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Dun-Xian Tan

Publications and source records attributed to Dun-Xian Tan.

At least 19 recordsLinked to original sources
PubMed2006

Inhibition of neuronal nitric oxide synthase activity by N1-acetyl-5-methoxykynuramine, a brain metabolite of melatonin.

We assessed the effects of melatonin, N(1)-acetyl-N (2)-formyl-5-methoxykynuramine (AFMK) and N(1)-acetyl-5-methoxykynuramine (AMK) on neuronal nitric oxide synthase (nNOS) activity in vitro and in rat striatum in vivo. Melatonin and AMK (10(-11)-10(-3) m), but not AFMK, inhibited nNOS activity in vitro in a dose-response manner. The IC(50) value for AMK (70 microm) was significantly lower than for melatonin (>1 mm). A 20% nNOS inhibition was reached with either 10(-9) m melatonin or 10(-11) m AMK. AMK inhibits nNOS by a non-competitive mechanism through its binding to Ca(2+)-calmodulin (CaCaM). The inhibition of nNOS elicited by melatonin, but not by AMK, was blocked with 0.05 mm norharmane, an indoleamine-2,3-dioxygenase inhibitor. In vivo, the potency of AMK to inhibit nNOS activity was higher than that of melatonin, as a 25% reduction in rat striatal nNOS activity was found after the administration of either 10 mg/kg of AMK or 20 mg/kg of melatonin. Also, in vivo, the administration of norharmane blocked the inhibition of nNOS produced by melatonin administration, but not the inhibition produced by AMK. These data reveal that AMK rather than melatonin is the active metabolite against nNOS, which may be inhibited by physiological levels of AMK in the rat striatum.

Animals↗
PubMed2006

Protective effects of melatonin in experimental free radical-related ocular diseases.

Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine with a range of antioxidative properties. Melatonin is endogenously produced in the eye and in other organs. Current evidence suggests that melatonin may act as a protective agent in ocular conditions such as photo-keratitis, cataract, glaucoma, retinopathy of prematurity and ischemia/reperfusion injury. These diseases are sight-threatening and they currently remain, for the most part, untreatable. The pathogenesis of these conditions is not entirely clear but oxidative stress has been proposed as one of the causative factors. Elevated levels of various reactive oxygen and nitrogen species have been identified in diseased ocular structures. These reactants damage the structure and deplete the eye of natural defense systems, such as the antioxidant, reduced glutathione, and the antioxidant enzyme superoxide dismutase. Oxidative damage in the eye leads to apoptotic degeneration of retinal neurons and fluid accumulation. Retinal degeneration decreases visual sensitivity and even a small change in the fluid content of the cornea and crystalline lens is sufficient to disrupt ocular transparency. In the eye, melatonin is produced in the retina and in the ciliary body. Continuous regeneration of melatonin in the eye offers a frontier antioxidative defense for both the anterior and posterior eye. However, melatonin production is minimal in newborns and its production gradually wanes in aging individuals as indicated by the large drop in circulating blood concentrations of the indoleamine. These individuals are possibly at risk of contracting degenerative eye diseases that are free radical-based. Supplementation with melatonin, a potent antioxidant, in especially the aged population should be considered as a prophylaxis to preserve visual functions. It may benefit many individuals worldwide, especially in countries where access to medical facilities is limited.

Antioxidants↗
PubMed2006

Inhibitory effect of melatonin on diquat-induced lipid peroxidation in vivo as assessed by the measurement of F2-isoprostanes.

