Antiangiogenic Function of Antithrombin is Dependent on its Conformational Variation: Implication for Other Serpins

Azhar, Asim; Singh, Pratap; Rashid, Qudsia; Naseem, Asma; Khan, Mohammad Sazzad; Jairajpuri, Mohamad Aman

doi:10.2174/0929866511320040004

Cited by 5 publications

(3 citation statements)

References 48 publications

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“…SOD3 is a secreted enzyme responsible for the redox balance in specific tissues, including ECs, preventing oxidative damage and preserving nitric oxide (NO) availability (Fukai and Ushio-Fukai, 2011). SERPIN5 is a glycoprotein that can inhibit serine proteases, including plasminogen activators (Azhar et al, 2013). Our results are thus indicative of endothelial dysfunction in B. besnoiti infected BAEC.…”

Section: Early Parasite Adaptation To Intracellular Lifestyle Seems To Modulate Host Tca Cycle Metabolic Machinery and Down Regulates Mecmentioning

confidence: 81%

RNA-Seq Analyses Reveal That Endothelial Activation and Fibrosis Are Induced Early and Progressively by Besnoitia besnoiti Host Cell Invasion and Proliferation

Jiménez-Meléndez

Ramakrishnan

Hehl

et al. 2020

Front. Cell. Infect. Microbiol.

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The pathogenesis of bovine besnoitiosis and the molecular bases that govern disease progression remain to be elucidated. Thus, we have employed an in vitro model of infection based on primary bovine aortic endothelial cells (BAEC), target cells during the acute infection. Host-parasite interactions were investigated by RNA-Seq at two post-infection (pi) time points: 12 hpi, when tachyzoites have already invaded host cells, and 32 hpi, when tachyzoites have replicated for at least two generations. Additionally, the gene expression profile of B. besnoiti tachyzoites was studied at both pi time points. Up to 446 differentially expressed B. taurus genes (DEGs) were found in BAEC between both pi time points: 249 DEGs were up-regulated and 197 DEGs were down-regulated at 32 hpi. Upregulation of different genes encoding cytokines, chemokines, leukocyte adhesion molecules predominantly at 12 hpi implies an activation of endothelial cells, whilst upregulation of genes involved in angiogenesis and extracellular matrix organization was detected at both time points. NF-κB and TNF-α signaling pathways appeared to be mainly modulated upon infection, coordinating the expression of several effector proteins with proinflammatory and pro-fibrotic phenotypes. These mediators are thought to be responsible for macrophage recruitment setting the basis for chronic inflammation and fibrosis characteristic of chronic besnoitiosis. Angiogenesis regulation also predominated, and this multistep process was evidenced by the upregulation of markers involved in both early (e.g., growth factors and matrix metalloproteinases) and late steps (e.g., integrins and vasohibin). Besnoitia besnoiti ortholog genes present in other Toxoplasmatinae members and involved in the lytic cycle have shown to be differentially expressed among the two time points studied, with a higher expression at 32 hpi (e.g., ROP40, ROP5B, MIC1, MIC10). This study gives molecular clues on B. besnoiti-BAECs interaction and shows the progression of type II endothelial cell activation upon parasite invasion and proliferation.

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Section: Early Parasite Adaptation To Intracellular Lifestyle Seems To Modulate Host Tca Cycle Metabolic Machinery and Down Regulates Mecmentioning

confidence: 81%

RNA-Seq Analyses Reveal That Endothelial Activation and Fibrosis Are Induced Early and Progressively by Besnoitia besnoiti Host Cell Invasion and Proliferation

Jiménez-Meléndez

Ramakrishnan

Hehl

et al. 2020

Front. Cell. Infect. Microbiol.

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“…TAT is a sensitive marker of thrombin production and an indicator of activation of the coagulation system. [18][19][20] Its formation is the best time to judge the anticoagulant treatment, and it can rise in the prethrombotic state. Thus, evaluation of TAT levels is suitable for the early diagnosis of thrombotic diseases and for monitoring thrombolytic therapy.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic and Prognostic Value of TAT, PIC, TM, and t-PAIC in Malignant Tumor Patients With Venous Thrombosis

