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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Physical rehabilitation of patients with heart diseases is a well-known therapeutical method used in patients with heart failure. However there is no consensus regarding rehabilitation program for these patients. The aim of this study was to assess tolerance of physical exercise and parameters of heart rate variability in patients with chronic heart failure who were exercised using different models of training. 42 patients (mean age 55.9 +/- 8.2) with chronic heart failure (NYHA class II and III) were included into this study. They were divided randomly into three groups, each number 14 patients: group A--patients who were trained according to model with progressive increase of workload, group B--patients with interval training, and group C--patients who were not trained at all. The study groups did not differ in average age, BMI, NYHA class, or pharmacological treatment. All patients from groups A and B were rehabilitated during six months, 3 times per week for 1.0 hour each time. All patients were submitted to the following examinations before and after six months of training: echocardiography, cardiopulmonary exercise test and 24-hour ECG recording with evaluation of time-domain HRV parameters. In groups A and B we observed an improvement in exercise capacity, which was more pronounced in group A. This improvement was observed as increase in total exercise time when compared with group B and C (839.1 +/- 98.3 sec vs 472.4 +/- 39.7 sec vs 347.92 +/- 61.0 sec respectively at p < 0.0001), and increase in workload (6.28 +/- 0.8 MET vs 3.9 +/- 0.2 MET vs 2.6 +/- 0.63 MET respectively in the study groups). We also found improved cardiopulmonary exercise test. After six months we observed significant differences in all parameters between group A and C, and in VO2max between group B and C (16.5 +/- 1.9 vs 14.1 +/- 1.9 ml/kg/min, p < 0.01) and in VE/VCO2 (37.8 +/- 4.2 vs 40.4 +/- 6.7 l/min, p < 0.01). After 6 months we also found significant differences between group A and B in HRV parameters which reflect total activity of the autonomous system (SDNN--174.0 vs 96.0 at p < 0.0001; SDANNI--138.1 vs 83.2 at p < 0.0001) and between group A and group C (174.0 vs 78.4, p < 0.0001). In parameters that reflect parasympathetical activity of the autonomous system there were significant changes between group A and group B (rMSSD--42.5 vs 24.7 at p < 0.001, pNN50 18.5 vs 4.2, p < 0.001) and between group A and group C (rMSSD--42.5 vs 16.7 at p < 0.001, pNN50 18.5 vs 4.2 at p < 0.001). Regular exercise training in patients with chronic heart failure, using especially the progressive increase of workload, improves exercise capacity without any negative influence on systolic and diastolic function parameters of the left ventricle. In these patients we may also observe beneficial changes in HRV parameters.
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PMID:[Cardiopulmonary exercise test and heart rate variability in patients with congestive heart failure who underwent physical rehabilitation]. 1505 45

In the last three decades, numerous reports have shown that patients with chronic pulmonary disease and with heart failure with hypoxemia cleared drugs at a lower rate than healthy volunteers. As a consequence decreased clearance, drug toxicity is frequent in these patients. The reduction in drug clearance is due to a decrease in activity of cytochrome P450 isoforms, partly associated to the hypoxemia. With in vivo animal models, acute moderate hypoxia (PaO2 of around 35-50 mm Hg) reduces the clearance of drugs biotransformed by CYP1A1, CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP2E1, although hypoxia does not affect the clearance of drugs biotransformed by CYP3A6. Ex vivo and in vitro experiments demonstrate that hypoxia down-regulates CYP1A1, CYP1A2, CYP2B6, CYP2C9 and CYP2C19, decrease preceded by a reduction in activity. On the other hand, acute moderate hypoxia up-regulates CYP3A6. The changes in protein expression are preceded by modifications in the mRNA coding for the proteins. The effect of hypoxia on hepatic cytochrome P450 is carried out by serum mediators, e.g. interferon-gamma, interleukin-1beta, and interleukin-2 are responsible for the decrease in activity and in expression of cytochrome P450 isoforms, and erythropoietin accounts for the increase in CYP3A6. Probably several mechanisms underlie and contribute to the decrease in activity and down-regulation of cytochrome P450 isoforms by hypoxia, e.g. reducing potentiation factors, inducing repressor elements and activating negative regulatory elements. The up-regulation of CYP3A6 implies a PTK- and p42/44MAPK-dependent stabilization/activation, nuclear translocation of HIF-1 and AP-1, binding to CYP3A6 promoter, and transactivation of the gene to induce CYP3A6 expression.
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PMID:Effect of hypoxia on cytochrome P450 activity and expression. 1518 Apr 95

