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Biomedical subjects

Y Huang

Publications and source records attributed to Y Huang.

At least 595 records · Page 33Linked to original sources
PubMed1998

Activation of protein kinase C delta by the c-Abl tyrosine kinase in response to ionizing radiation.

The c-Abl protein tyrosine kinase is activated by ionizing radiation (IR) and certain other DNA-damaging agents. The present studies demonstrate that c-Abl associates constitutively with protein kinase C delta (PKCdelta). The results show that the SH3 domain of c-Abl interacts directly with PKCdelta. c-Abl phosphorylates and activates PKCdelta in vitro. We also show that IR treatment of cells is associated with c-Abl-dependent phosphorylation of PKCdelta and translocation of PKCdelta to the nucleus. These findings support a functional interaction between c-Abl and PKCdelta in the cellular response to genotoxic stress.

Cesium Radioisotopes↗
PubMed1998

Bcr-Abl exerts its antiapoptotic effect against diverse apoptotic stimuli through blockage of mitochondrial release of cytochrome C and activation of caspase-3.

Bcr-Abl expression in leukemic cells is known to exert a potent effect against apoptosis due to antileukemic drugs, but its mechanism has not been elucidated. Recent reports have indicated that a variety of apoptotic stimuli cause the preapoptotic mitochondrial release of cytochrome c (cyt c) into cytosol, which mediates the cleavage and activity of caspase-3 involved in the execution of apoptosis. Whether Bcr-Abl exerts its antiapoptotic effect upstream to the cleavage and activation of caspase-3 or acts downstream by blocking the ensuing degradation of substrates resulting in apoptosis, has been the focus of the present studies. In these, we used (1) the human acute myelogenous leukemia (AML) HL-60 cells that are stably transfected with the bcr-abl gene (HL-60/Bcr-Abl) and express p185 Bcr-Abl; and (2) the chronic myelogenous leukemia (CML)-blast crisis K562 cells, which have endogenous expression of p210 Bcr-Abl. Exposure of the control AML HL-60 cells to high-dose Ara-C (HIDAC), etoposide, or sphingoid bases (including C2 ceramide, sphingosine, or sphinganine) caused the accumulation of cyt c in the cytosol, loss of mitochondrial membrane potential (MMP), and increase in the reactive oxygen species (ROS). These preapoptotic events were associated with the cleavage and activity of caspase-3, resulting in the degradation of poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) and DNA fragmentation factor (DFF), internucleosomal DNA fragmentation, and morphologic features of apoptosis. In contrast, in HL-60/Bcr-Abl and K562 cells, these apoptotic stimuli failed to cause the cytosolic accumulation of cyt c and other associated mitochondrial perturbations, as well as the failure to induce the activation of caspase-3 and apoptosis. While the control HL-60 cells showed high levels of Bcl-2 and barely detectable Bcl-xL, HL-60/Bcr-Abl cells expressed high levels of Bcl-xL and undetectable levels of Bcl-2, a pattern of expression similar to the one in K562 cells. Bax and caspase-3 expressions were not significantly different between HL-60/Bcr-Abl or K562 versus HL-60 cells. These findings indicate that Bcr-Abl expression blocks apoptosis due to diverse apoptotic stimuli upstream by preventing the cytosolic accumulation of cyt c and other preapoptotic mitochondrial perturbations, thereby inhibiting the activation of caspase-3 and execution of apoptosis.

Antineoplastic Agents↗
PubMed1998

Regulation of Rad51 function by c-Abl in response to DNA damage.

The Rad51 protein, a homolog of bacterial RecA, functions in DNA double-strand break repair and genetic recombination. Whereas Rad51 catalyzes ATP-dependent pairing and strand exchange between homologous DNA molecules, regulation of this function is unknown. The c-Abl tyrosine kinase is activated by ionizing radiation and certain other DNA-damaging agents. Here we demonstrate that c-Abl interacts constitutively with Rad51. We show that c-Abl phosphorylates Rad51 on Tyr-54 in vitro. The results also show that treatment of cells with ionizing radiation induces c-Abl-dependent phosphorylation of Rad51. Phosphorylation of Rad51 by c-Abl inhibits the binding of Rad51 to DNA and the function of Rad51 in ATP-dependent DNA strand exchange reactions. These findings represent the first demonstration that Rad51 is regulated by phosphorylation and support a functional role for c-Abl in regulating Rad51-dependent recombination in the response to DNA damage.

Cell Line↗
PubMed1998

Involvement of endothelium in relaxant action of glibenclamide on the rat mesenteric artery.

