Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of microenvironmental factors on the regulation of intracellular pH (pHi) in MGH U1 cells and EMT-6 cells was studied using the fluorescent pH probe 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein. Na+/H+ exchange and Na(+)-dependent Cl-/HCO3- exchange were found to be present in both cell types. The activity of both exchangers was dependent on pHi, with low levels of activity at neutral pH and an increase in activity as pHi fell. The level of extracellular pH (pHe) also influenced the operation of the exchangers, with a fall in activity as pHe was reduced over the range 7.4-6.6. This effect was more marked for the Na(+)-dependent Cl-/HCO3- exchanger than for the Na+/H+ antiporter, suggesting that under conditions of reduced pHe the Na+/H+ antiporter is the major mechanism for regulation of pHi. Neither 6 h of radiobiological hypoxia nor variations in the extracellular [Ca2+] over the range 1-6 mM had an effect on the regulation of pHi, while extracellular lactate (5-10 mM) caused a small, concentration-dependent decrease in the combined activity of both exchangers. We conclude that under the microenvironmental conditions found in some regions of tumors, Na+/H+ exchange may be the major method of regulation of pHi.
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PMID:Regulation of intracellular pH in tumor cell lines: influence of microenvironmental conditions. 132 90

The effects of uremia-induced chronic acidosis on fractional protein synthesis rate (FSR), degradation (FDR) and protein tissue growth (FRG) in skeletal muscle were examined in young rats fed a 30% protein diet. This diet induced acidosis in UA rats, which was corrected by NaHCO3 supplementation in UB rats. Blood pH and plasma HCO3- were 7.22 +/- 0.01 and 15.2 +/- 0.8 mmol/l in UA rats vs. 7.41 +/- 0.01 and 25.8 +/- 0.9 in UB rats. Both UA and UB groups had similar renal function and food intake. Acidosis impaired weight gain (4.0 +/- 0.3 vs. 5.0 +/- 0.4 g/day, p < 0.05) and length gain (0.31 +/- 0.02 vs. 0.42 +/- 0.02 cm/day, p < 0.001). UA and UB rats showed similar muscle FSR (10.4 +/- 0.5 vs. 10.8 +/- 0.5%/day) and RNA content (6.3 +/- 0.2 vs. 6.2 +/- 0.2 micrograms/g protein). UA rats had lower FGR than UB rats (3.9 +/- 0.8 vs. 5.9 +/- 0.6%/day, p < 0.05). Therefore, muscle FDR was increased in UA rats (6.30 +/- 0.99 vs. 5.10 +/- 0.7%/day).
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PMID:Protein synthesis and growth in uremic rats with and without chronic metabolic acidosis. 146 69

The effect was established of an Eimeria adenoeides infection in turkey-poults on the body temperature and the acid-alkaline balance. Used were a total of 100 turkey-poults at the age of 3 weeks, divided into two groups of 50 each. The birds of the first group were kept as controls, and those of the second group were infected at the rate of 80 000-90 000 oocysts of the Eimeria adenoeides species. During the time of the most strongly manifested clinical symptoms (on the 6th and 7th day) part of the turkey-poults of the second group that exhibited signs of agony were taken away to form a third group. It was found that the body temperature dropped during the time of the most strongly expressed clinical symptoms. An ABL-3 unit (Radiometer, Denmark) was used to record the following blood indices: pH value of blood, PCO2 in mm Hg, PO2 in mm Hg, HCO3 in mmol/l, and BE in mmol/l. It was judged by the values of these indices that up to the fifth day following infection there set in a compensated metabolic acidosis, while on the sixth and the seventh day the metabolic acidosis was already decompensated.
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PMID:[Changes in the acid-base equilibrium of turkey poults infected with Eimeria adenoeides]. 408 94

The changes of the acid-base- and blood-gas parameters were continuously measured during a two-day food abstinence (but fluid intake free of calories) by means of the blood-gas-automaton ABL 1 with the help of 20 test persons. The denutrition causes a decrease of the metabolic components and of the pCO2, but not of the blood-pH and pO2. The decrease of the concentrations of BE (about 2 mmol/l) as well as HCO3 and TCO2 (in each case 2-3 mmol/l) caused by abstain from food are no indication for a therapy.
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PMID:[Effect of food deprivation on acid-base and blood-gas parameters]. 681 80

