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PubMed1982

Plasminogen activator: the major secreted neutral protease of cultured skeletal muscle cells.

Clonal mouse skeletal muscle cells which differentiate in culture and form synapses with neuronal cells were found to secrete high levels of protease activity as measured with an 125I-fibrin assay. The secreted proteolytic activity was more than 90% dependent upon the presence of plasminogen in the medium, and had a pH optimum at 7 to 8. This activity was not inhibited by n-ethylmaleimide, pepstatin, EDTA, or EGTA. At millimolar concentrations, greater than 90% inhibition was obtained with either soybean trypsin inhibitor, epsilon aminocaproic acid, Trasylol, or leupeptin. Almost complete inhibition occurred with 1 mM diisopropylfluorophosphate suggesting the presence of a serine residue at the catalytic site. In contrast to the high levels of secreted activity, a lower steady-state level of cell-associated protease activity was detected in cell lysates. The high level of plasminogen activator secreted into the medium of cultured muscle cells suggests a role for such extracellular protease activity in myogenesis during development and remodeling following muscle injury. Such information may be useful in understanding the initial degeneration of neuromuscular contacts in experimental and pathologic denervation.

Animals↗

PubMed1986

Identification of the cellular mechanisms responsible for platelet-derived growth factor induced alterations in cytoplasmic vinculin distribution.

Exposure of quiescent density arrested BALB/c-3T3 cells (clone A31) to platelet-derived growth factor (PDGF; 6-12 ng/ml) results in a rapid, reversible, time- and dose-dependent removal of vinculin from adhesion plaques (Herman and Pledger, 1985). Potential cellular mechanisms involved in PDGF-induced removal of vinculin from adhesion plaques were examined. Removal of vinculin from adhesion plaques following exposure of cells to PDGF was temperature dependent, occurred in many fibroblast cell lines, and could be mimicked by 12-tetradecanoyl phorbol-13-acetate (TPA; 5-125 nM) or melittin (0.35 microM). Unlike the effect of PDGF, TPA- or melittin-induced vinculin disruption was not reversible. The removal of vinculin from adhesion plaques was inhibited by trifluoroperazine (TFP; 2.5 microM). 8-(N,N-diethylamino) octyl-3,4,5-trimethoxy benzoate (TMB-8; 1.0 microM), mepacrine (220 microM), n-alpha-p-tosyl-L-lysine chloromethylketone (TLCK; 100 microM), phenylmethoxysulphonylfluoride (PMSF; 500 microM), and epsilon-aminocaproic acid (epsilon-ACA; 100 microM); however, amiloride (100 microM), A23187 (20 microM), and chloroquine (1 mM) were unable to inhibit this effect. Melittin disruption of vinculin was inhibited by (in order of decreasing effectiveness) mepacrine greater than TMB-8 greater than TFP greater than leupeptin greater than PMSF, whereas A23187 and amiloride had no effect. The return of vinculin to adhesion plaques following PDGF treatment required de novo mRNA transcription and protein synthesis and was associated with PDGF-stimulated synthesis of vinculin. The observation that both PDGF- and melittin-induced removal of vinculin from adhesion plaques is inhibited by mepacrine suggests that phospholipase activation may be an early and important step in PDGF-induced disruption of vinculin from adhesion plaques. In addition, TFP, TMB-8 and protease inhibitor inhibition of both the PDGF and melittin effects on vinculin distribution, coupled with the finding that TPA can mimic the PDGF or melittin response, suggests that Ca2+, calmodulin, protein kinase C, and/or proteolysis may play an important role(s) in the removal of vinculin from adhesion plaques following PDGF addition. The lack of effect of A23187 addition on vinculin distribution suggests that alterations in cellular Ca2+ is necessary but not sufficient for vinculin removal from adhesion plaques.

Amiloride↗

PubMed1994

Human Co115 colon carcinoma cells potentiate the degradation of laminin mediated by tissue-type plasminogen activator.

