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Lipid Mediators (lipid + mediator)
Kinds of Lipid Mediators Selected AbstractsRole of ceramide kinase in peroxisome proliferator-activated receptor beta-induced cell survival of mouse keratinocytesFEBS JOURNAL, Issue 15 2008Kiyomi Tsuji Ceramide (Cer) is known to be a lipid mediator in apoptosis and to have an important role in cell fate, via control of intracellular Cer levels. Recently, ceramide kinase (CerK) was identified as an enzyme that converts Cer to ceramide 1-phosphate (C1P). We examined potential functions of CerK in the regulation of keratinocyte survival, and the possible involvement of peroxisome proliferator-activated receptor beta (PPAR,). PPAR, is known to be a nuclear receptor acting as a ligand-inducible transcription factor and has been implicated in the control of keratinocyte survival. In the mouse keratinocyte cell line SP1, serum starvation induced cell death and the accumulation of intracellular Cer, an apoptotic event. However, apoptosis was inhibited by activation of PPAR,. Interestingly, activation of PPAR, enhanced the mRNA expression of CerK and CerK activity. Furthermore, the cell survival effect of PPAR, was greatly diminished in keratinocytes isolated from CerK-null mice. Chromatin immunoprecipitation revealed that, in vivo, PPAR, binds to the CerK gene via a sequence located in the first intron. Electrophoretic mobility-shift assays confirmed that PPAR, associates with this sequence in vitro. These findings indicated that CerK gene expression was directly regulated by PPAR,. In conclusion, our results demonstrate that PPAR,-mediated upregulation of CerK gene expression is necessary for keratinocyte survival against serum starvation-induced apoptosis. [source] Specificity of a new lipid mediator produced by testicular and peritoneal macrophages on steroidogenesisINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 5 2000Lukyanenko Macrophage-derived factor (MDF) is a lipophilic factor produced by rat testicular and peritoneal macrophages that maximally stimulates testosterone production by rat Leydig cells through a steroidogenic acute regulatory protein independent mechanism. The purpose of the present study was to determine whether MDF is also produced by human macrophages, and/or if it acts on human steroidogenic cells. We also studied the tissue-specific functions of MDF by determining if it also acts on steroidogenic cells of the ovary and adrenal glands and, if so, does it require new protein synthesis. It was found that MDF was produced by human peritoneal macrophages, and was capable of stimulating human steroidogenic cells. In terms of tissue specificity, it was found that primary cultures of rat adrenocortical cells respond to MDF with increased secretion of aldosterone and corticosterone, as did rat granulosa cells by producing progesterone. MDF acted in the presence of cycloheximide, indicating that it does not require new protein synthesis. These results indicate that MDF may have significant therapeutic potential and provide a basis for future studies concerning its physiological role in humans. These results further suggest that MDF is not only involved in paracrine regulation of Leydig cells, but also has the potential for the local regulation of steroidogenesis in both granulosa and adrenal cortical cells. [source] Prostaglandin F2, upregulates interleukin-6 production in human gingival fibroblastsJOURNAL OF PERIODONTAL RESEARCH, Issue 2 2001Kazuyuki Noguchi Prostaglandin F2,(PGF2,) is a bioactive lipid mediator which has been suggested to be involved in the pathogenesis of periodontal disease. However, the roles of PGF2, in periodontal lesions are poorly understood. In the present study, we investigated the effect of PGF2, on interleukin (IL)-6 production in human gingival fibroblasts (HGF). PGF2,stimulated IL-6 production in a time- and concentration-dependent fashion. IL-1, and tumor necrosis factor ,(TNF,), proinflammatory cytokines, induced IL-6 production in a time-dependent manner, and PGF2,synergistically enhanced IL-6 production induced by IL-1, and TNF,. IL-6 mRNA was expressed in PGF2, -stimulated HGF, and PGF2, increased IL-6 mRNA levels induced by IL-1, and TNF,. Fluprostenol, a selective FP receptor agonist, could mimic PGF2, -induced IL-6 production. Since FP receptors are coupled to elevation of intracellular calcium and activation of protein kinase C (PKC), the mechanism of IL-6 production by PGF2, was investigated using TMB-8, an inhibitor of Ca2+ mobilization from intracellular stores, and calphostin C, an inhibitor of PKC. TMB-8 significantly suppressed PGF2, -induced IL-6 production, whereas calphostin C showed a stimulatory effect on PGF2, -induced IL-6 production. From these data, we suggest that PGF2, upregulates IL-6 production through FP receptors in HGF, that PGF2, synergistically enhances IL-6 production in IL-1,- and TNF,-stimulated HGF, and that PGF2, -induced IL-6 production may be dependent on intracellular Ca2+ mobilization and be downregulated by PKC activation. PGF2, may be involved in the pathogenesis of periodontal disease by enhancing IL-6 levels in periodontal lesions. [source] ,-Tocopheryl phosphate , An active lipid mediator?MOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 5 2010Jean-Marc Zingg Abstract The vitamin E (,-tocopherol, ,T) derivative, ,-tocopheryl phosphate (,TP), is detectable in small amounts in plasma, tissues, and cultured cells. Studies done in vitro and in vivo suggest that ,T can become phosphorylated and ,TP dephosphorylated, suggesting the existence of enzyme(s) with ,T kinase or ,TP phosphatase