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[PMID]:29307829
[Au] Autor:Li Z; Qu M; Sun Y; Wan H; Chai F; Liu L; Zhang P
[Ad] Endereço:Department of Oncology, Sanya People's Hospital, Sanya 572000, China.
[Ti] Título:Blockage of cytosolic phospholipase A2 alpha sensitizes aggressive breast cancer to doxorubicin through suppressing ERK and mTOR kinases.
[So] Source:Biochem Biophys Res Commun;496(1):153-158, 2018 01 29.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Advanced breast cancer is resistant to chemotherapy and its underlying mechanisms are not fully explored. In this work, we identified cytosolic phospholipase A2 alpha (cPLA2α) as a novel target to overcome chemoresistance in breast cancer. We demonstrated the increased transcriptional and translational expression of cPLA2α in breast cancer cells to acute and chronic exposure to doxorubicin. cPLA2α upregulation is also observed in breast cancer patients in response to chemotherapy. Inhibition of cPLA2α using two pharmacological inhibitors significantly enhances doxorubicin's effects to almost complete suppression in breast cancer cell growth, survival and migration. Similarly, depletion of cPLA2α significantly sensitizes breast cancer cells to doxorubicin treatment. We further found that cPLA2α inhibition led to decreased phosphorylation of ERK, mTOR, S6 and 4EBP1, suggesting the suppression of ERK and mTOR signaling pathways. These findings indicate the positive roles of cPLA2α in breast cancer cell growth, survival, migration and response to chemotherapy. Our work also highlights the therapeutic value of blocking cPLA2α to overcome chemoresistance in breast cancer.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Neoplasias da Mama/tratamento farmacológico
Doxorrubicina/administração & dosagem
MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores
Fosfolipases A2 do Grupo IV/metabolismo
Inibidores de Fosfolipase A2/administração & dosagem
Serina-Treonina Quinases TOR/antagonistas & inibidores
[Mh] Termos MeSH secundário: Antibióticos Antineoplásicos/administração & dosagem
Antibióticos Antineoplásicos/farmacologia
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Apoptose/efeitos dos fármacos
Neoplasias da Mama/metabolismo
Neoplasias da Mama/patologia
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Doxorrubicina/farmacologia
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Sinergismo Farmacológico
Ativação Enzimática/efeitos dos fármacos
Seres Humanos
Invasividade Neoplásica
Inibidores de Fosfolipase A2/farmacologia
Resultado do Tratamento
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antibiotics, Antineoplastic); 0 (Phospholipase A2 Inhibitors); 80168379AG (Doxorubicin); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 3.1.1.4 (Group IV Phospholipases A2); EC 3.1.1.4 (PLA2G4A protein, human)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180109
[St] Status:MEDLINE


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[PMID]:29248447
[Au] Autor:Echeverría S; Leiguez E; Guijas C; do Nascimento NG; Acosta O; Teixeira C; Leiva LC; Rodríguez JP
[Ad] Endereço:Laboratorio de Investigación en Proteínas, Instituto de Química Básica y Aplicada del Nordeste Argentino (UNNE - CONICET), Argentina.
[Ti] Título:Evaluation of pro-inflammatory events induced by Bothrops alternatus snake venom.
