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[PMID]:27292189
[Au] Autor:Schewe M; Franken PF; Sacchetti A; Schmitt M; Joosten R; Böttcher R; van Royen ME; Jeammet L; Payré C; Scott PM; Webb NR; Gelb M; Cormier RT; Lambeau G; Fodde R
[Ad] Endereço:Department of Pathology, Erasmus MC Cancer Institute, Rotterdam 3000CA, The Netherlands.
[Ti] Título:Secreted Phospholipases A2 Are Intestinal Stem Cell Niche Factors with Distinct Roles in Homeostasis, Inflammation, and Cancer.
[So] Source:Cell Stem Cell;19(1):38-51, 2016 Jul 07.
[Is] ISSN:1875-9777
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The intestinal stem cell niche provides cues that actively maintain gut homeostasis. Dysregulation of these cues may compromise intestinal regeneration upon tissue insult and/or promote tumor growth. Here, we identify secreted phospholipases A2 (sPLA2s) as stem cell niche factors with context-dependent functions in the digestive tract. We show that group IIA sPLA2, a known genetic modifier of mouse intestinal tumorigenesis, is expressed by Paneth cells in the small intestine, while group X sPLA2 is expressed by Paneth/goblet-like cells in the colon. During homeostasis, group IIA/X sPLA2s inhibit Wnt signaling through intracellular activation of Yap1. However, upon inflammation they are secreted into the intestinal lumen, where they promote prostaglandin synthesis and Wnt signaling. Genetic ablation of both sPLA2s improves recovery from inflammation but increases colon cancer susceptibility due to release of their homeostatic Wnt-inhibitory role. This "trade-off" effect suggests sPLA2s have important functions as genetic modifiers of inflammation and colon cancer.
[Mh] Termos MeSH primário: Fosfolipases A2 do Grupo II/metabolismo
Fosfolipases A2 do Grupo X/metabolismo
Homeostase
Inflamação/patologia
Neoplasias Intestinais/enzimologia
Neoplasias Intestinais/patologia
Intestinos/patologia
Nicho de Células-Tronco
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Animais
Diferenciação Celular
Linhagem da Célula
Dinoprostona/biossíntese
Inflamação/enzimologia
Doenças Inflamatórias Intestinais/genética
Doenças Inflamatórias Intestinais/patologia
Neoplasias Intestinais/genética
Espaço Intracelular/metabolismo
Camundongos Endogâmicos C57BL
Organoides/metabolismo
Celulas de Paneth/enzimologia
Celulas de Paneth/patologia
Fosfoproteínas/metabolismo
Fosforilação
Células-Tronco/patologia
Via de Sinalização Wnt
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Phosphoproteins); 0 (Yap protein, mouse); EC 3.1.1.4 (Group II Phospholipases A2); EC 3.1.1.4 (Group X Phospholipases A2); EC 3.1.1.4 (Pla2g10 protein, mouse); EC 3.1.1.4 (Pla2g2a protein, mouse); K7Q1JQR04M (Dinoprostone)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170719
[Lr] Data última revisão:
170719
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160614
[St] Status:MEDLINE


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[PMID]:26828067
[Au] Autor:Murase R; Sato H; Yamamoto K; Ushida A; Nishito Y; Ikeda K; Kobayashi T; Yamamoto T; Taketomi Y; Murakami M
[Ad] Endereço:From the Lipid Metabolism Project and School of Pharmacy, Showa University, Tokyo 142-8555, Japan.
[Ti] Título:Group X Secreted Phospholipase A2 Releases ω3 Polyunsaturated Fatty Acids, Suppresses Colitis, and Promotes Sperm Fertility.
