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Biomedical subjects

D Zhu

Publications and source records attributed to D Zhu.

At least 19 recordsLinked to original sources
PubMed2006

Heavy metal leaching from mine tailings as affected by organic amendments.

A column experiment was conducted to investigate Zn, Cd, and Pb leaching from mine tailings as affected by the addition of organic amendments. Composted yard waste, composted cattle manure, and cattle manure aged for one month increased heavy metal leaching from mine tailings when compared to an unamended control. Aged cattle manure and composted cattle manure significantly increased Zn concentration in the leachate. The maximum Zn concentration in leachate from the manure-amended treatments was as high as 3.7 mg/L, whereas Zn concentrations from the control were less than 0.7 mg/L. All organic amendments increased Cd leachate concentrations. The presence of aged cattle manure greatly increased Pb concentrations in the leachate from less than 10 microg/L for the control treatment to higher than 60 microg/L. Lead concentration in leachate was positively correlated with inorganic carbon, total organic carbon, total carbon and bicarbonate. Although organic amendments increased Zn, Cd, and Pb leaching when compared with the control treatment, Zn concentrations were lower than the 5 mg/L secondary drinking water standard, and Pb concentrations were only minimally higher than the 15 microg/L drinking water standard. Cadmium concentrations from manure treatments exceeded the 5 microg/L drinking water standard but only during the first 15 days. Organic amendments may encourage establishment of vegetation in mining areas that may minimize heavy metal contamination through runoff and erosion. However, increased risk due to heavy metal leaching in the presence of organic amendments should be carefully considered.

Metals, Heavy↗
PubMed2006

The BCL2 major breakpoint region (mbr) regulates gene expression.

BCL2 expression is finely tuned by a variety of environmental and endogenous stimuli and regulated at both transcriptional and post-transcriptional levels. Our previous investigations demonstrated that the BCL2 major breakpoint region (mbr) in the 3'-UTR upregulates reporter gene expression, which implies that this region possessed intrinsic regulatory function. However, the effect of the mbr on BCL2 expression, and the underlying regulatory mechanisms, remain to be elucidated. To assess the direct effect of the mbr on the transcriptional activity of the BCL2 gene, we employed targeted homologous recombination to establish a mbr(+)/mbr(-) heterozygous Nalm-6 cell line and then compared the transcriptional activity and apoptotic effect on transcription between the wild type and targeted alleles. We found that deletion of the mbr significantly decreased the transcriptional activity of the corresponding allele in the mbr(+)/mbr(-) cell. The BCL2 allele deleted of the mbr had a slower response to apoptotic stimuli than did the wild type allele. The regulatory function of the mbr was mediated through SATB1. Overexpression of SATB1 increased BCL2 expression, while knockdown of SATB1 with RNAi decreased BCL2 expression. Our results clearly indicated that the mbr could positively regulate BCL2 gene expression and this regulatory function was closely related to SATB1.

3' Untranslated Regions↗
PubMed2006

Interference with nuclear factor kappa B and c-Jun NH2-terminal kinase signaling by TRAF6C small interfering RNA inhibits myeloma cell proliferation and enhances apoptosis.

The tumor necrosis factor receptor (TNFR)-associated factor (TRAF) family of six adaptor proteins (TRAF1-6) links the TNFR superfamily to the nuclear factor kappa B (NF-kappaB) and activator protein-1 (AP-1) transcriptional activators. Unlike other TRAFs, TRAF6 is also involved in Toll-like/interleukin (IL)-1 receptor (TIR) signal transduction. Thus, inhibition of TRAF6 function could interrupt both CD40 (TNFR family) and IL-1 growth signals, pathways critical to myeloma proliferation. To block TRAF6-mediated IL-1 signaling, we constructed small interfering RNA (siRNA) against TRAF6. We found that siRNA targeting the TRAF6 C-terminal (siTRAF6C) receptor interaction domain specifically reduced only TRAF6 protein expression, without affecting TRAF2 or 5 levels, and substantially interfered with IL-1-induced NF-kappaB and c-Jun/AP-1 activation. Inhibition by siTRAF6C was concentration-dependent. SiTRAF6C also significantly reduced myeloma proliferation and enhanced apoptosis in a similar dose-dependent fashion in vitro. More importantly, marked siTRAF6C growth inhibition was detected in vivo when these cells were implanted into the bone marrow of irradiated normal mice. In contrast, introduction of siRNA derived from the TRAF6 Zn-finger domain or an irrelevant siRNA construct failed to alter cell growth or cell death. These studies suggest that TRAF6 may be a new molecular target to block cell signal transduction important for the survival and proliferation of multiple myeloma cells.

