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Biomedical subjects

R Yu

Publications and source records attributed to R Yu.

At least 37 records · Page 2Linked to original sources
PubMed2001

Mice lacking pituitary tumor transforming gene show testicular and splenic hypoplasia, thymic hyperplasia, thrombocytopenia, aberrant cell cycle progression, and premature centromere division.

Tumorigenic pituitary tumor transforming gene (PTTG) is a mammalian homolog of Xenopus securin that inhibits chromatid separation, is overexpressed in many human tumor types, and mediates transcriptional activation. Loss of yeast securin Pds1p or Drosophila securin pimples is lethal. Here we show that mice lacking PTTG (PTTG -/-) are, surprisingly, viable and fertile; but they have testicular and splenic hypoplasia, thymic hyperplasia, and thrombocytopenia. PTTG -/- mouse embryo fibroblasts exhibited aberrant cell cycle progression with prolonged G2-M phase and binucleated and multinucleated nuclei with increased aneuploidy. PTTG -/- mouse embryo fibroblast metaphases contained quadriradial, triradial, and chromosome breaks, as well as premature centromere division. The results show that PTTG functions to maintain chromosome stability, cell cycle progression, and appropriate cell division. Moreover, mammalian sister chromatid separation, an important transition in the cell cycle, is likely regulated by mechanisms in addition to securin.

Animals↗
PubMed2001

Activation of MAPK by TRH requires clathrin-dependent endocytosis and PKC but not receptor interaction with beta-arrestin or receptor endocytosis.

To determine whether the interaction of the TRH receptor with beta-arrestin is necessary for TRH activation of MAPK, cells expressing either intact or truncated, internalization-defective TRH receptors were transfected with a beta-arrestin-green fluorescent protein conjugate. In cells expressing the wild-type pituitary TRH receptor, TRH caused translocation of the beta-arrestin-green fluorescent protein conjugate from the cytosol to the plasma membrane within 30 sec. After 5 min, the beta-arrestin-green fluorescent protein conjugate was visible in vesicles, where it colocalized with rhodamine-labeled TRH. In hypertonic sucrose, the beta-arrestin-green fluorescent protein conjugate translocated to the plasma membrane after TRH addition but did not internalize. In cells expressing the truncated TRH receptor, TRH did not cause translocation of the beta-arrestin-green fluorescent protein conjugate. TRH activated MAPK strongly in cells expressing intact or truncated TRH receptors, indicating that the receptor does not need to bind beta-arrestin or internalize. MAPK activation by TRH, epidermal growth factor, and phorbol ester was strongly inhibited by hypertonic sucrose and concanavalin A, which block movement of proteins into coated pits and coated pit assembly. Hypertonic sucrose did not affect MAPK activation in cells overexpressing MAPK kinase 1. Dominant negative dynamin, which blocks conversion of coated pits to vesicles, also reduced receptor internalization and TRH activation of MAPK. TRH activation of MAPK required PKC but was insensitive to pertussis toxin and did not require ras, epidermal growth factor receptor kinase, or PI3K. These results show that the TRH receptor itself does not need to bind beta-arrestin or undergo sequestration to activate MAPK but that the endocytic pathway must be intact.

Arrestins↗
PubMed2001

Modulation of proliferating cell nuclear antigen in the bronchial epithelium of smokers.

Clinical chemoprevention trials seek to intervene in the carcinogenic process to suppress, reverse, or delay the development of invasive cancer. Dysregulated cell growth is a hallmark of epithelial carcinogenesis, and proliferating cell nuclear antigen (PCNA) is a marker of dysregulated proliferation that is highly expressed in non-small cell lung cancers. Squamous metaplasia of the bronchial epithelium is found in chronic smokers and has been considered an early premalignant change. To evaluate the effect of 13-cis-retinoic acid (13-cRA) on PCNA modulation, we evaluated PCNA expression in a total of 706 bronchial biopsy specimens from histologically normal, hyperplastic, metaplastic, and dysplastic bronchial tissues obtained from 86 healthy smokers at baseline, of whom 69 subjects had completed 6 months of treatment on a randomized placebo-controlled chemoprevention trial of 13-cRA and had repeat bronchoscopic biopsies. PCNA expression was evaluated with respect to bronchial metaplasia and as an intermediate end point for response in the trial. In the bronchial biopsies obtained from six standardized pretreatment and posttreatment sites, high PCNA expression correlated significantly with more advanced histological grade (P < 0.001). Furthermore, smoking cessation during therapy correlated well with reduced PCNA expression (P = 0.006), although multivariate analysis indicated that this reduction in PCNA expression was associated with the reversal of squamous metaplasia. The level of PCNA expression appeared to correlate with the level of epidermal growth factor receptor expression both at baseline and at 6 months. In those patients who ceased smoking during the intervention, the 13-cRA also appeared to be more effective than placebo in reducing PCNA expression (P = 0.034 in all of the layers; P = 0.026 in basal layers). The efficacy of 13-cRA in the down-regulation of PCNA in quitters was independent of baseline PCNA expression levels. Our study demonstrated that increased PCNA expression was associated with histological progression from normal bronchial epithelium to squamous metaplasia and dysplasia. The modulation of PCNA by 13-cRA in patients who quit smoking suggests a potentially important role for regulating this proliferation marker in retinoid chemoprevention studies of former smokers.

