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Qi Zhang

Publications and source records attributed to Qi Zhang.

At least 37 records · Page 2Linked to original sources
PubMed2006

Aberrant regulation of synovial T cell activation by soluble costimulatory molecules in rheumatoid arthritis.

T cell activation and function are critically regulated by positive and negative costimulatory molecules. Aberrant expression and function of costimulatory molecules have been associated with persistent activation of self-reactive T cells in autoimmune diseases such as rheumatoid arthritis (RA). In this study, initial analysis of costimulatory molecules led to the unexpected observation that, in addition to CD80, several negative regulators (e.g., CTLA-4, programmed death-1 (PD-1), and PD ligand-1) were overexpressed in synovial T cells and macrophages derived from RA patients as opposed to controls. The expression of CD80 and PD ligand-1 on monocytes could be induced in vitro by IFN-gamma and TNF-alpha that were produced abundantly in RA-derived synovial fluid (SF). Furthermore, the soluble form of negative costimulatory molecules occurred at high concentrations in sera and SF of RA patients and correlated with titers of rheumatoid factor in RA patients. In particular, the levels of soluble PD-1 were found to correlate significantly with those of TNF-alpha in SF derived from RA patients. Detailed characterization of soluble PD-1 revealed that it corresponded to an alternative splice variant (PD-1Deltaex3) and could functionally block the regulatory effect of membrane-bound PD-1 on T cell activation. Our data indicate a novel pathogenic pathway in which overexpression of negative costimulatory molecules to restrict synovial inflammation in RA is overruled by the excessive production of soluble costimulatory molecules.

Adult↗
PubMed2006

Hypoxia induces the activation of human hepatic stellate cells LX-2 through TGF-beta signaling pathway.

Hypoxia is a common environmental stress factor and is also associated with various physiological and pathological conditions such as fibrogenesis. The activation of hepatic stellate cells (HSCs) is the key event in the liver fibrogenesis. In this study, the behavior of human HSCs LX-2 in low oxygen tension (1% O2) was analyzed. Upon hypoxia, the expression of HIF-1alpha and VEGF gene was induced. The result of Western blotting showed that the expression of alpha-SMA was increased by hypoxic stimulation. Furthermore, the expression of MMP-2 and TIMP-1 genes was increased. Hypoxia also elevated the protein expression of the collagen type I in LX-2 cells. The analysis of TGF-beta/Smad signaling pathway showed that hypoxia potentiated the expression of TGF-beta1 and the phosphorylation status of Smad2. Gene expression profiles of LX-2 cells induced by hypoxia were obtained by using cDNA microarray technique.

Anaerobiosis↗
PubMed2006

Production of recombinant ScFv antibodies against methamidophos from a phage-display library of a hyperimmunized mouse.

A recombinant phage display library was generated using splenocyte mRNA isolated from a Balb/c mouse hyperimmunized with a hapten conjugate that mimicked the structure of methamidophos, one of the most acutely toxic organophosphate pesticides. Three recombinant single-chain variable fragment (scFv) antibodies with the highest specificity for methamidophos, termed 28D4, 29D0, and 36B2, were produced via a stringent selection protocol. In a competitive enzyme-linked immunosorbent assay, the IC50 values for 28D4, 29D0, and 36B2 were 46.25, 35.39, and 17.99 ng/mL, respectively. The cross-reactivity of the three scFv antibodies with other organophosphate pesticides was below 0.1% except for acephate (O,S-dimethyl acetylphosphoramidothioate). Nucleotide and deduced amino acid sequences indicated that the respective heavy chains and light chains of the three scFvs were involved in the distinctive VDJ segment rearrangements associated with somatic hypermutations during the process of several immunizations with higher dosages of immunogen. Taken together, these data constitute the first detailed description of an immunoassay that utilizes scFvs against the methamidophos, an analyte with a simple structure and low molecular mass (141 Da).

Animals↗
PubMed2006

Cilostazol, a phosphodiesterase 3 inhibitor, protects mice against acute and late ischemic brain injuries.