Animals↗
PubMed2006

Airway hyperresponsiveness induced by repetitive intraperitoneal injection of lipopolysacharide and the involvement of inflammation and nitric oxide in guinea pigs.

OBJECTIVE: Airway hyperresponsiveness (AHR) is involved in bronchial asthma and chronic obstructive pulmonary disease (COPD) and produces respiratory symptoms. Lipopolysaccharide (LPS) has been found to be significantly related to the severity of asthma. However, its clinical mechanism still remains controversial. This study investigated the in vivo effect of repetitive intraperitoneal administration of lipopolysaccharide (LPS) on airway hyperresponsiveness (AHR) in guinea pigs and the possible involvement of inflammation, nitric oxide (NO) and nitric oxide synthase (NOS). METHODS: There were two exposure groups for intraperitoneal LPS injection: (1) LPS was given at a dose of 1 mg x kg(-1), followed by sterile saline (NS) 1 ml x kg(-1) 8 h later every 24 h; (2) LPS was given at a dose of 0.5 mg x kg(-1) two times with an interval of 8 h every 24 h. Each exposure regime was repeated 4 times. Control animals were given NS and 6 naive guinea pigs were used as baseline control. Determinations were made 24 h after each exposure. RESULTS: Persistent AHR occurred 24 h after the third and fourth exposures to LPS in the first exposure group (at one dose), but occurred earlier after the exposures to LPS in the second exposure group (at divided doses). The numbers of total cells and neutrophils were elevated initially but subsided subsequently in LPS-treated groups. No evidence of morphological changes in the small airways was found 24 h after any of the exposures. The Ca(2+)-dependent and Ca(2+)-independent NOS activities (mainly produced by iNOS) in the BALF, as well as the production of NO, were significantly elevated 24 h after any of third and fourth exposures in LPS-treated groups. CONCLUSIONS: Our results demonstrate that repetitive intraperitoneal LPS can induce persistent AHR which occurs earlier when the frequency of injection increase, and an elevation of NO production and iNOS activity may be involved in is systemic-LPS-induced AHR.

Animals↗
PubMed2006

GABA-site antagonism and pentobarbital actions do not depend on the alpha-subunit type in the recombinant rat GABA receptor.

AIM: The roles of alpha-subunits on the gamma-aminobutyric acid (GABA)-site antagonism and pentobarbital actions were examined in rat recombinant GABA(A) receptors in Xenopus oocytes. METHODS: Experiments were performed with binary and ternary GABA(A) receptors containing alpha1-, alpha4- or alpha5-subunit by the two-electrode voltage-clamp technique. RESULTS: The potency of GABA was significantly higher in the alpha1beta2, alpha4beta2 and alpha5beta2 receptors compared with the alpha1beta2gamma2L, alpha4beta2gamma2L and alpha5beta2gamma2L receptors. However, the alpha5beta2 receptor possessed significantly lower GABA efficacy compared with the alpha5beta2gamma2L receptor. While the gamma2-subunit was essential to the potency of GABA, its influence on the apparent GABA-site antagonism was less profound. The antagonist affinity constants (K(B)) of bicuculline inhibition and slopes of Schild plots were similar between all types of ternary and binary receptors except alpha5beta2 receptor which was not tested. The pK(B)s and IC(50)s of the GABA-site antagonism were not significantly different between the alpha1beta2gamma2L, alpha4beta2gamma2L and alpha5beta2gamma2L receptors. Bicuculline blocked pentobarbital-activated currents in a reversible and non-competitive manner with the alpha1beta2gamma2L, alpha4beta2gamma2L, and alpha5beta2gamma2L receptors, indicating an allosteric inhibition of the GABA-site. No significant difference of bicuculline potencies in inhibiting GABA- and pentobarbital-activated currents was found between the alpha1beta2gamma2L, alpha4beta2gamma2L and alpha5beta2gamma2L receptors. CONCLUSION: The GABA-site antagonism does not depend on the subtype of alpha-subunits. Similarly, pentobarbital activates ternary receptors composed of different alpha-subunits in a bicuculline-sensitive manner. The potencies of bicuculline to inhibit pentobarbital-activated currents are identical with receptors containing alpha1, alpha4 or alpha5-subunit. The alpha1beta2 and alpha4beta2 receptors possess higher GABA potencies compared with the alpha1beta2gamma2L and alpha4beta2gamma2L receptors.

