UNIPROT:P43026 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UNIPROT:P43026 (lipopolysaccharide)
62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SK&F 105809 [2-(4- methylsulfinylphenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2- a] imidazole] was determined to be a prodrug for the sulfide metabolite SK&F 105561 [2-(4- methylthiophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a] imidazole] which inhibited interleukin-1 (IL-1) production in vitro and both 5-lipoxygenase (5-LO) and prostaglandin H (PGH) synthase activities in vitro and ex vivo. SK&F 105561 inhibited partially purified 5-LO with a half-maximal concentration (IC50) of 3 microM. This inhibition was reversible, independent of preincubation time, and dependent on the concentration of the substrate arachidonic acid. SK&F 105561 also inhibited purified PGH synthase with the potency dependent on the level of peroxidase activity. The IC50 was 100 microM in the absence of peroxidase activity, whereas an IC50 of 3 microM was observed in the presence of peroxidase activity. Using human monocytes, SK&F 105561 inhibited A23187-stimulated prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) production with IC50 values of 0.1 and 2 microM, respectively. In addition, IL-1 production by lipopolysaccharide-stimulated human monocytes was also inhibited (IC50 2 microM). Oral administration of SK&F 105809 to rats resulted in a dose-related generation of SK&F 105561 and in the inhibition of thromboxane B2 and LTB4 production ex vivo with a half-maximal dose (ED50) of 15 and 60 mg/kg, respectively. SK&F 105561 showed weak inhibitory activity on 12-lipoxygenase with an IC50 of greater than 200 microM. Neither SK&F 105561 nor SK&F 105809 inhibited the stimulated-turnover of arachidonic acid-containing phospholipids in human monocytes or the activity of cell-free phospholipases A2 and C. Moreover, neither SK&F 105561 nor SK&F 105809 antagonized the binding of LTB4 or leukotriene D4 to membrane receptors. From these results, SK&F 105561, the active principle of SK&F 105809, acts as an inhibitor of both inflammatory cytokine and eicosanoid production.
...
PMID:Pharmacology of the pyrroloimidazole, SK&F 105809--I. Inhibition of inflammatory cytokine production and of 5-lipoxygenase- and cyclooxygenase-mediated metabolism of arachidonic acid. 190 24

We examined whether inhibitors of the arachidonic acid cascade inhibited nitric oxide (NO) production, as measured by nitrite concentration, either in macrophages or by their cytosolic fractions. Nitrite production by peritoneal macrophages from mice receiving OK-432 treatment was significantly inhibited by phospholipase A2 inhibitors [dexamethasone and 4-bromophenacyl bromide (4-BPB)], lipoxygenase inhibitors [nordihydroguaiaretic acid (NDGA) and ketoconazole] and a glutathione S-transferase (leukotrienes LTA4-LTC4) inhibitor (ethacrynic acid). However, caffeic acid and esculetin, inhibitors of 5- and 12-lipoxygenase respectively, were not inhibitory. On the other hand, indomethacin, a cyclooxygenase inhibitor, slightly inhibited whereas another inhibitor, ibuprofen, did not. Inhibition of the nitrite production by dexamethasone, 4-BPB, NDGA and ethacrynic acid was also demonstrated when the macrophages were restimulated ex vivo with OK-432 or with lipopolysaccharide. The inhibitory activity of dexamethasone, NDGA and ethacrynic acid was significantly reduced by ex vivo restimulation with OK-432, whereas that of 4-BPB was hardly affected. Furthermore, the inhibitory activity of dexamethasone, NDGA and ethacrynic acid was much higher when the macrophages were continuously exposed to the agents than when they were pulsed. Meanwhile, inhibition by 4-BPB was almost the same with either treatment. In addition, the inhibitory activity of these agents was not blocked with L-arginine, a substrate of NO synthases, or with arachidonate metabolites (LTB4, LTC4 and LTE4). Ethacrynic acid and 4-BPB, but not dexamethasone and NDGA, also inhibited nitrite production by the cytosolic fractions from OK-432-restimulated peritoneal macrophages, and the inhibitory activity of 4-BPB was superior to that of ethacrynic acid. These agents, however, did not inhibit nitrite production from sodium nitroprusside, a spontaneous NO-releasing compound. These results indicate that dexamethasone, 4-BPB, NDGA and ethacrynic acid inhibited the production of NO by macrophages through at least two different mechanisms: one was inhibited by dexamethasone, NDGA and ethacrynic acid and the other by 4-BPB. Furthermore, 4-BPB and ethacrynic acid directly inhibited the activity of the NO synthase in macrophages, suggesting that the agents work by binding to the active site(s) of the enzyme.
...
PMID:Inhibition of macrophage nitric oxide production by arachidonate-cascade inhibitors. 769 96

