Biomedical subjects

L Qiao

Publications and source records attributed to L Qiao.

At least 19 recordsLinked to original sources

PubMed2006

Potent antitumor efficacy of XAF1 delivered by conditionally replicative adenovirus vector via caspase-independent apoptosis.

XAF1 is a newly identified tumor-suppressor gene that can antagonize XIAP and sensitize cells to other cell death triggers. In this study, we utilized ZD55, a conditionally replicative adenovirus (CRAd) similar to ONYX-015 as the vector to transfer XAF1 into the tumor cells to evaluate its antitumor efficacy in vitro and in vivo. Potent and specific cytopathic effect (CPE) was observed upon infection with ZD55-XAF1 in tumor cell lines. Importantly, ZD55-XAF1 exhibited a superior suppression of tumor growth in an animal model of colorectal carcinoma in nude mice compared with Ad-XAF1 (E1-deleted replication-defective viral) and ONYX-015. Complete eradication of the established tumors was observed in four of eight mice. Our data also showed that infection with ZD55-XAF1 resulted in caspase-independent apoptosis. Although caspase-3, poly(ADP-ribose) polymerase were mildly activated in response to ZD55-XAF1 infection, pretreatment with pan-caspase inhibitor hardly influence its apoptosis-inducing activity. In summary, our study strongly suggested that ZD55-XAF1 could serve as an effective gene-virotherapy strategy and has highly potential against human cancers.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Guiding chemical pulses through geometry: Y junctions.

We study computationally and experimentally the propagation of chemical pulses in complex geometries. The reaction of interest, CO oxidation, takes place on single crystal Pt(110) surfaces that are microlithographically patterned; they are also addressable through a focused laser beam, manipulated through galvanometer mirrors, capable of locally altering the crystal temperature and thus affecting pulse propagation. We focus on sudden changes in the domain shape (corners in a Y-junction geometry) that can affect the pulse dynamics; we also show how brief, localized temperature perturbations can be used to control reactive pulse propagation. The computational results are corroborated through experimental studies in which the pulses are visualized using reflection anisotropy microscopy.

Journal Article↗

PubMed2006

Geometry-induced pulse instability in microdesigned catalysts: the effect of boundary curvature.

We explore the effect of boundary curvature on the instability of reactive pulses in the catalytic oxidation of on microdesigned Pt catalysts. Using ring-shaped domains of various radii, we find that the pulses disappear (decollate from the inert boundary) at a turning point bifurcation, and we trace this boundary in both physical and geometrical parameter space. These computations corroborate experimental observations of pulse decollation.

Journal Article↗

PubMed2001

Ionizing radiation modulates vascular endothelial growth factor (VEGF) expression through multiple mitogen activated protein kinase dependent pathways.

We investigated the role of radiation-induced mitogen activated protein kinase (MAPK) pathway activity in the regulation of proliferation, cell survival and vascular endothelial growth factor (VEGF) production in primary astrocytes and in T9 and RT2 glioblastoma cells derived from Fisher 344 rats. In these cells, ionizing radiation (2 Gy) caused activation of the MAPK pathway which was blocked by specific inhibitor drugs. Blunting of radiation-induced MAPK activity weakly enhanced radiation-induced apoptosis 24 h after exposure in RT2 cells. Furthermore, blunting of MAPK activation weakly enhanced the ability of radiation to reduce RT2 cell growth in clonogenic growth assays. These findings argue that inhibition of MAPK signaling reduces proliferation and enhances cell killing by ionizing radiation in transformed astrocytes. Proliferation and survival of cancer cells has been linked in vivo to enhanced expression of angiogenic growth factors. Recently we demonstrated that the gene product of a novel rodent radiation-responsive gene, progression elevated gene 3 (PEG-3), could enhance vascular endothelial growth factor (VEGF) promoter activity in rodent fibroblasts, leading to increased VEGF protein levels and tumorigenic behavior in vivo. Thus PEG-3 and VEGF expression could be expected to directly correlate with the oncogenic potential of transformed cells. RT2 cells expressed more PEG-3 and VEGF protein than T9 cells, and were more tumorigenic in vivo than T9 cells. Radiation activated the PEG-3 promoter via MAPK signaling and ectopic over-expression of PEG-3 enhanced both basal MAPK activity and basal VEGF promoter activity. Basal MAPK activity partially correlated with basal VEGF promoter activity and VEGF protein levels in primary astrocytes, T9 and RT2 cells. Radiation increased the activity of the VEGF promoter and VEGF protein levels in primary astrocytes, T9 and RT2 cells which were dependent upon MAPK function. Furthermore, inhibition of AP-1 transcription factor signaling by dominant negative c-Jun (TAM67) also significantly reduced basal, and to a lesser extent radiation-induced, VEGF promoter function in RT2 cells. Collectively, our data demonstrate that radiation-induced MAPK signaling can both protect cells from radiation-induced cell death as well as enhance protein levels of pro-angiogenic factors such as VEGF. Enhanced VEGF expression in RT2 cells may be mediated via MAPK and JNK pathway signaling which converges upon the AP-1 transcription factor complex.

