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Biomedical subjects

H T Zhang

Publications and source records attributed to H T Zhang.

35 records · Page 2Linked to original sources
PubMed1997

Nitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not basic fibroblast growth factor-induced angiogenesis.

Systemic administration of the nitric oxide (NO) synthase inhibitor Nomega-nitro--arginine methyl ester (L-NAME) to rabbits bearing a corneal implant blocked vascular endothelial growth factor (VEGF), but not basic fibroblast growth factor (bFGF)-induced angiogenesis. L-NAME completely blocked angiogenesis induced by VEGF-transfected MCF-7 breast carcinoma cells and the cells remained dormant in the cornea. Postcapillary endothelial cell migration and growth induced by VEGF were blocked by both the NO synthase inhibitor Nomega-mono-methyl--arginine and by the guanylate cyclase inhibitor LY 83583. We conclude that NO is a downstream imperative of VEGF-, but not bFGF-induced angiogenesis, and propose that the NO synthase/guanylate cyclase pathway is a potential target for controlling tumor angiogenesis in response to VEGF. Our studies support recent evidence that VEGF and bFGF induce angiogenesis by different mechanistic pathways using the alphavbeta5 and alphavbeta3 integrins, respectively.

Animals↗
PubMed1997

An angiogenic role for the neurokines midkine and pleiotrophin in tumorigenesis.

Recent analysis of bladder tumors has correlated expression of the neurokine midkine (MK) with poor patient survival. To examine a role for MK and the related pleiotrophin (PTN) in tumorigenesis, they were overexpressed in MCF-7 breast carcinoma cells. Expression had no effect on in vitro growth but conferred a growth advantage in vivo. Enhanced tumor growth correlated with increased vascular density and endothelial proliferation, implicating an angiogenic role for MK and PTN. Angiogenic activity of MK and PTN was confirmed in the rabbit corneal assay. Our data therefore identify two novel targets for antiangiogenic drug development.

Animals↗
PubMed1997

Trans receptor inhibition of human glioblastoma cells by erbB family ectodomains.

Our aim has been to understand the features of erbB receptor homo- and heterodimer assembly to develop approaches to disrupt receptor activation. We have developed a general approach to cause erbB receptor-specific trans inhibition of human neoplasia. The clonal progression of human astrocytomas to a more malignant phenotype often involves the amplification and overexpression of the epidermal growth factor receptor (EGFr) gene. We have selectively targeted the EGFr in human glioblastoma cells with kinase-deficient mutants of the erbB family derived from the ectodomain of the Neu oncogene that are able to form heterodimers with EGFr and inhibit EGFr-dependent phenotypes. In EGFr-positive U87MG human glioblastoma cells, expression of the Neu ectodomain inhibits EGF-, but not platelet-derived growth factor-, induced DNA synthesis; inhibits cell proliferation in the presence of EGF, but not platelet-derived growth factor; inhibits the ability of U87MG to form colonies in soft agar; and inhibits transforming efficiency in athymic mice. These studies establish that EGFr-mediated signal transduction is important in the maintenance of malignant glioma, and that trans receptor inhibition is a novel way to abrogate abnormal growth of these tumors. Neu ectodomains will be useful in determining the manner in which the EGFr contributes to glial tumorigenesis and in the design of pharmaceuticals that disable erbB family oncoproteins. In addition, these studies provide a rationale for the application of the Neu ectodomain in gene therapy approaches to human malignant glioma and, potentially, to other systemic epithelial malignancies expressing erbB family receptors.

Animals↗
PubMed1997

Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses.

Wilson disease (WD) is an autosomal recessive disorder characterized by toxic accumulation of copper in the liver and subsequently in the brain and other organs. On the basis of sequence homology to known genes, the WD gene (ATP7B) appears to be a copper-transporting P-type ATPase. A search for ATP7B mutations in WD patients from five population samples, including 109 North American patients, revealed 27 distinct mutations, 18 of which are novel. A composite of published findings shows missense mutations in all exons-except in exons 1-5, which encode the six copper-binding motifs, and in exon 21, which spans the carboxy-terminus and the poly(A) tail. Over one-half of all WD mutations occur only rarely in any population sample. A splice-site mutation in exon 12 accounts for 3% of the WD mutations in our sample and produces an in-frame, 39-bp insertion in mRNA of patients homozygous, but not heterozygous, for the mutation. The most common WD mutation (His1069Glu) was represented in approximately 38% of all the WD chromosomes from the North American, Russian, and Swedish samples. In several population cohorts, this mutation deviated from Hardy-Weinberg equilibrium, with an overrepresentation of homozygotes. We did not find a significant correlation between His1069Glu homozygosity and several clinical indices, including age of onset, clinical manifestation, ceruloplasmin activity, hepatic copper levels, and the presence of Kayser-Fleischer rings. Finally, lymphoblast cell lines from individuals homozygous for His1069Glu and 4 other mutations all demonstrated significantly decreased copper-stimulated ATPase activity.

