3.4.21.5: thrombin
This is an abbreviated version!
For detailed information about thrombin, go to the full flat file.
Word Map on EC 3.4.21.5
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3.4.21.5
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platelet
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anticoagulant
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heparin
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thrombosis
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bleeding
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endothelial
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artery
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thromboplastin
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collagen
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agonist
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thromboembolism
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coronary
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procoagulant
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adp
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antithrombotic
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venous
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fibrinolysis
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thrombus
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hemorrhage
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hemostatic
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hirudin
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plasminogen
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antiplatelet
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thrombomodulin
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protease-activated
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arachidonic
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plasmin
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thromboxane
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intravascular
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viii
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d-dimers
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atrial
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thrombocytopenia
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aspirin
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aptamer
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hypercoagulability
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willebrand
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warfarin
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percutaneous
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p-selectin
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rivaroxaban
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platelet-rich
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unfractionated
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coagulopathy
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prothrombotic
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embolism
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haemostasis
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diagnostics
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analysis
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hemophilia
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biotechnology
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thrombolytic
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nutrition
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synthesis
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clopidogrel
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medicine
- 3.4.21.5
- platelet
-
anticoagulant
- heparin
- thrombosis
- bleeding
- endothelial
- artery
- thromboplastin
- collagen
- agonist
- thromboembolism
- coronary
-
procoagulant
- adp
-
antithrombotic
- venous
-
fibrinolysis
- thrombus
- hemorrhage
-
hemostatic
- hirudin
- plasminogen
-
antiplatelet
- thrombomodulin
-
protease-activated
-
arachidonic
- plasmin
-
thromboxane
-
intravascular
- viii
-
d-dimers
- atrial
- thrombocytopenia
- aspirin
- aptamer
- hypercoagulability
- willebrand
- warfarin
-
percutaneous
-
p-selectin
- rivaroxaban
-
platelet-rich
-
unfractionated
- coagulopathy
-
prothrombotic
- embolism
-
haemostasis
- diagnostics
- analysis
- hemophilia
- biotechnology
-
thrombolytic
- nutrition
- synthesis
- clopidogrel
- medicine
Reaction
selective cleavage of Arg-/-Gly bonds in fibrinogen to form fibrin and release fibrinopeptides A and B =
Synonyms
activated factor II, alpha-thrombin, alphaTh, beta-thrombin, blood-coagulation factor II, activated, blood-coagulation factor IIa, clotting factor IIa, EC 3.4.4.13, factor IIa, fibrinogenase, thrombase, thrombin, E, thrombin-C, thrombofort, TLE2, topical, tropostasin
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General Information
General Information on EC 3.4.21.5 - thrombin
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malfunction
metabolism
physiological function
additional information
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in the transgenic TRAMP mouse model of prostate cancer inhibition of endogenous thrombin by hirudin retards spontaneous tumor growth. Inhibition of thrombin may lead to tumor dormancy
malfunction
