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)

Ethyl 5-(p-chlorophenoxy)-3-hydroxy-3-methylpentanoate (HMP), a new hypocholesterolemic compound, was evaluated in male rats at dosage levels ranging from 25-800 mg/kg/day and in SEA Japanese quail at approximately 200 mg/kg/day. In the rat, the atherogenic lipoprotein cholesterol, that is, the combination of very low density plus low density lipoprotein cholesterol (VLDL-C + LDL-C), was reduced 20-27% at dosage levels over 100 mg/kg/day, while high density lipoprotein cholesterol (HDL-C) and total serum cholesterol (TSC) were significantly decreased 25-46%, respectively, at all dose levels of HMP. Liver weights with HMP treatment were significantly elevated (11-26%) in the rat. HMP was not active in the SEA Japanese quail, since an initial reduction in artery cholesterol could not be confirmed in subsequent tests.
Atherosclerosis
PMID:Activity of ethyl 5-(p-chlorophenoxy)-3-hydroxy-3-methylpentanoate, a new hypocholesterolemic compound, in male rats and SEA Japanese quail. 722 99

Accelerated coronary atherosclerosis in cardiac transplants (cardiac allograft vasculopathy, CAV) is characterized by coronary intimal hyperplasia. Acidic fibroblast growth factor (aFGF) is a potent mitogen for vascular smooth muscle cells and endothelial cells, and its expression is increased in cardiac allografts, suggesting it may play a role in the pathogenesis of CAV. The activity of aFGF is dependent on binding to transmembrane receptors. To investigate whether receptors for aFGF are also induced after transplantation, polymerase chain reaction, in situ hybridization, and immunohistochemistry were used to analyze expression of four receptors for aFGF (FGFR1-FGFR4). Expression of mRNA encoding extracellular immunoglobulin-like domains of FGFR1 was increased 35-fold in cardiac allografts compared with normal hearts and was predominantly present in cardiac myocytes and vascular structures. Alternatively spliced mRNA that encodes transmembrane forms of FGFR1, which contain the signal-transducing tyrosine kinase domains, was induced in allografts during rejection, in infiltrating cells, vascular structures, and myocytes. In vitro experiments showed that differential expression of FGF receptor isoforms was induced by aFGF, and also by IL-6 and TGF-beta, which are expressed in cardiac allografts during rejection. The results show that expression of both aFGF and its receptors is altered in cardiac allografts and suggest that these events are important in the pathogenesis of CAV.
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PMID:Modification of alternative messenger RNA splicing of fibroblast growth factor receptors in human cardiac allografts during rejection. 752 91

Steroids diffuse through polysiloxone at a constant rate, and steroids placed in the vagina rapidly pass through the vaginal epithelium into the circulation. Combining these principles led to the development of contraceptive vaginal rings (CVR) consisting of various progestins, with and without oestrogen, placed in flexible polysiloxone, doughnut-shaped devices. As occurs with oral contraceptives, the CVRs containing progestin plus oestrogen are left in the vagina for 3 weeks and removed for 1 week to allow withdrawal bleeding, while CVRs releasing a small dose of progestins without oestrogen are left in the vagina continuously for several months. Large-scale, clinical trials were performed with a low dose levonorgestrel-releasing-only CVR by the WHO. At 1 year, continuation rates were about 50 per 100 women with 17.2 per 100 discontinuing for menstrual problems and 4.5 for pregnancy. Two sizes of a CVR containing levonorgestrel and oestradiol were studied in a multinational trial organized by the Population Council. At the end of 1 year, about half the women were continuing with the method, one-quarter had discontinued because of bleeding problems, and pregnancy rates were between 1 and 2 per 100 women. The CVR was well accepted by women and their partners, but because of lowered HDL-cholesterol levels and accelerated atherosclerosis in female monkeys, further development of this formulation was discontinued. Recently, phase II clinical trials with CVRs containing combinations of NET-acetate plus ethinyloestradiol and 3-ketodesogestrel plus ethinyloestradiol have been undertaken. These CVRs provide good bleeding control, inhibit ovulation consistently and do not have an adverse effect on serum lipids. Phase III trials with these two types of CVRs will be initiated shortly.
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PMID:Vaginal contraceptive rings. 848 60

