzke C.F., De Medeiros M.H.G., Di Mascio P. Oxidation of melatonin by singlet molecular oxygen (O2(1Δg)) produces N1-acetyl-N2-formyl-5-methoxykynurenine. J. Pineal Res. 2003;35:131-137.

    Not in our library10.1034/j.1600-079x.2003.00066.x

  285. 285.

    Fischer T.W., Sweatman T.W., Semak I., Sayre R.M., Wortsman J., Slominski A. Constitutive and UV-induced metabolism of melatonin in keratinocytes and cell-free systems. FASEB J. 2006;20:E897-E907.

    Not in our library10.1096/fj.05-5227fje

  286. 286.

    Bonnefont-Rousselot D., Collin F., Jore D., Gardès-Albert M. Reaction mechanism of melatonin oxidation by reactive oxygen species in vitro. J. Pineal Res. 2011;50:328-335.

    Not in our library10.1111/j.1600-079x.2010.00847.x

  287. 287.

    Tan D.X., Manchester L.C., Burkhardt S., Sainz R.M., Mayo J.C., Kohen R., Shohami E., Huo Y.S., Hardeland R., Reiter R.J. N1-acetyl-N2-formyl-5-methoxykynuramine, a biogenic amine and melatonin metabolite, functions as a potent antioxidant. FASEB J. 2001;15:2294-2296.

    Not in our library10.1096/fj.01-0309fje

  288. 288.

    Burkhardt S., Reiter R.J., Tan D.X., Hardeland R., Cabrera J., Karbownik M. DNA oxidatively damaged by chromium(III) and H2O2 is protected by the antioxidants melatonin, N1-acetyl-N2-formyl-5-methoxykynuramine, resveratrol and uric acid. Int. J. Biochem. Cell Biol. 2001;33:775-783.

    Not in our library10.1016/s1357-2725(01)00052-8

  289. 289.

    Manda K., Ueno M., Anzai K. AFMK, a melatonin metabolite, attenuates X-ray-induced oxidative damage to DNA, proteins and lipids in mice. J. Pineal Res. 2007;42:386-393.

    Not in our library10.1111/j.1600-079x.2007.00432.x

  290. 290.

    Galano A., Tan D.X., Reiter R.J. On the free radical scavenging activities of melatonin’s metabolites, AFMK and AMK. J. Pineal Res. 2013;54:245-257.

    Not in our library10.1111/jpi.12010

  291. 291.

    Manda K., Ueno M., Anzai K. Space radiation-induced inhibition of neurogenesis in the hippocampal dentate gyrus and memory impairment in mice: Ameliorative potential of the melatonin metabolite, AFMK. J. Pineal Res. 2008;45:430-438.

    Not in our library10.1111/j.1600-079x.2008.00611.x

  292. 292.

    Liu X., Chen Z., Chua C.C., Ma Y.S., Youngberg G.A., Hamdy R., Chua B.H.L. Melatonin as an effective protector against doxorubicin-induced cardiotoxicity. Am. J. Physiol. Heart Circ. Physiol. 2002;283:H254-H263.

    Not in our library10.1152/ajpheart.01023.2001

  293. 293.

    Hardeland R., Tan D.X., Reiter R.J. Kynuramines, metabolites of melatonin and other indoles: The resurrection of an almost forgotten class of biogenic amines. J. Pineal Res. 2009;47:109-126.

    Not in our library10.1111/j.1600-079x.2009.00701.x

  294. 294.

    Schaefer M., Hardeland R. The melatonin metabolite N1-acetyl-5-methoxykynuramine is a potent singlet oxygen scavenger. J. Pineal Res. 2009;46:49-52.

    Not in our library10.1111/j.1600-079x.2008.00614.x

  295. 295.

    Maharaj D.S., Anoopkumar-Dukie S., Glass B.D., Antunes E.M., Lack B., Walker R.B., Daya S. The identification of the UV degradants of melatonin and their ability to scavenge free radicals. J. Pineal Res. 2002;32:257-261.

