Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stroke is a devastating disease and a leading cause of death and disability. Currently, the only FDA approved therapy for acute ischemic stroke is the intravenous administration of the thrombolytic medication, recombinant tissue plasminogen activator (tPA). However, this treatment has many contraindications and can have dangerous side effects such as intra-cerebral hemorrhage. These treatment limitations have led to much interest in potential adjunctive therapies, such as therapeutic hypothermia (T <or 35 degrees C) and ultrasound enhanced thrombolysis. Such interest may lead to combining these therapies with tPA to treat stroke, however little is known about the effects of temperature on the thrombolytic efficacy of tPA. In this work, we measure the temperature dependence of the fractional clot mass loss Deltam(T) resulting from tPA exposure in an in vitro human clot model. We find that the temperature dependence is well described by an Arrhenius temperature dependence with an effective activation energy E(eff) of 42.0 +/- 0.9 kJ mole(-1). E(eff) approximates the activation energy of the plasminogen-to-plasmin reaction of 48.9 kJ mole(-1). A model to explain this temperature dependence is proposed. These results will be useful in predicting the effects of temperature in future lytic therapies.
 ...
PMID:Arrhenius temperature dependence of in vitro tissue plasminogen activator thrombolysis. 1750 82

The snake-venom thrombin-like enzymes (SVTLEs) are a class of serine proteinases that show fibrinogen-clotting and esterolytic activities. Most TLEs convert fibrinogen to fibrin by releasing either fibrinopeptide A or fibrinopeptide B and cannot activate factor XIII. The enzymes hydrolyze fibrinogen to produce non-cross-linked fibrins, which are susceptible to the lytic action of plasmin. Because of these physiological properties, TLEs have important medical applications in myocardial infarction, ischaemic stroke and thrombotic diseases. Here, a three-step chromatography procedure was used to purify saxthrombin (AAP20638) from Gloydius saxatilis venom to homogeneity. Its molecular weight is about 30 kDa as estimated by SDS-PAGE. A saxthrombin crystal was obtained using the hanging-drop vapour-diffusion method and diffracted to a resolution limit of 1.43 A. The crystal belongs to space group C2, with unit-cell parameters a = 97.23, b = 52.21, c = 50.10 A, beta = 96.72 degrees , and the Matthews coefficient (V(M)) was calculated to be 2.13 A(3) Da(-1) with one molecule in the asymmetric unit.
 ...
PMID:Purification, crystallization and preliminary X-ray diffraction analysis of saxthrombin, a thrombin-like enzyme from Gloydius saxatilis venom. 1767 73

Plasma level of von Willebrand factor (vWF) is a useful marker not only for endothelial dysfunction, but also for left atrial thrombogenesis. We measured plasma levels of vWF antigen and other coagulation and fibrinolysis markers in 183 consecutive patients with acute ischemic stroke and compared these data between patients with and without atrial fibrillation (AF). vWF correlated with severity, outcome, and infarct size and were significantly higher in the AF group than in the non-AF group. The positive correlations of vWF with plasmin-alpha2 plasmin inhibitor complex and soluble fibrin monomer complex, and higher levels of vWF in patients with than without spontaneous echo contrast, indicate thrombogenesis in the left atrium. Plasma levels of vWF may reflect thrombogenesis in patients with AF.
J Stroke Cerebrovasc Dis
PMID:Increased von Willebrand factor in acute stroke patients with atrial fibrillation. 1790 39

The "systemic inflammatory response" is a multifaceted defensive reaction of the body to surgical trauma and cardiopulmonary bypass (CPB), characterized by systemic activation of fibrinolysis, coagulation, complement, immune cells, platelets, and oxidative pathways, all overlaid onto localized trauma to the grafted vessel or vascular beds susceptible to ischemia/reperfusion. There is going to be no single magic bullet to diminish such a broad host defense response to surgery. The best chance lies with combinatorial--or promiscuous--pharmacotherapy. Combinations of anti-fibrinolytics, anti-coagulants targeted higher up the coagulation cascade, anti-thrombin receptor therapy, improved coated circuits, anti-complement, anti-leukocyte, and antioxidant therapies may blunt sufficient arms of the systemic inflammatory response to be clinically effective. The alternative is a promiscuous drug like aprotinin, which targets plasmin in the fibrinolytic pathway, kallikrein in the coagulation pathway, thrombin receptors on platelets and endothelium, and leukocytes at the extravasation step. Because of the overriding safety concerns relating to the use of anti-fibrinolytics in cardiothoracic surgery, any future combinatorial or promiscuous pharmacotherapy involving anti-fibrinolytics will require solid underpinning with a known mechanism of action and clinical safety data powered to detect well-defined adverse events (stroke, myocardial injury, renal failure requiring dialysis), preferably in isolation and not as a composite endpoint.
 ...
PMID:Pharmacologic strategies for combating the inflammatory response. 1829 23