[So] Source:J Biol Chem;291(13):6895-911, 2016 Mar 25.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Within the secreted phospholipase A2(sPLA2) family, group X sPLA2(sPLA2-X) has the highest capacity to hydrolyze cellular membranes and has long been thought to promote inflammation by releasing arachidonic acid, a precursor of pro-inflammatory eicosanoids. Unexpectedly, we found that transgenic mice globally overexpressing human sPLA2-X (PLA2G10-Tg) displayed striking immunosuppressive and lean phenotypes with lymphopenia and increased M2-like macrophages, accompanied by marked elevation of free ω3 polyunsaturated fatty acids (PUFAs) and their metabolites. Studies usingPla2g10-deficient mice revealed that endogenous sPLA2-X, which is highly expressed in the colon epithelium and spermatozoa, mobilized ω3 PUFAs or their metabolites to protect against dextran sulfate-induced colitis and to promote fertilization, respectively. In colitis, sPLA2-X deficiency increased colorectal expression of Th17 cytokines, and ω3 PUFAs attenuated their production by lamina propria cells partly through the fatty acid receptor GPR120. In comparison, cytosolic phospholipase A2(cPLA2α) protects from colitis by mobilizing ω6 arachidonic acid metabolites, including prostaglandin E2 Thus, our results underscore a previously unrecognized role of sPLA2-X as an ω3 PUFA mobilizerin vivo, segregated mobilization of ω3 and ω6 PUFA metabolites by sPLA2-X and cPLA2α, respectively, in protection against colitis, and the novel role of a particular sPLA2-X-driven PUFA in fertilization.
[Mh] Termos MeSH primário: Colite/genética
Colo/enzimologia
Ácidos Graxos Ômega-3/biossíntese
Fertilidade/genética
Fosfolipases A2 do Grupo X/genética
Espermatozoides/enzimologia
[Mh] Termos MeSH secundário: Animais
Ácido Araquidônico/antagonistas & inibidores
Ácido Araquidônico/biossíntese
Colite/induzido quimicamente
Colite/enzimologia
Colite/terapia
Colo/patologia
Sulfato de Dextrana
Ácidos Graxos Ômega-3/secreção
Ácidos Graxos Ômega-6/biossíntese
Ácidos Graxos Ômega-6/secreção
Expressão Gênica
Perfilação da Expressão Gênica
Fosfolipases A2 do Grupo X/secreção
Seres Humanos
Interleucina-17/biossíntese
Masculino
Camundongos
Camundongos Transgênicos
Fosfolipases A2/genética
Fosfolipases A2/metabolismo
Receptores Acoplados a Proteínas-G/genética
Receptores Acoplados a Proteínas-G/metabolismo
Contagem de Espermatozoides
Motilidade Espermática
Espermatozoides/patologia
Células Th17/metabolismo
Células Th17/patologia
Transgenes
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Fatty Acids, Omega-3); 0 (Fatty Acids, Omega-6); 0 (Interleukin-17); 0 (O3far1 protein, mouse); 0 (Receptors, G-Protein-Coupled); 27YG812J1I (Arachidonic Acid); 9042-14-2 (Dextran Sulfate); EC 3.1.1.4 (Group X Phospholipases A2); EC 3.1.1.4 (PLA2G10 protein, human); EC 3.1.1.4 (Phospholipases A2)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:170403
[Lr] Data última revisão:
170403
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160202
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.715672


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[PMID]:26711221
[Au] Autor:Pruzanski W; Kopilov J; Kuksis A
[Ad] Endereço:St. Michael's Hopital, Toronto, Canada; University of Toronto, Toronto, Canada. Electronic address: drwpruzanski@bellnet.ca.
[Ti] Título:Hydrolysis of lipoproteins by sPLA2's enhances mitogenesis and eicosanoid release from vascular smooth muscle cells: Diverse activity of sPLA2's IIA, V and X.
[So] Source:Prostaglandins Other Lipid Mediat;122:64-8, 2016 Jan.
[Is] ISSN:1098-8823
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mitogenesis of Vascular Smooth Muscle Cells (VSMC) plays an important role in atherogenesis. Until recently, the effect of lipid subfractions has not been clarified. Secretory phospholipases A2 (sPLA2's) hydrolyse glycerophospholipids and release pro-inflammatory lyso-lipids, oxidized and non-oxidized fatty acids and isoprostanes. They localize in the vascular wall. We hypothesized that structurally similar sPLA2's may exert different impact on VSMC. The influence of sPLA2's, IIA, V, X, HDL, LDL, and hydrolysis products was tested on mitogenesis of VSMC, i.e., the early effect on the cell membrane phospholipids, and on PGE2 and LTB4 release, i.e., late effect of Cyclooxygenase and 5-lipooxygenase activity in VSMC. Mitogenesis was significantly enhanced by HDL and LDL, and by products of sPLA2 hydrolysis. Hydrolysis of HDL or LDL enhanced mitogenic activity in order V>X>IIA. The release of PGE2 was enhanced by group X sPLA2 and by HDL hydrolyzed by groups V and X. LDL and its hydrolysis products enhanced the release of PGE2 in order X>V>IIA. The release of LTB4 was markedly increased by LDL and HDL, and by hydrolytic products of group V and X, but not group IIA sPLA2. Our study demonstrates a diverse interaction of pro-inflammatory sPLA2's with HDL and LDL affecting both mitogenesis and eicosanoid release from VSMC, therefore potentially enhancing their pro-atherogenic activity.
