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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Structural modifications to the photoinactive benzophenoxazine Nile blue A have led to three novel derivatives which include 5-ethylamino-9-diethylaminobenzo[a]phenoxazinium (EtNBA), 5-ethylamino-9-diethylaminobenzo[a]phenothiazinium (EtNBS), and 5-ethylamino-9-diethylaminobenzo[a]phenoselenazinium (EtNBSe) chlorides. The incorporation of sulfur and selenium into the benzophenoxazine moiety results in lipophilic, red-absorbing (650-660 nm) chromophores which possess significantly increased singlet oxygen yields (0.025 and 0.65, respectively, compared to 0.005 for EtNBA). This study examines the photosensitizing efficacies and pharmacokinetics in vitro in the EMT-6 murine mammary sarcoma cell line as well as the physicochemical, photochemical, and redox properties of these new analogues. Comparisons with Photofrin II, the only photosensitizer available clinically, were made in an attempt to high-light their different pharmacological characteristics. The photodynamic activity of the benzophenoxazine dyes correlates with their ability to generate the phototoxin singlet oxygen and increases in the following order: EtNBA < EtNBS << EtNBSe. At an extracellular dye concentration of 0.5 microM, the light dose required to kill approximately 50% of the cells was 2.0 and < 0.5 J/cm2 for the sulfur and selenium dyes, respectively. The light dose required to kill approximately 50% of the cells for both EtNBA and Photofrin II could not be determined because of their weak phototoxic effect under these conditions. At a light dose of 3.3 J/cm2, EtNBSe is approximately 1000 times more phototoxic than Photofrin II. All three benzophenoxazine derivatives are characterized by a similar uptake/efflux pattern in vitro consisting of a rapid and extensive cellular accumulation followed by a slow efflux rate. Contrary to their rapid uptake, 50% of the accumulated EtNBS and EtNBSe is retained intracellularly after a 6-h period in dye-free medium. Video-enhanced fluorescence microscopy corroborates the rapid uptake measurements as well as indicating the intracellular localization of the dyes in both living and thermally inactivated cells. Low extracellular dye concentrations (0.05 microM) result in a punctate fluorescence pattern in the perinuclear region, while higher dye concentrations (> 0.1 microM) lead to additional fluorescence in the cytoplasm, cytomembranes, and other organelles but apparently not the nucleus. Absorption spectrometry revealed that living cells rapidly reduce the dyes to their colorless leuko form (photoinactive) if oxygen is not readily available in the environment. It is shown that the cellular reduction is an enzymatic process and that an oxygen-free and cell-free medium containing both the coenzyme NADH and the hydride transfer enzyme diaphorase is capable of reducing the dyes to the colorless leuko form.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Phototoxicity, redox behavior, and pharmacokinetics of benzophenoxazine analogues in EMT-6 murine sarcoma cells. 849 21

We performed a side-by-side comparison of the ability of four blood gas analyzers (IL-1312, Corning-178, AVL-995, and ABL-330) to measure PO2 across a wide range under controlled laboratory conditions. Samples of fresh whole human blood, tonometered with analytic quality gas, were prepared with partial pressures of oxygen from 0 to 283 mm Hg. Fifteen determinations were made at 16 levels of tonometric PO2 (tPO2) on each of the four blood gas analyzers. The bias, precision, and root mean squared error (RMSE) of the PO2 measurement relative to tPO2 were determined for each analyzer at each tPO2 level. Mean bias and precision across the range tested were 2.78 +/- 1.29 mm Hg (IL), -0.35 +/- 1.91 (Corning), 2.14 +/- 1.43 (AVL), and 3.00 +/- 1.47 (ABL). RMSE was 3.28, 2.61, 3.57, and 2.41 for IL, AVL, ABL, and Corning, respectively. Percent RMSE (RMSE/tPO2 x 100%), ranged from 0.9% (AVL at 75 mm Hg PO2 and IL at 283 mm Hg tPO2) to 9.1% (IL at 29 mm Hg tPO2). Three analyzers (AVL, ABL, and Corning) showed a statistically significant (p < 0.0001) correlation between RMSE and tPO2, and no correlation between percent RMSE and tPO2. This demonstrates that, for these instruments, accuracy is a function of the magnitude of the tPO2 value. IL did not show a significant correlation between RMSE and tPO2 but did demonstrate a significant negative correlation (r = -0.78, p > 0.001) between percent RMSE and tPO2, indicating that, for this analyzer, accuracy is not a function of tPO2. The differences in PO2 measurements between pairs of analyzers were also examined.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Performance characteristics and interanalyzer variability of PO2 measurements using tonometered human blood. 850 45