activity, respectively. As a supplement in animal studies, ,TP can reach plasma concentrations similar to ,T and only a part is dephosphorylated; thus, ,TP may act both as pro-vitamin E, but also as phosphorylated form of vitamin E with possibly novel regulatory activities. Many effects of ,TP have been described: in the test tube ,TP modulates the activity of several enzymes; in cell culture ,TP affects proliferation, apoptosis, signal transduction, and gene expression; in animal studies ,TP prevents atherosclerosis, ischemia/reperfusion injury, and induces hippocampal long-term potentiation. At the molecular level, ,TP may act as a cofactor for enzymes, as an active lipid mediator similar to other phosphorylated lipids, or indirectly by altering membrane characteristics such as lipid rafts, fluidity, and curvature. In this review, the molecular and cellular activities of ,TP are examined and the possible functions of ,TP as a natural compound, cofactor and active lipid mediator involved in signal transduction and gene expression discussed. [source] Platelet-activating factor and human meningiomasNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 6 2006Y. Denizot Meningiomas are common primary intracranial tumours. Platelet-activating factor (PAF) is an inflammatory and angiogenic lipid mediator involved in several types of cancer. The presence of PAF receptor (PAF-R) transcripts, the levels of PAF, the phospholipase A2 activity (PLA2, the enzymatic activity implicated in PAF formation) and the PAF acetylhydrolase activity (AHA, the PAF degrading enzyme) were investigated in 49 human meningiomas. PAF-R transcripts, PAF, PLA2 and AHA were detected in meningiomas. However, their levels did not correlate with biological parameters such as the tumour grade, the presence of associated oedema, necrosis, mitotic index as well as intensity of the neovascularization and chronic inflammatory response. In conclusion, PAF is present in meningiomas where it might act on tumour growth by altering the local angiogenic and/or cytokine networks as previously suggested for human breast and colorectal cancer. [source] The Role of Platelet-activating Factor in the Mammalian Female Reproductive TractREPRODUCTION IN DOMESTIC ANIMALS, Issue 6 2008U Tiemann Contents Platelet-activating factor (PAF) is a potent lipid mediator produced by various cell types of mammals and is involved in an inflammatory-like process with increased vascular permeability. Platelet-activating factor exerts its actions through the activation of specific PAF receptors (PAF-R) found in cells and tissues of the female reproductive tract. The aim of this article was summarized briefly in the current research on the role of PAF in female reproductive functions. Platelet-activating factor has been implicated in processes of ovulation, implantation and parturition because of its angiogenic and growth factor properties. This factor is influenced by ovarian steroid hormones in bringing about changes in the uterus and is a candidate molecule for initial embryo,maternal dialogue. Tissue concentrations of PAF are regulated by the equilibrium between biosynthesis and degradation by PAF-acetylhydrolase (PAF-AH). Antagonists of PAF interfere with ovulation and implantation. Platelet-activating factor, its receptor, and PAF-AH activity play an important role in the maintenance of pregnancy. [source] ORIGINAL ARTICLE: Expression of Autotaxin, an Ectoenzyme that Produces Lysophosphatidic Acid, in Human PlacentaAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 2 2009Yuki Iwasawa Problem, Lysophosphatidic acid (LPA) is a bioactive lipid mediator and thought to play an important role in pregnancy. Plasma LPA is produced by autotaxin (ATX), and ATX activity in plasma increases during pregnancy paralleled with gestational weeks and decreases to near the non-pregnant level soon after delivery. However, the source of increased ATX during pregnancy is still uncertain. We hypothesized that the source of increased ATX might be placenta. Method of study, We investigated the protein and mRNA expression of ATX in human placenta using immunohistochemistry and RT-PCR, respectively. Results, At all 3 gestational trimesters, immunohistochemical staining for placenta tissues revealed the most marked positive staining of ATX protein in trophoblasts. Real-time PCR revealed that mRNA amounts of ATX in placenta tissues paralleled with gestational weeks, i.e. ATX level in plasma. Conclusion, These findings suggest that trophoblasts might produce ATX and its bioactive resultant substance, LPA, paralleled with gestational weeks. [source] The identification of a phospholipase B precursor in human neutrophilsFEBS JOURNAL, Issue 1 2009Shengyuan Xu A phospholipase B (PLB) precursor was purified from normal human granulocytes using Sephadex G-75, Mono-S cation-exchange and hydroxyapatite columns. The molecular mass of the protein was estimated to be , 130 kDa by gel filtration and 22 and 42 kDa by SDS/PAGE. Tryptic peptide and sequence analyses by MALDI-TOF and tandem mass spectrometry (MS/MS) identified the protein as a FLJ22662 (Homo sapiens) gene product, a homologue of the amoeba Dictyostelium discoideum PLB. The native protein needed modifications to acquire deacylation activity against phospholipids including phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine and lysophospholipids. Enzyme activity was associated with fragments derived from the 42 kDa fragment. The enzyme revealed a PLB nature by removing fatty acids from both the sn -1 and sn -2 positions of phospholipids. The enzyme is active at a broad pH range with an optimum of 