A potential role for lipoxygenase (LO) products and reactive oxygen species (ROS) in mouse B-lymphocyte activation and differentiation was investigated. Previously published investigations with the nonspecific 5-LO (EC 1.13.11.34) and 12-LO (EC 1.13.11.31) inhibitors such as nordihydroguaiaretic acid (NDGA) and 6,7-dihydroxycoumarin (Esculetin), are misleading in that they suggest lymphocyte LO activity is required for activation and differentiation of these cells. In initial support of this concept, we report that NDGA and Esculetin completely inhibited B-lymphocyte activation mediated by either membrane immunoglobulin (mIg), or the lipopolysaccharide (LPS) receptor. NDGA and Esculetin completely inhibited cell enlargement and proliferation, exhibiting half maximal inhibitory concentrations (IC50S) of approximately 1 x 10(-6) M. In contrast, the highly specific 5-LO inhibitors BAY X 1005, MK-886 and Wy 50,295 did not inhibit cell enlargement or proliferation. Moreover, 5,8,11-eicosatriynoic acid (ETI) which inhibits 5- and 12-LO, and 5, 8, 11, 14-eicosatetraynoic acid (ETYA) which inhibits all known LOs did not affect B-lymphocyte proliferation. Interestingly, NDGA and Esculetin are antioxidants, unlike BAY X 1005, MK-886, Wy 50,295, ETI and ETYA. Our hypothesis was that the antioxidant activities of NDGA and Esculetin were reponsible for inhibiting B-lymphocyte activation and proliferation and we speculated that ROS and not LO activity was required for both processes. Additional antioxidants such as butylated hydroxy toluene, o-phenanthroline, thiourea, and alpha-tocopherol (vitamin E), also inhibited B-lymphocyte proliferation induced by either the LPS or mIg receptors. These agents exhibited IC50S of 1 x 10(-8) M, 5 x 10(-10) M, 6 x 10(-3) M and 5 x 10(-5) M, respectively. When resting B-lymphocytes were treated with a source of ROS (1 x 10(-5) M H2O2), cells enlarged in a temperature-sensitive manner, which is similar to LPS-induced enlargement. Both NDGA and Esculetin completely inhibited H2O2-induced enlargement. These results further indicate that ROS are required for B-lymphocyte activation and proliferation. Similar results were obtained for B-lymphocyte differentiation. NDGA and Esculetin completely inhibited the development of plasma cells and displayed IC50S of 5 x 10(-6) M. Conversely, BAY X 1005, MK-886, Wy 50,295, ETI, and ETYA did not block the formation of plasma cells. Therefore, ROS are also crucial for differentiation into plasma cells. These experiments are the first to directly illustrate that intracellular ROS mediate B-lymphocyte activation, proliferation and differentiation and that LO products are not required for these processes.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:Reactive oxygen species and not lipoxygenase products are required for mouse B-lymphocyte activation and differentiation. 792 3

