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D X Tan

Publications and source records attributed to D X Tan.

70 records · Page 4Linked to original sources
PubMed1993

[Ca(2+)+Mg2+]-dependent ATPase activity in rat pineal gland.

[Ca(2+)+Mg2+]-dependent ATPase activity in the pineal gland of the rat was examined. The enzyme possesses an apparent Km (Ca2+) of 0.23 microM, and moderately high affinity for Mg2+ and ATP (Km = 53.2 microM and Km = 86.4 microM, respectively). The ATPase activity is sensitive to low concentrations (I50 approximately 1 microM) of vanadate, which specifically inhibits Ca(2+)-ATPase in the plasma membranes of the erythrocyte, cardiomyocytes and synapses. The calmodulin antagonist trifluoperazine reduced significantly Ca(2+)-stimulated, Mg(2+)-dependent ATP hydrolysis. The [Ca(2+)+Mg2+]-dependent ATPase in rat pineal gland exhibits very high affinity for Ca2+, is highly vanadate sensitive and appears to require calmodulin. The enzyme is similar to the Ca(2+)-ATPase of the erythrocyte, cardiomyocytes and synaptic plasma membranes. These new findings may help to elucidate the mechanisms of intracellular calcium homeostasis and the effect of the enzyme on the synthesis of melatonin in the pineal gland.

Adenosine Triphosphate↗
PubMed1993

The pineal hormone melatonin inhibits DNA-adduct formation induced by the chemical carcinogen safrole in vivo.

Melatonin inhibits DNA-adduct formation induced by the chemical carcinogen safrole in a dose-dependent manner. Total DNA-adduct formation after in vivo administration of 300 mg/kg safrole measured by 32P-postlabeling analysis of carcinogen-modified DNA in rat liver was 36,751 +/- 2290 counts/min/10 micrograms DNA. Coadministration of 300 mg/kg safrole with either 0.2 mg/kg (low dose) or 0.4 mg/kg (high dose) melatonin reduced DNA-adduct formation induced by safrole to 22,182 +/- 987 counts/min/10 micrograms DNA and 462 +/- 283 counts/min/10 micrograms DNA, respectively. Circulating melatonin concentrations at the termination of the study in safrole, low melatonin and high melatonin groups were 50 +/- 8, 3140 +/- 430 and 10,040 +/- 2610 pg/ml serum, respectively. The results suggest that melatonin protects against safrole associated DNA damage.

Animals↗
PubMed1993

Reduction in pineal N-acetyltransferase activity and pineal and serum melatonin levels in rats after their exposure to red light at night.

Pineal gland N-acetyltransferase (NAT) activity and pineal and serum levels of melatonin declined linearly in albino rats exposed to different irradiances (low, 170 microW/cm2; moderate, 420 microW/cm2; high, 1040 microW/cm2) red light during the middle of the night. High intensity red light (1040 microW/cm2) was as effective as white light (670 microW/cm2) in suppressing pineal NAT activity and pineal and serum melatonin levels. The lowered melatonin levels and the reduction in NAT activity following exposure to red light suggest that red light cannot be regarded as 'safe' light when studying circadian melatonin production in the albino rat, at least at the intensities used in this experiment.

Animals↗
PubMed1993

Nuclear localization of melatonin in different mammalian tissues: immunocytochemical and radioimmunoassay evidence.

Melatonin was detected by an improved immunocytochemical technique in the cell nuclei of most tissues studied including several brain areas, pineal gland, Harderian gland, gut, liver, kidney, and spleen from rodents and primates. Cryostat sections from tissues fixed in Bouin's fluid, formalin, or acetone/ethanol were used. The nuclear staining appeared primarily associated with the chromatin. The nucleoli did not exhibit a positive reaction. The melatonin antiserum was used in the range of 1:500 to 1:5,000. Incubation of the antibody with an excess of melatonin resulted in the complete blockade of nuclear staining. Pretreatment of the sections with proteinase K (200-1,000 ng/ml) prevented the positive immunoreaction. In a second aspect of the study, we estimated the concentration of melatonin by means of radioimmunoassay in the nuclear fraction of several tissues including cerebral cortex, liver, and gut. The subcutaneous injection of melatonin (500 micrograms/kg) to rats resulted, after 30 min, in a rapid increase in the nuclear concentration of immunoreactive melatonin which varied in a tissue-dependent manner. However, samples collected 3 h after the injection showed that melatonin levels had decreased to control values. Pinealectomy in rats resulted in a clear reduction in the nuclear content of melatonin in the cerebral cortex and liver but not in the gut. The results of these studies suggest that melatonin may interact with nuclear proteins and that the indole may have an important function at the nuclear level in a variety of mammalian tissues.