Cilostazol, a selective inhibitor of phosphodiesterase 3, exerts neuroprotective effects on acute brain injury after cerebral ischemia in rats. However, it is unknown whether cilostazol affects the subacute or chronic ischemic injury. In the present study, we evaluated the dose- and time-dependent effects of cilostazol on acute ischemic brain injury and the long-lasting effect on the late (subacute/chronic) injury in mice with focal cerebral ischemia induced by transient middle cerebral artery occlusion. We found that pre-treatment of cilostazol (injected i.p. at 30 min before ischemia) significantly ameliorated the acute injury 24 h after ischemia, and the effective doses were 3-10 mg/kg. The post-treatment of cilostazol (10 mg/kg) was effective on the acute injury when it was injected 1 and 2 h after ischemia. In addition, for the late injury, post-treatment of cilostazol (10 mg/kg, i.p., for 7 consecutive days after ischemia) attenuated neurological dysfunctions, brain atrophy and infarct volume. It also inhibited astrocyte proliferation/glial scar formation and accelerated the angiogenesis in the ischemic boundary zone 7 and 28 days after ischemia. Thus, we conclude that cilostazol protects against not only the acute injury, but also the late injury in mice with focal cerebral ischemia; especially it can modify brain remodeling, astrogliosis and angiogenesis.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2006

General approach to quantum-classical hybrid systems and geometric forces.

We present a general theoretical framework for a hybrid system that is composed of a quantum subsystem and a classical subsystem. We approach such a system with a simple canonical transformation which is particularly effective when the quantum subsystem is dynamically much faster than the classical counterpart, which is commonly the case in hybrid systems. Moreover, this canonical transformation generates a vector potential which, on one hand, gives rise to the familiar Berry phase in the fast quantum dynamics and, on the other hand, yields a Lorentz-like geometric force in the slow classical dynamics.

Journal Article↗
PubMed2006

Pathogenic cellulase assay of pine wilt disease and immunological localization.

The pine wilt disease caused by Bursaphelenchus xylophilus (BX), also known as the pine wood nematode (PWN), is the most devastating disease of pine trees. In this work, a high molecular weight B. xylophilus cellulase antigen (BXCa) was purified from total homogenates of nematodes. BXCa was found to be able to hydrolyze carboxymethyl cellulose (CMC) efficiently (155.65 U/mg) and to have an approximate molecular mass of 58.9 kDa. We harvested anti-BXCa antibodies and performed immunocytochemical assays, which revealed the localization of cellulase pools in the esophageal gland cells of the PWN. It was also discovered that cellulase was secreted from the stylet and was used to hydrolyze cellulose to facilitate the PWN entering host cells. These results are consistent with other plant parasitical nematodes. Interestingly, strong fluorescence signals from cellulase staining were observed in tracheid cells in naturally infected pine wood, in addition to ray cells and the resin canal zone. These results strongly suggest that the cellulase released by the PWN is one of the pathogenic substances of pine wilt disease and is responsible for the development of the early symptoms of the disease.

Animals↗
PubMed2006

Increased safety with preserved antitumoral efficacy on hepatocellular carcinoma with dual-regulated oncolytic adenovirus.

PURPOSE: A dual-regulated adenovirus variant CNHK500, in which human telomerase reverse transcriptase promoter drove the adenovirus 5 (Ad5) E1a gene and hypoxia-response promoter controlled the E1b gene, was engineered. This virus has broad anticancer spectrum and higher specificity compared with mono-regulated adenovirus CNHK300. The objective of the current study is to show its antitumor selectivity and therapeutic potential. EXPERIMENTAL DESIGN: The antitumor specificity of human telomerase reverse transcriptase and hypoxia response promoters was evaluated in a panel of tumor and normal cells. Under the control of these promoters, the tumor-selective expression of E1a and E1b genes was evaluated. Further in vitro antitumor specificity and potency of this virus were characterized by viral replication and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Subsequently, hepatocellular carcinoma xenografts were established to evaluate CNHK500 antitumor efficacy in vivo by different routes of virus administration and different dosages. RESULTS: Human telomerase reverse transcriptase and hypoxia response promoters were activated in a tumor-selective manner or under hypoxia treatment in a broad panel of cells. Selective adenoviral early gene expression, efficient viral replication, and oncolysis were observed in all tested cancer cells with more attenuated replication capacity in normal cells. Significant regression of hepatocellular carcinoma xenografts and prolonged survival were observed by either i.t. or i.v. administration. CONCLUSIONS: CNHK500 greatly reduced side effects in normal cells via dual control of adenoviral essential genes while still preserving potent antitumor efficacy on broad-spectrum cancer cells in vitro and in vivo. It can be used as a powerful therapeutic agent not only for liver cancers but also for other solid tumors.