[So] Source:Chem Biol Interact;281:24-31, 2018 Feb 01.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Inflammation is a major local feature of envenomation by bothropic snakes being characterized by a prominent local edema, pain, and extensive swelling. There are reports demonstrating that whole Bothrops snake venoms and toxins isolated from them are able to activate macrophages functions, such as phagocytosis, production of reactive oxygen, cytokines and eicosanoids, however, little is known about the effects of Bothrops alternatus (B.a.) venom on macrophages. In this work, we evaluated the proinflammatory effects of B.a. venom with in vivo and in vitro experiments using the Raw 264.7 cell line and mouse peritoneal macrophages. We detected that B.a. venom augments cell permeability (2-fold), and cellular extravasation (mainly neutrophils), increase proinflammatory cytokines IL1 (∼300-fold), IL12 (∼200-fold), and TNFα (∼80-fold) liberation and induce the expression of enzymes related to lipid signaling, such as cPLA and COX-2. Additionally, using lipidomic techniques we detected that this venom produces a release of arachidonic acid (∼10 nMol/mg. Protein) and other fatty acids (16:0 and 18:1 n-9c). Although much of these findings were described in inflammatory processes induced by other bothropic venoms, here we demonstrate that B.a. venom also stimulates pro-inflammatory pathways involving lipid mediators of cell signaling. In this sense, lipidomics analysis of macrophages stimulated with B.a. venom evidenced that the main free fatty acids are implicated in the inflammatory response, and also demonstrated that this venom, is able to activate lipid metabolism even with a low content of PLA .
[Mh] Termos MeSH primário: Bothrops/metabolismo
Macrófagos Peritoneais/efeitos dos fármacos
Venenos de Serpentes/toxicidade
[Mh] Termos MeSH secundário: Animais
Ácido Araquidônico/análise
Ácido Araquidônico/metabolismo
Permeabilidade da Membrana Celular/efeitos dos fármacos
Células Cultivadas
Ciclo-Oxigenase 2/metabolismo
Citocinas/metabolismo
Edema/etiologia
Ácidos Graxos/análise
Ácidos Graxos/metabolismo
Cromatografia Gasosa-Espectrometria de Massas
Fosfolipases A2 do Grupo IV/metabolismo
Interleucina-1/metabolismo
Interleucina-12/metabolismo
Macrófagos Peritoneais/citologia
Macrófagos Peritoneais/metabolismo
Masculino
Camundongos
Neutrófilos/efeitos dos fármacos
Neutrófilos/imunologia
Neutrófilos/metabolismo
Células RAW 264.7
Fator de Necrose Tumoral alfa/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytokines); 0 (Fatty Acids); 0 (Interleukin-1); 0 (Snake Venoms); 0 (Tumor Necrosis Factor-alpha); 187348-17-0 (Interleukin-12); 27YG812J1I (Arachidonic Acid); EC 1.14.99.1 (Cyclooxygenase 2); EC 3.1.1.4 (Group IV Phospholipases A2)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180129
[Lr] Data última revisão:
180129
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171218
[St] Status:MEDLINE


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[PMID]:28808157
[Au] Autor:Bhowmick R; Clark S; Bonventre JV; Leong JM; McCormick BA
[Ad] Endereço:School of Chemical Engineering, Oklahoma State University, Stillwater, Oklahoma, USA.
[Ti] Título:Cytosolic Phospholipase A α Promotes Pulmonary Inflammation and Systemic Disease during Streptococcus pneumoniae Infection.
[So] Source:Infect Immun;85(11), 2017 Nov.
[Is] ISSN:1098-5522
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pulmonary infection by is characterized by a robust alveolar infiltration of neutrophils (polymorphonuclear cells [PMNs]) that can promote systemic spread of the infection if not resolved. We previously showed that 12-lipoxygenase (12-LOX), which is required to generate the PMN chemoattractant hepoxilin A (HXA ) from arachidonic acid (AA), promotes acute pulmonary inflammation and systemic infection after lung challenge with As phospholipase A (PLA ) promotes the release of AA, we investigated the role of PLA in local and systemic disease during infection. The group IVA cytosolic isoform of PLA (cPLA α) was activated upon infection of cultured lung epithelial cells and was critical for AA release from membrane phospholipids. Pharmacological inhibition of this enzyme blocked -induced PMN transepithelial migration Genetic ablation of the cPLA isoform cPLA α dramatically reduced lung inflammation in mice upon high-dose pulmonary challenge with The cPLA α-deficient mice also suffered no bacteremia and survived a pulmonary challenge that was lethal to wild-type mice. Our data suggest that cPLA α plays a crucial role in eliciting pulmonary inflammation during pneumococcal infection and is required for lethal systemic infection following lung challenge.