The ability of the antiangiogenic agents TNP-470 and minocycline, singly or in combination, to potentiate the antitumor effects of several cytotoxic therapies was assessed in the murine EMT-6 mammary carcinoma as well as in two drug resistant sublines of that tumor designated EMT-6/CTX and EMT-6/CDDP. The antiangiogenic agents alone or in combination did not alter the growth of the tumors. However, their administration along with cyclophosphamide, CDDP, or thiotepa substantially increased the tumor growth delay produced by these cytotoxic therapies in tumors responsive to the drugs--the increase was about 2-fold for TNP-470 and minocycline together. In drug resistant tumors, treatment with the antiangiogenic agents did not reverse drug resistance but did increase the effect of the cytotoxic drugs. Treatment with TNP-470/minocycline also increased the oxygenation of each of the three tumors. Thus, TNP-470/minocycline administration increased the efficacy of fractionated radiation therapy, especially when used along with a perflubron emulsion oxygen delivery agent/carbogen. These results indicate that treatment regimens including therapies directed toward the proliferating normal cells within a tumor mass as well as therapies directed toward the malignant cells can produce improved outcomes.
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PMID:Potentiation of cytotoxic therapies by TNP-470 and minocycline in mice bearing EMT-6 mammary carcinoma. 853 70

To obtain information about the relationship between different types of circulatory insufficiency, a series of oxygen parameters and plasma lactate, we have performed a pilot study comprising five patients with circulatory insufficiency. Plasma lactate was measured on a Stat Profile 7 (NOVA Biomedical, USA) and pH/blood gases on an ABL 520 (Radiometer Medical A/S, Denmark). Plasma lactate seems to be inversely related to base excess (BE), whereas no relationship to venous oxygen tension pO2(v) of the vein draining the inadequately perfused region seemed to exist. In one patient we made simultaneous measurements from v. cava inferior., v. cava superior., a. pulmonalis and a. radialis. Simultaneously sampled plasma lactate from different sites differed up to 0.6 mmol/L with the highest value obtained from v. cava inferior. This pilot study indicates that the increase of plasma lactate may vary with the type of circulatory disturbance and the sampling site.
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PMID:Lactate, pH, and blood gas analysis in critically ill patients. 859 89

Distal transcutaneous oxygen pressure measurement (TcPo2) is a noninvasive method of evaluating tissular hypoxemia in peripheral arterial disease. The poststress area of hypoxemia is a usefull technique for globally quantifying different parameters represented by TcPo2 curves during exercise. Although its use is increasingly widespread, the reproducibility of this method is poorly documented. TcPo2 was monitored three times at twenty-four hour intervals in 5 patients with stage II obliterative arterial disease during a treadmill walking test. In order to get uniform measurement conditions, each patient remained lying and then stood until TcPo2 became stable. The stress duration was calculated so that the pain step could not be reached. TcPo2 curves were digitized and a specific image analyzer was used to make replicate measurements. The area under the curve was computed, the horizontal axis determining the mean TcPo2 value at rest, the vertical axis representing the end of the exercise period. The corresponding areas under the curves ranged from 34 to 2212 mm2 (573.60; SD 826). Significant correlation coefficients were obtained among replicate measurements (first-second day, first-third day). However, owing to the wide range of area values, the authors decided to compute and use the coefficient of variation (STD/mean), since it was more representative of reproducibility. The mean of its value for 5 patients was 21%. Observation of the examination conditions resulted in several findings, especially the ability of certain patients to adapt their efforts to the exercise. These results indicate that TcPo2 poststress area measurements are reproducible, but the conditions of the exercise have to be rigorously defined and may still be improved.
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PMID:TcPo2 measurement reproducibility during stress in stage II obliterative arterial disease. 861 4

