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Biomedical subjects

Z Zhu

Publications and source records attributed to Z Zhu.

At least 199 records · Page 11Linked to original sources
PubMed1999

WHI-05, a novel bromo-methoxy substituted phenyl phosphate derivative of zidovudine, is a dual-action spermicide with potent anti-HIV activity.

Heterosexual transmission of HIV to women is the fastest-growing mode of transmission. In a systematic effort to develop a microbicide capable of preventing HIV transmission as well as providing fertility control, novel phenyl phosphate derivatives of 3'-azido-3'-deoxythymidine (zidovudine, ZDV) have been identified that exhibit potent anti-HIV and spermicidal activities. This study reports the synthesis, characterization, and preclinical formulation of compound WHI-05, 5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-methoxyphenyl) methoxyalaninyl phosphate. The anti-HIV activities of WHI-05 and ZDV were compared by measuring p24 antigen production and reverse transcriptase activity as markers of viral replication using human peripheral blood mononuclear cells (PBMC) infected with both ZDV-sensitive and ZDV-resistant strains of HIV. The sperm immobilizing activity (SIA) of WHI-05 was compared with that of ZDV and nonoxynol-9 (N-9) by computer-assisted sperm analysis (CASA). The effect of WHI-05 on sperm membrane integrity was examined by high resolution, low voltage scanning electron microscopy (HR-LVSEM). The in vitro cytotoxicity profile of WHI-05 versus N-9 were compared using normal human vaginal, ectocervical, and endocervical epithelial cells. The in vivo vaginal tolerance, absorption, and toxicity of a 2% WHI-05 gel-microemulsion was tested in the rabbit. Whereas ZDV displayed potent anti-HIV activity but lacked SIA, WHI-05 elicited both potent anti-HIV activity and SIA. WHI-05 inhibited the replication of ZDV-sensitive as well as ZDV-resistant strains of HIV in PBMC. CASA combined with HR-LVSEM demonstrated that WHI-05-induced SIA was not associated with membrane damage. Unlike, N-9, the spermicidal activity of WHI-05 was not associated with cytotoxicity to reproductive tract epithelial cells. Repetitive intravaginal application of a 2% WHI-05 gel-microemulsion did not damage the vaginal epithelium or cause local inflammation in the rabbit model. As a potent anti-HIV agent that has spermicidal activity and is devoid of mucosal toxicity, WHI-05 shows a unique clinical potential to become the active ingredient for a vaginal contraceptive for women who are at high risk for acquiring HIV by heterosexual vaginal transmission.

Animals↗
PubMed1999

Inhibition of tumor growth and metastasis by targeting tumor-associated angiogenesis with antagonists to the receptors of vascular endothelial growth factor.

Angiogenesis, the formation of new blood vessels, is essential for both tumor growth and metastasis. Recent advances in our understanding of the molecular mechanisms underlying the angiogenesis process and its regulation have led to the discovery of a variety of pharmaceutical agents with anti-angiogenic activity. The potential application of these angiogenesis inhibitors is currently under intense clinical and pre-clinical investigation. Compelling evidence suggests that vascular endothelial growth factor (VEGF) and its receptors play critical roles in tumor-associated angiogenesis, and that they represent good targets for therapeutic intervention. This has been demonstrated in a variety of animal tumor models in which disabling the function of VEGF and its receptors was shown to inhibit both tumor growth and metastasis. We have produced a panel of antibodies directed against the VEGF receptor 2, KDR/F1k-1. These antibodies potently block VEGF/KDR/F1k-1 interaction, and inhibit VEGF-stimulated activation of the receptor and proliferation of human endothelial cells. Further, the antibodies significantly inhibited tumor-associated angiogenesis in several animal models. Antagonists of VEGF and/or its receptors may offer higher specificity towards tumors with reduced side effects, and may be less likely to elicit drug resistance compared to conventional therapy. Anti-angiogenesis therapy represents a novel strategy for the treatment of cancer and other human disorders where pathological angiogenesis is involved.

Angiogenesis Inhibitors↗
PubMed1999

Synthesis of meso-tetra-(3,5-dibromo-4-hydroxylphenyl)-porphyrin and its application to second-derivative spectrophotometric determination of lead in clinical samples.