7.4. Immunoblotting of neutrophil postnuclear supernatant using antibodies against the 42 kDa fragment detected a band at a molecular mass of 42 kDa, indicating a neutrophil origin of the novel PLB precursor. The existence of the PLB precursor in neutrophils and its enzymatic activity against phospholipids suggest a role in the defence against invading microorganisms and in the generation of lipid mediators of inflammation. [source] Molecular mechanisms underlying inflammatory lung diseases in the elderly: Development of a novel therapeutic strategy for acute lung injury and pulmonary fibrosis,GERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 3 2005Takahide Nagase In the elderly, inflammatory lung diseases, including acute lung injury and pulmonary fibrosis, are significant in terms of both mortality and difficulty in management. Acute respiratory distress syndrome (ARDS) is an acute lung injury and the mortality rate for ARDS ranges from 40 to 70% despite intensive care. Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disorder of the lung parenchyma. No useful drugs are currently available to treat IPF. However, molecular mechanisms underlying these lung diseases are little understood and the development of a novel therapeutic strategy is urgently needed. Platelet-activating factor (PAF) and metabolites of arachidonic acid, i.e. eicosanoids, are lipid mediators that have various biological effects. A key enzyme for the production of these inflammatory mediators, including eicosanoids and PAF, is phospholipase A2. In particular, cytosolic PLA2 (cPLA2) is especially important. The purpose of this article is to report novel findings regarding the role of PAF and cPLA2 in lung inflammatory diseases, especially, acute lung injury and pulmonary fibrosis. To address this question, we used mutant mice, i.e. PAFR transgenic mice, PAFR gene-disrupted mice and cPLA2 gene-disrupted mice. We have shown that PAF and eicosanoids, downstream mediators of cPLA2, may be involved in the pathogenesis of ARDS and IPF, which are important diseases in the elderly. Although there exist extreme differences in clinical features between ARDS and IPF, both diseases are fatal disorders for which no useful drugs are currently available. On the basis of recent reports using mutant mice, cPLA2 might be a potential target to intervene in the development of pulmonary fibrosis and acute lung injury in the elderly. [source] Mast cells and eicosanoid mediators: a system of reciprocal paracrine and autocrine regulationIMMUNOLOGICAL REVIEWS, Issue 1 2007Joshua A. Boyce Summary:, When activated by specific antigen, complement, or other transmembrane stimuli, mast cells (MCs) generate three eicosanoids: prostaglandin (PG)D2, leukotriene (LT)B4, and LTC4, the parent molecule of the cysteinyl leukotrienes (cysLTs). These diverse lipid mediators, which are generated from a single cell membrane-associated precursor, arachidonic acid, can initiate, amplify, or dampen inflammatory responses and influence the magnitude, duration, and nature of subsequent immune responses. PGD2 and cysLTs, which were originally recognized for their bronchoconstricting and vasoactive properties, also serve diverse and pivotal functions in effector cell trafficking, antigen presentation, leukocyte activation, matrix deposition, and fibrosis. LTB4 is a powerful chemoattractant for neutrophils and certain lymphocyte subsets. Thus, MCs can contribute to each of these processes through eicosanoid generation. Additionally, MCs express G-protein-coupled receptors specific for cysLTs, LTB4, and another eicosanoid, PGE2. Each of these receptors can regulate MC functions in vivo by autocrine and paracrine mechanisms. This review focuses on the biologic functions for MC-associated eicosanoids, the regulation of their production, and the mechanisms by which eicosanoids may regulate MC function in host defense and disease. [source] Dihomo-,-linolenic acid inhibits tumour necrosis factor-, production by human leucocytes independently of cyclooxygenase activityIMMUNOLOGY, Issue 3 2003Maaike M. B. W. Dooper Summary Dietary oils (such as borage oil), which are rich in ,-linolenic acid (GLA), have been shown to be beneficial under inflammatory conditions. Dihomo-GLA (DGLA) is synthesized directly from GLA and forms a substrate for cyclooxygenase (COX) enzymes, resulting in the synthesis of lipid mediators (eicosanoids). In the present study, the immunomodulatory effects of DGLA were investigated and compared with those of other relevant fatty acids. Freshly isolated human peripheral blood mononuclear cells (PBMC) were cultured in fatty acid (100 µm)-enriched medium for 48 hr. Subsequently, cells were stimulated with lipopolysaccharide (LPS) for 20 hr and the cytokine levels were measured, in supernatants, by enzyme-linked immunosorbent assay (ELISA). Phospholipids were analysed by gas chromatography. Fatty acids were readily taken up, metabolized and incorporated into cellular phospholipids. Compared with the other fatty acids tested, DGLA exerted pronounced modulatory effects on cytokine production. Tumour necrosis factor-, (TNF-,) and interleukin (IL)-10 levels were reduced to 60% of control levels, whereas IL-6 levels were not affected by DGLA. Kinetic studies showed that peak levels of TNF-,, occurring early after LPS addition, were inhibited strongly, whereas IL-10 levels were not affected until 15 hr after stimulation. Both the reduction of cytokine levels and the decrease in arachidonic acid levels in these cells, induced by DGLA, were dose dependent, suggesting a shift in eicosanoid-subtype synthesis. However, although some DGLA-derived