N-isopropyl-p[123I]iodoamphetamine (IMP) has been used as a flow tracer for SPECT, and measurement of cerebral blood flow (CBF) using IMP has been performed by conventional microsphere model method (MS method). Recently, the ARG method for measuring CBF by using IMP with one SPECT scan and one point blood sampling has been developed. This method was based on two-compartment model. In the present study, normal CBF values were measured in ten male healthy subjects (mean age +/- S.D.: 29.8 +/- 6.01, age range: 23-41) by the ARG and the MS methods. The mean CBF values (+/- S.D.) for the ARG method in which the Vd value was assumed to be 50 ml/ml were 41.7 +/- 9.4, 31.1 +/- 5.0, 40.7 +/- 9.7, 41.5 +/- 10.0, 38.2 +/- 9.2, 39.0 +/- 9.4, 41.9 +/- 10.6, 38.7 +/- 8.0 and 30.0 +/- 7.7 ml/100 ml/min in the cerebellum, pons, thalamus, basal ganglia, frontal, temporal, parietal, occipital lobe cortex and centrum semiovale, respectively. The mean CBF values for the MS method were 46.8 +/- 8.4, 37.5 +/- 5.6, 45.8 +/- 8.6, 46.5 +/- 8.9, 43.7 +/- 8.3, 44.4 +/- 8.7, 46.8 +/- 9.3, 44.3 +/- 7.3 and 36.3 +/- 8.1 ml/100 ml/min, respectively. The mean CBF values in the cerebral cortex region for the ARG method were lower than those previously reported by PET. This would be caused by low first-pass extraction fraction of IMP compared with oxygen-15 labeled water. The mean CBF values for the MS method were higher than those for the ARG method against previous studies. As reasons for this, errors in estimation of the SPECT brain counts at 8 min in the MS method were considered.
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PMID:[Normal CBF values by the ARG method using IMP SPECT: comparison with a conventional microsphere model method]. 872 Nov 6

A newly developed water-soluble phosphor suitable for measuring oxygen pressure in the blood (Green 2W) was used for noninvasive, in vivo imaging of oxygen distribution in the vascular systems of mice. Oxygen quenches the phosphorescence of Green 2W, measured in the presence of 2% albumin, according to the Stern-volmer relationship. This oxygen-dependent quenching of phosphorescence has been used to obtain digital maps of the oxygen distribution in the tissue vasculature. EMT-6 mammary carcinoma tumors were grown by injecting 1 x 10(6) cells in 0.1-ml carrier into the subcutaneous space over the muscle on the hindquarter. When the tumors were approximately 8 mm in diameter, 300 micrograms of phosphorescence probe (Green 2W; absorption maximum 636 nm) was injected into the tail vein. The mice were immobilized with intraperotoneal Ketamine (133 mg/kg) and Xylazine (10 mg/kg) and illuminated with flashes (< 4-microseconds t1/2) of light of 630 +/- 12 nm. The emitted phosphorescence (790-nm maximum) was imaged an intensified CCD camera. Images were collected beginning at 30, 50, 80, 120, 180, 240, 420, and 2500 microseconds after the flash and used to calculate digital maps of the phosphorescence lifetimes and oxygen pressure. Both the illumination light and the phosphorescence were in the near-infrared region of the spectrum, where tissue has greatly decreased absorbance. The light therefore readily passed through the skin and centimeter thicknesses of tissue. The oxygen maps could be obtained by illuminating from the side of the mouse opposite the camera (and tumor). The tumors were readily observed as regions with oxygen pressures substantially below those of the surrounding tissue. Thus, phosphorescence measurements can noninvasively detect volumes of tissue with below-normal oxygen pressure in the presence of much larger volumes of tissue with normal oxygen pressures. In addition, tissue oxygen pressures can be monitored in real time, even through centimeter thicknesses of tissue.
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PMID:Noninvasive imaging of the distribution in oxygen in tissue in vivo using near-infrared phosphors. 878 20

