Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Aspergillus nidulans gene coding for acetamidase (amdS) was introduced into A. niger by transformation. Twelve Amd+ transformants were analysed genetically. The amdS inserts were located in seven different linkage groups. In each transformant the plasmid was integrated in only a single chromosome. Our (non-transformed) A. niger strains do not grow on acetamide and are more resistant to fluoroacetamide than the transformants. Diploids hemizygous for the amdS insert have the Amd+ phenotype. We exploited the opportunity for two-way selection in A. niger: transformants can be isolated based on the Amd+ phenotype, whereas counter-selection can be performed using resistance to fluoroacetamide. On this basis we studied the phenotypic stability of the heterologous amdS gene in A. niger transformants as well as in diploids. Furthermore, we mapped the plasmid insert of transformant AT1 to the right arm of chromosome VI between pabA1 and cnxA1, providing evidence for a single transformational insert. The results also show that the amdS transformants of A. niger can be used to localize non-selectable recessive markers and that the method meets the prerequisites for efficient mitotic mapping. We suggest the use of amdS transformants for mitotic gene mapping in other fungi.
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PMID:Genetic analysis of amdS transformants of Aspergillus niger and their use in chromosome mapping. 227 31

The pharmacological properties of TH-142177 (N-n-butyl-N-[2'-(1-H-tetrazole-5-yl) biphenyl-4-yl]-methyl-(N-carboxymethyl-benzylamino)-acetamide), a novel antagonist of the angiotensin II (AII) AT1 receptor, were studied in vitro and in vivo, and compared to those of losartan. In the rat isolated aorta, TH-142177 produced parallel shifts to the right of the concentration-response curves for AII-induced contractions without affecting the maximal response (pA2 = 9.07). The inhibitory potency of TH-142177 in the aorta was about three times greater than that of losartan. TH-142177 completely inhibited the specific binding of [125I]AII to AT1 receptor in rat aortic membranes (Ki = 1.6 x 10(-8) M), whereas specific [125I]AII binding to AT2 receptor in bovine cerebellum and human myocardium was not affected by concentrations of TH-142177 up to 10(-5) M. Losartan also inhibited the [125I]AII binding to rat aortic membranes (Ki = 2.2 x 10(-8) M). Following the intravenous administration to anesthetized normotensive rats, TH-142177 dose-dependently inhibited the increase in systolic blood pressure induced by an intravenous bolus injection of AII that was 1.5 times less potent than losartan. Furthermore, the oral administration of TH-142177 to conscious renal hypertensive rats exerted a dose-dependent reduction of systolic blood pressure without significantly effecting the heart rate. TH-142177 was at least three times more potent than losartan. These results demonstrate that TH-142177 is a potent and selective antagonist of AT1 receptors and by oral administration has a long-lasting antihypertensive activity.
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PMID:Pharmacological profile of TH-142177, a novel orally active AT1-receptor antagonist. 934 92

We investigated the effects of TH-142177 (N-n-butyl-N-[2'-(1-H-tetrazole-5-yl) biphenyl-4-yl]-methyl-(N-carboxy methyl-benzylamino)-acetamide), a novel selective antagonist of angiotensin II type 1-receptor (AT1-R) on angiotensin II (AII)-induced proliferation and migration of vascular smooth muscle cells (VSMC), and on neointimal formation in the rat carotid artery after balloon injury, and on the intracellular signaling by the stimulation of AT1-R. High affinity AII receptor sites were detected in rat VSMC by the use of [125I]Sar1,Ile8-AII. TH-142177 and losartan competed with [125I]Sar1,Ile8-AII for the binding sites in VSMC in a monophasic manner, although PD123177, a selective antagonist of angiotensin II type 2-receptor (AT2-R), had little inhibitory effect, demonstrating the predominant existence of AT1-R in rat VSMC. TH-142177 prevented AII-induced DNA synthesis and migration, with a significant inhibition of 74 and 55%, respectively, at the concentration of 100 nM. AII-induced activation of p21ras, mitogen-activated protein kinase (p42MAPK and p44MAPK), and protein kinase C was significantly (50-78%) inhibited by TH-142177 (100 nM), suggesting that the activation of these enzymes is mediated through the stimulation of AT1-R. Balloon-injured left carotid arteries in rats showed extensive neointimal thickening, and TH-142177 (3 mg/kg) brought out a marked decrease in the neointimal thickening after balloon injury. In conclusion, TH-142177 inhibited AII-induced proliferation and migration of rat VSMC and neointimal formation in the carotid artery after balloon injury, and these effects may be related, in part, to the suppression of ras, p42MAPK and p44MAPK, and protein kinase C activities through the blockade of AT1-R. Thus, TH-142177 may have therapeutic potential for the treatment of vascular diseases such as atherosclerosis and restenosis.
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PMID:Effects of TH-142177 on angiotensin II-induced proliferation, migration and intracellular signaling in vascular smooth muscle cells and on neointimal thickening after balloon injury. 1037 31