The plasminogen activation (PA) system of human Co115 colon carcinoma cells was investigated. Analysis at the levels of protein and mRNA of cultured cells and of histozymography of tumor xenografts in nude mice showed that Co115 cells produce only tissue type PA (t-PA) and no urokinase (u-PA). Also, mRNA for the u-PA receptor and for PA inhibitor type 2 (PAI-2), but not for PAI-1, were detected. We developed a quantitative degradation assay using glutaraldehyde-immobilized 125I-laminin to investigate the capacity of Co115 cells to degrade laminin. Laminin degradation by Co115 cells was completely inhibited by 100 micrograms/ml of polyclonal anti-t-PA IgG, by the plasmin inhibitors aprotinin (100 micrograms/ml) or epsilon-aminocaproic acid (EACA; at 0.3 M), but not by antibodies against u-PA or u-PAR nor by nonimmune IgG. Cycloheximide-treated Co115 cells were unable to degrade laminin but increased laminin degradation induced by conditioned medium of Co115 cells or recombinant t-PA. No potentiation was observed when Co115 cells and laminin were kept separated by Transwell inserts. Our results suggest that Co115 human colon carcinoma cells degrade laminin by potentiating t-PA-mediated plasminogen activation at the cell surface which requires close contact between tumor cells and laminin substrate.

Animals↗

PubMed1981

Inhibition of mouse blastocyst attachment and outgrowth by protease inhibitors.

Effects of protease inhibitors on development of mouse blastocysts and fibrinolytic activity of trophoblast were examined by growing embryos on monolayers of decidual cells in the presence of inhibitors. Nitrophenol-p-guanidino benzoate (NPGB) was the most effective inhibitor; 10(-4) M NPGB inhibited attachment and trophoblast outgrowth by 24% and 66%, respectively, and inhibited the fibrinolytic activity of trophoblast by 86%. The effects of NPGB were reversible, as demonstrated by the embryos' ability to attach and resume normal development when transferred to NPGB-free medium. Soybean trypsin inhibitor and epsilon-aminocaproic acid were less effective than NPGB in inhibiting blastocyst development. When 10(-4) M NPGB and 350 microgram/ml of soybean trypsin inhibitor were added together, blastocyst development and fibrinolytic activity were inhibited more severely than when either inhibitor was added alone. We suggest that at least two types of proteolytic activities in mouse blastocysts are involved in implantation, attachment requiring trypsin-like activity, and trophoblast outgrowth requiring both plasminogen activator and trypsin-like activity.

Animals↗

PubMed2005

Esters of 6-aminohexanoic acid as skin permeation enhancers: The effect of branching in the alkanol moiety.

In order to investigate the effect of branching and cyclization in the hydrophobic part of skin permeation enhancers, 17 novel branched-chain and cyclic 6-aminohexanoic acid esters were prepared. Their permeation enhancing activity was evaluated in vitro using human skin and theophylline as a model drug, and compared to that of the corresponding linear-chain analogues. The results showed that chain branching and cyclization has a negative influence on the enhancing activity of 6-aminohexanoates. For example, the enhancement ratios (ERs) of dodecan-1-yl, dodecan-2-yl, dodecan-4-yl, and cyclododecyl ester were 39.7, 29.3, 3.1, and 2.2, respectively. No significant change in the optimum length of the chain was observed. Dodecan-2-yl 6-aminohexanoate, the most active branched derivative, still maintains a remarkable enhancing activity (ER 29.3). Presumably, the relatively small degree of branching of these molecules does not prevent them from interacting with the lipid components of the stratum corneum. However, a higher degree of branching, cyclization of the chain, and presence of an aromatic ring resulted in a loss of activity.

Alcohols↗

PubMed1979

Chemical reactions in cephalosporin allergy: high-pressure liquid chromatographic analysis of cephalosporin aminolysis kinetics.

Cephalosporin reaction with protein amino groups is fundamental to cephalosporin allergy. Cephalothin and cefazolin reaction kinetics with epsilon-aminocaproic acid, B-alanine, and glycine in aqueous solution were investigated. All reactions were conducted at 35 degrees and 0.5 ionic strength and were followed by ion-exchange high-pressure liquid chromatography. The aminolysis rate constants can be expressed as terms representing uncatlyzed or water-catalyzed amine reaction, self-assited nucleophilic reaction, and hydroxide-ion-catalayzed nucleophilic amine attack on the beta-lactam moiety. Cephalothin and cefazolin react with amines as readily as penicillin G. The UV spectra of several cephalothin-glycine reaction products were recorded, and their possible structures are discussed.

