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)

Most low-molecular-weight drugs are short-lived species in the circulatory system, being rapidly eliminated by glomerular filtration in the kidney. However, binding to human serum albumin (HSA) can slow clearance and prolong lifetime profile in vivo. In this study, we have engineered a gentamicin derivative with affinity to albumin by linking three (2-sulfo)-9-fluorenylmethoxycarbonyl (FMS) to three amino groups of gentamicin C(1). FMS(3)-gentamicin associates with HSA with a K(a) value of (1.31 +/- 0.2) x 10(5) M(-1). It has less than 1% the antibacterial potency of native gentamicin. Upon incubation at pH 8.5 and 37 degrees C, the FMS moieties from FMS(3)-gentamicin undergo slow hydrolysis (t(1/2) = 8.0 +/- 0.2 h), leading to a linear regeneration of the antibacterial potency with a t(1/2) value of 11 +/- 0.7 h. FMS(3)-gentamicin is a long-lived species in the rat circulatory system. Following a single subcutaneous or intravenous administration, it maintains a prolonged pharmacokinetic profile with a peak and a "through" concentration of immuno/antibacterial active gentamicin exceeding 4-5 times the duration obtained by administered native gentamicin. To sum up, an approach aimed at elongating the lifetime of low-molecular-weight drugs in vivo has been examined here with gentamicin. Two to three FMS per mole of compound are to be introduced to obtain an albumin associating affinity of K(d) = 7.6-9.2 microM and, hence, to significantly extend the drug's lifetime in situ following administration. By use of this technology, the loss of pharmacological potency with derivatization is of no consequence, since FMS moieties are hydrolyzed and activity is generated at physiological conditions.
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PMID:N-[(2-Sulfo)-9-fluorenylmethoxycarbonyl](3)-gentamicin C(1) is a long-acting prodrug derivative. 1221 67

Some metabolic and hormonal changes in women using longacting injectables as a contraceptive method were examined. The 2 main injectables utilized were depomedroxyprogesterone acetate (DMPA), given every 90 +or- 5 days, and norethisterone enanthate (NET/EN) injected every 60 +or- 5 days. None of the studied cases became pregnant during injectable use, indicating the high contraceptive efficacy of the method. No statistically significant changes were observed in hemoglobin, hematocrit, all protein fractions including albumin, alpha1, alpha2 beta, gamma immunoglobulins IgG, IgA, and IgM after 6 and 12 months in both groups of injectable users as compared with the preinjection values. Statistically significant suppression of the estimated hormones, Follitropin, Luteotropin, and Estradiol-17beta were detected in both groups of NET/EN and DMPA users, after 6 and 12 months, as compared with the preinjection values.
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PMID:Some metabolic and hormonal changes in women using long acting injectable contraceptives. 1231 39

An affinity purification procedure is employed for the isolation of FL-specific binding proteins from MM6 cell membranes using magnetobeads coated with glycated polylysine and elution with FL and glycated 6-aminocaproic acid. Two main binding proteins were identified as membrane-bound nucleolin and cellular myosin heavy chain, which are glycosylated. This study shows that in these cells binding of short-term glycated albumin leads to activation of PKC, especially its isoform epsilon and this is linked to translocation of AP-1 and NF-kappaB into the nucleus. Consequently, an increased formation of IL-1ss mRNA is observed. The PKC inhibitor GO6976 prevents all these effects. Glycated albumin also stimulates activation of PTK. The PTK inhibitor genistein prevents activation of AP-1 indicating that PTK is also involved in this process, whereas NF-kappaB translocation is only dependent on PKC activation.
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PMID:Binding of Amadori glucose-modified albumin by the monocytic cell line MonoMac 6 activates protein kinase C epsilon protein tyrosine kinases and the transcription factors AP-1 and NF-kappaB. 1244 66

Persistent proteinuria has been indicated to be a major risk factor for the development of tubulointerstitial damage through a process of proinflammatory molecule expression. Monocyte chemoattractant protein-1 (MCP-1) was shown to contribute to recruitment of immune cells into the renal interstitium in acute and chronic renal diseases. However, the molecular mechanisms by which proteinuria causes MCP-1 expression in proximal tubular cells have not been fully clarified. In this study, we examined whether albumin overload-induced MCP-1 expression was regulated by mitogen-activated protein kinase (MAPK) in mouse proximal tubular (mProx) cells. Exposure of mProx cells to delipidated bovine serum albumin (BSA) induced mRNA and protein expression of MCP-1 in a time- and dose-dependent manner. BSA activated extracellular signal-regulated kinase (ERK1/2) and p38 MAPK. The MEK inhibitor U-0126 partially suppressed BSA-induced MCP-1 expression and MCP-1 promoter/luciferase reporter activity. U-0126 also inhibited an increase in nuclear factor-kappaB and activator protein-1 DNA-binding activity of MCP-1 promoter by protein overload in mProx cells. In addition, we found that U-0126 inhibited BSA-induced nuclear factor-kappaB reporter activity and inhibitory protein degradation in mProx cells. In conclusion, these findings indicate that ERK signaling is involved in BSA-induced MCP-1 expression in mProx cells.
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PMID:Involvement of ERK pathway in albumin-induced MCP-1 expression in mouse proximal tubular cells. 1251 35