Trastuzumab is a humanised monoclonal antibody against the extracellular domain of HER2 (human epidermal growth factor receptor-2) that is overexpressed in about 25% of human breast cancers. It has shown clinical benefit in HER2-positive breast cancer cases when used alone or in combination with chemotherapy. Trastuzumab increases the response rate to chemotherapy and prolongs survival when used in combination with taxanes. In this article, we review the clinical trials where trastuzumab has been administered together with docetaxel, and we present the results of the trastuzumab expanded access programme (EAP) in the UK. Combination of trastuzumab with docetaxel results in similar response rates and time-to-progression with the trastuzumab/paclitaxel combinations. The toxicity of the combination and the risk of heart failure are low. The clinical data for the docetaxel/trastuzumab combination indicate a favourable profile from both the efficacy and the safety point of view and confirm the feasibility and safety of trastuzumab administration both as monotherapy and in combination with docetaxel.
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PMID:Safety and efficacy of the combination of trastuzumab with docetaxel for HER2-positive women with advanced breast cancer. A review of the existing clinical trials and results of the expanded access programme in the UK. 1531 58

Fifteen patients with refractory AML were treated in a phase 1 study with SU11248, an oral kinase inhibitor of fms-like tyrosine kinase 3 (Flt3), Kit, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) receptors. Separate cohorts of patients received SU11248 for 4-week cycles followed by either a 2- or a 1-week rest period. At the starting dose level of 50 mg (n = 13), no dose-limiting toxicities were observed. The most frequent grade 2 toxicities were edema, fatigue, and oral ulcerations. Two fatal bleedings possibly related to the disease, one from a concomitant lung cancer and one cerebral bleeding, were observed. At the 75 mg dose level (n = 2), one case each of grade 4 fatigue, hypertension, and cardiac failure was observed, and this dose level was abandoned. All patients with FLT3 mutations (n = 4) had morphologic or partial responses compared with 2 of 10 evaluable patients with wild-type FLT3. Responses, although longer in patients with mutated FLT3, were of short duration. Reductions of cellularity and numbers of Ki-67(+), phospho-Kit(+), phospho-kinase domain-containing receptor-positive (phospho-KDR(+)), phospho-signal transducer and activator of transcription 5-positive (phospho-STAT5(+)), and phospho-Akt(+) cells were detected in bone marrow histology analysis. In summary, monotherapy with SU11248 induced partial remissions of short duration in acute myeloid leukemia (AML) patients. Further evaluation of this compound, for example in combination with chemotherapy, is warranted.
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PMID:A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. 1545 12

The sodium-calcium exchanger (NCX) was considered to play an important role in arrhythmogenesis under certain conditions such as heart failure or calcium overload. In the present study, the effect of SEA-0400, a selective inhibitor of the NCX, was investigated on early and delayed afterdepolarizations in canine ventricular papillary muscles and Purkinje fibres by applying conventional microelectrode techniques at 37 degrees C. The amplitude of both early and delayed afterdepolarizations was markedly decreased by 1 microM SEA-0400 from 26.6+/-2.5 to 14.8+/-1.8 mV (n=9, P<0.05) and from 12.5+/-1.7 to 5.9+/-1.4 mV (n=3, P<0.05), respectively. In enzymatically isolated canine ventricular myocytes, SEA-0400 did not change significantly the L-type calcium current and the intracellular calcium transient, studied using the whole-cell configuration of the patch-clamp technique and Fura-2 ratiometric fluorometry. It is concluded that, through the reduction of calcium overload, specific inhibition of the NCX current by SEA-0400 may abolish triggered arrhythmias.
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PMID:Selective inhibition of sodium-calcium exchanger by SEA-0400 decreases early and delayed after depolarization in canine heart. 1550 49