Adenoviridae↗
PubMed2006

Induction of indefinite survival of fully mismatched cardiac allografts and generation of regulatory cells by sarpogrelate hydrochloride.

BACKGROUND: At initiation of the immunologic response, platelets rapidly release chemical mediators such as serotonin (5-hydroxytryptamine, [5-HT]) and cytokines. Sarpogrelate hydrochloride (SH), a selective 5-HT2-receptor antagonist, is used to treat patients with peripheral arterial disease. We investigated the effect of SH on the alloimmune response in a murine cardiac transplantation model. METHODS: CBA mice underwent transplantation of a C57BL/10 heart and received a short course of SH treatment. Survival of the allograft was recorded. An adoptive transfer study was performed to determine whether regulatory cells were generated. Immunohistochemistry studies of intercellular adhesion molecule 1 (ICAM-1), histological, cell-proliferation, and cytokine assessments were performed. RESULTS: Untreated CBA mice rejected C57BL/10 cardiac grafts acutely (median survival time [MST], 8 days). In mice given 10 mg/kg of SH, all allografts survived indefinitely (MST, >100 days); these mice also had significantly prolonged survival of donor-specific skin grafts but acute rejection of third-party skin grafts. Secondary CBA recipients given not only whole but also CD4 splenocytes from primary SH-treated CBA recipients with C57BL/10 cardiac allograft had indefinite survival of C57BL/10 hearts (MST, >100 days). SH inhibited upregulation of ICAM-1 on endothelial cells in the allografts. Graft acceptance and hyporesponsiveness were confirmed by the histological and cell-proliferation studies, respectively. Production of interleukin-4 and interleukin-10 from splenocytes of SH-treated transplant recipients increased compared to that from splenocytes of untreated recipients. CONCLUSION: SH induced indefinite survival of fully allogeneic cardiac allografts, generated CD4 regulatory cells, inhibited ICAM-1 expression in the allografts, and upregulated IL-4 and IL-10 production.

Animals↗
PubMed2006

Electrochemically partitioned assembly of organosulfur monolayers and nanoparticles.

Partitionally assembled organosulfur monolayers were prepared by using an electrochemically assisted assembly method on gold films that were preseparated into two regions insulated from each other. Cyclic voltammetry (CV) and X-ray photoelectron spectroscopy (XPS) were employed to characterize the n-dodecanethiol (DDT) and the 11-mercaptoundecanoic acid (MUA) monolayers, which were separately assembled on different substrate regions. CV results indicated that both the DDT- and MUA-coated gold electrodes showed a blocking property toward the negatively charged redox probe Fe(CN)6(3-). However, when positively charged Ru(NH3)6(3+) was used as the redox probe, the MUA- and DDT-modified electrodes showed quasireversible and blocking CV features, respectively. These phenomena were attributed to different interactions between the negatively charged MUA surface and the negatively or positively charged redox probes. XPS spectra obtained on the MUA modified region exhibited an O(1s) peak and a small discrete C(1s) peak, which arose from the oxygen and the carbon atoms in the carboxylic acid groups, respectively. For the DDT-modified region, these two peaks were absent. CV and XPS experimental results provided strong evidence that different SAMs were selectively deposited onto different regions of the preexisting patterns of the substrate by electrochemically partitioned assembly. The partitionally assembled sulfur-based monolayers with different terminal groups were used to form location-selective nanoparticle assemblies. This electrochemically partitioned assembly technique has great potential in controllable constructions of molecular layers and nanostructures on different surface microarchitectures that are closely integrated on one substrate but insulated from each other.

Journal Article↗
PubMed2006

Gene therapy using adenovirus-mediated full-length anti-HER-2 antibody for HER-2 overexpression cancers.

