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Biomedical subjects

W Tang

Publications and source records attributed to W Tang.

At least 199 records · Page 11Linked to original sources
PubMed1997

Equations for the calculation of the protein catabolic rate from predialysis and postdialysis urea concentrations and residual renal clearance in stable hemodialysis patients.

Several simple equations exist for the calculation of K1/V from predialysis (Cpre) and postdialysis (Cpost) measurements of urea concentration. Analogous equations are needed for precise determination of patients protein catabolic rate (nPCR) from Cpre and Cpost. In this study we develop three simple nPCR equations from urea mass balance theory. The equations, which include a term for residual function, may be applied to any session of the week for patient dialyzed three times weekly who are in steady state with respect to dialysis dose and protein catabolism. The precision of each equation was tested with Cpre Cpost data obtained from steady state simulations of 540 patients without residual renal clearance (KR) and 972 simulated patients with significant residual KR. The simplest equation has the form: [formula: see text] where V is urea distribution volume and a and d are constants varying with session of the week. When compared to nPCR values calculated from formal urea kinetic modeling, the error determined with this formula never exceeded 5% for the midweek or final session. A more complicated equation of the form: [formula: see text] provided nPCR estimates with a maximum error < 1.3% for any dialysis session of the week and for KR up to 4 ml/min for a 70-kg patient. The only data required for the latter equation are Cpre, Cpost, length of dialysis session, volume ultrafiltered (delta BW), and an approximate value of the patient's urea distribution volume. The proposed equations permit nPCR to be calculated simply and accurately for stable patients dialyzed three times a week.

Algorithms↗
PubMed1997

Myelinated nerve fibre analysis of the human small splanchnic nerve.

The aim of the present study is to analyse nerve fibres of the human small splanchnic nerve in relation to the ageing process. The analysis was conducted with the use of a new staining method that makes it possible to discriminate various structures of the nervous tissue. An image-analysing digitiser, a microscope with a drawing tube and a personal computer for storing data and performing statistical analyses were employed in this study. We examined 30 human small splanchnic nerves which were taken from cadaver specimens (20 males and 10 females) aged from 44 to 96 years. Our report may provide a first information concerning the ageing process of the human small splanchnic nerve. The results indicate that a decrease in transverse area and perimeter of myelinated axons in one of the important changes occurring in the human small splanchnic nerve with the ageing process.

Adult↗
PubMed1997

[Preliminary study on the arsenic trioxide-induced NB4 cell apoptosis and its molecular mechanisms].

OBJECTIVE: To illustrate the possible cellular and molecular mechanisms of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL). METHODS: APL cell line NB4 was used for in vitro studies. The effect of As2O3 on APL was studied by using flow cytometry, DNA electrophoresis, Narthern blotting and Western blotting. RESULTS: As2O3 induced NB4 cell apoptosis, while not inhibiting the growth and survival of two other leukemic cell lines (HL-60 and U937). Furthermore, As2O3 effectively down-regulated the expression of bcl-2 gene without changing the mRNA levels of other apoptosis-associated genes (including p53, c-myc, bax and bcl-XL). CONCLUSION: These might be one of the molecular mechanisms of As2O3 induced NB4 cell apoptosis.

Animals↗
PubMed1997

[Effects of arsenic trioxide on the subcellular localization of PML/PML-RARalpha protein in leukemic cells].

OBJECTIVE: In order to illustrate the possible roles of PML-RARalpha protein in arsenic trioxide (AsO3)-induced NB4 cell apoptosis. METHODS: Effects of As2O3 on the subcellular localization of PML-RARalpha in NB4 cells were studied. RESULTS: (1) Anti-PML serum staining was reduced and PML granules emerged in the perinuclear cytoplasm in a diffuse pattern in HL-60 cells under As2O3 treatment; (2) abnormal PML/PML-RARalpha granules were decreased; (3) NB4 cells accumulated anti-PML serum staining granules in the cytoplasms were increased and similar accumulation also found in apoptotic cells; and (4) pretreatment with all-trans retinoic acid (ATRA) for 24 or 48 hours did not alter the As2O3 effects. CONCLUSION: As2O3-induced apoptosis was independent of the retinoic acid signal pathway, and it might be regulated by PML/PML-RARalpha and/or other related genes.

