Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protective effect of melatonin on lipopolysaccharide (LPS)-induced oxidative damage in phenobarbital-treated rats was measured using the following parameters: changes in total glutathione (tGSH) concentration, levels of oxidized glutathione (GSSG), the activity of the antioxidant enzyme glutathione peroxidase (GSH-PX) in both brain and liver, and the content of cytochrome P450 reductase in liver. Melatonin was injected intraperitoneally (ip, 4mg/kg BW) every hour for 4 h after LPS administration; control animals received 4 injections of diluent. LPS was given (ip, 4 mg/kg) 6 h before the animals were killed. Prior to the LPS injection, animals were pretreated with phenobarbital (PB), a stimulator of cytochrome P450 reductase, at a dose 80 mg/kg BW ip for 3 consecutive days. One group of animals received LPS together with Nw-nitro-L-arginine methyl ester (L-NAME), a blocker of nitric oxide synthase (NOS) (for 4 days given in drinking water at a concentration of 50 mM). In liver, PB, in all groups, increased significantly both the concentration of tGSH and the activity of GSH-PX. When the animals were injected with LPS the levels of tGSH and GSSG were significantly higher compared with other groups while melatonin and L-NAME significantly enhanced tGSH when compared with that in the LPS-treated rats. Melatonin alone reduced GSSG levels and enhanced the activity of GSH-PX in LPS-treated animals. Additionally, LPS diminished the content of cytochrome P450 reductase with this effect being largely prevented by L-NAME administration. Melatonin did not change the content of P450 either in PB- or LPS-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Melatonin administration prevents lipopolysaccharide-induced oxidative damage in phenobarbital-treated animals. 759 65

The protective effect of melatonin against lipopolysaccharide (LPS)-induced oxidative damage was examined in vitro. Lung, liver, and brain malonaldehyde (MDA) plus 4-hydroxyalkenals (4-HDA) concentrations were measured as indices of induced membrane peroxidative damage. Homogenates of brain, lung, and liver were incubated with LPS at concentrations of either 1, 10, 50, 200, or 400 micrograms/ml for 1 h and, in another study, LPS at a concentration of 400 micrograms/ml for either 0, 15, 30, or 60 min. Melatonin at increasing concentrations from 0.01-3 mM either alone or together with LPS (400 micrograms/ml) was used. Liver, brain, and lung MDA + 4-HDA levels increased after LPS at concentrations of 10, 50, 200 or 400 micrograms/ml; this effect was concentration-dependent. The highest levels of lipid peroxidation products were observed after tissues were incubated with an LPS concentration of 400 micrograms/ml for 60 min; in liver and lung this effect was totally suppressed by melatonin and partially suppressed in brain in a concentration-dependent manner. In addition, melatonin alone was effective in brain at concentrations of 0.1 to 3 mM, in lung at 2 to 3 mM, and in liver at 0.1 to 3 mM; in all cases, the inhibitory effects of melatonin on lipid peroxidation were always directly correlated with the concentration of melatonin in the medium. The results show that the direct effect of LPS on the lipid peroxidation following endotoxin exposure is markedly reduced by melatonin.
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PMID:Melatonin reduces both basal and bacterial lipopolysaccharide-induced lipid peroxidation in vitro. 858 67

That free radical destruction of macromolecules is a basis of aging and age-related diseases has considerable experimental support. Melatonin, a hormone produced in organisms as diverse as algae and humans, is believed to have evolved coincident with aerobic metabolism. In all organisms melatonin is produced primarily during the daily period of darkness, with only small amounts being synthesized during the day. In mammals including man, melatonin is produced by and secreted from the pineal gland during the night; however, the night-time production of melatonin falls markedly with aging such that in senescent animals a night-time melatonin rise is barely measurable. This may be significant in terms of aging in the light of recent observations which show that melatonin is a highly efficient free radical scavenger and antioxidant both in vitro and in vivo. In vitro, melatonin has been shown to directly scavenge both the hydroxyl and peroxyl radical, and it does so more efficiently than other known antioxidants. Furthermore, melatonin greatly potentiates the efficiency of previously-discovered endogenous and exogenous antioxidants. In vivo, both physiological and pharmacological levels of melatonin reportedly counteract the devastatingly destructive actions of free radical generating chemicals. For example, melatonin effectively combats DNA damage in rats given massive doses of the chemical carcinogen safrole, and the indole overcomes much of the genomic damage inflicted by ionizing radiation. Also, lipid peroxidation induced by either paraquat, bacterial lipopolysaccharide or H2O2 is highly significantly reduced by concurrent melatonin administration. Finally, cataracts produced in newborn rats by the depletion of the endogenous antioxidant glutathione are prevented by melatonin. These findings provide evidence that melatonin is operative in the cell nucleus, in the aqueous cytosol and in lipid-rich cellular membranes as an antioxidant. Considering this, the loss of this potent antioxidant during aging may be consequential in terms of cellular and organismal aging as well as the onset of age-related diseases. These experimental results from a variety of sources suggest that a more determined approach to the study of melatonin as an anti-aging factor is warranted.
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PMID:Oxygen radical detoxification processes during aging: the functional importance of melatonin. 871