We tested the hypothesis that Kupffer cells modulate sinusoidal endothelial cell function in the liver. Rats were treated with Kupffer cell-depleting agents (gadolinium chloride and liposome-encapsulated dichloromethylene diphosphonate) or with inhibitors of phospholipase A2 or leukotriene A4 synthase (dexamethasone and diethylcarbamazine, respectively). Hyaluronan uptake by the isolated, perfused liver was measured as an index of the functional state of the sinusoidal endothelial cell. Plasma hyaluronan concentration was also determined. Three hours after Escherichia coli lipopolysaccharide administration (100 micrograms/100 gm body wt, intravenously) plasma hyaluronan levels were significantly increased (280% to 320%), whereas hepatic hyaluronan uptake was markedly decreased (approximately 76%). Pretreatment with gadolinium chloride (0.5 mg/100 gm body wt, intravenously, 21 hr before saline solution or lipopolysaccharide administration), liposome-encapsulated dichloromethylene diphosphonate (40 mumol/100 gm body wt, intravenously, 44 hr before saline solution or lipopolysaccharide injection), dexamethasone (40 micrograms/100 gm body wt, intravenously, 1 hr before saline solution or lipopolysaccharide administration) or diethylcarbamazine (repeated doses, 10 mg/100 gm body wt, intravenously, 1 hr before saline solution or lipopolysaccharide injection) counteracted the lipopolysaccharide inhibitory effect on hepatic hyaluronan uptake. With the exception of gadolinium chloride, all other agents also prevented the lipopolysaccharide-induced increase in plasma hyaluronan concentration. Gadolinium chloride only attenuated the lipopolysaccharide effect on plasma hyaluronan level. Taken together with earlier results from our laboratory, these data indicate that: (a) Kupffer cell activation by lipopolysaccharide results in suppression of hyaluronan uptake by sinusoidal endothelial cells and (b) such modulation of endothelial cell function is likely mediated by products of the lipoxygenase pathway of arachidonate metabolism.
...
PMID:Modulation of hepatic sinusoidal endothelial cell function by Kupffer cells: an example of intercellular communication in the liver. 829 3

Epithelial lipoxygenases of bovine cornea were investigated in organ culture models. Subcellular fractions of the epithelium were incubated with(14)C-labelled arachidonate and the metabolites were analysed. Bovine corneal epithelial cells contain 15-lipoxygenase type 2 and 12-lipoxygenases of the leukocyte and the platelet types. The 15-lipoxygenase activity was prominent in the cytosolic fraction. Twelve- and 15-lipoxygenases occurred in the microsomal fraction, where the 15-lipoxygenase activity appeared to be favoured by low protein levels. The lipoxygenase activities strongly declined within 24 hr when the cornea was covered with cell culture medium, but were maintained with high activity in an air interface organ culture model for at least 72 hr. Cultured corneas were studied in pairs in the air interface model under influence of inflammatory stimuli. The epithelial 15- and 12-lipoxygenase activities were only slightly augmented by treatment with 12-O-tetradecanoyl-phorbol-13-acetate (10 microM, 8-72 hr), and remained unchanged after treatment with lipopolysaccharide (1-100 microgram ml(-1), 8-72 hr) or UV irradiation (301 nm, 0.17 J cm(-2); 8-24 hr). In some experiments, 5-lipoxygenase activity was detectable, as judged from liquid chromatography-mass spectrometry and chiral chromatography. Reverse transcription-polymerase chain reaction and Northern blot analysis were therefore used to identify mRNA of 5-lipoxygenase and related enzymes in bovine epithelium. 5-Lipoxygenase was detected as an amplicon of 695 bp, which had 91% nucleotide sequence identity with human 5-lipoxygenase and by Northern blot as a 3.0 kb mRNA. Leukotriene A(4)hydrolase was detected with the same techniques. The amino acid sequence of a 612 bp fragment was 90% identical with human leukotriene A(4)hydrolase and the size of the mRNA was 2.7 kb. The two enzymes were also detected in human corneal epithelium by reverse transcription-polymerase chain reaction.
...
PMID:Studies of lipoxygenases in the epithelium of cultured bovine cornea using an air interface model. 1088 Feb 76