Antineoplastic Agents↗
PubMed1997

[In vitro study on arsenic trioxide-inducing apoptosis in primary acute promyelocytic leukemie cells].

OBJECTIVE: To illustrate mechanisms of arsenic trioxide(As2O3) in the treatment of acute promyelocytic leukemia (APL). METHODS: Cell-DNA content distribution, CD11b and CD33 antigens and nitroblue tetrazolium (NBT) reduction were evaluated in fresh APL cells from six APL patients treated in vitro with As2O3. RESULTS: As2O3 had double effects on the cells inducing apoptosis and inducing partial differentiation at higher and at lower drug concentrations, respectively. As2O3 (0.1 approximately 2.0 micromol/L) could rapidly modulate and degrade APL-specific marker molecule PML-RARalpha protein, which could play an important role in the effects of As2O3 on APL cells. CONCLUSION: As2O3 had double effects (induction of apoptosis and partial differentiation) on APL cells through the modulation and degradation of PML-RARalpha proteins.

Apoptosis↗
PubMed1997

A comparative investigation of 2-propyl-4-pentenoic acid (4-ene VPA) and its alpha-fluorinated analogue: phase II metabolism and pharmacokinetics.

An earlier study in rats revealed that alpha-fluorination of 2-propyl-4-pentenoic acid (4-ene VPA), a toxic metabolite of the anticonvulsant drug valproic acid, would avert its metabolism via beta-oxidation and eliminate the drug-related hepatotoxicity. This investigation was carried out to compare 4-ene VPA and the alpha-fluorinated analogue (alpha-fluoro-4-ene VPA) for their pharmacokinetic and protein binding properties. Male Sprague-Dawley rats were dosed with either 4-ene VPA or alpha-fluoro-4-ene VPA i.p. at 1.4 mmol/kg. Blood was collected from the tail vein at various time points and serum samples were prepared. Urine was collected for 24 hr. A second set of rats was treated the same but sacrificed 1 hr post dose, and the livers were homogenized in a Tris-buffer. Protein binding was assessed via ultrafiltration of the naive serum samples spiked with either of the drugs. The serum drug concentration-time profiles of 4-ene VPA and alpha-fluoro-4-ene VPA seemed to resemble one another during the initial 200 min within which differences were reported for their effects on mitochondrial GSH. A second serum peak concentration was observed for 4-ene VPA at approximately 300 min, which was attributed to the extensive glucuronidation of the drug and enterohepatic circulation. The alpha-fluoro-4-ene VPA, on the other hand, did not show these properties with its major phase II metabolite being the corresponding L-glutamine conjugate. The toxic metabolite (E)-2-propyl-2,4-pentadienoic acid and its N-acetylcysteine conjugate were detected only in 4-ene VPA treated rats. Liver concentrations of 4-ene VPA and alpha-fluoro-4-ene VPA were 0.96 +/- 0.11 and 0.89 +/- 0.19 micromol/g of wet liver, respectively, at 1 hr after the dose. Comparable and parallel serum free drug levels were apparent for the two drugs over a concentration range of 0.25 to 2.9 micromol/ml. Taken together, the data seem to suggest that the reported distinction in the ability of 4-ene VPA and alpha-fluoro-4-ene VPA to produce liver toxicity in the rat resides in differences in their metabolism rather than in their pharmacokinetic properties.

Animals↗
PubMed1997

[Potency of CPR without artificial breathing].

Recent experimental studies reported by several independent groups demonstrated that in the initial interventions of cardiopulmonary resuscitation (CPR), airway protection (A) and artificial breathing (B) are not essential for successful recovery from cardiac arrest. In this study, we reviewed and compared those reports to investigate individual effects of A and B on initial CPR. Airway protection: Spontaneous gasping during cardiac arrest is accompanied by upper airway protective reflexes such as head tilt and open mouth. Gasping promoted CO2 elimination from the nose in animals without A. Breathing: Gasping and precordial compression generated ventilation up to 150 and 100 ml.kg-1. min-1 respectively during cardiac arrest. Arterial blood gas analyses demonstrated that CPR without B developed hypercarbia, but maintained oxygen tensions in physiological levels. The frequency of chest compression is in the range of high frequency ventilation, which might allow for successful oxygenation regardless of limited tidal volumes. A series of experimental studies for CPR without A or B call for establishment of a simple CPR method for bystanders, namely "Just compress the chest".