The fibrinolytic system includes a broad spectrum of proteolytic enzymes with physiological and pathophysiological functions in several processes, such as haemostatic balance, tissue remodeling, tumor invasion, angiogenesis and reproduction. The main enzyme of the plasminogen activator system is plasmin, which is responsible for the degradation of fibrin into soluble degradation products. The activation of plasminogen into plasmin is mediated by two types of activators, urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). The activity of both is regulated by specific plasminogen activator inhibitors (PAIs). There are 3 types of PAIs described so far but the most important fibrinolytic inhibitor in vivo is PAI type 1 (PAI-1). Among others, the presence of metabolic syndrome and the -675 4G/5G promoter polymorphism are known to be modulators of PAI-1 levels. Besides their fibrinolytic profile, plasmin and plasminogen activators are implicated in tissue proliferation and cellular adhesion, as they can proteolytically degrade the extracellular matrix and regulate the activation of both growth factors and matrix metalloproteinases. By all these means, the fibrinolytic system is also involved in physiological processes, and in pathological situations such as thrombosis, arteriosclerosis, endometriosis and cancer. PAI 1 has been studied in different settings with thrombotic pathophysiology, such as coronary artery disease and ischaemic stroke. Controversial results have been published and concerns about study designs or presence of confounders have been claimed to be responsible of them. Recently, its involvement in adverse thrombotic events related to the modern drug-eluting coronary stents has renewed the interest of its study. PAI-1 also plays an important role in signal transduction, cell adherence, and migration. Indeed, studies of several types of cancers, including breast cancer, have shown that increased uPA and PAI-1 levels are associated with aggressive tumor behavior and poor prognosis. Endometriosis is defined by the presence of endometrial glands and stroma outside the uterus with marked ability to attach and invade the peritoneum. It is one of the most frequent benign gynecological diseases that affect women with pelvic pain or infertility during their reproductive age. Immune system disorders, genetic predisposition, altered peritoneal environment and endometrial alterations are believed to increase the susceptibility to endometriosis. The plasminogen activator system may be involved in this process, where local extracellular proteolysis plays a crucial role. Altered expression of several components of the fibrinolytic system in both eutopic and ectopic endometrium and peritoneal fluid of women with the disease has been implicated not only in the onset, but also in the progression of the endometriotic lesions.
 ...
PMID:Fibrinolysis: the key to new pathogenetic mechanisms. 1847

Thrombin activatable fibrinolysis inhibitor [carboxypeptidase B2 (plasma), CPB2] is a basic carboxypeptidase, which inhibits fibrinolysis by cleaving the C-terminal lysine residues on plasmin-modified partially degraded fibrin. Plasma CPB2 concentrations have been reported to be under the control of numerous single nucleotide polymorphisms located in the regulatory and coding regions of the gene encoding CPB2 (CPB2). High functional CPB2 levels have been found to be associated with an increased risk for ischemic stroke. The present study investigated CPB2 antigen levels and associated CPB2 polymorphisms in an acute onset non-cardioembolic stroke population compared with an age- and sex-matched healthy control population. This is, to the best of our knowledge, the first such study done in an Asian Indian population. CPB2 antigen levels were significantly associated with the disease phenotype (P < 0.001) and with CPB2 polymorphisms (P < 0.001). The haplotypes generated on analysis of the genotypic data accounted for 21% of the natural variation in the CPB2 antigenic levels. However none of the haplotype combinations generated showed any association with disease phenotype and therefore could not explain for the difference in CPB2 antigen levels between cases and controls.
 ...
PMID:Thrombin activatable fibrinolysis inhibitor gene polymorphisms are associated with antigenic levels in the Asian-Indian population but may not be a risk for stroke. 1898 91

Tissue-type plasminogen activator (tPA) is an extracellular protease that converts plasminogen into plasmin. For tPA to generate plasmin under biologic conditions, a cofactor must first bring tPA and plasminogen into physical proximity. Fibrin provides this cofactor for tPA-mediated plasmin generation in blood. Despite being naturally devoid of fibrin(ogen), tPA-mediated plasmin formation also occurs in the brain. The fibrin-like cofactor(s) that facilitates plasmin formation in the injured brain has remained unknown. Here we show that protein aggregates formed during neuronal injury provide a macromolecular, nonfibrin cofactor that promotes tPA-mediated plasmin formation and subsequent cell breakdown. The binding of plasminogen and tPA to these protein aggregates occurs via distinct mechanisms. Importantly, nonneuronal cell types also exhibit this cofactor effect upon injury, indicating a general phenomenon. This novel cofactor identified in nonviable cells has ramifications for ischemic stroke where tPA is used clinically and where plasmin activity within the injured brain is unwanted. A means of selectively inhibiting the binding of tPA to nonviable cells while preserving its association with fibrin may be of benefit for the treatment of ischemic stroke.
 ...
PMID:A nonfibrin macromolecular cofactor for tPA-mediated plasmin generation following cellular injury. 1958 97