Amines↗

PubMed1991

Characterization of gelatin-degrading metalloproteinase activities of the Dunning rat prostate tumor grown in nude mice.

Proteinase activities in the Dunning R-3327 prostatic tumor grown in nude mice and the dorsal lobe of the normal Copenhagen rat prostate were characterized using gelatin-containing SDS-polyacrylamide gel electrophoresis. Calcium-stimulated activities of approximately 33, 42, 64, 71, 76, 85, 98, 115, and 120 Kd as well as a 91 Kd calcium-independent proteinase were detected in the tumor, whereas the dorsal prostate showed calcium-dependent activities of approximately 62 and 80 Kd and a calcium-independent activity much greater than 120 Kd. The zymographic calcium-dependent proteinase patterns in the other rat prostatic lobes (a 62 Kd proteinase in the anterior lobe; 59, 62, and 67 Kd forms in the ventral lobe; and 52, 62, and 72 Kd activities in the lateral lobe) were distinctive from that of the tumor and of the dorsal lobe. The calcium-dependent and -independent proteinases of the tumor were active over a broad range of pH values with optimal activity near pH 8.0-8.4. The calcium-dependent activities were inhibited by EDTA and EGTA. Barium and strontium could partially substitute for calcium. The calcium-independent activities were not affected by these chelators nor by the proteinase inhibitors benzamidine, epsilon-aminocaproic acid, tranexamic acid, hydrocinnamic acid, or iodoacetate. Similarly, the metalloproteinase activities were not affected by the latter inhibitors. There was little change in the predominant molecular forms (64, 71, and 76 Kd) of proteinase following castration of tumor-bearing nude mice; however, the 98 Kd calcium-dependent activity decreased and the 91 Kd calcium-independent activity increased as a result of this treatment.

Adenocarcinoma↗

PubMed1993

Synthesis of a hydrophilic affinity matrix for the purification of the vasoactive intestinal peptide receptor.

Vasoactive intestinal peptide (VIP) was assembled on a polyacrylamide gel using a combination of the Boc and Fmoc peptide synthesis strategies. Before the synthesis, the polymeric matrix functionalized with sarcosine methylester was treated with ethylenediamine in order to form primary amine reaction sites (0.3 mmol/g). Then a six-carbon spacer arm, Boc-aminocaproic acid, was coupled to the gel after activation with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) reagent. After acidolysis of the Boc protecting group, the derivative Boc-asparaginyl (xanthenyl)-4-(oxymethyl)phenylacetic acid was introduced into the polyacrylamide resin. Leucine-27 and isoleucine-26 were incorporated into the peptide chain as Boc-protected derivatives while the subsequent amino acids were all introduced as Fmoc residues. All couplings were achieved with BOP reagent in presence of diisopropylethylamine. The synthesis proceeded easily and only asparagine-9 required a double coupling step. After completion of the VIP assemblage, the side-chain protecting groups were removed by reaction with trifluoroacetic acid containing appropriate scavengers. A sample of peptide-resin was treated with hydrofluoric acid and the quality of the synthetic VIP-COOH material, obtained after cleavage, was assessed by reverse-phase HPLC and fast atom bombardment mass spectrometry. The compatibility with aqueous solutions of the polyacrylamide resin loaded with VIP (0.15 mmol/g), as well as its ability to be utilized as an affinity matrix for VIP receptors, was demonstrated using solubilized receptor preparation made from porcine liver membrane. After a single-step affinity chromatography, no binding activity was anymore detectable in the pass-through fraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Acrylic Resins↗

PubMed1995

A fluorescence quench and dequench assay of fibrinogen polymerization, fibrinogenolysis, or fibrinolysis.

