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Biomedical subjects

Z Duan

Publications and source records attributed to Z Duan.

At least 19 recordsLinked to original sources
PubMed2003

Paclitaxel resistance: molecular mechanisms and pharmacologic manipulation.

It has been approximately ten years since the Food and Drug Administration (FDA) approved paclitaxel for the treatment of platinum resistant epithelial ovarian carcinoma. Since the approval, the drug has found therapeutic applications in a variety of schedules and in a wide variety of epithelial malignancies. Its novel mechanism of action provided the hope that it would demonstrate anti-neoplastic activity in multidrug resistant tumor cells. Unfortunately, as with other chemotherapeutic drugs, resistance is commonly seen. Laboratory investigation has defined a wide variety of resistance mechanisms including overexpression of multidrug resistance (MDR-1) gene, molecular changes in the target molecule (betatubulin), changes in apoptotic regulatory and mitosis checkpoint proteins, and more recently changes in lipid composition and potentially the overexpression of interleukin 6 (IL-6). This review describes the in vitro molecular data that define and support the various mechanisms of resistance and critically evaluates the evidence for the participation of these mechanisms in clinically relevant paclitaxel resistance. This review also explores pharmacologic attempts to modulate paclitaxel resistance, principally through inhibition of the MDR-1 drug efflux pump. Future avenues for drug resistance research and its pharmacologic manipulation in the clinic are discussed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Overexpression of IL-6 but not IL-8 increases paclitaxel resistance of U-2OS human osteosarcoma cells.

The cytokines IL-6, initially recognized as a regulator of immune and inflammatory response and IL-8, a potential regulator of angiogenesis, also regulate the growth of many tumor cells. Human cancer cells selected for multidrug resistance to common chemotherapeutic agents demonstrate increased expression of IL-6 and IL-8. To determine whether IL-6 or IL-8 overexpression contributes directly to the drug resistant phenotype, IL-6 or IL-8 cDNA were introduced into the paclitaxel sensitive human osteosarcoma cell line U-2OS using the pIRESneo bicistronic expression vector. Interleukin-6 and IL-8 transfectants were selected for either high IL-6 or IL-8 secretion and evaluated in drug resistance assays. Two IL-6 and two IL-8 secreting clones express IL-6 or IL-8 levels of 10 ng/ml and 1 ng/ml in culture, while parental U-2OS and pIRESneo vector transfected control cells express IL-6 and IL-8 levels of 0.005 ng/ml and 0.1 ng/ml, respectively. MTT cytotoxicity with IL-6 transfected cells demonstrates a five-fold increase in resistance to paclitaxel and a four-fold increase in resistance to doxorubicin as compared to U-2OS. There are no changes in mitoxantrone or topotecan resistance in the IL-6 transfectants as compared to parental U-2OS. Northern analysis of IL-6 transfectants demonstrates that the resistant phenotype is not related to increased levels of MDR-1, MRP-1, or LRP. Western analysis also confirms that P-glycoprotein levels are not altered in IL-6 transfectants. Further supporting an MDR-1 independent mechanism of drug resistance, verapamil cannot reverse paclitaxel resistance in transfected cells, findings further supported by rhodamine 123 exclusion data. Treatment of IL-6 transfected cells with paclitaxel, compared with drug-sensitive parental U-2OS, shows U-2OS(IL-6) are significantly more resistant to apoptosis induced by paclitaxel and exhibit decreased proteolytic activation of caspase-3. In contrast U-2OS(IL-8) transfectants demonstrate no appreciable increase in paclitaxel resistance when compared with parental cells. In summary, while both IL-6 and IL-8 are overexpressed in paclitaxel resistant cell lines, only IL-6 has the potential to contribute directly to paclitaxel and doxorubicin resistance in U-2OS. This resistance is through a non-MDR-1 pathway.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Role of NF-Y in in vivo regulation of the gamma-globin gene.

The duplicated CCAAT box is required for gamma gene expression. We report here that the transcriptional factor NF-Y is recruited to the duplicated CCAAT box in vivo. A mutation of the duplicated CCAAT box that severely disrupts the NF-Y binding also reduces the accessibility level of the gamma gene promoter, affects the assembly of basal transcriptional machinery, and increases the recruitment of GATA-1 to the locus control region (LCR) and the proximal promoter and the recruitment of transcription cofactor CBP/p300 to the LCR. These findings suggest that recruitment of NF-Y to the duplicated CCAAT box plays a role in the chromatin opening of the gamma gene promoter as well as in the communication between the gamma gene promoter and the LCR.