Adenosine Triphosphatases↗
PubMed1997

[Regulation of the central opioidergic nervous system on the emotional state of anxiety and its possible mechanisms].

The spontaneous withdrawal from morphine in morphine-dependent rats significantly decreased the duration of active interaction in social interaction test and the number of licks during the shock-punished period in Vogel's conflict procedure, which were attenuated by buspirone, a 5-HT1A agonist, as well as para-chlorophenylalanine (PCPA), an inhibitor of tryptophan hydroxylase. Naltrexone (NTX), a potent opioid receptor antagonist, also dose- and time-dependently reduced both indices mentioned above, which was blocked by morphine or PCPA and was enhanced by 5-hydroxytryptophan, a precursor of 5-HT. In the test of neurotransmitter releases in rat brain slices, both morphine-withdrawal and NTX enhanced high potassium(30mM)-induced 5-HT release in slices of the area of the raphe nucleus. These results suggested that both morphine-withdrawal and NTX produced anxieties in morphine-dependent and normal rats, respectively, which were mediated by the central 5-HTergic neurotransmission. Central opioidergic neurons inhibited 5-HTergic neurons tonically and presynaptically. Such an effect was reduced or blocked by NTX, or during morphine-withdrawal, and 5-HTergic neurons were disinhibited, leading to a state of anxiety.

Animals↗
PubMed1996

Anxiogenic effect of naltrexone in social interaction test in rats.

AIM: To study the anxiogenic effect of naltrexone (Nal) on the emotional state of rats. METHODS: The duration of active interaction was measured in the social interaction test in rats. RESULTS: Without influence on the locomotor activity, Nal (0.1-50 mg.kg-1) dose- and time-dependently decreased the duration of active interaction, which was antagonized by morphine (5 mg.kg-1) or fenclonine (Fen, 150 mg.kg-1 x 3 d) and was enhanced by 5-hydroxytryptophan (5-HTP, 50 mg.kg-1). CONCLUSION: Nal produced anxiety via its blockade of opioid receptors; central opioidergic neurons were involved in the regulation of anxiety through their tonic inhibitions in serotonergic neurons.

Animal Communication↗
PubMed1995

Thymidine phosphorylase is angiogenic and promotes tumor growth.

Platelet-derived endothelial cell growth factor was previously identified as the sole angiogenic activity present in platelets; it is now known to be thymidine phosphorylase (TP). The effect of TP on [methyl-3H]thymidine uptake does not arise from de novo DNA synthesis and the molecule is not a growth factor. Despite this, TP is strongly angiogenic in a rat sponge and freeze-injured skin graft model. Neutralizing antibodies and site-directed mutagenesis confirmed that the enzyme activity of TP is a condition for its angiogenic activity. The level of TP was found to be elevated in human breast tumors compared to normal breast tissue (P < 0.001). Overexpression of TP in MCF-7 breast carcinoma cells had no effect on growth in vitro but markedly enhanced tumor growth in vivo. These data and the correlation of expression in tumors with malignancy identify TP as a target for antitumor strategies.

Animals↗
PubMed1995

Enhancement of tumor growth and vascular density by transfection of vascular endothelial cell growth factor into MCF-7 human breast carcinoma cells.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a secreted endothelial-specific growth factor that is angiogenic in vivo. It is commonly expressed in a range of carcinomas. PURPOSE: The study was designed to investigate the effect of constitutive expression of VEGF on tumor formation by estrogen-dependent human MCF-7 breast carcinoma cells. METHODS: A full-length complementary DNA encoding the shortest isoform of VEGF (VEGF121) was stably transfected into MCF-7 cells. Transfected clones were screened for VEGF121 messenger RNA (mRNA) expression by ribonuclease protection analysis and for secretion of VEGF121 protein by Western blot analysis. Secretion of biologically active VEGF121 by transfectants was confirmed by 1) a competitive radioreceptor-binding assay, 2) stimulation of the growth of microvascular endothelial cells in vitro, and 3) potent angiogenic activity in the rabbit corneal assay. Tumor models were then established by subcutaneously implanting wild-type or VEGF121-transfected MCF-7 cells, together with either mouse BALB/3T3 clone A31 fibroblasts or human MDA-435S breast carcinoma cells, into ovariectomized nude mice either with or without a separately implanted slow-release estrogen pellet. Tumor vascularity was quantitatively assessed by capillary vessel counting after staining with the pan-endothelial marker CD31. RESULTS: Stable VEGF121-overexpressing MCF-7 cells were isolated and designated V12 cells. When implanted into the rabbit cornea, V12 cells elicited a strong directional outgrowth of capillaries. The growth rate of V12 cells in vitro was indistinguishable from that of MCF-7 wild-type cells. V12 cells formed faster growing tumors than did wild-type cells (P < .01) when xenografted subcutaneously into nude mice with either 3T3 fibroblasts or MDA-435S cells. Tumors formed from V12 cells were more vascular (P < .01) and showed a heterogeneous distribution of vessels when compared with the homogeneous distribution seen in tumors formed from wild-type cells. VEGF121 overexpression had no effect on hormone dependence or tamoxifen sensitivity of tumor formation by MCF-7 cells in mice. No macroscopic evidence for metastasis from subcutaneous implants was obtained. CONCLUSIONS: VEGF121 expression by breast carcinoma cells confers a growth advantage in vivo but not in vitro. Tumors formed by V12 transfectants were more vascular than those formed by wild-type MCF-7 cells, and we surmise that the growth advantage arises from increased tumor vascularization induced by VEGF121. IMPLICATIONS: Tumor formation by V12 cells could provide a useful model for the assessment of anti-angiogenic drugs.