[Mh] Termos MeSH primário: Eicosanoides/secreção
Lipoproteínas/metabolismo
Miócitos de Músculo Liso/metabolismo
Fosfolipases A2 Secretórias/metabolismo
[Mh] Termos MeSH secundário: Araquidonato 5-Lipoxigenase/metabolismo
Células Cultivadas
Dinoprostona/secreção
Fosfolipases A2 do Grupo II/metabolismo
Fosfolipases A2 do Grupo V/metabolismo
Fosfolipases A2 do Grupo X/metabolismo
Seres Humanos
Hidrólise
Leucotrieno B4/secreção
Lipoproteínas HDL/metabolismo
Lipoproteínas LDL/metabolismo
Mitose
Músculo Liso Vascular/citologia
Prostaglandina-Endoperóxido Sintases/metabolismo
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Eicosanoids); 0 (Lipoproteins); 0 (Lipoproteins, HDL); 0 (Lipoproteins, LDL); 1HGW4DR56D (Leukotriene B4); EC 1.13.11.34 (Arachidonate 5-Lipoxygenase); EC 1.14.99.1 (Prostaglandin-Endoperoxide Synthases); EC 3.1.1.4 (Group II Phospholipases A2); EC 3.1.1.4 (Group V Phospholipases A2); EC 3.1.1.4 (Group X Phospholipases A2); EC 3.1.1.4 (PLA2G2A protein, human); EC 3.1.1.4 (PLA2G5 protein, human); EC 3.1.1.4 (Phospholipases A2, Secretory); K7Q1JQR04M (Dinoprostone)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151230
[St] Status:MEDLINE


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[PMID]:26655718
[Au] Autor:Abi Nahed R; Martinez G; Escoffier J; Yassine S; Karaouzène T; Hograindleur JP; Turk J; Kokotos G; Ray PF; Bottari S; Lambeau G; Hennebicq S; Arnoult C
[Ad] Endereço:From the Université Grenoble Alpes, F-38000 Grenoble, France, the Institut Albert Bonniot, INSERM U823, La Tronche F-38700, France.
[Ti] Título:Progesterone-induced Acrosome Exocytosis Requires Sequential Involvement of Calcium-independent Phospholipase A2ß (iPLA2ß) and Group X Secreted Phospholipase A2 (sPLA2).
[So] Source:J Biol Chem;291(6):3076-89, 2016 Feb 05.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Phospholipase A2 (PLA2) activity has been shown to be involved in the sperm acrosome reaction (AR), but the molecular identity of PLA2 isoforms has remained elusive. Here, we have tested the role of two intracellular (iPLA2ß and cytosolic PLA2α) and one secreted (group X) PLA2s in spontaneous and progesterone (P4)-induced AR by using a set of specific inhibitors and knock-out mice. iPLA2ß is critical for spontaneous AR, whereas both iPLA2ß and group X secreted PLA2 are involved in P4-induced AR. Cytosolic PLA2α is dispensable in both types of AR. P4-induced AR spreads over 30 min in the mouse, and kinetic analyses suggest the presence of different sperm subpopulations, using distinct PLA2 pathways to achieve AR. At low P4 concentration (2 µm), sperm undergoing early AR (0-5 min post-P4) rely on iPLA2ß, whereas sperm undergoing late AR (20-30 min post-P4) rely on group X secreted PLA2. Moreover, the role of PLA2s in AR depends on P4 concentration, with the PLA2s being key actors at low physiological P4 concentrations (≤2 µm) but not at higher P4 concentrations (~10 µm).
