Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: CAS:54845-95-3 (15(S)-HETE)
 131 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

15-hydroxyeicosatetraenoic acid (15-HETE) is an eicosanoid, formed by the actions of 15-lipoxygenase, epoxygenases, and cyclooxygenases on arachidonic acid, whose tissue levels are often elevated during inflammation. The present study demonstrates that 15(S)-HETE is a potent inhibitor of polymorphonuclear neutrophil (PMN) migration across cytokine-activated endothelium in vitro. 15(S)-HETE is rapidly esterified into PMN phospholipids, and we report that 15-(S)-HETE-remodeled PMN displayed blunted adhesion to, and migration across, human endothelial cells that had been activated with either interleukin-1 beta or tumor necrosis factor-alpha Several lines of evidence suggested that 15(S)-HETE inhibited PMN transmigration by attenuating PMN responsiveness to endothelial cell-derived platelet-activating factor (PAF). The inhibitory action of 15(S)-HETE on transmigration was not restricted by the profile of adhesion molecules expressed by cytokine-activated endothelium. Interleukin-1 beta and tumor necrosis factor-alpha induce PAF production by endothelium, and PMN migration across cytokine-activated endothelium was inhibited by a PAF receptor antagonist. PMN migration across endothelium in response to exogenous PAF was dramatically inhibited following exposure of PMN to 15(S)-HETE. Furthermore, 15(S)-HETE-remodeled PMN displayed impaired cytoskeletal and adhesion responses when stimulated by exogenous PAF, two pivotal events in PMN migration across activated endothelium. 15(S)-HETE seemed to attenuate PMN responsiveness to PAF by inhibiting membrane-associated signal transduction events. In keeping with this interpretation, remodeling of PMN phospholipids with 15(S)-HETE was associated with a sixfold reduction in the affinity of specific high-affinity PAF receptors for their ligand and impaired PAF-triggered IP3 generation. In contrast, PMN adhesion responses stimulated by calcium ionophore or activators of protein kinase C remained intact. These results provide further evidence that 15(S)-HETE may be an important endogenous inhibitor of PMN-endothelial cell interaction that serves to limit or reverse neutrophil-mediated inflammation in vivo.
 ...
PMID:15-Hydroxyeicosatetraenoic acid inhibits neutrophil migration across cytokine-activated endothelium. 808 39

Human prostaglandin G/H synthase (hPGHS)-1 and hPGHS-2, key enzymes in the formation of prostanoids from arachidonic acid, were expressed at high levels in COS-7 cells using a T7 RNA polymerase/vaccinia virus expression system. The open reading frame of hPGHS-2 cloned into vaccinia virus without its natural 5' and 3' untranslated regions directed only low levels of hPGHS-2 enzyme activity in COS-7 cells. High-level hPGHS-2 expression was achieved by appending the 3' untranslated region of hPGHS-1 to the hPGHS-2 open reading frame, with subsequent expression of the hybrid mRNA using vaccinia virus. Enzymatically active recombinant hPGHS-1 and hPGHS-2 were present as glycosylated proteins in the microsomal fraction prepared from infected cells, whereas recombinant hPGHS-1 and hPGHS-2 prepared from the microsomal fraction of cells treated with tunicamycin, an inhibitor of N-linked glycosylation, were enzymatically inactive. The major prostanoid products formed by microsomes from COS-7 cells containing either recombinant hPGHS-1 or hPGHS-2 after incubation with arachidonic acid were prostaglandin D2 and E2, with lower levels of prostaglandin F2 alpha and 6-keto-prostaglandin F1 alpha. A range of potencies were observed for various nonsteroidal anti-inflammatory drugs as inhibitors of prostaglandin E2 synthesis by hPGHS-1 and hPGHS-2. Recombinant hPGHS-1 and hPGHS-2 both produced 15- and 11-hydroxyeicosatetraenoic acid (HETE) from arachidonic acid, with 15-HETE production by hPGHS-2 being stimulated 5-fold by preincubation with aspirin. Chiral phase high performance liquid chromatography analysis showed that aspirin-treated hPGHS-2 produced 15(R)-HETE, with no detectable 15(S)-HETE.
 ...
PMID:Overexpression of human prostaglandin G/H synthase-1 and -2 by recombinant vaccinia virus: inhibition by nonsteroidal anti-inflammatory drugs and biosynthesis of 15-hydroxyeicosatetraenoic acid. 811 74