Animals↗
PubMed2001

[Chlamydia pneumoniae infection in patients with chronic obstructive pulmonary disease].

OBJECTIVE: To investigate the association of chlamydia pneumoniae infection with chronic obstructive pulmonary disease (COPD). METHODS: 61 patients with acute exacerbations of COPD, 35 patients with stable COPD and 26 healthy subjects were selected. Chlamydia pneumoniae-specific serum IgG, IgA, IgM antibodies were measured by microimmunofluorescence method. Chlamydia pneumoniae DNA in sputum were detected by nested polymerase chain reaction. RESULTS: The prevalence of acute chlamydia pneumoniae infection in COPD patients with acute exacerbation was significantly higher (31.1%) than that in patients with stable COPD (P < 0.05) and in healthy subjects (P < 0.01). The prevalences of chronic chlamydia pneumoniae infection in COPD patients with acute exacerbations (21.3%) and stable COPD patients (31.4%) were higher than that in healthy subjects (P < 0.05) The level of geometric mean titer of the serum IgA antibodies was the highest in COPD patients with acute exacerbations (20.5), intermediately elevated in stable COPD patients (10.8) and lowest in healthy subjects (3.6). CONCLUSION: Acute chlamydia pneumoniae infection is a rather frequent event in acute exacerbation of COPD, and chronic chlamydia pneumoniae infection may be involved in pathogenesis of COPD.

Acute Disease↗
PubMed2001

[Profile of telomerase and telomerase RNA expression in nasopharyngeal carcinogenesis of rats induced by N, N'dinitrosopiperazine (DNP)].

OBJECTIVE: To investigate the profile of telomerase and telomerase RNA expression in nasopharyngeal carcinogenesis (NPC) induced by N, N'dinitrosopiperazine (DNP) and examined histolofically. METHODS: Nasopharyngeal carcinomas of rats were induced by DNP and examined histologically. PCR-ELISA and nested RT-PCR were used to assay telomerase and telomerase RNA expression at different stages in the nasopharyngeal tissues of rats. RESULTS: During the carcinogenesis process, telomerase activity increased along with the formation of a nasopharyngeal carcinoma. Telomerase expression was positively related with nasopharyngeal carcinogenesis. Telomerase RNA expression was present and did not change during the NPC process. Expression of telomease RNA was earlier than telomerase activation. Telomerase activation and telomerase RNA expressin were also detected in the pre-cancerous nasopharyngeal lesions. CONCLUSION: Telomerase activation may participate in the onset and progression of NPC, and is an early step in NPC.

Animals↗
PubMed2000

Observation of Coriolis Coupling between nu(2) + 4nu(4) and 7nu(4) in Acetylene &Xtilde;(1)Sigma(+)(g) by Stimulated Emission Pumping Spectroscopy.

Stimulated emission pumping (SEP) spectroscopy has been used to examine a low energy region (E(vib) approximately 4400 cm(-1)) of &Xtilde;(1)Sigma(+)(g) acetylene at higher resolution than was possible in previous dispersed fluorescence studies. The expected bright state, nu(2) + 4nu(4), is observed to be coupled to the nearly degenerate 7nu(4) state by a Coriolis mechanism. A least-squares analysis yields values for zero-order vibrational energies, rotational constants, and a Coriolis-coupling coefficient that are all consistent with expectations. Calculated relative intensities of SEP transitions, accounting for interference due to axis-switching effects, are also consistent with observations. Implications of the observed Coriolis resonance with regard to global acetylene vibrational dynamics are also discussed. Copyright 2000 Academic Press.

Journal Article↗
PubMed2000

A logic for biological systems.

This paper proposes a specification language, hybrid projection temporal logic of modelling, analyzing and verifying biological systems which can be considered, in general, to be hybrid systems consisting of a non-trivial mixture of discrete and continuous components. The syntax and semantics of the logic are presented, and some examples of hybrid systems are modelled to illustrate the formalism.

Antigen-Antibody Reactions↗
PubMed2000

[Summary of 42 patients with acute aortic occlusion].