A new very sensitive and selective chromogenic reagent, meso-tetra-(3,5-dibromo-4-hydroxylphenyl)porphyrin [T(DBHP)P], was synthesized and studied for the determination of trace lead in detail. In 0.10 mol l-1 NaOH medium, lead reacts with T(DBHP)P to form a 1:2 yellow complex, which gives a maximum absorption at 479 nm; 0-0.48 microgram ml-1 Pb(II) obeyed Beer's law. The molar absorptivity of the complex and Sandell's sensitivity are 2.5 x 10(5) 1 mol-1 cm-1 and 0.000812 microgram cm-2, respectively. Second-derivative spectrophotometry is better than conventional spectrophotometry in sensitivity and selectivity, and its limit of quantification, limit of detection and relative standard deviation are 0.70 ng ml-1, 0.21 ng ml-1 and 1.0%, respectively. Ca (3250-fold), Mg (2000-fold), Sr (1000-fold), Ba (750-fold), Al (1000-fold), Bi (500-fold), Fe (2000-fold), Co (750-fold), Ni (1000-fold), Cu (750-fold), Zn (1250-fold), Cd (2500-fold) and Ag (550-fold) do not interfere with the determination of lead. The chromogenic system is remarkably superior to other reagents, especially porphyrin compounds. The influence caused by oxygen in air or in solution can be easily eliminated by adding Na2SO3. The reaction is very stable, the stability constant of the complex being 1.2 x 10(45). The chromogenic reaction is completed within 1 min at room temperature when 8-hydroxylquinoline is used as catalyst. The proposed method has been applied to the direct determination of trace lead in clinical samples. The accuracy and precision are both very satisfactory.

Humans↗
PubMed1999

Effect of energy restriction on tissue size regulation during chemically induced mammary carcinogenesis.

Energy restriction (ER) has documented beneficial effects on numerous diseases including cancer, yet the mechanism(s) that accounts for these effects is unknown. Experiments were designed to determine the effect of ER: (i) on the growth and development of the mammary gland; (ii) on the growth of carcinomas induced in the mammary gland by treatment with 1-methyl-1-nitrosourea (MNU); (iii) on rates of cell proliferation and apoptosis in pre-malignant and malignant mammary lesions. Mammary carcinogenesis was induced in female Sprague-Dawley rats by the i.p. administration of MNU (50 mg MNU/kg body wt) at 21 days of age. Rats were randomized to one of four dietary treatment groups: ad libitum fed or restriction of calorie intake to 90, 80 or 60% of ad libitum intake. ER reduced the ductal extension of the mammary gland into the fat pad in proportion to its effect on growth measured as body weight, however, the reduction in ductal branching, breast density and carcinoma volume by ER was greater than its effect on body weight. An animal's breast density was predictive of its carcinogenic response, irrespective of the level of ER imposed. While ER inhibited cell proliferation and induced apoptosis in pre-malignant and malignant mammary gland lesions, the magnitude of these effects make it unlikely that they fully account for the protective effects of ER against mammary carcinogenesis.

Adipose Tissue↗
PubMed1999

Growth factor receptors are differentially expressed in cancers of the papilla of vater and pancreas.

