Publications by authors named "Sergio Rosales-Corral"

31 Publications

Part-time cancers and role of melatonin in determining their metabolic phenotype.

Life Sci 2021 May 8;278:119597. Epub 2021 May 8.

Departamento de Biologia Estrutural e Funcional, Instituto de Biociencias, Botucatu, Sao Poalo 18618-689, Brazil.

This brief review describes the association of the endogenous pineal melatonin rhythm with the metabolic flux of solid tumors, particularly breast cancer. It also summarizes new information on the potential mechanisms by which endogenously-produced or exogenously-administered melatonin impacts the metabolic phenotype of cancer cells. The evidence indicates that solid tumors may redirect their metabolic phenotype from the pathological Warburg-type metabolism during the day to the healthier mitochondrial oxidative phosphorylation on a nightly basis. Thus, they function as cancer cells only during the day and as healthier cells at night, that is, they are only part-time cancerous. This switch to oxidative phosphorylation at night causes cancer cells to exhibit a reduced tumor phenotype and less likely to rapidly proliferate or to become invasive or metastatic. Also discussed is the likelihood that some solid tumors are especially aggressive during the day and much less so at night due to the nocturnal rise in melatonin which determines their metabolic state. We further propose that when melatonin is used/tested in clinical trials, a specific treatment paradigm be used that is consistent with the temporal metabolic changes in tumor metabolism. Finally, it seems likely that the concurrent use of melatonin in combination with conventional chemotherapies also would improve cancer treatment outcomes.
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http://dx.doi.org/10.1016/j.lfs.2021.119597DOI Listing
May 2021

Anti-Warburg Effect of Melatonin: A Proposed Mechanism to Explain its Inhibition of Multiple Diseases.

Int J Mol Sci 2021 Jan 14;22(2). Epub 2021 Jan 14.

Centro de Investigacion Biomedica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco CP45150, Mexico.

Glucose is an essential nutrient for every cell but its metabolic fate depends on cellular phenotype. Normally, the product of cytosolic glycolysis, pyruvate, is transported into mitochondria and irreversibly converted to acetyl coenzyme A by pyruvate dehydrogenase complex (PDC). In some pathological cells, however, pyruvate transport into the mitochondria is blocked due to the inhibition of PDC by pyruvate dehydrogenase kinase. This altered metabolism is referred to as aerobic glycolysis (Warburg effect) and is common in solid tumors and in other pathological cells. Switching from mitochondrial oxidative phosphorylation to aerobic glycolysis provides diseased cells with advantages because of the rapid production of ATP and the activation of pentose phosphate pathway (PPP) which provides nucleotides required for elevated cellular metabolism. Molecules, called glycolytics, inhibit aerobic glycolysis and convert cells to a healthier phenotype. Glycolytics often function by inhibiting hypoxia-inducible factor-1α leading to PDC disinhibition allowing for intramitochondrial conversion of pyruvate into acetyl coenzyme A. Melatonin is a glycolytic which converts diseased cells to the healthier phenotype. Herein we propose that melatonin's function as a glycolytic explains its actions in inhibiting a variety of diseases. Thus, the common denominator is melatonin's action in switching the metabolic phenotype of cells.
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http://dx.doi.org/10.3390/ijms22020764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828708PMC
January 2021

Circadian disruption, melatonin rhythm perturbations and their contributions to chaotic physiology.

Adv Med Sci 2020 Sep 4;65(2):394-402. Epub 2020 Aug 4.

Department of Cell Systems and Anatomy, UT Health, San Antonio, TX, USA.

The aim of this report is to summarize the data documenting the vital nature of well-regulated cellular and organismal circadian rhythms, which are also reflected in a stable melatonin cycle, in supporting optimal health. Cellular fluctuations in physiology exist in most cells of multicellular organisms with their stability relying on the prevailing light:dark cycle, since it regulates, via specialized intrinsically-photoreceptive retinal ganglion cells (ipRGC) and the retinohypothalamic tract, the master circadian oscillator, i.e., the suprachiasmatic nuclei (SCN). The output message of the SCN, as determined by the light:dark cycle, is transferred to peripheral oscillators, so-called slave cellular oscillators, directly via the autonomic nervous system with its limited distribution. and indirectly via the pineal-derived circulating melatonin rhythm, which contacts every cell. Via its regulatory effects on the neuroendocrine system, particularly the hypothalamo-pituitary-adrenal axis, the SCN also has a major influence on the adrenal glucocorticoid rhythm which impacts neurological diseases and psychological behaviors. Moreover, the SCN regulates the circadian production and secretion of melatonin. When the central circadian oscillator is disturbed, such as by light at night, it passes misinformation to all organs in the body. When this occurs the physiology of cells becomes altered and normal cellular functions are compromised. This physiological upheaval is a precursor to pathologies. The deterioration of the SCN/pineal network is often a normal consequence of aging and its related diseases, but in today's societies where manufactured light is becoming progressively more common worldwide, the associated pathologies may also be occurring at an earlier age.
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http://dx.doi.org/10.1016/j.advms.2020.07.001DOI Listing
September 2020

Melatonin Mitigates Mitochondrial Meltdown: Interactions with SIRT3.

Int J Mol Sci 2018 Aug 18;19(8). Epub 2018 Aug 18.

Departamento de Fisiologia, Instituto de Biotecnologia, Universidad de Granada, Avenida de Conocimiento S/U, 18016 Granada, Spain.

Melatonin exhibits extraordinary diversity in terms of its functions and distribution. When discovered, it was thought to be uniquely of pineal gland origin. Subsequently, melatonin synthesis was identified in a variety of organs and recently it was shown to be produced in the mitochondria. Since mitochondria exist in every cell, with a few exceptions, it means that every vertebrate, invertebrate, and plant cell produces melatonin. The mitochondrial synthesis of melatonin is not photoperiod-dependent, but it may be inducible under conditions of stress. Mitochondria-produced melatonin is not released into the systemic circulation, but rather is used primarily in its cell of origin. Melatonin's functions in the mitochondria are highly diverse, not unlike those of sirtuin 3 (SIRT3). SIRT3 is an NAD+-dependent deacetylase which regulates, among many functions, the redox state of the mitochondria. Recent data proves that melatonin and SIRT3 post-translationally collaborate in regulating free radical generation and removal from mitochondria. Since melatonin and SIRT3 have cohabitated in the mitochondria for many eons, we predict that these molecules interact in many other ways to control mitochondrial physiology. It is predicted that these mutual functions will be intensely investigated in the next decade and importantly, we assume that the findings will have significant applications for preventing/delaying some age-related diseases and aging itself.
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http://dx.doi.org/10.3390/ijms19082439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121285PMC
August 2018

Mitochondria: Central Organelles for Melatonin's Antioxidant and Anti-Aging Actions.

