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Translational initiatives in thrombolytic therapy

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《医学前沿（英文）》 2017年第11卷第1期页码 1-19 doi: 10.1007/s11684-017-0497-8

摘要：

Once thrombi have formed as part of the pathology defining myocardial infarction, ischemic stroke, peripheral arterial disease, deep venous thrombosis or other embolic disorders, the only clinically meaningful thrombolytic agents available for reversing the thrombogenic process are various plasminogen activators. These agents are enzymes that reverse fibrin polymerization underlying the coagulation process by converting endogenous plasminogen to plasmin, which cleaves the fibrin network to form increasingly smaller protein fragments, a process known as fibrinolysis. For the most part, the major clinically used thrombolytics, tissue plasminogen activator, urokinase and streptokinase, as well as the experimentally investigated agent staphylokinase, are the products of recombinant DNA technology, which permits molecular optimization of clinical efficacy. In all cases of molecular optimization and targeting, however, the primary challenge of thrombolytic therapy remains hemorrhagic side effects, which are especially devastating when they occur intracerebrally. Currently, the best strategy to ameliorate this adverse effect is nanoparticulate encapsulation or complexation, and many strategies of this sort are being actively pursued. This review summarizes the variety of targeted and untargeted thrombolytic formulations that have been investigated in preclinical studies.

关键词： thrombolytics nanomedicine plasminogen activators

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Chemotactic effect of urokinase-type plasminogen activator on mouse spermatozoa

DING Xiaofang, LI Honggang, XIONG Chengliang

《医学前沿（英文）》 2008年第2卷第2期页码 195-199 doi: 10.1007/s11684-008-0037-7

摘要： The aim of this study is to investigate the chemotactic effect of urokinase-type plasminogen activator (uPA) on mouse spermatozoa. Capillary assays were applied to study the chemotactic activity of ascending and descending gradients of uPA. Firstly, the chemotactic effect of an ascending gradient of uPA on mouse spermatozoa was observed by counting the number of spermatozoa that migrated into the capillary after incubation with uPA for 5, 10, 20, and 30 min, respectively, compared with that after incubation with F10. Twenty minutes was a suitable incubation time to obtain a plateau of sperm accumulation. Meanwhile, to confirm the specific effect of uPA on mouse sperm chemotaxis, uPA inhibitor (PAI-1) and anti-uPAR rabbit IgG were added to the test solution containing 20 U/mL uPA, respectively. To exclude the possibility that PAI-1 and anti-uPAR rabbit IgG may affect sperm accumulation nonspecifically, PAI-1 and anti-uPAR rabbit IgG were added to F10, respectively. It was found that the chemotactic effect of uPA was neutralized completely by PAI-1 and anti-uPAR rabbit IgG. PAI-1 and anti-uPAR rabbit IgG had no neutralizing effect on the sperm chemotactic effect. Lastly, the sperm chemotaxis response to a descending gradient of uPA was also observed. Taken together, the results suggest that uPA can induce sperm chemotaxis by binding to its receptor on the sperm membrane and may act as a chemoattractant in precontacting sperm-egg communication thereby increasing the chance encounter of spermatozoa and eggs.

关键词： chemotactic activity receptor uPA inhibitor F10 chemoattractant

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Annexin A2-S100A10 heterotetramer is upregulated by PML/RARα fusion protein and promotes plasminogen-dependent

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《医学前沿（英文）》 2017年第11卷第3期页码 410-422 doi: 10.1007/s11684-017-0527-6

摘要：

Aberrant expression of annexin A2-S100A10 heterotetramer (AIIt) associated with PML/RARα fusion protein causes lethal hyperfibrinolysis in acute promyelocytic leukemia (APL), but the mechanism is unclear. To facilitate the investigation of regulatory association between ANXA2 and promyelocytic leukemia/retinoic acid receptor a (PML/RARα) fusion protein, this work was performed to determine the transcription start site of ANXA2 promoter with rapid amplification of 5′-cDNA ends analysis. Zinc-induced U937/PR9 cells expressed PML/RARα fusion protein, and resultant increases in ANXA2 transcripts and translational expressions of both ANXA2 and S100A10, while S100A10 transcripts remained constitutive. The transactivation of ANXA2 promoter by PML/RARα fusion protein was 3.29±0.13 fold higher than that by control pSG5 vector or wild-type RARα. The overexpression of ANXA2 in U937 transfected with full-length ANXA2 cDNA was associated with increased S100A10 subunit, although S100A10 transcripts remained constitutive. The tPA-dependent initial rate of plasmin generation (IRPG) in zinc-treated U937/PR9 increased by 2.13-fold, and cell invasiveness increased by 27.6%. Antibodies against ANXA2, S100A10, or combination of both all remarkably inhibited the IRPG and invasiveness in U937/PR9 and NB4. Treatment of zinc-induced U937/PR9 or circulating APL blasts with all-trans retinoic acid (ATRA) significantly reduced cell surface ANXA2 and S100A10 and associated reductions in IRPG and invasiveness. Thus, PML/RARα fusion protein transactivated the ANXA2 promoter to upregulate ANXA2 and accumulate S100A10. Increased AIIt promoted IRPG and invasiveness, both of which were partly abolished by antibodies against ANXA2 and S100A10 or by ATRA.

关键词： annexin A2-S100A10 heterotetramer PML/RARα fusion protein plasmin cell invasion acute promyelocytic leukemia

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Clinical and genetic risk factors for venous thromboembolism in Chinese population

Chen WANG PhD, MD, Zhen-Guo ZHAI PhD, MD, Ying H. SHEN PhD, MD, Lan ZHAO PhD, MD,

《医学前沿（英文）》 2010年第4卷第1期页码 29-35 doi: 10.1007/s11684-010-0012-y

摘要： Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, carries significant mortality and morbidity. The most important and effective way to reduce VTE incidence is to identify the patients at risk and give necessary prevention. VTE is a multifactorial and complicated disorder. Major risk factors for VTE include surgery and trauma, acute medical illness, active cancer and pregnancy. Genetic factors increase susceptibility to the disease and are useful in predicting the development of VTE. Gene-gene and gene-environment interactions alter and magnify the clinical picture in this disorder. This brief review summarizes some selected clinical and genetic risk factors for VTE based on the current research in China.

关键词： risk factor stroke prothrombin plasminogen activator inhibitor type-1 polymorphism thrombophilia biomarker