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)

Genipin, the aglycone of geniposide, is metabolically produced from the geniposide in body tissues. The purpose of this study is to clarify some pharmacological actions of genipin. Genipin showed concentration-dependent inhibition on lipid peroxidation induced by Fe++/ascorbate in rat brain homogenate. Genipin exhibited significant topical antiinflammatory effect shown as an inhibition of croton oil-induced ear edema in mice. Nitric oxide (NO) synthesis by inducible nitric oxide synthase (iNOS) is increased in inflammatory diseases and leads to cellular injury. Genipin concentration-dependently (50-300 microM) inhibited NO production and iNOS expression upon stimulation by lipopolysaccharide/interferon-gamma (IFN-gamma) in RAW 264.7, a murine macrophage cell line. Genipin markedly blocked lipopolysaccharide-evoked degradation of inhibitor-kappaB-beta (IkappaB-beta), indicating that it exhibits inhibitory effect on NO production through the inhibition of nuclear factor-kappaB (NF-kappaB) activation. It was also shown to contain potent antiangiogenic activity in a dose-dependent manner, which was detected by chick embryo chorioallantoic membrane assay. In summary, we demonstrate that genipin possesses antiinflammatory and is a specific hydroxyl radical scavenger. Its antiangiogenic and NO production-inhibitory properties are also presented.
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PMID:Antiinflammatory effects of genipin, an active principle of gardenia. 1524 71

Antioxidants have been shown to be effective in attenuating acute lung injury. In this study, we determine the effects of various antioxidants by different mechanisms on the lipopolysaccharide (LPS)-induced changes. LPS was administered intravenously at a dose of 10 mg/kg to anesthetized rats. LPS induced a significant decrease in blood pressure (P < 0.01) and increased exhaled nitric oxide (NO) from 3.60+/-0.18 to 35.53+/-3.23 ppb (P < 0.01) during an observation period of 4 h. Plasma nitrate concentrations also increased from 0.61+/-0.06 to 1.54+/-0.22 micromol/l (P < 0.05). LPS-induced oxygen radical release from white blood cells isolated from rat peripheral blood also increased significantly (P < 0.001). After the experiment, the lung weight was obtained and lung tissues were taken for the determination of mRNA expression of inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta) and manganese superoxide dismutase (MnSOD). Histological examination of the lungs was also performed. In the control group injected with saline solution, mRNA expressions of iNOS, IL-1beta, TNF-alpha and MnSOD were absent. Four hours after LPS administration, mRNA expressions of iNOS, IL-1beta, and MnSOD were significantly enhanced, but TNF-alpha was not discernibly expressed. LPS also caused a twofold increase in lung weight. Pathological examination revealed endothelial cell damage and interstitial edema. Various antioxidants were given 1 h after LPS administration. These agents include SOD, catalase (CAT), SOD + CAT or vitamin C (ascorbic acid). These antioxidants effectively reversed the systemic hypotension, reduced the quantity of exhaled NO and plasma nitrate concentration, and prevented acute lung injury. Administration of various antioxidants also significantly attenuated LPS-induced oxygen radical release by rat white blood cells. LPS induced mRNA expressions of MnSOD and iNOS were significantly depressed by these antioxidants. However, only SOD + CAT and vitamin C inhibited the mRNA expression of IL-1beta. These results suggest that oxygen radicals are responsible for LPS-induced lung injury. Antioxidants can attenuate the lung injury by inhibiting mRNA expressions of iNOS and IL-1beta.
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PMID:Effects of various antioxidants on endotoxin-induced lung injury and gene expression: mRNA expressions of MnSOD, interleukin-1beta and iNOS. 1561 28

