UNIPROT:P43026 - FACTA Search

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)

Idiosyncratic reactions occur in a small fraction (typically <5%) of the population taking therapeutic drugs. Chlorpromazine (CPZ) is a phenothiazine, antipsychotic drug that has caused several idiosyncratic responses during its therapeutic use. Clinical evidence suggests that conditions associated with inflammation are risk factors for the appearance of these responses. Accordingly, we tested the hypothesis that an inflammatory stimulus, bacterial lipopolysaccharide (LPS), renders animals susceptible to CPZ-induced idiosyncratic reactions seen in humans. Male Sprague-Dawley rats (200-250 g) were fasted for 24 h. A small dose of LPS (7.4 x 10(6) EU/kg from Escherichia coli) or its vehicle (saline) was administered by tail vein 2 h before an intraperitoneal injection of CPZ (70 mg/kg) or its vehicle (saline). Cholestasis and hepatocellular necrosis were evaluated as increased concentrations of serum bile acids and bilirubin and increased activities of alkaline phosphatase, gamma-glutamyltransferase, alanine aminotransferase, and aspartate aminotransferase. With the exception of bile acids, these serum markers were elevated in animals treated with LPS/CPZ. Histopathological lesions in liver sections were consistent with these findings. Elevated serum creatine kinase activity, which is associated with human idiosyncratic responses to phenothiazines, was also found in animals treated with LPS/CPZ, but not with either LPS or CPZ alone. These results raise the possibility that concurrent, modest inflammation may underlie susceptibility of individuals to certain idiosyncratic reactions and may form the basis for an animal model with which to understand and predict drug idiosyncrasy.
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PMID:Underlying endotoxemia augments toxic responses to chlorpromazine: is there a relationship to drug idiosyncrasy? 1180 5

Selective cardiotoxicity of doxorubicin (DOX) remains a significant and dose-limiting clinical problem. The mechanisms implicated are not yet fully defined but may involve the production of reactive oxygen species or expression of cytokines. Although patients with advanced congestive heart failure express elevated circulating levels of tumour necrosis factor-alpha (TNFalpha), little is known about the prognostic importance and regulation of TNF in the heart in cardiac disease states. Here we tested whether the expression of TNFalpha, along with oxidative stress, is associated with the development of DOX-induced cardiomyopathy (DOX-CM) and whether concurrent treatment with taurine (Taur), an antioxidant, or rolipram (Rolp), a TNFalpha inhibitor, offer a certain protection against DOX cardiotoxic properties. DOX (cumulative dose, 12 mg kg(-1)) was administered to rats in six equal (intraperitoneal) injections over a period of 6 weeks. Cardiomyopathy was evident by myocardial cell damage, which was characterized by a dense indented nucleus with peripheral heterochromatin condensation and distorted mitochondria, as well as significant increase in serum levels of creatine kinase and lactate dehydrogenase. DOX also induced an increment (P<0.001) in serum TNF and plasma nitric oxide levels. The extent of left ventricular (LV) superoxide anion, lipid peroxide measured as malondialdehyde, catalase and calcium content were markedly elevated, whereas superoxide dismutase, total and non-protein-bound thiol were dramatically decreased in DOX-treated rats. Exaggeration of DOX-CM was achieved by intraperitoneal injection of lipopolysaccharide (LPS) (1 mg kg(-1)) 18 h before sampling and evaluated by highly significant increase in heart enzymes (P<0.001), oxidative stress biomarkers and TNFalpha production. Pre- and co-treatment of DOX or DOX-LPS rats with Taur (1% daily supplemented in drinking water, 10 days before and concurrent with DOX) or Rolp (3 mg kg(-1), intraperitoneally, one dose before DOX administration then every 2 weeks throughout the experimental period) ameliorated the deleterious effect of both DOX and LPS on the aforementioned parameters. Meanwhile, it is noteworthy that Rolp exhibited a more preferable effect on serum TNFalpha level. Taur and rolipram also restored the myocardial apoptosis induced by DOX. In conclusion, a cumulative dose of DOX affected free radical and TNFalpha production in the heart of an experimental cardiomyopathy animal model. The current results suggest that down-regulation of these radicals and cytokines could be maintained by using the free radical scavenger Taur or, more favourably, the TNFalpha inhibitor Rolp.
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PMID:Protection against doxorubicin cardiomyopathy in rats: role of phosphodiesterase inhibitors type 4. 1523 Oct 41

