Search

Bariatric surgery restores glucose tolerance in many, but not all, severely obese subjects with type 2 diabetes (T2D). We aimed to evaluate the plasma protein profiles associated with the T2D remission after obesity surgery. We recruited seventeen women with severe obesity submitted to bariatric procedures, including six non-diabetic patients and eleven patients with T2D. After surgery, diabetes remitted in 7 of the 11 patients with T2D. Plasma protein profiles at baseline and 6 months after bariatric surgery were analyzed by two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization-time-of-flight/time-of-flight coupled to mass spectrometry (MALDI-TOF/TOF MS). Remission of T2D following bariatric procedures was associated with changes in alpha-1-antichymotrypsin (SERPINA 3, p &lt, 0.05), alpha-2-macroglobulin (A2M, p &lt, 0.005), ceruloplasmin (CP, p &lt, 0.05), fibrinogen beta chain (FBG, p &lt, 0.05), fibrinogen gamma chain (FGG, p &lt, 0.05), gelsolin (GSN, p &lt, 0.05), prothrombin (F2, p &lt, 0.05), and serum amyloid p-component (APCS, p &lt, 0.05). The resolution of diabetes after bariatric surgery is associated with specific changes in the plasma proteomic profiles of proteins involved in acute-phase response, fibrinolysis, platelet degranulation, and blood coagulation, providing a pathophysiological basis for the study of their potential use as biomarkers of the surgical remission of T2D in a larger series of severely obese patients.

Lipoprotein(a) (Lp(a)) is one of the most important risk factors for the development of calcific aortic valve stenosis (CAVS). However, the mechanisms through which Lp(a) causes CAVS are currently unknown. Our objectives were to characterize the Lp(a) proteome and to identify proteins that may be differentially associated with Lp(a) in patients with versus without CAVS. Our second objective was to identify genes that may be differentially regulated by exposure to high versus low Lp(a) levels in explanted aortic valves from patients with CAVS. We isolated Lp(a) from the blood of 21 patients with CAVS and 22 volunteers and performed untargeted label-free analysis of the Lp(a) proteome. We also investigated the transcriptomic signature of calcified aortic valves from patients who underwent aortic valve replacement with high versus low Lp(a) levels (n = 118). Proteins involved in the protein activation cascade, platelet degranulation, leukocyte migration, and response to wounding may be associated with Lp(a) depending on CAVS status. The transcriptomic analysis identified genes involved in cardiac aging, chondrocyte development, and inflammation as potentially influenced by Lp(a). Our multi-omic analyses identified biological pathways through which Lp(a) may cause CAVS, as well as key molecular events that could be triggered by Lp(a) in CAVS development.

Envenomation by viperid snakes may lead to severe bleeding, consumption coagulopathy, and thrombotic microangiopathy symptoms. The exact etiology or toxins responsible for thrombotic microangiopathy symptoms after snake envenomation remain obscure. Snake C-type lectin-like proteins (snaclecs) are one of the main non-enzymatic protein constituents in viper venoms, of which a majority are considered as modulators of thrombosis and hemostasis. In this study, we demonstrated that two snaclecs (mucetin and stejnulxin), isolated and identified from Protobothrops mucrosquamatus and Trimeresurus stejnegeri venoms, directly induced platelet degranulation and clot-retraction in vitro, and microvascular thrombosis has been confirmed in various organs in vivo. These snaclecs reduced cerebral blood flow and impaired motor balance and spatial memories in mice, which partially represent the thrombotic microangiopathy symptoms in some snakebite patients. The functional blocking of these snaclecs with antibodies alleviated the viper venom induced platelet activation and thrombotic microangiopathy-like symptoms. Understanding the pathophysiology of thrombotic microangiopathy associated with snake envenoming may lead to emerging therapeutic strategies.

Background: Hypercoagulative conditions play a key role in venous thromboembolism (VTE). Inflammation is currently linked to VTE, but the potential role of circulating microparticles and oxidative stress (OxS) must be elucidated. The aim of this study was to evaluate platelet-derived microparticles and surrogate OxS biomarkers in patients diagnosed with VTE through a case&ndash, control study. Methods: Platelet-derived microparticles (MPs), pro-thrombinase-induced clotting time assay (PiCT), phospholipids (PLPs), malondialdehyde (MDA), 4-hydroxynonenale (4-HNE), thiobarbituric acid reactive substances (TBARs), superoxide dismutase (SOD), and galectin-3 (Gal-3) were measured in VTE patients and in healthy controls. Results: PLPs, 4-HNE, TBARs, and Gal-3 were higher in VTE patients compared to controls, conversely, SOD was lower. A significant non-linear regression between OxS biomarkers and the markers of platelet degranulation was found. Conclusion: Our results suggest that OxS and platelet degranulation are concomitant pathophysiological mechanisms in VTE.