Animals↗
PubMed1993

The significance of the metabolism of the neurohormone melatonin: antioxidative protection and formation of bioactive substances.

Recent findings suggest that the ability of melatonin to enter all body tissues and to be metabolized, enzymatically or nonenzymatically, in any of them results in a spectrum of effects, which exceed substantially those transduced by membrane receptors. These actions comprise the formation of various bioactive compounds such as N-acetylserotonin, 5-methoxytryptamine, N,N-dimethyl-5-methoxytryptamine, 5-methoxytryptophol, cyclic 2-hydroxymelatonin, pinoline, and 5-methoxylated kynuramines. Apart from enzymatic metabolism, nonenzymatic reactions with free radicals, in particular the superoxide anion and the hydroxyl radical, represent a new and significant aspect of melatonin's biological role. Melatonin represents the most potent physiological scavenger of hydroxyl radicals found to date, and recent findings suggest an essential role of this indoleamine for protection from hydroxyl radical-induced carcinogenesis and neurodegeneration.

Animals↗
PubMed1993

Unusual responses of nocturnal pineal melatonin synthesis and secretion to swimming: attempts to define mechanisms.

The effect of swimming at night on rat pineal melatonin synthesis was compared with that of light exposure at night. Rats were forced to swim at 0030 hr (lights out at 2000 hr) and sacrificed by decapitation 15 and 30 min later, immediately after swimming. Other groups of animals were exposed to white light (650 muW/cm2) for 15 and 30 min at same time. Swimming caused a rapid and highly significant drop in the melatonin content in the pineal gland; however, the activity of N-acetyltransferase (NAT), the supposed rate limiting enzyme in the melatonin production, was not changed. Despite the drop in pineal melatonin levels, serum concentrations of the indole remained elevated in the rats that swam. In contrast, melatonin levels in the pineal and serum of light exposed rats fell precipitously, accompanied by a significant suppression of NAT activity. Since we anticipated that the strenuous exercise associated with swimming may induce release of artrial natriuretic peptide (ANP) from the heart, which in turn could cause the release of pineal melatonin, in a second study we injected physiological saline intravenously to stretch the cardiac muscle and release ANP. Three milliliters of normal saline was injected during the day into the jugular vein of anesthetized rats that were pretreated with isoproterenol to stimulate pineal melatonin production. Animals were killed 15 min after the saline injection, and pineal NAT activity and pineal melatonin levels were measured. The saline injections caused no alteration in the elevated levels of either NAT or melatonin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Melatonin, hydroxyl radical-mediated oxidative damage, and aging: a hypothesis.

Melatonin is a very potent and efficient endogenous radical scavenger. The pineal indolamine reacts with the highly toxic hydroxyl radical and provides on-site protection against oxidative damage to biomolecules within every cellular compartment. Melatonin acts as a primary non-enzymatic antioxidative defense against the devastating actions of the extremely reactive hydroxyl radical. Melatonin and structurally related tryptophan metabolites are evolutionary conservative molecules principally involved in the prevention of oxidative stress in organisms as different as algae and rats. The rate of aging and the time of onset of age-related diseases in rodents can be retarded by the administration of melatonin or treatments that preserve the endogenous rhythm of melatonin formation. The release of excitatory amino acids such as glutamate enhances endogenous hydroxyl radical formation. The activation of central excitatory amino acid receptors suppress melatonin synthesis and is therefore accompanied by a reduced detoxification rate of hydroxyl radicals. Aged animals and humans are melatonin-deficient and more sensitive to oxidative stress. Experiments investigating the effects of endogenous excitatory amino acid antagonists and stimulants of melatonin biosynthesis such as magnesium may finally lead to novel therapeutic approaches for the prevention of degeneration and dysdifferentiation associated with diseases related to premature aging.

Aging↗
PubMed1993

In vivo and in vitro effects of the pineal gland and melatonin on [Ca(2+) + Mg2+]-dependent ATPase in cardiac sarcolemma.

The possible diurnal variation in cardiac [Ca(2+) + Mg2+]-dependent ATPase (Ca2+ pump) activity and the influence of pinealectomy and melatonin on this enzyme in rat heart have been studied. Lowest levels of cardiac sarcolemmal membrane [Ca(2+) + Mg2+]-dependent ATPase activity were measured in late afternoon in rats kept under a 14:10 light:dark cycle. Late in the dark phase the enzyme activity began to increase with the rise continuing until 0900, 3 hr after light onset. These time-dependent changes in [Ca(2+) + Mg2+]-dependent ATPase activity did not occur in either pinealectomized or light-exposed rats suggesting that melatonin, secreted from the pineal gland during the night, induces the change in [Ca(2+) + Mg2+]-dependent ATPase activity, In vitro studies in which cardiac tissue was incubated in the presence of melatonin over a wide range of doses showed that this indole stimulated the Ca2+ pump. The half-maximal effect of melatonin was observed at a melatonin concentration of 28 ng/ml. These findings suggest that the daily change in [Ca(2+) + Mg2+]-dependent ATPase activity in the sarcolemma of heart tissue is a result of the circadian rhythm in pineal melatonin production and secretion. These findings may be applicable to normal cardiac physiology.

