Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0012739 (disseminated intravascular coagulation)
 8,673 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of tissue factor (TF) by activated monocytes in several diseases leads to disseminated intravascular coagulation. Lipopolysaccharide (LPS)-induced monocyte TF expression is downregulated by the nuclear hormone all-trans retinoic acid (ATRA). In this study, we examined the mechanism by which ATRA inhibits monocyte TF expression. We show that ATRA selectively inhibited LPS induction of TF expression in human monocytes and monocytic THP-1 cells without affecting LPS induction of tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8). Inhibition of TF expression occurred at the level of transcription as determined by nuclear run-on. ATRA did not significantly alter the binding or functional activity of the transcription factors c-Fos/c-Jun and c-Rel/p65, which are required for LPS induction of the TF promoter in monocytic cells. In contrast to the ATRA inhibition of the endogenous TF gene, LPS induction of the cloned TF promoter was not inhibited by ATRA in transiently transfected THP-1 cells. Our results demonstrate that ATRA selectively inhibited LPS-induced TF gene transcription in human monocytic cells by a mechanism that does not involve repression of AP-1- or NF-kappaB-mediated transcription.
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PMID:Retinoic acid selectively inhibits lipopolysaccharide induction of tissue factor gene expression in human monocytes. 953 96

A general methodology is described that allows the solid-phase synthesis of depsides and depsipeptides from chiral alpha-hydroxy- and alpha-amino acids. The results of studies with different protecting groups for the alpha-hydroxy acids and coupling systems for depside bond formation are presented. The oligomers were prepared using a Wang-type linker with final TFA/CH(2)Cl(2) cleavage. Depside linkage of the THP-protected acids (THP = tetrahydropyranyl) to the resin-bound chains was achieved with DIC/DMAP (DIC = diisopropylcarbodiimide, DMAP = 4-(dimethylamino)pyridine) and monitored by a color test with 4-(p-nitrobenzyl)pyridine. THP deprotection was achieved with p-TsOH in CH(2)Cl(2)/MeOH and was monitored by GC. Following the established procedure, depsides made up from the same enantiomer (i.e., H-[L-Man](8)-OH, 25), by both enantiomers (i.e., H-[D-Man-L-Man](4)-OH, 26), or by different hydroxy acids in the same chain (i.e., H-[L-Lac-L-Hiv](3)-OH, 27) were prepared with an average yield of 95-97% per cycle. The linear precursor of the valinomycin analogue 30 ([L-Val-D-Man-D-Val-L-Lac](3)) was entirely synthesized on resin and cyclized in solution. Cyclization of the open-chain depsides is the final step in the preparation of a new class of chiral alpha-hydroxyester macrocycles.
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PMID:A General Methodology for Automated Solid-Phase Synthesis of Depsides and Depsipeptides. Preparation of a Valinomycin Analogue. 1167 17

The enhanced extrinsic coagulation in response to inflammation could contribute to disseminated intravascular coagulation, often manifesting cardiovascular complications. The complex mechanism remains unclear and effective management is not well established. The ability of protamine to offset bacterial endotoxin (LPS)-induced tissue factor (TF)-initiated extrinsic coagulation was demonstrated in human peripheral blood monocytes and cultured human leukaemia THP-1 monocytes, which was consistent with the inhibition of rabbit brain thromboplastin (rbTF) procoagulant activity in a cell-free in vitro model. Protamine significantly prolonged prothrombin time, further confirming the downregulation of the extrinsic pathway. However, thrombin time remained unaltered. Chromogenic assays were performed to dissect the extrinsic pathway, identifying inhibitory site(s). Protamine significantly inhibited factor VII (FVII) activation but not the dissected FX activation. The amidolytic activities of FVIIa and FXa were unaffected. The inhibited FVII activation in the presence of protamine was confirmed by the diminished FVIIa formation on Western blot analyses. Protamine preferentially inhibited TF-catalysed FVII activation, downregulating the extrinsic cascade. Protamine could be of anticoagulant significance in the management of the extrinsic hypercoagulation.
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PMID:Protamine inhibits tissue factor-initiated extrinsic coagulation. 1170 41

