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Russel J Reiter

Publications and source records attributed to Russel J Reiter.

At least 19 recordsLinked to original sources
PubMed2026

Resurrection biology: Melatonin as a modulator of anastasis (Review).

Although apoptosis is regarded as an irreversible and terminal process, recent research has identified anastasis as a cellular mechanism that enables cell recovery even after the activation of executioner caspases. While important in supporting tissue homeostasis following mild or transient injury, anastasis presents significant challenges in oncology, as cancer cells may exploit this phenomenon to evade chemotherapy, subsequently acquiring aggressive traits such as genomic instability, stem‑like properties, and increased metastatic capacity. N‑acetyl‑5‑methoxytryptamine (melatonin), recognized for its antioxidant activity and role as a mitochondrial regulator, has been associated with several biological processes that overlap with pathways involved in anastasis, including mitochondrial bioenergetics, redox homeostasis, and DNA repair mechanisms. However, direct evidence supporting a role for melatonin in regulating anastasis remains limited. The present review consolidated current insights into the molecular regulation of anastasis, examining its biphasic transcriptional profile and oncogenic consequences, while exploring the mechanistic links between melatonin biology and pathways relevant to apoptotic recovery and evaluating the therapeutic prospects of melatonin in targeting anastasis as a strategy to mitigate tumor recurrence and improve clinical outcomes.

Melatonin↗
PubMed2003

Protective effect of melatonin against mitochondrial injury induced by ischemia and reperfusion of rat liver.

Melatonin, a pineal secretory product, is a potent scavenger of a variety of free radicals. The aim of this study was to investigate the effect of melatonin on the prevention of mitochondrial injury induced by hepatic ischemia and reperfusion. Rats were subjected to 70 min of hepatic ischemia and 2 h of reperfusion. Fifteen minutes prior to ischemia and at reperfusion, animals received vehicle or melatonin (10 mg/kg body weight) intraperitoneally. In the vehicle-treated animals, the respiratory control index, ADP/O, State 3 respiration and dinitrophenol-induced uncoupled respiration decreased markedly after ischemia/reperfusion and were restored by melatonin administration. Similarly, pH change coupled with mitochondrial energy transfer was suppressed by ischemia/reperfusion with the effects being reduced by melatonin treatment. Mitochondrial lipid peroxidation was elevated in the ischemic/reperfused vehicle-treated livers, but this elevation was attenuated by melatonin. Mitochondrial glutathione peroxidase activity decreased in the vehicle-treated group with this decrease being reduced by melatonin treatment. Electron microscopic studies demonstrated that treatment with melatonin restored to near normal the ischemia/reperfusion-induced disorganization of mitochondrial structure. Melatonin protects against mitochondrial injury which reduces mitochondrial oxidative stress and improves ischemia/reperfusion-induced hepatic energy metabolism.

Animals↗
PubMed2003

Melatonin: a novel protective agent against oxidative injury of the ischemic/reperfused heart.

This brief review summarizes the recently obtained evidence which illustrates the beneficial effects of the endogenously produced antioxidant, melatonin, in reducing tissue damage and reversing cardiac pathophysiology in models of experimental ischemia/reperfusion. The report also describes the actions of other antioxidants, especially vitamin E and antioxidative enzymes, in altering the degree of ischemia/reperfusion damage in the heart. Based on the data available, melatonin seems to have advantages over other antioxidants tested in terms of ameliorating the hypoxia and reoxygenation-induced damage. While the bulk of the studies that have used melatonin to overcome cardiac injury following transient arterial occlusion and subsequent reperfusion have used pharmacological doses to achieve protection, two recent reports have further shown that merely reducing endogenous circulating concentrations of melatonin (by surgical removal of a source of melatonin, i.e. the pineal gland) exaggerates the degree of injury and reduces survival of animals as a result of induced ischemia/reperfusion of the heart. These findings are consistent with observations in other organs where the loss of physiological concentrations of melatonin results in increased oxidative damage during hypoxia and reoxygenation. These findings have implications for the elderly since in the aged endogenous levels of melatonin are naturally reduced thereby possibly predisposing them to more severe cardiac damage during a heart attack. To date, the bulk of the studies relating to the protective actions of melatonin in reducing cardiac ischemia/reperfusion injury have used the rat as the experimental model. Considering the high efficacy of melatonin in limiting ischemia/reperfusion damage as well as melatonin's low toxicity, the studies should be expanded to include other species and models of cardiac ischemia/reperfusion. The results of these investigations would help to clarify the potential importance of the use of melatonin in situations of oxidative damage to the heart in humans.