We present a kinetic assay based on the use of fluorescein isothiocyanate (FITC)-labeled fibrinogen as a fluoroactive substrate. The multiple FITCs bound to fibrinogen experienced quenching due to their close proximity. The thrombin-induced polymerization of FITC-fibrinogen led to additional fluorescence quenching due to enhanced neighbor-neighbor interactions in protofibrils and protofibril aggregates. The initial rate of quenching was directly dependent on the thrombin concentration at either low or high ionic strength. The final extent of quenching during polymerization with thrombin could be modulated by prevailing ionic strength and thrombin concentration suggesting that the quenching was due to fibril extension as well as aggregation. The full extent of quenching was greatly reduced by addition to the reaction of unlabeled fibrinogen or Gly-Pro-Arg-Pro, as expected for quenching due to neighbor-neighbor interactions. In contrast to polymerization, cleavage of fibrinogen by plasmin released FITC-labeled fragments free of proximity-based quenching that resulted in a large intensity increase as lysis proceeded--a process termed dequenching. The majority of the dequenching signal during fibrinogenolysis occurred during the generation of fragment X which proceeded as a first-order process with respect to fibrinogen-bound plasmin with kcat = 0.479 s-1. The Kd of active plasmin to fibrinogen was calculated to be 0.42 microM. Addition of epsilon-aminocaproic acid (epsilon ACA)-plasmin complex to FITC-fibrinogen produced little dequenching, demonstrating a requirement for binding in order to initiate lysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Fibrinogen↗

PubMed2001

Biotinylation sites of tumor necrosis factor-alpha determined by liquid chromatography-mass spectrometry.

Tumor pretargeting with biotinylated antibody/avidin complexes improves the therapeutic index of systemically administered biotin-tumor necrosis factor (TNF) conjugates. Since the number of biotins in this conjugate is known to be critical for activity, we have characterized the structure of different biotin-TNF conjugates, prepared by reaction with d-biotinyl-6-aminocaproic acid N-hydroxysuccinimide ester and identified the biotinylation sites by trypsin digestion, reverse-phase chromatography, and electrospray mass spectrometry analyses. The results have shown that N-terminal valine is a preferential biotinylation site at pH 5.8, half of biotins being located on the alpha-amino group of this residue in a conjugate bearing one biotin/trimer (on average). Moreover, evidence has been obtained to suggest that the remaining part of biotins are linked to the epsilon-amino group of lysine 128, 112, and 65, while lysine 11, 90, and 98 were practically unmodified. No evidence of O-biotinylation of serine, threonine and tyrosine was obtained.

Amino Acid Sequence↗

PubMed1995

Analysis of the plasminogen system on rat glomerular epithelial cells.

Rat glomerular epithelial cells were grown to confluency on semipermeable tissue culture inserts and the plasminogen system of these cells was analyzed using enzyme assays, Western analysis, zymography, and reverse transcriptase-PCR. The glomerular epithelial cells are capable of activating exogenous plasminogen to plasmin by endogenous plasminogen activators. The cells produce both tissue-plasminogen activator and urokinase-plasminogen activator with urokinase being the prominent activator. Both activators are present primarily on the basolateral side of the cells with urokinase found primarily at the cell surface presumably bound to its receptor and tissue-plasminogen activator found primarily in the matrix secreted by the cells on the semipermeable insert. The cells also produce plasminogen activator inhibitor-1 and urokinase-plasminogen activator receptor. Inhibition of plasminogen activation occurred with plasminogen activator inhibitor-1, anti-catalytic anti-tissue-plasminogen activator antibody, epsilon-aminocaproic acid, which inhibits the binding of plasminogen through its lysine binding sites, and amiloride, which specifically inhibits urokinase.

Animals↗

PubMed2000

Helicobacter pylori interactions with plasminogen.