eicosanoids similarly reduced TNF-, levels, the effects of DGLA were probably not mediated by COX products, as the addition of indomethacin did not alter the effects of DGLA. In conclusion, these results suggest that DGLA affects cytokine production by human PBMC independently of COX activation. [source] Regulation of Wnt/,-catenin pathway by cPLA2, and PPAR,JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2008Chang Han Abstract Cytosolic phospholipase A2, (cPLA2,) is a rate-limiting key enzyme that releases arachidonic acid (AA) from membrane phospholipid for the production of biologically active lipid mediators including prostaglandins, leukotrienes and platelet-activating factor. cPLA2, is translocated to nuclear envelope in response to intracellular calcium increase and the enzyme is also present inside the cell nucleus; however, the biological function of cPLA2, in the nucleus remains unknown. Here we show a novel role of cPLA2, for activation of peroxisome proliferator-activated receptor-, (PPAR,) and ,-catenin in the nuclei. Overexpression of cPLA2, in human cholangiocarcinoma cells induced the binding of PPAR, to ,-catenin and increased their association with the TCF/LEF response element. These effects are inhibited by the cPLA2, siRNA and inhibitors as well as by siRNA knockdown of PPAR,. Overexpression of PPAR, or treatment with the selective PPAR, ligand, GW501516, also increased ,-catenin binding to TCF/LEF response element and increased its reporter activity. Addition of AA and GW501516 to nuclear extracts induced a comparable degree of ,-catenin binding to TCF/LEF response element. Furthermore, cPLA2, protein is present in the PPAR, and ,-catenin binding complex. Thus the close proximity between cPLA2, and PPAR, provides a unique advantage for their efficient functional coupling in the nucleus, where AA produced by cPLA2, becomes immediately available for PPAR, binding and subsequent ,-catenin activation. These results depict a novel interaction linking cPLA2,, PPAR, and Wnt/,-catenin signaling pathways and provide insight for further understanding the roles of these key molecules in human cells and diseases. J. Cell. Biochem. 105: 534,545, 2008. © 2008 Wiley-Liss, Inc. [source] Brain regulation of food intake and appetite: molecules and networksJOURNAL OF INTERNAL MEDICINE, Issue 4 2005C. BROBERGER Abstract. In the clinic, obesity and anorexia constitute prevalent problems whose manifestations are encountered in virtually every field of medicine. However, as the command centre for regulating food intake and energy metabolism is located in the brain, the basic neuroscientist sees in the same disorders malfunctions of a model network for how integration of diverse sensory inputs leads to a coordinated behavioural, endocrine and autonomic response. The two approaches are not mutually exclusive; rather, much can be gained by combining both perspectives to understand the pathophysiology of over- and underweight. The present review summarizes recent advances in this field including the characterization of peripheral metabolic signals to the brain such as leptin, insulin, peptide YY, ghrelin and lipid mediators as well as the vagus nerve; signalling of the metabolic sensors in the brainstem and hypothalamus via, e.g. neuropeptide Y and melanocortin peptides; integration and coordination of brain-mediated responses to nutritional challenges; the organization of food intake in simple model organisms; the mechanisms underlying food reward and processing of the sensory and metabolic properties of food in the cerebral cortex; and the development of the central metabolic system, as well as its pathological regulation in cancer and infections. Finally, recent findings on the genetics of human obesity are summarized, as well as the potential for novel treatments of body weight disorders. [source] The significance of platelet-activating factor and fertility in the male primate: a reviewJOURNAL OF MEDICAL PRIMATOLOGY, Issue 1 2005William E. Roudebush Abstract:, Since its discovery nearly 30 years ago platelet-activating factor (PAF) has emerged as one of the more important lipid mediators known. PAF (1- O -alkyl-2- O -acetyl- sn -glycero-3-phosphorylcholine) exists endogenously as a mixture of molecular species with structural variants of the alkyl moiety. PAF is a novel potent signaling phospholipid that has unique pleiotropic biological properties in addition to platelet activation. PAF also plays a significant role in reproduction and is present in the sperm of a number of primate species. PAF content in squirrel monkey sperm is significantly higher during the breeding season than the non-breeding season. PAF content in rhesus sperm has a significant relationship with sperm motility. PAF content in human sperm has a positive correlation with seminal parameters and pregnancy outcomes. The enzymes (lyso-PAF-acetyltransferase and PAF-acetylhydrolase) necessary for PAF activation and deactivation are present in primate sperm. PAF-acetylhydrolase may act as a ,decapacitation factor'. Removal of this enzyme during capacitation promotes PAF synthesis increasing primate motility and fertilization. PAF also plays a significant role in the fertilization process, enhancing the fertilization rates of oocytes. Enhanced embryo development has also been reported in oocytes fertilized with PAF-treated sperm. Exogenous PAF will also significantly improve primate artificial insemination pregnancy outcomes. PAF antagonists inhibit sperm motility, acrosome reaction, and fertilization thus suggesting the presence of receptors for PAF. The PAF-receptor is present on primate sperm, with