Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of the rho15(ts) mutation on the expression of Escherichia coli deo operon's genes is studied. In relation to the regulatory deoR and cytR genes, the rho15 mutation causes in wild type genome 2,5-fold increase in both thymidine phosphorylase (deoA gene) and purine nucleoside phosphorylase (deoD gene) activity, while the deoxyriboaldolase activity controlled by the proximal deoC gene almost does not differ in the rho+ and rho15 strains. The effect of rho15 for the expression of the deo genes in constitutive deoR genome depends on the allele of crp gene: in the crp+ bacteria rho15 leads to a decrease, while in the crp bacteria - to an essential increase in the activity of deo enzymes. These data suggest a possible role of CRP protein as an inhibitor of transcription initiated from deoP promoter. The presence of rho15 in a bacterial genome leads to the complete block of the cytP promoter activity under conditions of both induction of deo enzymes by cytidine and their depression in cytR genome. Based on these data, it is proposed that proximal to cytP promoter, i. e. between deoP and ctyP a Rho-dependent attenuator is located which is usually responsible for termination of the deoP-initiated transcription. An activity of the inner deo operon OP3 promoter is possibly also inhibited in the rho15 genome as shown by the data on the absence of induction of purine nucleoside phosphorylase by inosine in the rho15 bacteria.
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PMID:[Disturbance of the tandem promotor functioning of the Escherichia coli K-12 deo-operon in the genome of the rho15(ts) mutant for the transcription termination factor]. 703 Aug 66

A brief summary of recent studies of pharmacomechanical coupling is presented, with emphasis on the role of GTP-binding proteins and Ca(2+)-independent regulation of contraction (Ca(2+)-sensitization/desensitization) through regulatory myosin light chain (MLC20) phosphorylation and dephosphorylation. Pharmacomechanical regulation of cytosolic [Ca2+] is largely, though not solely, controlled by the phosphatidylinositol cascade and Ca(2+)-pumps of the plasma membrane and the sarcoplasmic reticulum. The monomeric GTPase, RhoA, is a major upstream component of Ca(2+)-sensitization. Its crystal structure and apparently obligatory translocation to the plasma membrane for activation of its downstream effectors are described. Inhibition of RhoA activity by a membrane-permeant ADP-ribosylating bacterial exoenzyme, DC3B, causes severe depression of the tonic component of agonist-induced contraction, suggesting that this component is largely due to Ca(2+)-sensitization. A relatively specific inhibitor (Y27632) of Rho-kinase, a downstream effector of Ca(2+)-sensitization (Uehata et al 1997), also inhibits oxytoxin-induced Ca(2+)-sensitization of myometrium. The major mechanism of physiological, G-protein-coupled Ca(2+)-sensitization is through inhibition of smooth muscle myosin phosphatase (SMPP-1M), whereas conventional or novel protein kinase Cs play very little or no role in this process. Mechanisms of Ca(2+)-desensitization include inhibition of myosin light chain kinase and activation of SMPP-1M. Activation of SMPP-1M in phasic smooth muscle can be attributed, at least in part, to the synergistic phosphatase activating activities of a cyclic nucleotide-dependent kinase and its major substrate, telokin.
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PMID:From pharmacomechanical coupling to G-proteins and myosin phosphatase. 988 67

1. The effects of Rho-kinase inhibitor, fasudil, and of a more specific Rho-kinase inhibitor, hydroxyfasudil, on pacing-induced myocardial ischaemia were determined in anaesthetized open-chest dogs. 2. The dogs were subjected to left anterior descending coronary artery (LAD) stenosis producing a sufficient ischaemia as measured by ST-segment depression on electrocardiograms only when the hearts were paced 60 beats min(-1) above the baseline. After a recovery (nonpacing) period, drugs or saline were infused intravenously over 30 min. The animals were again subjected to 5 min of pacing 25 min after the initiation of the treatment. 3. Hydroxyfasudil (0.1 and 0.3 mg kg(-1)) and fasudil (0.3 mg kg(-1)) suppressed the ST-segment depression. Hydroxyfasudil and fasudil also increased the regional blood flow of the LAD perfused endomyocardium region in the canine model of effort angina. 4. To determine the flow profile for hydroxyfasudil in dogs, blood flow in three vascular beds was measured. Hydroxyfasudil (0.3 mg kg(-1) for 30 min) significantly increased coronary blood flow and vertebral blood flow, without significantly changing the femoral blood flow. 5. Hydroxyfasudil had no inotropic or chronotropic effect on the isolated hearts of guinea-pigs. Hydroxyfasudil (2 mg kg(-1) for 20 min) did not affect the PR or QTc interval in anaesthetized dogs. 6. Inhibition of Rho-kinase appears to protect myocardium subjected to pacing-induced ischaemia through the increase in the regional myocardial blood flow. Hydroxyfasudil may be categorized as a novel type of anti-anginal drug, without any inotropic or chronotropic effects.
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PMID:Antianginal effects of hydroxyfasudil, a Rho-kinase inhibitor, in a canine model of effort angina. 1173 49