The effect of Cu plate on the cellular function was investigated by two different methods: an extraction method (Method I) and a direct contact method (Method II). In Method I, the supernatant of the culture medium, which had been pre-incubated with Cu plate, was added to mouse macrophage-like Raw 264.7 cells. This supernatant dose-dependently inhibited the proliferation and nitric oxide (NO) production by lipopolysaccharide-stimulated Raw 264.7 cells. In Method II, human promyelocytic leukemic HL-60 cells in suspension were incubated with culture medium which contained Cu plate. The direct contact with Cu plate rapidly suppressed the proliferation and MnSOD and Cu/ZnSOD activities. The suppressed proliferation and SOD activity reverted to or exceeded the control level by sodium ascorbate, whereas N-acetyl-L-cysteine (NAC) only reactivated the proliferation, but not the SOD activity. ESR spectroscopy showed that contact with Cu plate slightly diminished the hydroxyl radical (generated by Fenton reaction), without affecting the intensity of NO (produced from NOC-7) and DPPH radical. The present study suggests that two representative antioxidants, such as sodium ascorbate and NAC, protect the cells from Cu-induced cytotoxicity via different mechanisms.
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PMID:Protection by antioxidants of copper-induced decline of proliferation and SOD activity. 1581 49

This study was designed to investigate the protective effects of vitamin C and vitamin A on oxidative renal tissue damage. Male Wistar rats were given an intraperitoneal injection of 0.5 ml saline (control) or 0.5 ml solution of lipopolysaccharide (10 mg/kg), which caused endotoxemia. Immediately (within 5 min) after the endotoxin injection, the endotoxemic rats were untreated or treated with intraperitoneal injection of vitamin A (195 mg/kg bw), vitamin C (500 mg/kg bw) or their combination. After 24 hours, tissue and blood samples were obtained for histopathological and biochemical investigation. Endotoxin injection caused renal tissue damage and increased erythrocyte and tissue malondialdehyde (MDA) and serum nitric oxide (NO), urea and creatinine concentrations, but decreased the superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) activities compared to the parameters of control animals. Treatment with vitamin C or with vitamins C and A significantly decreased the MDA levels and serum NO, urea and creatinine levels, recovered the antioxidant enzyme activities (SOD, GSH-Px and CAT), and prevented the renal tissue damage in endotoxemic rats. In contrast, vitamin A alone did not change the altered parameters except for creatinine levels. Notably, the better effects were observed when vitamins A and C given together. It is concluded that vitamin C treatment, alone or its combination with vitamin A, may be beneficial in preventing endotoxin-induced oxidative renal tissue damage and shows potential for clinical use.
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PMID:Protective effects of vitamin C, alone or in combination with vitamin A, on endotoxin-induced oxidative renal tissue damage in rats. 1643 30

Sublethal exposure to Escherichia coli endotoxin [lipopolysaccharide (LPS)] attenuates the lethal effects of subsequent insults associated with oxidative stress, such as higher LPS dose, septic peritonitis, and ischemia. Because administration of the antioxidant ascorbate protects against these same insults and injection of dehydroascorbic acid (DHAA) protects against ischemia, the hypothesis that sublethal LPS increases endogenous ascorbate concentration and recycling (i.e., synthesis from DHAA) was tested. Injection of LPS [5 x 10(6) endotoxin units/kg body weight, i.p.] in mice caused a temporary inhibition of food intake, which was significant by 20 h and recovered within 3 d. LPS increased ascorbate concentration in adrenal gland, heart, kidney, and liver. LPS had similar effects in wild-type and Slc23a2+/- mice despite the latter's deficiency in the ascorbate transporter SVCT2. In liver, the ascorbate response to LPS was not accompanied by change in glutathione concentration. LPS decreased gulonolactone oxidase activity, which is rate-limiting for de novo synthesis of ascorbate from glucose, but increased the rate of DHAA reduction to ascorbate. In conclusion, sublethal endotoxin increases ascorbate recycling in liver and ascorbate concentration in liver, adrenal gland, heart, and kidney. The enhanced rate of ascorbate production from DHAA may protect these organs against the reactive oxygen species produced by subsequent, potentially lethal challenges.
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PMID:Endotoxin increases ascorbate recycling and concentration in mouse liver. 1617 5