Mean values of extracellular pH (pHe) in tumours tend to be about 0.5 pH units lower than in normal tissues, whereas values of intracellular pH (pHi) in tumours and normal tissues are similar. Previous studies have shown that drugs that acidify cells at lower pHe such as nigericin, used alone or with agents that inhibit the regulation of pHi, have toxicity to cultured cells at pHe < 6.5 in short-term exposure; these agents also lead to modest anti-tumour effects in mice when given acutely. To evaluate the long-term effects of these drugs at levels of pHe that might occur commonly in tumours, we exposed cells for up to 72h at pHe 6.8 or 7.2 in vitro. Nigericin (0.033 microM) caused time-dependent cell killing of murine KHT and EMT-6 cells at pHe 6.8 (but not at pHe 7.2) with a surviving fraction approximately 5 x 10(-3) after 72 h exposure. Cell killing was increased in the presence of 4,4-diisothiocyanstilbene 2,2-disulphonic acid (DIDS), an inhibitor of Na+-dependent HCO3-/CI- exchange, and to a lesser extent in the presence of 5-(N-ethyl-N-isopropyl) amiloride (EIPA), an inhibitor of Na+/H+ exchange. Cell killing was exquisitely sensitive to the level of pHe. Osmotic pumps were used to obtain a 72 h continuous infusion of nigericin in mice; this led to dose-dependent killing of cells in KHT tumours with surviving fraction of approximately 0.1 at maximum tolerated doses. Hydralazine, which may cause tumour hypoxia and lower pHi as well as pHe, caused cytotoxity when given alone by chronic infusion, and enhanced the cytotoxicity due to nigericin. The addition of DIDS and/or EIPA (using two pumps) further enhanced anti-tumour toxicity, with a surviving fraction of approximately 0.002 at tolerated doses of the four drugs used to treat KHT tumours. The experiments demonstrate the activity of drugs that inhibit the regulation of pHi against murine tumours when delivered by chronic infusion.
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PMID:The chronic administration of drugs that inhibit the regulation of intracellular pH: in vitro and anti-tumour effects. 864 75

Mouse melanoma B16 cells are characterized by the predominant presence of ganglioside GM3 and adhere to lactosylceramide- or Gg3-coated plates through interaction of GM3 with lactosylceramide or Gg3, whereby not only adhesion but also spreading and enhancement of cell motility occur (Kojima, N., Hakomori, S. (1991) J. Biol. Chem. 266, 17552-17558). We now report that the adhesion process is based essentially on a glycosphingolipid-enriched microdomain (GEM) at the B16 cell surface, since >90% of GM3 present in the original cells is found in GEM, and GEM is also enriched in several signal transducer molecules, e.g. c-Src, Ras, Rho, and focal adhesion kinase (FAK). GEM was isolated as a low density membranous fraction by homogenization of B16 cells in lysis buffer under two different conditions (i.e. buffer containing 1% Triton X-100, or hypertonic sodium carbonate without detergent), followed by sucrose density gradient centrifugation. A close association of GM3 with c-Src, Rho, and FAK was indicated by co-immunoprecipitation of GM3 present in GEM by anti-GM3 monoclonal antibody DH2, followed by Western blotting with antibodies directed to these transducer molecules. The following data indicate that GEM is a structural and functional unit for initiation of GM3-dependent cell adhesion coupled with signal transduction. 1) Tyrosine phosphorylation in FAK was greatly enhanced in B16 cells adhered to Gg3-coated plates but was minimal in cells adhered to GM3-coated, GlcCer-coated, or noncoated plates. 2) GTP loading on Ras and Rho increased significantly when cells were adhered to Gg3-coated plates, compared with GM3-coated, GlcCer-coated, or noncoated plates. Since Ras and Rho are closely associated with GM3 in GEM, cell adhesion/stimulation through GM3 in GEM may induce activation of Ras and Rho through enhanced GTP binding.
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PMID:GM3-enriched microdomain involved in cell adhesion and signal transduction through carbohydrate-carbohydrate interaction in mouse melanoma B16 cells. 953 3

The Anion Cl-/HCO3- Exchangers AE1, AE2, and AE3 are membrane pH regulatory ion transporters ubiquitously expressed in vertebrate tissues. Besides relieving intracellular alkaline and CO2 loads, the AEs have an important function during development and cell death and play a central role in such cellular properties as cell shape, metabolism, and contractility. The activity of AE(s) are regulated by neurohormones. However, little is known as to the intracellular signal transduction pathways that underlie this modulation. We show here that, in cardiomyocytes that express both AE1 and AE3, the purinergic agonist, ATP, triggers activation of anion exchange. The AE activation is observed in cells in which AE3 expression was blocked but not in cells microinjected with neutralizing anti-AE1 antibodies. ATP induces tyrosine phosphorylation of AE1, activation of the tyrosine kinase Fyn, and association of both Fyn and FAK with AE1. Inhibition of Src family kinases in vivo by genistein, herbimycin A, or ST638 prevents purinergic activation of AE1. Microinjection of either anti-Cst.1 antibody or recombinant CSK, both of which prevent activation of Src family kinase, significantly decreases ATP-induced activation of AE. Microinjection of an anti-FAK antibody as well as expression in cardiomyocytes of Phe397 FAK dominant negative mutant, also prevents purinergic activation of AE. Therefore, tyrosine kinases play a key role in acute regulation of intracellular pH and thus in cell function including excitation-contraction coupling of the myocardium.
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PMID:Src family tyrosine kinase regulates intracellular pH in cardiomyocytes. 964 55

