Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034065 (pulmonary embolism)
 14,979 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thromboxane A2 (TXA2) is a key mediator of platelet aggregation and smooth muscle contraction. Its action is mediated by its G protein-coupled receptor of which two isoforms, termed TPalpha and TPbeta, occur in humans. TXA2 has been implicated in pathologies such as cardiovascular diseases, pulmonary embolism, atherosclerosis, and asthma. This study describes the pharmacological characterization of BM-613 [N-n-pentyl-N'-[2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl]urea], a new combined TXA2 receptor antagonist and TXA2 synthase inhibitor. It exhibits a strong affinity for human platelet TP receptors (IC50 = 1.4 nM), TPalpha and TPbeta expressed in COS-7 cells (IC(50) = 2.1 and 3.1 nM, respectively), and TPs expressed in human coronary artery smooth muscle cells (IC50 = 29 microM). BM-613 shows a weak ability to prevent contraction of isolated rat aorta (ED50 = 1.52 microM) and guinea pig trachea (ED50 = 2.5 microM) induced by TXA2 agonist U-46619 (9.11-dideoxy-9.11-methanoepoxy-prostaglandin F2). Besides, BM-613 antagonizes TPalpha (IC50 = 0.11 microM) and TPbeta (IC50 = 0.17 microM) calcium mobilization induced by U-46619 and inhibits human platelet aggregation induced by U-46619 (ED50 = 0.278 microM), arachidonic acid (ED50 = 0.375 microM), and the second wave of ADP. BM-613 also dose dependently prevents TXA2 production by human platelets (IC50 = 0.15 microM). In a rat model of ferric chloride-induced thrombosis, BM-613 significantly reduces weight of formed thrombus by 79, 49, and 28% at 5, 2, and 1 mg/kg i.v., respectively. In conclusion, BM-613 is a dual and potent TP receptor antagonist and TXA2 synthase inhibitor characterized by a strong antiplatelet and antithrombotic potency. These results suggest that BM-613 could be a potential therapeutic drug for thrombotic disorders.
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PMID:In vitro and in vivo pharmacological characterization of BM-613 [N-n-pentyl-N'-[2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl]urea], a novel dual thromboxane synthase inhibitor and thromboxane receptor antagonist. 1562 21

A protein S (PS) abnormality is a hereditary risk factor for thromboembolism. A 33-year-old female had a left deep vein thrombosis (DVT) and mild pulmonary embolism (PE). Her PS antigen level was 34.7% and the activity level was less than 10%. Genetic analysis identified three missense mutations in PS: the D38Y mutation in exon 3, and the T589I mutation and P626L mutations in exon 15. The D38Y mutation has not been reported previously. An analysis of the patient's family revealed that all members of the family had some PS gene mutation. The D38Y and T589I mutations were both in same allele, the P626L mutation was in another allele. The expression of PS mutations in COS-7 cells revealed that PS activity and antigen were markedly decreased in the D38Y mutation but not in the T589I mutation. The expression of the P626L mutation in baby hamster kidney (BHK) cells showed the PS activity and antigen to be markedly decreased in comparison to the wild type.
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PMID:Analysis three abnormal Protein S genes in a patient with pulmonary embolism. 2018 78

We report two compound heterozygous mutants that caused severe type I protein C (PC) deficiency in two independent Chinese families.PC antigen was determined by enzyme-linked immunosorbent assay (ELISA), and PC activity was measured by chromogenic assay. Genetic mutations were screened with polymerase chain reaction (PCR) followed by direct sequencing. PC mutants were transiently expressed in COS-7 cells for the evaluation of PC secretory activity and function. The subcellular location was visualised by immunofluorescence assay. The structural analysis of mutation was performed as well.Compound heterozygous mutations of Arg178Trp and Asp255His with reduced PC activity and antigen levels were identified in Proband 1, a 28-year-old male with deep vein thrombosis (DVT) and pulmonary embolism. The other mutations of Leu-34Pro and Thr295Ile with reduced PC activity and antigen levels were identified in Proband 2, a 19-year-old male with DVT. The PC activities with Arg178Trp, Asp255His, Leu-34Pro and Thr295Ile mutations decreased significantly. Immunofluorescence assay demonstrated that only trace amount of PC with novel Thr295Ile mutation was transported to the Golgi apparatus. Subsequent structural analysis indicated severe impairments of intracellular folding and secretion.The two rare compound heterozygous mutations could cause type I PC deficiency via impairment of secretory activity of PC.
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PMID:Hereditary protein C deficiency caused by compound heterozygous mutants in two independent Chinese families. 2539 54