Cardiac hypertrophy and heart failure occur in association to alterations in glucose uptake and metabolism. Phenylephrine, among other hypertrophic agonists, has been reported to increase expression of GLUT1 in neonatal rat cardiac myocytes by activating transcription. However, the specific cis- or trans-acting factors in the GLUT1 gene that are targeted by this agonist remain elusive. Here we describe that the activity of the -99/+134 basal promoter of rat GLUT1 is increased by phenylephrine. Nevertheless, this is not mediated by previously described binding sites (GC-box, MG1E) in the promoter. Rather, the TATA box is required by the agonist to activate transcription from the promoter. Interestingly, The Ras-ERK mitogen-activated protein (MAP) kinase pathway is involved in the actions of phenylephrine on GLUT1 transcription, and the effects of Ras on the activity of the promoter depend on the integrity of the TATA box. Our data indicate that phenylephrine induces the expression of the TBP-associated factor TAF(II)250 mRNA, which increases in parallel to the expression of GLUT1, suggesting that altering the expression of basal transcription factors could be one mechanism by which phenylephrine may regulate the activity of the GLUT1 promoter.
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PMID:Phenylephrine requires the TATA box to activate transcription of GLUT1 in neonatal rat cardiac myocytes. 1580 44

Brain natriuretic peptide (BNP) was isolated originally from porcine brain extracts but was soon defined as a cardiac natriuretic hormone. Together with the highly homologous atrial natriuretic peptide, it forms a dual natriuretic peptide system of the heart. The main stimulus for proBNP synthesis and secretion from cardiac myocytes is myocyte stretch. On secretion, the propeptide is split into the biologically active BNP and the remaining part of the prohormone N-terminal proBNP (NT-proBNP). In heart failure increased wall stretch, neurohormonal activation and hypoxia stimulate BNP secretion. The recently demonstrated production of BNP by stimulated cardiac fibroblasts is of uncertain pathophysiologic importance. In contrast to atrial natriuretic peptide, BNP is a constitutively secreted hormone with relatively little intracellular storage of mature peptide. In the normal state, the atrium is the main cardiac production site, but as heart failure develops, there is a profound activation of ventricular NT-proBNP synthesis. BNP acts on distant tissues and causes diuresis, vasodilatation, and decreased renin and aldosterone secretion. Known mechanisms of BNP clearance from plasma include binding to the natriuretic peptide clearance receptor type-C and proteolysis by peptidase NEP 24.11. NT-proBNP has a longer half-life and thus higher plasma concentration than BNP. It probably is cleared from plasma by renal excretion and possibly other unknown pathways.
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PMID:NT-ProBNP: the mechanism behind the marker. 1594 7

PTEN is an important tumor suppressor gene. Hereditary mutation of PTEN causes tumor-susceptibility diseases such as Cowden disease. We used the Cre-loxP system to generate an endothelial cell-specific mutation of Pten (Tie2CrePten) in mice. Tie2CrePten(flox/+) mice displayed enhanced tumorigenesis due to an increase in angiogenesis driven by vascular growth factors. This effect was partially dependent on the PI3K subunits p85alpha and p110gamma. In vitro, Tie2CrePten(flox/+) endothelial cells showed enhanced proliferation/migration. Tie2CrePten(flox/flox) mice died before embryonic day 11.5 (E11.5) due to bleeding and cardiac failure caused by impaired recruitment of pericytes and vascular smooth muscle cells to blood vessels, and of cardiomyocytes to the endocardium. These phenotypes depend strongly on p110gamma rather than on p85alpha and were associated with decreased expression of Ang-1, VCAM-1, connexin 40, and ephrinB2 but increased expression of Ang-2, VEGF-A, VEGFR1, and VEGFR2. Pten is thus indispensable for normal cardiovascular morphogenesis and post-natal angiogenesis, including tumor angiogenesis.
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PMID:The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis. 1610 12