OBJECTIVE: To compare growth factor receptor expression in papilla of Vater cancer and pancreatic cancer. SUMMARY BACKGROUND DATA: Cancer of the papilla of Vater has a much better prognosis than pancreatic cancer. Earlier symptoms may result in earlier diagnosis, but different biologic growth behaviors and genetic alterations might also be explanations. PATIENTS AND METHODS: Surgical specimens from papilla of Vater cancers (24 patients) and pancreatic cancers (80 patients), normal papilla of Vater tissues (20 patients), and normal pancreatic tissues (24 patients) were frozen and fixed. The authors compared the expression of the epidermal growth factor receptor (EGFR) and c-erbB2 and c-erbB3 by Northern blot, in situ hybridization, and immunohistochemistry. RESULTS: In papilla of Vater cancer, Northern blots showed comparable EGFR and c-erbB2 mRNA expression but significantly lower c-erbB3 mRNA levels than in normal papilla. In pancreatic cancer, mRNA expression was enhanced compared with normal controls for EGFR (4-fold), c-erbB2 (2.5-fold), and c-erbB3 (5.2-fold). In situ hybridization confirmed this and showed mRNA expression only in cancer cells. EGFR immunohistochemical staining scores were comparable in papilla of Vater cancer (1.17 +/- 0.22) and normal papilla (1.42 +/- 0.25). Staining scores for c-erbB2 (2.72 +/- 0.40 vs. 3.89 +/- 0.37) and c-erbB3 (2.78 +/- 0.35 vs. 3.89 +/- 0.53) were slightly lower than controls in papilla of Vater cancer. In pancreatic cancer, immunostaining scores for EGFR, c-erbB2, and c-erbB3 were significantly higher than controls. CONCLUSION: Members of the EGFR family show similar or lower expression in papilla of Vater cancer than in normal controls. In pancreatic cancer, these receptors are upregulated. This supports the hypothesis that papilla of Vater cancer and pancreatic cancer have biologic differences that may contribute to the different growth of these tumors.

Adult↗
PubMed1999

Localization of periplasmic redox proteins of Alcaligenes faecalis by a modified general method for fractionating gram-negative bacteria.

A lysozyme-osmotic shock method is described for fractionation of Alcaligenes faecalis which uses glucose to adjust osmotic strength and multiple osmotic shocks. During phenylethylamine-dependent growth, aromatic amine dehydrogenase, azurin, and a single cytochrome c were localized in the periplasm. Their induction patterns are different from those for the related quinoprotein methylamine dehydrogenase and its associated redox proteins.

Alcaligenes↗
PubMed1999

Sequence and insertion sites of murine melanoma-associated retrovirus.

We previously showed that B16 melanoma cells produce ecotropic melanoma-associated retrovirus (MelARV) which encodes a melanoma-associated antigen recognized by MM2-9B6 monoclonal antibody. The biological significance of MelARV in melanoma formation remains unknown. We found that infection of normal melanocytes with MelARV resulted in malignant transformation. It is likely that MelARV emerged from the defective Emv-2 provirus, a single copy of ecotropic provirus existing in the genome of C57BL/6 mice. In the present study, we cloned and sequenced the full-length MelARV genome and its insertion sites and we completed sequencing of the Emv-2 provirus. Our data show that MelARV has a typical full-length retroviral genome with high homology (98.54%) to Emv-2, indicating a close relationship between both viruses. MelARV probably emerged as a result of recombination between Emv-2 and an endogenous nonecotropic provirus. Some observed differences in the gag and pol regions of MelARV might account for the restoration of productivity and infectivity of a novel retrovirus that somatically emerged during melanoma formation. MelARV does not contain any oncogene and therefore might induce transformation by insertional mutagenesis. We sequenced two insertion sites of MelARV. The first insertion site represents the 3' coding region of the c-maf proto-oncogene at 67.0 centimorgans (cM) on chromosome 8. The c-maf proto-oncogene encodes a basic leucine zipper protein homologous to c-fos and c-jun. Insertion of MelARV in BL6 melanoma cells resulted in the up-regulation of c-maf. It is noteworthy that the Emv-2 provirus is also inserted into a noncoding region at 61.0 cM on the same chromosome 8. The second insertion site is the 3' noncoding region of the DNA polymerase gamma (PolG) gene on chromosome 7. The expression of PolG was not affected by the MelARV insertion. Further investigation of the biological significance of MelARV in melanoma formation is being undertaken.

Animals↗
PubMed1999

Dexamethasone regulation of lung epithelial cell and fibroblast interleukin-11 production.