15(S)-Hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid (15-HETE) exerted a time- and concentration-dependent inhibition of superoxide anion (O2-) production and exocytosis of both azurophil and specific granule constituents from human polymorphonuclear neutrophils (PMN) stimulated with the receptor-specific agonists, N-formylmethionylleucylphenylalanine (FMLP), platelet-activating factor, and leukotriene B4, but not that elicited by phorbol 12-myristate 13-acetate. 15-HETE did not alter the binding of FMLP to its specific receptors on PMN but, rather, appeared to interfere with a subsequent process in signal transduction. Receptor-coupled production of inositol 1,4,5-trisphosphate (InsP3) and increases in cytosolic free calcium elicited with FMLP, platelet-activating factor, and leukotriene B4 were suppressed by 15-HETE. 15-HETE did not, however, inhibit the mobilization of 45Ca from intracellular stores elicited by the addition of InsP3 to permeabilized PMN. 15-HETE suppressed O2- production and increases in intracellular [Ca2+] induced when cell-surface receptors were bypassed and the PMN were activated directly by the guanine nucleotide-binding protein (G protein) activators aluminum fluoride (AlF4-) and mastoparan. 15-HETE, however, did not perturb all G protein functions because cAMP production in FMLP-activated PMN was essentially unaffected by 15-HETE. These data support the proposition that 15-HETE modulates receptor-triggered activation of PMN either by uncoupling G protein stimulation of phospholipase C or by directly inhibiting phospholipase C, thus inhibiting the InsP3-dependent rise in intracellular [Ca2+] that is prerequisite for PMN responsiveness to receptor agonists.
 ...
PMID:Transmembrane signaling in human polymorphonuclear neutrophils: 15(S)-hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid modulates receptor agonist-triggered cell activation. 839 15

15-Lipoxygenase is expressed in foamy macrophages of atherosclerotic lesions and has been implicated in the oxidative modification of low density lipoprotein during early stages of atherogenesis. To establish an animal model of 15-lipoxygenase overexpression, we created transgenic rabbits that express at high level the human 15-lipoxygenase in monocyte-derived macrophages but not in liver, heart, kidney, lung, or other tissues. The expression level of the enzyme in monocyte-derived macrophages is comparable to that of interleukin 4 (IL4)-treated human monocytes, but more than 20-fold higher than in macrophages of normal rabbits. The transgenic enzyme oxygenates linoleic acid to 13S-hydroperoxy-9, 11 (Z,E)-octadecadienoic acid (13-HODE), and arachidonic acid to a mixture of 12S-hydroperoxy-5, 8, 10, 14 (Z,Z,E,Z)-eicosatetraenoic acid (12S-HETE), and 15S-hydroperoxy-5, 8, 11, 14 (Z,Z,Z,E)-eicosatetraenoic acid (15S-HETE). The 12-HETE/15-HETE ratio varied between 0.3 and 5.4, indicating a remarkable variability in the positional specificity of the transgenic enzyme. Macrophages from normal rabbits consistently produced 12S-HETE as the major oxygenation product. 15-Lipoxygenase-overexpressing rabbits may be used for further mechanistic studies on the implication of lipoxygenase in atherogenesis; they are also an ideal model for testing the in vivo action of 15-lipoxygenase inhibitors.
 ...
PMID:Transgenic rabbits with the integrated human 15-lipoxygenase gene driven by a lysozyme promoter: macrophage-specific expression and variable positional specificity of the transgenic enzyme. 852 42

5-Lipoxygenase activation of human blood polymorphonuclear cells (PMN) from asthmatic patients (asthmatics) was studied to investigate whether differences may exist with healthy subjects (controls). The respective cell capacities to produce lipoxins (LXs), leukotrienes, and 5(S), 15(S)-dihydroxyeicosatetraenoic acid [5(S),15(S)-diHETE] were compared under in vitro stimulation by ionophore A23187, with or without exogenous 15(S)-hydroxyeicosatetraenoic acid [15(S)-diHETE]. Eicosanoids were analyzed by elution with an isocratic reverse-phase high performance liquid chromatography system, and their profiles, detected by simultaneous monitoring at 302, 280, and 246 nm, were evaluated on the basis of chromatographic behavior: UV spectral characteristics and coelution with synthetic standards. In the presence of exogenous 15(S)-HETE, human PMN were able to produce LXs and 5(S),15(S)-diHETE, PMN from asthmatics were able to produce 5(S), 5(S),15(S)-diHETE, and LXs from endogenous sources, whereas in the same experimental conditions, no detectable amounts of these compounds were released by PMN from controls. The levels of 5(S),15(S)-diHETE, and LXs biosynthesized from endogenous arachidonic acid were highly correlated. Two different LX patterns were observed involving two possible metabolic pathways: (a) via the intermediate 5,6-epoxytetraene alone for LXs generation from exogenous 15(S)-HETE; and (b) via 5,6- and/or 14,15-epoxytetraenes leading to the formation of an enzyme-bound delocalized carbocation for LXs generation from endogenous arachidonate, respectively. The enhanced 5-lipoxygenase activation of blood PMN from asthmatics and the metabolism of exogenous 15(S)-HETE may reflect a priming induced by various mediators released from environmental cells, and could be considered as a model of transcellular signalization between PMN and endothelial cells.
 ...
PMID:5(S),15(S)-dihydroxyeicosatetraenoic acid and lipoxin generation in human polymorphonuclear cells: dual specificity of 5-lipoxygenase towards endogenous and exogenous precursors. 866 21