    Not in our library10.1034/j.1600-079x.2002.01866.x

  296. 296.

    León J., Escames G., Rodríguez M.I., López L.C., Tapias V., Entrena A., Camacho E., Carrión M.D., Gallo M.A., Espinosa A., et al. Inhibition of neuronal nitric oxide synthase activity by N1-acetyl-5-methoxykynuramine, a brain metabolite of melatonin. J. Neurochem. 2006;98:2023-2033.

    Not in our library10.1111/j.1471-4159.2006.04029.x

  297. 297.

    Hardeland R., Backhaus C., Fadavi A., Hess M. N1-acetyl-5-methoxykynuramine contrasts with other tryptophan metabolites by a peculiar type of NO scavenging: Cyclization to a cinnolinone prevents formation of unstable nitrosamines. J. Pineal Res. 2007;43:104-105.

    Not in our library10.1111/j.1600-079x.2007.00431.x

  298. 298.

    Tapias V., Escames G., López L.C., López A., Camacho E., Carrión M.D., Entrena A., Gallo M.A., Espinosa A., Acuña-Castroviejo D. Melatonin and its brain metabolite N1-acetyl-5-methoxykynuramine prevent mitochondrial nitric oxide synthase induction in Parkinsonian mice. J. Neurosci. Res. 2009;87:3002-3010.

    Not in our library10.1002/jnr.22123

  299. 299.

    Tan D.X., Manchester L.C., Reiter R.J., Plummer B.F., Hardies L.J., Weintraub S.T., Vijayalaxmi, Shepherd A.M.M. A novel melatonin metabolite, cyclic 3-hydroxymelatonin: A biomarker of in vivo hydroxyl radical generation. Biochem. Biophys. Res. Commun. 1998;253:614-620.

    Not in our library10.1006/bbrc.1998.9826

  300. 300.

    Tan D.X., Hardeland R., Manchester L.C., Poeggeler B., Lopez-Burillo S., Mayo J.C., Sainz R.M., Reiter R.J. Mechanistic and comparative studies of melatonin and classic antioxidants in terms of their interactions with the ABTS cation radical. J. Pineal Res. 2003;34:249-259.

    Not in our library10.1034/j.1600-079x.2003.00037.x

  301. 301.

    López-Burillo S., Tan D.X., Rodriguez-Gallego V., Manchester L.C., Mayo J.C., Sainz R.M., Reiter R.J. Melatonin and its derivatives cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine and 6-methoxymelatonin reduce oxidative DNA damage induced by Fenton reagents. J. Pineal Res. 2003;34:178-184.

    Not in our library10.1034/j.1600-079x.2003.00025.x

  302. 302.

    Kim T.K., Lin Z., Tidwell W.J., Li W., Slominski A.T. Melatonin and its metabolites accumulate in the human epidermis in vivo and inhibit proliferation and tyrosinase activity in epidermal melanocytes in vitro. Mol. Cell. Endocrinol. 2015;404:1-8.

    Not in our library10.1016/j.mce.2014.07.024

  303. 303.

    Maharaj D.S., Maharaj H., Antunes E.M., Maree D.M., Nyokong T., Glass B.D., Daya S. 6-Hydroxymelatonin protects against quinolinic-acid-induced oxidative neurotoxicity in the rat hippocampus. J. Pharm. Pharmacol. 2005;57:877-881.

    Not in our library10.1211/0022357056424

  304. 304.

    Pierrefiche G., Topall G., Courboin G., Henriet I., Laborit H. Antioxidant activity of melatonin in mice. Res. Commun. Chem. Pathol. Pharmacol. 1993;80:211-224.

    Not in our library

  305. 305.

    Maharaj D.S., Walker R.B., Glass B.D., Daya S. 6-Hydroxymelatonin protects against cyanide induced oxidative stress in rat brain homogenates. J. Chem. Neuroanat. 2003;26:103-107.