The aim of this study was to develop a new model of vasopressin-induced chronic myocardial damage based on sustained ST-segment depression in electrocardiogram (ECG) with progression of myocardial fibrosis in rats. Furthermore, using this model, we examined the prophylactic potential of fasudil, a Rho-kinase inhibitor, against myocardial damage induced by vasopressin. In 10-week old male Donryu rats, intravenous administration of arginine vasopressin (0.5 iu/kg) induced significant ST-segment depression. Two days and one week after the administration of vasopressin, ST-segment depression was -0.19 +/- 0.02 and -0.14 +/- 0.02 mV, respectively. Fasudil (10 and 30 mg/kg, p.o.) significantly attenuated the ST-segment depression induced by vasopressin. One week after the administration of vasopressin, the percent area of myocardial fibrosis in control animals (0.42 +/- 0.11%, p < 0.01) was significantly greater than that in normal animals (0.05 +/- 0.01%). Fasudil (10 and 30 mg/kg) significantly prevented the development of the fibrosis. We present a new model of chronic myocardial damage based on sustained ST-segment depression with progression of myocardial fibrosis in rats, and suggest that this model may be useful to investigate the treatment of chronic angina. Inhibition of Rho-kinase is efficacious in preventing the ECG change and development of fibrosis induced by vasopressin in this model.
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PMID:Effects of Rho-kinase inhibitor on vasopressin-induced chronic myocardial damage in rats. 1240 49

Rho-kinase plays an important role in calcium sensitization for vascular smooth muscle (VSMC) contraction and may be involved in the inappropriate coronary vasoconstriction during exercise-induced myocardial ischemia. In this multicenter phase II study, the anti-anginal effect of fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil after oral administration, was examined in patients with stable effort angina. In the phase IIa trial, after a 2-week washout period of anti-anginal drugs, 45 patients received increasing doses of fasudil (5, 10, and 20 mg TID for every 2 weeks). The fasudil treatment significantly prolonged the maximum exercise time and the time to the onset of 1-mm ST segment depression on treadmill exercise test (both p < 0.01), whereas blood pressure and heart rate during exercise were unchanged before and after the treatment. Higher doses of fasudil (20 and 40 mg TID) were subsequently tested in 22 patients in the same manner with similar positive results. In the phase IIb trial, after a 2-week washout period of anti-anginal drugs, 125 patients were assigned, in a double-blind manner, to a 4-week oral treatment with a different dose of fasudil (5, 10, 20, or 40 mg TID) and treadmill exercise test was performed before and after the treatment. Again, both maximum exercise time and time to the onset of 1-mm ST segment depression were prolonged in all groups. A significant dose-response relation was noted across the treatment groups for the exercise tolerance index that was determined by the combined effect of exercise time and ST segment depression (p = 0.006). Fasudil was well tolerated in both trials without any serious adverse reactions. These results suggest the efficacy and adequate safety profile of fasudil, the first drug in a novel class of vasodilators, for the treatment of stable effort angina.
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PMID:Anti-anginal effect of fasudil, a Rho-kinase inhibitor, in patients with stable effort angina: a multicenter study. 1240 84

Erectile dysfunction is a condition that is estimated to affect more than 30 million men in the United States alone. The prevalence of erectile dysfunction is increased with age and is often secondary to diseases such as depression, hypertension and diabetes. Causes of erectile dysfunction include physical injury to the cavernosum and abnormal cerebral and peripheral nervous system functioning. However, many cases of erectile dysfunction are the result of dysfunctional signaling in the cavernosal vasculature. This article will detail the important role of a vasoconstrictor mechanism mediated by the small G-protein RhoA and a downstream serine/threonine kinase, Rho-kinase, in the maintenance of penile flaccidity. Recent evidence demonstrates that inhibition of endogenous Rho-kinase initiates an erectile response in an in vivo rat model. These initial findings introduce a novel potential therapeutic approach for the treatment of erectile dysfunction.
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PMID:Rho-kinase as a potential target for the treatment of erectile dysfunction. 1280 26

Basal ganglia abnormalities on magnetic resonance imaging predict neurodevelopmental impairment in newborns with perinatal depression. We determined the value of a clinical encephalopathy score as a predictor of abnormal magnetic resonance imaging results in newborns with perinatal depression. We assigned a neonatal encephalopathy score to 101 newborns. The encephalopathy score, based on alertness, feeding, tone, respiratory status, reflexes, and seizure activity, was assigned once daily. The maximum score from the first 3 days of life was compared with abnormal magnetic resonance imaging results present globally or solely in the basal ganglia.Eighty-one percent of patients manifested abnormalities on any magnetic resonance imaging sequence, and 37% manifested abnormalities in the basal ganglia alone. The encephalopathy score correlated well with magnetic resonance imaging abnormalities in the basal ganglia (Spearman Rho = 0.335, P < 0.0001). Newborns with mild and severe encephalopathy had likelihood ratios of 0.41 and 7.4, respectively, for abnormal basal ganglia magnetic resonance imaging results. Newborns with moderate encephalopathy (composing 47% of the cohort) manifested basal ganglia abnormalities with a likelihood ratio of 0.785. Severe clinical encephalopathy correlates with abnormal basal ganglia magnetic resonance imaging results, and mild encephalopathy correlates with a normal magnetic resonance imaging result. However, standard clinical criteria do not alter the prior risk of abnormal basal ganglia magnetic resonance imaging results for newborns with moderate encephalopathy.
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PMID:Encephalopathy as a predictor of magnetic resonance imaging abnormalities in asphyxiated newborns. 1287 94