Melatonin is a powerful antioxidant and free radical scavenger. A large body of in vivo and in vitro evidence shows that melatonin effectively inhibits membrane lipid peroxidation; this damage was based on the measurement of malondialdehyde and/or 4-hydroxynonenal levels. In the current study, for the first time using a more sensitive and specific biomarker, i.e. F2-isoprostanes, we investigate the effect of melatonin on diquat-induced lipid peroxidation in Fischer 344 rats. When diquat (40 mg/kg body weight) was intraperitoneally injected into rats, the levels of liver F2-isoprostanes were significantly increased at 1, 3, and 6 hr while plasma free F2-isoprostanes concentrations were augmented at 3, 6, and 12 hr after administration of the toxin. In addition, the plasma alanine aminotransferase activity level was measured as a parameter of hepatoxicity; the activity of this enzyme was augmented at 3, 6, and 12 hr after diquat administration when compared with levels of this constituent in untreated control rats. Pretreatment with melatonin (20 mg/kg) 30 min before diquat administration resulted in a significant reduction in both tissue and plasma F2-isoprostanes levels, and plasma alanine aminotransferase activity. These findings, using a sensitive and specific index of lipid peroxidation, show that the hepatoxicity of diquat, at least partially, is a consequence of reactive oxygen species-induced lipid damage. Melatonin's protective effects likely relate to its direct free radical scavenging ability and/or due to other antioxidative processes induced by the indole.

Alanine Transaminase↗
PubMed2006

Urinary metabolites and antioxidant products of exogenous melatonin in the mouse.

Exogenous melatonin is widely used for sleep disorders and has potential value in neuroprotection, cardioprotection and as an antioxidant. Here, a novel method is described for the determination of melatonin and six metabolites in mouse urine by use of LC-MS/MS and GC-MS. LC-MS/MS is used for the measurement of melatonin, N1-acetyl-5-methoxykynuramine (AMK), N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and 6-hydroxymelatonin (6-HMEL), while GC/MS is used for the determination of N-[2-(5-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-ethyl]-acetamide (2-OMEL) and cyclic 3-hydroxymelatonin (3-HMEL) with detection limits on column of 0.02-0.5 pmol, depending on the metabolite. Following oral administration of melatonin to mice, a 0-24 hr urine collection revealed the presence of melatonin (0.2% dose), 6-HMEL (37.1%) and NAS (3.1%) comprising >90% of the total metabolites; AMK and AFMK were also detected at 0.01% each; 2-OMEL was found at 2.2% of the dose, which is >100 times more than the AMK/AFMK pathway, and comprises >5% of the melatonin-related material detected in mouse urine. 3-HMEL was largely found as a sulfate conjugate. These studies establish sensitive assays for determination of six melatonin metabolites in mouse urine and confirm the potential for antioxidant activity of melatonin through the identification in vivo of AMK and AFMK, ring-opened metabolites with a high capacity for scavenging reactive oxygen species.

Animals↗
PubMed2005

Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages.

Inflammation is a complex phenomenon involving multiple cellular and molecular interactions which must be tightly regulated. Cyclooxygenase-2 (COX) is the key enzyme that catalyzes the two sequential steps in the biosynthesis of PGs from arachidonic acid. The inducible isoform of COX, namely COX-2, plays a critical role in the inflammatory response and its over-expression has been associated with several pathologies including neurodegenerative diseases and cancer. Melatonin is the main product of the pineal gland with well documented antioxidant and immuno-modulatory effects. Since the action of the indole on COX-2 has not been previously described, the goal of the present report was to test the effect of melatonin on the activities of COX-2 and inducible nitric oxide synthase (iNOS), using lipopolysaccharide (LPS)-activated RAW 264.7 macrophages as a model. Melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), prevented COX-2 activation induced by LPS, without affecting COX-1 protein levels. The structurally related compound 6-methoxy-melatonin only partially prevented the increase in COX-2 protein levels induced by the toxin. Likewise melatonin prevented iNOS activation and reduced the concentration of products from both enzymes, PGE(2) and nitric oxide. Another endogenous antioxidant like N-acetyl-cysteine (NAC) did not reduced COX-2 significantly. The current finding corroborates a role of melatonin as an anti-inflammatory agent and, for the first time, COX-2 and iNOS as molecular targets for either melatonin or its metabolites AFMK and AMK. These anti-inflammatory actions seem not to be exclusively mediated by the free radical scavenging properties of melatonin. As a consequence, the present work suggests these substances as a new class of potential anti-inflammatory agents without the classical side effects due to COX-1 inhibition.