Molecules 2018 Feb 24;23(2). Epub 2018 Feb 24.

Department of Cellular and Structural Biology UT Health San Antonio, San Antonio, SD 78229, USA.

Melatonin, along with its metabolites, have long been known to significantly reduce the oxidative stress burden of aging cells or cells exposed to toxins. Oxidative damage is a result of free radicals produced in cells, especially in mitochondria. When measured, melatonin, a potent antioxidant, was found to be in higher concentrations in mitochondria than in other organelles or subcellular locations. Recent evidence indicates that mitochondrial membranes possess transporters that aid in the rapid uptake of melatonin by these organelles against a gradient. Moreover, we predicted several years ago that, because of their origin from melatonin-producing bacteria, mitochondria likely also synthesize melatonin. Data accumulated within the last year supports this prediction. A high content of melatonin in mitochondria would be fortuitous, since these organelles produce an abundance of free radicals. Thus, melatonin is optimally positioned to scavenge the radicals and reduce the degree of oxidative damage. In light of the "free radical theory of aging", including all of its iterations, high melatonin levels in mitochondria would be expected to protect against age-related organismal decline. Also, there are many age-associated diseases that have, as a contributing factor, free radical damage. These multiple diseases may likely be deferred in their onset or progression if mitochondrial levels of melatonin can be maintained into advanced age.
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http://dx.doi.org/10.3390/molecules23020509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017324PMC
February 2018

Melatonin as a mitochondria-targeted antioxidant: one of evolution's best ideas.

Cell Mol Life Sci 2017 11 1;74(21):3863-3881. Epub 2017 Sep 1.

Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, 78229, USA.

Melatonin is an ancient antioxidant. After its initial development in bacteria, it has been retained throughout evolution such that it may be or may have been present in every species that have existed. Even though it has been maintained throughout evolution during the diversification of species, melatonin's chemical structure has never changed; thus, the melatonin present in currently living humans is identical to that present in cyanobacteria that have existed on Earth for billions of years. Melatonin in the systemic circulation of mammals quickly disappears from the blood presumably due to its uptake by cells, particularly when they are under high oxidative stress conditions. The measurement of the subcellular distribution of melatonin has shown that the concentration of this indole in the mitochondria greatly exceeds that in the blood. Melatonin presumably enters mitochondria through oligopeptide transporters, PEPT1, and PEPT2. Thus, melatonin is specifically targeted to the mitochondria where it seems to function as an apex antioxidant. In addition to being taken up from the circulation, melatonin may be produced in the mitochondria as well. During evolution, mitochondria likely originated when melatonin-forming bacteria were engulfed as food by ancestral prokaryotes. Over time, engulfed bacteria evolved into mitochondria; this is known as the endosymbiotic theory of the origin of mitochondria. When they did so, the mitochondria retained the ability to synthesize melatonin. Thus, melatonin is not only taken up by mitochondria but these organelles, in addition to many other functions, also probably produce melatonin as well. Melatonin's high concentrations and multiple actions as an antioxidant provide potent antioxidant protection to these organelles which are exposed to abundant free radicals.
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http://dx.doi.org/10.1007/s00018-017-2609-7DOI Listing
November 2017

Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis.

Int J Mol Sci 2017 Apr 17;18(4). Epub 2017 Apr 17.

Department of Molecular Medicine, UT Health, San Antonio, TX 78229, USA.

There is highly credible evidence that melatonin mitigates cancer at the initiation, progression and metastasis phases. In many cases, the molecular mechanisms underpinning these inhibitory actions have been proposed. What is rather perplexing, however, is the large number of processes by which melatonin reportedly restrains cancer development and growth. These diverse actions suggest that what is being observed are merely epiphenomena of an underlying more fundamental action of melatonin that remains to be disclosed. Some of the arresting actions of melatonin on cancer are clearly membrane receptor-mediated while others are membrane receptor-independent and involve direct intracellular actions of this ubiquitously-distributed molecule. While the emphasis of melatonin/cancer research has been on the role of the indoleamine in restraining breast cancer, this is changing quickly with many cancer types having been shown to be susceptible to inhibition by melatonin. There are several facets of this research which could have immediate applications at the clinical level. Many studies have shown that melatonin's co-administration improves the sensitivity of cancers to inhibition by conventional drugs. Even more important are the findings that melatonin renders cancers previously totally resistant to treatment sensitive to these same therapies. Melatonin also inhibits molecular processes associated with metastasis by limiting the entrance of cancer cells into the vascular system and preventing them from establishing secondary growths at distant sites. This is of particular importance since cancer metastasis often significantly contributes to death of the patient. Another area that deserves additional consideration is related to the capacity of melatonin in reducing the toxic consequences of anti-cancer drugs while increasing their efficacy. Although this information has been available for more than a decade, it has not been adequately exploited at the clinical level. Even if the only beneficial actions of melatonin in cancer patients are its ability to attenuate acute and long-term drug toxicity, melatonin should be used to improve the physical wellbeing of the patients. The experimental findings, however, suggest that the advantages of using melatonin as a co-treatment with conventional cancer therapies would far exceed improvements in the wellbeing of the patients.
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http://dx.doi.org/10.3390/ijms18040843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412427PMC
April 2017

Diabetes and Alzheimer disease, two overlapping pathologies with the same background: oxidative stress.

Oxid Med Cell Longev 2015 26;2015:985845. Epub 2015 Feb 26.

Department of Structural Biology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.