Amino Acid Chloromethyl Ketones↗

PubMed2001

Apoptosis: one of the mechanisms that maintains unresponsiveness of the intestinal mucosal immune system.

Intestinal mucosa is constantly exposed to environmental AGS: Activation of lamina propria (LP) T cells by luminal Ags may lead to the production of inflammatory cytokines and subsequent mucosal inflammation and tissue damage. However, in normal circumstances, LP T cells do not respond to antigenic stimulation. The mechanisms of this unresponsiveness in healthy subjects are not fully understood. In this study, we found by in vivo analysis that, except for T cells in lymph nodules of the mucosa, 15% of LP T cells underwent apoptosis in normal individuals. In contrast, there was a marked reduction in apoptosis of LP T cells in patients with inflammatory bowel disease (Crohn's disease and ulcerative colitis) and those with specific colitis. Our findings suggest that apoptosis might be a mechanism that turns off mucosal T cell responses to environmental Ags in healthy subjects, and resistance to apoptosis could be an important cause of mucosal immune dysregulation and tissue inflammation in colitis.

Apoptosis↗

PubMed2001

Rational design, synthesis, and biological evaluation of rigid pyrrolidone analogues as potential inhibitors of prostate cancer cell growth.

In view of its role in tumor promotion and signal transduction, protein kinase C (PKC) has proven to be an exciting target for cancer therapy. With the aid of molecular modeling, we rationally designed and stereoselectively synthesized a new class of rigidified pyrrolidone-based PKC activators. Pyrrolidone 15 was found to exhibit reasonable affinity for PKCdelta, with lower affinity for the other isozymes tested. Pyrrolidone 2 causes the dose-dependent induction of apoptosis in LNCaP prostate cancer cells. This apoptotic effect could be markedly potentiated by the use of LNCaP cells overexpressing the PKCalpha or delta isozymes.

Antineoplastic Agents↗

PubMed2001

Studies toward the total synthesis of clavulactone.

Synthetic studies directed toward a total synthesis of clavulactone are reported. In light of the analysis made in our previous work, cyclopentane 4a (a key intermediate in the present work) was synthesized through a radical-mediated ring closure of a rationally designed substrate 25. Using HWE reactions, the lower and upper side-chains of 4a were converted into an allyl chloride and an allyl cyanohydrin, respectively. Subsequent treatment of the allyl chloride/cyanohydrin in a highly diluted THF solution with sodium bis(trimethylsiliyl)amide led to intramolecular alkylation and thus completed a major endeavor in synthesizing the dolabellane framework, construction of the eleven-membered ring. SmI(2)-mediated lactonization as a model reaction for the formation of the alpha,beta-unsaturated delta-lactone segment of clavulactone is also described.

Animals↗

PubMed2001

PEA3 sites within the progression elevated gene-3 (PEG-3) promoter and mitogen-activated protein kinase contribute to differential PEG-3 expression in Ha-ras and v-raf oncogene transformed rat embryo cells.