The present report describes the complex effect of glibenclamide, an antidiabetic sulfonylurea agent, on the rat isolated mesenteric artery. Although glibenclamide concentration dependently reversed the relaxant effect of pinacidil, an activator of ATP-sensitive K+ channels (the concentration for half-maximum reversal effect was 0.56 microM with endothelium and 0.17 microM without endothelium), in the artery precontracted with phenylephrine (1 microM), it relaxed phenylephrine-induced sustained contraction at higher concentrations (IC50: 4.4+/-1.1 microM with endothelium and 226.1+/-44.2 microM without endothelium). The relaxant effect of glibenclamide was partially inhibited by pretreatment of the artery with either NG-nitro-L-arginine (10-100 microM) or methylene blue (1 microM). Indomethacin (10 microM) had no effect. Moreover, glibenclamide also concentration dependently (3-500 microM) reduced the sustained contraction induced by 60 mM K+ (IC50: 99.5+/-16.1 microM). The relaxation induced by glibenclamide was not affected by various putative K+ channel blockers such as charybdotoxin (100 nM), tetraethylammonium ions (1 mM), apamin (100 nM) and 4-aminopyridine (1 mM). The results indicate an involvement of the endothelium, probably of nitric oxide, in the relaxation induced by glibenclamide in the endothelium-intact rat mesenteric arteries. The inhibitory effect of glibenclamide on the high-K+-induced contraction suggests that glibenclamide may interfere with Ca2+ influx, which in turn affects intracellular Ca2+ levels in arterial smooth muscle, leading to reduction of muscle contractility. It is suggested that two distinct pharmacological effects induced by glibenclamide may be mediated through different glibenclamide binding sites, however, the data show an overlap of concentrations of glibenclamide for producing the two effects in rat isolated mesenteric arteries.

Animals↗
PubMed1998

Characterization of gag and pol sequences from long-term survivors of human immunodeficiency virus type 1 infection.

We previously identified a group of 10 long-term survivors (LTS) of human immunodeficiency virus type 1 (HIV-1) infection. Extensive biological analysis revealed that some of these individuals do well, at least in part, because they possess weakened or attenuated viruses. Also, previously, to determine the genotype associated with the attenuated phenotype in vivo, we characterized nef, vif, vpr, vpu, env, and LTR in our cohort of LTS. In this study, we analyzed gag and pol genes derived from eight individuals in our cohort. For each subject multiple full-length gag and pol clones were obtained for analysis. In most cases, the sequences derived from the LTS had an intact open reading frame. At the protein level, there were no discernible differences between the sequences derived from LTS and those derived from patients with AIDS. Thus, no common defect in gag and pol was found in our cohort. One individual (subject SF), however, had only Gag-defective proviral sequences (10 of 10) in his peripheral blood mononuclear cells. Furthermore, longitudinal studies of the samples collected from SF over a 2-year period showed that all p17 gag clones sequenced (24 of 24) were defective due to G-to-A hypermutations. This viral defect in Gag may provide the molecular basis for this individual's extremely low viral load and long-term asymptomatic state. These results, together with previous findings in our LTS cohort, reinforce the notion that it is unlikely that a single common viral genetic determinant accounts for the lack of disease progression in all cases. Multiple host and viral factors undoubtedly contribute to the well-being of LTS of HIV-1 infection.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Large molecule and particulate uptake in the nasal cavity: the effect of size on nasal absorption.

One of the characteristics influencing the increased interest in the nasal cavity as a site for systemic drug delivery is the ability of large molecules to permeate through the nasal mucosa into the systemic circulation. Compilations of data regarding the absorption of large therapeutic agents, peptides and proteins in particular, along with more systematic studies using polymeric compounds have shown that for compounds larger than 1000 Da, bioavailability can be directly predicted from a knowledge of molecular weight. In general, the bioavailability of these large molecules ranges from 0.5 to 5%. Particulate uptake also occurs in the nasal mucosa, and particles up to approximately 1 µm have been shown to rapidly enter the bloodstream following intranasal administration. The unique barrier properties of this mucosal delivery site give it great promise as a route for the systemic administration of large molecules.

Journal Article↗
PubMed1998

Studies on the cyanobacterial family C DNA polymerase.

Our studies showed that family C DNA polymerase (pol III) of the cyanobacterium Synechocystis sp. strain PCC 6803 is phylogenetically close to the Gram-negative dna E group, rather than to the Gram-positive group. However, in contrast to the dna E genes of most of the eubacteria, the cyanobacterial dna E gene has split into two genes, dna E1 and dna E2. The evolutionary origin of the split dna E gene is discussed.