altered transcript levels and distribution patterns on abnormal cells. Whereas, the exact mechanism of PAF in sperm function and reproduction is uncertain, its importance in normal primate fertility is substantial. [source] Modulation of inflammation in brain: a matter of fatJOURNAL OF NEUROCHEMISTRY, Issue 3 2007Akhlaq A. Farooqui Abstract Neuroinflammation is a host defense mechanism associated with neutralization of an insult and restoration of normal structure and function of brain. Neuroinflammation is a hallmark of all major CNS diseases. The main mediators of neuroinflammation are microglial cells. These cells are activated during a CNS injury. Microglial cells initiate a rapid response that involves cell migration, proliferation, release of cytokines/chemokines and trophic and/or toxic effects. Cytokines/chemokines stimulate phospholipases A2 and cyclooxygenases. This results in breakdown of membrane glycerophospholipids with the release of arachidonic acid (AA) and docosahexaenoic acid (DHA). Oxidation of AA produces pro-inflammatory prostaglandins, leukotrienes, and thromboxanes. One of the lyso-glycerophospholipids, the other products of reactions catalyzed by phospholipase A2, is used for the synthesis of pro-inflammatory platelet-activating factor. These pro-inflammatory mediators intensify neuroinflammation. Lipoxin, an oxidized product of AA through 5-lipoxygenase, is involved in the resolution of inflammation and is anti-inflammatory. Docosahexaenoic acid is metabolized to resolvins and neuroprotectins. These lipid mediators inhibit the generation of prostaglandins, leukotrienes, and thromboxanes. Levels of prostaglandins, leukotrienes, and thromboxanes are markedly increased in acute neural trauma and neurodegenerative diseases. Docosahexaenoic acid and its lipid mediators prevent neuroinflammation by inhibiting transcription factor NF,B, preventing cytokine secretion, blocking the synthesis of prostaglandins, leukotrienes, and thromboxanes, and modulating leukocyte trafficking. Depending on its timing and magnitude in brain tissue, inflammation serves multiple purposes. It is involved in the protection of uninjured neurons and removal of degenerating neuronal debris and also in assisting repair and recovery processes. The dietary ratio of AA to DHA may affect neurodegeneration associated with acute neural trauma and neurodegenerative diseases. The dietary intake of docosahexaenoic acid offers the possibility of counter-balancing the harmful effects of high levels of AA-derived pro-inflammatory lipid mediators. [source] Gas chromatography,mass spectrometry analysis of endogenous cannabinoids in healthy and tumoral human brain and human cells in cultureJOURNAL OF NEUROCHEMISTRY, Issue 2 2001Mauro Maccarrone Endocannabinoids are lipid mediators thought to modulate central and peripheral neural functions. We report here gas chromatography,electron impact mass spectrometry analysis of human brain, showing that lipid extracts contain anandamide and 2-arachidonoylglycerol (2-AG), the most active endocannabinoids known to date. Human brain also contained the endocannabinoid-like compounds N -oleoylethanolamine, N -palmitoylethanolamine and N -stearoylethanolamine. Anandamide and 2-AG (0.16 ± 0.05 and 0.10 ± 0.05 nmol/mg protein, respectively) represented 7.7% and 4.8% of total endocannabinoid-like compounds, respectively. N -Palmitoyethanolamine was the most abundant (50%), followed by N -oleoyl (23.6%) and N -stearoyl (13.9%) ethanolamines. A similar composition in endocannabinoid-like compounds was found in human neuroblastoma CHP100 and lymphoma U937 cells, and also in rat brain. Remarkably, human meningioma specimens showed an approximately six-fold smaller content of all N -acylethanolamines, but not of 2-AG, and a similar decrease was observed in a human glioblastoma. These ex vivo results fully support the purported roles of endocannabinoids in the nervous system. [source] Interactions between neural membrane glycerophospholipid and sphingolipid mediators: A recipe for neural cell survival or suicideJOURNAL OF NEUROSCIENCE RESEARCH, Issue 9 2007Akhlaq A. Farooqui Abstract The neural membranes contain phospholipids, sphingolipids, cholesterol, and proteins. Glycerophospholipids and sphingolipids are precursors for lipid mediators involved in signal transduction processes. Degradation of glycerophospholipids by phospholipase A2 (PLA2) generates arachidonic acid (AA) and docosahexaenoic acids (DHA). Arachidonic acid is metabolized to eicosanoids and DHA is metabolized to docosanoids. The catabolism of glycosphingolipids generates ceramide, ceramide 1-phosphate, sphingosine, and sphingosine 1-phosphate. These metabolites modulate PLA2 activity. Arachidonic acid, a product derived from glycerophospholipid catabolism by PLA2, modulates sphingomyelinase (SMase), the enzyme that generates ceramide and phosphocholine. Furthermore, sphingosine 1-phosphate modulates cyclooxygenase, an enzyme responsible for eicosanoid production in brain. This suggests that an interplay and cross talk occurs between lipid mediators of glycerophospholipid and glycosphingolipid metabolism in brain tissue. This interplay between metabolites of glycerophospholipid and sphingolipid metabolism may play an important role in initiation and maintenance of oxidative stress associated with neurologic disorders as well as in neural cell proliferation, differentiation, and apoptosis. Recent studies indicate that PLA2 and SMase inhibitors can be used as neuroprotective and anti-apoptotic agents. Development of novel inhibitors of PLA2 and SMase may be useful for the treatment of oxidative stress, and apoptosis associated with neurologic disorders such as stroke, Alzheimer disease, Parkinson disease, and head and spinal cord injuries. © 2007 Wiley-Liss, Inc. [source] Areca nut extracts-activated secretion of leukotriene B4, and phosphorylation of p38 mitogen-activated protein kinase and elevated intracellular calcium concentrations in human polymorphonuclear leukocytesJOURNAL OF PERIODONTAL RESEARCH, Issue 5 2007S.