Biomedical subjects

D M Zhu

Publications and source records attributed to D M Zhu.

At least 19 recordsLinked to original sources

PubMed2006

Lead inhibited N-methyl-D-aspartate receptor-independent long-term potentiation involved ryanodine-sensitive calcium stores in rat hippocampal area CA1.

Lead exposure is known to be associated with cognitive dysfunction in children. Impairment of the induction of long-term potentiation (LTP) has been reported in area CA1 of rat hippocampus following lead exposure in vivo and in vitro. The present study was carried out to investigate whether the alterations of N-methyl-d-aspartate (NMDA) receptor-independent LTP following lead exposure involve internal calcium stores in hippocampus CA1 synapses. Monosynaptic field excitatory postsynaptic potentials in hippocampal slice area CA1 were recorded using the whole-cell patch-clamp upon acute lead treatment, and these studies were coupled with calcium imaging experiments to observe internal calcium changes in cultured hippocampal neurons. Inhibiting calcium release by ryanodine significantly reduced NMDA receptor-independent LTP, and depletion of internal calcium stores with thapsigargin blocked this form of LTP. Caffeine, an agonist of ryanodine receptors, enhanced this form of LTP. However, caffeine-enhanced NMDA receptor-independent LTP was depressed after bath application of lead. Moreover, lead further decreased ryanodine- and thapsigargin-reduced NMDA receptor-independent LTP. Calcium imaging also confirmed that lead had an effect on internal calcium release and uptake. Taken together, these results demonstrated that lead inhibited NMDA receptor-independent LTP by action on calcium release and uptake by ryanodine-sensitive stores in rat hippocampal area CA1.

Aniline Compounds↗

PubMed2001

Surveillance of bacterial resistance among isolates in Shanghai in 1999.

We report here surveillance data on the bacterial resistance of clinical isolates from 11 Shanghai hospitals in 1999, for guidance in the clinical use of antibacterial agents. Of the 14,855 strains collected, 5130 (34.5%) were Gram-positive cocci and 9725 (65.5%) were Gram-negative bacilli. The most common organisms in descending order of frequency, were: Escherichia coli (16%), coagulase-negative staphylococci (CNS; 14.3%), Klebsiella spp. (12.3%), Staphylococcus aureus (11.5%), Pseudomonas aeruginosa (9.2%), Acinetobacter spp. (8.1%), and Enterococcus spp. (6.6%). Methicillin-resistant strains accounted for 64% and 77% of S. aureus and CNS, respectively. The methicillin-sensitive strains were susceptible to most agents tested, while most methicillin-resistant strains were resistant to these agents. No vancomycin-resistant staphylococci were identified. Vancomycin-resistant strains accounted for 3.6% of Enterococcus fecalis and 1.7% of E. fecium. E. coli strains resistant to piperacillin, gentamicin, and fluoroquinolones accounted for 50% or more of the strains, and the resistance rates of Klebsiella spp., Enterobacter spp., Citrobacter spp., and Acinetobacter spp. to third-generation cephalosporins had increased markedly compared with rates in recent years. Resistance rates of P. aeruginosa to ceftazidime and imipenem (27% and 20%, respectively) had also increased compared with rates in recent years. A national strategy on the limited and prudent use of antibiotics is urgently needed.

Anti-Bacterial Agents↗

PubMed2001

Postantibiotic effects of eleven antimicrobials on five bacteria.

AIM: To investigate the postantibiotic effects (PAE) of different classes of antimicrobials against five different types of bacteria. METHODS: Minimal inhibitory concentrations (MIC) were determined by twofold macrodilution in broth. The antimicrobial agents were eliminated by washing method after the bacteria were exposed to antimicrobials for 1 h or 2 h. Growth curves were followed by viable counts, and then the PAE were calculated. RESULTS: Macrolides induced PAE of 3.10 h to 4.15 h on S aureus, and 1.85 h to 3.3 h against S pneumoniae, which were longer than PAE induced by other tested antimicrobials (P<0.01). Macrolides induced PAE of 1 h to 4 h against H influenzae, with azithromycin producing the longest PAE of 4 h. Ciprofloxacin and amikacin induced PAE of 1.38 h to 2.00 h on E coli and K pneumoniae, which were longer than that of beta-lactams, piperacillin, cefazolin, or cefotaxime, with PAE of 0.1 h to 0.5 h (P<0.01). CONCLUSION: Different classes of antimicrobials induce different periods of PAE. As an important pharmacodynamic parameter, PAE provide reference data for the determination of the optimal dosing regimen and reasonable use of antimicrobials.