Animals↗
PubMed2005

Melatonin mitigates mitochondrial malfunction.

Melatonin, or N-acetyl-5-methoxytryptamine, is a compound derived from tryptophan that is found in all organisms from unicells to vertebrates. This indoleamine may act as a protective agent in disease conditions such as Parkinson's, Alzheimer's, aging, sepsis and other disorders including ischemia/reperfusion. In addition, melatonin has been proposed as a drug for the treatment of cancer. These disorders have in common a dysfunction of the apoptotic program. Thus, while defects which reduce apoptotic processes can exaggerate cancer, neurodegenerative disorders and ischemic conditions are made worse by enhanced apoptosis. The mechanism by which melatonin controls cell death is not entirely known. Recently, mitochondria, which are implicated in the intrinsic pathway of apoptosis, have been identified as a target for melatonin actions. It is known that melatonin scavenges oxygen and nitrogen-based reactants generated in mitochondria. This limits the loss of the intramitochondrial glutathione and lowers mitochondrial protein damage, improving electron transport chain (ETC) activity and reducing mtDNA damage. Melatonin also increases the activity of the complex I and complex IV of the ETC, thereby improving mitochondrial respiration and increasing ATP synthesis under normal and stressful conditions. These effects reflect the ability of melatonin to reduce the harmful reduction in the mitochondrial membrane potential that may trigger mitochondrial transition pore (MTP) opening and the apoptotic cascade. In addition, a reported direct action of melatonin in the control of currents through the MTP opens a new perspective in the understanding of the regulation of apoptotic cell death by the indoleamine.

Animals↗
PubMed2005

Interactions between melatonin and nicotinamide nucleotide: NADH preservation in cells and in cell-free systems by melatonin.

Interactions of melatonin and nicotinamide adenine dinucleotide (NADH) have been studied in different experimental models including NADH-promoted oxyhemoglobin oxidation, vanadate-induced NADH oxidation and paraquat-induced NADH depletion in cultured PC12 cells. Our findings indicate that melatonin preserves NADH levels under oxidative stress both in cell-free systems and in cultured PC12 cells. These interactions likely involve electron donation by melatonin and reduction of the NAD radical. As a result, the NAD radical is recycled to NADH and melatonin is oxidized to N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK). NADH is a central molecule at the crossroads between energy metabolism and the antioxidant defense system in organisms. Recycling of NADH by melatonin might improve the efficiency of NADH as an energy carrier and as an antioxidant. Interactions between melatonin and NADH may be implicated in mitochondrial metabolism.

Animals↗
PubMed2005

When melatonin gets on your nerves: its beneficial actions in experimental models of stroke.

This article summarizes the evidence that endogenously produced and exogenously administered melatonin reduces the degree of tissue damage and limits the biobehavioral deficits associated with experimental models of ischemia/reperfusion injury in the brain (i.e., stroke). Melatonin's efficacy in curtailing neural damage under conditions of transitory interruption of the blood supply to the brain has been documented in models of both focal and global ischemia. In these studies many indices have been shown to be improved as a consequence of melatonin treatment. For example, when given at the time of ischemia or reperfusion onset, melatonin reduces neurophysiological deficits, infarct volume, the degree of neural edema, lipid peroxidation, protein carbonyls, DNA damage, neuron and glial loss, and death of the animals. Melatonin's protective actions against these adverse changes are believed to stem from its direct free radical scavenging and indirect antioxidant activities, possibly from its ability to limit free radical generation at the mitochondrial level and because of yet-undefined functions. Considering its high efficacy in overcoming much of the damage associated with ischemia/reperfusion injury, not only in the brain but in other organs as well, its use in clinical trials for the purpose of improving stroke outcome should be seriously considered.

Animals↗
PubMed2005

Physiological ischemia/reperfusion phenomena and their relation to endogenous melatonin production: a hypothesis.