-L. Hung Background and Objective:, Polymorphonuclear leukocytes are the major source of leukotriene B4, which is synthesized via the 5-lipoxygenase pathway. Activation of the 5-lipoxygenase pathway is regulated by intracellular calcium and the phosphorylation of p38 mitogen-activated protein kinase (MAPK). The impact of areca nut extracts on the biosynthesis of leukotriene B4 by human polymorphonuclear leukocytes was evaluated, and some of the possible mechanisms underlying the responses were examined. Material and Methods:, Polymorphonuclear leukocytes were treated with various concentrations of areca nut extracts. The concentrations of leukotriene B4 released into the supernatants were evaluated using enzyme immunoassay. The phosphorylation of p38 MAPK was monitored using immunoblotting, and the cytosolic calcium kinetics were assessed fluorometrically using Fura-2. Results:, Exposure of polymorphonuclear leukocytes to areca nut extracts led to a dose-dependent increase in the production of leukotriene B4, with levels peaking at 30 min and decreasing thereafter. Areca nut extracts enhanced the phosphorylation of p38 MAPK, an enzyme known to activate 5-lipoxygenase. Incubation with areca nut extracts also resulted in a rapid elevation of intracellular calcium concentrations in polymorphonuclear leukocytes. The induction of leukotriene B4 by areca nut extracts was suppressed with the p38 MAPK inhibitor, SB203580, or with the intracellular calcium chelator, BAPTA-AM. Conclusion:, The interaction of areca nut extracts with polymorphonuclear leukocytes activated the arachidonic acid metabolic cascade. Incubation of polymorphonuclear leukocytes with areca nut extracts resulted in the activation of intracellular events, such as phosphorylation of p38 MAPK and Ca2+ mobilization, involved in the release of pro-inflammatory lipid mediators. The results of this study emphasize the potential importance of polymorphonuclear leukocytes as a source of leukotriene B4, which may modulate the inflammatory response in areca chewers. [source] Leukotriene pathway genetics and pharmacogenetics in allergyALLERGY, Issue 6 2009N. P. Duroudier Leukotrienes (LT) are biologically active lipid mediators known to be involved in allergic inflammation. Leukotrienes have been shown to mediate diverse features of allergic conditions including inflammatory cell chemotaxis/activation and smooth muscle contraction. Cysteinyl leukotrienes (LTC4, LTD4 and, LTE4) and the dihydroxy leukotriene LTB4 are generated by a series of enzymes/proteins constituting the LT synthetic pathway or 5-lipoxygenase (5-LO) pathway. Their function is mediated by interacting with multiple receptors. Leukotriene receptor antagonists (LTRA) and LT synthesis inhibitors (LTSI) have shown clinical efficacy in asthma and more recently in allergic rhinitis. Despite growing knowledge of leukotriene biology, the molecular regulation of these inflammatory mediators remains to be fully understood. Genes encoding enzymes of the 5-LO pathway (i.e. ALOX5, LTC4S and LTA4H) and encoding for LT receptors (CYSLTR1/2 and LTB4R1/2) provide excellent candidates for disease susceptibility and severity; however, their role remains unclear. Preliminary data also suggest that 5-LO pathway/receptor gene polymorphism can predict patient responses to LTSI and LTRA; however, the exact mechanisms require elucidation. The aim of this review was to summarize the recent advances in the knowledge of these important mediators, focusing on genetic and pharmacogenetic aspects in the context of allergic phenotypes. [source] Increased prostaglandin E2 levels in the airway of patients with eosinophilic bronchitisALLERGY, Issue 1 2008B. Sastre Background:, Eosinophilic bronchitis is a common cause of chronic cough, which like asthma is characterized by sputum eosinophilia, but unlike asthma there is no variable airflow obstruction or airway hyperresponsiveness. We tested the hypothesis that the different airway function in patients with eosinophilic bronchitis and asthma could be caused by an imbalance in the production of bronchoconstrictor (LTC4) and bronchoprotective (prostaglandin E2; PGE2) lipid mediators. Methods:, We measured cytokines levels, proinflammatory mediators and eicosanoids concentration in sputum from 13 subjects with nonasthmatic eosinophilic bronchitis, 13 subjects with asthma, and 11 healthy control subjects. Cytokines mRNA levels were measured by real time PCR, proinflammatory mediators, PGE2, and LTC4 were measured by enzyme immunoassays. Results:, The median sputum eosinophil count was not statistically different in patients with asthma (7.95%) and eosinophilic bronchitis (15.29%). The levels of mRNA specific to interleukin-5 (IL-5), IL-4, IL-10, IL-13, interferon , (IFN-,), IL-2, vascular endothelial growth factor and transforming growth factor , were similar in both conditions. In addition, no differences were found between asthma and eosinophilic bronchitis in proinflammatory cytokines, such as IL-8, IFN-, and tumor necrosis factor , (TNF-,) levels. Sputum cysteinyl-leukotrienes concentration was raised both in eosinophilic bronchitis and asthma patients. We found that induced sputum PGE2 concentrations were significantly