Reactive oxygen species are autocrine and paracrine modulators of cell behavior. Hydrogen peroxide, a cellular oxidant, has been shown to stimulate mesangial cell proliferation. In the present study we analyzed the H2O2-induced early signaling events. Immunofluorescence analysis revealed a H2O2 induced dose-dependent increase in tyrosine phosphorylation. Short treatment (2 or 5 min) with 5 mM H2O2 induced a mitogenic response and a significant (P < 0.01) increase in the number of cells compared to non-treated controls. Proteins extracted from H2O2 (0.1 to 10 mM) treated cells were separated on SDS-PAGE and subjected to immunoblot analysis with anti-phosphotyrosine. A dose-dependent induction of tyrosine phosphorylation of 180 kDa, 120 kDa and 60 kDa proteins was observed within 1 to 10 minutes. By sequentially using immunoprecipitation and immunoblotting the 180 kDa tyrosine phosphorylated band was shown to represent both PDGF alpha- and beta-receptors. The tyrosine phosphorylated 60 kDa protein was identified as the cytoplasmic protein tyrosine kinase pp60c-src. The c-src phosphorylation was associated with an inhibition of c-src kinase activity, suggesting phosphorylation of tyrosine 527 in the c-src regulatory domain. Pretreatment with catalase completely abrogated the H2O2-induced PDGF receptor and c-src tyrosine phosphorylation. These data support the notion that the activation of a signaling pathway involving the PDGF receptors and c-src contributes to the mitogenic effects of reactive oxygen species.
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PMID:Oxidative stress induces tyrosine phosphorylation of PDGF alpha-and beta-receptors and pp60c-src in mesangial cells. 880 85

To investigate whether the exercise intensity affects sweating efficiency (eta sw) during exercise under mild environmental conditions, six healthy males, aged 22 +/- 2 years, performed three bicycle ergometer exercises at varying intensities (73W: Ex-1, 103W: Ex-2 and 133W: Ex-3) for 40 min under the conditions of 25 degrees C room temperature, 50% relative humidity and 0.3-0.4 m s-1 wind velocity. Heart rate, oxygen consumption, rectal temperature (Tre), mean skin temperature (Tsk; 4 skin sites) and total sweat rate were determined intermittently throughout the experiments. Moreover, heat loss by evaporation (E), radiation (R), convection (C) and eta sw were calculated using the heat balance equations. The findings concerning thermoregulatory parameters under the three experimental conditions were summarized as follows: (1) the higher the exercise intensity, the larger the values of Tre and Tsk at the end of exercise and E, R and C during exercise (2) the mean values +/- SE of eta sw were 55.4 +/- 5.1, 63.2 +/- 5.2 and 58.5 +/- 1.9% for Ex-1, Ex-2 and Ex-3, respectively. The results suggest that exercise intensity would have no effect on eta sw in this mild thermal environment.
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PMID:The influence of exercise intensity on sweating efficiency of the whole body in a mild thermal condition. 885 27

The purpose was to investigate the mechanism for the excessive exercise hyperthermia following deconditioning (reduction of physical fitness). Rectal (Tre) and mean skin (Tsk) temperatures and thermoregulatory responses were measured in six men [mean (SD) age, 32 (6) years; mass, 78.26 (5.80) kg; surface area, 1.95 (0.11) m2; maximum oxygen uptake (VO2max), 48 (6) ml.min-1.kg-1; whilst supine in air at dry bulb temperature 23.2 (0.6) degree C, relative humidity 31.1 (11.1)% and air speed 5.6 (0.1) m.min-1] during 70 min of leg cycle exercise [51 (4)% VO2max] in ambulatory control (AC), or following 6 h of chair rest (CR), 6 degree head-down bed rest (BR), and 20 degree (WI20) and 80 degree (WI80) foot-down water immersion [water temperature, 35.0 (0.1) degree C]. Compared with the AC exercise delta Tre [mean (SD) 0.77 (0.13) degree C (*P < 0.05), after WI80 0.96 (0.13) degree C*, and after WI20 1.03 (0.09) degree C*. All Tsk responded similarly to exercise: they decreased (NS) by 0.5-0.7 degree C in minutes 4-8 and equilibrated at +0.1 to +0.5 degree C at 60-70. Skin heat conductance was not different among the five conditions (range = 147-159 kJ.m-2.h-1.degree C-1). Results from an intercorrelation matrix suggested that total body sweat rate was more closely related to Tre at 70 min (Tre70) than limb sweat rate or blood flow. Only 36% of the variability in Tre70 could be accounted for by total sweating, and less than 10% from total body dehydration. It would appear that multiple factors are involved which may include change in sensitivity of thermo- and osmoreceptors.
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PMID:Exercise thermoregulation after 6 h of chair rest, 6 degrees head-down bed-rest, and water immersion deconditioning in men. 885 98


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