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high glucose enhances smooth muscle cell responsiveness to thrombin through transcriptional upregulation of PAR-4, which may play an important role in the vascular complications of diabetes
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PAR-1 signaling to NF-kappaB in endothelial cells via protein kinase C signaling, CARMA3/Bcl10/MALT1, CBM, signalosome, and IkappaB kinase, and involving thrombin, pathway regulation, overview. The CBM signalosome controls thrombin-dependent monocyte/endothelial adhesion. The process is different in lymphocytes where CARMA1 is active instead of CARMA3
metabolism
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thrombin induces NF-kappaB activation and IL-8/CXCL8 expression in human lung epithelial cells by a Rac1-dependent PI3K/Akt pathway. Treatment of cells with thrombin causes activation of Rac and Akt. Thrombin induces NF-kappaB activation and protein expression through multiple signaling pathways such as PKCalpha/c-Src, Rac1, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, IkappaB kinases, and PI3K/Akt, overview
metabolism
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thrombin induces NF-kappaB activation and IL-8/CXCL8 expression in lung epithelial cells by a Rac1-dependent PI3K/Akt pathway. Treatment of cells with thrombin causes activation of Rac and Akt. Thrombin induces NF-kappaB activation and protein expression through multiple signaling pathways such as PKCalpha/c-Src, Rac1, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, IkappaB kinases, and PI3K/Akt, overview
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after treating JR-FL Env-expressing 293T cells with various concentrations of thrombin and subsequent coculture for 14 h, thrombin effect turns out to be a concentration-dependent fusion enhancement, thrombin can enhance the fusion mediated by R5-tropic HIV-1 gp160
physiological function
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HUVEC cells stimulated with thrombin (10 nM) exhibit an increased amount of actin filaments (show increased cell stiffness) when compared to unstimulated cells
physiological function
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in thrombin- and collagen-stimulated platelets, protein kinase A is activated by cAMP-independent mechanisms involving dissociation of the catalytic subunit of protein kinase A from an nuclear factor kappaB-IkappaBalpha-catalytic subunit of protein kinase complex. Thrombin and collagen cause platelet activation and fine-tune this response by initiating downstream nuclear factor kappaB-dependent protein kinase A catalytic subunit activation, as a novel feedback inhibitory signaling mechanism for preventing undesired platelet activation
physiological function
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in vitro, thrombin and ADP increase the formation of platelet-monocyte aggregates and platelet-granulocyte aggregates as well as tissue factor mRNA expression
physiological function
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O4+ and proteolipid protein-positive oligodendrocytes display a robust intracellular calcium level rise following thrombin stimulation. Thrombin-induced Ca2+ increase in oligodendrocytes is mediated by protease-activated receptor-1 activation and downstream signaling through G(q/11) and phospholipase C, resulting in Ca2+ recruitment from intracellular compartments
physiological function
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the degeneration of the dopaminergic neurons of rats is observed after intranigral injection of thrombin
physiological function
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thrombin activates protease-activated receptor 1 and induces a myofibroblast phenotype in normal lung fibroblasts resembling the phenotype of scleroderma lung myofibroblasts
physiological function
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thrombin activates protease-activated receptors 1, 3, and 4, but not 2
physiological function
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thrombin activation of proteinase-activated receptor 1 potentiates the myofilament Ca2+ sensitivity and induces vasoconstriction in porcine pulmonary arteries, the contractile effect of thrombin is abolished by either 4-aminidophenyl methane-sulfonyl fluoride or the proteinase-activated receptor 1 antagonist SCH79797, while it is mimicked by proteinase-activated receptor 1-activating peptide but not proteinase-activated receptor 4-activating peptide
physiological function
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thrombin does not affect expression of cell-associated pro-matrix metalloproteinase-2 (pro-MMP-2) protein. Thrombin activates pro-MMP-2 in the absence of elevated pro-MMP-2 expression and secretion in CSMCs, and thrombin induces cerebrovascular smooth muscle cells mitogenesis involving its action on MMP-2
physiological function
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thrombin down-regulates the transforming growth factor-beta-mediated synthesis of collagen and fibronectin by human proximal tubule epithelial cells through the endothelial protein C receptor-dependent activation of protease-activated receptor-1. The activation of protease-activated receptor-1 by thrombin inhibits the tumor necrosis factor -alpha-mediated synthesis of interleukin-6 and interleukin-8 and downregulates the transforming growth factor -beta-mediated expression of extracellular matrix proteins
physiological function