PURPOSE: Therapeutic monoclonal antibody is increasingly applied in many clinical applications, although complicated technologies and high cost still limit their wide applications. To obtain the sustained serum antibody concentration with one single injection and lower the cost of antibody protein therapy, an adenovirus-mediated full-length antibody gene therapy was developed. EXPERIMENTAL DESIGN: Full-length antibody light-chain and heavy-chain sequences were linked with internal ribosome entry site and constructed into adenoviral vector under the control of cytomegalovirus promoter. Antibody expression in vitro and in vivo were tested with ELISA, and its antitumor efficacy was evaluated in SKOV-3-inoculated nude mice. RESULTS: Ad5-TAb-generated anti-HER-2 antibody presented the similar binding specificity with commercial trastuzumab. A single i.v. injection of 2 x 10(9) plaque-forming units of Ad5-TAb per mouse resulted in not only a sustained over 40 microg/mL serum antibody level for at least 4 weeks but also significant tumor elimination in the ovarian cancer SKOV-3-inoculated nude mice. CONCLUSIONS: An in vivo full-length antibody gene delivery system allows continuous production of a full-length antibody at high concentration after a single administration. Bioactive antibody macromolecules can be generated via gene transfer in vivo. All the data suggest that this novel adenovirus-mediated antibody gene delivery can be used for the exploitation of antibodies, without being hampered by the sophisticated antibody manufacture techniques and high cost, and, furthermore, can shorten the duration and reduce the expense of antibody developments.

Adenoviridae↗
PubMed2006

Reliability of serum assays of iron status in postmenopausal women.

PURPOSE: The aim of the study is to determine the reliability during a 2-year period of several newly developed iron-related assays to assess their potential for use in prospective epidemiologic studies. METHODS: We assessed the temporal reliability of several iron-related assays by using three serum samples collected at yearly intervals from 50 postmenopausal participants in a large prospective study. RESULTS: We observed high reliability coefficients for ferritin (0.78; 95% confidence interval [CI], 0.67-0.86), soluble transferrin receptor (sTfR; 0.79; 95% CI, 0.69-0.87), sTfR/ferritin ratio (0.74; 95% CI, 0.62-0.83), and hepcidin (0.89; 95% CI, 0.84-0.94). In a subset of 30 women, lower reliability was observed for serum iron (0.50; 95% CI, 0.29-0.70), unsaturated iron-binding capacity (0.55; 95% CI, 0.34-0.73), total iron-binding capacity (0.60; 95% CI, 0.40-0.76), and serum transferrin saturation rate (0.44; 95% CI, 0.22-0.65). The reliability of anti-5-hydroxymethyl-2'-deoxyuridine autoantibody titers, a biomarker of oxidized DNA damage, one of the mechanisms by which iron is thought to impact disease risk, was very high (0.97, 95% CI, 0.5-0.99). CONCLUSIONS: Our results show that some newly developed iron-related assays could be useful tools to assess iron-disease associations in prospective cohorts that collect a single blood sample.

Adult↗
PubMed2006

2,6-Disubstituted N-arylsulfonyl piperidines as gamma-secretase inhibitors.

A novel piperidine series of gamma-secretase inhibitors, potentially useful for the treatment of Alzheimer's disease, is disclosed. SAR investigation revealed the requirement for cis-stereochemistry of the substituents attached to the core, which resulted in the chair-like diaxial conformation of the piperidine ring. The series was optimized to provide inhibitors with IC(50)'s in the single-digit nanomolar range. Absolute stereochemistry of the active enantiomer was assigned.

Alzheimer Disease↗
PubMed2006

Effects of rhDecorin on TGF-beta1 induced human hepatic stellate cells LX-2 activation.

Decorin is a small leucine-rich extracellular matrix proteoglycan composed of a core protein with a single glycosaminoglycan (GAG) chain near the N-terminus and N-glycosylated at three potential sites. Decorin is involved in the regulation of formation and organization of collagen fibrils, modulation of the activity of growth factors such as transforming growth factor beta (TGF-beta), and exerts other effects on cell proliferation and behavior. Increasing evidences show that decorin plays an important role in fibrogenesis by regulating TGF-beta, a key stimulator of fibrosis, and by directly modulating the degradation of extracellular matrix (ECM) from activated hepatic stellate cells (HSCs). In this study, the core protein of human decorin was cloned and expressed in Escherichia coli. The purified recombinant human decorin (rhDecorin) significantly inhibited the proliferation of LX-2 cells, a human HSC cell line, stimulated by TGF-beta1. RT-PCR result showed that the expression of metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were reduced by rhDecorin in LX-2 cells stimulated by TGF-beta1. Furthermore, the protein expression of smooth muscle-alpha-actin (alpha-SMA), collagen type III and phosphorylated Smad2 (p-Smad2) was significantly decreased in the presence of rhDecorin. rhDecorin also reduced fibrillogenesis of collagen type I in a dose-dependent manner. Gene expression profiles of LX-2 cells stimulated by TGF-beta1 in the presence and the absence of rhDecorin were obtained by using cDNA microarray technique and differentially expressed genes were identified to provide further insight into the molecular action mechanism of decorin on LX-2 cells.

