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Can Inhibitors of Snake Venom Phospholipases A₂ Lead to New Insights into Anti-Inflammatory Therapy in Humans? A Theoretical Study.

ABSTRACT: Human phospholipase A₂ (hPLA₂) of the IIA group (HGIIA) catalyzes the hydrolysis of membrane phospholipids, producing arachidonic acid and originating potent inflammatory mediators. Therefore, molecules that can inhibit this enzyme are a source of potential anti-inflammatory drugs, with different action mechanisms of known anti-inflammatory agents. For the study and development of new anti-inflammatory drugs with this action mechanism, snake venom PLA₂ (svPLA₂) can be employed, since the svPLA₂ has high similarity with the human PLA₂ HGIIA. Despite the high similarity between these secretory PLA₂s_, it is still not clear if these toxins can really be employed as an experimental model to predict the interactions that occur with the human PLA₂ HGIIA and its inhibitors. Thus, the present study aims to compare and evaluate, by means of theoretical calculations, docking and molecular dynamics simulations, as well as experimental studies, the interactions of human PLA₂ HGIIA and two svPLA₂s_,Bothrops toxin II and Crotoxin B (BthTX-II and CB, respectively). Our theoretical findings corroborate experimental data and point out that the human PLA₂ HGIIA and svPLA₂ BthTX-II lead to similar interactions with the studied compounds. From our results, the svPLA₂ BthTX-II can be used as an experimental model for the development of anti-inflammatory drugs for therapy in humans.

SUBMITTER: Sales TA

PROVIDER: S-EPMC5705956 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Can Inhibitors of Snake Venom Phospholipases A₂ Lead to New Insights into Anti-Inflammatory Therapy in Humans? A Theoretical Study.

Sales Thaís A TA Marcussi Silvana S da Cunha Elaine F F EFF Kuca Kamil K Ramalho Teodorico C TC

Toxins 20171025 11

Human phospholipase A₂ (<i>h</i>PLA₂) of the IIA group (HGIIA) catalyzes the hydrolysis of membrane phospholipids, producing arachidonic acid and originating potent inflammatory mediators. Therefore, molecules that can inhibit this enzyme are a source of potential anti-inflammatory drugs, with different action mechanisms of known anti-inflammatory agents. For the study and development of new anti-inflammatory drugs with this action mechanism, snake venom PLA₂ (<i>sv</i>PLA₂) can be employed, sin ...[more]

PMID: 29068410

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Project description:Bothrops envenomation is a public health problem in Brazil. Despite the advances in the knowledge of the pathogenesis of systemic and local effects induced by Bothrops venom, the target tissues to this venom are not completely characterised. As preadipocytes are important cells of the adipose tissue and synthesize inflammatory mediators, we investigated the ability of B. moojeni snake venom (Bmv) to stimulate an inflammatory response in 3T3-L1 preadipocytes in vitro, focusing on (1) the release of PGE2, IL-6, TNF-α, MCP-1, KC, leptin and adiponectin; (2) the mechanisms involved in PGE2 release and (3) differentiation of these cells. Cytotoxicity of Bmv was determined by MTT assay. The concentrations of PGE2, cytokines and adipokines were quantified by EIA. Participation of the COX-1 and COX-2 enzymes, NF-κB and PGE2 receptors (EP1-4) was assessed using a pharmacological approach, and protein expression of the COX enzymes and P-NF-κB was analysed by western blotting. Preadipocyte differentiation was quantified by Oil Red O staining. Bmv (1 μg/mL) induced release of PGE2, IL-6 and KC and increased expression of COX-2 in preadipocytes. Basal levels of TNF-α, MCP-1, leptin and adiponectin were not modified. Treatment of cells with SC560 (COX-1 inhibitor) and NS398 (COX-2 inhibitor) inhibited Bmv-induced PGE2 release. Bmv induced phosphorylation of NF-κB, and treatment of the cells with TPCK and SN50, which inhibit distinct NF-κB domains, significantly reduced Bmv-induced PGE2 release, as did the treatment with an antagonist of PGE2 receptor EP1, unlike treatment with antagonists of EP2, EP3 or EP4. Bmv also induced lipid accumulation in differentiating cells. These results demonstrate that Bmv can activate an inflammatory response in preadipocytes by inducing the release of inflammatory mediators; that PGE2 production is mediated by the COX-1, COX-2 and NF-κB pathways; and that engagement of EP1 potentiates PGE2 synthesis via a positive feedback mechanism. Our findings highlight the role of the adipose tissue as another target for Bmv and suggest that it contributes to Bothrops envenomation by producing inflammatory mediators.

Dataset Information

Can Inhibitors of Snake Venom Phospholipases A₂ Lead to New Insights into Anti-Inflammatory Therapy in Humans? A Theoretical Study.

Publications

Can Inhibitors of Snake Venom Phospholipases A₂ Lead to New Insights into Anti-Inflammatory Therapy in Humans? A Theoretical Study.

Similar Datasets

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