[Mh] Termos MeSH primário: Reação Acrossômica/efeitos dos fármacos
Acrossomo/enzimologia
Exocitose/efeitos dos fármacos
Fosfolipases A2 do Grupo VI/metabolismo
Fosfolipases A2 do Grupo X/metabolismo
Progesterona/farmacologia
[Mh] Termos MeSH secundário: Animais
Fosfolipases A2 do Grupo VI/genética
Fosfolipases A2 do Grupo X/genética
Masculino
Camundongos
Camundongos Knockout
Progesterona/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
4G7DS2Q64Y (Progesterone); EC 3.1.1.4 (Group VI Phospholipases A2); EC 3.1.1.4 (Group X Phospholipases A2); EC 3.1.1.4 (Pla2g6 protein, mouse)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:170205
[Lr] Data última revisão:
170205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151215
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M115.677799


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[PMID]:26139511
[Au] Autor:Hallstrand TS; Lai Y; Hooper KA; Oslund RC; Altemeier WA; Matute-Bello G; Gelb MH
[Ad] Endereço:Division of Pulmonary and Critical Care, the Department of Medicine, University of Washington, Seattle, Wash. Electronic address: tealh@uw.edu.
[Ti] Título:Endogenous secreted phospholipase A2 group X regulates cysteinyl leukotrienes synthesis by human eosinophils.
[So] Source:J Allergy Clin Immunol;137(1):268-277.e8, 2016 Jan.
[Is] ISSN:1097-6825
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Phospholipase A2s mediate the rate-limiting step in the formation of eicosanoids such as cysteinyl leukotrienes (CysLTs). Group IVA cytosolic PLA2α (cPLA2α) is thought to be the dominant PLA2 in eosinophils; however, eosinophils also have secreted PLA2 (sPLA2) activity that has not been fully defined. OBJECTIVES: To examine the expression of sPLA2 group X (sPLA2-X) in eosinophils, the participation of sPLA2-X in the formation of CysLTs, and the mechanism by which sPLA2-X initiates the synthesis of CysLTs in eosinophils. METHODS: Peripheral blood eosinophils were obtained from volunteers with asthma and/or allergy. A rabbit polyclonal anti-sPLA2-X antibody identified sPLA2-X by Western blot. We used confocal microscopy to colocalize the sPLA2-X to intracellular structures. An inhibitor of sPLA2-X (ROC-0929) that does not inhibit other mammalian sPLA2s, as well as inhibitors of the mitogen-activated kinase cascade (MAPK) and cPLA2α, was used to examine the mechanism of N-formyl-methionyl-leucyl-phenylalanine (fMLP)-mediated formation of CysLT. RESULTS: Eosinophils express the mammalian sPLA2-X gene (PLA2G10). The sPLA2-X protein is located in the endoplasmic reticulum, golgi, and granules of eosinophils and moves to the granules and lipid bodies during fMLP-mediated activation. Selective sPLA2-X inhibition attenuated the fMLP-mediated release of arachidonic acid and CysLT formation by eosinophils. Inhibitors of p38, extracellular-signal-regulated kinases 1/2 (p44/42 MAPK), c-Jun N-terminal kinase, and cPLA2α also attenuated the fMLP-mediated formation of CysLT. The sPLA2-X inhibitor reduced the phosphorylation of p38 and extracellular-signal-regulated kinases 1/2 (p44/42 MAPK) as well as cPLA2α during cellular activation, indicating that sPLA2-X is involved in activating the MAPK cascade leading to the formation of CysLT via cPLA2α. We further demonstrate that sPLA2-X is activated before secretion from the cell during activation. Short-term priming with IL-13 and TNF/IL-1ß increased the expression of PLA2G10 by eosinophils. CONCLUSIONS: These results demonstrate that sPLA2-X plays a significant role in the formation of CysLTs by human eosinophils. The predominant role of the enzyme is the regulation of MAPK activation that leads to the phosphorylation of cPLA2α. The sPLA2-X protein is regulated by proteolytic cleavage, suggesting that an inflammatory environment may promote the formation of CysLTs through this mechanism. These results have important implications for the treatment of eosinophilic disorders such as asthma.
[Mh] Termos MeSH primário: Cisteína/imunologia
Eosinófilos/imunologia
Fosfolipases A2 do Grupo X/imunologia
Leucotrienos/imunologia
[Mh] Termos MeSH secundário: Adulto
Linhagem Celular
Feminino
Seres Humanos
Hipersensibilidade/imunologia
Masculino
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Leukotrienes); 0 (cysteinyl-leukotriene); EC 3.1.1.4 (Group X Phospholipases A2); K848JZ4886 (Cysteine)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:170904
[Lr] Data última revisão:
170904
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:150704
[St] Status:MEDLINE


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[PMID]:26001724
[Au] Autor:Kinghorn KJ; Castillo-Quan JI; Bartolome F; Angelova PR; Li L; Pope S; Cochemé HM; Khan S; Asghari S; Bhatia KP; Hardy J; Abramov AY; Partridge L
[Ad] Endereço:1 Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK 2 Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK k.kinghorn@ucl.ac.uk.