[Mh] Termos MeSH primário: Células Epiteliais/imunologia
Fosfolipases A2 do Grupo IV/imunologia
Interações Hospedeiro-Patógeno
Pulmão/imunologia
Infecções Pneumocócicas/imunologia
Pneumonia Bacteriana/imunologia
[Mh] Termos MeSH secundário: Animais
Ácido Araquidônico/imunologia
Ácido Araquidônico/metabolismo
Bacteriemia/genética
Bacteriemia/imunologia
Bacteriemia/prevenção & controle
Linhagem Celular Tumoral
Fatores Quimiotáticos/imunologia
Fatores Quimiotáticos/metabolismo
Clorobenzoatos/farmacologia
Cinamatos/farmacologia
Cicloexanonas/farmacologia
Inibidores Enzimáticos/farmacologia
Células Epiteliais/efeitos dos fármacos
Células Epiteliais/enzimologia
Células Epiteliais/microbiologia
Fosfolipases A2 do Grupo IV/antagonistas & inibidores
Fosfolipases A2 do Grupo IV/deficiência
Fosfolipases A2 do Grupo IV/genética
Seres Humanos
Pulmão/efeitos dos fármacos
Pulmão/enzimologia
Pulmão/microbiologia
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Knockout
Infiltração de Neutrófilos/efeitos dos fármacos
Neutrófilos/efeitos dos fármacos
Neutrófilos/imunologia
Neutrófilos/microbiologia
Infecções Pneumocócicas/genética
Infecções Pneumocócicas/microbiologia
Infecções Pneumocócicas/mortalidade
Pneumonia Bacteriana/genética
Pneumonia Bacteriana/microbiologia
Pneumonia Bacteriana/mortalidade
Streptococcus pneumoniae/efeitos dos fármacos
Streptococcus pneumoniae/genética
Streptococcus pneumoniae/patogenicidade
Análise de Sobrevida
Migração Transendotelial e Transepitelial/efeitos dos fármacos
Migração Transendotelial e Transepitelial/imunologia
ortoaminobenzoatos/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chemotactic Factors); 0 (Chlorobenzoates); 0 (Cinnamates); 0 (Cyclohexanones); 0 (Enzyme Inhibitors); 0 (ortho-Aminobenzoates); 110683-10-8 (4-amylcinnamoylanthranilic acid); 27YG812J1I (Arachidonic Acid); 83654-05-1 (1,6-bis(cyclohexyloximinocarbonyl)hexane); 99754-06-0 (2-(4-amylcinnamoyl)amino-4-chlorobenzoic acid); EC 3.1.1.4 (Group IV Phospholipases A2)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171025
[Lr] Data última revisão:
171025
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170816
[St] Status:MEDLINE


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[PMID]:28684316
[Au] Autor:Yun B; Lee H; Powell R; Reisdorph N; Ewing H; Gelb MH; Hsu KL; Cravatt BF; Leslie CC
[Ad] Endereço:Department of Pediatrics, National Jewish Health, Denver, CO, 80206, USA.
[Ti] Título:Regulation of calcium release from the endoplasmic reticulum by the serine hydrolase ABHD2.
[So] Source:Biochem Biophys Res Commun;490(4):1226-1231, 2017 Sep 02.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The serine hydrolase inhibitors pyrrophenone and KT195 inhibit cell death induced by A23187 and H O by blocking the release of calcium from the endoplasmic reticulum and mitochondrial calcium uptake. The effect of pyrrophenone and KT195 on these processes is not due to inhibition of their known targets, cytosolic phospholipase A and α/ß-hydrolase domain-containing (ABHD) 6, respectively, but represent off-target effects. To identify targets of KT195, fibroblasts were treated with KT195-alkyne to covalently label protein targets followed by click chemistry with biotin azide, enrichment on streptavidin beads and tryptic peptide analysis by mass spectrometry. Although several serine hydrolases were identified, α/ß-hydrolase domain-containing 2 (ABHD2) was the only target in which both KT195 and pyrrophenone competed for binding to KT195-alkyne. ABHD2 is a serine hydrolase with a predicted transmembrane domain consistent with its pull-down from the membrane proteome. Subcellular fractionation showed localization of ABHD2 to the endoplasmic reticulum but not to mitochondria or mitochondrial-associated membranes. Knockdown of ABHD2 with shRNA attenuated calcium release from the endoplasmic reticulum, mitochondrial calcium uptake and cell death in fibroblasts stimulated with A23187. The results describe a novel mechanism for regulating calcium transfer from the endoplasmic reticulum to mitochondria that involves the serine hydrolase ABHD2.