Animals↗
PubMed2004

Dynamic aspects of acute tolerance to allopregnanolone evaluated using anaesthesia threshold in male rats.

BACKGROUND: It is unclear if allopregnanolone (AlloP) anaesthesia can induce tolerance. Acute tolerance is defined as altered sensitivity to a drug during a single continuous exposure. METHODS: Induction of acute tolerance to AlloP was studied in male rats using a threshold technique of deep anaesthesia. AlloP was infused at a dose rate of 4.0 mg kg(-1) min(-1). The infusion was stopped when a burst suppression of 1 s or more (the "silent second", SS) occurred in the EEG. To maintain anaesthesia, the infusion was restarted when no SS had been seen in the EEG for 1 min. This interrupted targeted infusion towards an EEG end-point (SS) was continued until 30, 60 or 90 min of anaesthesia had been reached. At these times the rats were killed and AlloP concentrations in serum, muscle, fat and different brain regions were determined by radioimmunoassay. RESULTS: Maintenance dose rate (MDR) was calculated using 20-min intervals. During anaesthesia the MDR increased (P<0.001) from 0.67 (sem 0.03) mg kg(-1) min(-1) (in the interval 10-30 min) to 0.98 (0.04) mg kg(-1) min(-1) (in the interval 65-85 min). After 60 min a slight increase in MDR was observed. After 90 min of anaesthesia the AlloP concentrations in the hippocampus and brainstem had increased by more than 50% compared with control values of 25.2 (1.13) and 52.7 (5.81) nmol g(-1) respectively, and after 60 min to around 40%. At 30 min no increase was seen in any brain region analysed. CONCLUSIONS: Measurements in vivo and in vitro record acute tolerance to AlloP occurring with a delay.

Adipose Tissue↗
PubMed2004

Factors associated with transmission of severe acute respiratory syndrome among health-care workers in Singapore.

Between 1 and 22 March 2003, a nosocomial outbreak of Severe Acute Respiratory Syndrome (SARS) occurred at the Communicable Disease Centre in Tan Tock Seng Hospital, Singapore, the national treatment and isolation facility for patients with SARS. A case-control study with 36 cases and 50 controls was conducted of factors associated with the transmission of SARS within the hospital. In univariate analysis, contact with respiratory secretions elevated the odds ratio to 6.9 (95 % CI 1.4-34.6, P= 0.02). Protection was conferred by hand washing (OR 0.06, 95% CI 0.007-0.5, P=0.03) and wearing of N95 masks (OR 0.1, 95% CI 0.03-0.4, P=0.001). Use of gloves and gowns had no effect. Multivariate analysis confirmed the strong role of contact with respiratory secretions (adjusted OR 21.8, 95 % CI 1.7 274.8, P=0.017). Both hand washing (adjusted OR 0.07, 95 % CI 0.008-0.66, P=0.02) and wearing of N95 masks (adjusted OR 0.1, 95% CI 0.02-0.86, P=0.04) remained strongly protective but gowns and gloves had no effect.

Adult↗
PubMed2004

In vitro assessment of intestinal permeability and hepatic metabolism of 4'-bromoflavone, a promising cancer chemopreventive agent.

1. The intestinal permeability and hepatic metabolism of the investigational cancer chemoprevention agent 4'-bromoflavone were investigated in vitro using human intestinal Caco-2 cell monolayers, human liver microsomes and human hepatocytes. Liquid chromatography-mass spectrometry and tandem mass spectrometry were used for quantitative analysis in support of the Caco-2 cell studies and for the characterization of metabolites of 4'-bromoflavone. 2. The Caco-2 cell model indicated that 4'-bromoflavone would be absorbed by the intestine at a moderate rate by means of direction-independent, passive diffusion. There was no indication of active transport or efflux. 3. Three monohydroxylated metabolites and one monohydroxylated, hydrated metabolite of 4'-bromoflavone were detected at relatively low levels in the human liver microsomal and hepatocyte incubations. The structures of these metabolites were confirmed by comparison with synthetic standards. Hydroxylation occurred on the A-ring of 4'-bromoflavone but not on the B-ring, probably due to deactivation of the B-ring by bromine. No phase II metabolites were detected following incubation of 4'-bromoflavone in these in vitro systems. 4. In conclusion, these studies predict that 4'-bromoflavone should show moderate oral bioavailability, and that it would probably be excreted as unchanged compound and monohydroxylated metabolites. The results might be helpful in the design of clinical trials and in the interpretation of pharmacokinetic studies of 4'-bromoflavone.