Animals↗
PubMed1997

Time course of alpha-fluorinated valproic acid in mouse brain and serum and its effect on synaptosomal gamma-aminobutyric acid levels in comparison to valproic acid.

To prevent the hepatotoxicity of valproic acid (VPA), a fluorine substituent was introduced at the alpha-position to eliminate the formation of putative toxic metabolites through mitochondrial beta-oxidation. Although the alpha-fluorinated VPA analogue (alpha-fluoro VPA) is more acidic (pK(a) = 3.55) than VPA (pK(a) = 4.80), the lipophilicity of these two compounds, as determined by their log P values, were similar when compared at pH 2.5. Brain, serum and urine samples were prepared from mature male CD-1 mice treated with either alpha-fluoro VPA or VPA for quantitation of drug concentrations. Brain synaptosomes were isolated to determine gamma-aminobutyric acid levels. After equivalent doses of 0.83 mmol/kg, alpha-fluoro VPA was characterized by its slower access into mouse brain, compared to VPA. The peak concentration of alpha-fluoro VPA in mouse brain was achieved 45 min later than in the serum, whereas the peak brain level of VPA coincided with the peak serum level occurring within 15 min. Simultaneous curve fitting of both brain and serum drug concentrations using a two-compartment model indicated that alpha-fluoro VPA, like VPA, may be asymmetrically transported across the blood-brain-barrier. This property of alpha-fluoro VPA was also reflected in its low brain-to-serum concentration ratio of 0.09 at the peak brain drug concentration (0.16 for VPA). The primary beta-oxidation metabolite of VPA was not found in the serum and urine of mice treated with alpha-fluoro VPA. Although the glucuronide was a major metabolite of VPA (28.5% of the dose), alpha-fluoro VPA was observed to conjugate extensively with L-glutamine (33.3% of the dose). Alpha-fluoro VPA appeared to persist in the general circulation, which, in turn, may contribute to the apparent slow elimination of the drug from the brain. The fluorinated compound was demonstrated to have anticonvulsant activity in the 1,5-pentamethylenetetrazole seizure test and to be capable of increasing brain synaptic gamma-aminobutyric acid, the ED50 being 1.70 mmol/kg. These results suggest that alpha-fluoro VPA has potential as a new anticonvulsant drug.

Animals↗
PubMed1997

[Double effects of arsenic trioxide (As2O3) on acute promyelocytic leukemic cell line].

OBJECTIVE: To investigate the effects of a wide range of concentrations of As2O3 on NB4 cells. METHODS: Cell morphology, cell-DNA content distribution, CD11b and CD33 antigens and nitroblue tetrazolium (NBT) reductions were evaluated in an APL cell line NB4 cells with or without As2O3 treatment. In addition, immunofluorescent analysis for APL marker molecule PML-RAR alpha was also performed. RESULTS: 1-2 mumol/L of As2O3 treated NB4 cells presented morphologically some features of apoptotic cells such as intact cell membrane, chromatin condensation and nuclear fragmentation. Sub-G1 cells, whose percentage presents concentration and time-dependency, were observed by flow cytometer. Otherwise, NB4 cells with the treatment of As2O3 at 0.1-0.25 mumol/L for a long time (10 days) have differentiation-related morphology, and their differentiation antigens CD11b and CD33 were also modulated to some extent. In addition, 0.1-2 mumol/L of As2O3 could rapidly and effectively modulate and degradate PML/PML-RAR alpha proteins. CONCLUSION: As2O3 had double effects (induction of apoptosis and imcomplete differentiation) on NB4 cells, which could associate with rapid modulation and degradation of PML/PML-RAR alpha proteins.

Antineoplastic Agents↗
PubMed1997

[An image analysis of the morphological changes of LH cells during LH release peak induced by LHRH in male rats].