There are several oxidative stress-related pathways interconnecting Alzheimer's disease and type II diabetes, two public health problems worldwide. Coincidences are so compelling that it is attractive to speculate they are the same disorder. However, some pathological mechanisms as observed in diabetes are not necessarily the same mechanisms related to Alzheimer's or the only ones related to Alzheimer's pathology. Oxidative stress is inherent to Alzheimer's and feeds a vicious cycle with other key pathological features, such as inflammation and Ca(2+) dysregulation. Alzheimer's pathology by itself may lead to insulin resistance in brain, insulin resistance being an intervening variable in the neurodegenerative disorder. Hyperglycemia and insulin resistance from diabetes, overlapping with the Alzheimer's pathology, aggravate the progression of the neurodegenerative processes, indeed. But the same pathophysiological background is behind the consequences, oxidative stress. We emphasize oxidative stress and its detrimental role in some key regulatory enzymes.
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http://dx.doi.org/10.1155/2015/985845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357132PMC
December 2015

Extrapineal melatonin: sources, regulation, and potential functions.

Cell Mol Life Sci 2014 Aug 20;71(16):2997-3025. Epub 2014 Feb 20.

Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Avda. del Conocimiento s/n, Armilla, 18100, Granada, Spain,

Endogenous melatonin is synthesized from tryptophan via 5-hydroxytryptamine. It is considered an indoleamine from a biochemical point of view because the melatonin molecule contains a substituted indolic ring with an amino group. The circadian production of melatonin by the pineal gland explains its chronobiotic influence on organismal activity, including the endocrine and non-endocrine rhythms. Other functions of melatonin, including its antioxidant and anti-inflammatory properties, its genomic effects, and its capacity to modulate mitochondrial homeostasis, are linked to the redox status of cells and tissues. With the aid of specific melatonin antibodies, the presence of melatonin has been detected in multiple extrapineal tissues including the brain, retina, lens, cochlea, Harderian gland, airway epithelium, skin, gastrointestinal tract, liver, kidney, thyroid, pancreas, thymus, spleen, immune system cells, carotid body, reproductive tract, and endothelial cells. In most of these tissues, the melatonin-synthesizing enzymes have been identified. Melatonin is present in essentially all biological fluids including cerebrospinal fluid, saliva, bile, synovial fluid, amniotic fluid, and breast milk. In several of these fluids, melatonin concentrations exceed those in the blood. The importance of the continual availability of melatonin at the cellular level is important for its physiological regulation of cell homeostasis, and may be relevant to its therapeutic applications. Because of this, it is essential to compile information related to its peripheral production and regulation of this ubiquitously acting indoleamine. Thus, this review emphasizes the presence of melatonin in extrapineal organs, tissues, and fluids of mammals including humans.
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http://dx.doi.org/10.1007/s00018-014-1579-2DOI Listing
August 2014

Melatonin in the biliary tract and liver: health implications.

Curr Pharm Des 2014 ;20(30):4788-801

Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, Texas, USA.

Melatonin is a widely-produced and ubiquitously-distributed molecule with multiple critical functions in all organs and organisms. These functions are mediated by both receptor-mediated and receptor-independent actions of the indole. This survey reviews the reports documenting the presence and function of melatonin in the hepatobiliary system. The published data document the exceptionally high concentrations of melatonin in the bile; herein, we speculate on the significance of these high melatonin levels to the function of the biliary tree. Moreover, we suggest that the elevated concentrations of melatonin in the bile fluid may be a consequence of its recirculation in what is referred to as the enterohepatic circulation. The article also examines the published reports related to melatonin levels in hepatocytes, which appear to be independent of pineal-derived melatonin. In both the biliary system and liver, melatonin provides protection against free radicals in cells of these organs. This is particularly important in these organs since they are under constant assault by highly toxic agents/processes that could compromise their critical physiology. As in other tissues, melatonin provides hepatocytes and cholangiocytes with a buffer against free radicals that are persistently produced and thereby this indole protects against oxidative molecular damage and metabolic dysfunction. Melatonin achieves this protection via the diverse free radical scavenging mechanisms of it and its metabolites (known as the antioxidant cascade), due to its ability to reduce electron leakage from the respiratory complexes in the inner mitochondrial membrane (radical avoidance) and as a result of the stimulation of antioxidative enzymes.
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http://dx.doi.org/10.2174/1381612819666131119105826DOI Listing
April 2015

Melatonin and stable circadian rhythms optimize maternal, placental and fetal physiology.

Hum Reprod Update 2014 Mar-Apr;20(2):293-307. Epub 2013 Oct 16.

Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA.

Background: Research within the last decade has shown melatonin to have previously-unsuspected beneficial actions on the peripheral reproductive organs. Likewise, numerous investigations have documented that stable circadian rhythms are also helpful in maintaining reproductive health. The relationship of melatonin and circadian rhythmicity to maternal and fetal health is summarized in this review.

Methods: Databases were searched for the related published English literature up to 15 May 2013. The search terms used in various combinations included melatonin, circadian rhythms, biological clock, suprachiasmatic nucleus, ovary, pregnancy, uterus, placenta, fetus, pre-eclampsia, intrauterine growth restriction, ischemia-reperfusion, chronodisruption, antioxidants, oxidative stress and free radicals. The results of the studies uncovered are summarized herein.

Results: Both melatonin and circadian rhythms impact reproduction, especially during pregnancy. Melatonin is a multifaceted molecule with direct free radical scavenging and indirect antioxidant activities. Melatonin is produced in both the ovary and in the placenta where it protects against molecular mutilation and cellular dysfunction arising from oxidative/nitrosative stress. The placenta, in particular, is often a site of excessive free radical generation due to less than optimal adhesion to the uterine wall, which leads to either persistent hypoxia or intermittent hypoxia and reoxygenation, processes that cause massive free radical generation and organ dysfunction. This may contribute to pre-eclampsia and other disorders which often complicate pregnancy. Melatonin has ameliorated free radical damage to the placenta and to the fetus in experiments using non-human mammals. Likewise, the maintenance of a regular maternal light/dark and sleep/wake cycle is important to stabilize circadian rhythms generated by the maternal central circadian pacemaker, the suprachiasmatic nuclei. Optimal circadian rhythmicity in the mother is important since her circadian clock, either directly or indirectly via the melatonin rhythm, programs the developing master oscillator of the fetus. Experimental studies have shown that disturbed maternal circadian rhythms, referred to as chronodisruption, and perturbed melatonin cycles have negative consequences for the maturing fetal oscillators, which may lead to psychological and behavioral problems in the newborn. To optimize regular circadian rhythms and prevent disturbances of the melatonin cycle during pregnancy, shift work and bright light exposure at night should be avoided, especially during the last trimester of pregnancy. Finally, melatonin synergizes with oxytocin to promote delivery of the fetus. Since blood melatonin levels are normally highest during the dark period, the propensity of childbirth to occur at night may relate to the high levels of melatonin at this time which work in concert with oxytocin to enhance the strength of uterine contractions.