[Mh] Termos MeSH primário: Cálcio/metabolismo
Retículo Endoplasmático/metabolismo
Hidrolases/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Linhagem Celular
Relação Dose-Resposta a Droga
Fosfolipases A2 do Grupo IV/antagonistas & inibidores
Fosfolipases A2 do Grupo IV/deficiência
Fosfolipases A2 do Grupo IV/metabolismo
Peróxido de Hidrogênio/antagonistas & inibidores
Peróxido de Hidrogênio/farmacologia
Hidrolases/antagonistas & inibidores
Camundongos
Camundongos Knockout
Inibidores de Fosfolipase A2/farmacologia
Pirrolidinas/farmacologia
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Phospholipase A2 Inhibitors); 0 (Pyrrolidines); 0 (pyrrophenone); BBX060AN9V (Hydrogen Peroxide); EC 3.- (Hydrolases); EC 3.1.1.- (Abhd2 protein, mouse); EC 3.1.1.4 (Group IV Phospholipases A2); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171028
[Lr] Data última revisão:
171028
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170708
[St] Status:MEDLINE


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[PMID]:28649002
[Au] Autor:Fu H; He Y; Qi L; Chen L; Luo Y; Chen L; Li Y; Zhang N; Guo H
[Ad] Endereço:Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China; The Key Laboratory of Tianjin Cancer Prevention and Treatment, National Clinical Research Center for Cancer, Tianjin, 300060, China; Tianjin University of Traditional Chinese Medicine,
[Ti] Título:cPLA2α activates PI3K/AKT and inhibits Smad2/3 during epithelial-mesenchymal transition of hepatocellular carcinoma cells.
[So] Source:Cancer Lett;403:260-270, 2017 Sep 10.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Cytosolic phospholipase A2α (cPLA2α), a key phospholipase that regulates lipid metabolism, plays an important role in tumor progression. In the present study of hepatocellular carcinoma (HCC), cPLA2α was overexpressed in highly metastatic HCC cell lines. Immunohistochemical staining showed increased levels of cPLA2α at the invasive edges of HCC, and a clinicopathological analysis of samples from 111 patients revealed that its expression level was linked with micro-vascular invasion and cirrhosis. Knockdown of cPLA2α inhibited migration, probably due to its role in actin polymerization. Overexpression of cPLA2α promoted cell migration and invasion. Based on the mechanistic analysis, our data suggested that cPLA2α mediate epidermal growth factor (EGF) induced epithelial-mesenchymal transition (EMT) through PI3K/AKT/ERK pathway. cPLA2α activity was required for the transforming growth factor-(TGF)-ß-induced EMT. However, cPLA2α inhibited Smad2/3 activation and promoted the activation of the PI3K/AKT/ERK pathway. A xenograft tumor transplant model confirmed the role of cPLA2α in HCC invasion and metastasis. Based on the mechanistic analysis, cPLA2α mediated both EGF- and TGF-ß-induced EMT, which are essential for HCC metastasis. cPLA2α is a potentially target for novel therapies of HCC.