Aged↗
PubMed2003

Antioxidant activity of melatonin in Chinese hamster ovarian cells: changes in cellular proliferation and differentiation.

Melatonin is an endogenously generated molecule with free radical scavenging and antioxidant properties. Here, we studied the antiproliferative role of melatonin and other antioxidants on transformed Chinese hamster ovarian cells. Melatonin reduces cell proliferation in a dose- and time-dependent manner. Natural antioxidants which appear in edible plants including resveratrol and vitamin E mimicked the effect of melatonin. Flow cytometer analysis revealed that melatonin treatment reduces the number of cells in S-phase and increases cells in both G0/G1 and G2/M gaps. In addition, melatonin, as well as trolox, caused a clear morphological change by inducing the cells to become spindle shaped and fibroblast-like. Its effect is a reversible phenomenon that disappeared when melatonin was withdrawn from the culture medium. GSH levels are increased after melatonin treatment but pharmacologically blockade of GSH synthesis did not abolish melatonin's antiproliferative effect. Reduction of cell proliferation and the apparent induction of cell differentiation overlapped with melatonin's ability to change the intracellular redox state of CHO cells. We conclude that the cellular redox state may be involved in cellular transformation caused by antioxidants such as melatonin and trolox.

Animals↗
PubMed2003

Melatonin protects the central nervous system of rats against toluene-containing thinner intoxication by reducing reactive gliosis.

Neuroprotective effects of melatonin against free radical damage have been studied extensively. Thinner containing 60-70% toluene is a neurotoxic mixture which is widely used as an aromatic industrial solvent. This product has been shown to cause functional and structural changes in the central nervous system. Toluene generates reactive oxygen species (ROS) and the toxic effects relating to these reactants. In the present study we investigated glial reactivity in hippocampus, cortex and cerebellum and the expression of glial fibrillary acidic protein (GFAP) after exposure of rats to toluene vapor (3000 ppm) for 45 days. We also examined the protective effects of melatonin against gliosis. Western blots demonstrated a marked elevation in total GFAP, a specific marker for astrocytes, by thinner fume inhalation in the hippocampus (P<0.001), cortex (P<0.01) and cerebellum (P<0.05) of rats. Melatonin administration prevented the increase of total GFAP induced by thinner fume inhalation. Thinner exposure caused a significant increase of lipid peroxidation products (malondialdehyde and 4-hydroxyalkenals) in all brain regions (P<0.01 for each region), and this elevation was also was inhibited by melatonin. Furthermore, melatonin augmented glutathione levels in all brain regions (P<0.05 for each region) investigated. In conclusion, melatonin treatment may provide neuroprotection against toluene neurotoxicity by increasing the survival of glial cells possibly by directly scavenging ROS and by indirectly augmenting their antioxidant capacity.

Animals↗
PubMed2003

Melatonin and pinoline prevent aluminium-induced lipid peroxidation in rat synaptosomes.

The serum concentrations of aluminum, a metal potentially involved in the pathogenesis of Alzheimer's disease, increase with age. Also, intense and prolonged exposure to aluminum may result in dementia. Melatonin and pinoline are two well known antioxidants that efficiently reduce lipid peroxidation due to oxidative stress. Herein, we investigated the effects of melatonin and pinoline in preventing aluminum promotion of lipid peroxidation when the metal was combined with FeCl3 and ascorbic acid in rat synaptosomal membranes. Lipid peroxidation was estimated by quantifying malondialdehyde (MDA) and 4-hydroxyalkenal (4-HDA) concentrations in the membrane suspension. Under the experimental conditions used herein, the addition of aluminum (0.0001 to 1 mmol/L) enhanced MDA + 4-HDA formation in the synaptosomes. Melatonin and pinoline reduced, in a concentration-dependent manner, lipid peroxidation due to aluminum, FeCl3 and ascorbic acid in the synaptosomal membranes. These results suggest that the indoleamine melatonin and the beta-carboline pinoline may potentially act as neuroprotectant agents in the therapy of those diseases with elevated aluminum concentrations in the tissues.

Alkenes↗
PubMed2003

Acutely administered melatonin restores hepatic mitochondrial physiology in old mice.