Septic shock is still the major cause of death in surgical intensive care units. Both gram-positive (G+) and gram-negative (G-) bacteria have been isolated in the blood of a large portion of septic patients, and these polymicrobial infections often have a higher mortality than infections due to a single organism. Cell wall fragments from G+ and G- bacteria synergise to cause shock and multiple organ dysfunction in vivo (G+/G- shock). Male Wistar rats were anaesthetised and received a coadministration of wall fragments from G+ and G- bacteria, Staphilococcus aureus (S. aureus) peptidoglycan [0.3 mg/kg, intravenously (i.v.)] and Escherichia coli (E. coli) lipopolysaccharide (1 mg/kg, i.v.) or vehicle (saline, 1 ml/kg, i.v.). G+/G- shock for 6 h resulted in an increase in serum levels of creatinine (indicator of renal dysfunction), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (gamma-GT), bilirubin (markers for hepatic injury and dysfunction) and creatine kinase (CK, an indicator of neuromuscular, skeletal muscle or cardiac injury). Pretreatment of rats with the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist 15d-prostaglandin J2 (0.3 mg/kg, i.v., 30 min prior to G+/G-) reduced the multiple organ injury/dysfunction caused by coadministration of peptidoglycan+lipopolysaccharide. The selective PPAR-gamma antagonist GW9662 (2-Chloro-5-nitrobenzanilide) (1 mg/kg, i.v., given 45 min prior to G+/G-) abolished the protective effects of 15d-prostaglandin J2. 15d- prostaglandin J2 did not affect the biphasic fall in blood pressure or the increase in heart rate caused by administration of peptidoglycan+lipopolysaccharide. The mechanism(s) of the protective effect of this cyclopentenone prostaglandin are-at least in part-PPAR-gamma dependent, as the protection afforded by 15d-prostaglandin J2 was reduced by the PPAR-gamma antagonist GW9662. We propose that 15d-prostaglandin J2 or other ligands for PPAR-gamma may be useful in the therapy of the organ injury associated with septic shock.
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PMID:15d-prostaglandin J2 reduces multiple organ failure caused by wall-fragment of Gram-positive and Gram-negative bacteria. 1536 8

Nicorandil (NCR), a KATP channel opener, has been reported to preserve microvascular integrity in patients with reperfused myocardial infarction. We tested the hypothesis that NCR suppresses myocardial ischemia and reperfusion injury via the attenuation of cytokine production. Forty patients who underwent coronary artery bypass graft surgery were studied. The patients were randomly divided into two groups, i.e., the patients with NCR (4-6 mg/h; N group, n = 20) or without NCR (C group, n = 20). Cardiac surgery was performed under anesthesia using fentanyl and propofol. Blood were sampled at the time of induction of anesthesia, pre-cardiopulmonary bypass, 60 min after aortic occlusion, and 60, 120, and 180 min after declamping the aorta. The activation of NF-kappaB, expression of adhesion molecules, and cytokine production were evaluated in blood samples from the control volunteers by flow cytometric analysis with or without lipopolysaccharide (LPS) stimulation in vitro. Serum IL-6 and IL-8 levels in both groups increased 60 min after declamping the aorta compared with the preoperative value (P < 0.001); the increases of these parameters in N group were lower than those in C group (P < 0.05). Serum creatine kinase with muscle and brain subunits and troponin-T levels increased 60 min after declamping the aorta in two groups (P < 0,001), but the increases of both parameters in N group were lower than those in C group (P < 0.05). NF-kappaB activation, CD11b/CD18 expression, and the production of TNF-alpha, IL-8, and IL-6 in monocytes and granulocytes were inhibited by NCR in vitro. NCR suppressed the increase of inflammatory cytokines such as IL-6 and IL-8 levels, and reduced myocardial reperfusion injury. The inhibition on NF-kappaB activation, adhesion molecule expression, and cytokine production may be one of the important mechanisms of myocardial protection of NCR.
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PMID:Nicorandil attenuates NF-kappaB activation, adhesion molecule expression, and cytokine production in patients with coronary artery bypass surgery. 1604 78

