Fibrinolysis and Proteolysis最新文献

{"title":"The urokinase plasminogen activator system as a novel target for tumour therapy","authors":"M. Schmitt ,&nbsp;O.G. Wilhelm ,&nbsp;U. Reuning ,&nbsp;A. Krüger ,&nbsp;N. Harbeck ,&nbsp;E. Lengyel ,&nbsp;H. Graeff ,&nbsp;B. Gänsbacher ,&nbsp;H. Kessler ,&nbsp;M. Bürgle ,&nbsp;J. Stürzebecher ,&nbsp;S. Sperl ,&nbsp;V. Magdolen","doi":"10.1054/fipr.2000.0079","DOIUrl":"https://doi.org/10.1054/fipr.2000.0079","url":null,"abstract":"<div><p>Substantial data have been collected for numerous types of solid cancer, including cancer of the breast, the gastrointestinal and urological tract, the lung, and the brain, demonstrating a strong clinical value of the plasminogen activation system in predicting disease recurrence and survival in cancer patients. Elevated levels of certain members of the plasminogen activation system, the serine protease uPA (urokinase-type plasminogen activator), its receptor (uPA-R; CD87), and inhibitor (PAI-1), in tumour tissue or blood emphasize their fundamental role in tumour invasion and metastasis and provide the rationale for novel therapeutic strategies. uPA, besides its proteolytic action toward the extracellular matrix, in concert with uPA-R, PAI-1, and integrins contributes to tumour cell proliferation, adhesion, and migration. Several technical methods of affecting tumour growth and metastasis by targeting the uPA-system in cancer patients at the gene and protein level have been explored: (1) antisense oligodeoxynucleotides to uPA, uPA-R, or PAI-1; (2) antisense oligonucleotides to signal transduction pathway components such as Rel (NF-κ B), affecting uPA but not PAI-1 synthesis; (3) viral vectors delivering genes for components of the plasminogen activation system; (4) soluble, recombinant uPA-R as a scavenger for uPA; (5) monoclonal antibodies directed to uPA or uPA-R blocking uPA/uPA-R interaction; (6) enzymatically inactive uPA to compete for active uPA binding to uPA-R; (7) linear and cyclic uPA-derived peptides to block uPA/uPA-R interaction; (8) toxins, coupled to uPA or fractions thereof to kill tumour cells; (9) naturally occurring inhibitors to uPA and its derivatives for inhibition of uPA proteolytic activity; and (10) synthetic inhibitors to uPA to inhibit uPA proteolytic activity. There is substantial hope that substances designed to affect or turn off the plasminogen activation system will eventually be administered to cancer patients thereby opening a new vista for tumour biology-based, individualized cancer therapy.</p></div>","PeriodicalId":100526,"journal":{"name":"Fibrinolysis and Proteolysis","volume":"14 2","pages":"Pages 114-132"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1054/fipr.2000.0079","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71825678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent developments in thrombolytic therapy","authors":"D. Collen, H. Lijnen","doi":"10.1054/FIPR.2000.0070","DOIUrl":"https://doi.org/10.1054/FIPR.2000.0070","url":null,"abstract":"Abstract One approach to the treatment of thrombosis consists of infusing thrombolytic agents to dissolve the blood clot and to restore tissue perfusion and oxygenation. Thrombolytic agents are plasminogen activators which activate the blood fibrinolytic system by activation of the proenzyme, plasminogen, to the active enzyme plasmin. Plasmin in turn digests fibrin to soluble degradation products. Inhibition of the fibrinolytic system occurs both at the level of the plasminogen activators, by plasminogen activator inhibitors, and at the level of plasmin, mainly by α2-antiplasmin. Streptokinase, anisoylated plasminogen streptokinase activator complex (APSAC) and two-chain urokinase-type plasminogen activator (tcu-PA) induce extensive systemic plasmin generation; α2-antiplasmin inhibits circulating plasmin but may become exhausted during thrombolytic therapy, since its plasma concentration is only about half that of plasminogen. As a result plasmin, which has a broad substrate specificity, will degrade several plasma proteins, such as fibrinogen, coagulation factors V, VIII and XII, and von Willebrand factor. These thrombolytic agents are, therefore, considered to be non-fibrin-specific. In contrast, the physiologic plasminogen activators, tissue-type plasminogen activator (t-PA) and single-chain u-PA (scu-PA), as well as the bacterial plasminogen activator staphylokinase, are more fibrin-specific because they activate plasminogen preferentially at the fibrin surface and less in the circulation, albeit