Studies were undertaken to define the effects of corticosteroids on stromal cell interleukin (IL)-11 production. Unstimulated A549 epithelial-like cells produced modest amounts of IL-11, and transforming growth factor (TGF)-beta1 was a potent, dose-dependent stimulator of A549 cell IL-11 elaboration. Dexamethasone inhibited the levels of basal and TGF-beta1-stimulated IL-11 elaboration in a dose-dependent fashion. In the setting of TGF-beta1 stimulation, dexamethasone caused a >90% decrease in IL-11 production at 10(-6) M, a 50% decrease in IL-11 production at approximately 1 x 10(-9) M, and significant inhibition at 10(-10) M. This dexamethasone-induced inhibition was reversed by the glucocorticoid-receptor antagonist RU-486. Dexamethasone also inhibited respiratory syncytial virus, rhinovirus, and TGF-beta1-stimulated IL-11 production by MRC-5 lung fibroblasts. In all cases, dexamethasone caused comparable changes in IL-11 mRNA accumulation. Nuclear run-on studies demonstrated that dexamethasone caused a modest (</=40%) decrease in TGF-beta1-stimulated IL-11 gene transcription. Actinomycin D pulse-chase experiments demonstrated that dexamethasone simultaneously destabilized IL-11 mRNA. Dexamethasone also inhibited TGF-beta1-stimulated IL-11 promoter-driven luciferase activity but did not diminish activator protein-1 binding to IL-11 promoter sequences. Glucocorticoids inhibit lung cell IL-11 production via a complex mechanism that involves the inhibition of IL-11 gene transcription and the destabilization of IL-11 mRNA.

Cell Death↗
PubMed1999

Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production.

Interleukin (IL)-13 is a pleiotropic cytokine produced in large quantities by activated CD4(+) Th2 lymphocytes. To define further its potential in vivo effector functions, the Clara cell 10-kDa protein promoter was used to express IL-13 selectively in the lung, and the phenotype of the resulting transgenic mice was characterized. In contrast to transgene-negative littermates, the lungs of transgene-positive mice contained an inflammatory response around small and large airways and in the surrounding parenchyma. It was mononuclear in nature and contained significant numbers of eosinophils and enlarged and occasionally multinucleated macrophages. Airway epithelial cell hypertrophy, mucus cell metaplasia, the hyperproduction of neutral and acidic mucus, the deposition of Charcot-Leyden-like crystals, and subepithelial airway fibrosis were also prominently noted. Eotaxin protein and mRNA were also present in large quantities in the lungs of the transgene-positive, but not the transgene-negative, mice. IL-4, IL-5, granulocyte-macrophage colony-stimulating factor, and monocyte chemoattractant protein-5 were not similarly detected. Physiological evaluations revealed significant increases in baseline airways resistance and airways hyperresponsiveness (AHR) to methacholine in transgene-positive animals. Thus, the targeted pulmonary expression of IL-13 causes a mononuclear and eosinophilic inflammatory response, mucus cell metaplasia, the deposition of Charcot-Leyden-like crystals, airway fibrosis, eotaxin production, airways obstruction, and nonspecific AHR. IL-13 may play an important role in the pathogenesis of similar responses in asthma or other Th2-polarized tissue responses.

Airway Resistance↗
PubMed1999

AZT-5'-(p-bromophenyl methoxyalaninyl phosphate) as a potent and non-toxic anti-human immunodeficiency virus agent.

The potency and selectivity index of the AZT-phenyl phosphate derivatives in thymidine kinase (TK)-deficient T cells were substantially enhanced by introducing a single para-bromo substitutent in the phenyl moiety. AZT-5'-(p-bromophenyl methoxyalaninyl phosphate) was 43-fold more potent than AZT-5'-(phenyl methoxyalaninyl phosphate) and was fivefold more potent than AZT in inhibiting human immunodeficiency virus (HIV) replication in TK-deficient CEM cells.

Anti-HIV Agents↗
PubMed1999

Nerve growth factor expression correlates with perineural invasion and pain in human pancreatic cancer.