Mortality remains high in chronic heart failure (CHF) because under ACE inhibitor treatment other neurohumoral systems remain/become (de)activated, such as the endothelin and atrial natriuretic peptide pathways. Dual endothelin-converting enzyme-neutral endopeptidase (ECE-NEP) inhibition exerts beneficial effects in experimental CHF, but whether "triple" ACE-ECE-NEP inhibition is superior to ACE or ECE-NEP inhibition is unknown. We compared, in rats with CHF, ACE-ECE-NEP to ACE or ECE-NEP inhibition in terms of left ventricular (LV) hemodynamics and remodeling. Benazepril (2 mg/kg/d) or the ECE-NEP inhibitor CGS26303 (10 mg/kg/d) were administered alone or in combination (subcutaneously for 28 days starting 7 days after coronary ligation). ACE-ECE-NEP inhibition reduced blood pressure more markedly than ACE or ECE-NEP inhibition. All treatments increased cardiac output to the same extent, but ACE-ECE-NEP inhibition reduced LV diameter and LV end-diastolic pressure more markedly than ACE or ECE-NEP inhibition. The reduction of LV weight and collagen accumulation in the "viable" myocardium was most pronounced after ACE-ECE-NEP inhibition. These results, obtained in experimental CHF, illustrate a further improvement of LV hemodynamics and structure after ACE-ECE-NEP inhibition compared with either ACE or ECE-NEP inhibition, but whether this is associated with a further improvement of exercise tolerance and/or survival remains to be determined.
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PMID:Triple ACE-ECE-NEP inhibition in heart failure: a comparison with ACE and dual ECE-NEP inhibition. 1611 47

Extracellular matrix (ECM) turnover is regulated by matrix metalloproteinases (MMPs) and plays an important role in cardiac remodeling. Previous studies from our lab demonstrated an increase in gelatinolytic-MMP-2 and -9 activities in endocardial tissue from ischemic cardiomyopathic (ICM) and idiopathic dilated cardiomyopathic (DCM) hearts. The signaling mechanism responsible for the left ventricular (LV) remodeling, however, is unclear. Administration of cardiac specific inhibitor of metalloproteinase (CIMP) prevented the activation of MMP-2 and -9 in ailing to failing myocardium. Activation of MMP-2 and -9 leads to induction of proteinase activated receptor-1 (PAR-1). We hypothesize that the early induction of MMP-9 is a key regulator for modulating intracellular signaling through activation of PAR and various downstream events which are implicated in development of cardiac fibrosis in an extracellular receptor mediated kinase-1 (ERK-1) and focal adhesion kinase (FAK) dependent manner. To test this hypothesis, explanted human heart tissues from ICM and DCM patients were obtained at the time of orthotopic cardiac transplants. Quantitative analysis of MMP-2 and -9 gelatinolytic activities was made by real-time quantitative zymography. Gel phosphorylation staining for PAR-1 showed a significant increase in ICM hearts. Western blot and RT-PCR analysis and in-situ labeling, showed significant increased expression of PAR-1, ERK-1and FAK in ICM and DCM. These observations suggest that the enhanced expression and potentially increased activity of LV myocardial MMP-9 triggers the signal cascade instigating cardiac remodeling. This early mechanism for the initiation of LV remodeling appears to have a role in end-stage human heart failure.
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PMID:Early induction of matrix metalloproteinase-9 transduces signaling in human heart end stage failure. 1620 18


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