Ischemia/reperfusion is a frequently encountered phenomenon in organisms. Prolonged ischemia followed then by reperfusion results in severe oxidative injury in tissues and organs; however, some species can tolerate such events better than others. In nature, arousal from hibernation and resurfacing from diving causes animals to experience classic ischemia/reperfusion and, somehow, these animals cope well with the potential oxidative stress. It has been documented that during these physiological ischemia/reperfusion events, the activities of several antioxidant enzymes and the levels of some small-molecular-weight antioxidants become elevated. For example, the potent small-molecular-weight antioxidant melatonin often attains especially high levels during these physiological ischemia/reperfusion events including during arousal from hibernation or in the newborns during delivery. Highly elevated melatonin production during these physiological ischemia/reperfusion episodes exhibits several features. First, this high melatonin production is transient and fits well with the time schedule of the physiological ischemia/reperfusion period; therefore, it is not related to the normal endogenous melatonin rhythm. Yet, this transient peak protects the animals from destructive oxidative processes that occur during these transition periods. Second, these high levels of melatonin seem to derive from several organs since pinealectomy does not totally reduce circulating levels of this agent. Third, high melatonin production present at arousal from hibernation or in the newborns at birth does not appear to be controlled by light, i.e., it occurs both during the day and at night, and the amplitudes of elevated melatonin levels are equivalent at these times. The significance of these findings is discussed herein. Based on currently available data, we hypothesize that melatonin plays an important role in the physiological ischemia/reperfusion, i.e., as a member of antioxidant defense system, to protect against the potential oxidative injury induced by the physiological ischemia/reperfusion.

Animals↗
PubMed2005

Melatonin and Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. It is characterized by a progressive loss of dopamine in the substantia nigra and striatum. However, over 70% of dopaminergic neuronal death occurs before the first symptoms appear, which makes either early diagnosis or effective treatments extremely difficult. Only symptomatic therapies have been used, including levodopa (l-dopa), to restore dopamine content; however, the use of l-dopa leads to some long-term pro-oxidant damage. In addition to a few specific mutations, oxidative stress and generation of free radicals from both mitochondrial impairment and dopamine metabolism are considered to play critical roles in PD etiology. Thus, the use of antioxidants as an important co-treatment with traditional therapies for PD has been suggested. Melatonin, or N-acetyl-5-methoxy-tryptamine, an indole mainly produced in the pineal gland, has been shown to have potent endogenous antioxidant actions. Because neurodegenerative disorders are mainly caused by oxidative damage, melatonin has been tested successfully in both in vivo and in vitro models of PD. The present review provides an up-to-date account of the findings and mechanisms involved in neuroprotection of melatonin in PD.

Animals↗
PubMed2004

Melatonin and mitochondrial function.

Melatonin is a natural occurring compound with well-known antioxidant properties. In the last decade a new effect of melatonin on mitochondrial homeostasis has been discovered and, although the exact molecular mechanism for this effect remains unknown, it may explain, at least in part, the protective properties found for the indoleamine in degenerative conditions such as aging as well as Parkinson's disease, Alzheimer's disease, epilepsy, sepsis and other injuries such as ischemia-reperfusion. A common feature in these diseases is the existence of mitochondrial damage due to oxidative stress, which may lead to a decrease in the activities of mitochondrial complexes and ATP production, and, as a consequence, a further increase in free radical generation. A vicious cycle thus results under these conditions of oxidative stress with the final consequence being cell death by necrosis or apoptosis. Melatonin is able of directly scavenging a variety of toxic oxygen and nitrogen-based reactants, stimulates antioxidative enzymes, increases the efficiency of the electron transport chain thereby limiting electron leakage and free radical generation, and promotes ATP synthesis. Via these actions, melatonin preserves the integrity of the mitochondria and helps to maintain cell functions and survival.

Animals↗
PubMed2004

Melatonin as a radioprotective agent: a review.