The enhanced extrinsic tissue factor (TF)-initiated coagulation, often resulting from sepsis, could lead to disseminated intravascular coagulation presenting cardiovascular complications. Using model human leukaemia THP-1 monocytes, we studied monocytic TF (mTF) hypercoagulation and its regulation. After an 8 h exposure to bacterial endotoxin [lipopolysaccharide (LPS); 100 ng/ml], mTF activity was significantly upregulated as the result of the enhanced mTF synthesis. Thereafter, LPS induction declined, exhibiting a "quiescent-desensitizing' phenomenon. Such diminished LPS induction was,however,associated with sustained LPS-enhanced mTF synthesis, revealing the possible occurrence of a post-translational downregulation. It was noted that LPS desensitization was accompanied by the increased expression of myristoylated alanine-rich C kinase substrate (Marcks). In contrast, A23187 (20 micromol/l) or Quin-2AM (20 micromol/l) drastically activated mTF activity without detectable effect on mTF synthesis; both of which showed that sustained functional upregulation during 24 h culture did not enhance Marcks expression. These inverse correlations between mTF activity upregulation and Marcks expression suggested that Marcks could be inhibitory. Marcks phosphorylation site domain (151-175) (Marcks PSD) readily inhibited mTF-dependent FVII activation and diminished FVIIa formation in LPS-challenged cells. As a result, Marcks PSD offset LPS-induced mTF hypercoagulation upon inclusion in the single-stage clotting assays. The anticoagulant activity was confirmed by showing that Marcks PSD significantly blocked rabbit brain thromboplastin (rbTF) procoagulation and inhibited rbTF-dependent FVII activation as well as FVIIa formation. Our study suggests that Marcks expression plays a role in a novel cellular modulation to downregulate mTF hypercoagulation.
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PMID:Possible role of Marcks in the cellular modulation of monocytic tissue factor-initiated hypercoagulation. 1213 48

The extrinsic hypercoagulation often resulting from sepsis could contribute to disseminated intravascular coagulation and cardiovascular complications. The effective prevention and intervention remained largely complex and unclear. In a cell model of human leukemia THP-1 monocytes following bacterial endotoxin (LPS) exposure, we show the novel anticoagulant ability of polyamino acid (polyAA) to suppress the extrinsic hypercoagulation. LPS-induced monocytic tissue factor (mTF) procoagulation was readily offset by poly-L-lysine (PLK), poly-L-arginine (PLR), or poly-L-ornithine (POR) included in single-stage clotting assays. IC50 was estimated at 0.35, 0.30, or 0.58 microM for PLR, POR, or PLK, respectively, whereas, poly-L-asparatic acid (PLD) remained ineffective. In a separate approach, inclusion of cationic polyAA in human plasma significantly prolonged prothrombin time, confirming the depressed extrinsic coagulation. In chromogenic assays dissecting the extrinsic pathway, we further determined the inhibitory site(s). PLK, PLR, or POR significantly inhibited LPS-induced FVII activation, which was consistent with the diminished FVIIa formation shown on Western blotting analysis. In contrast, polyAA did not show any additional effect on either FVIIa/FXa amidolytic activities or mTF/FVIIa-catalyzed FX activation. Nor did polyAA show any effect on FVII activation directly catalyzed by FXa. Taken together, PLK, PLR, or POR preferentially inhibited mTF-dependent FVII activation, accounting for their novel anticoagulant activities. PolyAA might present the specific antagonists to arrest the extrinsic hypercoagulation following inflammation.
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PMID:Novel anticoagulant activity of polyamino acid offsets bacterial endotoxin-induced extrinsic hypercoagulation: downregulation of monocytic tissue factor-dependent FVII activation. 1450 32

Stromal cell-derived factor-1 (SDF-1) is a CXC chemokine that activates and directs the migration of leukocytes that have CXCR4, which is the unique receptor for SDF-1. Although SDF-1/CXCR4 interaction has been implicated in various inflammatory conditions, its role in modulating coagulation has not been determined. We studied the plasma SDF-1 levels in 90 patients with suspected disseminated intravascular coagulation (DIC) and we found that circulating SDF-1 was significantly increased in the overt DIC patients and was also increased in overt DIC patients who have a poor outcome. We then tested in vitro whether SDF-1 can affect the expression of monocyte tissue factor (TF) and endothelial thrombomodulin (TM), and both of these play important roles in coagulopathy. SDF-1 did not affect the expression of surface TF protein and its function and the TF mRNA level in both monocytes and the monocytic leukemia cell line THP-1. SDF-1 also did not change the surface TM expression of endothelial cells. SDF-1 could enhance low-dose ADP induced platelet aggregation, although it failed by itself to induce aggregation. These findings suggest that plasma SDF-1 might be closely associated with hypercoagulability though its action as a platelet activator.
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PMID:Plasma level of stromal derived factor-1 (SDF-1) is increased in disseminated intravascular coagulation patients who have poor outcomes: in vitro effect of SDF-1 on coagulopathy. 1723 27