Conclusions: A number of conclusions naturally evolve from the data summarized in this review: (i) melatonin, of both pineal and placental origin, has essential functions in fetal maturation and placenta/uterine homeostasis; (ii) circadian clock genes, which are components of all cells including those in the peripheral reproductive organs, have important roles in reproductive and organismal (fetal and maternal) physiology; (iii) due to the potent antioxidant actions of melatonin, coupled with its virtual absence of toxicity, this indoleamine may have utility in the treatment of pre-eclampsia, intrauterine growth restriction, placental and fetal ischemia/reperfusion, etc. (iv) the propensity for parturition to occur at night may relate to the synergism between the nocturnal increase in melatonin and oxytocin.
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http://dx.doi.org/10.1093/humupd/dmt054DOI Listing
September 2014

A walnut-enriched diet reduces the growth of LNCaP human prostate cancer xenografts in nude mice.

Cancer Invest 2013 Jul 11;31(6):365-73. Epub 2013 Jun 11.

Department of Cellular and Structural Biology, University of Texas Health Science Center , San Antonio, Texas, USA.

It was investigated whether a standard mouse diet (AIN-76A) supplemented with walnuts reduced the establishment and growth of LNCaP human prostate cancer cells in nude (nu/nu) mice. The walnut-enriched diet reduced the number of tumors and the growth of the LNCaP xenografts; 3 of 16 (18.7%) of the walnut-fed mice developed tumors; conversely, 14 of 32 mice (44.0%) of the control diet-fed animals developed tumors. Similarly, the xenografts in the walnut-fed animals grew more slowly than those in the control diet mice. The final average tumor size in the walnut-diet animals was roughly one-fourth the average size of the prostate tumors in the mice that ate the control diet.
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http://dx.doi.org/10.3109/07357907.2013.800095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3709881PMC
July 2013

Peripheral reproductive organ health and melatonin: ready for prime time.

Int J Mol Sci 2013 Apr 2;14(4):7231-72. Epub 2013 Apr 2.

Department of Cellular and Structural Biology, UT Health Science Center at San Antonio, San Antonio, TX 78229, USA.

Melatonin has a wide variety of beneficial actions at the level of the gonads and their adnexa. Some actions are mediated via its classic membrane melatonin receptors while others seem to be receptor-independent. This review summarizes many of the published reports which confirm that melatonin, which is produced in the ovary, aids in advancing follicular maturation and preserving the integrity of the ovum prior to and at the time of ovulation. Likewise, when ova are collected for in vitro fertilization-embryo transfer, treating them with melatonin improves implantation and pregnancy rates. Melatonin synthesis as well as its receptors have also been identified in the placenta. In this organ, melatonin seems to be of particular importance for the maintenance of the optimal turnover of cells in the villous trophoblast via its ability to regulate apoptosis. For male gametes, melatonin has also proven useful in protecting them from oxidative damage and preserving their viability. Incubation of ejaculated animal sperm improves their motility and prolongs their viability. For human sperm as well, melatonin is also a valuable agent for protecting them from free radical damage. In general, the direct actions of melatonin on the gonads and adnexa of mammals indicate it is an important agent for maintaining optimal reproductive physiology.
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http://dx.doi.org/10.3390/ijms14047231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3645684PMC
April 2013

The universal nature, unequal distribution and antioxidant functions of melatonin and its derivatives.

Mini Rev Med Chem 2013 Mar;13(3):373-84

Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, Texas, USA.

Melatonin is an uncommonly widely distributed molecule. It is found throughout the plant and animal kingdoms, i.e., perhaps in every living organism. Within vertebrate organisms, melatonin also has an extremely wide distribution, seemingly being capable of entering every cell and all subcellular compartments. So-called morphophysiological barriers, e.g., the blood-brain barrier, are no impediment to the passage of melatonin and it has a multitude of confirmed functions. We have hypothesized that melatonin originally evolved as a free radical scavenger and during evolution it acquired other important and essential actions. Due to the multi-faceted actions of melatonin and its metabolites as direct free radical scavengers and indirect antioxidants, these agents have been used to abate oxidative damage in a diverse variety of experimental models where free radical destruction is a component. When compared with classic, better-known antioxidants, melatonin is better in terms of limiting destruction of intracellular macromolecules when the damage is a consequence of excessive oxygen or nitrogen-based toxic reactants. Considering the vast array of experimental data that has accumulated which documents melatonin's high efficacy and lack of, or minimal, toxicity over a very wide dose range, it is essential that the usefulness of this agent be more thoroughly tested at the clinical level. The findings from experimental models of numerous diseases overwhelming confirm that this indoleamine would likely have great benefit in aiding humans suffering with conditions that have as their basis tissue and molecular damage resulting from oxygen and nitrogen-based reactants.
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http://dx.doi.org/10.2174/1389557511313030006DOI Listing
March 2013

Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin's primary function and evolution in eukaryotes.

J Pineal Res 2013 Mar 9;54(2):127-38. Epub 2012 Nov 9.

Department of Cellular and Structural Biology, The University of Texas, Health Science Center, San Antonio, TX 78229, USA.