The relationship between the peak of LH release induced by exogenous LHRH and morphological change of LH cells in male rats was investigated by ABC Affinity histochemistry and qualitatively characterized by Medical Image Processing System-I. The serum LH concentration was determined by RIA. During the period of basal secretion of LH (3.76 +/- 0.39 ng/ml), the LH cells might be assigned at a storage state. Most of such cells (56.7%) are round and large, and their cross sectional areas are larger then 340 micron 2, usually containing large vacuoles, while the smaller cells of X-sectional area less then 190 micron 2 counted only 2% of the total population. Thirty minutes after injection of LHRH the serum LH level increased significantly (6.46 +/- 1.6 ng/ml, P < 0.01), there appeared a lot of small angular cells, the average cross sectional areas of LH cells decreased significantly (P < 0.0001). When LHRH was injected at sixty minutes, the LH level reached a peak (18.78 +/- 0.79 ng/ml), the number of the large cells decreased to only 4%, while the small cells increased to 66%, vacuoles were almost disapperanced and a large part of cells (52.6%) became irregular. Thereafter, the LH serum gradually subsided to its original basal level with attendant resumption of the morphology of the LH cells at storage state. It appears that the morphological changes, such as size, shape, vacuoles and so on, of the LH cells may serve as an important index for showing the effect of LHRH on LH secretion.

Animals↗
PubMed1996

Targeted expression of IL-11 in the murine airway causes lymphocytic inflammation, bronchial remodeling, and airways obstruction.

Interleukin-11 is a pleotropic cytokine produced by lung stromal cells in response to respiratory viruses, cytokines, and histamine. To further define its potential effector functions, the Clara cell 10-kD protein promoter was used to express IL-11 and the airways of the resulting transgene mice were characterized. In contrast to transgene (-) littermates, the airways of IL-11 transgene (+) animals manifest nodular peribronchiolar mononuclear cell infiltrates and impressive airways remodeling with subepithelial fibrosis. The inflammatory foci contained large numbers of B220(+) and MHC Class II(+) cells and lesser numbers of CD3(+), CD4(+), and CD8(+) cells. The fibrotic response contained increased amounts of types III and I collagen, increased numbers of alpha smooth muscle actin and desmin-containing cells and a spectrum of stromal elements including fibroblasts, myofibroblasts, and smooth muscle cells. Physiologic evaluation also demonstrated that 2-mo-old transgene (+) mice had increased airways resistance and non-specific airways hyperresponsiveness to methacholine when compared with their transgene (-) littermates. These studies demonstrate that the targeted expression of IL-11 in the mouse airway causes a B and T cell-predominant inflammatory response, airway remodeling with increased types III and I collagen, the local accumulation of fibroblasts, myofibroblasts, and myocytes, and obstructive physiologic dysregulation. IL-11 may play an important role in the inflammatory and fibrotic responses in viral and/or nonviral human airway disorders.

Airway Obstruction↗
PubMed1996

Does coronary artery screening by electron beam computed tomography motivate potentially beneficial lifestyle behaviors?

We evaluated the extent to which cardiovascular risk-reducing behaviors are initiated as a result of knowledge of newly detected coronary artery disease, based on test results from noninvasive electron beam computed tomography (EBCT). A total of 703 men and women, aged 28 to 84 years, asymptomatic and without prior coronary disease, who had a baseline EBCT coronary artery scan and basic medical history and risk factor information completed a follow-up survey questioning them about health behaviors undertaken since their scan. Baseline calcium scores were significantly higher in those who subsequently reported consulting with a physician, or reported new hospitalization, coronary revascularization, beginning aspirin usage, blood pressure medications, cholesterol-lowering therapy, decreasing dietary fat, losing weight, beginning vitamin E, and under more worry (all p <0.01). Other factors, including reducing time worked, obtaining life insurance, losing employment, increased work absenteeism, increasing exercise, or stopping smoking were not associated with coronary calcium. In logistic regression, after adjusting for age, gender, pre-existing high cholesterol, high blood pressure, cigarette smoking, and a positive family history of coronary disease, the natural log of total calcium score remained associated with new aspirin usage, new cholesterol medication, consulting with a physician, losing weight, decreasing dietary fat, new coronary revascularization (all p <0.01), but also new hospitalization (p <0.05) and increased worry (p <0.001). The results suggest that potentially important risk-reducing behaviors may be reinforced by the knowledge of a positive coronary artery scan, independent of preexisting coronary risk factor status.