Escherichia coli↗

PubMed2000

Thermal conductance and wettability of xenon on resorcinol-formaldehyde aerogels.

We have performed thermal conductivity and adsorption isotherm measurements to investigate the system formed by Xe adsorbed on resorcinol-formaldehyde (RF) aerogel. Below 80 K, the thermal conductivity of the Xe/RF-aerogel system is essentially identical to that of the bare RF aerogel; however, above this temperature the thermal conductivity of the system increases significantly above that of the bare aerogel. Adsorption isotherm measurements indicate that Xe incompletely wets the RF aerogel below Xe's bulk triple point temperature. The thickness of the Xe film that forms on the RF aerogel decreases with decreasing temperature. By 80 K the total amount of Xe present on the aerogel in equilibrium with the saturated vapor pressure is less than the amount needed to form about 1.5 atomic layers of Xe on the substrate. We attribute the observed changes in the thermal conductivity of the Xe/aerogel system to changes in the wettability of the aerogel by the Xe film.

Journal Article↗

PubMed2000

Frost heave in physisorbed films: vapor flow and substrate effects.

The magnitude of vapor flow accompanying the surface-melted liquid flow in physisorbed multilayer films due to thermomolecular pressures was estimated. It was found that the vapor flow is significant compared to the flow of the surface-melted liquid in thick films. As the flows continue, the film thickness profile evolves into one determined by a dynamic equilibrium of vapor pressure. The flow of surface-melted liquid stops when the dynamic equilibrium is reached.

Journal Article↗

PubMed2000

Inositol tetrakisphosphate as a frequency regulator in calcium oscillations in HeLa cells.

Cellular signaling mediated by inositol (1,4,5)trisphosphate (Ins(1, 4,5)P(3)) results in oscillatory intracellular calcium (Ca(2+)) release. Because the amplitude of the Ca(2+) spikes is relatively invariant, the extent of the agonist-mediated effects must reside in their ability to regulate the oscillating frequency. Using electroporation techniques, we show that Ins(1,4,5)P(3), Ins(1,3,4, 5)P(4), and Ins(1,3,4,6)P(4) cause a rapid intracellular Ca(2+) release in resting HeLa cells and a transient increase in the frequency of ongoing Ca(2+) oscillations stimulated by histamine. Two poorly metabolizable analogs of Ins(1,4,5)P(3), Ins(2,4,5)P(3), and 2,3-dideoxy-Ins(1,4,5)P(3), gave a single Ca(2+) spike and failed to alter the frequency of ongoing oscillations. Complete inhibition of Ins(1,4,5)P(3) 3-kinase (IP3K) by either adriamycin or its specific antibody blocked Ca(2+) oscillations. Partial inhibition of IP3K causes a significant reduction in frequency. Taken together, our results indicate that Ins(1,3,4,5)P(4) is the frequency regulator in vivo, and IP3K, which phosphorylates Ins(1,4, 5)P(3) to Ins(1,3,4,5)P(4), plays a major regulatory role in intracellular Ca(2+) oscillations.

Antibodies↗

PubMed2000

Cathepsin inhibition induces apoptotic death in human leukemia and lymphoma cells.

We examined the effects of cathepsin inhibitor 1 (CATI-1), a selective inhibitor of cysteine cathepsins, on human leukemia and lymphoma cells. CATI-1 induced apoptosis in all 12 cell lines tested. Apoptosis of CATI-1-treated leukemia/lymphoma cells was caspase-independent, p53-independent, BAX-independent as well as MAP kinase-independent. Our findings provide unprecedented experimental evidence that cathepsins play a pivotal role for the survival of human leukemia/lymphoma cells. Therefore, cathepsin inhibitors may provide the basis for new treatment programs against leukemia and lymphoma.