via different mechanisms. Plasmin, associated with the fibrin surface, is protected from rapid inhibition by α2-antiplasmin because its lysine-binding sites are not available, and may thus efficiently degrade the fibrin of a thrombus. Several mutants and variants, mainly of fibrin-specific plasminogen activators, are being evaluated in clinical trials in patients with acute myocardial infarction.","PeriodicalId":100526,"journal":{"name":"Fibrinolysis and Proteolysis","volume":"03 1","pages":"66-72"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86276186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fibrinogen functions and fibrin assembly","authors":"M. Mosesson","doi":"10.1054/FIPR.2000.0054","DOIUrl":"https://doi.org/10.1054/FIPR.2000.0054","url":null,"abstract":"Abstract Fibrinogen and fibrin play important roles in clot formation, fibrinolysis, cellular and matrix interactions, inflammation, and wound healing. These biological events are regulated to a large extent by clot formation itself and by complementary interactions between specific reactive sites on fibrin(ogen) and extrinsic molecules such as enzymes, proteins including other clotting factors, or cell receptors. Fibrinogen is comprised of two sets of three polypeptide chains termed Aα, Bβ, and γ, all six of which are joined by disulfide bridges to form the amino-terminal E domain. The molecules are elongated trinodular structures consisting of two globular outer D domains that are connected to its central E domain by a coiled-coil segment. These domains contain constitutive binding sites (e.g. Da, Db, γXL, D:D, γ′, thrombin substrate, platelet receptor, leukocyte integrin receptor) as well as interactive sites that become expressed as a result of fibrinogen cleavage by thrombin or that are exposed as a consequence of polymerization (e.g. t-PA binding sites). Other relevant constitutive sites in fibrinogen include two thrombin substrate recognition sites in each E domain plus a high-affinity non-substrate thrombin binding site in each γ′ chain that that also binds factor XIII. Constitutive binding sites on fibrinogen participate in fibrin assembly by self-association (γXL or D:D) or by complementary association with exposed fibrin sites (Da to EA and Db to E B ). Other relevant constitutive sites in fibrin include a low-affinity thrombin-binding site in the fibrin E domain that evidently remains as a residual of the substrate binding site. Fibrin polymerization is initiated by thrombin cleavage of fibrinopeptide A (FPA) from fibrinogen Aα chains, exposing two E domain E A sites. Cleavage of fibrinopeptide B (FPB) from Bβ chains exposes another E domain polymerization site, E B , that also interacts with platelets, fibroblasts and endothelial cells. Fibrin generation is followed by end-to-middle intermolecular D-to-E associations forming linear and equilaterally branched double-stranded fibrils, and is accompanied by lateral fibril associations that form multi-stranded fibers. Concomitantly, thrombin-activated factor XIIIa introduces covalent crosslinks into these polymers, mainly between γ chains (at γXL sites forming γ-dimers) and α chains (α-polymers), to complete the mature clot network structure.","PeriodicalId":100526,"journal":{"name":"Fibrinolysis and Proteolysis","volume":"11 1","pages":"182-186"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85229980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current technologies in gene expression profiling: applications to cardiovascular research","authors":"S. V. Soest, A. Horrevoets, N. Beauchamp, H. Pannekoek","doi":"10.1054/FIPR.2000.0055","DOIUrl":"https://doi.org/10.1054/FIPR.2000.0055","url":null,"abstract":"","PeriodicalId":100526,"journal":{"name":"Fibrinolysis and Proteolysis","volume":"55 1","pages":"73-81"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86260776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging regulatory mechanisms for fibrinolytic gene expression","authors":"M. Koziczak, L. Montero, F. Maurer, Y. Nagamine","doi":"10.1054/FIPR.2000.0053","DOIUrl":"https://doi.org/10.1054/FIPR.2000.0053","url":null,"abstract":"Fibrinolytic genes are involved in many biological processes, such as fibrinolysis, wound healing, inflammation and tumor metastasis, some of which rely on non-catalytic properties of the gene products. Reflecting the broad biological functions, expression of these genes is controlled by several mechanisms. Since the identification of fibrinolytic genes 2 decades ago, a vast amount of information has