    Not in our library10.1016/s0891-0618(03)00034-6

  306. 306.

    Janjetovic Z., Nahmias Z.P., Hanna S., Jarrett S.G., Kim T.K., Reiter R.J., Slominski A.T. Melatonin and its metabolites ameliorate ultraviolet B-induced damage in human epidermal keratinocytes. J. Pineal Res. 2014;57:90-102.

    Not in our library10.1111/jpi.12146

  307. 307.

    Dellegar S.M., Murphy S.A., Bourne A.E., Dicesare J.C., Purser G.H. Identification of the factors affecting the rate of deactivation of hypochlorous acid by melatonin. Biochem. Biophys. Res. Commun. 1999;257:431-439.

    Not in our library10.1006/bbrc.1999.0438

  308. 308.

    Agozzino P., Avellone G., Bongiorno D., Ceraulo L., Filizzola F., Natoli M.C., Livrea M.A., Tesoriere L. Melatonin: Structural characterization of its non-enzymatic mono-oxygenate metabolite. J. Pineal Res. 2003;35:269-275.

    Not in our library10.1034/j.1600-079x.2003.00086.x

  309. 309.

    Abbaszadeh A., Haddadi G.H., Haddadi Z. Melatonin role in ameliorating radiation-induced skin damage: From theory to practice (A review of literature). J. Biomed. Phys. Eng. 2017;7:127-136.

    Not in our library

  310. 310.

    Mayo J.C., Sainz R.M., Antolín I., Rodriguez C. Ultrastructural confirmation of neuronal protection by melatonin against the neurotoxin 6-hydroxydopamine cell damage. Brain Res. 1999;818:221-227.

    Not in our library10.1016/s0006-8993(98)01262-1

  311. 311.

    Wu Z.H., Zhang H., Wang X.Y., Yang R., Liu B., Liu Y., Zhao W.P., Feng H.Y., Xue L.G., Hao J.F., Niu B.T., Wang Z.H. Protective effects of melatonin against12C6+beam irradiation-induced oxidative stress and DNA injury in the mouse brain. Adv. Space Res. 2012;49:196-203.

    Not in our library10.1016/j.asr.2011.09.007

  312. 312.

    Laothong U., Pinlaor P., Hiraku Y., Boonsiri P., Prakobwong S., Khoontawad J., Pinlaor S. Protective effect of melatonin against Opisthorchis viverrini-induced oxidative and nitrosative DNA damage and liver injury in hamsters. J. Pineal Res. 2010;49:271-282.

    Not in our library10.1111/j.1600-079x.2010.00792.x

  313. 313.

    Bekyarova G., Tzaneva M., Hristova M. Melatonin protects against burn-induced hepatic oxidative injury by inducing HO-1 via the Nrf2 pathway. Vet. Med. (Praha). 2015;60:621-628.

    Not in our library10.17221/8530-vetmed

  314. 314.

    Deng Y., Zhu J., Mi C., Xu B., Jiao C., Li Y., Xu D., Liu W., Xu Z. Melatonin antagonizes Mn-induced oxidative injury through the activation of keap1-Nrf2-ARE signaling pathway in the striatum of mice. Neurotox. Res. 2014;27:156-171.

    Not in our library10.1007/s12640-014-9489-5

  315. 315.

    Ding K., Wang H., Xu J., Li T., Zhang L., Ding Y., Zhu L., He J., Zhou M. Melatonin stimulates antioxidant enzymes and reduces oxidative stress in experimental traumatic brain injury: The Nrf2-ARE signaling pathway as a potential mechanism. Free Radic. Biol. Med. 2014;73:1-11.

    Not in our library10.1016/j.freeradbiomed.2014.04.031

  316. 316.

    Guo Y., Sun J., Li T., Zhang Q., Bu S., Wang Q., Lai D. Melatonin ameliorates restraint stress-induced oxidative stress and apoptosis in testicular cells via NF-κB/iNOS and Nrf2/ HO-1 signaling pathway. Sci. Rep. 2017;7:9599.