Cell Proliferation↗
PubMed2006

Salivary mutans streptococci counts as indicators in caries risk assessment in 6-7-year-old Chinese children.

OBJECTIVES: This study aimed to determine whether salivary mutans streptococci (MS) counts in Chinese children had any value in the prediction of new caries in the permanent dentition in the age interval of 6.5-8.5 years. METHODS: Four hundred and thirty-three 6-7-year-old children participated in this 2-year longitudinal study. Salivary MS counts were obtained at baseline with the spatula method. Dentin and enamel caries was recorded at baseline and at the follow-up, 2 years later. Spearman's correlation coefficients were computed. Past caries experience variables at baseline were entered into a multiple regression model with caries increment of the permanent dentition as dependent variable. MS counts were subsequently entered into the model to assess the additional caries predictive value. RESULTS: Spearman's correlation coefficient for MS counts and caries experience of the primary dentition at baseline was 0.48 and for MS counts and caries increment in the permanent dentition 0.12. In the multiple regression model caries increment of the permanent dentition had an adjusted R2 of 0.17 when the past caries experience variables were entered. Adding MS counts in the regression model did not change the R2 value. CONCLUSIONS: Salivary MS counts did not add any caries predictive value when past caries experience variables were used as caries predictors in this Chinese child population.

Child↗
PubMed2006

Studies to investigate the in vivo therapeutic window of the gamma-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY411,575) in the CRND8 mouse.

Accumulation of amyloid beta-peptide (Abeta) is considered a key step in the etiology of Alzheimer's disease. Abeta is produced by sequential cleavage of the amyloid precursor protein by beta- and gamma-secretase enzymes. Consequently, inhibition of gamma-secretase provides a promising therapeutic approach to treat Alzheimer's disease. Preclinically, several gamma-secretase inhibitors have been shown to reduce plasma and brain Abeta, although they also produce mechanism-based side effects, including thymus atrophy and intestinal goblet cell hyperplasia. The present studies sought to establish an efficient screen for determining the therapeutic window of gamma-secretase inhibitors and to test various means of maximizing this window. Six-day oral administration of the gamma-secretase inhibitor N(2)-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N(1)-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide (LY411,575) reduced cortical Abeta(40) in young (preplaque) transgenic CRND8 mice (ED(50) approximately 0.6 mg/kg) and produced significant thymus atrophy and intestinal goblet cell hyperplasia at higher doses (>3 mg/kg). The therapeutic window was similar after oral and subcutaneous administration and in young and aged CRND8 mice. Both the thymus and intestinal side effects were reversible after a 2-week washout period. Three-week treatment with 1 mg/kg LY411,575 reduced cortical Abeta(40) by 69% without inducing intestinal effects, although a previously unreported change in coat color was observed. These studies demonstrate that the 3- to 5-fold therapeutic window for LY411,575 can be exploited to obtain reduction in Abeta levels without induction of intestinal side effects, that intermittent treatment could be used to mitigate side effects, and that a 6-day dosing paradigm can be used to rapidly determine the therapeutic window of novel gamma-secretase inhibitors.

Administration, Oral↗
PubMed2006

JAK2(V617F): Prevalence in a large Chinese hospital population.

Recently, the JAK2(V617F) mutation was found in patients with myeloproliferative disorders (MPDs), including most with polycythemia vera (PV). The mutant JAK2 has increased kinase activity, and it was shown to be pathogenic in mouse models. Herein, we analyzed blood samples randomly collected from a clinical laboratory. Surprisingly, as many as 37 samples from a total of 3935 were found positive for the JAK2 mutation. However, only one of these samples had blood test results indicative for probable PV, but several had nonhematologic diseases. On average, samples with the mutation had normal red cell counts but significantly higher white blood cell and platelet counts, although most were within the normal range. The data suggest that the JAK2(V617F) mutation is apparently much more common than MPDs. Its occurrence may be a prelude to full blood cell abnormalities and other diseases, but it cannot by itself diagnose MPDs.

Adult↗