Mitochondria and chloroplasts are major sources of free radical generation in living organisms. Because of this, these organelles require strong protection from free radicals and associated oxidative stress. Melatonin is a potent free radical scavenger and antioxidant. It meets the criteria as a mitochondrial and chloroplast antioxidant. Evidence has emerged to show that both mitochondria and chloroplasts may have the capacity to synthesize and metabolize melatonin. The activity of arylalkylamine N-acetyltransferase (AANAT), the reported rate-limiting enzyme in melatonin synthesis, has been identified in mitochondria, and high levels of melatonin have also been found in this organelle. From an evolutionary point of view, the precursor of mitochondria probably is the purple nonsulfur bacterium, particularly, Rhodospirillum rubrum, and chloroplasts are probably the descendents of cyanobacteria. These bacterial species were endosymbionts of host proto-eukaryotes and gradually transformed into cellular organelles, that is, mitochondria and chloroplasts, respectively, thereby giving rise to eukaryotic cells. Of special importance, both purple nonsulfur bacteria (R. rubrum) and cyanobacteria synthesize melatonin. The enzyme activities required for melatonin synthesis have also been detected in these primitive species. It is our hypothesis that mitochondria and chloroplasts are the original sites of melatonin synthesis in the early stage of endosymbiotic organisms; this synthetic capacity was carried into host eukaryotes by the above-mentioned bacteria. Moreover, their melatonin biosynthetic capacities have been preserved during evolution. In most, if not in all cells, mitochondria and chloroplasts may continue to be the primary sites of melatonin generation. Melatonin production in other cellular compartments may have derived from mitochondria and chloroplasts. On the basis of this hypothesis, it is also possible to explain why plants typically have higher melatonin levels than do animals. In plants, both chloroplasts and mitochondria likely synthesize melatonin, while animal cells contain only mitochondria. The high levels of melatonin produced by mitochondria and chloroplasts are used to protect these important cellular organelles against oxidative stress and preserve their physiological functions. The superior beneficial effects of melatonin in both mitochondria and chloroplasts have been frequently reported.
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http://dx.doi.org/10.1111/jpi.12026DOI Listing
March 2013

Alterations in Lipid Levels of Mitochondrial Membranes Induced by Amyloid-β: A Protective Role of Melatonin.

Int J Alzheimers Dis 2012 16;2012:459806. Epub 2012 May 16.

Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229, USA.

Alzheimer pathogenesis involves mitochondrial dysfunction, which is closely related to amyloid-β (Aβ) generation, abnormal tau phosphorylation, oxidative stress, and apoptosis. Alterations in membranal components, including cholesterol and fatty acids, their characteristics, disposition, and distribution along the membranes, have been studied as evidence of cell membrane alterations in AD brain. The majority of these studies have been focused on the cytoplasmic membrane; meanwhile the mitochondrial membranes have been less explored. In this work, we studied lipids and mitochondrial membranes in vivo, following intracerebral injection of fibrillar amyloid-β (Aβ). The purpose was to determine how Aβ may be responsible for beginning of a vicious cycle where oxidative stress and alterations in cholesterol, lipids and fatty acids, feed back on each other to cause mitochondrial dysfunction. We observed changes in mitochondrial membrane lipids, and fatty acids, following intracerebral injection of fibrillar Aβ in aged Wistar rats. Melatonin, a well-known antioxidant and neuroimmunomodulator indoleamine, reversed some of these alterations and protected mitochondrial membranes from obvious damage. Additionally, melatonin increased the levels of linolenic and n-3 eicosapentaenoic acid, in the same site where amyloid β was injected, favoring an endogenous anti-inflammatory pathway.
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http://dx.doi.org/10.1155/2012/459806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3362052PMC
August 2012

Accumulation of exogenous amyloid-beta peptide in hippocampal mitochondria causes their dysfunction: a protective role for melatonin.

Oxid Med Cell Longev 2012 13;2012:843649. Epub 2012 May 13.

Centro de Investigación Biomédica de Occidente del Instituto Mexicano del Seguro Social, Sierra Mojada 800 Colonia Independencia, 44340 Guadalajara, JAL, Mexico.

Amyloid-beta (Aβ) pathology is related to mitochondrial dysfunction accompanied by energy reduction and an elevated production of reactive oxygen species (ROS). Monomers and oligomers of Aβ have been found inside mitochondria where they accumulate in a time-dependent manner as demonstrated in transgenic mice and in Alzheimer's disease (AD) brain. We hypothesize that the internalization of extracellular Aβ aggregates is the major cause of mitochondrial damage and here we report that following the injection of fibrillar Aβ into the hippocampus, there is severe axonal damage which is accompanied by the entrance of Aβ into the cell. Thereafter, Aβ appears in mitochondria where it is linked to alterations in the ionic gradient across the inner mitochondrial membrane. This effect is accompanied by disruption of subcellular structure, oxidative stress, and a significant reduction in both the respiratory control ratio and in the hydrolytic activity of ATPase. Orally administrated melatonin reduced oxidative stress, improved the mitochondrial respiratory control ratio, and ameliorated the energy imbalance.
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http://dx.doi.org/10.1155/2012/843649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3359765PMC
September 2012

Role of melatonin in the regulation of autophagy and mitophagy: a review.

Mol Cell Endocrinol 2012 Sep 1;361(1-2):12-23. Epub 2012 May 1.

Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229, USA.

Oxidative stress plays an essential role in triggering many cellular processes including programmed cell death. Proving a relationship between apoptosis and reactive oxygen species has been the goal of numerous studies. Accumulating data point to an essential role for oxidative stress in the activation of autophagy. The term autophagy encompasses several processes including not only survival or death mechanisms, but also pexophagy, mitophagy, ER-phagy or ribophagy, depending of which organelles are targeted for specific autophagic degradation. However, whether the outcome of autophagy is survival or death and whether the initiating conditions are starvation, pathogens or death receptors, reactive oxygen species are invariably involved. The role of antioxidants in the regulation of these processes, however, has been sparingly investigated. Among the known antioxidants, melatonin has high efficacy and, in both experimental and clinical situations, its protective actions against oxidative stress are well documented. Beneficial effects against mitochondrial dysfunction have also been described for melatonin; thus, this indoleamine seems to be linked to mitophagy. The present review focuses on data and the most recent advances related to the role of melatonin in health and disease, on autophagy activation in general, and on mitophagy in particular.
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http://dx.doi.org/10.1016/j.mce.2012.04.009DOI Listing
September 2012

Gene regulation by melatonin linked to epigenetic phenomena.