[Mh] Termos MeSH primário: Carcinoma Hepatocelular/enzimologia
Transição Epitelial-Mesenquimal
Fosfolipases A2 do Grupo IV/metabolismo
Neoplasias Hepáticas/enzimologia
Fosfatidilinositol 3-Quinase/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
Proteína Smad2/metabolismo
Proteína Smad3/metabolismo
[Mh] Termos MeSH secundário: Animais
Carcinoma Hepatocelular/genética
Carcinoma Hepatocelular/secundário
Adesão Celular
Movimento Celular
Proliferação Celular
Ativação Enzimática
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Feminino
Regulação Enzimológica da Expressão Gênica
Regulação Neoplásica da Expressão Gênica
Fosfolipases A2 do Grupo IV/genética
Células Hep G2
Seres Humanos
Neoplasias Hepáticas/genética
Neoplasias Hepáticas/patologia
Masculino
Camundongos Endogâmicos BALB C
Camundongos Nus
Meia-Idade
Invasividade Neoplásica
Fosforilação
Interferência de RNA
Transdução de Sinais
Fatores de Tempo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (SMAD2 protein, human); 0 (SMAD3 protein, human); 0 (Smad2 Protein); 0 (Smad3 Protein); EC 2.7.1.137 (Phosphatidylinositol 3-Kinase); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 3.1.1.4 (Group IV Phospholipases A2); EC 3.1.1.4 (PLA2G4A protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170627
[St] Status:MEDLINE


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[PMID]:28602806
[Au] Autor:Stremmel W; Staffer S; Wannhoff A; Pathil A
[Ad] Endereço:Department of Internal Medicine, University Hospital of Heidelberg, INF 410, 69120 Heidelberg, Germany. Electronic address: wolfgang.stremmel@med.uni-heidelberg.de.
[Ti] Título:The overall fatty acid absorption controlled by basolateral chylomicron excretion under regulation of p-JNK1.
[So] Source:Biochim Biophys Acta;1862(9):917-928, 2017 09.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Suppression of fatty acid absorption is one goal to fight obesity. However, the responsible molecular mechanism is poorly understood. Aim of the present study was the search for the key regulator of the overall fatty acid absorption mechanism and its pharmaceutical modulation. As experimental tool we employed the polarized human intestinal tumor derived cell line CaCo2. Here we showed that influx of fatty acids is mediated by an apical heterotetrameric plasma membrane protein complex of which the calcium-independent membrane phospholipase A (iPLA ß) is one constituent. The newly synthesized bile acid-phospholipid conjugate ursodeoxycholate-lysophosphatidylethanolamide (UDCA-LPE) blocked iPLA ß, which structurally disrupted the fatty acid-uptake complex. Furthermore, the inhibition of iPLA ß lead to reduction of cytosolic lysophosphatidylcholine (LPC) production which suppressed p-JNK1, as a central regulator of metabolism. In a concerted action low p-JNK1 levels prohibited synthesis of the members of the fatty acid uptake complex as well as of apolipoprotein B and the connected members of the basolateral vesicular chylomicron excretion machinery, thereby inhibiting cellular lipid excretion. The basolateral chylomicron release was shown to determine the overall fatty acid-absorption capacity as rate limiting step, whereas apical uptake replenishes the cellular stores, enabling continuous transcellular movement of fatty acids. In conclusion, the UDCA-LPE mediated inhibition of p-JNK1 represents a powerful tool to control intestinal absorption of fatty acids and, thus may be employed as a drug to treat obesity.
[Mh] Termos MeSH primário: Quilomícrons/metabolismo
Ácidos Graxos/metabolismo
Proteína Quinase 8 Ativada por Mitógeno/metabolismo
[Mh] Termos MeSH secundário: Animais
Apolipoproteínas B/metabolismo
Ácidos e Sais Biliares/metabolismo
Células CACO-2
Cálcio/metabolismo
Linhagem Celular Tumoral
Membrana Celular/metabolismo
Feminino
Fosfolipases A2 do Grupo IV/metabolismo
Seres Humanos
Lisofosfatidilcolinas/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Ácido Ursodesoxicólico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Apolipoproteins B); 0 (Bile Acids and Salts); 0 (Chylomicrons); 0 (Fatty Acids); 0 (Lysophosphatidylcholines); 724L30Y2QR (Ursodeoxycholic Acid); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 8); EC 3.1.1.4 (Group IV Phospholipases A2); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170613
[St] Status:MEDLINE


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[PMID]:28336330
[Au] Autor:Su X; Liu S; Zhang X; Lam SM; Hu X; Zhou Y; Chen J; Wang Y; Wu C; Shui G; Lu M; Pei R; Chen X
[Ad] Endereço:State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing, China.