Direct fibrinolytics are proteolytic enzymes that degrade fibrin without requiring an intermediate step of plasminogen activation. This review summarizes the current information available for five such agents, namely, plasmin (the prototypical form), three derivatives of plasmin (mini-plasmin, micro-plasmin, and delta-plasmin), and alfimeprase, a recombinant variant of a snake venom alpha-fibrinogenase, fibrolase. Biochemical attributes of molecular size, fibrin binding and inhibitor neutralization are compared. Preclinical investigations that assess the potential for thrombolytic efficacy in vitro and in animal models of vascular occlusion and for hemostatic safety in animal models of bleeding are detailed. Clinical potential has been assessed in patients with peripheral arterial and graft occlusion, acute ischemic stroke, and access catheter and hemodialysis shunt occlusions. The direct fibrinolytic agents have impressive biochemical and preclinical foundations for ultimate clinical application. However, clinical trial results for micro-plasmin and alfimeprase have not measured up to their anticipated benefit. Plasmin has thus far shown encouraging hemostatic safety, but efficacy data await completion of clinical trials. Whether direct fibrinolytics will provide clinical superiority in major thrombotic disorders over currently utilized indirect fibrinolytics such as tissue plasminogen activator remains to be determined.
 ...
PMID:Direct fibrinolytic agents: biochemical attributes, preclinical foundation and clinical potential. 1994 77

Recent studies showed that soluble annexin A2 dramatically increases tissue plasminogen activator (tPA)-mediated plasmin generation in vitro, and reduces thrombus formation in vivo. Here, we hypothesize that combining annexin A2 with tPA can significantly enhance thrombolysis efficacy, so that lower doses of tPA can be applied in ischemic stroke to avoid neurotoxic and hemorrhagic complications. In vitro activity assays confirmed tPA-specific amplification of plasmin generation by recombinant annexin A2. In a rat focal embolic stroke model, combination therapy with tPA and recombinant annexin A2 protein at 2 h post-ischemia decreased the effective dose required for tPA by four-fold and reduced brain infarction. Combining annexin A2 with tPA also lengthened the time window for thrombolysis. Compared with tPA (10 mg/kg) alone, the combination of annexin A2 (5 mg/kg) plus low-dose tPA (2.5 mg/kg) significantly enhanced fibrinolysis, attenuated mortality, brain infarction, and hemorrhagic transformation, even when administered at 4 h post-ischemia. Combination with recombinant annexin A2, the effective thrombolytic dose of tPA can be decreased. As a result, brain hemorrhage and infarction are reduced, and the time window for stroke reperfusion prolonged. Our present findings provide a promising new approach for enhancing tPA-based thrombolytic stroke therapy.
 ...
PMID:Annexin A2 combined with low-dose tPA improves thrombolytic therapy in a rat model of focal embolic stroke. 2006 77

Development of obesity is associated with extensive modifications in adipose tissue involving adipogenesis, angiogenesis and extracellular matrix proteolysis. The fibrinolytic (plasminogen/plasmin) system contributes to these processes. The main physiological inhibitor of the fibrinolytic system, plasminogen activator inhibitor-1 (PAI-1), is expressed in murine and human adipose tissues, and high PAI-1 levels predispose to thrombotic complications. The potential role of PAI-1 in development of adipose tissue remains, however, enigmatic. We have used nutritionally induced obesity models in wild-type and transgenic mice to study the role of the fibrinolytic system in the development of obesity. Our main findings are: 1) Obesity is associated with markedly enhanced plasma levels of PAI-1; 2) The effect of PAI-1 on in vivo adipose tissue development is concentration-dependent; 3) PAI-1 does not play a significant role in adipogenesis but may affect angiogenesis; 4). Tissue-type plasminogen activator (t-PA), the main target of PAI-1, impairs adipose tissue development; 5) PAI-1 contributes to the deleterious effect of obesity on the outcome of thrombotic ischemic stroke; and 6) The use of synthetic low Mr inhibitors of PAI-1 may have the potential to reduce obesity. These studies thus support a role for fibrinolytic activity and suggest that its modulation may allow to affect development of adipose tissue.
 ...
PMID:Functional role of the fibrinolytic system in development of adipose tissue. 2008 50


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>