Apoptosis↗

PubMed2000

Z-Phe-Gly-NHO-Bz, an inhibitor of cysteine cathepsins, induces apoptosis in human cancer cells.

An increasing number of studies indicate that cysteine cathepsins contribute to cancer progression, invasion, and metastasis. Here we provide experimental evidence that the cathepsin inhibitor Z-Phe-Gly-NHO-Bz induces rapid apoptotic death in human cancer cell lines. Notably, the Z-Phe-Gly-NHO-Bz-induced apoptosis exhibited independence of p53, caspases, and mitogen-activated protein (MAP) kinases. Taken together, our results prompt the hypothesis that cysteine cathepsin(s) is a universal survival factor for cancer cells, and its inhibition leads to cancer cell apoptosis. The exquisite sensitivity of human cancer cells to CATI-1 indicates that this compound and its derivatives may provide the basis for new treatment programs against a broad spectrum of malignancies.

Apoptosis↗

PubMed2000

Calpain inhibitor II induces caspase-dependent apoptosis in human acute lymphoblastic leukemia and non-Hodgkin's lymphoma cells as well as some solid tumor cells.

Calpain is a calcium-dependent cysteine protease that is implicated in calcium-dependent cell death, and calpain inhibitors are generally considered as inhibitors of apoptosis. To the contrary, in the present study, we found that calpain inhibitor II (CPI-2) triggers rapid apoptosis in acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) cells. All target cell lines were killed by CPI-2, including: ALL-1, a multidrug-resistant BCR-ABL fusion transcript-positive t(9;22) pro-B ALL cell line; RS4;11, a highly radiation-resistant MLL-AF4 fusion transcript-positive t(4;11) pre-pre B ALL cell line; RAMOS, a highly radiation-resistant and p53-deficient Burkitt's lymphoma cell line; DAUDI, a Burkitt's leukemia/lymphoma cell line; NALM-6, a pre-B ALL cell line; and JURKAT and MOLT-3, two T-lineage ALL/NHL cell lines. CPI-2-induced apoptosis in LYN-deficient and BTK-deficient subclones of the DT-40 lymphoma B cell line as effectively as it did in wild-type DT-40 cells. Thus, CPI-2-induced apoptosis is not dependent on the protein tyrosine kinases LYN or BTK. Notably, caspase inhibitor I effectively inhibited CPI-2-induced apoptosis, suggesting that the inhibition of a CPI-2-susceptible protease results in caspase activation, leading to apoptosis in ALL/NHL cells. Unlike the high calpain-expressing ALL/NHL cell lines, myeloid leukemia cell lines HL-60/AML, K562/CML, and U937/AMML, or solid tumor cell lines BT-20/breast cancer, PC-3/prostate cancer, U373/glioblastoma, and HeLa/epitheloid cancer, were not susceptible to the cytotoxicity of CPI-2. Taken together, our results identify calpain as a new molecular target for the treatment of ALL and NHL. CPI-2 and its analogues represent a promising new class of antileukemia/lymphoma agents that deserves further development.

Agammaglobulinaemia Tyrosine Kinase↗

PubMed1999

Quantitative high-performance liquid chromatography-based detection method for calphostin C, a naturally occurring perylenequinone with potent antileukemic activity.