Five 100 g batches of a carbonate apatite (the intermediate) were produced by heating an aqueous slurry of CaCO3 and CaHPO4 with an overall Ca/P mole ratio of 5/3 with vigorous stirring. Each intermediate produced by boiling off water was heated in vacuum at 1100 degrees C to remove carbonate, then steamed at 900 degrees C to ensure complete hydroxylation. Comparison of calculated and observed X-ray diffraction patterns showed final products containing 50-100 wt% monoclinic hydroxyapatite (remainder hexagonal). Rietveld refinements in P6(3)/m gave structures similar to several hydroxyapatite standards, including NIST SRM 2910, although there was no evidence from X-ray diffraction that the latter was in the monoclinic form. Refinements from standards and final products were slightly different from published single crystal data for Holly Springs hydroxyapatite. This is attributed to known impurities in mineral hydroxyapatite and indicates that parameters from the Rietveld refinements are closer to the true values for pure hydroxyapatite. Rietveld refinements for intermediates showed small, but significant differences from the final product, the largest being in O1x, O2x and O(H)z. All P-O bond lengths were shorter than in the final product, resulting in a 3.2% lower PO4 tetrahedron volume. The occupancies of P and Ca(2) were reduced. These differences are attributed to partial replacement of PO4(3) by CO3(2-) ions.
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PMID:Preparation and characterisation of monoclinic hydroxyapatite and its precipitated carbonate apatite intermediate. 1070 62

The cellular processes involved in metal metabolism in molluscs are reviewed, with emphasis on the contribution of microscopy (AMG, ARG, EPMA, and SIMS) to both basic research of metal cell biology and applied environmental research. In molluscs, metal uptake may occur by facilitated diffusion, active transport, or endocytosis, and can be enhanced by MT synthesis or formation of mineralized granules. In aquatic molluscs, gills constitute a key interface for dissolved metal uptake, where metals are bound to MT, incorporated into lysosomes, and released basally towards the blood plasma and circulating hemocytes. However, particulate metal uptake is mainly achieved via the digestive tract by endocytosis; further metals are transferred first to lysosomes and then to residual bodies, especially in the digestive cells of the digestive gland. Additionally, metals can be accumulated selectively in specific cell types. As ligands pools differ from cell to cell, different metals may be retained in different cell types. Class "a" metals are localized in cells with granules composed of carbonate, oxalate, phosphate, and sulfate (oxygen donors), whereas "b" metals are associated with those cell types rich in sulfur and nitrogen ligands (sulfur donors). In molluscs, oxygen donors occur in connective tissue calcium cells and basophilic cells, whereas sulfur donors are present in digestive cells, podocytes, nephrocytes, and rhogocytes. Hemocytes, which constitute the most relevant system for metal transport between tissues, move around the body and may penetrate tissues and remove metals from the inner medium to be accumulated in lysosomes as nondigested products. Rhogocytes also participate in metal mobilization, accumulation, and release. The assessment of metal levels in target cells of sentinel molluscs by microscopic techniques provides an early-warning measure, with promising applications as an exposure biomarker for environmental monitoring programs.
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PMID:Cellular and subcellular distribution of metals in molluscs. 1187 13

The aim of this study was to verify if the degree of pre-HD acidosis and its correction post-HD is related to body fluid expansion during the interdialytic period. Twelve uremic patients without major problems, with stable hematocrit, with regular and similar HD-session characteristics, but widely varying amounts of body fluid expansion in the interdialytic period were included. Blood samples were collected from arterial line pre- and post-HD, anaerobically in heparinized syringes, for determination of HCO3-, pH and PaCO2 (radiometer Copenhagen ABL 300 Acid-Base Laboratory), in two similar HD-sessions for each patient (12 patients, 24 HD-sessions). The percentage (%) of body weight gain in the interdialytic period was also estimated. For each patient, the mean value of parameters studied in the two HD-sessions was used for the evaluation of findings. According to mean values (+/-SD) of HCO3-, pH and PaCO2 Pre-HD (18.26+/-1.99 mmol/L, 7.31+/-0.03, 36.27+/-2.5 mmHg respectively) and post-HD (26.37+/-1.7, 7.43+/-0.03, 38.43+/-2.10 respectively) patients are acidotic pre-HD and slightly alkalemic post-HD. Correlation between the percentage (%) of interdialytic body weight gain (IBWG) and the values of HCO3-, pH and PaCO2, Pre-HD (r=-0.814, p<0.001; r=-0.931, p<0.001; r=0, 100 NS; respectively) and post-HD (r=-0.958, p<0.001; r=-0.937, p<0.001; r=-0.504 NS; respectively) indicates a significant and negative relationship of IBWG% with HCO3- and pH pre- and post-HD, but not with PCO2. In conclusion, the negative relationship of IBWG% with HCO3- and pH pre- and post-HD indicates that the body fluid expansion during the interdialytic period contributes to a dilutional acidosis pre-HD, but not to a contraction alkalosis post-HD, by the elimination of fluid during the HD-session.
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PMID:Pre-HD dilution acidosis, without post-HD contraction alkalosis in uremic patients. 1265 47


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