Animals↗
PubMedDate not supplied

Actions of melatonin in the reduction of oxidative stress. A review.

Melatonin was discovered to be a direct free radical scavenger less than 10 years ago. Besides its ability to directly neutralize a number of free radicals and reactive oxygen and nitrogen species, it stimulates several antioxidative enzymes which increase its efficiency as an antioxidant. In terms of direct free radical scavenging, melatonin interacts with the highly toxic hydroxyl radical with a rate constant equivalent to that of other highly efficient hydroxyl radical scavengers. Additionally, melatonin reportedly neutralizes hydrogen peroxide, singlet oxygen, peroxynitrite anion, nitric oxide and hypochlorous acid. The following antioxidative enzymes are also stimulated by melatonin: superoxide dismutase, glutathione peroxidase and glutathione reductase. Melatonin has been widely used as a protective agent against a wide variety of processes and agents that damage tissues via free radical mechanisms.

Animals↗
PubMedDate not supplied

Inhibitory effect of melatonin on products of lipid peroxidation resulting from chronic ethanol administration.

Despite decades of research, the role of free radicals in alcohol-induced organ injury is still a matter of debate. The present work was designed to investigate the potential protective effect of melatonin, a reported radical scavenger and antioxidant, on free radical toxicity induced by chronic ethanol administration. The major end-point of oxidative damage measured in this report was lipid peroxidation. Four groups of male Sprague-Dawley rats were used. The first group served as untreated controls and received a daily injection of alcoholic (<1% ethanol) saline. The second group of rats received daily at 18:00 a single subcutaneous injection of melatonin (10 mg/kg). Group 3 rats received only ethanol (3 g/kg) for 30 consecutive days; the ethanol was given at 18:30. The final group of rats was given both melatonin and ethanol with melatonin preceding ethanol by 30 min. Products of lipid peroxidation [malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA)] were measured in the brain, heart, liver, lung and testes. At the conclusion of the study, MDA + 4-HDA levels were significantly increased in brains, hearts, lungs and testes, but not livers, of alcohol-treated compared with control rats. The percentage increases in lipid peroxidation products were 21.8%, 28.8%, 35.9% and 45.3% for brain, heart, lung and testes, respectively. In animals given melatonin 30 min before ethanol, the increases in MDA + 4-HDA levels were significantly reduced in all organs investigated, with levels not different from those in control rats. Based on these findings, it is speculated that melatonin's direct and indirect antioxidative actions inhibited alcohol-induced lipid peroxidation. These results suggest a new strategy for the treatment of alcohol-related diseases using melatonin as an antioxidant to reduce the damage inflicted by aggressive radical species.

Alcoholism↗
PubMedDate not supplied

The oxidant/antioxidant network: role of melatonin.

Melatonin is now known to be a multifaceted free radical scavenger and antioxidant. It detoxifies a variety of free radicals and reactive oxygen intermediates including the hydroxyl radical, peroxynitrite anion, singlet oxygen and nitric oxide. Additionally, it reportedly stimulates several antioxidative enzymes including glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase and superoxide dismutase; conversely, it inhibits a prooxidative enzyme, nitric oxide synthase. Melatonin also crosses all morphophysiological barriers, e.g., the blood-brain barrier, placenta, and distributes throughout the cell; these features increase the efficacy of melatonin as an antioxidant. Melatonin has been shown to markedly protect both membrane lipids and nuclear DNA from oxidative damage. In every experimental model in which melatonin has been tested, it has been found to resist macromolecular damage and the associated dysfunction associated with free radicals.

Animals↗
PubMedDate not supplied

Cyclic 3-hydroxymelatonin: a melatonin metabolite generated as a result of hydroxyl radical scavenging.