Transformation of normal cloned rat embryo fibroblast (CREF) cells with cellular oncogenes results in acquisition of anchorage-independent growth and oncogenic potential in nude mice. These cellular changes correlate with an induction in the expression of a cancer progression-promoting gene, progression elevated gene-3 (PEG-3). To define the mechanism of activation of PEG-3 as a function of transformation by the Ha-ras and v-raf oncogenes, evaluations of the signaling and transcriptional regulation of the approximately 2.0 kb promoter region of the PEG-3 gene, PEG-Prom, was undertaken. The full-length and various mutated regions of the PEG-Prom were linked to a luciferase reporter construct and tested for promoter activity in CREF and oncogene-transformed CREF cells. An analysis was also performed using CREF cells doubly transformed with Ha-ras and the Ha-ras specific suppressor gene Krev-1, which inhibits the transformed phenotype in vitro. These assays document an association between expression of the transcription regulator PEA3 and PEG-3. The levels of PEA3 and PEG-3 RNA and proteins are elevated in the oncogenically transformed CREF cells, and reduced in transformation and tumorigenic suppressed Ha-ras/Krev-1 doubly transformed CREF cells. Enhanced tumorigenic behavior, PEG-3 promoter function and PEG-3 expression in Ha-ras transformed cells were all dependent upon increased activity within the mitogen-activated protein kinase (MAPK) pathway. Electrophoretic mobility shift assays and DNase I footprinting experiments indicate that PEA3 binds to sites within the PEG-Prom in transformed rodent cells in an area adjacent to the TATA box in a MAPK-dependent fashion. These findings demonstrate an association between Ha-ras and v-raf transformation of CREF cells with elevated PEA3 and PEG-3 expression, and they implicate MAPK signaling via PEA3 as a signaling cascade involved in activation of the PEG-Prom.

Animals↗

PubMed2001

Hepatitis B virus X protein increases expression of p21(Cip-1/WAF1/MDA6) and p27(Kip-1) in primary mouse hepatocytes, leading to reduced cell cycle progression.

Previously, we have linked prolonged intense mitogen-activated protein kinase (MAP kinase; MAPK) signaling in hepatocytes to increased expression of p21(Cip-1/WAF1/MDA6) (p21) and p16(INK4a) (p16), that leads to a p21-dependent growth arrest. In this study, we investigated the impact of hepatitis B virus X protein (pX) expression on MAPK-modulated cell cycle progression in primary mouse hepatocytes. In hepatocytes, expression of pX enhanced protein levels of p21 and p27, but not of p16. The elevated levels of p21 and p27 correlated with reduced DNA synthesis in wild-type (+/+) hepatocytes and with a weak stimulation of DNA synthesis in p21 null (-/-) cells. Antisense p27 messenger RNA (mRNA) (p27as) increased DNA synthesis in +/+ and p21 -/- cells, and pX blunted this effect in +/+ cells. In p21 -/- cells, however, p27as permitted pX to further stimulate DNA synthesis. These data argue that a reduced ability to enhance expression of both p21 and p27 is required to fully reveal the growth-potentiating properties of pX. This finding also implies that depending on the functional status of the p21 and p27 genes, expression of pX can have 2 very different effects on hepatocyte proliferation. Prolonged intense MAPK signaling reduced DNA synthesis in +/+ cells and enhanced DNA synthesis in p21 -/- cells. The enhancement of DNA synthesis in p21 -/- cells was blocked by pX, and the effect of pX was abrogated by p27as. Furthermore in p21 -/- cells, overexpression of p16 blocked MAPK-stimulated DNA synthesis, and this effect was partially reversed by p27as. These data argue that p27 can also cooperatively interact with p16 to inhibit DNA synthesis in hepatocytes. Collectively, our findings show that reduced expression of p16, p21, and p27, which can occur during hepatocellular carcinoma, enhances the ability of MAPK signaling and pX to cause proliferation in hepatocytes. Thus loss of cyclin kinase inhibitor function may play an important role in the process of tumor progression after chronic hepatitis B virus infection.

Animals↗

PubMed2001

MAPK dependence of DNA damage repair: ionizing radiation and the induction of expression of the DNA repair genes XRCC1 and ERCC1 in DU145 human prostate carcinoma cells in a MEK1/2 dependent fashion.