OBJECTIVE: To summarize the experience of diagnosis and treatment in 42 patients with acute aortic occlusion. METHODS: Clinic data were analyzed. The emergency surgery of retrograde catheter thrombolectomy of transaortic thromboembolism were done, and the propathy and complications were treated simultaneously. RESULTS: Normal blood flow were restored just after operation. Four patients died of myonephropathic metabolic syndrome and heart failure. 38 patients were followed up for 0.5 to 4 years. Among them, 36 were followed for more than 1 year. A better effectiveness was achieved in 28 patients. Two patients died of recurrence accompanied with heart failure. CONCLUSION: Early diagnosis and treatment may increase the curative ratio and decrease the mortality in patients with acute aortic occlusion.

Acute Disease↗
PubMed2000

[Time course of TGF beta 1 and VEGF expression in experimental vein grafts].

OBJECTIVE: To investigate time course of TGF beta(1) and VEGF expression and their role in intimal hyperplasia. METHODS: In situ hybridization and immunohistochemical technique were used to detect the time course of intimal hyperplasia, time course of TGF beta(1) mRNA and protein expression of TGF beta(1) and VEGF. RESULTS: After autogenous vein replacement, the obvious neointima was seen at 2 weeks, and peaked at 8 weeks. The expression of TGF beta(1) mRNA peaked at 1 week and decreased gradually, but at 10 weeks, its positive cell percentage was still 10.1%. Both protein expression of TGF beta(1) and VEGF in VSMCs increased from 24 hours after grafting and peaked at 2 weeks. Their positive cell percentages were 40.6% and 36.6% respectively. After 4 weeks, their expression decreased at 8 weeks, the positive cell percentages were 8.9% and 13.8% respectively. CONCLUSIONS: TGF beta(1) plays an important part in ECM accumulation by promoting ECM synthesis and decreasing ECM degradation. VEGF plays the key role in reendothelialization. They may affect each other and cooperated in the formation of intimal hyperplasia.

Animals↗
PubMed1999

Structural analysis and mapping of DNase I hypersensitivity of HS5 of the beta-globin locus control region.

The beta-globin locus control region (LCR) is a cis regulatory element that is located in the 5' part of the locus and confers high-level erythroid lineage-specific and position-independent expression of the globin genes. The LCR is composed of five DNase I hypersensitive sites (HSs), four of which are formed in erythroid cells. The function of the 5'-most site, HS5, remains unknown. To gain insights into its function, mouse HS5 was cloned and sequenced. Comparison of the HS5 sequences of mouse, human, and galago revealed two extensively conserved regions, designated HS5A and HS5B. DNase I hypersensitivity mapping revealed that two hypersensitive sites are located within the HS5A region (designated HS5A(major) and HS5A(minor)), and two are located within the HS5B region (HS5B(major), HS5B(minor)). The positions of each of these HSs colocalize with either GATA-1 or Ap1/NF-E2 motifs, suggesting that these protein binding sites are implicated in the formation of HS5. Gel retardation assays indicated that the Ap1/NF-E2 motifs identified in murine HS5A and HS5B interact with NF-E2 or similar proteins. Studies of primary murine cells showed that HS5 is formed in all hemopoietic tissues tested (fetal liver, adult thymus, and spleen), indicating that this HS is not erythroid lineage specific. HS5 was detected in murine brain but not in murine kidney or adult liver, suggesting that this site is not ubiquitous. The presence of GATA-1 and NF-E2 motifs (which are common features of the DNase I hypersensitive sites of the LCR) suggests that the HS5 is organized in a manner similar to that of the other HSs. Taken together, our results suggest that HS5 is an inherent component of the beta-globin locus control region.

Animals↗
PubMed1999

Structure-based ligand design by dynamically assembling molecular building blocks at binding site.

