scholarly journals Singapore Grouper Iridovirus Disturbed Glycerophospholipids Homeostasis: Cytosolic Phospholipase A2 Was Essential for Virus Replication

2021 ◽  
Vol 22 (22) ◽  
pp. 12597
Author(s):  
Na Ni ◽  
Jiaying Zheng ◽  
Wenji Wang ◽  
Linyong Zhi ◽  
Qiwei Qin ◽  
...  
Keyword(s):  
Phospholipase A2 ◽  
Ectopic Expression ◽  
Cytosolic Phospholipase A2 ◽  
Economic Losses ◽  
Key Enzymes ◽  
Cytosolic Phospholipase ◽  
Aquaculture Industry ◽  
Infected Cells ◽  
First Time

Singapore grouper iridovirus (SGIV), belonging to genus Ranavirus, family Iridoviridae, causes great economic losses in the aquaculture industry. Previous studies demonstrated the lipid composition of intracellular unenveloped viruses, but the changes in host-cell glyceophospholipids components and the roles of key enzymes during SGIV infection still remain largely unknown. Here, the whole cell lipidomic profiling during SGIV infection was analyzed using UPLC-Q-TOF-MS/MS. The lipidomic data showed that glycerophospholipids (GPs), including phosphatidylcholine (PC), phosphatidylserine (PS), glycerophosphoinositols (PI) and fatty acids (FAs) were significantly elevated in SGIV-infected cells, indicating that SGIV infection disturbed GPs homeostasis, and then affected the metabolism of FAs, especially arachidonic acid (AA). The roles of key enzymes, such as cytosolic phospholipase A2 (cPLA2), 5-Lipoxygenase (5-LOX), and cyclooxygenase (COX) in SGIV infection were further investigated using the corresponding specific inhibitors. The inhibition of cPLA2 by AACOCF3 decreased SGIV replication, suggesting that cPLA2 might play important roles in the process of SGIV infection. Consistent with this result, the ectopic expression of EccPLA2α or knockdown significantly enhanced or suppressed viral replication in vitro, respectively. In addition, the inhibition of both 5-LOX and COX significantly suppressed SGIV replication, indicating that AA metabolism was essential for SGIV infection. Taken together, our results demonstrated for the first time that SGIV infection in vitro disturbed GPs homeostasis and cPLA2 exerted crucial roles in SGIV replication.

The role of cytosolic phospholipase A2 in gastric damage induced by helicobacter pylori infection: in vivo and in vitro studies

2000 ◽  
Vol 118 (4) ◽  
pp. A732-A733
Author(s):  
Gerardo Nardone ◽  
Eileen Holicky ◽  
Jim R. Uhl ◽  
Vittorio Colantuoni ◽  
Lina Sabatino ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Phospholipase A2 ◽  
Cytosolic Phospholipase A2 ◽  
In Vitro Studies ◽  
Helicobacter Pylori Infection ◽  
Gastric Damage ◽  
Cytosolic Phospholipase

Role of cytosolic phospholipase A2 in vivo and in vitro

1999 ◽  
Vol 59 (1-6) ◽  
pp. 37
Author(s):  
Takao Shimizu ◽  
Naonori Uozumi ◽  
Noriaki Nakatani ◽  
Tetsuya Hirabayashi ◽  
Kazuhiko Kume
Keyword(s):  
Phospholipase A2 ◽  
Cytosolic Phospholipase A2 ◽  
Cytosolic Phospholipase

scholarly journals Fexofenadine inhibits TNF signaling through targeting to cytosolic phospholipase A2 and is therapeutic against inflammatory arthritis

2019 ◽  
Vol 78 (11) ◽  
pp. 1524-1535 ◽  
Author(s):  
Ronghan Liu ◽  
Yuehong Chen ◽  
Wenyu Fu ◽  
Shuya Wang ◽  
Yazhou Cui ◽  
...  
Keyword(s):  
Phospholipase A2 ◽  
Inflammatory Arthritis ◽  
Catalytic Domain ◽  
Cytosolic Phospholipase A2 ◽  
Inflammatory Rheumatic Diseases ◽  
Cytosolic Phospholipase ◽  
Tnf Α ◽  
Approved Drugs

ObjectiveTumour necrosis factor alpha (TNF-α) signalling plays a central role in the pathogenesis of various autoimmune diseases, particularly inflammatory arthritis. This study aimed to repurpose clinically approved drugs as potential inhibitors of TNF-α signalling in treatment of inflammatory arthritis.MethodsIn vitro and in vivo screening of an Food and Drug Administration (FDA)-approved drug library; in vitro and in vivo assays for examining the blockade of TNF actions by fexofenadine: assays for defining the anti-inflammatory activity of fexofenadine using TNF-α transgenic (TNF-tg) mice and collagen-induced arthritis in DBA/1 mice. Identification and characterisation of the binding of fexofenadine to cytosolic phospholipase A2 (cPLA2) using drug affinity responsive target stability assay, proteomics, cellular thermal shift assay, information field dynamics and molecular dynamics; various assays for examining fexofenadine inhibition of cPLA2 as well as the dependence of fexofenadine’s anti-TNF activity on cPLA2.ResultsSerial screenings of a library composed of FDA-approved drugs led to the identification of fexofenadine as an inhibitor of TNF-α signalling. Fexofenadine potently inhibited TNF/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) signalling in vitro and in vivo, and ameliorated disease symptoms in inflammatory arthritis models. cPLA2 was isolated as a novel target of fexofenadine. Fexofenadine blocked TNF-stimulated cPLA2 activity and arachidonic acid production through binding to catalytic domain 2 of cPLA2 and inhibition of its phosphorylation on Ser-505. Further, deletion of cPLA2 abolished fexofenadine’s anti-TNF activity.ConclusionCollectively, these findings not only provide new insights into the understanding of fexofenadine action and underlying mechanisms but also provide new therapeutic interventions for various TNF-α and cPLA2-associated pathologies and conditions, particularly inflammatory rheumatic diseases.