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thrombin elevates transcripts for interleukin-6, CXCL8, and CCL11 genes and also enhances release of interleukin-6 and CXCL8 protein from human aortic smooth muscle cell, thrombin promotes proinflammatory phenotype in human vascular smooth muscle cell
physiological function
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thrombin enhances the migration of chondrosarcoma cells by increasing matrix metalloproteinase-2 and matrix metalloproteinase-13 expression through the protease-activated receptor/phospholipase C/protein kinase Calpha/c-Src/nuclear factor-kappaB signal transduction pathway
physiological function
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thrombin facilitates invasion of ovarian cancer along peritoneum by inducing monocyte differentiation toward tumor-associated macrophage-like cells. Thrombin induces monocytes differentiation into M2-like macrophages with tumor-associated macrophage characteristics. Thrombin does not influence monocytes phagocytosis function significantly
physiological function
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thrombin induces the activation of p38MAPK in human platelets, thrombin increases tyrosine phosphorylation in a concentration-dependent mannerin, resting or in thrombin stimulated platelets total protein tyrosine phosphorylation, p38MAPK, and cytosolic phospholipase A2 phosphorylation are increased
physiological function
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thrombin induces the expression of oncostatin M via AP-1 activation in human monocyte-derived macrophages, peripheral blood monocytes, and human plaque macrophages up to 16.8fold after 24 h. Thrombin induces phosphorylation of ERK1/2 and p38 in monocyte-derived macrophages. A functional AP-1 site is required for oncostatin M promoter activation by thrombin
physiological function
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thrombin is a key enzyme in the coagulation cascade. Proteolysis of prothrombin and thrombin generates antimicrobial activity
physiological function
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thrombin is involved in blood coagulation and wound healing, thrombin may be a potential regulator of early fracture healing, which results in accelerated bone healing and hypertrophic callus. Activation of PAR-1 by thrombin may be one key regulator of COX-2 expression immediately following injury. Thrombin exerts multiple effects upon osteoblasts including stimulating proliferation, and inhibiting osteoblast differentiation and apoptosis. The pro-inflammatory effects of thrombin are mediated through activation of endothelial cells, smooth muscle cells, and platelets as well as release of cellular mediators. Thrombin also induces brain inflammation by activating microglia
physiological function
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thrombin is the key terminal enzyme of coagulation, does also promote angiogenesis and stimulates tumor-platelet adhesion, adhesion to endothelium, tumor implantation, tumor cell growth and metastasis. Thrombin also exerts direct effects on cancer cells by activation of the cell cycle through downregulation of p27(Kip1) and induction of Skp2, and cyclins D and A. MicroRNA 222, which inhibits p27(Kip1), is upregulated by thrombin
physiological function
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thrombin promotes the release of interleukin-8 from alveolar epithelial A549 cells via a mechanism partially involving activation of protease-activated receptor-1, maximal interleukin-8 release is observed in cells incubated with serum-free medium containing 25 nM thrombin (3.6fold increase compared to cells incubated with serum-free medium alone)
physiological function
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thrombin stimulates arginase I transcription activation and enzyme activity in rat aortic endothelial cells through activating protein-1 activation
physiological function
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thrombin stimulates retinal pigment epithelium cell proliferation by promoting c-Fos-mediated cyclin D1 expression, thrombin induces the biphasic expression of c-Fos
physiological function
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thrombin stimulation induces matrix metalloproteinase-9 secretion of monocytes dose- and time-dependently (0-8 units/ml thrombin), inhibition of thrombin-induced matrix metalloproteinase-9 secretion by either MEK inhibitor or p38 kinase inhibitor reveals that the thrombin effect is mediated by both ERK1/2 and p38 pathways
physiological function
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thrombin transiently inhibits adenylyl cyclase 6, the Ca2+-elevating agent thrombin increases endothelial permeability and decreases cAMP levels
physiological function
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mechanism of melanoma-associated thrombin activity and von Willebrand factor release from endothelial cell and in vitro mechanisms by which two human metastatic melanoma cell lines, MV3 and WM9, transform the vascular endothelium into a prothrombotic activated state, protective effect of heparins, overview. Low-molecular-weight heparins inhibit melanoma cell-triggered thrombin generation
physiological function