    Not in our library10.1038/s41598-017-09943-2

  317. 317.

    Jumnongprakhon P., Govitrapong P., Tocharus C., Pinkaew D., Tocharus J. Melatonin protects methamphetamine-induced neuroinflammation through NF-κB and Nrf2 pathways in glioma cell line. Neurochem. Res. 2015;40:1448-1456.

    Not in our library10.1007/s11064-015-1613-2

  318. 318.

    Jumnongprakhon P., Govitrapong P., Tocharus C., Tocharus J. Melatonin promotes blood-brain barrier integrity in methamphetamine-induced inflammation in primary rat brain microvascular endothelial cells. Brain Res. 2016;1646:182-192.

    Not in our library10.1016/j.brainres.2016.05.049

  319. 319.

    Jumnongprakhon P., Govitrapong P., Tocharus C., Tocharus J. Melatonin improves methamphetamine-induced blood brain barrier impairment through NADPH oxidase-2 in primary rat brain microvascular endothelium cells. Brain Res. 2016;1646:393-401.

    Not in our library10.1016/j.brainres.2016.06.014

  320. 320.

    Kleszczyński K., Zillikens D., Fischer T.W. Melatonin enhances mitochondrial ATP synthesis, reduces reactive oxygen species formation, and mediates translocation of the nuclear erythroid 2-related factor 2 resulting in activation of phase-2 antioxidant enzymes (γ-GCS, HO-1, NQO1) in ultraviolet radiation-treated normal human epidermal keratinocytes (NHEK). J. Pineal Res. 2016;61:187-197.

    Not in our library10.1111/jpi.12338

  321. 321.

    Chen L.Y., Renn T.Y., Liao W.C., Mai F.D., Ho Y.J., Hsiao G., Lee A.W., Chang H.M. Melatonin successfully rescues hippocampal bioenergetics and improves cognitive function following drug intoxication by promoting Nrf2- ARE signaling activity. J. Pineal Res. 2017;63:e12417.

    Not in our library10.1111/jpi.12417

  322. 322.

    Negi G., Kumar A., Sharma S.S. Melatonin modulates neuroinflammation and oxidative stress in experimental diabetic neuropathy: Effects on NF-κB and Nrf2 cascades. J. Pineal Res. 2011;50:124-131.

    Not in our library10.1111/j.1600-079x.2010.00821.x

  323. 323.

    Parada E., Buendia I., León R., Negredo P., Romero A., Cuadrado A., López M.G., Egea J. Neuroprotective effect of melatonin against ischemia is partially mediated by alpha-7 nicotinic receptor modulation and HO-1 overexpression. J. Pineal Res. 2014;56:204-212.

    Not in our library10.1111/jpi.12113

  324. 324.

    Santofimia-Castaño P., Clea Ruy D., Garcia-Sanchez L., Jimenez-Blasco D., Fernandez-Bermejo M., Bolaños J.P., Salido G.M., Gonzalez A. Melatonin induces the expression of Nrf2-regulated antioxidant enzymes via PKC and Ca2+ influx activation in mouse pancreatic acinar cells. Free Radic. Biol. Med. 2015;87:226-236.

    Not in our library10.1016/j.freeradbiomed.2015.06.033

  325. 325.

    Shang B., Shi H., Wang X., Guo X., Wang N., Wang Y., Dong L. Protective effect of melatonin on myenteric neuron damage in experimental colitis in rats. Fundam. Clin. Pharmacol. 2016;30:117-127.

    Not in our library10.1111/fcp.12181

  326. 326.

    Tao R.R., Huang J.Y., Shao X.J., Ye W.F., Tian Y., Liao M.H., Fukunaga K., Lou Y.J., Han F., Lu Y.M. Ischemic injury promotes Keap1 nitration and disturbance of antioxidative responses in endothelial cells: A potential vasoprotective effect of melatonin. J. Pineal Res. 2013;54:271-281.