Coronary artery disease (CAD) is a major cause of end-stage cardiac disease. Although profound efforts have been made to illuminate the pathogenesis, the molecular mechanisms of CAD remain to be analyzed. To identify the candidate genes in the advancement of CAD, microarray dataset GSE23766 was downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were identified, and pathway and gene ontology (GO) enrichment analyses were performed. The protein-protein interaction network was constructed and the module analysis was performed using the Biological General Repository for Interaction Datasets (BioGRID) and Cytoscape. Additionally, target genes-miRNA regulatory network and target genes-TF regulatory network were constructed and analyzed. There were 894 DEGs between male human CAD samples and female human CAD samples, including 456 up regulated genes and 438 down regulated genes. Pathway enrichment analyses revealed that DEGs (up and down regulated) were mostly enriched in the superpathway of steroid hormone biosynthesis, ABC transporters, oxidative ethanol degradation III and Complement and coagulation cascades. Similarly, geneontology enrichment analyses revealed that DEGs (up and down regulated) were mostly enriched in the forebrain neuron differentiation, filopodium membrane, platelet degranulation and blood microparticle. In the PPI network and modules (up and down regulated), MYC, NPM1, TRPC7, UBC, FN1, HEMK1, IFT74 and VHL were hub genes. In the target genes-miRNA regulatory network and target genes&mdash, TF regulatory network (up and down regulated), TAOK1, KHSRP, HSD17B11 and PAH were target genes. In conclusion, the pathway and GO ontology enriched by DEGs may reveal the molecular mechanism of CAD. Its hub and target genes, MYC, NPM1, TRPC7, UBC, FN1, HEMK1, IFT74, VHL, TAOK1, KHSRP, HSD17B11 and PAH were expected to be new targets for CAD. Our finding provided clues for exploring molecular mechanism and developing new prognostics, diagnostic and therapeutic strategies for CAD.

Garcinol, an anti-inflammatory and anti-carcinogenic polyisoprenylated benzophenone isolated from Garcinia plants, stimulates tumor cell apoptosis and suicidal erythrocyte death, but supports the survival of hepatocytes and neurons. The present study explored whether the substance influences platelet function and/or apoptosis. To this end, we exposed murine blood platelets to garcinol (33 &micro, M, 30 min) without and with activation by collagen-related peptide (CRP) (2&ndash, 5 &micro, g/mL) or thrombin (0.01 U/mL), flow cytometry was employed to estimate cytosolic Ca2+-activity ([Ca2+]i) from Fluo-3 fluorescence, platelet degranulation from P-selectin abundance, integrin activation from &alpha, IIb&beta, 3 integrin abundance, caspase activity utilizing an Active Caspase-3 Staining kit, phosphatidylserine abundance from annexin-V-binding, relative platelet volume from forward scatter, and aggregation utilizing staining with CD9-APC and CD9-PE. As a result, in the absence of CRP and thrombin, the exposure of the platelets to garcinol did not significantly modify [Ca2+]i, P-selectin abundance, activated &alpha, 3 integrin, annexin-V-binding, cell volume, caspase activity, and aggregation. Exposure of platelets to CRP or thrombin was followed by a significant increase of [Ca2+]i, P-selectin abundance, &alpha, 3 integrin activity, annexin-V-binding, caspase activity, and aggregation, as well as significant cell shrinkage. All effects of CRP were strong and significant, those of thrombin were only partially and slightly blunted in the presence of garcinol. In conclusion, garcinol blunts CRP-induced platelet activity, apoptosis and aggregation.

The aim of the study was to compare proteomic data on the effects of spaceflight factors on the human body, including both real space missions and ground-based experiments. LC&ndash, MS/MS-based proteomic analysis of blood plasma samples obtained from 13 cosmonauts before and after long-duration (169&ndash, 199 days) missions on the International Space Station (ISS) and for five healthy men included in 21-day-long head-down bed rest (HDBR) and dry immersion experiments were performed. The semi-quantitative label-free analysis revealed significantly changed proteins: 19 proteins were significantly different on the first (+1) day after landing with respect to background levels, 44 proteins significantly changed during HDBR and 31 changed in the dry immersion experiment. Comparative analysis revealed nine common proteins (A1BG, A2M, SERPINA1, SERPINA3, SERPING1, SERPINC1, HP, CFB, TF), which changed their levels after landing, as well as in both ground-based experiments. Common processes, such as platelet degranulation, hemostasis, post-translational protein phosphorylation and processes of protein metabolism, indicate common pathogenesis in ground experiments and during spaceflight. Dissimilarity in the lists of significantly changed proteins could be explained by the differences in the dynamics of effective development in the ground-based experiments. Data are available via ProteomeXchange using the identifier PXD013305.