Calphostin C is a potent inhibitor of protein kinase C and can induce Ca2+-dependent apoptosis in human ALL cells. Further development of calphostin C will require detailed pharmacodynamic studies in preclinical animal models. Therefore, we established a sensitive and accurate high-performance liquid chromatography (HPLC)-based quantitative detection method for the measurement of calphostin C levels in plasma. Extraction of calphostin C from plasma was performed by precipitation of plasma protein using acetonitrile and an aliquot of extracted supernatant was injected onto a Hewlett-Packard HPLC system constituting a 250x4 mm LiChrospher 100, RP-18 (5 microm) in conjunction with a 4x4 mm LiChrospher 100, RP-18 guard column (5 microm). The eluted compounds were detected by diode array detection set at a wavelength of 479 nm. Acetonitrile-water containing 0.1% trifluoroacetic acid and 0.1% triethylamine (70:30, v/v) was used as the mobile phase. The average extraction recovery from plasma was 97.3%. Good linearity (r>0.999) was observed throughout the concentration range of 0.05-40 microM for calphostin C in 50 microl of plasma. Intra- and inter-assay variabilities were less than 6% in plasma. The lowest detection limit of calphostin C in 50 microl plasma was 0.02 microM at a signal-to-noise ratio of approximately 3. The availability of this assay will now permit detailed pharmacodynamic and pharmacokinetic studies of calphostin C in vivo.

Animals↗

PubMed1999

Pharmacokinetic features and metabolism of calphostin C, a naturally occurring perylenequinone with antileukemic activity.

PURPOSE: To examine the pharmacokinetic features and metabolism of calphostin C, a naturally occurring perylenequinone with potent antileukemic activity. METHODS: HPLC-based quantitative detection methods were used to measure calphostin C levels in lysates of leukemic cells and in plasma of mice treated with calphostin C. The plasma concentration-time data were analyzed using the WinNonlin program. In vitro esterases and a microsome P450 preparation in conjunction with a LC-MS(API-EI) system were used to study the metabolism of calphostin C. RESULTS: An intracellular exposure level (AUC0-6h) of 257 microM x h was achieved after in vitro treatment of NALM-6 cells with calphostin C at a 5 microM final concentration in culture medium. After intraperitoneal (i.p.) injection of a 40 mg/kg nontoxic bolus dose of calphostin C, the estimated Cmax was 2.9 microM, which is higher than the effective in vitro concentration of calphostin C against leukemic cells. Drug absorption after i.p. administration was rapid with an absorption half-life of 24.2 min and the estimated t(max) was 63.0 min. Calphostin C was cleared with an elimination half-life of 91.3 min. An inactive and smaller metabolite (calphostin B) was detected in plasma of calphostin C-treated mice with a t(max) of 41.3 min. Esterase (but not P450) treatment of calphostin C in vitro yielded an inactive metabolite (calphostin B) of the same size and elution profile. CONCLUSIONS: Target plasma calphostin C concentrations of potent antileukemic activity can be reached in mice at nontoxic dose levels. This pilot pharmacokinetic study of calphostin C combined with the availability of the described quantitative HPLC method for its detection in cells and plasma provide the basis for future preclinical evaluation of calphostin C and its potential as an anti-leukemic drug.

Animals↗

PubMed1999

Effects of physisorption of xenon on the thermal conductivity of resorcinol-formaldehyde aerogels.

The effects of adsorption of xenon to the thermal conductivity of a resorcinol-formaldehyde aerogel were investigated in a temperature range from 20 to 120 K. It was found that at temperatures below 75 K, the adsorbed xenon has little effect on the thermal conductivity. Rapid rises of the thermal conductivity develop at temperatures around 75-80 K with magnitudes roughly proportional to the amount of xenon adsorbed. The effect is explained as due to adsorbed xenon atoms that enhance the neck connection between aerogel particles.

Journal Article↗

PubMed1999

A requirement for protein kinase C inhibition for calcium-triggered apoptosis in acute lymphoblastic leukemia cells.

We have evaluated the cytotoxicities of the combinations of calcium mobilizers and PKC inhibitors against human acute lymphoblastic leukemia (ALL) cells. Here we report that calcium mobilizers alone or PKC inhibitors alone do not induce apoptosis in human ALL cells. However, the combinations of calcium mobilizers with potent inhibitors of PKC cause significant apoptosis in ALL cells. Our results provide experimental evidence that PKC blocks Ca2+-triggered apoptosis in human ALL cells. Thus, PKC inhibitors can be used to enhance the antileukemic activity of chemical or biological agents that trigger an apoptotic calcium signal in ALL cells. The exquisite sensitivity of ALL cells to calcium-dependent apoptosis in the presence of PKC inhibitors could provide the basis for new treatment programs against ALL.