In order to obtain information about the developmental mechanisms of restenosis after angioplasty, we investigated an association between the expression of platelet-derived growth factors (PDGFs) and neointimal cell accumulation in rabbit femoral arteries subjected to balloon angioplasty. Northern analysis demonstrated that mRNA expression of PDGF B-chain (PDGF-B) increased markedly in the injured arteries, peaking at day 7 (sevenfold), and the transcripts remained augmented until day 21. Also transcripts of PDGF beta-receptor (PDGFR-beta) and alpha-receptor increased by 3- and 2.5-fold, respectively, but those of PDGF A-chain showed only a slight increase (1.5-fold). In situ hybridization and immunohistochemistry demonstrated the concordant expression of mRNA and protein for PDGF-B in the smooth muscle cells (SMCs) of injured vessels throughout the experiment. PDGF-B expression peaked in neointimal SMCs at day 7. In accordance with PDGF-B expression, cellular proliferation in neointima peaked at day 7, being followed by a dramatic increase of neointimal areas thereafter. Further, we demonstrated PDGFR-beta immunoreactivity in these neointimal cells with PDGF-B expression. Our data provide evidence that PDGF-B may stimulate vascular SMC proliferation and contribute to neointimal formation after angioplasty.
Atherosclerosis 1996 Jul
PMID:Expression of platelet-derived growth factor B-chain in neointimal smooth muscle cells of balloon injured rabbit femoral arteries. 880 Apr 90

Hemodynamic forces play a key role in inducing atherosclerosis-implicated gene expression in vascular endothelial cells. To elucidate the signal transduction pathway leading to such gene expression, we studied the effects of fluid shearing on the activities of upstream signaling molecules. Fluid shearing (shear stress, 12 dynes/cm2 [1 dyne = 10(-5)N]) induced a transient and rapid activation of p21ras and preferentially activated c-Jun NH2 terminal kinases (JNK1 and JNK2) over extracellular signal-regulated kinases (ERK-1 and ERK-2). Cotransfection of RasN17, a dominant negative mutant of Ha-Ras, attenuated the shear-activated JNK and luciferase reporters driven by 12-O-tetradecanoylphorbol-13-acetate-responsive elements. JNK(K-R) and MEKK(K-M), the respective catalytically inactive mutants of JNK1 and MEKK, also partially inhibited the shear-induced luciferase reporters. In contrast, Raf301, ERK(K71R), and ERK(K52R), the dominant negative mutants of Raf-1, ERK-1, and ERK-2, respectively, had little effect on the activities of these reporters. The activation of JNK was also correlated with increased c-Jun transcriptional activity, which was attenuated by a negative mutant of Son of sevenless. Thus, mechanical stimulation exerted by fluid shearing activates primarily the Ras-MEKK-JNK pathway in inducing endothelial gene expression.
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PMID:The Ras-JNK pathway is involved in shear-induced gene expression. 888 24

PD 089828, a novel protein tyrosine kinase inhibitor of a new structural class, the 6-aryl-pyrido-[2,3-d]pyrimidines, was identified by screening a compound library with assays that measured protein tyrosine kinase activity. PD 089828 was found to inhibit human full-length fibroblast growth factor (FGF) receptor-1 (FGFR-1), platelet-derived growth factor (PDGF) receptor beta subunit (PDGFR-beta), Src nonreceptor tyrosine kinase (c-Src) and epidermal growth factor (EGF) receptor (EGFR) tyrosine kinases with half-maximal inhibitory potencies (IC50 values) of 0.15 +/- 0.02 (n = 4), 0.18 +/- 0.04 (n = 3), 1.76 +/- 0.28 (n = 4) and 5.47 +/- 0.78 (n = 6) microM, respectively. PD 089828 was further characterized as an ATP competitive inhibitor of the growth factor receptor tyrosine kinases (FGFR-1, PDGFR-beta and EGFR) but a noncompetitive inhibitor of c-Src tyrosine kinase with respect to ATP. In addition, PD 089828 inhibited PDGF- and EGF-stimulated receptor autophosphorylation in vascular SMC (VSMC) and basic FGF-mediated tyrosine phosphorylation in A121 cells with IC50 values similar to the potencies observed for inhibition of receptor tyrosine kinase activity. The inhibition of PDGF receptor autophosphorylation in VSMC by PD 089828 occurred rapidly, with maximal effects reached within 5 min of drug exposure. Inhibition after single exposure was long lasting but also rapidly reversible, occurring within 5 min after drug removal. The PDGF-induced association of downstream signaling proteins, including phosphoinositide-3-kinase (PI-3K), growth factor receptor binding protein-2 (GRB2), SH-2 domain and collagen like (Shc) and phospholipase Cgamma (PLCgamma), with VSMC PDGF receptors was also blocked as a result of the inhibition of PDGF-stimulated receptor autophosphorylation by PD 089828. PD 089828 also inhibited the PDGF-induced tyrosine phosphorylation of the 44- and 42-kDa mitogen-activated protein kinase isoforms. Moreover, the effects of PD 089828 were demonstrated in functional assays in which PDGF-stimulated DNA synthesis, PDGF-directed migration and serum-stimulated growth of VSMC were all inhibited to the same extent as PDGF receptor autophosphorylation (IC50 = 0.8, 4.5 and 1.8 microM, respectively). These results highlight the biological characteristics of PD 089828 as a novel, broadly active protein tyrosine kinase inhibitor with long-lasting but reversible cellular effects. The potential therapeutic use of these broadly acting, nonselective inhibitors as antiproliferative and antimigratory agents could extend to such diseases as cancer, atherosclerosis and restenosis in which redundancies in growth-signaling pathways are known to exist.
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PMID:Inhibition of growth factor-mediated tyrosine phosphorylation in vascular smooth muscle by PD 089828, a new synthetic protein tyrosine kinase inhibitor. 919 Aug 82