Eicosanoids have been implicated in colon carcinogenesis, but very little is known on the potential role of leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs) in this process; such compounds are produced by colonocytes and tumor infiltrating leukocytes. We studied the effect of LTB4, LTB4 methyl ester, LTB5, 12(R)-HETE, 12(S)-HETE and 15(S)-HETE (10(-10), 10(-8), 10(-6) M) on the proliferation rate, the cell cycle distribution, and the rate of apoptosis in HT-29 and HCT-15 human colon carcinoma cells. Our data show that LTB4, a lipoxygenase product, increased the proliferation rate of both cell lines in a time- and concentration-dependent manner. In HT-29 cells the concentration-response curve was bell-shaped (maximal effect at 10(-8) M). The proliferative effects of LTB4 in HT-29 cells were inhibited by SC-41930, a competitive antagonist of LTB4, suggesting the existence of an LTB4 receptor in epithelial cells. The methyl ester of LTB4 stimulated the proliferation of these cells, but LTB5, an isomer of LTB4 derived from eicosapentaenoic acid, did not. Of the HETEs, only 12(R)-HETE, a P-450 product, stimulated the proliferation of both cell lines; the other HETEs, all lipoxygenase products, failed to affect the proliferation of these cells. None of these eicosanoids had any effect on cell cycle distribution or apoptosis in either cell line. Taken together with our previous data showing that PGs stimulate colon cancer cell proliferation (Qiao et al. (1995) Biochim. Biophys. Acta 1258, 215-223), these findings indicate that arachidonic acid products synthesized via at least three different pathways (cyclooxygenase, lipoxygenase, P-450) may not be able to modulate the growth of colon cancer, and suggest a potential role in human colon carcinogenesis for LTB4 and 12(R)-HETE.
 ...
PMID:The effect of leukotrienes B and selected HETEs on the proliferation of colon cancer cells. 867 90

Dual-laser flow cytometry, based on the properties of the DNA-binding dyes Hoechst 33342 and propidium iodide, was used, with light and electron microscopy and DNA fragmentation studies, to define the influence of lipoxygenase-derived eicosanoids on apoptosis of human polymorphonuclear neutrophils (PMN) in vitro. Apoptosis was characterized by progression through an early apoptotic phase characterized by condensation of chromatin and coalescence of nuclear lobes, to a late apoptotic phase characterized by nuclear degradation and evanescence, and secondary necrosis. Prolonged exposure of PMN to leukotriene B4 (LTB4) afforded dose-dependent inhibition of constitutive PMN apoptosis (percentage of normal and apoptotic PMN, respectively, after aging for 18 h: vehicle, 30.5 +/- 2.7% and 61.8 +/- 3.2%; LTB4 10(-7) M, 57.6 +/- 1.2% and 37.6 +/- 1.0%) and apoptosis triggered by the classic peptide chemoattractant FMLP. In contrast, apoptosis was not affected by the LTB4 precursor 5(S)-hydroxyeicosatetraenoic acid (HETE), the omega-oxidation LTB4 metabolites 20-hydroxy-LTB4 and 20-carboxy-LTB4, the cysteinyl leukotriene LTC4, the 15-lipoxygenase product 15(S)-HETE, or the lipoxygenase interaction product lipoxin A4. The anti-apoptotic effect of LTB4 was mimicked by 20,20,20-trifluoro-LTB4, LTB4-dimethylamide, and 14,15-dehydro-LTB4, and was blunted by pertussis toxin and genistein, inhibitors of G alpha i GTP-binding proteins and tyrosine kinases, respectively, but not by staurosporine, 15(S)-HETE, or lipoxin A4. This unique pharmacologic profile suggested that LTB4 attenuated apoptosis through activation of cell surface receptors and signaling events distinct from those involved with PMN trafficking, degranulation, and respiratory bursts.
 ...
PMID:Sequential morphologic events during apoptosis of human neutrophils. Modulation by lipoxygenase-derived eicosanoids. 881 21