Zhou

Zhang

Zheng

et al. 2020

Clin Appl Thromb Hemost

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Background: Venous thromboembolism (VTE) is an important complication in patients with malignant tumors. Its exact diagnosis and treatment are still lacking. We used a high-sensitive chemiluminescence method to detect thrombin–antithrombin III complex (TAT), plasmin-α2-plasmininhibitor complex (PIC), thrombomodulin (TM), and tissue plasminogen activator–inhibitor complex(t-PAIC) in combination with D-dimer and fibrin degradation product (FDP) to analyze their diagnostic and prognostic value in patients with malignant tumors. Methods: In total, 870 patients with confirmed malignant tumors were included, 82 of whom had diagnosed VTE; 200 healthy individuals were classified as the control group. The TAT, PIC, TM, and t-PAIC were detected using Sysmex HISCL5000 automated analyzers, whereas FDP and D-dimer were detected using Sysmex CS5100 coagulation analyzer. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic efficiency. Survival probabilities were determined using Kaplan–Meier analysis, and multivariate analyses were performed using a Cox regression model. Results: Compared with healthy controls, patients with malignant tumors showed significantly elevated TAT, PIC, TM, t-PAIC, D-dimer, and FDP. Similarly, compared with patients in the non-thrombosis group, those in the thrombosis group showed significantly elevated levels of the above mentioned markers. Logistic regression analysis showed that TAT, PIC, TM, t-PAIC, D-Dimer, and FDP were all associated with VTE. ROC analysis showed that “TAT+PIC+TM+t-PAIC+D-dimer+FDP”showed the highest sensitivity and specificity. Patients with elevated TAT, PIC, TM, and t-PAIC had a significantly shorter survival. Multivariate Cox survival analysis showed that TM and t-PAIC were significantly associated with poor prognosis. In addition, the incidence of VTE was significantly lower in patients with malignant tumors who were treated with low-molecular-weight heparin (LMWH), and their survival period was significantly longer than that of patients with malignant tumors who were not treated with LMWH. Conclusion: TAT, PIC, TM, and t-PAIC combined with D-dimer and FDP were better than the application of a single marker in the diagnosis of VTE in patients with malignant tumors. TAT and PIC can be used as sensitive markers in the diagnosis of VTE but not as prognostic markers. TM and t-PAIC might be independent prognostic indicators in patients with malignant tumors, regardless of the state of thrombus.

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“…Binding of TM with thrombin can reduce the activity of thrombin and enhance the activity of protein C (12). TAT depends on ATIII, and indicates the activation of the coagulation system (22). PIC reflects the balance of the fibrinolysis and anti-fibrinolysis system and the rise of PIC level can indicate the activation of plasmin (23).…”

Section: Discussionmentioning

confidence: 99%

Thrombomodulin (TM), thrombin-antithrombin complex (TAT), plasmin-α2-plasmininhibitor complex (PIC), and tissue plasminogen activator-inhibitor complex (t-PAIC) assessment of fibrinolytic activity in postpartum hemorrhage: a retrospective comparative cohort study

Wang¹,

Zhong²,

Du³

et al. 2022

Ann Transl Med

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Background: Detecting the changes of coagulation function in the early stage of postpartum hemorrhage (PPH), which is the leading cause of maternal death, is the key to treatment this serious disease, however, there is less effective assessment methods. Thrombomodulin (TM), thrombin-antithrombin complex (TAT), plasmin-α2-plasmininhibitor complex (PIC), and tissue plasminogen activator-inhibitor complex (t-PAIC) are the new direct indicators for coagulation and fibrinolysis, and considered sensitive molecular markers of the fibrinolytic system changing. The aim of this study was to investigate the changes of these 4 new indicators in the early stage of PPH. Methods:We retrospectively reviewed the new coagulate indicators, TM, TAT, PIC, and t-PAIC, obtained from PPH patients at Guangzhou Women and Children's Medical Center from January 2021 to July 2021.According to the amount of blood loss, the patients were divided into 3 groups: Mild group (blood loss <1,500 mL, n=17), Severe group (blood loss ≥1,500 mL, n=24); another 12 women who did not experience PPH were selected as the Normal group (n=12). The four indicators were measured at the time of PPH happened, or immediately when baby was born in the Normal group, and evaluated for the prediction of PPH. Results:The t-PAIC level of the Severe group was significantly lower than the other 2 groups (Normal group vs. Mild group vs. Severe group: 13.9±2.0 vs. 9.4±1.8 vs. 7.5±0.9, P=0.020), and the PIC level was the highest (Normal group vs. Mild group vs. Severe group: 1.1±0.2 vs. 2.7±0.8 vs. 2.9±0.6, P=0.012). There was no significant difference in TM and TAT among the 3 groups. The odds ratio (OR) value of t-PAIC was 0.822, 95% confidence interval (CI): 0.697-0.970, P=0.020. The area under the curve (AUC) of PIC was 0.5, and t-PAIC was 0.775, the cut-off point was 6.295, the specificity was 75%, and the sensitivity was 75%.Conclusions: With the increasing of blood loss, t-PAIC decreased gradually, and is associated with severe PPH. This indicator may be a new predictor of PPH, and should be used in the early period of PPH for treatment.

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Antiangiogenic Function of Antithrombin is Dependent on its Conformational Variation: Implication for Other Serpins

Cited by 5 publications

References 48 publications

RNA-Seq Analyses Reveal That Endothelial Activation and Fibrosis Are Induced Early and Progressively by Besnoitia besnoiti Host Cell Invasion and Proliferation

RNA-Seq Analyses Reveal That Endothelial Activation and Fibrosis Are Induced Early and Progressively by Besnoitia besnoiti Host Cell Invasion and Proliferation

Diagnostic and Prognostic Value of TAT, PIC, TM, and t-PAIC in Malignant Tumor Patients With Venous Thrombosis

Thrombomodulin (TM), thrombin-antithrombin complex (TAT), plasmin-α2-plasmininhibitor complex (PIC), and tissue plasminogen activator-inhibitor complex (t-PAIC) assessment of fibrinolytic activity in postpartum hemorrhage: a retrospective comparative cohort study

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