Cyanobacteria↗
PubMed1998

Contrasting behavior of pentafluorophenoxyacetone and pentafluorobenzyloxyacetone in electron impact and electron capture mass spectrometry.

Towards the goal of finding new ketone electrophores suitable as molecular labels for electrophoric release tags, pentafluorophenoxyacetone (1) and pentafluorobenzyloxyacetone (2) were prepared. Both ketones were evaluated by electron capture (EC) and electron impact (EI) modes of mass spectrometry (MS). By EC-MS, 1 nearly gave a single ion (as desired), whereas 2 gave many ions. This behavior was completely reversed in EI-MS. To account for certain ion fragments in the EC mass spectrum of 2, an anion radical McLafferty-type rearrangement and loss of a carbene neutral were postulated. Electron impact of 1 gave an abundant ion at m/z 117 (C5F3+), which was suggested to be a diyne cation.

Acetone↗
PubMed1998

Test-retest variability of serotonin 5-HT2A receptor binding measured with positron emission tomography and [18F]altanserin in the human brain.

The role of serotonin in CNS function and in many neuropsychiatric diseases (e.g., schizophrenia, affective disorders, degenerative dementias) support the development of a reliable measure of serotonin receptor binding in vivo in human subjects. To this end, the regional distribution and intrasubject test-retest variability of the binding of [18F]altanserin were measured as important steps in the further development of [18F]altanserin as a radiotracer for positron emission tomography (PET) studies of the serotonin 5-HT2A receptor. Two high specific activity [18F]altanserin PET studies were performed in normal control subjects (n = 8) on two separate days (2-16 days apart). Regional specific binding was assessed by distribution volume (DV), estimates that were derived using a conventional four compartment (4C) model, and the Logan graphical analysis method. For both analysis methods, levels of [18F]altanserin binding were highest in cortical areas, lower in the striatum and thalamus, and lowest in the cerebellum. Similar average differences of 13% or less were observed for the 4C model DV determined in regions with high receptor concentrations with greater variability in regions with low concentrations (16-20%). For all regions, the absolute value of the test-retest differences in the Logan DV values averaged 12% or less. The test-retest differences in the DV ratios (regional DV values normalized to the cerebellar DV) determined by both data analysis methods averaged less than 10%. The regional [18F]altanserin DV values using both of these methods were significantly correlated with literature-based values of the regional concentrations of 5-HT2A receptors determined by postmortem autoradiographic studies (r2 = 0.95, P < 0.001 for the 4C model and r2 = 0.96, P < 0.001 for the Logan method). Brain uptake studies in rats demonstrated that two different radiolabeled metabolites of [18F]altanserin (present at levels of 3-25% of the total radioactivity in human plasma 10-120 min postinjection) were able to penetrate the blood-brain barrier. However, neither of these radiolabeled metabolites bound specifically to the 5-HT2A receptor and did not interfere with the interpretation of regional [18F]altanserin-specific binding parameters obtained using either a conventional 4C model or the Logan graphical analysis method. In summary, these results demonstrate that the test-retest variability of [18F]altanserin-specific binding is comparable to that of other PET radiotracers and that the regional specific binding of [18F]altanserin in human brain was correlated with the known regional distribution of 5-HT2A receptors. These findings support the usefulness of [18F]altanserin as a radioligand for PET studies of 5-HT2A receptors.

Adult↗
PubMed1998

Solution structure of the His12 --> Cys mutant of the N-terminal zinc binding domain of HIV-1 integrase complexed to cadmium.

The solution structure of His12 --> Cys mutant of the N-terminal zinc binding domain (residues 1-55; IN(1-55)) of HIV-1 integrase complexed to cadmium has been solved by multidimensional heteronuclear NMR spectroscopy. The overall structure is very similar to that of the wild-type N-terminal domain complexed to zinc. In contrast to the wild-type domain, however, which exists in two interconverting conformational states arising from different modes of coordination of the two histidine side chains to the metal, the cadmium complex of the His12 --> Cys mutant exists in only a single form at low pH. The conformation of the polypeptide chain encompassing residues 10-18 is intermediate between the two forms of the wild-type complex.

Binding Sites↗
PubMed1998

Unsolved problems in comparing brain sizes in Homo sapiens.