The establishment of the Norwegian Fractionation Project (Project) was of major importance in preserving national self-sufficiency when plasma, cryoprecipitate and small batch factor IX-concentrates were replaced by virus inactivated products in the last part of the 1980s. Fractionation was performed abroad by contract with Octapharma after tenders on the European market. All Norwegian blood banks (>50) participated in the Project. Total yearly production was 50-60 tons of mainly recovered plasma. From 1993 solvent detergent (SD) treated plasma has replaced other plasma for transfusion. The blood banks paid for the fractionation and/or viral inactivation process, while the plasma remained the property of the blood banks and the final products were returned to the blood banks. The Project sold surplus products to other Norwegian blood banks and the majority of the coagulation factor concentrates to The Institute of Haemophilia and Rikshospitalet University Hospital. Both plasma and blood bank quality was improved by the Project. Clinical experience with the products has been satisfactory and self-sufficiency has been achieved for all major plasma proteins and SD plasma, but a surplus exceeding 3 years consumption of albumin has accumulated due to decreasing clinical use.The Project has secured high yields of the fractionated products and the net income from the produced products is NOK 1115 (140 Euros or US dollars) per litre plasma. An increasing surplus of albumin and the possibility of significant sales abroad of currently not fractionated IVIgG, could lead to a reorganisation of the Project from that of a co-ordinator to a national plasma handling unit. This unit could buy the plasma from the blood banks and have the plasma fractionated by contract after tender, before selling the products back for cost recovery. The small blood banks could produce plasma for products for the Norwegian market, while surplus products from the larger blood banks which are certified for delivery of plasma for fractionation of products to be consumed in the European Community, could be sold on the international market.
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PMID:The Norwegian Plasma Fractionation Project--a 12 year clinical and economic success story. 1262 Feb 74

Although it is known that diabetic nephropathy is accelerated by hypertension, the mechanisms involved in this process are not clear. In this study we aimed to clarify these mechanisms using male Wistar fatty rats (WFR) as a type 2 diabetic model and male Wistar lean rats (WLR) as a control. Each group was fed a normal or high sodium diet from the age of 6 to 14 weeks. We determined the blood pressure and urinary albumin excretion (UAE). At the end of the study, the expressions of mitogen-activated protein kinases (MAPK) and transforming growth factor-beta1 (TGF-beta1) were examined in the isolated glomeruli by Western blot analysis, and the number of glomerular lesions was determined by conventional histology. High sodium load caused hypertension and a marked increase in UAE in the WFR but not in the WLR. Glomerular volume was increased in the hypertensive WFR. There was no difference among the four groups in the expression of c-Jun-NH2-terminal kinase (JNK). In contrast, the expressions of extracellular signal-regulated kinase 1/2 (ERK1/2) and its upstream regulator, MAPK/ERK kinase 1 (MEK1), were augmented in the hypertensive WFR. Expression of p38 MAPK was increased in the normotensive WFR, and further enhanced in the hypertensive WFR. Moreover, administration of high sodium load to WFR augmented the expression of TGF-beta1. In conclusion, systemic hypertension in WFR accelerates the diabetic nephropathy in type 2 diabetes via MEK-ERK and p38 MAPK cascades. TGF-beta1 is also involved in this mechanism.
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PMID:Hypertension accelerates diabetic nephropathy in Wistar fatty rats, a model of type 2 diabetes mellitus, via mitogen-activated protein kinase cascades and transforming growth factor-beta1. 1273 3

Recent experiments have unravelled novel signal transduction pathways that involve the SRC homology 2 (SH2) domain adapter protein SHB. SHB is ubiquitously expressed and contains proline rich motifs, a phosphotyrosine binding (PTB) domain, tyrosine phosphorylation sites and an SH2 domain and serves a role in generating signaling complexes in response to tyrosine kinase activation. SHB mediates certain responses in platelet-derived growth factor (PDGF) receptor-, fibroblast growth factor (FGF) receptor-, neural growth factor (NGF) receptor TRKA-, T cell receptor-, interleukin-2 (IL-2) receptor- and focal adhesion kinase- (FAK) signaling. Upstream of SHB in some cells lies the SRC-like FYN-Related Kinase FRK/RAK (also named BSK/IYK or GTK). FRK/RAK and SHB exert similar effects when overexpressed in rat phaeochromocytoma (PC12) and beta-cells, where they both induce PC12 cell differentiation and beta-cell proliferation. Furthermore, beta-cell apoptosis is augmented by these proteins under conditions that cause beta-cell degeneration. The FRK/RAK-SHB responses involve FAK and insulin receptor substrates (IRS) -1 and -2. Besides regulating apoptosis, proliferation and differentiation, SHB is also a component of the T cell receptor (TCR) signaling response. In Jurkat T cells, SHB links several signaling components with the TCR and is thus required for IL-2 production. In endothelial cells, SHB both promotes apoptosis under conditions that are anti-angiogenic, but is also required for proper mitogenicity, spreading and tubular morphogenesis. In embryonic stem cells, dominant-negative SHB (R522K) prevents early cavitation of embryoid bodies and reduces differentiation to cells expressing albumin, amylase, insulin and glucagon, suggesting a role of SHB in development. In summary, SHB is a versatile signal transduction molecule that produces diverse biological responses in different cell types under various conditions. SHB operates downstream of GTK in cells that express this kinase.
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PMID:The FRK/RAK-SHB signaling cascade: a versatile signal-transduction pathway that regulates cell survival, differentiation and proliferation. 1277 87