Adult↗
PubMed1996

p53-null cells are more sensitive to ultraviolet light only in the presence of caffeine.

We have shown previously that p53(-/-) fibroblasts show greater sensitization by caffeine to the lethal effects of ionizing radiation compared with p53(+/+) cells. Recently published data have suggested a possible role of p53 in nucleotide excision repair: an association of p53 and xeroderma pigmentosum group B protein and a greater sensitivity to cisplatin of RKO cells transfected with the E6 protein of human papilloma virus (inactivating p53). We show that p53(+/+) and p53(-/-) cells have equal sensitivity to germicidal UV light (as with ionizing radiation). However, the introduction of 2 mM caffeine led to a sensitization enhancement ratio (at 10% survival) of 1.8 in p53(-/-) cells, but only 1.3 in wild-type (p53+/+) cells. Lower doses of caffeine had less effect, and 0.1 mM caffeine resulted in no detectable sensitization of either cell type to UV light in contrast to X-rays. The differential sensitivity of p53(-/-) cells to X-rays and caffeine was thought to be due to override of the G2-M block to cell cycle progression. In response to UV light, cells accumulate in S phase, and the magnitude of S-phase accumulation was observed to be greater in p53(-/-) cells. Caffeine had little effect on the cell cycle distribution in p53(+/+) cells. However, for p53(-/-) cells, a greater proportion were in S phase after treatment with caffeine, and a complete loss of S-phase delay was observed after UV irradiation. In conclusion, the role of p53 in nucleotide excision repair appears to be of little significance for cell survival. Greater sensitization of p53(-/-) cells to caffeine could be mediated via override of S-phase delay.

Animals↗
PubMed1996

Structural studies of imidazole-cytochrome c: resonance assignments and structural comparison with cytochrome c.

Two-dimensional nuclear magnetic resonance spectroscopy (2D NMR) was used to obtain extensive proton resonance assignments of Im-cyt c complex which is a possible analog of a late folding intermediate of cytochrome c. Assignments were made nearly completely for the main-chain and the side-chain protons (all except Gly29). As starting points for the assignment of the Im-cyt c, a limited set of protons was initially assigned by use of 2D NMR magnetization transfer methods to correlated resonances in the Im-cyt c with assigned resonances in the native cyt c. The subsequent search focused on recognition of main-chain NOE connectivity patterns, with use of previously assigned residues to place NOE-connected segments within the amino acid sequence. The observed patterns of main-chain NOEs provided some structural information and suggested potentially significant differences between Im-cyt c and the native cyt c. Differences in NOEs involving side-chain protons were reported and analyzed. There was evidence for conformational changes induced by the breakage of Fe-S bond. It was concluded that the Im-cyt c had undergone a rearrangement of several regions forming the heme pocket of the protein. The structural understanding of these effects of the mutation may be essential to elucidate the changes in function and kinetic mechanism of cyt c folding.

Animals↗
PubMed1996

A site-directed mutagenesis of pro-urokinase which substantially reduces its intrinsic activity.