PURPOSE: To examine the role of mitogen-activated protein kinase (MAPK) signalling on the induction by ionizing radiation of the nucleotide excision repair gene (ERCC1), the X-ray cross-complementing group 1 protein (XRCC1) and the repair of radiation-induced DNA damage. MATERIALS AND METHODS: The expression of ERCC1 and XRCC1 was examined in DU145 human prostate cancer cells following exposure to ionizing radiation. We characterized the MAPK dependence of this expression through RT-PCR analysis, Western analysis, transcription inhibition and measurement of the activation of each promoter. Pre-exposure with the specific MEK1/2 inhibitor PD980059 (10 microM) was used to blunt radiation induction of MAPK without suppressing basal levels of MAPK activity. In addition, we examined the MAPK dependence of DNA damage repair by measuring radiation-induced micronucleus formation and the removal of and nicking activity associated with AP sites. RESULTS: Irradiation caused a time-dependent, MAPK-dependent increase in the protein levels of both ERCC1 and XRCC1. For each gene product, the protein level increase followed an increase in mRNA, which also was MAPK-dependent. Radiation also enhanced the activities of the ERCC1 and XRCC1 promoters in an MAPK-dependent fashion. Inhibition of transcription by DRB abolished the radiation-induced increase of ERCC1 and XRCC1 proteins. Inhibition of radiation-induced MAPK also diminished the ability of DU145 cells to remove AP sites and increased the number of cells displaying micronuclei following radiation exposure. CONCLUSIONS: These findings demonstrate a role for radiation-induced MAPK signalling in the regulation of DNA repair enzyme levels and DNA repair. Radiation-induced protein expression of ERCC1 and XRCC1 appears to require de novo transcription. These data suggest a significant role for MAPK signalling in the early response to DNA damage caused by ionizing radiation.

DNA Damage↗

PubMed2001

Deoxycholic acid (DCA) causes ligand-independent activation of epidermal growth factor receptor (EGFR) and FAS receptor in primary hepatocytes: inhibition of EGFR/mitogen-activated protein kinase-signaling module enhances DCA-induced apoptosis.

Previous studies have argued that enhanced activity of the epidermal growth factor receptor (EGFR) and the mitogen-activated protein kinase (MAPK) pathway can promote tumor cell survival in response to cytotoxic insults. In this study, we examined the impact of MAPK signaling on the survival of primary hepatocytes exposed to low concentrations of deoxycholic acid (DCA, 50 microM). Treatment of hepatocytes with DCA caused MAPK activation, which was dependent upon ligand independent activation of EGFR, and downstream signaling through Ras and PI(3) kinase. Neither inhibition of MAPK signaling alone by MEK1/2 inhibitors, nor exposure to DCA alone, enhanced basal hepatocyte apoptosis, whereas inhibition of DCA-induced MAPK activation caused approximately 25% apoptosis within 6 h. Similar data were also obtained when either dominant negative EGFR-CD533 or dominant negative Ras N17 were used to block MAPK activation. DCA-induced apoptosis correlated with sequential cleavage of procaspase 8, BID, procaspase 9, and procaspase 3. Inhibition of MAPK potentiated bile acid-induced apoptosis in hepatocytes with mutant FAS-ligand, but did not enhance in hepatocytes that were null for FAS receptor expression. These data argues that DCA is causing ligand independent activation of the FAS receptor to stimulate an apoptotic response, which is counteracted by enhanced ligand-independent EGFR/MAPK signaling. In agreement with FAS-mediated cell killing, inhibition of caspase function with the use of dominant negative Fas-associated protein with death domain, a caspase 8 inhibitor (Ile-Glu-Thr-Asp-p-nitroanilide [IETD]) or dominant negative procaspase 8 blocked the potentiation of bile acid-induced apoptosis. Inhibition of bile acid-induced MAPK signaling enhanced the cleavage of BID and release of cytochrome c from mitochondria, which were all blocked by IETD. Despite activation of caspase 8, expression of dominant negative procaspase 9 blocked procaspase 3 cleavage and the potentiation of DCA-induced apoptosis. Treatment of hepatocytes with DCA transiently increased expression of the caspase 8 inhibitor proteins c-FLIP-(S) and c-FLIP-(L) that were reduced by inhibition of MAPK or PI(3) kinase. Constitutive overexpression of c-FLIP-(s) abolished the potentiation of bile acid-induced apoptosis. Collectively, our data argue that loss of DCA-induced EGFR/Ras/MAPK pathway function potentiates DCA-stimulated FAS-induced hepatocyte cell death via a reduction in the expression of c-FLIP isoforms.