Sepsis causes brain dysfunction. Because neurotransmission requires high ascorbate and low dehydroascorbic acid (DHAA) concentrations in brain extracellular fluid, the effect of septic insult on ascorbate recycling (i.e., uptake and reduction of DHAA) and export was investigated in primary rat and mouse astrocytes. DHAA raised intracellular ascorbate to physiological levels but extracellular ascorbate only slightly. Septic insult by lipopolysaccharide and interferon-gamma increased ascorbate recycling in astrocytes permeabilized with saponin but decreased it in those with intact plasma membrane. The decrease was due to inhibition of the glucose transporter (GLUT1) that translocates DHAA because septic insult slowed uptake of the nonmetabolizable GLUT1 substrate 3-O-methylglucose. Septic insult also abolished stimulation by glutamate of ascorbate export. Specific nitric oxide synthase (NOS) inhibitors and nNOS and iNOS deficiency failed to alter the effects of septic insult. Inhibitors of NADPH oxidase generally did not protect against septic insult, because only one of those tested (diphenylene iodonium) increased GLUT1 activity and ascorbate recycling. We conclude that astrocytes take up DHAA and use it to synthesize ascorbate that is exported in response to glutamate. This mechanism may provide the antioxidant on demand to neurons under normal conditions, but it is attenuated after septic insult.
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PMID:Sepsis inhibits recycling and glutamate-stimulated export of ascorbate by astrocytes. 1619 26

To test whether ascorbic acid might be involved in the antioxidant defenses of inflammatory cells, we studied ascorbate uptake and recycling by quiescent and lipopolysaccharide-activated RAW264.7 murine macrophages. These cells concentrated ascorbate 100-fold in overnight culture, achieving steady-state concentrations of more than 10 mM at extracellular concentrations of 20-100 muM. This steep gradient was generated by high-affinity sodium-dependent ascorbate transport. The latter likely reflects function of the SVCT2 (SLC23A2), since this protein was detected on immunoblots. Dehydroascorbate, the two-electron oxidized form of ascorbate, was also taken up and reduced to ascorbate by the cells. Dehydroascorbate reduction required rapid recycling of GSH from GSSG by glutathione reductase. Activation of ascorbate-containing macrophages with lipopolysaccharide transiently depleted intracellular ascorbate without affecting GSH. Recovery of intracellular ascorbate required function of the SVCT2 transporter, the activity of which was modestly enhanced by lipopolysaccharide. Lipopolysaccharide treatment nearly doubled intracellular GSH concentrations over 2 h. Despite lipopolysaccharide-induced oxidant stress, this GSH increase was associated with a comparable increase in reduction of dehydroascorbate to ascorbate. These results show that macrophages maintain millimolar concentrations of ascorbate through function of the SVCT2 and that activated cells have an enhanced ability to transport and recycle ascorbate, possibly reflecting its role as an intracellular antioxidant.
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PMID:Macrophage uptake and recycling of ascorbic acid: response to activation by lipopolysaccharide. 1627 80

The role of inflammation and oxidative stress in the development of obesity and associated metabolic disorders is under debate. We investigated the redox metabolism in a non-diabetic obesity model, i.e. 11-week-old obese Zucker rats. Antioxidant enzyme activities, lipophilic antioxidant (alpha-tocopherol, coenzymes Q) and hydrophilic antioxidant (glutathione, vitamin C) contents and their redox state (% oxidized form), were studied in inguinal white fat and compared with blood and liver. The adipose tissues of obese animals showed a specific higher content of hydrophilic molecules in a lower redox state than those of lean animals, which were associated with lower lipophilic molecule content and lipid peroxidation. Conversely and as expected, glutathione content decreased and its redox state increased in adipose tissues of rats subjected to lipopolysaccharide-induced systemic oxidative stress. In these in vivo models, oxidative stress and obesity thus had opposite effects on adipose tissue redox state. Moreover, the increase in glutathione content and the decrease of its redox state by antioxidant treatment promoted in vitro the accumulation of triglycerides in preadipocytes. Taken together and contrary to the emergent view, our results suggest that obesity is associated with an intracellular reduced redox state that promotes on its own the development of a deleterious proadipogenic process.
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PMID:Adipose tissue proadipogenic redox changes in obesity. 1637 39