[Ti] Título:Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction.
[So] Source:Brain;138(Pt 7):1801-16, 2015 Jul.
[Is] ISSN:1460-2156
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The PLA2G6 gene encodes a group VIA calcium-independent phospholipase A2 beta enzyme that selectively hydrolyses glycerophospholipids to release free fatty acids. Mutations in PLA2G6 have been associated with disorders such as infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type II and Karak syndrome. More recently, PLA2G6 was identified as the causative gene in a subgroup of patients with autosomal recessive early-onset dystonia-parkinsonism. Neuropathological examination revealed widespread Lewy body pathology and the accumulation of hyperphosphorylated tau, supporting a link between PLA2G6 mutations and parkinsonian disorders. Here we show that knockout of the Drosophila homologue of the PLA2G6 gene, iPLA2-VIA, results in reduced survival, locomotor deficits and organismal hypersensitivity to oxidative stress. Furthermore, we demonstrate that loss of iPLA2-VIA function leads to a number of mitochondrial abnormalities, including mitochondrial respiratory chain dysfunction, reduced ATP synthesis and abnormal mitochondrial morphology. Moreover, we show that loss of iPLA2-VIA is strongly associated with increased lipid peroxidation levels. We confirmed our findings using cultured fibroblasts taken from two patients with mutations in the PLA2G6 gene. Similar abnormalities were seen including elevated mitochondrial lipid peroxidation and mitochondrial membrane defects, as well as raised levels of cytoplasmic and mitochondrial reactive oxygen species. Finally, we demonstrated that deuterated polyunsaturated fatty acids, which inhibit lipid peroxidation, were able to partially rescue the locomotor abnormalities seen in aged flies lacking iPLA2-VIA gene function, and restore mitochondrial membrane potential in fibroblasts from patients with PLA2G6 mutations. Taken together, our findings demonstrate that loss of normal PLA2G6 gene activity leads to lipid peroxidation, mitochondrial dysfunction and subsequent mitochondrial membrane abnormalities. Furthermore we show that the iPLA2-VIA knockout fly model provides a useful platform for the further study of PLA2G6-associated neurodegeneration.
[Mh] Termos MeSH primário: Proteínas de Drosophila/genética
Fosfolipases A2 do Grupo VI/genética
Fosfolipases A2 do Grupo X/genética
Peroxidação de Lipídeos/genética
Mitocôndrias/metabolismo
Estresse Oxidativo/genética
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Proteínas de Drosophila/metabolismo
Drosophila melanogaster
Fibroblastos/metabolismo
Técnicas de Inativação de Genes
Fosfolipases A2 do Grupo VI/metabolismo
Fosfolipases A2 do Grupo X/metabolismo
Seres Humanos
Espectrometria de Massas
Potencial da Membrana Mitocondrial/genética
Microscopia de Fluorescência
Mitocôndrias/patologia
Doenças Neurodegenerativas/genética
Doenças Neurodegenerativas/metabolismo
Doenças Neurodegenerativas/patologia
Reação em Cadeia da Polimerase Via Transcriptase Reversa
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Drosophila Proteins); EC 3.1.1.4 (Group VI Phospholipases A2); EC 3.1.1.4 (Group X Phospholipases A2); EC 3.1.1.4 (PLA2G6 protein, Drosophila); EC 3.1.1.4 (PLA2G6 protein, human)
[Em] Mês de entrada:1509
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:150524
[St] Status:MEDLINE
[do] DOI:10.1093/brain/awv132


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[PMID]:25964585
[Au] Autor:Kazama S; Kitayama J; Hiyoshi M; Taketomi Y; Murakami M; Nishikawa T; Tanaka T; Tanaka J; Kiyomatsu T; Kawai K; Hata K; Yamaguchi H; Nozawa H; Ishihara S; Sunami E; Watanabe T
[Ad] Endereço:Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan kaz-tky@umin.ac.jp.
[Ti] Título:Phospholipase A2 Group III and Group X Have Opposing Associations with Prognosis in Colorectal Cancer.