Propolis is a resinous material gathered by honey bees from the buds and bark of certain trees and plants, and used inside their hives. Characteristic components of propolis are many kinds of flavonoid aglycones. The methanol extract of a Brazilian propolis was fractionated by HPLC, and a tumoricidal substance was isolated and characterized as a new clerodane diterpenoid (PMS-1) with a molecular formula of C20H32O3 (MW: 320). We investigated the effects of PMS-1 on skin tumorigenesis and the development of skin tumors induced by 7,12-dimethylbenz(a)anthracene application on mouse back skin. It was tentatively concluded that PMS-1 reduced the incidence of skin tumors by inhibition of DNA synthesis in a de novo pathway, and suppressed the growth of the tumors by decreasing DNA synthesis in a salvage pathway.
 ...
PMID:Effects of a new clerodane diterpenoid isolated from propolis on chemically induced skin tumors in mice. 891 67

The ubiquitous hydroxylated fatty acids derived from arachidonic acid (HETEs) or linoleic acid (HODEs) exhibit diverse biological effects including chemotaxis, cell proliferation, and modulation of several enzymatic pathways, including the 5-lipoxygenase leading to the inflammatory leukotrienes. It was observed that 12(S)- and 15(S)-HETE and 13(S)-HODE (12- and 15-lipoxygenase-derived metabolites, respectively) inhibited the 5-lipoxygenase present in rat basophilic leukemia (RBL-1) cell homogenates whereas the 15(R) chiral enantiomer and the nonhydroxylated linoleic, oleic, and stearic acids were either less potent or ineffective. In examining the mechanism of this inhibition, the relative effectiveness of several fatty acids in displacing [3H]15-HETE bound to cytosol preparations were compared and the results indicated that these (S) hydroxy fatty acids and 5(S)-HETE were significantly more potent than either the 15(R) enantiomer, 15(S)-HETE methyl ester, arachidonic acid, or prostaglandin F2alpha. In order to identify the protein(s) that specifically binds HETEs, 15(S)-HETE biotin hydrazide was used as a probe to detect any HETE-protein complexes as this compound both inhibited the 5-lipoxygenase and interfered with the binding of [3H]15-HETE to cytosol preparations. SDS-PAGE analysis and chemiluminescent detection revealed that the major cytosolic proteins that bound this biotinylated probe had molecular masses of 43 and 51 kD. Fatty acid competition experiments indicated that the order of effectiveness in displacing this probe from these proteins was 13(S)-HODE > 5(S)-HETE approximately equal to 15(S)-HETE > > stearic acid approximately equal to arachidonic acid approximately equal to 15(R)-HETE. Amino acid sequence analysis showed that the 43 kD protein was actin. These findings suggest the possibility that actin may play a major role in the biological effects of monohydroxylated metabolites derived from cellular 5-, 12-, and 15-lipoxygenases.
 ...
PMID:Mono (S) hydroxy fatty acids: novel ligands for cytosolic actin. 968 51

The aim of this study was to investigate eicosanoid metabolism by human peripheral blood monocytes (PBM) from steroid-dependent asthmatic patients as compared to control subjects and untreated asthmatic patients. Eicosanoid biosynthesis by PBM isolated from venous blood using Percoll gradient centrifugation was evaluated following stimulation of 5 x 10(6) cells with calcium ionophore A23187, with or without exogenous 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE), and analyzed by reverse phase high performance liquid chromatography (RP-HPLC). Without 15(S)-HETE, PBM synthesized leukotriene B4 (LTB4) only (40 +/- 12 ng and 59 +/- 11 ng for untreated and steroid-dependent asthmatics, respectively). In the presence of 15(S)-HETE, PBM produced six-fold smaller amounts of leukotriene B4 (P < 0.0001). They also released 5(S),15(S)-dihydroxyeicosatetraenoic acid (5(S),15(S)-diHETE) in similar amounts for all the populations, whereas low amounts of lipoxins (LXs) were produced by PBM from asthmatics only (2.7 +/- 0.7 ng and 4.6 +/- 2.8 ng for untreated and steroid-dependent asthmatics, respectively). Moreover, PBM were also able to release an unknown compound containing conjugated triene chromophore. Cells from steroid-dependent asthmatic patients synthesized this unknown metabolite in higher amounts than controls and untreated asthmatics (133 +/- 18 ng vs 52 +/- 19 ng and 68 +/- 15 ng, respectively, P < 0.02). This work shows for the first time that human PBM are able to metabolize 15(S)-HETE and lead to lipoxins and to an unknown metabolite, with the amounts of the latter being enhanced by long-term corticosteroid treatment.
 ...
PMID:Generation of eicosanoids from 15(S)-hydroxyeicosatetraenoic acid in blood monocytes from steroid-dependent asthmatic patients. 976 31


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>