Natriuretic peptide system consists of three endogenous ligands, ANP (atrial natriuretic peptide), BNP (brain natriuretic peptide) and CNP (C-type natriuretic peptide), and three receptor subtypes, natriuretic peptide receptor (NPR)-A or guanylate cyclase (GC)-A and NPR-B or GC-B and C receptor (NPR-C). ANP and BNP are mainly secreted from the atrium and ventricle of the heart respectively to act as cardiac hormones whereas CNP is secreted from the endothelium to act as an endothelium-derived relaxing peptide. ANP and BNP regulate body fluid and blood pressure to reduce cardiac pre- and after-load. Recent molecular biology and developmental biotechnology demonstrated the physiological role of ANP and BNP for the determination of basal blood pressure. CNP can modulate the phenotype of vascular smooth muscle cells to regulate vascular remodeling. Therefore, natriuretic peptide system is implicated in the pathophysiology of hypertension, congestive heart failure atherosclerosis and renal diseases. Clinical application of natriuretic peptide system is actively going on progress. Determination of plasma ANP and BNP levels are useful for the evaluation of congestive heart failure, cardiac hypertrophy and acute myocardial infarction. Infusion of ANP improves acute heart failure. Application of NEP (neutral endopeptidase) inhibitor for the treatment of congestive heart failure and hypertension is under clinical trial.
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PMID:[Natriuretic peptide system]. 928 3

Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) have been linked to vascular smooth muscle cell (SMC) migration and proliferation leading to atherosclerosis, restenosis, and chronic allograft rejection. This study describes the effect of CGP 53716, a specific PDGFR tyrosine kinase inhibitor on SMC proliferation and migration in vitro and in neointimal formation in vivo. CGP 53716 inhibited dose dependently tyrosine phosphorylation of both the known PDGFRs: the PDGFR-alpha and PDGFR-beta. In primary rat SMC cultures, a dose-dependent inhibition of PDGF-AA and PDGF-BB induced migration, and tritiated thymidine incorporation of SMC was seen at nontoxic concentrations. After rat carotid artery ballooning injury in vivo, the migration of alpha-actin-positive cells on the luminal side of internal elastic lamina was decreased with 50 mg x kg(-1) x day(-1) of CGP 53716 from 38 +/- 10 (control group) to 4 +/- 2 (P<0.0001, Mann-Whitney U test, N=18). CGP 53716 did not inhibit the number of replicating bromodeoxyuridine (BrdU)-incorporating cells in the intima, media, or adventitia during BrdU labeling at 0-96 postoperative h, though it inhibited significantly (P<0.01) the replication of medial and intimal cells from 93 h onward. Intima/media ratio was inhibited by 40% after 14 days in the CGP 53716-treated group (P=0.028) after rat aortic denudation. The results indicate that inhibition of the PDGFR tyrosine kinase inhibits SMC migration and proliferation in vitro, SMC migration, and, to a lesser extent, proliferation after ballooning injury in vivo, confirming a causal role for activation of the PDGFR and the formation of neointimal lesions.
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PMID:Inhibition of platelet-derived growth factor receptor tyrosine kinase inhibits vascular smooth muscle cell migration and proliferation. 936 46