Antineoplastic Agents↗
PubMed2003

CMT with pyramidal features. Charcot-Marie-Tooth.

To determine whether Charcot-Marie-Tooth (CMT) with pyramidal features is genetically distinct from other dominantly inherited axonal neuropathies, the authors examined all chromosomal loci and genes for axonal CMT. Two families were identified with an axonal CMT phenotype with distal wasting, weakness, pes cavus, sensory loss, and mild pyramidal signs (including extensor plantar responses, mild increase in tone, and preserved or increased reflexes but no spastic gait). Linkage studies excluded CMT2A, 2B, 2D, 2E, and 2F; ALS4; and HMN2. There were no mutations in the PMP22, MPZ/Po, or EGR2 genes.

Adolescent↗
PubMed2002

Co-activation of the phosphatidylinositol-3-kinase/Akt signaling pathway by N-methyl-D-aspartate and TrkB receptors in cerebellar granule cell neurons.

Neuroprotective concentrations of N-methyl-D-aspartate (NMDA) promote survival of cerebellar granule cell neurons against glutamate excitotoxicity through a TrkB receptor-mediated brain-derived neurotrophic factor (BDNF) autocrine loop. However, the intracellular signaling pathway(s) are not clear. Our results show that PI-3 kinase/Akt is activated by either NMDA or BDNF displaying differential kinetics. BDNF and NMDA increased Akt phosphorylation within 5 minutes but maximal activation by NMDA was observed at 3 hours. Akt phosphorylation was completely blocked by the PI-3 kinase inhibitor LY294002. NMDA-mediated activation of Akt was completely blocked by MK-801 and partially blocked by the TrkB receptor inhibitor, K252a, indicating the requirement of TrkB receptors for maximal activation by NMDA. In contrast, BDNF-induced Akt phosphorylation was abolished by K252a, but not by the addition of MK-801. Therefore, the PI-3 kinase/Akt pathway is co-activated by NMDA and TrkB receptors. The kinetics of BDNF and NMDA-mediated activation of PI-3 kinase/Akt suggests that they have different roles in intraneuronal time-related events.

Animals↗
PubMed2002

Autosomal dominant juvenile amyotrophic lateral sclerosis and distal hereditary motor neuronopathy with pyramidal tract signs: synonyms for the same disorder?

Autosomal dominant juvenile amyotrophic lateral sclerosis (ALS) is a rare disorder and so far only one family has been reported. Genetic linkage studies mapped the disease locus to chromosome 9q34 (ALS4). The diagnosis of ALS in this family is based on the clinical signs with almost exclusively lower motor neurone pathology in combination with less prominent pyramidal tract signs. Atypical features include normal life expectancy, the absence of bulbar involvement and the symmetrical distal distribution of atrophy and weakness. We performed a molecular genetic study in three families that we had diagnosed as having distal hereditary motor neuronopathy, i.e. distal spinal muscular atrophy or spinal Charcot-Marie-Tooth syndrome, and found linkage to the ALS4 locus. The clinical phenotype in these three families, of different geographic origin (Austria, Belgium and England), is strikingly similar to the autosomal dominant juvenile ALS family except for a younger onset age in two of the distal hereditary motor neuronopathy families. These data suggest that ALS4 and distal hereditary motor neuronopathy with pyramidal tract signs may be one and the same disorder.

Adolescent↗
PubMed2002

The pattern of estradiol and progesterone differs in serum and tissue of benign and malignant ovarian tumors.

