Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the spontaneous and thrombin-induced activation of platelets and their release of platelet derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) at different pH values. Platelet activation was assayed with antibodies against P-selectin and performed in serum-free media. The release of PDGF and TGF-beta was determined by ELISA after 15 min and 12h. There was no activation at pH 5.0, while a time-dependent release of growth factors occurred at neutral and alkaline pH. The results suggest that release o f growth factors is not only dependent on platelet activation but also on incubation time and pH. Although the used serum-free experimental situation is different from normal conditions for platelets in vivo, the findings of a late release of growth factors may, nevertheless, be relevant to wound healing.
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PMID:Time- and pH-dependent release of PDGF and TGF-beta from platelets in vitro. 1285 Aug 32

Lysophosphatidic acid (LPA, 1-acyl-glycerol-3-phosphate) plays an important role in diverse biological responses including cell proliferation, differentiation, survival, migration, and tumor cell invasion. The most prominent source of LPA is platelets from which it is released after thrombin activation and is assumed to be an essential function of this lysophospholipid in cutaneous wound closure. Therefore, we examined the role of LPA on biological responses of keratinocytes. Although LPA potently enhances keratinocyte migration, it strongly induces growth arrest of proliferating epidermal cells. Thus, LPA possesses analogous actions to transforming growth factor-beta (TGF-beta), which is also released from degranulating platelets at wounded sites. In contrast to LPA, the intracellular signaling events of TGF-beta have been clearly identified and indicate that Smad3 is involved in chemotaxis and cell growth arrest of keratinocytes induced by this cytokine. Here we show that LPA, although it does not alter TGF-beta release is capable to activate Smad3 and results in a heteromerization with Smad4 and binding of the complex to its specific DNA-promoter elements. LPA completely fails to induce chemotaxis in Smad3-deficient cells, whereas growth inhibition is at least in part reduced. These findings indicate an essential role of Smad3 in diverse biological properties of LPA-stimulated keratinocytes.
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PMID:Lysophosphatidic acid interacts with transforming growth factor-beta signaling to mediate keratinocyte growth arrest and chemotaxis. 1548 69

Thrombin activates protease-activated receptor 1 (PAR1) on endothelial cells (ECs) and is critical for angiogenesis and vascular development. However, the mechanism underlying the proangiogenic effect of thrombin has not been elucidated yet. Here, we report the discovery of a novel functional link between thrombin-PAR1 and transforming growth factor-beta (TGF-beta) signaling pathways. We showed that thrombin via PAR1 induced the internalization of endoglin and type-II TGF-beta receptor (TbetaRII) but not type-I receptors in human ECs. This effect was mediated by protein kinase C-zeta (PKC-zeta) since specific inhibition of PKC-zeta caused an aggregation of endoglin or TbetaRII on cell surface and blocked their internalization by thrombin. Furthermore, acute and long-term pretreatment of ECs with thrombin or PAR1 peptide agonist suppressed the TGF-beta-induced serine phosphorylation of Smad2, a critical mediator of TGF-beta signaling. Moreover, activation of PAR1 led to a profound and spread cytosolic clustering formation of Smad2/3 and markedly prevented Smad2/3 nuclear translocation evoked by TGF-beta1. Since TGF-beta plays a crucial role in the resolution phase of angiogenesis, the down-regulation of TGF-beta signaling by thrombin-PAR1 pathway may provide a new insight into the mechanism of the proangiogenic effect of thrombin.
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PMID:Thrombin induces endocytosis of endoglin and type-II TGF-beta receptor and down-regulation of TGF-beta signaling in endothelial cells. 1552 64

Induction of bone tissue requires three elements: osteoprogenitor cells, osteoinductive factors, and a supporting extracellular matrix. In this study, we report on an experimental model in dogs of heterotopic bone tissue production, based on the integration of these osteo-inductive factors into abdominal implants. The implants consist of either a type I collagen sponge wrapped with periosteum and omentum or a type I collagen sponge embedded with demineralized bone powder, platelet-rich plasma, thrombin, and calcium chloride wrapped with omentum, with or without periosteum. Automated histomorphometric analysis showed an efficient production of trabecular bone, which corresponded to 50-70% of the total tissue composition 4 months after implant formation. High expression of the osteoinductive cytokines transforming growth factor-beta and bone morphogenetic proteins-2 and -4 was shown by immunohistochemistry in macrophages, endothelial cells from neoformed capillaries, osteoblasts, osteoclasts, and the mesenchymal tissue around the bone trabeculae. These approaches are novel and efficient surgical procedures to produce mature trabecular bone that could be used as a potential source of bone tissue for autotransplantation.
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PMID:Experimental induction of heterotopic bone in abdominal implants. 1555 56