Hydrogen sulfide (H2S) is a naturally occurring gaseous transmitter, which may play important roles in normal physiology and disease. Here, we investigated the role of H2S in the organ injury caused by severe endotoxemia in the rat. Male Wistar rats were subjected to acute endotoxemia (Escherichia coli lipopolysaccharide (LPS) 6 mg kg(-1) intravenously (i.v.) for 6 h) and treated with vehicle (saline, 1 ml kg(-1) i.v.) or DL-propargylglycine (PAG, 10-100 mg kg(-1) i.v.), an inhibitor of the H2S-synthesizing enzyme cystathionine-gamma-lyase (CSE). PAG was administered either 30 min prior to or 60 min after the induction of endotoxemia. Endotoxemia resulted in circulatory failure (hypotension and tachycardia) and an increase in serum levels of alanine aminotransferase and aspartate aminotransferase (markers for hepatic injury), lipase (indicator of pancreatic injury) and creatine kinase (indicator of neuromuscular injury). In the liver, endotoxemia induced a significant increase in the myeloperoxidase (MPO) activity, and in the expression and activity of the H2S-synthesizing enzymes CSE and cystathionine-beta-synthase. Administration of PAG either prior to or after the injection of LPS dose-dependently reduced the hepatocellular, pancreatic and neuromuscular injury caused by endotoxemia, but not the circulatory failure. Pretreatment of rats with PAG abolished the LPS-induced increase in the MPO activity and in the formation of H2S and in the liver. These findings support the view that an enhanced formation of H2S contributes to the pathophysiology of the organ injury in endotoxemia. We propose that inhibition of H2S synthesis may be a useful therapeutic strategy against the organ injury associated with sepsis and shock.
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PMID:Inhibition of endogenous hydrogen sulfide formation reduces the organ injury caused by endotoxemia. 1610 May 27

The primary purpose of this study was to measure the influence of ibuprofen use during the 160-km Western States Endurance Run on endotoxemia, inflammation, and plasma cytokines. Subjects included 29 ultramarathoners who consumed 600 and 1200 mg ibuprofen the day before and on race day, respectively, and 25 controls that competed in the race but avoided ibuprofen and all other medications. Blood and urine samples were collected the morning prior to and immediately following the race, and subjects recorded muscle soreness during the week following the race using a 10-point Likert scale (DOMS). Race time (25.8+/-.6 and 25.6+/-.8 h, respectively) and ratings of perceived exertion (RPE, 6-20 scale) (14.6+/-.4 and 14.5+/-.2, respectively) did not differ significantly between ibuprofen users and nonusers. Ibuprofen use compared to nonuse was linked to a smaller increase in urine creatinine (P=.038), higher plasma levels of lipopolysaccharide (group effect, P=.042), and greater increases (pre-to-post race) in serum C-reactive protein and plasma cytokine levels for interleukin (IL)-6, IL-10, IL-8, IL-1 ra, granulocyte colony-stimulating factor, monocyte chemotactic protein 1, and macrophage inflammatory protein 1 beta, but not tumor necrosis factor alpha. Post-race DOMS and serum creatine kinase levels did not differ significantly between ibuprofen users and nonusers (20,621+/-3565 and 13,886+/-3068 microcal/L, respectively, P=.163). In conclusion, ibuprofen use compared to nonuse by athletes competing in a 160-km race did not alter muscle damage or soreness, and was related to elevated indicators of endotoxemia and inflammation.
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PMID:Ibuprofen use, endotoxemia, inflammation, and plasma cytokines during ultramarathon competition. 1741 16

Exogenous lysophosphatidic acid (LPA) has been shown to beneficial in renal ischemia/reperfusion injury, wound healing and colitis. LPA acts via specific G-protein-coupled receptors and also peroxisome proliferator-activated receptor-gamma (PPAR-gamma). However, activation of PPAR-gamma is dependent on the presence of an unsaturated acyl chain. Here we investigate the effects of saturated LPA (18:0) and unsaturated LPA (18:1) on the organ injury associated with endotoxemia and the receptors mediating LPA activity. Male Wistar rats received either lipopolysaccharide (LPS, 6 mg/kg i.v.) or vehicle. The PPAR-gamma antagonist GW9662 (1 mg/kg i.v.), the LPA receptor antagonist Ki16425 (0.5 mg/kg i.v.) or vehicle was administered 30 min after LPS. LPA 18:0 or LPA 18:1 (1 mg/kg i.v.) or vehicle was administered 1 h after injection of LPS. Endotoxemia for 6 h resulted in an increase in serum levels of aspartate aminotransferase, alanine aminotransferase and creatine kinase. Therapeutic administration of LPA 18:0 or 18:1 reduced the organ injury caused by LPS. LPA 18:0 also attenuated the increase in plasma IL-1beta caused by LPS. Ki16425, but not GW9662, attenuated the beneficial effects of LPA 18:0, however, Ki16425 and GW9662 attenuated the beneficial effects of 18:1. In conclusion, LPA reduces the organ injury caused by endotoxemia in the rat. Thus, LPA may be useful in the treatment of shock of various aetiologies. The mechanism of action is related to acyl chain saturation, with LPA 18:0 acting via G-protein-coupled receptors and LPA 18:1 acting via G-protein-coupled receptors and PPAR-gamma.
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PMID:Lysophosphatidic acid reduces the organ injury caused by endotoxemia-a role for G-protein-coupled receptors and peroxisome proliferator-activated receptor-gamma. 1717 80