When brain size is compared across taxonomic levels, there is a clear relation between body parameters and brain size. It is generally stated that the correlation between brain size and body parameters becomes very small at the species level (Aboitiz, 1996), but this is not the case for Homo sapiens where there is a strong correlation between brain size and body size across racial groups that differ in body size. The control for body size across racial groups (and sexes) is rendered difficult because bodies do not just differ only in height and weight. Within groups different studies show weak and inconsistent brain size/body height correlations. A better understanding of brain size/body height relations must await better quality data and a better understanding of how exactly body parameters should be scaled between groups and sexes. We attribute the clear between-group and weak within-group correlations to the large variety of body sizes and body types in our species, a variety which is only equalled in selectively bred species of animals. At present, there is no meaningful basis for the comparison of brain sizes within and between racial groups and sexes.

Adult↗
PubMed1998

Whole body autoradiographic study on the distribution of 14C-D-serine administered intravenously to rats.

The distribution of radioactivities in rats following intravenous administration of 14C-D- or -L-serine was investigated by whole body autoradiography. The radioactivities were distributed throughout the whole body in both cases with the greatest amount being found in the pancreas. D- and L- Serine levels in the pancreas were determined by high-performance liquid chromatography with a chiral column which revealed, for the first time, the existence of D-serine in the rat pancreas (12.6 +/- 7.90 nmol/g wet tissue) together with a much higher concentration (924 +/- 116 nmol/g) of L-serine. The results suggested that exogenous D-serine of dietary origin contributed at least in part to the D-serine levels found in mammalian tissues. The accumulation of radioactivity in the kidney, especially in the corticomedullary area, even at 24 hr after administration of 14C-D-serine suggested a possible link between acute necrosis of the renal proximal tubules and the administration of a large dose of D-serine [Am J Pathol 77: 269-282 (1974)].

Animals↗
PubMed1998

Effect of aprotinin on the red cell immunity in cardiopulmonary bypass.

To investigate the effects of aprotinin on red cell (RC) immune function in the patients undergoing cardiopulmonary bypass (CPB), 20 patients who received valve replacement procedure were prospectively studied. The patients were randomly assigned to aprotinin group and control group. Red blood cell C3b receptor ratio (RC3bRR), red blood cell immune-component ratio (RICR), plasma C3, C4, CH50 and IgG level were determined before operation, at the end of CPB and 1st, 3rd, 7th postoperative days. Our results showed that: (1) The blood requirement was reduced in aprotinin group. (2) After bypass, plasma C3, C4, CH50 was maintained in aprotinin group, while they declined in control group. (3) Plasma level IgG fell in both groups, but at 7th postoperative day it recovered in aprotinin group while the level stayed at low level in control group. (4) The RC3bRR and RICR was mildly inhibited in aprotinin group. It is concluded that the impairment of RC immune function caused by CPB can be mitigated by aprotinin, which may be related to the effects of aprotinin in blood sparing, restriction of complement activation, and reduction of blood requirement which could mitigate the non-specific inflammatory reaction.

Adjuvants, Immunologic↗
PubMed1998

Focal grey matter heterotopias in monozygotic twins with developmental language disorder.

UNLABELLED: We describe 9-year-old monozygotic male twins with a developmental language disorder of the phonologic-syntactic type and learning difficulties. High-resolution MRI revealed bilateral parieto-temporal grey matter heterotopias in both twins, on the left more than on the right, and more pronounced in the more affected twin. This suggests a causal relationship between the heterotopias and the neuropsychological findings in this twin pair. CONCLUSION: Neuronal migration defects and ensuing focal heterotopias may be causally related to developmental language disorders.

Cerebral Cortex↗
PubMed1998

Lipid-free apolipoprotein (apo) A-I is converted into alpha-migrating high density lipoproteins by lipoprotein-depleted plasma of normolipidemic donors and apo A-I-deficient patients but not of Tangier disease patients.

Plasma of patients with Tangier disease (TD) is devoid of alpha-LpA-I (apolipoprotein A-I-containing lipoprotein), which in normolipidemic plasma constitutes the majority of high density lipoprotein (HDL). The residual amounts of apolipoprotein A-I (apo A-I) in TD plasma have electrophoretic prebeta1-LpA-I mobility. We have previously demonstrated that TD plasma does not convert prebeta1-LpA-I into alpha-LpA-I. In this study we found that plasmas of normolipidemic controls, apo A-I-deficient patients and patients with fish-eye disease, but not plasmas of six TD patients, convert biotinylated lipid-free apo A-I into alpha-LpA-I. Supplementation of plasma with free oleic acid or fatty acid free albumin neither inhibited conversion activity in normal plasmas nor reconstituted it in TD plasma. In normal plasma the conversion activity was assessed in HDL and in the lipoprotein-free fraction. The latter fraction, however, generated larger particles only in the presence of exogenous phospholipid vesicles. To obtain particles with alpha-mobility, these vesicles had to contain phosphatidylinositol and/or cholesterol. Lipoprotein-depleted TD plasma did not convert lipid-free apo A-I into alpha-LpA-I even in the presence of exogenous vesicles with phospholipids or cholesterol. Taken together we conclude that disturbed transfer of glycerophospholipds onto apo A-I or prebeta1-LpA-I prevents maturation of HDL and thereby possibly causes deficiency of HDL cholesterol in patients with TD. Moreover, the lack of alpha-LpA-I in TD plasma together with its failure to convert exogenous apo A-I into an alpha-migrating particle provide specific tests for the diagnosis of TD.