Damage to mitochondria as a result of the intrinsic generation of free radicals is theoretically involved in the processes of cellular aging. Herein, we investigated whether acutely administered melatonin, due to its free radical scavenging activity, would influence mitochondrial metabolism. Mitochondrial respiratory activity and respiratory chain complex I and IV activities in liver mitochondria from a strain of senescence-accelerated-prone mice (SAMP8) and a strain of senescence-accelerated-resistant mice (SAMR1) were measured when the animals were 12 months of age. Respiratory control index (RCI), ADP/O ratio, State 3 respiration and dinitrophenol (DNP)-dependent uncoupled respiration were significantly lower in SAMP8 than in SAMR1. In contrast, State 4 respiration was significantly higher in SAMP8 than in SAMR1. Activities of complexes I and IV in SAMP8 were significantly lower than in SAMR1. Melatonin administration (10mg/kg body weight, intraperitoneally) 1h prior to sacrifice significantly increased RCI, ADP/O ratio, State 3 respiration and DNP-induced uncoupled respiration in SAMP8 while also significantly reducing State 4 respiration in SAMP8. The injection of melatonin also significantly increased complex I activity in both mouse strains and complex IV activity in the liver of SAMP8 mice. These results document an age-related decrease in hepatic mitochondrial function in SAM which can be modified by an acute pharmacological injection of melatonin; the indole stimulated mitochondrial respiratory chain activity which would likely reduce deteriorative oxidative changes in mitochondria that normally occur in advanced age.

Aging↗
PubMed2003

Melatonin: clinical relevance.

This chapter reviews the neural connections between the retinas and the pineal gland and summarizes the role of the light:dark cycle and the biological clock, i.e. the suprachiasmatic nuclei, in regulating pineal melatonin synthesis and secretion. The cellular mechanisms governing the nocturnal production of melatonin are described together with the way in which the misuse of light interferes with the circadian melatonin cycle and the total quantity of the indole generated. The chapter describes the nature of the membrane melatonin receptors and their signal transduction mechanisms in peripheral organs. The clinical implications and potential uses of melatonin in terms of influencing the biological clock (e.g. sleep and jet lag), immune function, and cancer initiation and growth are noted. Additionally, the chapter includes a description of the newly discovered free radical scavenging and antioxidant activities of melatonin; it also includes a list of clinical situations in which melatonin has been used with beneficial effects.

Animals↗
PubMed2003

Mechanistic and comparative studies of melatonin and classic antioxidants in terms of their interactions with the ABTS cation radical.

Melatonin and classic antioxidants possess the capacity to scavenge ABTSb+ with IC50s of 4, 11, 15.5, 15.5, 17 and 21 microm for melatonin, glutathione, vitamin C, trolox, NADH and NADPH, respectively. In terms of scavenging ABTSb+, melatonin exhibits a different profile than that of the classic antioxidants. Classic antioxidants scavenge one or less ABTSb+, while each melatonin molecule can scavenge more than one ABTSb+, probably with a maximum of four. Classic antioxidants do not synergize when combined in terms of scavenging ABTSb+. However, a synergistic action is observed when melatonin is combined with any of the classic antioxidants. Cyclic voltammetry indicates that melatonin donates an electron at the potential of 715 mV. The scavenging mechanism of melatonin on ABTSb+ may involve multiple-electron donations via intermediates through a stepwise process. Intermediates including the melatoninyl cation radical, the melatoninyl neutral radical and cyclic 3-hydroxymelatonin (cyclic 3-OHM) and N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) seem to participate in these reactions. More interestingly, the pH of the solution dramatically modifies the ABTSb+ scavenging capacity of melatonin while pH changes have no measurable influence on the scavenging activity of classic antioxidants. An acidic pH markedly reduces the ABTSb+ scavenging capacity of melatonin while an increased pH promotes the interaction of melatonin and ABTSb+. The major melatonin metabolites that develop when melatonin interacts with ABTSb+ are cyclic 3-OHM and AFMK. Cyclic 3-OHM is the intermediate between melatonin and AFMK, and cyclic 3-OHM also has the ability to scavenge ABTSb+. Melatonin and the metabolites which are generated via the interaction of melatonin with ABTSb+, i.e. the melatoninyl cation radical, melatoninyl neutral radical and cyclic 3-OHM, all scavenge ABTSb+. This unique cascade action of melatonin, in terms of scavenging, increases its efficiency to neutralized ABTSb+; this contrasts with the effects of the classic antioxidants.

Antioxidants↗
PubMed2003

Melatonin, xanthurenic acid, resveratrol, EGCG, vitamin C and alpha-lipoic acid differentially reduce oxidative DNA damage induced by Fenton reagents: a study of their individual and synergistic actions.