PURPOSE: The reasons for the high frequency of perineural invasion and the presence of pain in pancreatic cancer are still not clear. Nerve growth factor (NGF) and its high-affinity receptor TrkA are involved in stimulating epithelial cancer cell growth and perineural invasion, as well as in pain generation in chronic benign disorders. PATIENTS AND METHODS: NGF and TrkA were examined by Northern blot analysis, in situ hybridization, and immunohistochemistry in 27 normal and 37 pancreatic cancer tissue samples. The molecular findings were correlated with the degree of perineural invasion, pain, and histopathologic tumor characteristics. RESULTS: Northern blot analysis indicated that NGF and TrkA mRNA levels were increased 2.7-fold and 5.6-fold, respectively (P <.05 and P <.05), in pancreatic cancer tissues compared with the normal pancreas tissue. As shown by in situ hybridization and immunohistochemistry, NGF was strongly present in the cytoplasm of pancreatic cancer cells. TrkA was intensely present in the perineurium of pancreatic nerves but not in the cancer cells. There was no difference in NGF and TrkA expression between early (stages I and II) and advanced (stage III) tumor stages and between well-/moderately differentiated (grades 1 and 2) and poorly differentiated (grade 3) tumors. However, tumors with high NGF/TrkA expression levels exhibited more frequent perineural invasion (P <.01). Furthermore, increased NGF/TrkA expression levels were associated with a higher degree of pain (P <. 01). CONCLUSION: Enhanced expression of the NGF/TrkA system may influence perineural invasion and may contribute to the pain syndrome in human pancreatic cancer.

Adult↗
PubMed1999

Thapsigargin-insensitive calcium pools in vascular smooth muscle cells.

Since sarcoplasmic Ca2+-ATPase may play an important role for the regulation of cytosolic free calcium concentration ([Ca2+]i) and may be altered in primary hypertension, the effects of thapsigargin and bradykinin on intracellular calcium pools in cultured vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats of the Münster strain (SHR) and normotensive Wistar-Kyoto (WKY) rats were investigated. VSMC were cultured on glass cover slips and [Ca2+]i was measured using the fluorescent dye fura2. To exclude transplasmamembrane calcium influx all experiments were performed in a calcium free medium. Thapsigargin, a selective inhibitor of the sarcoplasmic Ca2+-ATPase, and bradykinin, that is known to induce inositol trisphosphate release, dose dependently caused an increase of [Ca2+]i by emptying intracellular Ca2+ stores. The peak increase of [Ca2+]i after addition of saturation doses of thapsigargin (1 micromol/L) was not significantly different in the two strains (SHR: 69 +/- 11 nmol/L, n=24; WKY: 58 +/- 12 nmol/L, n=20; mean +/- SEM). When 10 micromol/L bradykinin was added after depletion of the thapsigargin-sensitive pools, still a release of [Ca2+]i could be observed. The bradykinin-induced [Ca2+]i increase was similar in the absence and presence of thapsigargin in VSMC from SHR (62 +/- 12 nmol/L, n=20; vs 52 +/- 18 nmol/L, n=22). In contrast, in the VSMC from WKY a significant reduction of the bradykinin induced [Ca2+]i-increase could be observed after the depletion of the thapsigargin sensitive calcium pools (70 +/- 8 nmol/L, n=21, vs. 33 +/- 7, n=20; p<0.002). It is concluded that bradykinin releases calcium from a pool that is not refilled by the common, thapsigargin-sensitive Ca2+-ATPase. In contrast to VSMC from normotensive WKY, in VSMC from spontaneously hypertensive rats thapsigargin and bradykinin sensitive pools may be regulated separately.

Animals↗
PubMed1999

The influence of acupuncture on the impedance measured by four electrodes on meridians.

The impedance on the pericardium merdian near Quze (P3) and control points in 12 cases was measured by a four electrodes impedance instrument. The amplitude of impedance was recorded before, during and after needling the Neiguan. The result showed that the mean impedance on the meridian and control points before the needling were 52.8 +/- 11.0 (omega) and 61.7 +/- 10.3 (omega) respectively which had significant difference (P<0.05). During the needling, impedance decreased significantly on the meridian by 9.2 +/- 5.6 (omega) (P<0.001) while impedance decreased by only 0.12 +/- 2.4 (omega) on control points without significance (P>0.05). The impedance changed back to 51.1 +/- 11.3 (omega) and 59.9 +/- 11.0 (omega) on the meridian and control points respectively during the 5-10 minutes after withdrawing the needling. In some cases, impedance changed intermittently during the needling. The experiment implies that interstitial fluid increases during the needling by axon reflection and blood capillary expanding which may be one of the mechanisms of acupuncture regulation.