Gene 2012 Jul 1;503(1):1-11. Epub 2012 May 1.

Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX 78229-3900, USA.

Many exogenous (e.g., toxins, chemicals, ultraviolet, cigarette smoke) and endogenous (e.g., hyperglycemia, dyslipidemia, cytokines, chemokines) agents disrupt the intracellular environment and result in a massive production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The molecular damage that ROS/RNS induce is referred to as nitrooxidative stress. The cellular consequences of nitrooxidative stress include lipid peroxidation, protein oxidation and DNA damage. Additionally, ROS and RNS deplete cellular defenses and initiate inflammation. It is widely accepted that nitrooxidative stress and inflammation play important roles in the pathogenesis of a variety of human diseases and sequelae. Several processes are crucial to overcome the damaging cellular events caused by nitrooxidative stress, e.g., scavenging both ROS and RNS, induction of defense mechanisms and alleviating/suppressing inflammation are essential. Both endogenous and pharmacological concentrations of melatonin have long been known to play role in the direct scavenging of ROS and RNS as well as inducing antioxidant defense mechanisms and ameliorating inflammation. The current review summarizes research related to two major transcription factors that participate in these processes and summarizes how melatonin regulates antioxidant and pro-inflammatory genes via epigenetic on/off mechanisms.
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http://dx.doi.org/10.1016/j.gene.2012.04.040DOI Listing
July 2012

Beneficial actions of melatonin in the management of viral infections: a new use for this "molecular handyman"?

Rev Med Virol 2012 Sep 18;22(5):323-38. Epub 2012 Apr 18.

Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, Texas, USA.

Melatonin (N-acetyl-5-methoxytryptamine) is a multifunctional signaling molecule that has a variety of important functions. Numerous clinical trials have examined the therapeutic usefulness of melatonin in different fields of medicine. Clinical trials have shown that melatonin is efficient in preventing cell damage under acute (sepsis, asphyxia in newborns) and chronic states (metabolic and neurodegenerative diseases, cancer, inflammation, aging). The beneficial effects of melatonin can be explained by its properties as a potent antioxidant and antioxidant enzyme inducer, a regulator of apoptosis and a stimulator of immune functions. These effects support the use of melatonin in viral infections, which are often associated with inflammatory injury and increases in oxidative stress. In fact, melatonin has been used recently to treat several viral infections, which are summarized in this review. The role of melatonin in infections is also discussed herein.
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http://dx.doi.org/10.1002/rmv.1714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169144PMC
September 2012

Emergence of naturally occurring melatonin isomers and their proposed nomenclature.

J Pineal Res 2012 Sep 14;53(2):113-21. Epub 2012 Feb 14.

Department of Cellular and Structural Biology, The University of Texas, Health Science Center at San Antonio, San Antonio, TX 78229, USA.

Melatonin was considered to be the sole member of this natural family. The emergence of naturally occurring melatonin isomers (MIs) has opened an exciting new research area. Currently, several MIs have been identified in wine, and these molecules are believed to be synthesized by either yeasts or bacteria. A tentative nomenclature for the MIs is proposed in this article. It will be important to explore whether all organisms have the capacity to synthesize MIs, especially under the conditions of environmental stress. These isomers probably share many of the biological functions of melatonin, but their activities seem to exceed those of melatonin. On basis of the limited available information, it seems that MIs differ in their biosynthetic pathways from melatonin. Especially in those compounds in which the aliphatic side chain is not attached to ring atom 3, the starting material may not be tryptophan. Also, the metabolic pathways of MIs remain unknown. This, therefore, is another promising area of research to explore. It is our hypothesis that MIs would increase the performance of yeasts and probiotic bacteria during the processes of fermentation. Therefore, yeasts producing elevated levels of these isomers might have a superior alcohol tolerance and be able to produce higher levels of alcohol. This can be tested by comparing existing yeast strains differing in alcohol tolerance. Selection for MIs may become a strategy for isolating more resistant yeast and Lactobacillus strains, which can be of interest for industrial alcohol production and quality improvements in bacterially fermented foods such as kimchi.
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http://dx.doi.org/10.1111/j.1600-079X.2012.00979.xDOI Listing
September 2012

Melatonin protection from chronic, low-level ionizing radiation.

Mutat Res Rev Mutat Res 2012 July-September;751(1):7-14. Epub 2011 Dec 15.

Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, United States.

In the current survey, we summarize the published literature which supports the use of melatonin, an endogenously produced molecule, as a protective agent against chronic, low-level ionizing radiation. Under in vitro conditions, melatonin uniformly was found to protect cellular DNA and plasmid super coiled DNA from ionizing radiation damage due to Cs(137) or X-radiation exposure. Likewise, in an in vivo/in vitro study in which humans were given melatonin orally and then their blood lymphocytes were collected and exposed to Cs(137) ionizing radiation, nuclear DNA from the cells of those individuals who consumed melatonin (and had elevated blood levels) was less damaged than that from control individuals. In in vivo studies as well, melatonin given to animals prevented DNA and lipid damage (including limiting membrane rigidity) and reduced the percentage of animals that died when they had been exposed to Cs(137) or Co(60) radiation. Melatonin's ability to protect macromolecules from the damage inflicted by ionizing radiation likely stems from its high efficacy as a direct free radical scavenger and possibly also due to its ability to stimulate antioxidative enzymes. Melatonin is readily absorbed when taken orally or via any other route. Melatonin's ease of self administration and its virtual absence of toxicity or side effects, even when consumed over very long periods of time, are essential when large populations are exposed to lingering radioactive contamination such as occurs as a result of an inadvertent nuclear accident, an intentional nuclear explosion or the detonation of a radiological dispersion device, i.e., a "dirty" bomb.
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http://dx.doi.org/10.1016/j.mrrev.2011.12.002DOI Listing
December 2011

Melatonin: new applications in clinical and veterinary medicine, plant physiology and industry.

Neuro Endocrinol Lett 2011 ;32(5):575-87

Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, TX, USA.