PD 166285, a novel protein tyrosine kinase inhibitor of a new structural class, the 6-aryl-pyrido[2,3-d]pyrimidines, was synthesized as the most potent and soluble analog of a series of small molecules originally identified by screening a compound library with assays that measured protein tyrosine kinase activity. PD 166285 was found to inhibit Src nonreceptor tyrosine kinase, fibroblast growth factor receptor-1, epidermal growth factor receptor and platelet-derived growth factor receptor beta subunit (PDGFR-beta), tyrosine kinases with half-maximal inhibitory potencies (IC50 values) of 8.4 +/- 2.3 nM (n = 6), 39.3 +/- 2.8 nM (n = 16), 87.5 +/- 13.7 nM (n = 6) and 98.3 +/- 7.9 nM (n = 16), respectively. PD 166285 also demonstrated inhibitory activity against mitogen-activated protein kinase (IC50 = 5 microM) and protein kinase C (IC50 = 22.7 microM). PD 166285 was further characterized as an ATP competitive inhibitor of Src nonreceptor tyrosine kinase, PDGFR-beta, fibroblast growth factor receptor-1 and epidermal growth factor receptor tyrosine kinases. In addition, PD 166285 inhibited PDGF- and EGF-stimulated receptor autophosphorylation in vascular smooth muscle cells (VSMCs) and A431 cells, respectively, and basic fibroblast growth factor-mediated tyrosine phosphorylation in Sf9 cells, with IC50 values of 6.5 nM, 1.6 microM and 97.3 nM, respectively, further establishing a tyrosine kinase mechanism of inhibition. The inhibition of PDGF receptor autophosphorylation in VSMCs by PD 166285 was long lasting and persisted for 4 days after a single 1-hr exposure followed by extensive washing. The PDGF-induced tyrosine phosphorylation of the 44- and 42-kDa mitogen-activated protein kinase isoforms was also blocked as a result of the inhibition of PDGF-stimulated receptor autophosphorylation by PD 166285 in VSMCs. The effects of PD 166285 were also demonstrated in functional assays of cell attachment, migration and proliferation, in which vascular cell adhesion to vitronectin, PDGF-directed chemotaxis and serum-stimulated cell growth were all potently inhibited with IC50 values of 80 yo 120 nM. Finally, PD 166285 uniquely demonstrated potent inhibition of phorbol ester-induced production of 92-kDa gelatinase A (MMP-9) in VSMC without affecting 72-kDa gelatinase B (MMP-2) as measured by gelatin zymography. These results highlight the biological characteristics of PD 166285 as a broadly active protein tyrosine kinase capable of potently inhibiting a number of kinase mediated cellular functions, including cell attachment, movement and replication. The potential therapeutic utility of this broadly acting inhibitor as an antiproliferative and antimigratory agent could extend to such diseases as cancer, atherosclerosis and restenosis, in which redundancies in protein kinase signaling pathways are known to exist.
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PMID:In vitro pharmacological characterization of PD 166285, a new nanomolar potent and broadly active protein tyrosine kinase inhibitor. 940 19

HB-EGF is a heparin-binding member of the EGF family that was initially identified in the conditioned medium of human macrophages. Soluble mature HB-EGF is proteolytically processed from a larger membrane-anchored precursor and is a potent mitogen and chemotactic factor for fibroblasts, smooth muscle cells but not endothelial cells. HB-EGF activates two EGF receptor subtypes, HER1 and HER4 and binds to cell surface HSPG. The transmembrane form of HB-EGF is a juxtacrine growth and adhesion factor and is uniquely the receptor for diphtheria toxin. HB-EGF gene expression is highly regulated, for example by cytokines, growth factors, and transcription factors such as MyoD. HB-EGF has been implicated as a participant in a variety of normal physiological processes such as blastocyst implantation and wound healing, and in pathological processes such as tumor growth, SMC hyperplasia and atherosclerosis.
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PMID:Heparin-binding EGF-like growth factor. 942 3


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