The ability of melatonin to influence lipopolysaccharide (LPS)-induced genotoxicity was tested using micronuclei as an index in both bone marrow and peripheral blood cells of rats. LPS was given as a single dose of 10 mg/kg. Melatonin (5 mg/kg) was injected prior to LPS administration and thereafter at 6 h intervals to the conclusion of the study (72 h). The number of micronucleated polychromatic erythrocytes increased significantly after LPS administration both in cells from peripheral blood and bone marrow. Melatonin administration to LPS-treated rats highly significantly reduced micronuclei formation in both peripheral blood and bone marrow cells beginning at 24 h after LPS administration and continuing to the end of the study. In blood the increase in micronuclei formation was time-dependent in LPS-treated rats with peak values being reached at 36-48 h. The ability of melatonin to reduce LPS-related genotoxicity is likely related to its antioxidant activity.
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PMID:Lipopolysaccharide-induced DNA damage is greatly reduced in rats treated with the pineal hormone melatonin. 873 78

Oxidative damage to the liver of lipopolysaccharide-treated rats was evaluated using four parameters: level of lipid peroxidation, changes in total GSH and GSSG concentrations and hepatic morphology. Bacterial lipopolysaccharide (10 mg/kg b.w.) was injected i.p. either at 6, 16 or 24 h before animals were killed. Lipopolysaccharide increased lipid peroxidation most dramatically when it is injected 6 h before killing. Hepatic total GSH increased after lipopolysaccharide in a time-dependent manner. The highest level of GSSG and largest GSSG/total GSH ratio were also observed in the group of animals injected with lipopolysaccharide 6 h before tissue collection. In a second study, lipopolysaccharide was injected 6 h before the animals were killed, with or without 1 mg/kg b.w. melatonin. Melatonin totally abolished lipopolysaccharide-induced increase in lipid peroxidation, exaggerated the rise in total GSH and reversed the increase in GSSG concentration. The liver showed obvious histological degenerative changes after lipopolysaccharide, effects that were counteracted by melatonin administration. The protection conferred by melatonin is presumably due to its antioxidant activity.
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PMID:Lipopolysaccharide-induced hepatotoxicity is inhibited by the antioxidant melatonin. 874 85

Melatonin, the chief secretory product of the pineal gland, was recently found to be a free radical scavenger and antioxidant. This review briefly summarizes the published reports supporting this conclusion. Melatonin is believed to work via electron donation to directly detoxify free radicals such as the highly toxic hydroxyl radical. Additionally, in both in vitro and in vivo experiments, melatonin has been found to protect cells, tissues and organs against oxidative damage induced by a variety of free radical generating agents and processes, e.g., the carcinogen safrole, lipopolysaccharide, kainic acid, Fenton reagents, potassium cyanide, L-cysteine, excessive exercise, glutathione depletion, carbon tetrachloride, ischemia-reperfusion, MPTP, amyloid beta (25-35 amino acid residue) protein, and ionizing radiation. Melatonin as an antioxidant is effective in protecting nuclear DNA, membrane lipids and possibly cytosolic proteins from oxidative damage. Also, melatonin has been reported to alter the activities of enzymes which improve the total antioxidative defense capacity of the organism, i.e., superoxide dimutase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase, and nitric oxide synthase. Most studies have used pharmacological concentrations or doses of melatonin to protect against free radical damage; in a few studies physiological levels of the indole have been shown to be beneficial against oxidative stress. Melatonin's function as a free radical scavenger and antioxidant is likely assisted by the ease with which it crosses morphophysiological barriers, e.g., the blood-brain barrier, and enters cells and subcellular compartments. Whether the quantity of melatonin produced in vertebrate species is sufficient to significantly influence the total antioxidative defense capacity of the organism remains unknown, but its pharmacological benefits seem assured considering the low toxicity of the molecule.
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PMID:Pharmacological actions of melatonin in oxygen radical pathophysiology. 919 81

The interrelationships between the immune system and the pineal hormone, melatonin, have been explored recently. The present studies investigated the effects of daily melatonin injections on reproductive and spleen function in male Syrian hamsters. Testes weights and serum testosterone levels were depressed after 8-10 weeks of daily melatonin injections. Melatonin-treated hamsters exhibited increased splenic lymphoproliferative responses to a polyclonal T-cell mitogen (concanavalin A (Con-A)), but decreased proliferation following stimulation with a polyclonal B-cell mitogen (lipopolysaccharide). It appears that daily melatonin injections in male hamsters increase the T-cell-mediated immune capacity while reducing the antibody-mediated immune potential. These data suggest that chronic, daily melatonin alters immune system responsiveness in hamsters by shifting the balance of cellular and humoral reactivity.
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PMID:Immune responsiveness of splenocytes after chronic daily melatonin administration in male Syrian hamsters. 927 19