Novel functions of melatonin continue to be uncovered. Those summarized in this report include actions at the level of the peripheral reproductive organs and include functions as an antioxidant to protect the maturing oocyte in the vesicular follicle and during ovulation, melatonin actions on the developing fetus particularly in relation to organizing the circadian system, its potential utility in combating the consequences of pre-eclampsia, reducing intrauterine growth restriction, suppressing endometriotic growths and improving the outcomes of in vitro fertilization/embryo transfer. The inhibitory effects of melatonin on many cancer types have been known for decades. Until recently, however, melatonin had not been tested as a protective agent against exocrine pancreatic tumors. This cancer type is highly aggressive and 5 year survival rate in individuals with pancreatic cancer is very low. Recent studies with melatonin indicate it may have utility in the treatment of these otherwise almost untreatable pancreatic cancers. The discovery of melatonin in plants has also opened a vast new field of research which is rapidly being exploited although the specific functions(s) of melatonin in plant organs remains enigmatic. Finally, the described application of melatonin's use as a chemical reductant in industry could well serve as a stimulus to further define the utility of this versatile molecule in new industrial applications.
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March 2012

Alzheimer's disease: pathological mechanisms and the beneficial role of melatonin.

J Pineal Res 2012 Mar 23;52(2):167-202. Epub 2011 Nov 23.

Centro de Investigación Biomédica de Occidente del Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, México.

Alzheimer's disease (AD) is a highly complex neurodegenerative disorder of the aged that has multiple factors which contribute to its etiology in terms of initiation and progression. This review summarizes these diverse aspects of this form of dementia. Several hypotheses, often with overlapping features, have been formulated to explain this debilitating condition. Perhaps the best-known hypothesis to explain AD is that which involves the role of the accumulation of amyloid-β peptide in the brain. Other theories that have been invoked to explain AD and summarized in this review include the cholinergic hypothesis, the role of neuroinflammation, the calcium hypothesis, the insulin resistance hypothesis, and the association of AD with peroxidation of brain lipids. In addition to summarizing each of the theories that have been used to explain the structural neural changes and the pathophysiology of AD, the potential role of melatonin in influencing each of the theoretical processes involved is discussed. Melatonin is an endogenously produced and multifunctioning molecule that could theoretically intervene at any of a number of sites to abate the changes associated with the development of AD. Production of this indoleamine diminishes with increasing age, coincident with the onset of AD. In addition to its potent antioxidant and anti-inflammatory activities, melatonin has a multitude of other functions that could assist in explaining each of the hypotheses summarized above. The intent of this review is to stimulate interest in melatonin as a potentially useful agent in attenuating and/or delaying AD.
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http://dx.doi.org/10.1111/j.1600-079X.2011.00937.xDOI Listing
March 2012

Glucose: a vital toxin and potential utility of melatonin in protecting against the diabetic state.

Mol Cell Endocrinol 2012 Feb 4;349(2):128-37. Epub 2011 Nov 4.

Department of Physiology, School of Medicine, Gulhane Military Medical Academy, Ankara, Turkey.

The molecular mechanisms including elevated oxidative and nitrosative reactants, activation of pro-inflammatory transcription factors and subsequent inflammation appear as a unified pathway leading to metabolic deterioration resulting from hyperglycemia, dyslipidemia, and insulin resistance. Consistent evidence reveals that chronically-elevated blood glucose initiates a harmful series of processes in which toxic reactive species play crucial roles. As a consequence, the resulting nitro-oxidative stress harms virtually all biomolecules including lipids, proteins and DNA leading to severely compromised metabolic activity. Melatonin is a multifunctional indoleamine which counteracts several pathophysiologic steps and displays significant beneficial effects against hyperglycemia-induced cellular toxicity. Melatonin has the capability of scavenging both oxygen and nitrogen-based reactants and blocking transcriptional factors which induce pro-inflammatory cytokines. These functions contribute to melatonin's antioxidative, anti-inflammatory and possibly epigenetic regulatory properties. Additionally, melatonin restores adipocyte glucose transporter-4 loss and eases the effects of insulin resistance associated with the type 2 diabetic state and may also assist in the regulation of body weight in these patients. Current knowledge suggests the clinical use of this non-toxic indoleamine in conjunction with other treatments for inhibition of the negative consequences of hyperglycemia for reducing insulin resistance and for regulating the diabetic state.
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http://dx.doi.org/10.1016/j.mce.2011.10.013DOI Listing
February 2012

Functional roles of melatonin in plants, and perspectives in nutritional and agricultural science.

J Exp Bot 2012 Jan 20;63(2):577-97. Epub 2011 Oct 20.

Department of Cellular and Structural Biology, The University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl, San Antonio, TX 78229, USA.

The presence of melatonin in plants is universal. Evidence has confirmed that a major portion of the melatonin is synthesized by plants themselves even though a homologue of the classic arylalkylamine N-acetyltransferase (AANAT) has not been identified as yet in plants. Thus, the serotonin N-acetylating enzyme in plants may differ greatly from the animal AANAT with regard to sequence and structure. This would imply multiple evolutionary origins of enzymes with these catalytic properties. A primary function of melatonin in plants is to serve as the first line of defence against internal and environmental oxidative stressors. The much higher melatonin levels in plants compared with those found in animals are thought to be a compensatory response by plants which lack means of mobility, unlike animals, as a means of coping with harsh environments. Importantly, remarkably high melatonin concentrations have been measured in popular beverages (coffee, tea, wine, and beer) and crops (corn, rice, wheat, barley, and oats). Billions of people worldwide consume these products daily. The beneficial effects of melatonin on human health derived from the consumption of these products must be considered. Evidence also indicates that melatonin has an ability to increase the production of crops. The mechanisms may involve the roles of melatonin in preservation of chlorophyll, promotion of photosynthesis, and stimulation of root development. Transgenic plants with enhanced melatonin content could probably lead to breakthroughs to increase crop production in agriculture and to improve the general health of humans.
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http://dx.doi.org/10.1093/jxb/err256DOI Listing
January 2012

Functional aspects of redox control during neuroinflammation.

Antioxid Redox Signal 2010 Jul;13(2):193-247

Lab. Desarrollo-Envejecimiento, Enfermedades Neurodegenerativas, División de Neurociencias, Centro de Investigación Biomédica de Occidente (CIBO) del Instituto Mexicano del Seguro Social (IMSS) , Guadalajara, Jalisco. Mexico.