[So] Source:Anticancer Res;35(5):2983-90, 2015 May.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Although secretory phospholipase A2 (sPLA2) has been shown to be involved in various biological processes, its specific roles in sub-types of cancer development remain to be elucidated. MATERIALS AND METHODS: We examined the expression of sPLA2 group III (GIII) in 142 patients with colorectal cancer using immunohistochemistry, and its correlation with clinicopathological features and outcomes. In addition, we examined the co-expression of sPLA2GIII and sPLA2GX using serial tissue sections to clarify the roles of both proteins in colorectal carcinogenesis. RESULTS: In 66 cases, diffuse staining of sPLA2GIII was seen; this was defined as the group with high expression. High expression was associated with a significantly higher rate of lymph node metastasis (p=0.02) and poorer survival (p=0.03) compared with low expression. Patients with low sPLA2GIII and high sPLA2GX expression had a significantly higher survival rate than those with high sPLA2GIII and low sPLA2GX expression (p=0.038). CONCLUSION: sPLA2GIII expression may be used as a risk factor for lymph node metastasis and a prognostic marker in colorectal cancer. In addition, sPLA2GIII and sPLA2GX may play opposing roles in colorectal carcinogenesis.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/genética
Neoplasias Colorretais/genética
Fosfolipases A2 do Grupo III/genética
Fosfolipases A2 do Grupo X/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Neoplasias Colorretais/patologia
Feminino
Regulação Neoplásica da Expressão Gênica
Fosfolipases A2 do Grupo III/biossíntese
Fosfolipases A2 do Grupo X/biossíntese
Seres Humanos
Metástase Linfática
Masculino
Meia-Idade
Prognóstico
Fatores de Risco
Taxa de Sobrevida
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); EC 3.1.1.4 (Group III Phospholipases A2); EC 3.1.1.4 (Group X Phospholipases A2)
[Em] Mês de entrada:1508
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150513
[St] Status:MEDLINE


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[PMID]:25583995
[Au] Autor:Guardiola M; Exeter HJ; Perret C; Folkersen L; Van't Hooft F; Eriksson P; Franco-Cereceda A; Paulsson-Berne G; Palmen J; Li K; Cooper JA; Khaw KT; Mallat Z; Ninio E; Karabina SA; Humphries SE; Boekholdt SM; Holmes MV; Talmud PJ
[Ad] Endereço:From the Center for Cardiovascular Genetics, Institute of Cardiovascular Science (M.G., H.J.E., J.P., K.W.L., J.A.C., S.E.H., P.J.T.), and Genetic Epidemiology Group, Department of Epidemiology and Public Health (M.V.H.), University College London, London, UK; Unitat de Recerca en Lípids i Arteriosc
[Ti] Título:PLA2G10 Gene Variants, sPLA2 Activity, and Coronary Heart Disease Risk.
[So] Source:Circ Cardiovasc Genet;8(2):356-62, 2015 Apr.
[Is] ISSN:1942-3268
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Observational studies report that secretory phospholipase A2 (sPLA2) activity is a marker for coronary heart disease (CHD) risk, and activity measures are thought to represent the composite activity of sPLA2-IIA, -V, and -X. The aim of this study was to use genetic variants of PLA2G10, encoding sPLA2-X, to investigate the contribution of sPLA2-X to the measure of sPLA2 activity and coronary heart disease (CHD) risk traits and outcome. METHODS AND RESULTS: Three PLA2G10 tagging single-nucleotide polymorphisms (rs72546339, rs72546340, and rs4003232) and a previously studied PLA2G10 coding single-nucleotide polymorphism rs4003228, R38C, were genotyped in a nested case: control cohort drawn from the prospective EPIC-Norfolk Study (2175 cases and 2175 controls). Meta-analysis of rs4003228 (R38C) and CHD was performed using data from the Northwick Park Heart Study II and 2 published cohorts AtheroGene and SIPLAC, providing in total an additional 1884 cases and 3119 controls. EPIC-Norfolk subjects in the highest tertile of sPLA2 activity were older and had higher inflammatory markers compared with those in the lowest tertile for sPLA2 activity. None of the PLA2G10 tagging single-nucleotide polymorphism nor R38C, a functional variant, were significantly associated with sPLA2 activity, intermediate CHD risk traits, or CHD risk. In meta-analysis, the summary odds ratio for R38C was odds ratio=0.97 (95% confidence interval, 0.77-1.22). CONCLUSIONS: PLA2G10 variants are not significantly associated with plasma sPLA2 activity or with CHD risk.