Hundreds of epidemiological studies have shown that exposure to ambient particulate matter (PM) is associated with dose-dependent increases in morbidity and mortality. While early reports focused on PM less than 10 microm (PM10), numerous studies have since shown that the effects can occur with PM stratified into ultrafine (UF), fine (FI), and coarse (CO) size modes despite the fact that these materials differ significantly in both evolution and chemistry. Furthermore the chemical makeup of these different size fractions can vary tremendously depending on location, meteorology, and source profile. For this reason, high-volume three-stage particle impactors with the capacity to collect UF, FI, and CO particles were deployed to four different locations in the United States (Seattle, WA; Salt Lake City, UT; Sterling Forest and South Bronx, NY), and weekly samples were collected for 1 mo in each place. The particles were extracted, assayed for a standardized battery of chemical components, and instilled into mouse lungs (female BALB/c) at doses of 25 and 100 microg. Eighteen hours later animals were euthanized and parameters of injury and inflammation were monitored in the bronchoalveolar lavage fluid and plasma. Of the four locations, the South Bronx coarse fraction was the most potent sample in both pulmonary and systemic biomarkers, with a strong increase in lung inflammatory cells as well as elevated levels of creatine kinase in the plasma. These effects did not correlate with lipopolysaccharide (LPS) or total zinc or sulfate content, but were associated with total iron. Receptor source modeling on the PM2.5 samples showed that the South Bronx sample was heavily influenced by emissions from coal fired power plants (31%) and mobile sources (22%). Further studies will assess how source profiles correlate with the observed effects for all locations and size fractions.
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PMID:Comparative toxicity of size-fractionated airborne particulate matter obtained from different cities in the United States. 1830 53

Apolipoprotein A-I (ApoA-I) is the major apolipoprotein of high density lipoprotein (HDL). To investigate the protective effect of ApoA-I against lipopolysaccharide (LPS)-induced systemic inflammation and multiple organ damage in mice, we established a human ApoA-I overexpression mouse model using recombinant adenovirus vector (AdV-AI). The histomorphologic analysis showed that AdV-AI administration greatly attenuated LPS-induced acute injury in lung and kidney. AdV-AI treatment also significantly inhibited LPS-induced increments of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-1beta levels in serum (P < 0.01, P < 0.05 and P < 0.05, respectively) and in bronchoalverolar lavage fluid (P < 0.05, respectively), and of serum creatine kinase and creatinine levels (P < 0.05, respectively). Moreover, we found that the increments of CD14 expression in liver and lung induced by LPS were significantly reduced by AdV-AI treatment (P < 0.05 and P < 0.01, respectively). In conclusion, adenovirus-mediated ApoA-I overexpression plays a protective effect against LPS-induced systemic inflammation and multiple organ damage in mice. Such effect may attribute partly to the suppression of inflammatory cytokine release and reduction of CD14 expression.
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PMID:Human ApoA-I overexpression diminishes LPS-induced systemic inflammation and multiple organ damage in mice. 1859 75

Osteoclasts differentiate from precursor cells of the monocyte-macrophage lineage and subsequently become activated to be competent for bone resorption through programs primarily governed by receptor activator of nuclear factor-kappaB ligand in cooperation with macrophage colony-stimulating factor. Proteins prominently expressed at late phases of osteoclastogenesis and with a supportive role in osteoclast function are potential therapeutic targets for bone-remodeling disorders. In this study, we used a proteomics approach to show that abundance of the brain-type cytoplasmic creatine kinase (Ckb) is greatly increased during osteoclastogenesis. Decreasing Ckb abundance by RNA interference or blocking its enzymatic activity with a pharmacological inhibitor, cyclocreatine, suppressed the bone-resorbing activity of osteoclasts grown in vitro via combined effects on actin ring formation, RhoA GTPase activity and vacuolar ATPase function. Activities of osteoclasts derived from Ckb-/- mice were similarly affected. In vivo studies showed that Ckb-/- mice were better protected against bone loss induced by ovariectomy, lipopolysaccharide challenge or interleukin-1 treatment than wild-type controls. Furthermore, administration of cyclocreatine or adenoviruses harboring Ckb small hairpin RNA attenuated bone loss in rat and mouse models. Our findings establish an important role for Ckb in the bone-resorbing function of osteoclasts and underscore its potential as a new molecular target for antiresorptive drug development.
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PMID:Brain-type creatine kinase has a crucial role in osteoclast-mediated bone resorption. 1872 77

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