[Ti] Título:Requirement of cytosolic phospholipase A2 gamma in lipid droplet formation.
[So] Source:Biochim Biophys Acta;1862(7):692-705, 2017 07.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Lipid droplet (LD) accumulation in hepatocytes is a typical character of steatosis. Hepatitis C virus (HCV) infection, one of the risk factors related to steatosis, induced LD accumulation in cultured cells. However, the mechanisms of which HCV induce LD formation are not fully revealed. Previously we identified cytosolic phospholipase A2 gamma (PLA2G4C) as a host factor upregulated by HCV infection and involved in HCV replication. Here we further revealed that PLA2G4C plays an important role in LD biogenesis and refined the functional analysis of PLA2G4C in LD biogenesis and HCV assembly. LD formation upon fatty acid and HCV stimulation in PLA2G4C knockdown cells was impaired and could not be restored by complementation with PLA2G4A. PLA2G4C was tightly associated in the membrane with the domain around the amino acid residues 260-292, normally in ER but relocated into LDs upon oleate stimulation. Mutant PLA2G4C without enzymatic activity was not able to restore LD formation in PLA2G4C knockdown cells. Thus, both the membrane attachment and the enzymatic activity of PLA2G4C were required for its function in LD formation. The participation of PLA2G4C in LD formation is correlated with its involvement in HCV assembly. Finally, PLA2G4C overexpression itself led to LD formation in hepatic cells and enhanced LD accumulation in the liver of high-fat diet (HFD)-fed mice, suggesting its potential role in fatty liver disease.
[Mh] Termos MeSH primário: Citosol/metabolismo
Fosfolipases A2 do Grupo IV/metabolismo
Gotículas Lipídicas/metabolismo
Metabolismo dos Lipídeos/fisiologia
[Mh] Termos MeSH secundário: Aminoácidos/metabolismo
Animais
Linhagem Celular
Citosol/virologia
Retículo Endoplasmático/metabolismo
Retículo Endoplasmático/virologia
Ácidos Graxos/metabolismo
Células HEK293
Hepacivirus/patogenicidade
Hepatite C/metabolismo
Hepatócitos/metabolismo
Hepatócitos/virologia
Seres Humanos
Gotículas Lipídicas/virologia
Fígado/metabolismo
Fígado/virologia
Masculino
Membranas/metabolismo
Membranas/virologia
Camundongos
Camundongos Endogâmicos C57BL
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Amino Acids); 0 (Fatty Acids); EC 3.1.1.4 (Group IV Phospholipases A2)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170325
[St] Status:MEDLINE


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[PMID]:28215748
[Au] Autor:Qi X; Shao M; Sun H; Shen Y; Meng D; Huo W
[Ad] Endereço:Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China. Electronic address: qixu16125@163.com.
[Ti] Título:Long non-coding RNA SNHG14 promotes microglia activation by regulating miR-145-5p/PLA2G4A in cerebral infarction.
[So] Source:Neuroscience;348:98-106, 2017 Apr 21.