Melatonin's actions in organisms are more widespread than originally envisaged. Over three decades ago, the changing pattern of nocturnal melatonin production was found to be the signal for the annual cycle of reproduction in photoperiodic species. Since then, melatonin's actions also have been linked to circadian rhythms, immune function, sleep, retinal physiology and endocrine functions in general. In recent years, however, the sphere of influence of melatonin was further expanded when the indole was found to be an effective free radical scavenger and antioxidant. Free radicals are toxic molecules, many being derived from oxygen, which are persistently produced and incessantly attack and damage molecules within cells; most frequently this damage is measured as peroxidized lipid products, carbonyl proteins, and DNA breakage or fragmentation. Collectively, the process of free radical damage to molecules is referred to as oxidative stress. Melatonin reduces oxidative stress by several means. Thus, the indole is an effective scavenger of both the highly toxic hydroxyl radical, produced by the 3 electron reduction of oxygen, and the peroxyl radical, which is generated during the oxidation of unsaturated lipids and which is sufficiently toxic to propagate lipid peroxidation. Additionally, melatonin may stimulate some important antioxidative enzymes, i.e., superoxide dismutase, glutathione peroxidase and glutathione reductase. In in vivo tests, melatonin in pharmacological doses has been found effective in reducing macromolecular damage that is a consequence of a variety of toxic agents, xenobiotics and experimental paradigms which induce free radical generation. In these studies, melatonin was found to significantly inhibit oxidative damage that is a consequence of paraquat toxicity, potassium cyanide administration, lipopolysaccharide treatment, kainic acid injection, carcinogen administration, carbon tetrachloride poisoning, etc., as well as reducing the oxidation of macromolecules that occurs during strenuous exercise or ischemia-reperfusion. In experimental models which are used to study neurodegenerative changes associated with Alzheimer's and Parkinson disease, melatonin was found to be effective in reducing neuronal damage. Its lack of toxicity and the ease with which melatonin crosses morphophysiological barriers and enters subcellular compartments are essential features of this antioxidant. Thus far, most frequently pharmacological levels of melatonin have been used to combat oxygen toxicity. The role of physiological levels of melatonin, which are known to decrease with age, is being investigated as to their importance in the total antioxidative defense capacity of the organism.
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PMID:Melatonin in relation to cellular antioxidative defense mechanisms. 928 72

Melatonin is an antioxidant. Since other antioxidants inhibit the production of tumor necrosis factor (TNF) induced by lipopolysaccharide, we investigated its effect on TNF production in vivo and in vitro and on lethality associated with endotoxic shock. Administration of melatonin to mice (5 mg/kg, s.c., 30 min before or simultaneously with lipopolysaccharide) inhibited serum TNF levels by 50-80% and improved survival of mice treated with a lethal dose of lipopolysaccharide. By studying other, structurally related, indolamines (N-acetyl-5-hydroxytryptamine, 5-methoxytryptamine and 5-hydroxytryptamine) we found a good correlation between antioxidant activity (for which the 5-methoxy group is essential) and the inhibition of TNF production in vivo and in vitro in mononuclear cells. Melatonin did not increase serum corticosterone and did not modify the elevation of serum corticosterone levels by lipopolysaccharide or by interleukin-1. Furthermore, it exerted its inhibitory effect in adrenalectomized or hypophysectomized mice also, indicating that its effect is independent of the hypothalamus-pituitary-adrenal axis.
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PMID:Mechanism of the inhibitory effect of melatonin on tumor necrosis factor production in vivo and in vitro. 957 Apr 74

The role of melatonin as an immunomodulator is well established. Recent reports showed that melatonin exerts protective effects in septic and hemorrhagic shock and in inflammation. The expression of the inducible isoform of nitric oxide synthase (iNOS) makes an important contribution to the pathophysiology of shock and inflammation. We studied, in cultured murine macrophages, the role of melatonin in the regulation of the expression of iNOS and defined the mode of melatonin's action. Our results show that melatonin, at 1 microM-1 mM, decreased the production of nitrite/nitrate (the breakdown products of NO) as well as the production of 6-keto-prostaglandin F1alpha (the major stable breakdown product of prostacyclin) in macrophages stimulated with bacterial lipopolysaccharide (10 microg/ml). We observed that melatonin reduces iNOS steady-state mRNA levels and iNOS protein expression in the same concentration range (1 microM-1 mM). Melatonin, up to 10 mM, exerted only a slight direct inhibitory effect on iNOS activity. Using iNOS promoter-luciferase constructs, we found that melatonin inhibits iNOS promoter activation. Inhibition of iNOS expression was associated with inhibition of activation of the transcription factor nuclear factor kappa B (NFkappaB). We conclude that melatonin inhibits NO production in immunostimulated macrophages mainly by inhibiting the expression of iNOS. This is due to inhibition of iNOS transcription, in part through inhibition of NFkappaB activation. Inhibition of iNOS-derived NO production by melatonin may contribute to the anti-inflammatory effects of this pineal secretory product.
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PMID:Melatonin inhibits expression of the inducible isoform of nitric oxide synthase in murine macrophages: role of inhibition of NFkappaB activation. 961 47


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