Animals↗

PubMed2001

Papillomavirus pseudovirus: a novel vaccine to induce mucosal and systemic cytotoxic T-lymphocyte responses.

Intestinal mucosa is a portal for many infectious pathogens. Systemic immunization, in general, does not induce a cytotoxic T-lymphocyte (CTL) response at the mucosal surface. Because papillomavirus (PV) naturally infects mucosa and skin, we determined whether PV pseudovirus, i.e., PV-like particles in which unrelated DNA plasmids are packaged, could generate specific mucosal immunity. We found that the pseudovirus that encoded the lymphocytic choriomeningitis virus gp33 epitope induced a stronger CTL response than a DNA vaccine (plasmid) encoding the same epitope given systemically. The virus-like particles that were used to make the pseudoviruses provided an adjuvant effect for induction of CTLs by the DNA vaccine. The PV pseudovirus pseudoinfected mucosal and systemic lymphoid tissues when administered orally. Oral immunization with the pseudovirus encoding human PV type 16 mutant E7 induced mucosal and systemic CTL responses. In comparison, a DNA vaccine encoding E7, when given orally, did not induce a CTL response in intestinal mucosal lymphoid tissue. Further, oral immunization with the human PV pseudovirus encoding E7 protected mice against mucosal challenge with an E7-expressing bovine PV pseudovirus. Thus, PV pseudovirus can be used as a novel vaccine to induce mucosal and systemic CTL responses.

Administration, Oral↗

PubMed2001

Leptin administration prevents spontaneous gestational diabetes in heterozygous Lepr(db/+) mice: effects on placental leptin and fetal growth.

Gestational diabetes mellitus (GDM) results from an interaction between susceptibility genes and the diabetogenic effects of pregnancy. During pregnancy, mice heterozygous for the lepin receptor (db/+) gain more weight, are glucose intolerant, and produce macrosomic fetuses compared with wild-type (+/+) mothers, suggesting that an alteration in leptin action may play a role in GDM and fetal overgrowth. To investigate whether leptin administration or pair-feeding can reduce adiposity and thereby prevent GDM and neonatal overgrowth, we examined energy balance, glucose and insulin tolerance, and fetal growth in pregnant db/+ and +/+ mice treated with recombinant human leptin-IgG during late pregnancy. Leptin reduced food intake and adiposity in pregnant db/+ mice to levels similar to pregnant +/+ mice and significantly reduced maternal weight gain. Maternal glucose levels were markedly lower during glucose and insulin challenge tests in leptin-treated db/+ mice relative to db/+ and pair-fed controls. Despite reduced energy intake and improved glucose tolerance, leptin administration did not reduce fetal overgrowth in offspring from db/+ mothers. Fetal and placental leptin levels were 1.3- to 1.5-fold higher in offspring from db/+ mothers and remained unchanged with leptin administration, whereas leptin treatment in +/+ mothers or pair-feeding decreased placental leptin concentration and reduced fetal birth weight. Our results provide evidence that leptin administration during late gestation can reduce adiposity and improve glucose tolerance in the db/+ mouse model of spontaneous GDM. However, fetal and placenta leptin levels are higher in db/+ mothers and are subject to reduced negative feedback in response to leptin treatment. These data suggest that alterations in placenta leptin may contribute to the regulation of fetal growth independently of maternal glucose levels.

Animals↗

PubMed2001

[Clinical assessment of the effect of intravenous patient controlled intravenous analgesia and epidural patient controlled epidural analgesia in postoperative analgesia].

OBJECTIVE: To compare the clinical effect and side-effect of intravenous patient controlled intravenous analgesia (PCIA) with patient controlled epidural analgesia (PCEA). METHODS: Two hundred and forty postoperative patients, who were randomly divided into three groups: group PCIA, group PCEA and control, 80 cases for each group, and the recovery of bowel movement, urinary retention, nausea, vomiting, pruritus, respiratory depression, postpartum hemorrhage, lactation and recovery of uterus were observed after operation. RESULTS: Overall patients in two PCA groups were satisfied with the postoperative analgesia. The incidence of urinary retention in group PCIA were significantly lower than that in group PCEA(P < 0.05). The recovery of bowel movement in group PCEA (17.51 +/- 10.33) was much bigger than that in group PCIA (28.70 +/- 16.36) (P < 0.05). There were no remarkable differences between two PCA groups in nausea, vomiting, respiratory depression and pruritus (P > 0.05). There were no remarkable differences between two PCA groups and control in the incidence of postpartum hemorrhage, lactation and recovery of uterus. CONCLUSIONS: Both PCIA and PCEA have excellent analgesic effect. PCIA has lower incidence of urinary retention, and has higher sedative incidence compared with PCEA.