    Not in our library10.1111/jpi.12009

  327. 327.

    Tripathi D.N., Jena G.B. Effect of melatonin on the expression of Nrf2 and NF-κB during cyclophosphamide-induced urinary bladder injury in rat. J. Pineal Res. 2010;48:324-331.

    Not in our library10.1111/j.1600-079x.2010.00756.x

  328. 328.

    Trivedi P.P., Jena G.B., Tikoo K.B., Kumar V. Melatonin modulated autophagy and Nrf2 signaling pathways in mice with colitis-associated colon carcinogenesis. Mol. Carcinog. 2016;55:255-267.

    Not in our library10.1002/mc.22274

  329. 329.

    Wang Z., Ma C., Meng C.J., Zhu G.Q., Sun X.B., Huo L., Zhang J., Liu H.X., He W.C., Shen X.M., et al. Melatonin activates the Nrf2-ARE pathway when it protects against early brain injury in a subarachnoid hemorrhage model. J. Pineal Res. 2012;53:129-137.

    Not in our library10.1111/j.1600-079x.2012.00978.x

  330. 330.

    Wang Z., Ni L., Wang J., Lu C., Ren M., Han W., Liu C. The protective effect of melatonin on smoke-induced vascular injury in rats and humans: A randomized controlled trial. J. Pineal Res. 2016;60:217-227.

    Not in our library10.1111/jpi.12305

  331. 331.

    Yu G.M., Kubota H., Okita M., Maeda T. The anti-inflammatory and antioxidant effects of melatonin on LPS-stimulated bovine mammary epithelial cells. PLoS ONE. 2017;12:e0178525.

    Not in our library10.1371/journal.pone.0178525

  332. 332.

    Wang Z., Guo S., Wang J., Shen Y., Zhang J., Wu Q. Nrf2/HO-1 mediates the neuroprotective effect of mangiferin on early brain injury after subarachnoid hemorrhage by attenuating mitochondria-related apoptosis and neuroinflammation. Sci. Rep. 2017;7:11883.

    Not in our library10.1038/s41598-017-12160-6

  333. 333.

    Wu C.C., Lu K.C., Lin G.J., Hsieh H.Y., Chu P., Lin S.H., Sytwu H.K. Melatonin enhances endogenous heme oxygenase-1 and represses immune responses to ameliorate experimental murine membranous nephropathy. J. Pineal Res. 2012;52:460-469.

    Not in our library10.1111/j.1600-079x.2011.00960.x

  334. 334.

    Ortiz-Franco M., Planells E., Quintero B., Acuña-Castroviejo D., Rusanova I., Escames G., Molina-López J. Effect of melatonin supplementation on antioxidant status and DNA damage in high intensity trained athletes. Int. J. Sports Med. 2017;38:1117-1125.

    Not in our library10.1055/s-0043-119881

  335. 335.

    Reiter R.J., Tan D.X., Manchester L.C., Pilar Terron M., Flores L.J., Koppisepi S. Medical implications of melatonin: receptor-mediated and receptor-independent actions. Adv. Med. Sci. 2007;52:11-28.

    Not in our library

  336. 336.

    Tomás-Zapico C., Coto-Montes A. A proposed mechanism to explain the stimulatory effect of melatonin on antioxidative enzymes. J. Pineal Res. 2005;39:99-104.

    Not in our library10.1111/j.1600-079x.2005.00248.x

  337. 337.

    Barlow-Walden L.R., Reiter R.J., Abe M., Pablos M., Menendez-Pelaez A., Chen L.D., Poeggeler B. Melatonin stimulates brain glutathione peroxidase activity. Neurochem. Int. 1995;26:497-502.

    Not in our library10.1016/0197-0186(94)00154-m

  338. 338.