Single-chain urokinase-type plasminogen activator or pro-urokinase is a zymogen with an intrinsic catalytic activity which is greater than that of most other zymogens. To study the structural basis for this activity, a three-dimensional homology model was calculated using the crystallographic structure of chymotrypsinogen, and the structure-function relationship was studied using site-directed mutagenesis and kinetic analysis. This model revealed a unique Lys300 in pro-urokinase which could form a weak interaction with Asp355, adjacent to the active site Ser356. It was postulated that this lysine, by its epsilon-amino group, may serve to pull Ser356 close to the active position, thereby inducing the higher intrinsic activity of pro-urokinase. This was consistent with the published finding that a homologous lysine (Lys416) in single chain tissue plasminogen activator when mutated to serine induced some reduction in activity. To test this hypothesis, a site-directed mutant with a neutral residue (Lys300-->Ala) was produced and characterized. The Ala300-pro-urokinase had a 40-fold lower amidolytic activity than that of pro-urokinase. It was also stable in plasma at much higher concentrations than pro-urokinase, reflecting much attenuated plasminogen activation. Plasmin activatability was comparable to that of pro-urokinase, but the resultant two-chain derivative (Ala300-urokinase) had a lower enzymatic activity (approximately 33% that of urokinase) due to a reduction of kcat. Interestingly, the KM of two-chain Ala300-urokinase against plasminogen was 5.8-fold lower than that of urokinase, being similar to that of pro-urokinase which has a KM about 5-fold lower than urokinase. In conclusion, the hypothesis that Lys300 is a key structural determinant of the high intrinsic activity of pro-urokinase was confirmed by these studies. This residue also appears to be important for the full expression of the enzymatic activity of urokinase.

Enzyme Activation↗
PubMed1996

E2F1 inhibition of transcription activation by myogenic basic helix-loop-helix regulators.

Cellular transcription factor E2F1 is thought to regulate the expression of genes important for cell cycle progression and cell proliferation. Deregulated E2F1 expression induces S-phase entry in quiescent cells and inhibits myogenic differentiation. We show here that E2F1 inhibits the activation of gene transcription by myogenic basic helix-loop-helix proteins myoD and myogenin. Transfection assay using different deletion constructs indicates that both the DNA binding and the transactivation domains of E2F1 are required for its inhibition of myoD transcription activation. However, the retinoblastoma protein (RB) binding domain is not required. Furthermore, co-transfection with the RB, which inhibits the transcription activity of E2F1, can also repress E2F1 inhibition of myoD transactivation. These results suggest an essential role of E2F1-mediated transcription in its inhibition of myogenesis.

Animals↗
PubMed1996

Cytotoxicity of unsaturated metabolites of valproic acid and protection by vitamins C and E in glutathione-depleted rat hepatocytes.

Valproic acid (VPA) and the unsaturated metabolites, 2-ene VPA and (E)-2,(Z)-3'-diene VPA, demonstrated dose-dependent cytotoxicity in primary cultures of rat hepatocytes, as evaluated by lactate dehydrogenase (LDH) leakage. Cellular glutathione (GSH) was depleted by adding buthionine sulfoximine (BSO) to the culture medium. Induction of cytochrome P450 by pretreatment of rats with phenobarbital or pregnenolone-16 alpha-carbonitrile enhanced the cytotoxicity of parent VPA in BSO-treated hepatocytes. The cytotoxicity of 4-ene VPA was apparent in BSO-treated hepatocytes with detectable loss of cell viability at 1 microM of added 4-ene VPA. Depletion of cellular GSH also increased the cytotoxicities of 2-ene VPA and (E)-2,(Z)-3'-diene VPA. The cytotoxicity of 2-ene VPA was comparable to or higher than that of VPA, producing loss of viability at concentrations > or = 5 mM. Time-course evaluation of hepatocyte response to 4-ene VPA in the GSH-depleted state revealed a delayed cytotoxicity with no effect during the first 12 h of exposure followed by a pronounced toxicity between 12 and 14 h. Two major GSH conjugates of 4-ene VPA metabolites, namely 5-GS-4-hydroxy VPA lactone and 5-GS-3-ene VPA, were detected in 4-ene VPA treated hepatocytes. Consistent with this finding, a 50% decrease in cellular GSH levels was observed following 4-ene VPA treatment. Under similar conditions, neither toxicity nor the GSH conjugated metabolite were detected in cells treated with the alpha-fluorinated 4-ene VPA analogue (alpha-F-4-ene VPA). The antioxidants, vitamin C and vitamin E, demonstrated a cytoprotective effect against 4-ene VPA-induced injury in GSH-depleted hepatocytes. These results are in support of hepatocellular bioactivation of VPA via 4-ene VPA to highly reactive species, which are detoxified by GSH. The susceptibility of hepatocytes to VPA metabolite-mediated cytotoxicity depends on cellular GSH homeostasis.

Analysis of Variance↗