Helicobacter pylori is the causative agent of chronic gastritis, peptic ulcer, and gastric malignancies. A number of virulence factors have been described including several adhesins, a cytotoxin, neutrophil-activating protein, and expression of binding of extracellular matrix proteins, like collagen type IV, laminin, and vitronectin. H. pylori strains commonly express binding of soluble plasminogen. Coccoid forms also express binding. Plasminogen binding was optimal at pH 7.0. The binding is mediated by two cell surface proteins of 42 and 57 kDa. Scatchard plot analysis showed a straight line with a K(d) of 7 x 10(-7) M. Lysine and E-aminocaproic acid inhibited binding. The binding domain on the plasminogen molecule is the fifth kringle, miniplasminogen. Plasminogen is converted to plasmin by tissue plasminogen activator. During H. pylori infection the activity of tissue plasminogen activator is decreased and that of urokinase increased. This is reversed after eradication therapy. The plasminogen binding and conversion to plasmin is the only proteolytic activity of H. pylori, and may enhance tissue penetration and be involved in carcinogenesis.

Extracellular Matrix↗

PubMed2002

Angiostatin binds to tyrosine kinase substrate annexin II through the lysine-binding domain in endothelial cells.

Angiostatin(AS), an internal fragment of plasminogen, is one of the most potent specific inhibitors of angiogenesis. Angiostatin treatment has resulted in the complete regression of human tumors implanted subcutaneously into nude mice and has great therapeutic value (O'Reilly et al., Nat. Med. 2, 689-692, 1996). Despite promising therapeutic value in the treatment of cancer, the mechanism of its action is still unknown. We found that angiostatin binds to a 35-kDa protein in bovine aortic endothelial (BAE) cells (Sharma et al., Proc. Am. Assoc. Cancer Res. 42, 568, A3050, 2002). In an attempt to begin to understand angiostatin's mechanism of action, we have purified and characterized this 35-kDa protein from BAE cells. Internal peptide sequence analysis of purified protein demonstrated (SLYYIQQDTK, SYSPYDMLESIK, and ALLYLXGGDD) 100% sequence identity with tyrosine kinase substrate annexin II. Solid phase binding analysis suggests that angiostatin specifically bound to purified annexin II immobilized on 96-well plastic plates. Hundred-fold molar excess of unlabeled AS and anti-annexin II antibody inhibited bindings 85 and 55%, respectively, suggesting specific interaction. Annexin II is a predominant receptor for angiostatin, since neutralizing the angiostatin by soluble receptor (annexin II) effectively blocks angiostatin's anti-EC activity. Similarly, saturating the annexin II receptor by plasminogen in endothelial cells also blocks angiostatin's activity. Both angiostatin and plasminogen bind to purified annexin II in BAE cells saturably with apparent K(d) values of 101 and 164 nM, respectively, for purified annexin II and K(d) values of 83 and 125 nM, respectively, for BAE cells. Anti-annexin II monoclonal antibody inhibited angiostatin and plasminogen binding to endothelial cells by 68 and 62%, respectively, supporting our in vitro studies that annexin II is a receptor for angiostatin. Angiostatin-binding protein/annexin II specifically expressed in endothelial cells but not in fibroblasts suggests its EC-specific function. Epsilon-aminocaproic acid, a lys analogue, effectively blocks angiostatin and annexin II interaction, indicating that the lysine-binding domain of AS is required for binding to annexin II. These results suggest that the antiangiogenic action of angiostatin may be mediated via interaction with annexin II. Identification of annexin II as a receptor for angiostatin provides further evidence that clotting and fibrinolytic pathways are directly involved in the angiogenic process.

Angiostatins↗

PubMed1987

Antifibrinolytic agents in subarachnoid haemorrhage.

For many years clinicians have used antifibrinolytic agents to try to reduce rebleeding after subarachnoid haemorrhage. Early studies of their effectiveness produced conflicting results. This paper re-evaluates the available trials and considers benefits in the light of potential complications. Present evidence conclusively demonstrates that epsilon-aminocaproic acid and tranexamic acid administered in standard dosage, reduce the risk of rebleeding but, as a result of an increased incidence of ischaemic complications, do not benefit patients' outcome.

Antifibrinolytic Agents↗

PubMed1989

Clinical disorders of fibrinolysis: a critical review.