Epidemiological studies have indicated a relationship between gonadal steroid hormones and ovarian cancer. A production of both estradiol and progesterone by ovarian cancers has been demonstrated. The local steroid concentrations and the putative relation to histopathological and clinical condition were investigated herein. Ovarian tissue, ovarian tumor cyst fluid, ovarian vein samples and peripheral serum concentrations of estradiol and progesterone in pre- and post-menopausal women, subdivided into groups with normal ovaries, benign, borderline and malignant ovarian tumors, were quantitatively assessed. Both ovarian tissue concentrations of estradiol and progesterone were more than 100-fold higher than in serum. Based on differences in concentrations between different ovarian tumor groups, the data is not coherent with the previously suggested increased production of estradiol and progesterone in ovarian cancer tissue, since post-menopausal women with ovarian cancer presented lower median tissue hormone levels, most pronounced between malignant and benign tumors; median (25 and 75 percentile) estradiol; 9.40 (6.67-15.50) vs 16.44 (12.49-23.20), p=0.02 and progesterone; 308 (240-575) vs 957 (553-1143) pmol/g wet weight, p<0.01, n=81. Lower concentrations of estradiol, but not progesterone, were found in ovarian cancer tissue, ovarian cyst fluid and peripheral serum in patients with FIGO stages 3 and 4 than in stages 1 and 2. The novel finding of a large ovarian tissue to serum difference of both estradiol and progesterone indicates an important role of ovarian tissue concentrations in tumor biology and raises the question of adequate doses of anti-hormonal therapy in women with ovarian cancer.

Cyst Fluid↗
PubMed2001

Transplant coronary artery disease: a novel model independent of cellular alloimmune response.

BACKGROUND: Allograft coronary atherosclerosis (TxCAD) is the leading cause of death after the first year after transplantation. TxCAD is believed to be a form of chronic rejection of the cardiac allografts. This study was undertaken to determine whether TxCAD could develop in the absence of a cellular alloimmune response. METHODS AND RESULTS: Inbred lean Zucker rats (>26 generations) served as donors and recipients of the cardiac grafts. Donor hearts were explanted at 60 or 90 days. Explanted hearts were processed for coronary artery histological analysis. Cytokine expression was determined by reverse transcription-polymerase chain reaction, and the presence of T cells within the explanted hearts was evaluated by immunohistochemistry. Forty-six transplantations were made, and TxCAD developed in all but one of the transplanted hearts. Overall, one third of the vessels examined were affected by TxCAD, and in roughly half of these vessels, the disease was severe. Native hearts were free of atherosclerosis. Interleukin-2 was absent from the transplanted hearts, and T cells were present in minimal amounts (<1 per low-power field). CONCLUSIONS: TxCAD developed in the absence of a cellular alloimmune response in these genetically similar donors and recipients. The observed TxCAD was significant and comparable to what is found in rat allografting models.

Animals↗
PubMed2001

Contrasting molecular pathology of colorectal carcinoma in Egyptian and Western patients.

Colorectal carcinoma is uncommon in Egypt, but a high proportion of cases occurs before age 40 years and in the rectum. We compared the molecular pathology of 59 representative Egyptian patients aged 10-72 to Western patients with sporadic, young-onset, or hereditary non-polyposis colorectal cancer syndrome (HNPCC)-associated carcinoma and found significant differences. Most Egyptian cancers were rectal (51%) and poorly differentiated (58%). High levels of microsatellite instability (MSI-H) were frequent (37%) and attributable in some cases (36%) to methylation of the promoter of the hMLH1 mismatch repair gene, but no MSI-H cancer had loss of hMSH2 mismatch repair gene product of the type seen with germline hMSH2 mutation in HNPCC. K-ras mutation was uncommon (11%). In subset analyses, high frequencies of MSI-H in rectal carcinomas (36%) and p53 gene product overexpression in MSI-H cancers (50%) were found. MSI-H and K-ras mutation in Egyptians under age 40 were unusual (17% and 0%, respectively), and schistosomiasis was associated with MSI and K-ras mutation. Cluster analysis identified 2 groups: predominantly young men with poorly differentiated mucinous and signet-ring cell colorectal carcinoma lacking K-ras mutation; older patients who had well- or moderately differentiated adenocarcinoma often with MSI-H, K-ras mutation and schistosomiasis. Our findings show that the molecular pathology of colorectal cancer in older as well as younger Egyptians has unique differences from Western patients, and schistosomiasis influences the molecular pathogenesis of some tumours.

Adolescent↗