Liver gene regulation of hemostasis-related factors is altered by experimental snake envenomation in mice

Sachetto, Ana Teresa Azevedo; Jensen, José Ricardo; Santoro, Marcelo Larami

doi:10.1371/journal.pntd.0008379

Cited by 9 publications

(10 citation statements)

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“…Fibrinogen level reaches 100 mg/dL in 24 h [49]. In mice, injection of B. jararaca venom upregulates hepatic mRNA synthesis of fibrinogen chains, which may explain the fast recovery of clotting tests and fibrinogen level, even without antivenom [50].…”

Section: Thrombocytopenia and Incoagulabilitymentioning

confidence: 99%

Bleeding and Thrombosis: Insights into Pathophysiology of Bothrops Venom-Related Hemostasis Disorders

Larréché

Chippaux

Chevillard

et al. 2021

IJMS

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Toxins from Bothrops venoms targeting hemostasis are responsible for a broad range of clinical and biological syndromes including local and systemic bleeding, incoagulability, thrombotic microangiopathy and macrothrombosis. Beyond hemostais disorders, toxins are also involved in the pathogenesis of edema and in most complications such as hypovolemia, cardiovascular collapse, acute kidney injury, myonecrosis, compartmental syndrome and superinfection. These toxins can be classified as enzymatic proteins (snake venom metalloproteinases, snake venom serine proteases, phospholipases A2 and L-amino acid oxidases) and non-enzymatic proteins (desintegrins and C-type lectin proteins). Bleeding is due to a multifocal toxicity targeting vessels, platelets and coagulation factors. Vessel damage due to the degradation of basement membrane and the subsequent disruption of endothelial cell integrity under hydrostatic pressure and tangential shear stress is primarily responsible for bleeding. Hemorrhage is promoted by thrombocytopenia, platelet hypoaggregation, consumption coagulopathy and fibrin(ogen)olysis. Onset of thrombotic microangiopathy is probably due to the switch of endothelium to a prothrombotic phenotype with overexpression of tissue factor and other pro-aggregating biomarkers in association with activation of platelets and coagulation. Thrombosis involving large-caliber vessels in B. lanceolatus envenomation remains a unique entity, which exact pathophysiology remains poorly understood.

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Section: Thrombocytopenia and Incoagulabilitymentioning

confidence: 99%

Bleeding and Thrombosis: Insights into Pathophysiology of Bothrops Venom-Related Hemostasis Disorders

Larréché

Chippaux

Chevillard

et al. 2021

IJMS

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“…C57BL/6 mice manifested a characteristic recovery in fibrinogen levels at 24 h [ 58 ], but it was less pronounced in Vwf -/- mice (p<0.05). In fact, Vwf -/- mice have been associated with deficiencies in pro-inflammatory proteins [ 63 , 64 ], which could explain the low recovery of fibrinogen levels [ 65 ].…”

Section: Resultsmentioning

confidence: 99%

“…been associated with deficiencies in pro-inflammatory proteins [63,64], which could explain the low recovery of fibrinogen levels [65].…”

Section: Plos Neglected Tropical Diseasesmentioning

confidence: 99%

“…Although rarely diagnosed, some patients bitten by B. jararaca also manifest thrombotic microangiopathy [73,74], but their ADAMTS13 levels were normal as well as in others bitten by other snakes [75], indicating that venom toxins are directly involved in the phenomena of activation of coagulation, endothelial injury, and red blood cell lysis and poikilocytosis. Paradoxically, mice that received BjV showed a decrease in Adamts13 mRNA synthesis in the liver [65]. Since ADAMTS13 is not only produced by the hepatic stellate cells in liver, but also by endothelial cells [76], gene expression of Adamts13 still needs to be studied in other organs, to evaluate whether negative feedback occurs.…”