increased in subjects with eosinophilic bronchitis (838.3 ± 612 pg/ml) when compared with asthmatic (7.54 ± 2.14 pg/ml) and healthy subjects (4 ± 1.3 pg/ml). Conclusion:, This data suggest that the difference in airway function observed in subjects with eosinophilic bronchitis and asthma could be due to differences in PGE2 production in the airways. [source] Lipoxins in asthma: potential therapeutic mediators on bronchial inflammation?ALLERGY, Issue 10 2004C. Bonnans Arachidonic acid metabolism represents an important source of mediators with ambivalent actions. Among these, lipoxins (LXs) are the first agents identified and recognized as anti-inflammatory endogenous lipid mediators, which are involved in the resolution of inflammation and are present in the airways of asthmatic patients. Lipoxins result mainly from the interaction between 5 and 15-lipoxygenases (LO) and their levels are modulated by the degree of bronchial inflammation as well as by the long-term glucocorticoid treatments. In the airways, LX synthesis is higher in mild asthmatics than in severe asthmatics, whereas in vitro chemokine release inhibition by LXs is more effective in cells from severe asthmatics than from mild asthmatics. LipoxinA4 effects on interleukin (IL)-8 released by blood mononuclear cells and on calcium influx in epithelial cells are mediated by the specific receptor ALX. Lipoxin generation by lung epithelial cells depends mainly on 15-LO activity. Mild asthmatics present higher 15-LOb expression at the epithelium level than severe patients, whereas the LX deficit in severe asthma is associated with an up-regulation of the 15-LOa expressions. Therefore, bronchial epithelial cells become a target for therapeutic intervention and LXs represent a potential therapeutic solution for bronchial inflammation resolution in asthma. [source] Lipidomic analysis of twenty-seven prostanoids and isoprostanes by liquid chromatography/electrospray tandem mass spectrometryRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 20 2006Mojgan Masoodi Prostanoids are potent mediators of many physiological and pathophysiological processes. Of the many analytical methodologies used for their qualitative and quantitative analysis, electrospray tandem mass spectrometry coupled to liquid chromatography (LC/ESI-MS/MS) offers a rapid, sensitive and versatile system applicable to lipidomic analyses. We have developed an LC/ESI-MS/MS assay for twenty-seven mediators including prostaglandins, prostacyclines, thromboxanes, dihydroprostaglandins and isoprostanes. The assay was liner over the concentration range 1,100 pg/µL. The limits of detection and quantitation were 0.5,50 and 2,100 pg, respectively, whilst recoveries were from 83,116% depending on the metabolite. The assay can be applied to the profiling of prostanoids produced by a variety of biological fluids and extracts including brain, liver, plasma and urine, thus facilitating our understanding of the role of these lipid mediators in health and disease, as well as assisting in drug development. Copyright © 2006 John Wiley & Sons, Ltd. [source] Signal transduction responses to lysophosphatidic acid and sphingosine 1-phosphate in human prostate cancer cellsTHE PROSTATE, Issue 14 2009Terra C. Gibbs Abstract BACKGROUND Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are lipid mediators that bind to G-protein-coupled receptors. In this study, signaling responses to 18:1 LPA and S1P were examined in parallel in three human prostate cancer cell lines: PC-3, Du145, and LNCaP. METHODS Receptor expression was assessed by RT-PCR, Northern blotting, and immunoblotting. Cellular responses to mediators were studied by proliferation assays, phosphoprotein immunoblotting, and phospholipid metabolism assays. RESULTS All cell lines express mRNA for both LPA and S1P receptors. PC-3 and Du145, but not LNCaP, proliferate in response to LPA and S1P. Epidermal growth factor (EGF), phorbol 12-myristate 13-acetate (PMA), LPA, and S1P induce activation of Erks in PC-3 and Du145; only EGF and PMA activate Erks in LNCaP. In Du145 and PC-3, Akt is activated by EGF, LPA, and S1P. Akt is constitutively active in LNCaP; EGF but not LPA or S1P stimulates further phosphorylation. FAK is phosphorylated in response to both LPA and S1P in PC-3 and Du145, but not in LNCaP. LPA and S1P stimulate phospholipase D (PLD) activity to varying extents in the different cell lines. Notably, both lipid mediators activate PLD in LNCaP. In Du145, LPA, but not S1P, activates PLD and enhances cellular production of LPA. CONCLUSIONS Although both LPA and S1P induce signal transduction in all prostate cancer cell lines studied, a proliferation response is observed only when the Erk, Akt, and FAK pathways are activated. Other responses to the lipid mediators, such as PLD activation, likely contribute to other cellular outcomes. Prostate 69: 1493,1506, 2009. © 2009 Wiley-Liss, Inc. [source] Elevated levels of leukotriene B4 and leukotriene E4 in bronchoalveolar lavage fluid from patients with scleroderma lung diseaseARTHRITIS & RHEUMATISM, Issue 6 2003Otylia Kowal-Bielecka Objective The leukotrienes are a family of arachidonic acid,derived lipid mediators with proinflammatory and profibrotic properties. The aim of this study was to analyze the role of leukotriene B4 (LTB4) and LTE4 in the pathogenesis of scleroderma lung disease (SLD). Methods Nineteen systemic sclerosis (SSc) patients with SLD, 11 SSc patients without SLD, and 10 healthy controls were studied. Bronchoalveolar lavage (BAL) fluid was obtained during routine bronchoscopy of the right middle lobe in all study subjects. Levels of LTB4 and LTE4 