AbstractNickel compounds are associated with lung and skin cancer incidence increase and accumulation of nickel in the body contributes to carcinogenesis. Upregulation of certain integrins in the primary tumor is associated with cancer metastasis and poor prognosis. However, the molecular mechanisms of nickel‐induced cancer metastasis are still unclear. The purpose of the present study was to investigate the effects of nickel chloride (NiCl2) on the progression of cancer during metastasis. The results of showed that NiCl2 induces the expression of integrin β3 mRNA and protein in a dose‐ and time‐dependent manner. Inhibition of integrin αvβ3 activation by ITGB3 ligand mimetics and GR144053, as well as downregulation of ITGB3 by lentiviral shRNA gene silencing, diminished NiCl2‐induced secretion of vascular endothelial growth factor‐a (VEGF‐a). Furthermore, pretreatment with type I TGF‐β receptor inhibitor, SB525334, suppressed the expression of ITGB3 at cell surface and secretion of VEGF‐a in NiCl2‐treated cells. In conclusion, NiCl2 induces the expression of ITGB3 through TGF‐β signaling activation, followed by increasing VEGF‐a secretion, revealing a novel role for ITGB3 in nickel compound‐induced cancer metastasis and tumor angiogenesis.

2019-07-01·Brain Research4区 · 医学

Neuroprotection and vasculoprotection using genetically targeted protease-ligands

4区 · 医学

Article

作者: Leung, Jennifer ; Lamb, Jessica A ; Rajput, Padmesh S ; Bai, Jilin ; Pereira, Benedict R ; Fernández, Jose Á ; Lyden, Patrick D ; Griffin, John H ; Lei, I-Farn

Thrombin and activated protein C (APC) are known coagulation factors that exhibit profound effects in brain by acting on the protease activated receptor (PAR). The wild type (WT) proteases appear to impact cell survival powerfully, and therapeutic forms of APC are under development. Engineered recombinant thrombin or APC were designed to separate their procoagulant or anticoagulant effects from their cytoprotective properties. We measured vascular disruption and neuronal degeneration after a standard rodent filament stroke model. For comparison to a robust anticoagulant, we used a GpIIb/IIIa inhibitor, GR144053. During 2 h MCAo both WT murine APC and its mutant, 5A-APC, significantly decreased neuronal death 30 min after reperfusion. During 4 h MCAo, only 5A-APC significantly protected neurons but both WT-APC and 5A-APC exacerbated vascular disruption during 4 h MCAo. Human APC mutants appeared to reduce 24 h neuronal injury significantly when given after 2 h delay after MCAo. In contrast, 24 h vascular damage was worsened by high doses of WT and mutant APCs, although only statistically significantly for high dose 3K3A-APC. Mutated thrombin worsened vascular damage significantly without affecting neuron damage. GR144053 failed to ameliorate vascular disruption or neuronal injury despite significant anticoagulation. Differential effects on neurons and the vasculature were demonstrated using wild-type and mutated proteases. The mutants murine 3K3A-APC and 5A-APC protected neurons in this rodent model but in high doses worsened vascular leakage. Cytoactive effects of plasma proteases may be separated from their coagulation effects. Further studies should explore impact of dose and timing on cytoactive and vasculoactive properties of these drugs.

2013-01-01·Arteriosclerosis, Thrombosis, and Vascular Biology1区 · 医学

Direct Observation of von Willebrand Factor Elongation and Fiber Formation on Collagen During Acute Whole Blood Exposure to Pathological Flow

1区 · 医学

Article

作者: Colace, Thomas V. ; Diamond, Scott L.

Objective— In severe stenosis, von Willebrand Factor (vWF) experiences millisecond exposures to pathological wall shear rates (γ w ). We sought to evaluate the deposition of vWF onto collagen surfaces under flow in these environments. Methods and Results— Distinct from viscometry experiments that last many seconds, we deployed microfluidic devices for single-pass perfusion of whole blood or platelet-free plasma over fibrillar type 1 collagen (<50 ms transit time) at pathological γ w or spatial wall shear rate gradients (grad γ w ). Using fluorescent anti-vWF, long thick vWF fibers (>20 μm) bound to collagen were visualized at constant γ w >30000 s –1 during perfusion of platelet-free plasma, a process enhanced by EDTA. Rapid acceleration or deceleration of EDTA platelet-free plasma at grad γ w =±1.1×10 5 to ±4.3×10 7 s –1 /cm did not promote vWF deposition. At 19400 s –1 , EDTA blood perfusion resulted in rolling vWF–platelet nets, although blood perfusion (normal Ca 2+ ) generated large vWF/platelet deposits that repeatedly embolized and were blocked by anti-glycoprotein Ib or the α IIb β 3 inhibitor GR144053 and did not require grad γ w . Blood perfusion at venous shear rate (200 s –1 ) produced a stable platelet deposit that was a substrate for massive but unstable vWF–platelet aggregates when flow was increased to 7800 s –1 . Conclusion— Triggered by collagen and enhanced by platelet glycoprotein Ib and α IIb β 3 , vWF fiber formation occurred during acute exposures to pathological γ w and did not require gradients in wall shear rate.

100 项与 GR-144053 相关的药物交易

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