Melatonin (N-acetyl-5-methoxytryptamine), the chief secretory product of the pineal gland in the brain, is well known for its functional versatility. In hundreds of investigations, melatonin has been documented as a direct free radical scavenger and an indirect antioxidant, as well as an important immunomodulatory agent. The radical scavenging ability of melatonin is believed to work via electron donation to detoxify a variety of reactive oxygen and nitrogen species, including the highly toxic hydroxyl radical. It has long been recognized that the damaging effects of ionizing radiation are brought about by both direct and indirect mechanisms. The direct action produces disruption of sensitive molecules in the cells, whereas the indirect effects ( approximately 70%) result from its interaction with water molecules, which results in the production of highly reactive free radicals such as *OH, *H, and e(aq)- and their subsequent action on subcellular structures. The hydroxyl radical scavenging ability of melatonin was used as a rationale to determine its radioprotective efficiency. Indeed, the results from many in vitro and in vivo investigations have confirmed that melatonin protects mammalian cells from the toxic effects of ionizing radiation. Furthermore, several clinical reports indicate that melatonin administration, either alone or in combination with traditional radiotherapy, results in a favorable efficacy:toxicity ratio during the treatment of human cancers. This article reviews the literature from laboratory investigations that document the ability of melatonin to scavenge a variety of free radicals (including the hydroxyl radical induced by ionizing radiation) and summarizes the evidence that should be used to design larger translational research-based clinical trials using melatonin as a radioprotector and also in cancer radiotherapy. The potential use of melatonin for protecting individuals from radiation terrorism is also considered.

Animals↗
PubMed2004

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

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.

Amyloid beta-Peptides↗
PubMed2004

Melatonin relieves the neural oxidative burden that contributes to dementias.

This report summarizes some of the many publications that document the beneficial actions of melatonin within the central nervous system. Of particular interest are the multiple functions of melatonin and its metabolites as ubiquitously acting direct free radical scavengers and indirect antioxidants. The fact that melatonin and the metabolic progeny that are formed when it scavenges toxic reactants are all effective in neutralizing destructive molecules greatly increases the efficacy of melatonin as a protection against by-products of oxygen and nitrogen that normally mutilate essential molecules. Of the large number of situations in which oxidative stress may be the cause of disease processes or debilitating conditions, the current review examines melatonin's protection within the central nervous system, particularly in experimental ischemia/reperfusion (stroke) injury, Alzheimer's disease, and parkinsonism. In each of these conditions, melatonin has been found to provide significant neural protection against both the morphophysiological damage and the biobehavioral consequences of these infirmities. The report concludes with the suggestion that melatonin, alone or in combination with other antioxidants, be considered for routine usage to potentially combat some of the neural ravages of aging.

Animals↗
PubMed2003

Melatonin-induced neuroprotection after closed head injury is associated with increased brain antioxidants and attenuated late-phase activation of NF-kappaB and AP-1.

Traumatic brain injury (TBI) is followed by massive production of reactive oxygen species (ROS), which mediate secondary cellular damage. Low molecular weight antioxidants (LMWA) constitute one of the defense mechanisms of the brain, and their levels correlate with post-TBI outcome. Melatonin, the main pineal hormone, possesses antioxidant properties. We investigated the effects of melatonin on neurobehavioral recovery, brain LMWA, and activation of the redox-sensitive transcription factors nuclear factor-kappaB (NF-kappaB) and AP-1 in mice subjected to closed head injury (CHI). Given 1 h after CHI, melatonin facilitated recovery during at least 1 wk (P<0.05) and decreased lesion size by approximately twofold (P<0.01). The dose response displayed a bell-shape, i.e., neuroprotection was achieved with 5 but not 1 or 10 mg/kg. At the neuroprotective dose, melatonin treatment was associated with sustained (4 days) elevation of brain LMWA, including ascorbic acid (P<0.05). In contrast, LMWA were unaffected by the administration of the neuroprotective endocannabinoid 2-arachidonoyl glycerol. Furthermore, melatonin did not alter early phase (24 h) CHI-induced activation of NF-kappaB and AP-1; however, it blocked the robust late-phase (8 days) activation of NF-kappaB and decreased that of AP-1 to below basal levels. Our results demonstrate that melatonin induces neuroprotection, presumably via potentiation of brain antioxidants and attenuation of NF-kappaB and AP-1 activation.

Animals↗