Angiogenesis governs the progression of multiple myeloma (MM). Circulating endothelial cells (CECs) contribute to angiogenesis and comprise mature ECs and endothelial progenitor cells (EPCs). The present study sought to characterize CECs and their relation to disease activity and therapeutic response in 31 consecutive patients with MM. CECs, identified as CD34(+)/CD146(+)/CD105(+)/CD11b(-) cells, were 6-fold higher in patients compared to controls and correlated positively with serum M protein and beta(2)-microglobulin. Circulating EPCs displayed late colony formation/outgrowth and capillary-like network formation on matrigel; these processes were inhibited after effective thalidomide treatment. Co-expression of vascular endothelial growth factor receptor-2 (KDR) and CD133 characterized EPCs in MM, and KDR mRNA elevations correlated with M protein levels. In vitro exposure of ECs to thalidomide or its derivative CC-5013 inhibited gene expression of the receptors for transforming growth factor-beta and thrombin. Thus, elevated levels of CECs and EPCs covary with disease activity and response to thalidomide, underscoring the angiogenic aspect of MM and suggesting that angioblastlike EPCs are a pathogenic biomarker and a rational treatment target in MM. The results also highlight the anti-angiogenic properties of thalidomide and CC-5013 and further elucidate possible mechanisms of their effectiveness against MM. (Blood. 2005;105:3286-3294).
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PMID:Circulating endothelial progenitor cells in multiple myeloma: implications and significance. 1561 73

Increased lung vascular permeability is an important contributor to respiratory failure in acute lung injury (ALI). We found that a function-blocking antibody against the integrin alphavbeta5 prevented development of lung vascular permeability in two different models of ALI: ischemia-reperfusion in rats (mediated by vascular endothelial growth factor [VEGF]) and ventilation-induced lung injury (VILI) in mice (mediated, at least in part, by transforming growth factor-beta [TGF-beta]). Knockout mice homozygous for a null mutation of the integrin beta5 subunit were also protected from lung vascular permeability in VILI. In pulmonary endothelial cells, both the genetic absence and blocking of alphavbeta5 prevented increases in monolayer permeability induced by VEGF, TGF-beta, and thrombin. Furthermore, actin stress fiber formation induced by each of these agonists was attenuated by blocking alphavbeta5, suggesting that alphavbeta5 regulates induced pulmonary endothelial permeability by facilitating interactions with the actin cytoskeleton. These results identify integrin alphavbeta5 as a central regulator of increased pulmonary vascular permeability and a potentially attractive therapeutic target in ALI.
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PMID:Integrin alphavbeta5 regulates lung vascular permeability and pulmonary endothelial barrier function. 1707 79

In lung vasculature, reversible constriction of smooth muscle cells exists in response to acute decrease in oxygen levels (hypoxia). Progressive and irreversible structural remodeling that reduces blood vessel lumen takes place in response to chronic hypoxia and results in pulmonary hypertension. Several studies have shown a role of serotonin in regulating acute and chronic hypoxic responses. In this review the contribution of serotonin, its receptors and transporter in lung hypoxic responses is discussed. Hypoxic conditions modify plasma levels of serotonin, serotonin transporter activity, and expression of 5-HT1B and 5-HT2B receptors. These appear to be required for pulmonary vascular cell proliferation, which depends on the ratio between reactive oxygen species and nitric oxide. A heterozygous mutation was identified in the 5-HT2B receptor gene of a patient who developed pulmonary hypertension after fenfluramines anorexigen treatment. This C-terminus truncated 5-HT2B mutant receptor presents lower nitric oxide coupling, and higher cell proliferation capacity than the wild-type receptor. Under low oxygen tension, cells increase the transcription of specific genes via stabilization of the transcription factor hypoxia-inducible factor (HIF)-1. Factors such as angiotensin II or thrombin that can also control HIF-1 pathway contribute to pulmonary vascular remodeling. The 5-HT2B receptor via phosphatidylinositol-3 kinase/Akt activates nuclear factor-kappaB, which is involved in the regulation of HIF-1 expression. Acontrol of HIF- 1 by 5-HT2B receptors explains why expression of pulmonary vascular remodeling factors, such as endothelin-1 or transforming growth factor-beta, which is HIF-1-alpha regulated, is not modified in hypoxic 5-HT2B receptor mutant mice. Understanding the detailed mechanisms involved in lung hypoxic responses may provide general insight into pulmonary hypertension pathogenesis.
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PMID:Functions of serotonin in hypoxic pulmonary vascular remodeling. 1740 58