[Mh] Termos MeSH primário: Doença das Coronárias
Fosfolipases A2 do Grupo X
Polimorfismo de Nucleotídeo Único
Característica Quantitativa Herdável
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Doença das Coronárias/sangue
Doença das Coronárias/enzimologia
Doença das Coronárias/genética
Feminino
Seguimentos
Fosfolipases A2 do Grupo X/sangue
Fosfolipases A2 do Grupo X/genética
Seres Humanos
Masculino
Metanálise como Assunto
Meia-Idade
Estudos Prospectivos
Fatores de Risco
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE; MULTICENTER STUDY; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 3.1.1.4 (Group X Phospholipases A2); EC 3.1.1.4 (PLA2G10 protein, human)
[Em] Mês de entrada:1601
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150114
[St] Status:MEDLINE
[do] DOI:10.1161/CIRCGENETICS.114.000633


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[PMID]:25443158
[Au] Autor:Inose Y; Kato Y; Kitagawa K; Uchiyama S; Shibata N
[Ad] Endereço:Graduate School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
[Ti] Título:Activated microglia in ischemic stroke penumbra upregulate MCP-1 and CCR2 expression in response to lysophosphatidylcholine derived from adjacent neurons and astrocytes.
[So] Source:Neuropathology;35(3):209-23, 2015 Jun.
[Is] ISSN:1440-1789
[Cp] País de publicação:Australia
[La] Idioma:eng
[Ab] Resumo:In acute stage of ischemic stroke, the surrounding zone of fresh infarcts is termed penumbra, where microglia are activated in response to damaged cell-derived proinflammatory mediators. Rescuing penumbra by regulating inflammatory activity would minimize infarct volume, which positively correlates with functional outcome. To elucidate mechanisms by which inflammation occurs in penumbra, we performed immunohistochemical investigations using autopsied human brains affected by acute, subacute and chronic stages of cerebral infarction as well as cell culture experiments using a murine microglia-derived cell line (BV-2). In penumbra of fresh infarcts, immunoreactivity for secretory phospholipase A2 group X (sPLA2 -X), which is responsible for the production and release of the proinflammatory mediator lysophosphatidylcholine (LPC), was intensely detected in neurons and astrocytes. Furthermore, immunoreactivities for the LPC receptors G protein-coupled receptor 132 (G2A) and P2X purinoreceptor 7 (P2X7R), as well as the CC chemokine monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR2, were detectable in activated microglia. Prior to cell culture experiments, it was confirmed that BV-2 cells were immunoreactive for ionized Ca(2+) -binding adaptor molecule 1 (Iba1), G2A, P2X7R, MCP-1 and CCR2. Reverse transcription-quantitative polymerase chain reaction analysis revealed that MCP-1 and CCR2 mRNA expression levels were significantly increased by LPC stimulation. The LPC-driven increase in MCP-1 transcripts was lowered by blockade of G2A or P2X7R or by inhibition of Rho-associated protein kinase (ROCK) or inhibitor of κBα kinase. The LPC-driven increase in CCR2 transcripts was lowered by blockade of G2A or P2X7R or by inhibition of ROCK, phosphatidylinositide 3-kinanse, extracellular signal-regulated kinase kinase, or p38 mitogen-activated protein kinase. The present results provide in vivo and in vitro evidence that in acute stage of ischemic stroke, the sPLA2 -X enzyme product LPC is released from neurons and astrocytes and stimulates penumbra microglia via G2A and P2X7R, thereby exerting the MCP-1/CCR2-mediated neurotoxicity through distinct cell-signaling pathways.
[Mh] Termos MeSH primário: Isquemia Encefálica/metabolismo
Encefalite/metabolismo
Microglia/metabolismo
Acidente Vascular Cerebral/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Animais
Astrócitos/metabolismo
Isquemia Encefálica/patologia
Linhagem Celular
Quimiocina CCL2/metabolismo
Feminino
Fosfolipases A2 do Grupo X/metabolismo
Seres Humanos
Lisofosfatidilcolinas/metabolismo
Masculino
Camundongos
Meia-Idade
Neurônios/metabolismo
Receptores CCR2/metabolismo
Transdução de Sinais
Acidente Vascular Cerebral/patologia
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ccl2 protein, mouse); 0 (Ccr2 protein, mouse); 0 (Chemokine CCL2); 0 (Lysophosphatidylcholines); 0 (Receptors, CCR2); EC 3.1.1.4 (Group X Phospholipases A2)
[Em] Mês de entrada:1602
[Cu] Atualização por classe:150602
[Lr] Data última revisão:
150602
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141203
[St] Status:MEDLINE
[do] DOI:10.1111/neup.12182


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[PMID]:25395618
[Au] Autor:Liu A; Ming JY; Fiskesund R; Ninio E; Karabina SA; Bergmark C; Frostegård AG; Frostegård J
[Ad] Endereço:From the Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (A.L., J.Y.M., R.F., A.G.F., J.F.); Sorbonne Universités, UPMC University Paris 06, INSERM UMR_S 1166, ICAN, Genomics and Pathophysiology of Cardiovascular Diseases Team, Paris, France (E.N.); Sorbonne Universités
[Ti] Título:Induction of dendritic cell-mediated T-cell activation by modified but not native low-density lipoprotein in humans and inhibition by annexin a5: involvement of heat shock proteins.