Embryonic stem (ES) cells are pluripotent cells derived from the inner cell mass of fertilized blastocysts in vitro. ES cells can be induced to undergo differentiation into potentially all cell types. The aim of this study is to examine the differentiating potential of mouse ES cells into hepatocytes in the presence of retinoic acid (RA), hepatocyte growth factor (HGF), and beta-nerve growth factor (beta-NGF). RA, HGF, and beta-NGF were added to the cell culture. Hepatocyte induction was confirmed morphologically, as well as biochemically, through immunohistochemical assays of alpha1-antitrypsin (alpha1-AT) and alfafetaprotein (AFP) expression and reverse-transcriptase polymerase chain reaction tests for the presence of albumin, transthyretin, glucose 6 phosphates, hepatic nuclear factor 4, and SAPK/ERK kinase-1 (SEK1) messenger RNA, produced only by functioning hepatocytes. Fifteen days after the addition of HGF and beta-NGF to the cell culture, many epithelioid cells were noticed. alpha1-AT, AFP, albumin, transthyretin, glucose 6 phosphates, hepatic nuclear factor 4, and SEK1 messenger RNA expression also was detected, indicating successful ES cell differentiation into functioning hepatocytes. However, in the presence of RA alone, only transthyretin messenger RNA was positive, whereas no other expression pertaining to functioning hepatocytes could be detected. In the presence of HGF and beta-NGF, mouse ES cells can differentiate into functioning hepatocytes, whereas RA function is limited.
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PMID:Generation of hepatocytes from cultured mouse embryonic stem cells. 1452 6

A method for diagnosis of alpha(o)-thalassemia was developed based on detection of accumulated PCR product using SYBR Green I, a double-stranded DNA binding dye, and a fluorescence-detecting thermocycler. Primers were designed to specifically amplify - -SEA and - -Thai deletions of alpha(o)-thalassemia. Albumin was selected as the reference gene. The comparative CT method was used to quantitate the target gene relative to the albumin gene. Dissociation curve analysis was used as a qualitative tool to distinguish different types of alpha(o)-thalassemia. In this study, the melting temperatures of the - -Thai and - -SEA deletions were 83 and 86 degrees C, respectively. Application of the assay for the diagnosis of alpha(o)-thalassemia heterozygotes and homozygotes is reported. The assay is highly robust and amenable to high throughput. It is thus a useful tool for the rapid detection of alpha(o)-thalassemia in populations with a high frequency of alpha(o)-thalassemia, - -SEA and - -Thai deletions.
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PMID:Rapid diagnosis of alpha(o)-thalassemia using the relative quantitative PCR and the dissociation curve analysis. 1464 Nov 39

Normal glomerular filtration depends on the combined properties of the three layers of glomerular capillary wall: glomerular endothelial cells (GEnC), basement membrane, and podocytes. Podocytes produce endothelial factors, including angiopoietin 1 (ang1), and vascular endothelial growth factor (VEGF), whereas GEnC express their respective receptors Tie2 and VEGFR2 in vivo. As ang1 acts to maintain the endothelium in other vascular beds, regulating some actions of VEGF, these observations suggest a mechanism whereby podocytes may direct the unique properties of the glomerular endothelium. This interaction was investigated by studies on the barrier properties of human GEnC in vitro. GEnC were examined for expression of endothelium-specific markers by immunofluorescence and Western blotting and for typical responses to TNF-alpha by a cell-based immunoassay. Expression of angiopoietin and VEGF receptors was examined similarly. Barrier properties of GEnC monolayers cultured on porous supports were investigated by measurement of transendothelial electrical resistance (TEER) and passage of labeled albumin. Responses to a cAMP analogue and thrombin were examined before those to ang1 and VEGF. Results confirmed the endothelial origin of GEnC and their expression of Tie2 and VEGFR2. GEnC formed monolayers with a mean TEER of 30 to 40 Omega/cm(2). The cAMP analogue and thrombin increased and decreased TEER by 34.4 and 14.8 Omega/cm(2), respectively, with corresponding effects on protein passage. Ang1 increased TEER by 11.4 Omega/cm(2) and reduced protein passage by 45.2%, whereas VEGF reduced TEER by 12.5 Omega/cm(2) but had no effect on protein passage. Both ang1 and VEGF modulate GEnC barrier properties, consistent with potential in vivo roles; ang1 stabilizing the endothelium and resisting angiogenesis while VEGF induces the high permeability to water, characteristic of the glomerular endothelium.
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PMID:Angiopoietin 1 and vascular endothelial growth factor modulate human glomerular endothelial cell barrier properties. 1497 58


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