Analgesia, Epidural↗

PubMed2001

[Studies on chemical constituents from Buddleja lindleyana Fert].

OBJECTIVE: To study the chemical constituents of Buddleja lindleyana. METHOD: Separation by chromatographic methods and identification by spectral analysis. RESULT: Seven compounds vanillic acid, daidzein octacosanoic acid, beta-sitosterol-3-O-beta-D-glucopyranoside, stigmasterol-3-O-beta-D-glucopyranoside, alpha-spinasterol-3-O-beta-D-glucopyranoside, betulin acid were isolated. CONCLUSION: All the compounds were obtained from this plant for the first time.

Buddleja↗

PubMed2001

[Clindamycin soluble suppository-production and its efficacy in treating bacterial vaginosis].

OBJECTIVE: To make the soluble suppository of clindamycin which is an effective drug for treatment of Bacterial vaginosis and to treat patients in clinical trials. METHODS: Outpatients who had vaginal infections from Sept. 1998 to Jan. 1999 were investigated. The diagnoses of bacterial vaginosis were made according to Amsel's criteria and 80 patients were included in this study. They were divided into two groups to be treated respectively by metronidanole suppository and clindamycin suppository which were made by our hospital pharmacy. RESULTS: The cure rate of metronidanole was 87.5% and that of clindamycin 90.3%; No significant difference was noted between the two groups(P > 0.05). The new clindamycin suppository was not irritant and it was easy to dissolve in vagina. There was no discontinued treatment because of side-effect. CONCLUSION: The clindamycin suppository does not irritate the mucosa of vagina, it is an efficacious remedy for bacterial vaginosis.

Administration, Intravaginal↗

PubMed2001

[Labyrinthine fistula caused by chronic suppurative otitis media].

OBJECTIVE: To study the clinical feature and surgical management of labyrinthine fistula caused by chronic suppurative otitis media (CSOM). METHOD: A retrospective study of 450 patients with CSOM who underwent radical mastoidectomy between the years 1992 to 1999 in Department of Otolaryngology, Xijing Hospital was conducted. RESULT: 20 patients (4.4%) with labyrinthine fistula caused by CSOM were found. The average history of ear drainage was 22 years, 18 patients (90%) had subjective hearing loss, and 13 patients (65%) had dizziness. The fistula test was positive in 9 patients (45%). 2 patients had anacusis in the affected ear. The preoperative pure tone average for bone conduction thresholds was less than 30 dB in 11 patients, between 31 and 50dB in 3 patients, and more than 51 dB in 4 patients. The ears with a positive fistula test had worse preoperative hearing than those with negative test (P < 0.01). The fistula was detected by CT in 2 of 9 patients. Cholesteatoma was present in 18 patients (90%) and granulation tissue was present in 2 patients (10%). The lateral semicircular canal was the site of labyrinthine fistula. The lesion at the site of fistula was completely removed in 17 patients and exteriorized in the remaining 3. CONCLUSION: There are no reliable methods at present for preoperative diagnosis of labyrinthine fistula, ultimately, the most reliable way to identify a fistula is during surgery. The method of manipulation of labyrinthine fistula is based on the concrete conditions of fistula and patient.

Adult↗

PubMed2001

[Studies on the chemical constituents of the herba of Cuscuta chinensis].

The chemical constituents of the herb of Cuscuta chinensis Lam. were investigated. Five compounds were isolated from petroleum ether and chloroform fraction. Their structures were identified as beta-sitosterol, d-sesamin, 9(R)-hydroxy-d-sesamin, d-pinoresinol and daucosterol by chemical and spectroscopical methods. All these compounds were isolated from the stem for the first time.

Chemical Fractionation↗