Neuroinflammation is a CNS reaction to injury in which some severe pathologies, regardless of their origin, converge. The phenomenon emphasizes crosstalk between neurons and glia and reveals a complex interaction with oxidizing agents through redox sensors localized in enzymes, receptors, and transcription factors. When oxidizing pressures cause reversible molecular changes, such as minimal or transitory proinflammatory cytokine overproduction, redox couples provide a means of translating the presence of reactive oxygen or nitrogen species into useful signals in the cell. Additionally, thiol-based redox sensors convey information about localized changes in redox potential induced by physiologic or pathologic situations. They are susceptible to oxidative changes and become key events during neuroinflammation, altering the course of a signaling response or the behavior of specific transcription factors. When oxidative stress augments the pressure on the intracellular environment, the effective reduction potential of redox pairs diminishes, and cell signaling shifts toward proinflammatory and proapoptotic signals, creating a vicious cycle between oxidative stress and neuroinflammation. In addition, electrophilic compounds derived from the oxidative cascade react with key protein thiols and interfere with redox signaling. This article reviews the relevant functional aspects of redox control during the neuroinflammatory process.
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http://dx.doi.org/10.1089/ars.2009.2629DOI Listing
July 2010

Cellular and biochemical actions of melatonin which protect against free radicals: role in neurodegenerative disorders.

Curr Neuropharmacol 2008 Sep;6(3):203-14

Laboratorio de Desarrollo-Envejecimiento, Enfermedades Neurodegenerativas, División de Neurociencias, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social, IMSS, Sierra Mojada 800 C.P. 44340 Guadalajara, Jalisco, México.

Molecular oxygen is toxic for anaerobic organisms but it is also obvious that oxygen is poisonous to aerobic organisms as well, since oxygen plays an essential role for inducing molecular damage. Molecular oxygen is a triplet radical in its ground-stage (.O-O.) and has two unpaired electrons that can undergoes consecutive reductions of one electron and generates other more reactive forms of oxygen known as free radicals and reactive oxygen species. These reactants (including superoxide radicals, hydroxyl radicals) possess variable degrees of toxicity. Nitric oxide (NO*) contains one unpaired electron and is, therefore, a radical. NO* is generated in biological tissues by specific nitric oxide synthases and acts as an important biological signal. Excessive nitric oxide production, under pathological conditions, leads to detrimental effects of this molecule on tissues, which can be attributed to its diffusion-limited reaction with superoxide to form the powerful and toxic oxidant, peroxynitrite.Reactive oxygen and nitrogen species are molecular "renegades"; these highly unstable products tend to react rapidly with adjacent molecules, donating, abstracting, or even sharing their outer orbital electron(s). This reaction not only changes the target molecule, but often passes the unpaired electron along to the target, generating a second free radical, which can then go on to react with a new target amplifying their effects.This review describes the mechanisms of oxidative damage and its relationship with the most highly studied neurodegenerative diseases and the roles of melatonin as free radical scavenger and neurocytoskeletal protector.
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http://dx.doi.org/10.2174/157015908785777201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2687933PMC
September 2008

Critical ischemia time in a model of spinal cord section. A study performed on dogs.

Eur Spine J 2007 Apr 23;16(4):563-72. Epub 2006 Sep 23.

Instituto Mexicano del Seguro Social, Orthopaedics, Guadalajara, Jalisco, Mexico.

Vascular changes after acute spinal cord trauma are important factors that predispose quadriplegia, in most cases irreversible. Repair of the spinal blood flow helps the spinal cord recovery. The average time to arrive and perform surgery is 3 h in most cases. It is important to determine the critical ischemia time in order to offer better functional prognosis. A spinal cord section and vascular clamping of the spinal anterior artery at C5-C6 model was used to determine critical ischemia time. The objective was to establish a critical ischemia time in a model of acute spinal cord section. Four groups of dogs were used, anterior approach and vascular clamp of spinal anterior artery with 1, 2, 3, and 4 h of ischemia and posterior hemisection of spinal cord at C5-C6 was performed. Clinical evaluation was made during 12 weeks and morphological evaluation at the end of this period. We obtained a maximal neurological coordination at 23 days average. Two cases showed sequels of right upper limb paresis at 1 and 3 ischemia hours. There was nerve conduction delay of 56% at 3 h of ischemia. Morphological examination showed 25% of damaged area. The VIII and IX Rexed's laminae were the most affected. The critical ischemia time was 3 h. Dogs with 4 h did not exhibit any recovery.
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http://dx.doi.org/10.1007/s00586-006-0222-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2229824PMC
April 2007

Kinetics of the neuroinflammation-oxidative stress correlation in rat brain following the injection of fibrillar amyloid-beta onto the hippocampus in vivo.

J Neuroimmunol 2004 May;150(1-2):20-8

Centro de Investigación Biomédica de Occidente del Instituto Mexicano del Seguro Social, Sierra Mojada 800, Colonia Independencia, CP 44340 Guadalajara, Jalisco, Mexico.

The purpose of this study was to describe-following the injection of a single intracerebral dose of fibrillar amyloid-beta(1-40) in vivo-some correlations between proinflammatory cytokines and oxidative stress indicators in function of time, as well as how these variables fit in a regression model. We found a positive, significant correlation between interleukin (IL)-1beta or IL-6 and the activity of the glutathione peroxidase enzyme (GSH-Px), but IL-1beta or IL-6 maintained a strong, negative correlation with the lipid peroxidation (LPO). The first 12 h marked a positive correlation between IL-6 and tumor necrosis factor-alpha (TNF-alpha), but starting from the 36 h, this relationship became negative. We found also particular patterns of behavior through the time for IL-1beta, nitrites and IL-6, with parallel or sequential interrelationships. Results shows clearly that, in vivo, the fibrillar amyloid-beta (Abeta) disrupts the oxidative balance and initiate a proinflammatory response, which in turn feeds the oxidative imbalance in a coordinated, sequential way. This work contributes to our understanding of the positive feedbacks, focusing the "cytokine cycle" along with the oxidative stress mediators in a complex, multicellular, and interactive environment.
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http://dx.doi.org/10.1016/j.jneuroim.2004.01.005DOI Listing
May 2004