3T3 Cells↗
PubMed1995

Production of human insulin in an E. coli system with Met-Lys-human proinsulin as the expressed precursor.

The construction of a gene encoding Lys-human proinsulin, its direct expression in E. coli, and the simple purification procedure are described here. The temperature inducible promotor was employed for induction in a very short time. The expression level could reach 20-30%. After simple downstream processing and only one step of Sephadex G50 purification, 150 mg recombinant Lys-human proinsulin with a purity of up to 90% could be obtained easily from 1 L of high density fermentation medium. The obtained product is in the form of Met-Lys-human proinsulin because of the failure of the bacterial host to remove the initiator methionine residue. The Lys-human proinsulin could be changed into human insulin by trypsin and carboxypeptidase B treatment in later steps. After separation with DEAE-Sephadex A25, human insulin with expected amino acid composition and full native biological activity could be obtained with a yield of 50 mg/L of fermentation medium.

Base Sequence↗
PubMed1994

[Effect of BN52021 on platelet activating factor induced aggregation of psoriatic polymorphonuclear neutrophils].

We investigated the aggregation of PMN from 20 psoriasis patients (PP) and 12 health persons (HP) to PAF and the effect of PAF antagonist BN 52021 on the aggregation. PAF induced a dose dependent aggregative response of polymorphonuclear neutrophils (PMN) from PP and HP. The aggregative responses of PMN from PP to lower concentrations of PAF were increased (P < 0.05) and to higher concentrations of PAF were not different to that of PMN from HP. BN 52021 could time- and dose-dependently inhibit the aggregation of PMN from PP and HP to PAF, and their IC50 was 1.3 x 10(-6) mol and 1.2 x 10(-6) mol respectively. It is suggested that PAF and PMN play an important pathophysiological role in the development of psoriasis, and application of PAF antagonists may be a new and effective approach to the management of psoriasis.

Adult↗
PubMed1993

[Potentiating effect of clonidine on anxiolytic action of buspirone in rats].

The anxiolytic effects of buspirone (Bus) and clonidine (Clo) were studied in the social interaction (SI) test and the elevated plus-maze (EPM) in rats. Bus 1 mg.kg-1 (ip, 15 min) and Clo 10 micrograms.kg-1 (ip, 15 min) prolonged the active interaction time (AIT) in the SI test. While neither Bus 0.3 mg.kg-1 nor Clo 3 micrograms.kg-1 was effective in this model, combination of them increased AIT. Yohimbine 30 micrograms.kg-1 (ip, 15 min before Bus) reversed such a potentiating effect. On the other hand. Bus 0.3 mg.kg-1 or/and Clo 3 micrograms.kg-1 did not affect the VI (variable interval) schedule-controlled behavior. In EPM test, neither Bus 0.5 mg.kg-1 nor Clo 30 micrograms.kg-1 increased the percentages of open-arms entries (OE%) or of the time spent in open-arms (OT%). But these 2 indices were increased by combining Bus 0.5 mg.kg-1 with Clo 30 micrograms.kg-1. The results suggested that Clo potentiated the anxiolytic effect of Bus probably by its alpha 2-adrenoceptor agonist action in SI and EPM tests.

Animals↗
PubMed1988

[Effects of allogeneic LAK cells on the function of immune system of the recipients].

SHR rats, 1 week of age, were i.p. inoculated with allogeneic JB LAK cells generated by 3-day incubation of spleen cells of JB rats in CM-IL 2. The spleens were removed 4 and 12 weeks later and their cells were tested for proliferative potential to mitogens and their response and production of IL2. The results demonstrated that the allo-LAK recipients showed no signs of acute or chronic GvH disease but showed immune response equivalent to or higher than the normal controls. Severe functional defects were observed in the newborn SHR rats after i.p. inoculation of allogeneic fresh spleen cells from JB rats. The results strongly suggest that allogeneic LAK cells be ineffective in terms of induction of GvH disease or GvH associated immunodeficiencies (GvHID). Therefore, this might be promising in clinical trials on cancer adoptive immunotherapy with allogeneic, instead of autologous, LAK cells.

Animals↗
PubMed1986

Sources of the anti-implantation alkaloid yuehchukene in the genus Murraya.

The genus Murraya has been widely used in traditional medicine in east Asia. In view of the recent isolation of the anti-implantation alkaloid yuehchukene from M. paniculata a search has now been made for other natural sources of this alkaloid within the genus. In this paper we report findings for nine taxa of Murraya.

Alkaloids↗