Adult↗
PubMed1998

Improved efficiency of energy transfer to external work in chronic cardiomyoplasty based on the pressure-volume relationship.

OBJECTIVE: Cardiomyoplasty is a surgical procedure to support the failing heart, in which a burst-stimulated latissimus dorsi muscle flap is transposed and wrapped around the ventricles. The effect of dynamic cardiac compression, implemented as cardiomyoplasty, on left ventricular performance remains controversial; the mechanism by which clinical symptoms are improved remains unclear. To investigate the mechanism for improvement of patients' symptoms, it is important to evaluate the effects of cardiomyoplasty on left ventricular energetics and on left ventricular systolic and diastolic function. We therefore evaluated the efficiency of energy transfer from the native pressure-volume area to external work under conditions of 1:3 skeletal muscle burst pacing in an animal model with chronic heart failure. METHODS: In seven Merino-Wether sheep, cardiomyoplasty was performed after stable heart failure was induced by staged coronary embolizations (ejection fraction < 35%). Hemodynamic assessment including the assessment of the pressure-volume relationship was performed 8 weeks after cardiomyoplasty when the latissimus dorsi muscle was fully trained. Instantaneous left ventricular pressure and volume were measured with a catheter-tipped manometer and a conductance catheter during steady-state conditions and after a transient inferior vena cava occlusion. The effect of dynamic cardiac compression on left ventricular systolic function was assessed by comparing pre-assisted and assisted beats and on diastolic function by comparing assisted and post-assisted beats. RESULT: The slope of the end-systolic pressure-volume relationship decreased by 30.5% +/- 27.8% (p = 0.02) during assisted beats. However, left ventricular pump performance improved by increasing stroke volume and external work by 35.9% +/- 36.0% (p = 0.03) and 9.7% +/- 6.8% (p = 0.03), respectively, resulting in a reduction of the volume intercept. As a result, the end-systolic pressure-volume relationship shifted to the left. The efficiency of energy transfer from the native pressure-volume area to the overall external work improved by 7.6% +/- 8.2% (p = 0.04). Cardiomyoplasty did not affect the time constant of left ventricular isovolumic pressure decline or the maximal rate of pressure decay, which suggested that cardiomyoplasty did not affect left ventricular relaxation. CONCLUSIONS: Dynamic cardiac compression in the form of cardiomyoplasty enhanced left ventricular pump performance without interrupting left ventricular filling. The ratio of energy transfer from the native pressure-volume area to the overall external work suggests a myocardial oxygen-sparing effect of cardiomyoplasty.

Animals↗
PubMed1998

Beta-adrenoceptor-mediated relaxation inhibited by tetrapentylammonium ions in rat mesenteric artery.

The aim of this study was to examine the contribution of K+ channel activation to beta-adrenoceptor-mediated relaxation in rat mesenteric arteries. Isoprenaline and fenoterol concentration-dependently relaxed the phenylephrine-preconstricted endothelium-intact arteries of the rat with EC50 values of 0.26 +/- 0.03 microM and 0.87 +/- 0.12 microM, respectively. Beta-adrenoceptor-mediated relaxation was significantly attenuated upon removal of endothelium. Tetrapentylammonium ions (TPA+) at low concentrations (1-5 microM) inhibited relaxations induced by beta-adrenoceptor agonists in arteries with and without endothelium, while glibenclamide (3 microM) had no effect. TPA+ (5 microM) inhibited isoprenaline-induced relaxation in the presence of either iberiotoxin (100 nM) or glibenclamide (3 microM). TPA+ did not alter forskolin-induced relaxation. In the presence of 60 mM extracellular K+, the relaxations induced by two agonists were reduced in endothelium-intact arteries and abolished in endothelium-denuded arteries. The present results suggest that the activation of TPA+-sensitive K+ channels contributes toward the relaxations mediated through beta- and beta2-adrenoceptor stimulation in rat mesenteric arteries.

Adrenergic beta-Agonists↗