DNA damage generated by oxygen-derived free radicals is related to mutagenesis, carcinogenesis and aging. In the last several years, hundreds of publications have confirmed that melatonin is a potent endogenous free radical scavenger. In the present in vitro study, we have examined the efficacy of three polyphenolic antioxidants, i.e. xanthurenic acid, resveratrol (3,4',5-trihydroxy-trans-stilbene) and (-)-epigallocatechin-3-gallate (EGCG) and two classical non-polyphenolic antioxidants, i.e. vitamin C (ascorbic acid) and alpha-lipoic acid (LA, 1,2-dithiolane-3-pentanoic acid) in inhibiting *OH-induced oxidative DNA damage. We compared the efficacy of these five antioxidants with the effectiveness of melatonin (N-acetyl-5-methoxytryptamine) and we also investigated the possible synergistic effects of melatonin with the other five molecules. Using high performance liquid chromatography (HPLC), the formation of 8-hydroxy-2-deoxyguanosine (8-OH-dG) in purified calf thymus DNA treated with the Fenton reagents, chromium(III) (as CrCl3) plus hydrogen peroxide (H2O2) (Cr(III)/H2O2), was measured in the presence or absence of the antioxidants alone or in combination with melatonin. 8-OH-dG is considered a biomarker of oxidative DNA damage. Among the antioxidants tested, melatonin was the most effective of these with an IC50 = 3.6 +/- 0.1 micro m. For the other antioxidants the IC50 values were as follows: xanthurenic acid (IC50 = 7.9 +/- 0.3), resveratrol (IC50 = 10.9 +/- 0.3), EGCG (IC50 = 5.7 +/- 0.3), vitamin C (IC50 = 16.9 +/- 0.5) and LA (IC50 = 38.8 +/- 0.7). These values differ from that of melatonin with a P < 0.01. Melatonin (1 micro M) reversed the pro-oxidant effect of resveratrol (0.5 micro M) and vitamin C (0.5 micro M), had an antagonistic effect when used in combination with EGCG (1 micro M) and it exhibited synergism in combination with vitamin C (0.5 micro M) and with LA (5 micro M).

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2003

Orally administered melatonin reduces oxidative stress and proinflammatory cytokines induced by amyloid-beta peptide in rat brain: a comparative, in vivo study versus vitamin C and E.

To determine the efficacy of antioxidants in reducing amyloid-beta-induced oxidative stress, and the neuroinflammatory response in the central nervous system (CNS) in vivo, three injections of fibrillar amyloid-beta (fAbeta) or artificial cerebrospinal fluid (aCSF) into the CA1 region of the hippocampus of the rat were made. Concomitantly, one of the three free radical scavengers, i.e. melatonin, vitamin C, or vitamin E was also administered. Besides being a free radical scavenger, melatonin also has immunomodulatory functions. Antioxidant treatment reduced significantly oxidative stress and pro-inflammatory cytokines. There were no marked differences between melatonin, vitamin C, and vitamin E regarding their capacity to reduce nitrites and lipoperoxides. However, melatonin exhibited a superior capacity to reduce the pro-inflammatory response induced by fAbeta.

Adjuvants, Immunologic↗
PubMed2003

Melatonin protects against lipid peroxidation and membrane rigidity in erythrocytes from patients undergoing cardiopulmonary bypass surgery.

The first aim of this study was to test whether there are changes in erythrocyte lipid peroxidation products and membrane fluidity during cardiac surgery involving cardiopulmonary bypass. Secondly, in vitro tests were performed to examine whether melatonin alters induced lipid peroxidation and reduced membrane fluidity in erythrocytes from these patients. Fifteen patients undergoing cardiac surgery involving cardiopulmonary bypass (CPB) were selected. Five blood samples were taken at different times during surgery for analysis of thiobarbituric acid reactive substances (TBARS) content and membrane fluidity of the erythrocytes. TBARS are an index of the level of lipid peroxidation. The results revealed an increase in TBARS levels and a parallel decrease in erythrocyte membrane fluidity (increased membrane rigidity) after the onset of CPB with respect to the reference sample. Likewise, in vitro induction of lipid peroxidation in the erythrocyte samples from CPB patients followed a similar pattern. The changes in TBARS levels and membrane fluidity were suppressed by pre-incubation of erythrocytes with melatonin prior to the induction (by 70 microm Fe2+ + 250 microm ascorbate) of lipid peroxidation in a concentration-dependent manner. The results constitute a persuasive argument for the use of melatonin for preventive and therapeutic purposes during CPB.

Antioxidants↗
PubMed2003

Melatonin inhibits telomerase activity in the MCF-7 tumor cell line both in vivo and in vitro.