    Pablos M.I., Agapito M.T., Gutierrez R., Recio J.M., Reiter R.J., Barlow-Walden L., Acuña-Castroviejo D., Menendez-Pelaez A. Melatonin stimulates the activity of the detoxifying enzyme glutathione peroxidase in several tissues of chicks. J. Pineal Res. 1995;19:111-115.

    Not in our library10.1111/j.1600-079x.1995.tb00178.x

  339. 339.

    Fischer T.W., Slominski A., Zmijewski M.A., Reiter R.J., Paus R. Melatonin as a major skin protectant: From free radical scavenging to DNA damage repair. Exp. Dermatol. 2008;17:713-730.

    Not in our library10.1111/j.1600-0625.2008.00767.x

  340. 340.

    Djordjevic B., Sokolovic D., Kocic G., Veljkovic A., Despotovic M., Basic J., Jevtovic-Stoimenov T., Sokolovic D.M. The effect of melatonin on the liver of rats exposed to microwave radiation. Bratisl. Lek. Listy. 2015;116:96-100.

    Not in our library10.4149/bll_2015_018

  341. 341.

    Koyu A., Naziroǧlu M., Ozguner F., Yilmaz H.R., Uz E., Cesur G. Caffeic acid phenethyl ester modulates 1800 MHz microwave-induced oxidative stress in rat liver. Electromagn. Biol. Med. 2005;24:135-142.

    Not in our library10.1080/15368370500253787

  342. 342.

    Meena R., Kumari K., Kumar J., Rajamani P., Verma H.N., Kesari K.K. Therapeutic approaches of melatonin in microwave radiations-induced oxidative stress-mediated toxicity on male fertility pattern of wistar rats. Electromagn. Biol. Med. 2014;33:81-91.

    Not in our library10.3109/15368378.2013.781035

  343. 343.

    Sokolovic D., Djordjevic B., Kocic G., Veljkovic A., Marinkovic M., Basic J., Jevtovic-Stoimenov T., Stanojkovic Z., Sokolovic D.M., Pavlovic V., et al. Melatonin protects rat thymus against oxidative stress caused by exposure to microwaves and modulates proliferation/apoptosis of thymocytes. Gen. Physiol. Biophys. 2013;32:79-90.

    Not in our library10.4149/gpb_2013002

  344. 344.

    De Souza-Pinto N.C., Eide L., Hogue B.A., Thybo T., Stevnsner T., Seeberg E., Klungland A., Bohr V.A. Repair of 8-oxodeoxyguanosine lesions in mitochondrial DNA depends on the oxoguanine DNA glycosylase (OGG1) gene and 8-oxoguanine accumulates in the mitochondrial DNA of OGG1-defective mice. Cancer Res. 2001;61:5378-5381.

    Not in our library

  345. 345.

    Mol C.D., Hosfield D.J., Tainer J.A. Abasic site recognition by two apurinic/apyrimidinic endonuclease families in DNA base excision repair: The 3′ ends justify the means. Mutat. Res. 2000;460:211-229.

    Not in our library10.1016/s0921-8777(00)00028-8

  346. 346.

    Brem R., Hall J. XRCC1 is required for DNA single-strand break repair in human cells. Nucleic Acids Res. 2005;33:2512-2520.

    Not in our library10.1093/nar/gki543

  347. 347.
    Effects of melatonin on DNA damage induced by cyclophosphamide in rats · 2013
    Not checked
  348. 348.

    Valizadeh M., Shirazi A., Izadi P., Tavakkoly Bazzaz J., Rezaeejam H. Expression levels of two dna repair-related genes under 8 gy ionizing radiation and 100 mg/kg melatonin delivery in rat peripheral blood. J. Biomed. Phys. Eng. 2017;7:27-36.

    Not in our library

  349. 349.

    Santoro R., Marani M., Blandino G., Muti P., Strano S. Melatonin triggers p53 Ser phosphorylation and prevents DNA damage accumulation. Oncogene. 2012;31:2931-2942.

    Not in our library10.1038/onc.2011.469

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