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pro-atherogenic effects of thrombin, thrombin is a potent modulator of endothelial function and, through stimulation of NF-kappaB, induces endothelial expression of intracellular adhesion molecule-1, ICAM-1, and vascular cell adhesion molecule-1, VCAM-1. These cell surface adhesion molecules recruit inflammatory cells to the vessel wall and thereby participate in the development of atherosclerosis, which is increasingly recognized as an inflammatory condition. The principal receptor for thrombin on endothelial cells is protease-activated receptor-1, PAR-1, a member of the G protein-coupled receptor superfamily. Thrombin induces phosphorylation of Akt and NF-kappaB-responsive gene transcription
physiological function
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the G-protein receptor-coupled agonist thrombin signal changes the structure of proteoglycans produced by vascular smooth muscle cells. Thrombin induces Akt activation and mediates proteoglycan synthesis, which is inhibited by TGF-beta receptor ALK V inhibition, which is not due to the release and autocrine/paracrine action of TGF-beta. A blockade of PAR-1 and ALK V inhibits thrombin-stimulated phosphorylation of Smad2. Regulations, overview
physiological function
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thrombin activates the PI3K/PDK1/Akt signaling, stimulating Akt Ser473, not Thr308, phosphorylation, which promotes cyclin D1 upregulation and RPE cell proliferation, overview. Thrombin proteolytic activation of protease-activated G protein coupled receptor-1 (PAR-1) activates PI3K and Akt. Thrombin-induced Akt stimulation promotes cyclin D1 accumulation through the phosphorylation/inhibition of GSK-3beta, thus preventing Thr286 cyclin D1 phosphorylation, nuclear export and degradation
physiological function
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thrombin evokes Ca2+ signaling in smooth muscle cell and induces smooth muscle cell migration and tumor necrosis factor alpha gene expression
physiological function
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thrombin induces NF-kappaB activation and IL-8/CXCL8 expression in human lung epithelial cells by a Rac1-dependent PI3K/Akt pathway. Treatment of cells with thrombin causes activation of Rac and Akt, the latter by Ser473 phosphorylation. Thrombin induces NF-kappaB activation and protein expression through multiple signaling pathways such as PKCalpha/c-Src, Rac1, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, IkappaB kinases, and PI3K/Akt, overview
physiological function
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thrombin induces NF-kappaB activation and IL-8/CXCL8 expression in lung epithelial cells by a Rac1-dependent PI3K/Akt pathway. Treatment of cells with thrombin causes activation of Rac and Akt. Thrombin induces NF-kappaB activation and protein expression through multiple signaling pathways such as PKCalpha/c-Src, Rac1, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, IkappaB kinases, and PI3K/Akt, overview
physiological function
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Thrombin is a multifunctional serine protease generated by the cleavage of prothrombin at sites of vascular injury, and promotes the conversion of fibrinogen to fibrin. thrombin induces monocyte chemoattractant protein 1, MCP-1, expression through Rho-kinase and subsequent p38MAPK/NF-kappaB signaling pathway activation in vascular endothelial cells leading to the development of atherosclerosis, the Rho/Rho-kinase signaling pathway plays a critical role in thrombin-mediated MCP-1 expression and function, Rho-kinase mediates thrombin-induced MCP-1 expression through p38MAPK and NF-jB activation, mechanism, overview
physiological function
thrombin is regulated via the extended active site region and anion-binding exosites I and II. Protease-activated receptor 3 residues 44-56 and protease-activated receptor 1 residues 49-62 bind to thrombin anion-binding exosite I and exhibit long range effects over to anion-binding exosite II. Hirudin residues 54-65 focus more on anion-binding exosite I and do not transmit influences over to anion-binding exosite II. D-Phe-Pro-Arg-chloromethyl ketone inhibition at the thrombin active site leads to further local and long range consequences to thrombin-anion-binding exosite I ligand complexes with the autolysis loop often most affected
physiological function
thrombin is the key enzyme in haemostasis and acts on several substrates involved in clot formation, platelet activation and feed-back regulation of its own formation. During activation of blood coagulation, FIIa is formed by proteolytic cleavage of prothrombin
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peptides of the C-terminal region of human thrombin are released upon proteolysis and identified in human wounds displaying length- and sequence-dependent antimicrobial, e.g. against Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, the Gram-positive bacterium Staphylococcus aureus, and the fungus Candida albicans, as well as immunomodulating effects. A peptide length of at least 20 amino acids is required for effective anti-inflammatory effects in macrophage models, as well as optimal antimicrobial activity
additional information
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the thrombin catalytic triad comprises residues His57, Asp102, and Ser195
additional information
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thrombin and trypsin directly activate vagal C-fibres in C57BL6 mouse lung via protease-activated receptor-1,i.e. PAR1, not via PAR3, PAR2, and PAR4, overview