During pregnancy, the uterus undergoes major functional and structural remodelling. It is well known that during the major part of pregnancy, the myometrium normally remains relatively quiescent but is able to generate powerful contractions at the time of parturition. However, the intracellular molecular events regulating myometrial contractility during pregnancy still remain poorly understood. We applied differential gene expression screening using cDNA array technology to probe myometrium samples from non-pregnant and mid-pregnant (15 days) rabbits. Among the differentially expressed genes, the farnesylated small G-protein of the Rho family, Rnd3, was found to be upregulated (3.6-fold) at mid-pregnancy. Upregulation of Rnd3 was confirmed at the protein level by a 3.4-fold increase in Rnd3 expression in mid-pregnant myometrium. Measurements of contractile properties of beta-escin permeabilized smooth muscle strips revealed that the upregulation of Rnd3 correlated with an inhibition of RhoA-Rho kinase-mediated Ca2+ sensitization at mid-pregnancy. Treatment of muscle strips from mid-pregnant myometrium with the farnesyl-transferase inhibitor manumycin A (10 muM) led to the recovery of RhoA-Rho kinase-dependent Ca2+ sensitization. At late pregnancy (31 days), upregulation of RhoA and Rho kinase expression was associated with an increase in Ca2+ sensitivity of contractile proteins that was inhibited by the Rho kinase inhibitor Y-27632 (10 muM). These data thus demonstrate the time-dependent regulation of the RhoA-Rho kinase-mediated Ca2+ sensitization during the course of pregnancy. The depression of this mechanism at mid-pregnancy followed by its constitutive activation near term is associated with a co-ordinated modulation of Rnd3, RhoA and Rho kinase expression. The RhoA-Rho kinase signalling pathway and its regulators might thus represent potential targets for the development of new treatments for pre-term labour.
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PMID:Modulation of RhoA-Rho kinase-mediated Ca2+ sensitization of rabbit myometrium during pregnancy - role of Rnd3. 1456 24

NHE3, the apical isoform of the Na(+)/H(+) exchanger, is central to the absorption of salt and water across the intestinal epithelium. We report that treatment of epithelial cells with toxin B of Clostridium difficile, a diarrheal pathogen, causes a pronounced inhibition of NHE3 activity, with little effect on the basolateral NHE1 isoform. Depression of NHE3 activity is accompanied by the translocation of apical exchangers to a subapical endomembrane compartment. Treatment of cells with toxin B increased the fraction of exchangers that were solubilized by nonionic detergents and induced dephosphorylation and extensive redistribution of ezrin. The Rho-kinase inhibitor, Y-27632, also altered the distribution and activity of NHE3. We suggest that inactivation of Rho-family GTPases by clostridial toxin B alters the interaction between NHE3 and the microvillar cytoskeleton, possibly by impairing the ability of ezrin to bridge the exchangers to filamentous actin. Detachment of NHE3 from the actin skeleton would facilitate its internalization, resulting in net disappearance from the apical surface. The consequent inhibition of transport is likely to contribute to the diarrheal effects of C. difficile.
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PMID:Inhibition and redistribution of NHE3, the apical Na+/H+ exchanger, by Clostridium difficile toxin B. 1507 17

An 86-year-old woman was admitted with unstable angina pectoris. Plain old balloon angioplasty (POBA) was performed for 90% stenosis at segment 7 of the left coronary artery with concomitant treatment with nitrate, calcium antagonists, and nicorandil. Five days after POBA, she again suffered chest pain at rest with ST depression by electrocardiography, despite increased doses of calcium-antagonist and nicorandil. Coronary arteriography showed no evidence of restenosis (50%) at the POBA site. The involvement of coronary artery spasm was considered and intravenous treatment with a Rho-kinase inhibitor, fasudil, was started, which resulted in disappearance of the anginal attacks. She refused to continue the fasudil treatment on day 5, which resulted in reappearance of anginal attacks. Third coronary angiography showed a 90% restenosis at POBA site and percutaneous coronary intervention was again performed. This case suggests that a Rho-kinase inhibitor is potentially effective to prevent anginal attacks in spastic angina.
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PMID:[Inhibition of Rho-kinase by fasudil preventing anginal attacks associated with spastic angina: a case report]. 1553 47


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