[Is] ISSN:1873-7544
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Activated microglia cells (MCs) are able to release a large amount of inflammatory cytokines after ischemic stroke, which exacerbates neuron damage. In this study, we explored the functional involvement of long non-coding RNA (lncRNA) SNHG14 and its potential regulatory mechanism in the activation of MCs. The mouse model of middle cerebral artery occlusion (MCAO) and microglia cell model of oxygen/glucose deprivation (OGD) were made. The expression of SNHG14, miR-145-5p and PLA2G4A protein expression was determined by quantitative real time PCR and western blot, respectively. Dual-luciferase assay was used to verify the direct binding of miR-145-5p and PLA2G4A. Flow cytometry was applied to measure neurons' apoptosis. SNHG14 highly expressed in ischemic cerebral tissues and BV-2 cells after OGD treatment. SNHG14 knockdown could remarkably inhibit BV-2 cells activation induced by OGD; while SNHG14 overexpression significantly promoted BV-2 cells activation, showing an increase of TNF-α and NO production and neurons' apoptosis rate. Additionally, SNHG14 knockdown promoted the expression of miR-145-5p and reduced PLA2G4A. Contrarily, SNHG14 overexpression inhibited miR-145-5p expression and increased PLA2G4A. Moreover, miR-145-5p overexpression also reversed the effect of OGD on BV-2 cells activation. Bioinformatics analysis and dual-luciferase assay supported that SNHG14 could bind directly to miR-145-5p and miR-145-5p-binding site was existed on 3'-UTR of PLA2G4A. MiR-145-5p mimic reversed the increase of PLA2G4A and reduced the high levels of TNF-α and NO in BV-2 cells induced by SNHG14 overexpression. SNHG14 increased the expression of PLA2G4A by inhibition of miR-145-5p, which resulted in the activation of MCs in cerebral infarction.
[Mh] Termos MeSH primário: Infarto Cerebral/metabolismo
Fosfolipases A2 do Grupo IV/metabolismo
MicroRNAs/metabolismo
Microglia/metabolismo
RNA Longo não Codificante/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose/fisiologia
Infarto Cerebral/genética
Infarto Cerebral/patologia
Modelos Animais de Doenças
Regulação da Expressão Gênica
Fosfolipases A2 do Grupo IV/genética
Camundongos
Camundongos Endogâmicos C57BL
MicroRNAs/genética
Microglia/patologia
Neurônios/metabolismo
Neurônios/patologia
RNA Longo não Codificante/genética
Fator de Necrose Tumoral alfa/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MIRN145 microRNA, mouse); 0 (MicroRNAs); 0 (Pla2g4a protein, mouse); 0 (RNA, Long Noncoding); 0 (Tumor Necrosis Factor-alpha); EC 3.1.1.4 (Group IV Phospholipases A2)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170221
[St] Status:MEDLINE


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[PMID]:28063500
[Au] Autor:Yun B; Leslie CC
[Ad] Endereço:National Jewish Health, Denver, CO, United States.
[Ti] Título:Cellular Assays for Evaluating Calcium-Dependent Translocation of cPLA α to Membrane.
[So] Source:Methods Enzymol;583:71-99, 2017.
[Is] ISSN:1557-7988
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The group IVA phospholipase A , commonly called cytosolic phospholipase A α (cPLA α), is a widely expressed enzyme that hydrolyzes membrane phospholipid to produce arachidonic acid and lysophospholipids, which are precursors for a number of bioactive lipid mediators. Arachidonic acid is metabolized through the cyclooxygenase and lipoxygenase pathways for production of prostaglandins and leukotrienes that regulate normal physiological processes and contribute to disease pathogenesis. cPLA α is composed of an N-terminal C2 domain and a C-terminal catalytic domain that contains the Ser-Asp catalytic dyad. The catalytic domain contains phosphorylation sites and basic residues that regulate the catalytic activity of cPLA α. In response to cell stimulation, cPLA α is rapidly activated by posttranslational mechanisms including increases in intracellular calcium and phosphorylation by mitogen-activated protein kinases. In resting cells, cPLA α is localized in the cytosol but translocates to membrane including the Golgi, endoplasmic reticulum, and the peri-nuclear membrane in response to increases in intracellular calcium. Calcium binds to the C2 domain, which promotes the interaction of cPLA α with membrane through hydrophobic interactions. In this chapter, we describe assays used to study the calcium-dependent translocation of cPLA α to membrane, a regulatory step necessary for access to phospholipid and release of arachidonic acid.