[So] Source:Arterioscler Thromb Vasc Biol;35(1):197-205, 2015 Jan.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Atherosclerosis is an inflammatory disease, where activated immunocompetent cells, including dendritic cells (DCs) and T cells are abundant in plaques. Low-density lipoprotein modified either by oxidation (oxLDL) or by human group X-secreted phospholipase A2 (LDLx) and heat shock proteins (HSP), especially HSP60 and 90, have been implicated in atherosclerosis. We previously reported that Annexin A5 inhibits inflammatory effects of phospholipids, decreases vascular inflammation and improves vascular function in apolipoprotein E(-/-) mice. Here, we focus on the LDLx effects on human DCs and T cells. APPROACH AND RESULTS: Human DCs were differentiated from peripheral blood monocytes, stimulated by oxLDL or LDLx. Naive autologous T cells were cocultured with pretreated DCs. oxLDL and LDLx, in contrast to LDL, induced DC-activation and T-cell proliferation. T cells exposed to LDLx-treated DCs produced interferon-γ, interleukin (IL)-17 but not IL-4 and IL-10. Annexin A5 abrogated LDLx effects on DCs and T cells and increased production of transforming growth factor-ß and IL-10. Furthermore, IL-10 producing T cells suppressed primary T-cell activation via soluble IL-10, transforming growth factor-ß, and cell-cell contact. Lentiviral-mediated shRNA knock-down HSP60 and 90 in DCs attenuated the effect of LDLx on DCs and subsequent T-cell proliferation. Experiments on DC and T cells derived from carotid atherosclerotic plaques gave similar results. CONCLUSIONS: Our data show that modified forms of LDL such as LDLx but not native LDL activate human T cells through DCs. HSP60 and 90 contribute to such T-cell activation. Annexin A5 promotes induction of regulatory T cells and is potentially interesting as a therapeutic agent.
[Mh] Termos MeSH primário: Anexina A5/metabolismo
Comunicação Celular
Chaperonina 60/metabolismo
Células Dendríticas/metabolismo
Proteínas de Choque Térmico HSP90/metabolismo
Lipoproteínas LDL/metabolismo
Ativação Linfocitária
Proteínas Mitocondriais/metabolismo
Subpopulações de Linfócitos T/metabolismo
[Mh] Termos MeSH secundário: Doenças das Artérias Carótidas/imunologia
Doenças das Artérias Carótidas/metabolismo
Doenças das Artérias Carótidas/patologia
Diferenciação Celular
Proliferação Celular
Células Cultivadas
Chaperonina 60/genética
Técnicas de Cocultura
Citocinas/metabolismo
Células Dendríticas/imunologia
Fosfolipases A2 do Grupo X/metabolismo
Proteínas de Choque Térmico HSP90/genética
Seres Humanos
Mediadores da Inflamação/metabolismo
Proteínas Mitocondriais/genética
Placa Aterosclerótica
Interferência de RNA
Transdução de Sinais
Subpopulações de Linfócitos T/imunologia
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Annexin A5); 0 (Chaperonin 60); 0 (Cytokines); 0 (HSP90 Heat-Shock Proteins); 0 (HSPD1 protein, human); 0 (Inflammation Mediators); 0 (Lipoproteins, LDL); 0 (Mitochondrial Proteins); 0 (oxidized low density lipoprotein); EC 3.1.1.4 (Group X Phospholipases A2)
[Em] Mês de entrada:1502
[Cu] Atualização por classe:141218
[Lr] Data última revisão:
141218
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141115
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.114.304342



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