In this study for the first time the relationship between melatonin and telomerase activity was investigated. Melatonin exhibits oncostatic properties, but the actual mechanism of action by which the indole reduces tumor cell activity is not clear. Telomerase is an enzyme responsible of telomere elongation and is activated in most human cancers. In the current in vivo study, eight nude mice received a MCF-7 xenograft and thereafter they were treated for 5 weeks with 0.1 mg/mL of melatonin in the drinking water. Melatonin treatment caused a significant reduction in the weight of tumors and reduced metastases when compared with the control group. As indicated by the Telomerase Repeats Amplification Protocol (TRAP) assay, a significant decrease in telomerase activity was observed in the group treated with melatonin. In related in vitro studies, cultured MCF-7 cells were treated with three different concentrations of melatonin and a control without indole treatment. A significant dose-dependent decrease in Telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase, mRNA expression was observed in the melatonin-treated cells. We also observed a significant reduction in TR, the RNA telomerase subunit, mRNA expression at physiological concentrations of melatonin (1 nm). Significant differences in TEP1, an associated telomerase protein, mRNA expression were also observed. In conclusion, melatonin influences telomerase both in vivo and in vitro, decreasing its activity in the tumors of nude mice and the mRNA expression of the TERT and TR subunits, essential factors for the proper function of the telomerase enzyme.

Animals↗
PubMed2003

Melatonin: a hormone, a tissue factor, an autocoid, a paracoid, and an antioxidant vitamin.

Melatonin, a derivative of an essential amino acid, tryptophan, was first identified in bovine pineal tissue and subsequently it has been portrayed exclusively as a hormone. Recently accumulated evidence has challenged this concept. Melatonin is present in the earliest life forms and is found in all organisms including bacteria, algae, fungi, plants, insects, and vertebrates including humans. Several characteristics of melatonin distinguish it from a classic hormone such as its direct, non-receptor-mediated free radical scavenging activity. As melatonin is also ingested in foodstuffs such as vegetables, fruits, rice, wheat and herbal medicines, from the nutritional point of view, melatonin can also be classified as a vitamin. It seems likely that melatonin initially evolved as an antioxidant, becoming a vitamin in the food chain, and in multicellular organisms, where it is produced, it has acquired autocoid, paracoid and hormonal properties.

Animals↗
PubMed2003

Oxidative damage to catalase induced by peroxyl radicals: functional protection by melatonin and other antioxidants.

Thermal decomposition by the azo initiator 2,2' azobis(2-amidinopropane) dihydrochloride (AAPH) has been widely used as a water-soluble source of free radical initiators capable of inducing lipid peroxidation and protein damage. Here, in a lipid-free system, AAPH alone (40 mM) rapidly induced protein modification and inactivation of the enzyme catalase (EC 1.11.1.6). Using SDS-PAGE, it was shown that protein band intensity is dramatically reduced after 4 h of incubation with AAPH, leading to protein aggregation. Several antioxidants including melatonin, glutathione (GSH) and trolox prevented catalase modification when used at a 250 microM concentration whereas ascorbate was only effective at 1 mM concentration. All the antioxidants tested reduced carbonyl formation although melatonin was the most effective in this regard. Enzyme inactivation caused by AAPH was also significantly reduced by the antioxidants and again melatonin was more efficient than the other antioxidants used in this study. Results shown here demonstrate that alkyl peroxyl radicals inactivate catalase and reduce the effectiveness of cells to defend against free radical damage; the damage to catalase can be prevented by antioxidants, especially melatonin.

Amidines↗
PubMed2003

Prophylactic effect of melatonin in reducing lead-induced neurotoxicity in the rat.

Oxidative stress is a likely molecular mechanism in lead neurotoxicity. Considering the antioxidant properties of melatonin, this study investigated the neuroprotective potential of melatonin in the hippocampus and corpus striatum of rats treated with lead. Three groups of male rats (control, lead acetate-treated [100 mg/kg], and lead acetate plus melatonin [10 mg/kg] for 21 consecutive days) were used. Levels of products of lipid peroxidation (LPO), glutathione (GSH) and superoxide dismutase (SOD) activity were measured in brain homogenates. Histological changes in the pyramidal cells of the hippocampus and the putamen of the corpus striatum were examined. The results documented increased LPO and decreased GSH and SOD activity in the brain homogenates of lead-treated rats. Histological observations revealed severe damage and a reduction in neuronal density in the hippocampus and corpus striatum. When melatonin was given to lead-treated rats, it almost completely attenuated the increase in LPO products and restored GSH levels and SOD activity. Also, the morphological damage was reduced and neuronal density was restored by melatonin. Considering the ease with which melatonin enters the brain, these results, along with previous observations, suggest that melatonin may be useful in combating free radical-induced neuronal injury that is a result of lead toxicity.

Animals↗