The lipoxygenase pathway has been implicated in the growth, migration, and contraction of vascular smooth muscle cells (VSMCs). However, the precise type of lipoxygenase present in the vascular wall has not been characterized. In this study, we used a specific reverse-transcriptase polymerase chain reaction method with 2 sets of specific primers on total RNA and polyA (+)RNA of normal human VSMCs prepared from umbilical artery. Two forms of platelet-type 12-lipoxygenase mRNA were present in human VSMCs: the already published form cloned from human erythroleukemia cells and a variant form of platelet-type 12-lipoxygenase, which includes 2 additional sequences consistent with the 2 introns (D and E). This novel form of 12-lipoxygenase poly A (+)RNA was downregulated by lipopolysaccharide (10 ug/ml) and upregulated by epidermal growth factor (100 ng/ml) but was not affected by angiotensin II (10(-7) mol/l). We developed a rabbit anti-human platelet-type 12-lipoxygenase polyclonal antibody directed against a 24-amino acid peptide encoded within exon 4. Western immunoblotting of protein extracted from VSMCs and umbilical artery and platelet extract with this antibody showed a coordinate 110-kDa protein and the already-described 70-kDa band detected in platelets and cord homogenate. Another 120-kDa protein was consistently detected in cord extracts but not in platelet or VSMC homogenates. The immunohistochemistry study performed with the same antibody showed extensive cytoplasmic staining of VSMCs. The specific role of these different forms of platelet-type 12-lipoxygenase is subject to further investigation.
...
PMID:A novel form of platelet-type 12-lipoxygenase mRNA in human vascular smooth muscle cells. 1164

Baicalein (5,6,7-trihydroxyflavone), a flavonoid originated from the root of Chinese medicinal herb Scutellaria baicalensis, has been shown to exert anti-inflammatory and antioxidant effects, and it is a well known inhibitor of 12-lipoxygenase. We have previously reported that neuroglia undergo nitric oxide (NO)-dependent and NO-independent apoptosis upon inflammatory activation. In the current work, we asked how anti-inflammatory baicalein influences autoregulatory apoptosis of activated microglia and their NO production. Baicalein attenuated NO production and apoptosis of lipopolysaccharide (LPS)-activated, but not interferon-gamma-activated, BV-2 mouse microglial cells as well as rat primary microglia cultures. The inhibition of NO production by baicalein was due to the suppression of inducible NO synthase induction. Moreover, baicalein inhibited LPS-induced nuclear factor-kappaB (NF-kappaB) activity in BV-2 cells without affecting caspase-11 activation, interferon regulatory factor-1 induction, or signal transducer and activator of transcription-1 phosphorylation. Transfection of BV-2 cells with a p65 subunit of NF-kappaB abolished the apoptosis-attenuating effects of baicalein, indicating that the inhibition of NF-kappaB is a major mechanism of action. Baicalein, however, did not significantly affect NO donor-mediated cytotoxicity, and the apoptosis-attenuating effects of baicalein were independent of 12-lipoxygenase inhibition. Based on our previous findings that activation-induced cell death (AICD) of microglia occurs through two separate pathways (NO-dependent pathway and caspase-11-dependent pathway), our current results suggest that baicalein selectively inhibits the NO-dependent apoptotic pathway of activated microglia by suppressing cytotoxic NO production. Also, the AICD-inhibiting effects of baicalein were specific for the inflammatory stimulus that activated microglia.
...
PMID:Flavonoid baicalein attenuates activation-induced cell death of brain microglia. 1260 97

Resident rat peritoneal macrophages synthesize a variety of prostanoids and leukotrienes from arachidonic acid. Overnight treatment with lipopolysaccharide (LPS) induces the synthesis of cyclooxygenase-2 (COX-2) and an altered prostanoid profile that emphasizes the preferential conversion of arachidonic acid to prostacyclin and prostaglandin E2. In these studies, we report that exposure to LPS also caused a strong suppression of 5-lipoxygenase but not 12-lipoxygenase activity, indicated by the inhibition of synthesis of both leukotriene B4 and 5-hydroxyeicosatetraenoic acid (5-HETE), but not of 12-HETE. Inhibition of 5-lipoxygenase activity by LPS was both time- and dose-dependent. Treatment of macrophages with prostaglandin E2 partially inhibited leukotriene synthesis, and cyclooxygenase inhibitors partially blocked the inhibition of leukotriene generation in LPS-treated cells. In addition to COX-2, nitric oxide synthase (NOS) was also induced by LPS. Treatment of macrophages with an NO donor mimicked the ability of LPS to significantly reduce leukotriene B4 synthesis. Inhibition of NOS activity in LPS-treated cells blunted the suppression of leukotriene synthesis. Inhibition of both inducible NOS and COX completely eliminated leukotriene suppression. Finally, macrophages exposed to prolonged LPS demonstrated impaired killing of Klebsiella pneumoniae and the combination of NOS and COX inhibitors restored killing to the control level. These results indicate that prolonged exposure to LPS severely inhibits leukotriene production via the combined action of COX and NOS products. The shift in mediator profile, to one that minimizes leukotrienes and emphasizes prostacyclin, prostaglandin E2 and NO, provides a signal that reduces leukocyte function, as indicated by impaired killing of Gram-negative bacteria.
...
PMID:Prolonged lipopolysaccharide inhibits leukotriene synthesis in peritoneal macrophages: mediation by nitric oxide and prostaglandins. 1451 57