scholarly journals Fexofenadine inhibits TNF signaling through targeting to cytosolic phospholipase A2 and is therapeutic against autoimmune diseases

2019 ◽  
Author(s):  
Ronghan Liu ◽  
Yuehong Chen ◽  
Shuya Wang ◽  
Yazhou Cui ◽  
Xiangli Zhang ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Phospholipase A2 ◽  
Catalytic Domain ◽  
Underlying Mechanism ◽  
Cytosolic Phospholipase A2 ◽  
Therapeutic Interventions ◽  
Cytosolic Phospholipase ◽  
Tnf Α

SUMMARYTNF-α signaling plays a central role in the pathogenesis of various diseases, particularly autoimmune diseases. Screening of a library composed of FDA approved drugs led to the identification of Terfenadine and its active metabolite Fexofenadine as inhibitors of TNF-α signaling. Both Fexofenadine and Terfenadine inhibited TNF/NF-κB signaling in vitro and in vivo, and ameliorated disease symptoms in various autoimmune disease models, including TNF-α transgenic mice, collagen-induced arthritis, and inflammatory bowel disease. Subsequent studies identified cytosolic phospholipase A2 (cPLA2) as a novel target of Fexofenadine. Fexofenadine blocked TNF-stimulated cPLA2 activity and arachidonic acid production through binding to catalytic domain 2 of cPLA2 and inhibition of its phosphorylation on Ser-505. Further, deletion of cPLA2 abolished Fexofenadine’s anti-TNF activity. Collectively, these findings not only provide new insights into the understanding of Fexofenadine action and underlying mechanism, but also provide new therapeutic interventions for various TNF-α and cPLA2-associated pathologies and conditions, particularly autoimmune diseases.

scholarly journals Inhibition of Group IVA Cytosolic Phospholipase A2 by Thiazolyl Ketones in Vitro, ex Vivo, and in Vivo

2014 ◽  
Vol 57 (18) ◽  
pp. 7523-7535 ◽  
Author(s):  
George Kokotos ◽  
Astrid J. Feuerherm ◽  
Efrosini Barbayianni ◽  
Ishita Shah ◽  
Mari Sæther ◽  
...  
Keyword(s):  
Phospholipase A2 ◽  
Ex Vivo ◽  
Cytosolic Phospholipase A2 ◽  
Cytosolic Phospholipase ◽  
Group Iva

scholarly journals Unique targeting of cytosolic phospholipase A2 to plasma membranes mediated by the NADPH oxidase in phagocytes

2003 ◽  
Vol 162 (4) ◽  
pp. 683-692 ◽  
Author(s):  
Zeev Shmelzer ◽  
Nurit Haddad ◽  
Ester Admon ◽  
Itai Pessach ◽  
Thomas L. Leto ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Phospholipase A2 ◽  
Plasma Membranes ◽  
Cytosolic Phospholipase A2 ◽  
Double Labeling ◽  
Cytosolic Phospholipase ◽  
Vitro Binding ◽  
Nadph Oxidase Complex ◽  
Specific Affinity

Cytosolic phospholipase A2 (cPLA2)–generated arachidonic acid (AA) has been shown to be an essential requirement for the activation of NADPH oxidase, in addition to its being the major enzyme involved in the formation of eicosanoid at the nuclear membranes. The mechanism by which cPLA2 regulates NADPH oxidase activity is not known, particularly since the NADPH oxidase complex is localized in the plasma membranes of stimulated cells. The present study is the first to demonstrate that upon stimulation cPLA2 is transiently recruited to the plasma membranes by a functional NADPH oxidase in neutrophils and in granulocyte-like PLB-985 cells. Coimmunoprecipitation experiments and double labeling immunofluorescence analysis demonstrated the unique colocalization of cPLA2 and the NADPH oxidase in plasma membranes of stimulated cells, in correlation with the kinetic burst of superoxide production. A specific affinity in vitro binding was detected between GST-p47phox or GST-p67phox and cPLA2 in lysates of stimulated cells. The association between these two enzymes provides the molecular basis for AA released by cPLA2 to activate the assembled NADPH oxidase. The ability of cPLA2 to regulate two different functions in the same cells (superoxide generation and eicosanoid production) is achieved by a novel dual subcellular localization of cPLA2 to different targets.

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