accumulated about the many signals, signaling pathways and mechanisms inducing their transcription. Our knowledge in this field is still expanding, and in this article we discuss two further emerging mechanisms by which expression of these genes is regulated: cell cycle-mediation and mRNA stability.","PeriodicalId":100526,"journal":{"name":"Fibrinolysis and Proteolysis","volume":"2 1","pages":"146-154"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75468315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular mechanisms for focal proteolysis and the regulation of the microenvironment","authors":"G. Murphy,&nbsp;V. Knäuper,&nbsp;S. Atkinson,&nbsp;J. Gavrilovic,&nbsp;D. Edwards","doi":"10.1054/fipr.2000.0068","DOIUrl":"https://doi.org/10.1054/fipr.2000.0068","url":null,"abstract":"","PeriodicalId":100526,"journal":{"name":"Fibrinolysis and Proteolysis","volume":"14 2","pages":"Pages 165-174"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1054/fipr.2000.0068","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71825679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic polymorphisms associated with thrombotic disorders in the Japanese population","authors":"M Murata","doi":"10.1054/fipr.2000.0064","DOIUrl":"https://doi.org/10.1054/fipr.2000.0064","url":null,"abstract":"<div><p>Genetic factors in combination with a number of environmental risk factors are involved in a predisposition to thrombotic disorders. Coronary artery disease (CAD) and ischemic cerebrovascular disease are typical human attributes that have a complex multifactorial etiology. There has been an increased awareness of the contribution of inherited factors for multifactorial disorders like thrombosis since the discovery of two prothrombotic mutations, the factor V Leiden and the prothrombin G20210A mutations, prevalent in Caucasian populations. Elevated plasma levels of homocysteine also constitute a risk factor for venous and arterial thrombosis. Thrombophilia is now thought to be common, not limited to rare conditions such as congenital deficiencies of the physiologic coagulation inhibitors.</p><p>It has long been thought that Japan has a lower incidence of thrombotic diseases, although there are only small differences in the prevalence of antithrombin, protein C, or protein S deficiencies. There are, however, critical differences in the prevalence of common polymorphisms relevant to thrombosis. The factor V Leiden and prothrombin mutations are absent in the Japanese, and a polymorphism of a platelet integrin, the glycoprotein IIIa 33Leu/Pro, which has a controversial relationship with arterial thrombosis in Caucasian populations, is very rare in Japan. Also, allele frequencies of some clinically relevant factors are different, including platelets and blood coagulation factors. Thus, a separate study is needed for each population with a distinct ethnic background.</p><p>In a number of allelic association studies involving patients with CAD, ischaemic stroke, peripheral artery disease, and vascular complications of diabetes, we found that the effect of genetic factors varied significantly depending on the characteristics of the cases and controls selected. A certain combination of multiple genetic risk factors was found to greatly increase the risk of stroke, particularly in young subjects.</p><p>Many genes are involved in determining the inter-individual variation in traits that define the onset and progression of disease, as well as the response to treatment. No single gene is expected to have a major impact on the determination of the risk of thrombosis. The ultimate goal of the clinical appreciation of polymorphic markers is to identify subgroups of individuals in which the disease can be best prevented, or who respond best to interventions.</p></div>","PeriodicalId":100526,"journal":{"name":"Fibrinolysis and Proteolysis","volume":"14 2","pages":"Pages 155-164"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1054/fipr.2000.0064","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71826241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular mechanisms for focal proteolysis and the regulation of the microenvironment","authors":"G. Murphy, V. Knäuper, S. Atkinson, J. Gavrilovic, D. Edwards","doi":"10.1054/FIPR.2000.0068","DOIUrl":"https://doi.org/10.1054/FIPR.2000.0068","url":null,"abstract":"","PeriodicalId":100526,"journal":{"name":"Fibrinolysis and Proteolysis","volume":"2014 1","pages":"165-174"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86488117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein C inhibitor (PAI-3): structure and multi-function","authors":"K. Suzuki","doi":"10.1054/fipr.2000.0063","DOIUrl":"https://doi.org/10.1054/fipr.2000.0063","url":null,"abstract":"<div><p>Protein C inhibitor (PCI) is a member of the serine protease inhibitor (serpin) family, which was initially found to be an inhibitor of activated protein C (APC) and later a potent inhibitor of the thrombin-thrombomodulin complex, suggesting that PCI plays a pivotal role in the regulation of the anticoagulant protein C pathway in human plasma. PCI is also known as a plasminogen activator inhibitor-3 (PAI-3), since this serpin was found in urine forming a complex with urokinase type-plasminogen activator (uPA). Human PCI also inhibits several other serine proteases involved in blood coagulation and fibrinolysis. Precursor proteins of PCI deduced from human, rhesus monkey, bovine, rabbit, rats and mouse cDNAs have sequence homology from 62 to 93%. Human PCI gene is located in a region involving genes of related serpins in chromosome 14q32.1. As regulatory mechanism of PCI gene expression, Sp1- and AP2-binding sites in the 5′-flanking region are the promoter and the enhancer, respectively. PCI mRNA is expressed in many organs, such as liver, kidney, spleen, pancreas, and reproductive organs (including testis, prostate, seminal vesicles and ovary in humans) and also in the liver and reproductive organs in bovines and rabbits; though in rats and mice only in the reproductive organs. PCI appears to play a role in the regulation of fertilization, presumably by inhibiting prostate specific antigen and acrosin in the male reproductive organs or by inhibiting protease(s) in the ovaries. In addition to the roles of PCI in coagulation, fibrinolysis and fertilization, human PCI is also suggested to regulate wound healing and renal tumour metastasis by inhibiting hepatocyte growth factor activator and uPA, respectively. Thus, PCI is a unique multi-functional serpin member playing several roles depending on species and organ tissues.</p></div>","PeriodicalId":100526,"journal":{"name":"Fibrinolysis and Proteolysis","volume":"14 2","pages":"Pages 133-145"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1054/fipr.2000.0063","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71826239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure and function of fibrinogen inferred from hereditary dysfibrinogens","authors":"M. Matsuda","doi":"10.1054/fipr.2000.0073","DOIUrl":"10.1054/fipr.2000.0073","url":null,"abstract":"<div><p>Fibrinogen is a 340-kDa plasma protein that participates in the final step of blood coagulation. Fibrinogen is composed of two identical molecular halves, each molecular half consisting of three non-identical Aα-, Bβ- and γ-chain subunits held together by multiple disulfide bonds. Fibrinogen is shown to have a trinodular structure, namely: one central nodule – the E domain – and two identical outer nodules – the D-domains – linked by two coiled-coil regions. After activation with thrombin, a pair of binding sites comprising Gly-Pro-Arg is exposed in the central domain, and combines with the complementary binding site ‘a’ in the outer D domain of another molecules. By crystallographic analysis, the α-amino group of Gly-1 is shown to be juxtaposed between Asp-364 and Asp-330 and the guanidino group of Arg-3 between the carboxyl group of Asp-364 and Gln-329 comprising the ‘a’ site. The half molecule-staggered, double-stranded protofibrils are thus formed. Upon abutment of two adjacent D domains on the same strand, D-D self association takes place involving Arg-275, Tyr-280 and Ser-300 of the γ-chain on the surface of the abutting two D domains. Thereafter, carboxy-terminal regions of the α-chains are untethered and interact with those of another protofibrils leading to the formation of thick fibrin bundles and networks. Although many enigmas still remain with regard to the exact mechanisms of these molecular interactions, they proceed in a highly ordered fashion.</p><p>In this review, these molecular interactions of fibrinogen and fibrin are discussed by introducing representative abnormal fibrinogen molecules at each step of fibrin clot formation.</p></div>","PeriodicalId":100526,"journal":{"name":"Fibrinolysis and Proteolysis","volume":"14 2","pages":"Pages 187-197"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1054/fipr.2000.0073","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"58524576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}