A structure-based ligand design method is proposed and tested. The method is based on stochastic dynamics simulation of multiple copies of molecular building blocks in the presence of a receptor molecule. The molecular building blocks are assembled into candidate compounds "on the fly" at given intervals during the simulation. In the algorithm, a special effort is made to explore different possible combinations of building blocks and to select an optimum combination. By repeating the cycle of deconstruction and reconstruction in a single simulation, a set of candidate compounds that can be built from the building blocks evolves and is dynamically optimized. The method was tested by breaking two known flexible human immunodeficiency virus type 1 protease inhibitors into building blocks and reassembling them in the active site of the enzyme. For the inhibitor L700417, a set of conformations was generated by the calculation. Among these, the original compound was recovered with the lowest energy at the experimentally observed binding site and in the correct conformation. For pepstatin, the experimentally observed binding mode of the backbone of the inhibitor was reproduced by a calculation in which the building blocks corresponding to the side-chain groups were omitted. Proteins 1999;36:462-470.

Algorithms↗
PubMed1999

TRAG-3, a novel gene, isolated from a taxol-resistant ovarian carcinoma cell line.

The mechanisms responsible for the development of the taxol resistance phenotype are unclear, and are likely explained by multiple mechanisms. To understand the molecular changes associated with drug resistance more fully, a taxol-resistant subline, derived from the human ovarian cancer cell line SKOV-3, was established through selection by culture in incrementally increasing taxol concentrations. Comparison of SKOV-3 to SKOV-3TR by differential display identifies a new gene, TRAG-3 (Taxol Resistance Associated Gene- 3). In comparison to the parental line, SKOV-3, TRAG-3 mRNA is overexpressed in the taxol-resistant cell line SKOV-3TR. The nucleotide sequence of the TRAG-3 cDNA contains an open reading frame of 333bp that predicts for a protein product of 110 amino acids. A GenBank search identifies a cosmid clone containing a genomic sequence corresponding to that of TRAG-3. DNA and protein analysis reveals that TRAG-3 has no homology to any known cDNAs or proteins. Northern analysis demonstrates that TRAG-3 is overexpressed in the taxol-resistant breast cancer cell line MDA 435TR as well as the doxorubicin-resistant multiple myeloma cell lines 8226/DOX40 and 8226/MDR10V. A survey of normal tissue shows minimal or absent TRAG-3 mRNA expression. Screening of a wide variety of cancer cell lines demonstrates TRAG-3 expression in many cell lines derived from different tissue types. In summary, TRAG-3 is a novel gene whose expression is associated with the chemotherapy-resistant and neoplastic phenotype.

Amino Acid Sequence↗
PubMed1999

Discovery of differentially expressed genes associated with paclitaxel resistance using cDNA array technology: analysis of interleukin (IL) 6, IL-8, and monocyte chemotactic protein 1 in the paclitaxel-resistant phenotype.

In an attempt to define the molecular changes associated with the paclitaxel-resistant phenotype in human cancer, a paclitaxel-resistant ovarian cancer cell line, SKOV-3TR, was established through stepwise selection in increasing paclitaxel concentrations. SKOV-3TR was cross- resistant to doxorubicin and vincristine and overexpressed multidrug resistance gene 1 but not multidrug resistance associated protein. SKOV-3TR and the paclitaxel-sensitive SKOV-3 parent line were characterized using human cDNA array technology that examined expression of a wide variety of genes involved in cell growth, signal transduction, cell death, and immune function. cDNA probes from reverse transcribed mRNAs of both paclitaxel-resistant and parent cells were compared to identify genes differentially expressed in the paclitaxel-resistant cells. Of 588 different human cDNA transcripts compared, 6 genes were found to be markedly decreased, and 12 genes increased in the resistant subline. Northern analysis and/or reverse transcription-PCR confirmed that 12 of these 18 genes were over- or underexpressed in SKOV-3TR. In addition, at least eight of the genes were found differentially expressed in several other paclitaxel- and/or doxorubicin-resistant cell lines, both those with increased multidrug resistance expression and those without. Included in the set of overexpressed genes were the cytokines/chemokines interleukin 6, interleukin 8, and monocyte chemotactic protein 1. ELISA assays confirm that mRNA overexpression of these cytokine/chemokines was associated with the increased secretion of these molecules in the tissue culture supernatant. Evaluation of supernatants from an expanded collection of paclitaxel- and Adriamycin-resistant cell lines demonstrated that all of the resistant lines had significant overexpression of at least one cytokine/chemokine as compared with their drug-sensitive parent line. The overexpression of these cytokines seemed to be stable and associated with a drug-resistant phenotype with only a modest induction of cytokine expression in the parent line with short-term paclitaxel exposure. These findings suggest that the development of paclitaxel resistance is accompanied by multiple changes in gene expression including stable alterations in selective chemokine and cytokine expression. The role these associated genetic changes have in the drug-resistant phenotype is discussed.