Antineoplastic Agents↗

PubMed1998

Modified ultrafiltration in paediatric cardiopulmonary bypass.

Cardiopulmonary bypass (CPB), a nonphysiological procedure, is associated with haemodilution and the inflammatory response, causing the accumulation of body water and organ dysfunction. The purpose of this study was to evaluate the efficacy of modified ultrafiltration. Forty paediatric patients undergoing cardiac operations were randomized into a control group and a modified ultrafiltration group. Blood cells, protein and cytokine concentrations were recorded for 24 h postoperatively. As the fluid was removed at 50 ml/min, both blood cells and protein were concentrated by modified ultrafiltration (p < 0.001). The tumour necrosis factor (TNF)-alpha concentration was increased and interleukin-8 (IL-8) and endothelin (ET) concentrations were unaltered after ultrafiltration. After correction for albumin, TNF-alpha concentration changed little, and IL-8 and ET concentrations (36.75 +/- 12.35, 42.89 +/- 15.54) were decreased significantly (21.47 +/- 13.87, 26.06 +/- 12.54) after ultrafiltration. Modified ultrafiltration is an effective method for removing excess tissue fluid and concentrating blood after CPB. This technique can also filter out some cytokines.

Blood Cell Count↗

PubMed1998

The carriage of Escherichia coli resistant to antibiotics in healthy populations in Shanghai.

Healthy populations represent the largest reservoir of bacteria resistant to antibiotics. We investigated the resistance of Escherichia coli to 12 antibiotics in fecal samples from untreated healthy populations in Shanghai, China by using Kirby-Bauer (K-B) method. The results showed that: (i) All subjects carried resistant strains of Escherichia coli. (ii) The carriage rates of Escherichia coli resistant to various antibiotics were different, less than 10% to amikacin and 30% to 100% to others. (iii) In the elder children group aged 10-11 years, the percentages of strains resistant to gentamicin, streptomycin, chloramphenicol, tetracycline, trimethoprim, and sulfamethoxazole were significantly lower than those in the younger group aged 5-6 years. In the adult group, the percentages of strains resistant to ampicillin, piperacillin, amikacin, streptomycin, chloramphenicol, tetracycline, trimethoprim, and sulfamethoxazole were significantly lower than those in the elder children group. (iv) The number of strains resistant to five or more antibiotics accounted for 31.8% in the younger children group, 23.7% in the elder children group, and 12.1% in the adult group. These findings suggest that all healthy people in Shanghai carry resistant strains of Escherichia coli in the intestine. The younger the populations, the higher the level of resistance of fecal Escherichia coli to antibiotics. Improvement of health behaviors and environmental sanitation and rational use of antibiotics could remarkedly decrease the resistant level of bacteria.

Adult↗

PubMed1998

Calphostin C triggers calcium-dependent apoptosis in human acute lymphoblastic leukemia cells.

Recent studies have demonstrated that the naturally occurring perylenequinone antibiotic calphostin C is a potent inhibitor of protein kinase C and can induce apoptosis in some tumor cell lines by an as yet unknown mechanism. Here we demonstrate that calphostin C induces dose-dependent apoptosis in DT40 chicken lymphoma B-cells, and targeted disruption of lyn, syk, btk, PLCgamma2, or IP3R genes does not prevent or attenuate its cytotoxicity. In our study, calphostin C also induced rapid apoptosis in human acute lymphoblastic leukemia (ALL) cell lines ALL-1 (BCR-ABL+ pre-pre-B ALL), RS4;11 (MLL-AF4+ pro-B ALL), NALM-6 (pre-B ALL), DAUDI (Burkitt's/B-cell ALL), MOLT-3 (T-ALL), and JURKAT (T-ALL), whereas other potent PKC inhibitors did not. In biochemical studies, calphostin C was discovered to induce rapid calcium mobilization from intracellular stores of ALL cell lines, and its cytotoxicity against ALL cell lines was well correlated with the magnitude of this calcium signal. Calphostin C-induced apoptosis was markedly suppressed by BAPTA/AM, a cell-permeable Ca2+ chelator as well as NiCl2, an inhibitor of Ca2+/Mg2+-dependent endonucleases. Inhibition of the Ca2+/calmodulin-dependent phosphatase calcineurin with perfluoreperazine dimadeate (a calmodulin antagonist) or cyclosporin A (a specific inhibitor of calcineurin) also reduced the magnitude of calphostin C-induced apoptosis in ALL cell lines. Calphostin C was capable of inducing calcium mobilization and apoptosis in freshly obtained primary leukemic cells from children with ALL. Taken together, our results provide unprecedented evidence that calphostin C triggers a Ca2+-dependent apoptotic signal in human ALL cells.