Acupuncture Therapy↗
PubMed1999

Effects of diagnostic levels of color Doppler ultrasound energy on the cell cycle of newborn rats.

Our objective was to evaluate the safety of diagnostic levels of color Doppler ultrasound energy in the field of obstetrics and to provide the experimental data for its clinical application. After insonating pregnant rats with diagnostic levels of color Doppler ultrasound energy, we studied the cell cycles of the newborn rats by flow cytometry and factorial analysis. We found that the deoxyribonucleic acid content was not affected in any phase of the cell cycle in newborn rats by any of the different insonation times and frequencies.

Animals↗
PubMed1999

[Comparison of internal fixation with mini-titanium plate and wire osteosynthesis in midface fractures].

OBJECTIVE: To compare clinical results of the internal fixation with wire and the internal fixation with mini-titanium plate in midface fractures. METHODS: By the coronal approach and supplementary incisions, forty patients with midface fractures were treated with wire osteosynthesis or rigid internal fixation (RIF) with mini-titanium plate. RESULTS: A good stability can not he obtained with wire osteosynthesis in the treatment of midface fractures. The supporting bony structure of midface can be reconstructed with mini-titanium plate RIF, which results in a sufficient three-dimensional stability of the fractured segments and an ideal facial configuration Mini-titanium plate RIF is more convenient and reliable than wire osteosynthesis in the difficult operation fields of the infraorbital margin and zygomaticomaxillary suture. CONCLUSION: Mini-titanium plate RIF is the best method for treatment of midface fractures.

Adult↗
PubMed1999

PCR assay for the inversion causing severe Hemophilia A and its application.

OBJECTIVE: To develop a new technique based on long distance polymerase chain reaction (LD-PCR) to replace Southern blotting method to detect Factor VIII (FVIII) gene inversion leading to severe Hemophilia A (HA) and carrier. METHODS: Four primers P, Q, A&B were designed and synthesized. P&Q is specific for 5' and 3' flanking regions of F8A1 respectively. A&B is specific for 5' and 3' flanking regions of F8A2/F8A3 respectively. LD-PCR with 3 primers and 3 temprature was set up, optimized and used to detect the inversion. RESULTS: The LD-PCR with primers P, Q, A&B, P, Q&B and P, Q&A can be used to detect the gene inversion and discriminate carrier from wild type. A blind analysis of 53 DNA samples from HA families was carried out by the LD-PCR and Southern blotting respectively. Two sets of the results were completely identical. They were 23 cases of inversion, 27 cases of wild type and 3 cases of carriers. The sensitivity and specificity of LD-PCR are both 100%. Three inversion hemizygotes and 4 female carriers were identified from 5 HA families by the LD-PCR technology. CONCLUSIONS: The LD-PCR with primer P, Q&B or P, Q, A&B can be used to detect the gene inversion and the carrier of inversion. Compared with Southern blotting, this technique is simple, rapid, inexpensive, more sensitive, accurate and non-isotopic.

Chromosome Inversion↗
PubMed1999

Amplified fragment length polymorphism analysis on D5S436 locus and its application to linkage analysis in gene diagnosis of asthma.

OBJECTIVES: To detect the polymorphism of D5S436 locus, and to carry out an amplified fragment length polymorphism (Amp-FLP) genotyping linkage analysis in asthma families. METHODS: Allele and genotype frequencies of the high polymorphic D5S436 locus were determined in 92 unrelated Chinese individuals by using polymerase chain reaction (PCR). The amplified fragments were separated by denaturing polyacrylamide gel electrophoresis and silver staining techniques. RESULTS: Eight alleles and 22 genotypes were observed in this population. The heterozygosity was 78.26%. The polymorphism information content (PIC) was 0.76. Amp-FLP genotyping linkage analyses were carried out in four asthma families, demonstrating that the locus was inherited according to Mendel's law and had a clear result. CONCLUSION: The PIC of D5S436 is high in Chinese individuals, so it could be used as a genetic marker of asthma in Chinese and might be useful in the gene diagnosis of asthma.

Alleles↗