The objective of this study was to test the hypothesis that the inflammatory response to lipopolysaccharide (LPS) in vivo is accompanied by down-regulation of toll-like receptor (TLR) 4 in adipose tissue, and a source of protected n-3 polyunsaturated fatty acid (PUFA) attenuates this response. Seventy-two castrated male pigs were individually fed either a control (CONT) diet, or the CONT diet containing 1.87% (LF) or 7.50% (HF) protected n-3 PUFA on a weight basis for 7 weeks. Adipose and muscle tissue biopsy samples were taken at Weeks 1, 2, 3, 4 and 7 to assess gene expression and/or confirm tissue enrichment with eicosapentaenoic acid and docosahexaenoic acid and reflected the n-3 PUFA contained in the diet. The LPS challenge was performed at week 7 and consisted of sequential injections of 10 and 2.5 mug LPS per kilogram of body weight 23 h apart. The LPS challenge resulted in a marked down-regulation (P=.004) of TLR4 at the protein level in the adipose tissue of challenged vs. control pigs, but LF and HF clearly blocked this response at the mRNA level. Although LF and HF also attenuated (P<.001) the LPS-induced acute febrile response and lowered (P<.002) serum concentrations of tumour necrosis factor alpha. Cyclooxygenase 2 and 12-lipoxygenase were readily expressed in porcine adipose tissue, but there was no effect of LF, HF or LPS on expression levels of these inflammatory mediators, or that of TNF and interleukin 6, at the conclusion of the challenge period. These findings indicate that adipose tissue responds to LPS administration in vivo by reducing TLR4 mRNA and protein abundance and that the anti-inflammatory effects of n-3 PUFA do not include down-regulation of TLR4 in adipose tissue.
...
PMID:n-3 PUFA attenuate lipopolysaccharide-induced down-regulation of toll-like receptor 4 expression in porcine adipose tissue but does not alter the expression of other immune modulators. 1743 24

Nitric oxide has been implicated in the pathogenesis of multiple sclerosis. However, it is still unclear whether nitric oxide plays a protective role or is deleterious. We have previously shown that peroxynitrite, a reaction product of nitric oxide and superoxide, is toxic to mature oligodendrocytes (OLs). The toxicity is mediated by intracellular zinc release, phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), activation of 12-lipoxygenase (12-LOX) and the formation of reactive oxygen species (ROS). In this study, we found that the donors of nitric oxide, dipropylenetriamine NONOate (DPT NONOate) and diethylenetriamine NONOate (DETA NONOate), protected OLs from peroxynitrite or zinc-induced toxicity. The protective mechanisms appear to be attributable to their inhibition of peroxynitrite- or zinc-induced ERK1/2 phosphorylation and 12-LOX activation. In cultures of mature OLs exposed to lipopolysaccharide (LPS), induction of inducible nitric oxide synthase (iNOS) generated nitric oxide and rendered OLs resistant to peroxynitrite-induced toxicity. The protection was eliminated when 1400W, a specific inhibitor of iNOS, was co-applied with LPS. Using MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, we found that nitrotyrosine immunoreactivity, an indicator of peroxynitrite formation, was increased in the spinal cord white matter, which correlated with the loss of mature OLs. Targeted gene deletion of the NADPH oxidase component gp91phox reduced clinical scores, the formation of nitrotyrosine and the loss of mature OLs. These results suggest that blocking the formation specifically of peroxynitrite, rather than nitric oxide, may be a protective strategy against oxidative stress induced toxicity to OLs.
...
PMID:Distinct role of nitric oxide and peroxynitrite in mediating oligodendrocyte toxicity in culture and in experimental autoimmune encephalomyelitis. 2151 Oct 12

1 2 Next >>