Breast Neoplasms↗
PubMed1999

[The relation-ship between apoptosis, apoptosis related-gene expression and proliferative activity in smooth muscle cell after autogenous vein grafting].

OBJECTIVE: To study the mechanism of graft vein stenosis. METHODS: A rat experimental model of autogenous vein graft was established by transplanting the right external jungular vein into the infrarenal abdominal aorta in 100 Wister rats. Electric microscope, TUNEL and immunohistochemical S-P technique were used to detect the apoptosis, the expression of apoptosis related-gene bcl-2 and bax and proliferation cell nuclear antigen (PCNA) of smooth muscle cells(SMCs) in vein graft. RESULTS: From 1 to 8 weeks after replacement, the expression of apoptosis and PCNA of SMCs was continuously higher than the control group (P < 0.01). From 1 to 2 weeks, the expression of TUNEL and PCNA showed peak value. From 1 to 2 weeks, the positive rate of apoptosis was lower than that of PCNA, but from 4 to 8 weeks, the positive rate of TUNEL was higher than that of PCNA. There was obvious positive correlation between the expression of TUNEL and PCNA (r = 0.813 P < 0.05). One to 2 weeks after vein grafting, bcl-2 positive rate increased and was more different than the control group and the group of 4 to 8 weeks after vein grafting (P < 0.010). CONCLUSIONS: The imbalance of proliferation and apoptosis may be related to the vessel remodeling and vein graft stenosis, and bcl-2 and bax protein may involve in the regulation of apoptosis of VSMC. Adopting the mixed strategy to regulate the balance between proliferation and apoptosis may be useful to prevent vein graft stenosis.

Animals↗
PubMed1999

[Relationship between PDGF-A, bFGF and proliferation of smooth muscle cells in vein grafts].

OBJECTIVE: To detect the relationship between platelet-derived growth factor-A (PDGF-A), basic fibroblast growth factor (bFGF), and proliferation of smooth muscle cells in vein grafts. METHODS: An animal model of autogenous vein graft was established by transplanting internal branch of the jugular vein to the common iliac artery by end-to-end anastomosis. 25 rats were used. The grafted veins were harvested at 6 h, 2 d, 1 w, 2 w and 4 w respectively after the operation. The expression of PDGF-A and bFGF in different stages after grafting procedure was observed immunohistochemically. RESULTS: The expression of PDGF-A peaked at 1 w, paralleled with proliferation of SMC, and was significantly higher than that at 6 h (P < 0.01). The expression of PDGF-A diminished gradually. At 4 w, it was significantly lower than that at 1 w (P < 0.01). bFGF demonstrated bimodal pattern of the expression: the first peak of expression occurred by 2 d and the second peak by 2 w. The difference was significantly compared with other stages. CONCLUSIONS: The expression of PDGF-A 1 contributed to migration and proliferation of SMC. Except for contributing to proliferation of SMC, bFGF perhaps took part in endothelization.

Animals↗
PubMed1999

[Effects of inflammatory infiltration on the formation of abdominal aortic aneurysm].

OBJECTIVE: To explore inflammatory infiltration and its effects on the formation of abdominal aortic aneurysm (AAA). METHODS: Immunohistochemical technique was used to detect lymphocyte (CD45 positive) and macrophage (CD68 positive) infiltration while in situ hybridization was applied to investigate the mRNA expression of Matrix Metalloproteinase-9 (MMP-9) in 20 cases of human AAA and 4 cases of normal human abdominal aortas. RESULTS: Inflammatory infiltration occurred in every case of AAA with various degree, and there was a parallel tendency between the degree of injury of abdominal aortic elastin and that of inflammatory infiltration in AAA. Inflammatory infiltration was not found in normal aortas. MMP-9 mRNA was detected in macrophages and lymphocytes in all 20 cases, in smooth muscle cells in 13, and not in normal abdominal aortas. CONCLUSIONS: Inflammatory infiltration attended and enhanced the formation of AAA through a complex of sequence of biochemical, cellular and immune events.

Aortic Aneurysm, Abdominal↗