We have developed a new method for the production of a dermal matrix equivalent. Human platelets were used to dilute human fibroblasts. The platelet mix was placed in a cell culture well. Addition of 200 microL of a thrombin solution caused gel formation. Gels were overlaid with standard Iscove's growth medium supplemented with 10% fetal bovine serum, insulin, and N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid buffer. Medium was exchanged regularly. Keratinocytes were plated on top of selected gels and elevated to the air-liquid interface. The gels were harvested weekly, fixed, cut, and stained with hematoxylin and eosin stains and immunostains for collagens I, III, and IV and cytokeratins. Digital image analysis was used to quantitate collagen production. Growth factors, including transforming growth factor-beta (TGF-beta), platelet-derived growth factor, and vitamin C were added. Staining identified fibroblasts within the gels with a surrounding fibrous matrix. Immunostaining for cytokeratin identified keratinocytes on the gel surface. Immunostaining revealed the fibrous matrix to be composed of collagen I and III and some collagen IV. Digital image analysis demonstrated that greater TGF-beta concentration resulted in greater collagen production. These differences were statistically significant. With development of this construct, a viable dermal/epidermal replacement may be possible. TGF-beta enhances collagen production by fibroblasts in this matrix.
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PMID:Production of a novel fibroblast-populated platelet matrix cocultured with keratinocytes. 1751 11

Using high-density oligonucleotide microarrays and functional network analyses, we examined whether MSCs derived from four different origins exhibited unique gene expression profiles individually and then compared the gene expression profiles of all MSCs with those of fetal organs. Our results indicated that within each group of MSCs from the same origin, the variability of the gene expression levels was smaller than that between groups of different origins. Functional genomic studies revealed the specific roles of MSCs from different origins. Our results suggest that amniotic fluid MSCs may initiate interactions with the uterus by upregulating oxytocin and thrombin receptors. Amniotic membrane MSCs may play a role in maintaining homeostasis of fluid and electrolytes by regulating the networks of endothelin, neprilysin, bradykinin receptors, and atrial natriuretic peptide. Cord blood MSCs may be involved in innate immune systems as the neonatal defense system against the earliest encountered pathogens. Adult bone marrow MSCs may be an important source not only of all blood lineages but also of bone formation. However, in spite of the different gene expression profiles seen in MSCs derived from different origins, a set of core gene expression profiles was preserved in these four kinds of MSCs. The core signature transcriptomes of all MSCs, when contrasted against those of fetal organs, included genes involved in the regulation of extracellular matrix and adhesion, transforming growth factor-beta receptor signaling, and the Wnt signaling pathways. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:Functional network analysis of the transcriptomes of mesenchymal stem cells derived from amniotic fluid, amniotic membrane, cord blood, and bone marrow. 1755 97

It is well documented that elevated levels of PAI-1 in plasma can decrease the fibrinolytic activity in blood with an associated increased risk of thrombus formation. A diverse range of molecules including bacterial lipopolysaccharide (LPS), the inflammatory mediators tumor necrosis factor alpha (TNFalpha) and interleukins, thrombin, transforming growth factor-beta (TGF-beta), and hormones regulate the synthesis of plasma PAI-1. Therefore, it is of clinical importance to restore the fibrinolytic balance. For a drug to be effective in controlling the synthesis of PAI-1, sufficient insight into the signal transduction pathways that control its regulation is desirable, which could serve as logical targets for the development of pharmaceuticals. Some key signaling pathways have been identified with the aid of pharmacological inhibitors, involved in the up-regulation of PAI-1 in context with several diseases, including obesity, insulin resistance, diabetic nephropathy, glomulonephritis, and pulmonary fibrosis. Furthermore, independent of its inhibitory activity PAI-1 mediates interactions with vitronectin (VN) and low density lipoprotein receptor-related protein (LRP) which modifies basic cell behaviors of proliferation, migration, and attachment. Intriguingly, it has been shown that both anti-fibrinolytic and non-fibrinolytic-related functions of PAI-1 may have overlapping roles in many diseases that are poorly understood. Tailoring knock-in mice with site-specific alterations that diminish the inhibitory activity, VN-binding, and LRP-binding activity of PAI-1 are useful tools for manipulation of biochemical properties, in vivo, and evaluating therapeutics.
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PMID:Targeting plasminogen activator inhibitor-1: role in cell signaling and the biology of domain-specific knock-in mice. 1789 50


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