[Mh] Termos MeSH primário: Cálcio/metabolismo
Expressão Gênica
Fosfolipases A2 do Grupo IV/metabolismo
Imagem Óptica/métodos
Proteínas Recombinantes de Fusão/metabolismo
Imagem com Lapso de Tempo/métodos
[Mh] Termos MeSH secundário: Adenoviridae/genética
Adenoviridae/metabolismo
Animais
Ácido Araquidônico
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Bioensaio
Domínio Catalítico
Citosol/metabolismo
Cães
Retículo Endoplasmático/metabolismo
Fibroblastos/citologia
Fibroblastos/metabolismo
Vetores Genéticos/genética
Vetores Genéticos/metabolismo
Complexo de Golgi/metabolismo
Proteínas de Fluorescência Verde/genética
Proteínas de Fluorescência Verde/metabolismo
Fosfolipases A2 do Grupo IV/genética
Seres Humanos
Interações Hidrofóbicas e Hidrofílicas
Proteínas Luminescentes/genética
Proteínas Luminescentes/metabolismo
Pulmão/citologia
Pulmão/metabolismo
Células Madin Darby de Rim Canino
Camundongos
Fosforilação
Cultura Primária de Células
Transporte Proteico
Proteínas Recombinantes de Fusão/genética
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Luminescent Proteins); 0 (Recombinant Fusion Proteins); 0 (enhanced cyan fluorescent protein); 0 (yellow fluorescent protein, Bacteria); 147336-22-9 (Green Fluorescent Proteins); 27YG812J1I (Arachidonic Acid); EC 3.1.1.4 (Group IV Phospholipases A2); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170811
[Lr] Data última revisão:
170811
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170109
[St] Status:MEDLINE


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[PMID]:27810597
[Au] Autor:Arnsmann M; Hanekamp W; Elfringhoff AS; Lehr M
[Ad] Endereço:Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrrensstr. 48, 48149 Münster, Germany.
[Ti] Título:Structure-activity relationship studies on 1-(2-oxopropyl)indole-5-carboxylic acids acting as inhibitors of cytosolic phospholipase A α: Effect of substituents at the indole 3-position on activity, solubility, and metabolic stability.
[So] Source:Eur J Med Chem;125:1107-1114, 2017 Jan 05.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Cytosolic phospholipase A α (cPLA α) is a key enzyme in the biosynthesis of pro-inflammatory lipid mediators and therefore represents an attractive target for the development of new anti-inflammatory drugs. Recently, we have found that 1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid (4) is a potent inhibitor of the enzyme. In this work, we evaluate the effect of butanoyl- and hexanoyl-substituents in position 3 of the indole scaffold of this compound bearing terminal groups of varying polarity. As a result, inhibitory potency was not affected considerably in most cases, while metabolic phase I and phase II in vitro stability and aqueous solubility could be influenced and modulated by the structural modifications performed.
[Mh] Termos MeSH primário: Fosfolipases A2 do Grupo IV/antagonistas & inibidores
Indóis/química
Indóis/farmacologia
Inibidores de Fosfolipase A2/química
Inibidores de Fosfolipase A2/farmacologia
[Mh] Termos MeSH secundário: Animais
Plaquetas/efeitos dos fármacos
Plaquetas/enzimologia
Ácidos Carboxílicos/química
Ácidos Carboxílicos/metabolismo
Ácidos Carboxílicos/farmacologia
Fosfolipases A2 do Grupo IV/metabolismo
Seres Humanos
Indóis/metabolismo
Fígado/metabolismo
Camundongos
Inibidores de Fosfolipase A2/metabolismo
Ratos
Solubilidade
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carboxylic Acids); 0 (Indoles); 0 (Phospholipase A2 Inhibitors); EC 3.1.1.4 (Group IV Phospholipases A2)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170217
[Lr] Data última revisão:
170217
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161105
[St] Status:MEDLINE



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