Much progress has recently been made in understanding the biochemistry and physiology of endogenous fibrinolysis. As a result, a better understanding of the mechanisms and clinical consequences of disordered fibrinolysis has emerged. Increased fibrinolytic activity is an uncommon but important cause of hemorrhagic disease. Congenital disorders of fibrinolysis which cause bleeding include increased plasma plasminogen activator activity and deficiency of alpha-2 antiplasmin. Acquired disorders associated with increased fibrinolytic activity and bleeding include liver cirrhosis, amyloidosis, acute promyelocytic leukemia, some solid tumors, and certain snake envenomation syndromes. Increased fibrinolysis is important to recognize because epsilon-aminocaproic acid (EACA) may be required to prevent or control bleeding. Diminished fibrinolytic activity has been associated with a variety of thrombotic disorders, but a direct cause-and-effect relationship has yet to be established. Congenital abnormalities of fibrinolysis associated with thrombosis include plasminogen deficiency, decreased endothelial generation of plasminogen activator activity, and certain abnormal fibrinogens. Thrombosis in these disorders is effectively managed with warfarin. Diminished fibrinolysis has also been reported in "idiopathic" venous thrombosis, oral contraceptive-induced and post-operative venous thrombosis, coronary artery disease, cerebrovascular disease, systemic lupus erythematosus, and thrombotic thrombocytopenic purpura, but the significance of abnormal fibrinolysis in these disorders is uncertain. Large, prospective studies of fibrinolytic variables as risk factors for vascular and thrombotic disease are needed to determine whether pharmacologic augmentation of impaired fibrinolysis could be useful in the prevention or treatment of these disorders.

Blood Coagulation Disorders↗

PubMed1978

Giant aneurysms in CT and angiography.

Giant intracranial aneurysms are frequently observed as incidental findings on CT and angiograms obtained for purposes other than subarachnoid hemorrhage, such as slowly evolving nerve palsy or hemiparesis. Since giant aneurysms often thrombose, the CT scan may demonstrate a larger aneurysmal volume than the angiogram. This paper presents CT and angiogram findings in cerebral aneurysms with a diameter of 25 mm-60 mm. The discussion covers: sort of aneurysm (congenital, arteriosclerotic); type and degree of thrombosis; long-term results after spontaneous thrombosis; and CT examination after using epsilon-aminocaproic acid.

Adult↗

PubMed1976

Evidence for the involvement of vasoactive constitutents of mast cells in axon reflex vasodilatation in the skin of the rat.

Axon reflex vasodilation following injury to the skin of the pinna of the ear was studied in rats by a thermometric method. Post-traumatic vaso-dilatation did not occur in animals treated with tyrosine ethyl ester, an inhibitor of chymotrypsin. Vasodilatation was not affected by treatment of the rats with chlorpheniramine (antihistamine) or cyproheptadine (antihistamine and anti-serotinin) or with aprotinin, soybean trypsin inhibitor, epsilon-aminocaproic acid or tosyl arginine methyl ester (inhibitors of trypsin and of some other proteinases). Taken in conjunction with the results of other investigations, these findings indicate that in the skin of the rat: (a) histamine and serotinin are not essential for the initiation of axon reflexes, and (b) the chymotrypsin-like proteinase of mast cell granules, released as the result of antidromic activity in sensory axons, may act as a kininogenase and be responsible for causing dilatation of arterioles at the efferent limb of the axon reflex.

Animals↗

PubMed1991

Biotinylation of transducin and G0 from bovine brain.

A method is described for modifying G proteins with biotin. With transducin, better results were obtained with the amino group-specific derivative BXNHS (biotinyl-epsilon-aminocaproic acid N-hydroxysuccinimide ester) as compared to the -SH-group specific reagent MBB (maleimidobutyrylbiocytin). Modification occurred under conditions preserving functional activity: Interaction of the biotinylated transducin with rod outer segment membranes was shown by its light-dependent association and by a GTP gamma S-binding assay. G0 from bovine brain was also biotinylated under conditions preserving its activity. Biotinyl-alpha 0 was shown to bind to a streptavidin Sepharose matrix. Biotinyl-G proteins, therefore, are proposed as tools for extracting proteins (receptors and effector systems), which interact under specific conditions with G proteins.

Animals↗