The pineal secretory product, melatonin, is a potent, endogenous hydroxyl radical (HO.) scavenger. When melatonin was incubated in different in vitro cell-free HO.-generating systems, a novel melatonin adduct was formed. The molecular weight of this new compound is 248. Its structure was found to be cyclic 3-hydroxymelatonin (3-OHM). A proposed reaction pathway suggests that 3-OHM is the footprint product of the interaction between melatonin with HO. 3-OHM was also detected in the urine of both rats and humans. This urinary metabolite is identical to the compound generated in the in vitro chemical reaction between HO. and melatonin. This provides direct evidence that melatonin, under physiological conditions, functions as an antioxidant to detoxify the most reactive and cytotoxic endogenous HO. When exogenous melatonin was administered to young rats, urinary 3-OHM levels increased significantly in the treated rats compared to those in controls. This indicates that even in young animals there is insufficient endogenously produced melatonin to detoxify the basal levels of the toxic HO. The accumulated damage induced by the escaped HO. that results when the HO. avoids detoxification over the course of a life time may directly or indirectly accelerate aging and aging-related diseases.

Aging↗
PubMedDate not supplied

Significance of melatonin in antioxidative defense system: reactions and products.

Melatonin is a potent endogenous free radical scavenger, actions that are independent of its many receptor-mediated effects. In the last several years, hundreds of publications have confirmed that melatonin is a broad-spectrum antioxidant. Melatonin has been reported to scavenge hydrogen peroxide (H(2)O(2)), hydroxyl radical (HO(.)), nitric oxide (NO(.)), peroxynitrite anion (ONOO(-)), hypochlorous acid (HOCl), singlet oxygen ((1)O(2)), superoxide anion (O(2)(-).) and peroxyl radical (LOO(.)), although the validity of its ability to scavenge O(2)(-). and LOO(.) is debatable. Regardless of the radicals scavenged, melatonin prevents oxidative damage at the level of cells, tissues, organs and organisms. The antioxidative mechanisms of melatonin seem different from classical antioxidants such as vitamin C, vitamin E and glutathione. As electron donors, classical antioxidants undergo redox cycling; thus, they have the potential to promote oxidation as well as prevent it. Melatonin, as an electron-rich molecule, may interact with free radicals via an additive reaction to form several stable end-products which are excreted in the urine. Melatonin does not undergo redox cycling and, thus, does not promote oxidation as shown under a variety of experimental conditions. From this point of view, melatonin can be considered a suicidal or terminal antioxidant which distinguishes it from the opportunistic antioxidants. Interestingly, the ability of melatonin to scavenge free radicals is not in a ratio of mole to mole. Indeed, one melatonin molecule scavenges two HO. Also, its secondary and tertiary metabolites, for example, N(1)-acetyl-N(2)-formyl-5-methoxykynuramine, N-acetyl-5-methoxykynuramine and 6-hydroxymelatonin, which are believed to be generated when melatonin interacts with free radicals, are also regarded as effective free radical scavengers. The continuous free radical scavenging potential of the original molecule (melatonin) and its metabolites may be defined as a scavenging cascade reaction. Melatonin also synergizes with vitamin C, vitamin E and glutathione in the scavenging of free radicals. Melatonin has been detected in vegetables, fruits and a variety of herbs. In some plants, especially in flowers and seeds (the reproductive organs which are most vulnerable to oxidative insults), melatonin concentrations are several orders of magnitude higher than measured in the blood of vertebrates. Melatonin in plants not only provides an alternative exogenous source of melatonin for herbivores but also suggests that melatonin may be an important antioxidant in plants which protects them from a hostile environment that includes extreme heat, cold and pollution, all of which generate free radicals.

Animals↗
PubMedDate not supplied

Pharmacology and physiology of melatonin in the reduction of oxidative stress in vivo.

This brief resume summarizes the evidence which shows that melatonin is a significant free radical scavenger and antioxidant at both physiological and pharmacological concentrations in vivo. Surgical removal of the pineal gland, a procedure which lowers endogenous melatonin levels in the blood, exaggerates molecular damage due to free radicals during an oxidative challenge. Likewise, providing supplemental melatonin during periods of massive free radical production greatly lowers the resulting tissue damage and dysfunction. In the current review, these findings are considered in terms of neurodegenerative diseases, cancer, ischemia/reperfusion injury and aging. Besides being a highly effective direct free radical scavenger and indirect antioxidant, melatonin has several features that make it of clinical interest. Thus, melatonin is readily absorbed when it is administered via any route, it crosses all morphophysiological barriers, e.g., blood-brain barrier and placenta, with ease, it seems to enter all parts of every cell where it prevents oxidative damage, it preserves mitochondrial function, and it has low toxicity. While blood melatonin levels are normally low, tissue levels of the indoleamine can be considerably higher and at some sites, e.g., in bone marrow cells and bile, melatonin concentrations exceed those in the blood by several orders of magnitude. What constitutes a physiological level of melatonin must be redefined in terms of the bodily fluid, tissue and subcellular compartment being examined.

Aging↗