E-WE thrombin, a protein C activator, reduces disease severity and spinal cord inflammation in relapsing-remitting murine experimental autoimmune encephalomyelitis.

作者: Sherman, Larry S ; Verbout, Norah G ; Su, Weiping ; Tucker, Erik I ; Jordan, Kelley ; McCarty, Owen Jt ; Pham, Peter ; Kohs, Tia Cl

ObjectiveRelapses in patients with relapsing-remitting multiple sclerosis (RRMS) are typically treated with high-dose corticosteroids including methylprednisolone. However, high-dose corticosteroids are associated with significant adverse effects, can increase the risk for other morbidities, and often do not impact disease course. Multiple mechanisms are proposed to contribute to acute relapses in RRMS patients, including neuroinflammation, fibrin formation and compromised blood vessel barrier function. The protein C activator, E-WE thrombin is a recombinant therapeutic in clinical development for its antithrombotic and cytoprotective properties, including protection of endothelial cell barrier function. In mice, treatment with E-WE thrombin reduced neuroinflammation and extracellular fibrin formation in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). We therefore tested the hypothesis that E-WE thrombin could reduce disease severity in a relapsing-remitting model of EAE.MethodsFemale SJL mice were inoculated with proteolipid protein (PLP) peptide and treated with E-WE thrombin (25 μg/kg; iv) or vehicle at onset of detectable disease. In other experiments, E-WE thrombin was compared to methylprednisolone (100 mg/kg; iv) or the combination of both.ResultsCompared to vehicle, administration of E-WE thrombin significantly improved disease severity of the initial attack and relapse and delayed onset of relapse as effectively as methylprednisolone. Both methylprednisolone and E-WE thrombin reduced demyelination and immune cell recruitment, and the combination of both treatments had an additive effect.ConclusionThe data presented herein demonstrate that E-WE thrombin is protective in mice with relapsing-remitting EAE, a widely used model of MS. Our data indicate that E-WE thrombin is as effective as high-dose methylprednisolone in improving disease score and may exert additional benefit when administered in combination. Taken together, these data suggest that E-WE thrombin may be an effective alternative to high-dose methylprednisolone for managing acute MS attacks.

2021-04-20·Nan fang yi ke da xue xue bao = Journal of Southern Medical University

[Effect of protein C activator from Agkistrodon acutus venom on early adaptive immune response of septic rats].

Article

作者: Wang, H ; Zhang, G ; Bao, P ; Sun, Y ; Wang, G

OBJECTIVETo investigate the effect of protein C activator (PCA) from Agkistrodon acutus venom (AAV) in modulating early adaptive immune response of septic rats.OBJECTIVERat models of sepsis were established by intraperitoneal injection of lipopolysaccharide (LPS; 10 mg/kg) in 36 SD rats, which were divided into 6 groups (n=6) for sample collection at 4, 6, 8, 12, 16 and 24 h after LPS injection, with 6 rats injected with saline as the control group. Another 36 rats were divided into two groups, and 30 min after LPS injection, the rats were treated with SEW2871 (a sphingosine-1-phosphate receptor 1 agonist; 0.5 mg/kg) or PCA group (0.1 mg/kg), and each group was divided into 3 groups (n=6) for sample collection at 6, 12 and 24 h after LPS injection. Plasma IL-4, S1P, IL-12 and IFN-γ levels of the rats were detected using ELISA, and the expressions of S1PR1 and CD103 in the mesenteric lymph nodes were detected with immunofluorescence assay.OBJECTIVEThe plasma levels of S1P, IL-12, IL-4 and IFN-γ (P < 0.05) and the expressions of S1PR1 and CD103 in the mesenteric lymph nodes (P < 0.05) all increased significantly in the rats 24 h after LPS injection; IFN-γ/IL-4 ratio increased progressively within 6 h after LPS injection and then subsided gradually. Compared with those in the corresponding sepsis model subgroups, the levels of S1P, IL-12 and IFN-γ increased while IL- 4 level decreased significantly (P < 0.05), and the expression of S1PR1 and CD103 were reduced significantly (P < 0.05) in SEW2871-treated rats; both the plasma level of IL-4 and the expression of S1PR1 in the mesenteric lymph nodes increased significantly in PCA-treated rats (P < 0.05).OBJECTIVEPCA can regulate the balance of inflammation and immune response in the early stage of sepsis in rats possibly through the S1P-S1PR1 pathway.

2016-12-01·Pharmaceutical Biology3区 · 医学

Agkistrodon acutus-purified protein C activator protects human umbilical vein endothelial cells against H₂O₂-induced apoptosis

3区 · 医学

ArticleOA

作者: Li, Xianwei ; Lu, Linming ; Zhang, Genbao ; Sun, Entao ; Nie, Liuwang ; Hong, Yun ; Li, Shu ; Jin, Xin

CONTEXTRecent studies show that the Agkistrodon acutus (Viperidae) (syn. Deinagkistrodon acutus) protein C activator (PCA) treats acute myocardial infarction and ischaemia-reperfusion animal models effectively, while the underlying mechanism remains unknown.OBJECTIVETo study the effect of PCA on the injury of human umbilical vein endothelial cells (HUVECs) induced by H₂O₂ and the underlying mechanism.MATERIALS AND METHODSPrimary cultured HUVECs were pretreated with PCA (20, 40 and 80 μg/mL) for 1 h, then HUVEC apoptosis was induced by 300 μmol/mL H₂O₂. Apoptosis was analyzed by AnnexinV-FITC/PI, and reactive oxygen species (ROS) level was tested by flow cytometry. Colorimetric methods were used to detect the levels of NO and IL-1. In addition, real-time PCR and western blot analyses were used to detect the expression of eNOS and phospho-p38/MAPK.RESULTSMorphological changes were induced by H₂O₂ in HUVECs. The cell survival rate was increased by 43.9, 64.0 and 80.6% in each PCA pretreated group (20, 40 and 80 μg/mL) compared to the model group. In each PCA pretreated group, oxidative stress level was also decreased to 54.7, 42.7 and 25.1%. Moreover, the level of IL-1 was decreased to 83.3, 62.2 and 30.7%. The level of NO was increased by 155.9, 232.4 and 317.6%. Apoptosis rate was decreased to 59.0, 47.7 and 32.7%. Phospho-p38 expression was downregulated, but eNOS expression was upregulated.DISCUSSION AND CONCLUSIONThe results suggest that PCA can effectively protect the endothelial cells from injury induced by H₂O₂, which may be associated with antioxidation, upregulation of eNOS and downregulation of p38-MAPK.

100 项与 Protein C activated(University of Sydney Union) 相关的药物交易

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