Section: Plos Neglected Tropical Diseasesmentioning

confidence: 99%

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Involvement of von Willebrand factor and botrocetin in the thrombocytopenia induced by Bothrops jararaca snake venom

et al. 2021

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Patients bitten by snakes consistently manifest a bleeding tendency, in which thrombocytopenia, consumption coagulopathy, mucous bleeding, and, more rarely, thrombotic microangiopathy, are observed. Von Willebrand factor (VWF) is required for primary hemostasis, and some venom proteins, such as botrocetin (a C-type lectin-like protein) and snake venom metalloproteinases (SVMP), disturb the normal interaction between platelets and VWF, possibly contributing to snakebite-induced bleedings. To understand the relationship among plasma VWF, platelets, botrocetin and SVMP from Bothrops jararaca snake venom (BjV) in the development of thrombocytopenia, we used (a) Wistar rats injected s.c. with BjV preincubated with anti-botrocetin antibodies (ABA) and/or Na2-EDTA (a SVMP inhibitor), and (b) VWF knockout mice (Vwf-/-) injected with BjV. Under all conditions, BjV induced a rapid and intense thrombocytopenia. In rats, BjV alone reduced the levels of VWF:Ag, VWF:CB, high molecular weight multimers of VWF, ADAMTS13 activity, and factor VIII. Moreover, VWF:Ag levels in rats that received BjV preincubated with Na2-EDTA and/or ABA tended to recover faster. In mice, BjV caused thrombocytopenia in both Vwf-/- and C57BL/6 (background control) strains, and VWF:Ag levels tended to decrease in C57BL/6, demonstrating that thrombocytopenia was independent of the presence of plasma VWF. These findings showed that botrocetin present in BjV failed to affect the extent or the time course of thrombocytopenia induced by envenomation, but it contributed to decrease the levels and function of plasma VWF. Thus, VWF alterations during B. jararaca envenomation are an ancillary event, and not the main mechanism leading to decreased platelet counts.

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“…[ 22 ] Interestingly, the gene interactions between Proc and Serpinc1 and Plg and Serpinf2 are related to liver function and regeneration. [ 23 ] However, humans made few studies on the role of SERPINF2 in HCC, so we will further investigate it.…”

Section: Discussionmentioning

confidence: 99%

Exploring novel independent prognostic biomarkers for hepatocellular carcinoma based on TCGA and GEO databases

Hou

2022

Medicine

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Background: Hepatocellular carcinoma (HCC) has become the fifth most common cancer globally, with the second-highest mortality rate and poor survival outcomes. In our research, we aimed to use The Cancer Genome Atlas and gene expression omnibus databases to identify potential genetic biomarkers to predict and improve the survival rate of HCC patients.Methods: In GSE60502, GSE76427, and GSE84402, we performed differential expression analysis to obtain differentially expressed genes (DEGs). In the The Cancer Genome Atlas database, the FPKM expression profile was subjected to weighted gene co-expression analysis to obtain modules closely related to HCC. We received common genes by intersecting the genes in the module with the differential genes. Then, we fused the common genes' expression profiles, survival time, and survival status for univariate, Least Absolute Shrinkage and Selection Operator, and multivariate COX regression analysis to obtain prognostic genes. Predictive genes were performed in K-M survival analysis and combined with clinical data for independent predictive analysis.Results: After differential expression analysis, GSE60502 obtained 1107 DEGs, GSE76427 obtained 424 DEGs, and GSE84402 obtained 1668 DEGs. Through weighted gene co-expression analysis analysis, we can see that the blue and brown modules were closely associated with HCC. After single and multivariate COX regression analysis, we found that suppressor of cytokine signaling 2 (SOCS2) and SERPINF2 were independent prognostic genes for HCC. After survival analysis, HCC patients with high expression of SOCS2 and SERPINF2 had a longer survival time. These 2 genes in normal liver tissues were higher than in HCC at the transcriptional level.Conclusion: SOCS2 and SERPINF2 were new independent prognostic genes of HCC. So, they may provide new treatment methods and measures for diagnosing HCC.Abbreviations: DEGs = differential expression genes, GEO = gene expression omnibus, GS = gene significance, HCC = hepatocellular carcinoma, LASSO = Least Absolute Shrinkage and Selection Operator, SOCS = inhibitors of the cytokine signaling, SOCS2 = suppressor of cytokine signaling 2, WGCNA = weighted gene co-expression network analysis.

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Liver gene regulation of hemostasis-related factors is altered by experimental snake envenomation in mice

Cited by 9 publications

References 68 publications

Bleeding and Thrombosis: Insights into Pathophysiology of Bothrops Venom-Related Hemostasis Disorders

Bleeding and Thrombosis: Insights into Pathophysiology of Bothrops Venom-Related Hemostasis Disorders

Involvement of von Willebrand factor and botrocetin in the thrombocytopenia induced by Bothrops jararaca snake venom

Exploring novel independent prognostic biomarkers for hepatocellular carcinoma based on TCGA and GEO databases

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