Antibiotics, Antineoplastic↗

PubMed1997

Low affinity interaction of human or rat T cell adhesion molecule CD2 with its ligand aligns adhering membranes to achieve high physiological affinity.

The mechanism by which low affinity adhesion molecules function to produce stable cell-cell adhesion is unknown. In solution, the interaction of human CD2 with its ligand CD58 is of low affinity (500 mM-1) and the interaction of rat CD2 with its ligand CD48 is of still lower affinity (40 mM-1). At the molecular level, however, the two systems are likely to be topologically identical. Fluorescently labeled glycosylphosphatidylinositol-anchored CD48 and CD58 were prepared and incorporated into supported phospholipid bilayers, in which the ligands were capable of free lateral diffusion. Quantitative fluorescence imaging was used to study the binding of cell surface human and rat CD2 molecules to the fluorescent ligands in contact areas between Jurkat cells and the bilayers. These studies provide two major conclusions. First, CD2/ligand interactions cooperate to align membranes with nanometer precision leading to a physiologically effective two-dimensional affinity. This process does not require the intact cytoplasmic tail of CD2. Second, the degree of membrane alignment that can be achieved by topologically similar receptors deteriorates with decreasing affinity. This suggests an affinity limit for the ability of this mode of cooperativity to achieve stable cell-cell adhesion at approximately 10 mM-1.

Animals↗

PubMed1996

Reversible phosphorylation as a controlling factor for sustaining calcium oscillations in HeLa cells: Involvement of calmodulin-dependent kinase II and a calyculin A-inhibitable phosphatase.

The role of reversible phosphorylation in histamine-induced Ca2+ oscillations in HeLa cells has been investigated by using various activators and inhibitors of protein kinases and phosphatases. Electroporation was employed to introduce impermeable materials into single cells, which proved to be a useful and convenient tool. Of the kinases examined, cAMP-dependent kinase, protein kinase C, and calmodulin-dependent kinase II (CaMK II), only CaMK II was essential. When added during oscillations, both W-7, a calmodulin antagonist, and KN-62, a specific CaMK II inhibitor, caused one large Ca2+ spike before halting the process. Introduction of the Ca2+/calmodulin-independent catalytic domain of CaMK II into the cells forestalled their response to histamine. These results show that intracellular Ca2+ cannot oscillate when CaMK II is locked in either the inactive or the stimulated state. External Ca2+ electroporated into cells preloaded with the catalytic domains was quickly removed (but not when the cells were pretreated with the endoplasmic reticulum Ca(2+)-ATPase inhibitor, tapsigargin), indicating that the ATP-driven Ca2+ pump was somehow activated by CaMK II. Protein phosphatase inhibitors calyculin A and okadaic acid abolished ongoing oscillations and, when added at low concentrations, prolonged the interspike interval. Immunoprecipitation experiments with 32P(i)-labeled cells provided the first evidence that inositol 1,4,5-trisphosphate receptor (IP3R) was phosphorylated by CaMK II in vivo. The extent of phosphorylation was increased in the presence of histamine, significantly enhanced by calyculin A, and greatly reduced by W-7. Our observations are consistent with the concept that repetitive phosphorylation-dephosphorylation cycles regulating IP3R and Ca2+ pumps are a controlling factor for sustained Ca2+ oscillations in HeLa, and possibly other, cells.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