were measured using enzyme immunoassay kits. Results Levels of LTB4 and LTE4 were significantly higher in SSc patients with SLD (251 ± 170 pg/ml and 479 ± 301 pg/ml, respectively), than those in patients without SLD (114 ± 86 and 159 ± 149 pg/ml) and those in normal controls (86 ± 49 and 110 ± 67 pg/ml). In the total group of patients with SSc, levels of both leukotrienes correlated positively with the total number of cells in the BAL fluid and correlated negatively with the forced vital capacity. After intravenous pulse therapy with cyclophosphamide in 6 patients, there was a significant reduction in the concentration of LTB4 (from 380 ± 196 pg/ml to 155 ± 123 pg/ml) but no significant difference in the levels of LTE4 (from 697 ± 325 pg/ml to 418 ± 140 pg/ml). Conclusion Our findings show that LTB4 and LTE4 levels are elevated in SSc patients with SLD and correlate with parameters of inflammation in the lungs. These results indicate that leukotrienes may contribute to the pathogenesis of SLD and may represent a new therapeutic target. [source] REVIEW: Aiming drug discovery at lysophosphatidic acid targetsBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2010Gabor Tigyi Lysophosphatidic acid (LPA, 1-radyl-2-hydroxy- sn -glycero-3-phosphate) is the prototype member of a family of lipid mediators and second messengers. LPA and its naturally occurring analogues interact with G protein-coupled receptors on the cell surface and a nuclear hormone receptor within the cell. In addition, there are several enzymes that utilize LPA as a substrate or generate it as a product and are under its regulatory control. LPA is present in biological fluids, and attempts have been made to link changes in its concentration and molecular composition to specific disease conditions. Through their many targets, members of the LPA family regulate cell survival, apoptosis, motility, shape, differentiation, gene transcription, malignant transformation and more. The present review depicts arbitrary aspects of the physiological and pathophysiological actions of LPA and attempts to link them with select targets. Many of us are now convinced that therapies targeting LPA biosynthesis and signalling are feasible for the treatment of devastating human diseases such as cancer, fibrosis and degenerative conditions. However, successful targeting of the pathways associated with this pleiotropic lipid will depend on the future development of as yet undeveloped pharmacons. [source] Molecular links between tumor angiogenesis and inflammation: inflammatory stimuli of macrophages and cancer cells as targets for therapeutic strategyCANCER SCIENCE, Issue 8 2008Mayumi Ono Both inflammation and angiogenesis are exacerbated by increased production of chemokines/cytokines, growth factors, proteolytic enzymes, proteoglycans, lipid mediators and prostaglandins. It has been reported that approximately 15,20% of all malignancies are initiated or exacerbated by inflammation. Initiation and progression of cancer are also closely linked to angiogenesis. Infiltration of macrophages is a dramatic and common feature of inflammation, angiogenesis and cancer, and has been recently highlighted in an attempt to develop novel strategies for treating cancer. The recruitment and infiltration of macrophages in the tumor microenvironment activates them to support the malignant progression of cancer cells, and these macrophages are called tumor-associated macrophages. In a model of experimental angiogenesis using mouse corneas, macrophages infiltrated tissue in response to inflammatory cytokines and produced chemokines and angiogenesis-promoting factors, such as vascular endothelial growth factor-A, interleukin-8, matrix metalloproteinases, prostanoids and reactive oxygen species. Moreover, in a cancer xenograft model, inflammatory stimuli by a representative inflammatory cytokine, interleukin-1,, enhanced tumor growth and angiogenesis with infiltration and activation of macrophages. Co-culture of cancer cells with macrophages synergistically stimulated production of various angiogenesis-related factors when stimulated by the inflammatory cytokine. This inflammatory angiogenesis in both mouse cornea and a tumor model was mediated, in part, by activation of nuclear factor ,B and activator protein 1 (Jun/Fos). Administration of either nuclear factor ,B-targeting drugs or cyclooxygenase 2 inhibitors or depletion of macrophages could block both inflammatory angiogenesis and tumor angiogenesis. Thus, both inflammatory and angiogenic responses in tumor stroma could be targets for development of anticancer therapeutic drugs. (Cancer Sci 2008; 99: 1501,1506) [source] Cysteinyl leukotrienes: multi-functional mediators in allergic rhinitisCLINICAL & EXPERIMENTAL ALLERGY, Issue 6 2006M. Peters-Golden Summary Cysteinyl leukotrienes (CysLTs) are a family of inflammatory lipid mediators synthesized from arachidonic acid by a variety of cells, including mast cells, eosinophils, basophils, and macrophages. This article reviews the data for the role of CysLTs as multi-functional mediators in allergic rhinitis (AR). We review the evidence that: (1) CysLTs are released from inflammatory cells that participate in AR, (2) receptors for CysLTs are located in nasal tissue, (3) CysLTs are increased in patients with AR and are released following allergen exposure, (4) administration of CysLTs reproduces the symptoms of AR, (5) CysLTs play roles in the maturation, as well as tissue recruitment, of inflammatory cells, and (6) a complex inter-regulation between CysLTs and a variety of other inflammatory mediators exists. [source] | |||||||||||||||||||||||||||||||