Bacterial and viral products, such as bacterial lipopolysaccharide (LPS), cause inducible (i) NO synthase (NOS) synthesis, which in turn produces massive amounts of nitric oxide (NO). NO, by inactivating enzymes and leading to cell death, is toxic not only to invading viruses and bacteria, but also to host cells. Injection of LPS induces interleukin (IL)-1beta, IL-1alpha, and iNOS synthesis in the anterior pituitary and pineal glands, meninges, and choroid plexus, regions outside the blood-brain barrier. Thereafter, this induction occurs in the hypothalamic regions (such as the temperature-regulating centers), paraventricular nucleus (releasing and inhibiting hormone neurons), and the arcuate nucleus (a region containing these neurons and axons bound for the median eminence). Aging of the anterior pituitary and pineal with resultant decreased secretion of pituitary hormones and the pineal hormone melatonin, respectively, may be caused by NO. The induction of iNOS in the temperature-regulating centers by infections may cause the decreased febrile response in the aged by loss of thermosensitive neurons. NO may play a role in the progression of Alzheimer's disease and parkinsonism. LPS similarly activates cytokine and iNOS production in the cardiovascular system leading to coronary heart disease. Fat is a major source of NO stimulated by leptin. As fat stores increase, leptin and NO release increases in parallel in a circadian rhythm with maxima at night. NO could be responsible for increased coronary heart disease as obesity supervenes. Antioxidants, such as melatonin, vitamin C, and vitamin E, probably play important roles in reducing or eliminating the oxidant damage produced by NO.
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PMID:The nitric oxide theory of aging revisited. 1639 88

Alzheimer's disease is characterized by extracellular beta-amyloid plaques, intraneuronal Tau-inclusions and cell death of cholinergic neurons. Recent evidence indicates that the vascular system may play an important role in the development of this progressive neurodegenerative disease. The aim of this study was to observe, if brain capillary endothelial cells (BCEC) may produce and secrete factors which induce cell death of cholinergic neurons, and if this effect is counteracted by (1) NGF, MK-801 or vitamin C, (2) modulated by experimentally-induced inflammation with interleukin-1beta and lipopolysaccharide (IL-1beta and LPS) or (3) by blocking of different intracellular signalling pathways. Cholinergic neurons were cultivated in organotypic brain slices of the nucleus basalis of Meynert and treated with conditioned medium derived from BCEC, supplemented with different protective factors. BCEC were stimulated with IL-1beta and LPS or different intracellular pathway inhibitors before collection of conditioned medium. Cholinergic neurons were detected by immunohistochemistry for choline-acetyltransferase. Possible effects on BCEC viability and proliferation were determined by nuclear staining, BrdU incorporation and release of nitrite and lactate-dehydrogenase. BCEC released factors that can kill cholinergic neurons. This neurotoxic effect was blocked by NGF and MK-801 (a NMDA-antagonist), but not by vitamin C. Pretreatment of BCEC with intracellular pathway inhibitors did not change the neurotoxicity, but pretreatment with IL-1beta and LPS abolished the neurotoxic effect. In summary, BCEC produce and secrete molecules which induce excitotoxic cell death of cholinergic neurons. It is concluded that excitotoxic factors secreted by vascular cells may contribute to the development of cholinergic neurodegeneration as it occurs in Alzheimer's disease.
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PMID:Cholinergic neurons degenerate when exposed to conditioned medium of primary rat brain capillary endothelial cells: counteraction by NGF, MK-801 and inflammation. 1670 75


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