Adult↗
PubMed2001

Synergistic protection of allopregnanolone and phenobarbital against maximal electroshock seizures in mice.

AIM: To examine the interactions of allopregnanolone and phenobarbital for the protection against seizures. METHODS: The protective activity of allopregnanolone and/or phenobarbital against seizures was studied in the C57 mice, using the maximal electroshock seizure (MES) test. The modulations by allopregnanolone and/or phenobarbital at the GABA(A) receptor were also characterized using the [3H]flunitrazepam binding in the membrane preparation of mouse cerebral cortex. RESULTS: Pretreatment with phenobarbital produced a dose-dependent protective effect against seizures. The ED50 value of phenobarbital was 2.61 (95 % confidence limits: 1.59 - 4.26) mg . kg-1. Likewise, the ED50 value of allopregnanolone was 0.11 (0.06 - 0.18) mg . kg-1. The combination of allopregnanolone and phenobarbital (1:20) resulted in an ED50 value of 0.73 (0.44 - 1.21) mg . kg-1 with the Q value smaller than 1. In measuring the enhancement of [3H]flunitrazepam binding, we found that the pattern for the concentration-effect curves of phenobarbital with or without allopregnanolone was consistent with that of the theoretical curves of functional synergism. CONCLUSION: There was a synergism between allopregnanolone and phenobarbital for the protective activity against seizures. Also there was a functional synergism between these two agents for the enhancement of [3H]flunitrazepam binding to the GABAA receptor complex in the brain.

Animals↗
PubMed2001

[Effects of selenium on hepatocellular protooncogene c-myc, c-fos and c-jun expression induced by cadmium in rats].

OBJECTIVES: This study was conducted to explore effects of selenium on hepatocellular protooncogene c-myc, c-fos and c-jun expression induced by cadmium in rats. METHOD: Both cadmium and selenium were given to rats by i.p. and there were 5 SD rats in each group. Protooncogene c-myc, c-fos and c-jun expression in rat liver cells was measured with Northern Dot Hybridization. RESULTS: The results showed that cadmium chloride at doses of 5, 10 or 20 mumol/kg, significantly induced proto-oncogene c-myc, c-fos and c-jun expression, and when sodium selenite at the dose of 5 mumol/kg was given at the time, the effect of cadmium chloride on hepatocellular protooncogene c-myc, c-fos and c-jun expression was inhibited. CONCLUSION: Selenium at certain doses could inhibit hepatocellular protooncogene c-myc, c-fos and c-jun expression induced by cadmium in rats.

Animals↗
PubMed2001

Increased activity of protein kinase C in alveolar macrophages in idiopathic pulmonary fibrosis.

OBJECTIVE: To investigate the changes on protein kinase C (PKC) activity of alveolar macrophages (AMs) in patients with idiopathic pulmonary fibrosis (IPF). METHODS: The PKC activity of AM in 9 healthy volunteers and 15 patients with IPF was investigated by measuring the radioactivity. RESULTS: The total, cytosolic and membrane PKC activity of AM in bronchoalveolar lavage fluid (BALF) from patients with IPF were higher than those from control group (P < 0.01, P < 0.05 and P < 0.05, respectively). The total and the membrane-associated PKC activity had a positive correlation with the number of cells in BALF (r = 0.8135, P < 0.01 and r = 0.5917, P < 0.05), respectively. CONCLUSION: As a bypass of transmembrane signal transduction, PKC was suggested to be involved in the origination and development of IPF.

Adult↗
PubMed2001

[Association of vascular endothelial growth factor expression with angiogenesis and tumor cell proliferation in human lung cancer].

OBJECTIVE: To evaluate the expression of vascular endothelial growth factor (VEGF) and the relation with angiogenesis and tumor cell proliferation in human lung cancer. METHODS: Expression of VEGF, angiogenesis, tumor cell proliferation in 63 cases of human lung cancer were examined immunohistochemically. Anti-VEGF(165)-Ab3 was used for VEGF expression, a monoclonal antibody directed against CD(34) to identify intratumoral microvessel density (iMVD) and the proliferating cell nuclear antigen (PCNA) as a marker of proliferating tumor cells. RESULTS: Positive staining for VEGF was obtained in 32 of the 63 cases (50.8%), iMVD varied from 4 to 138.7 (M = 36)/x 400 and the proportion of PCNA positive cells varied from 0 to 92% (M = 25.03%). iMVD in high-grade VEGF tumors was significantly higher than that in VEGF-negative tumors and low-grade VEGF tumors. PCNA labeling proliferation index in small cell lung cancer was higher than that in non-small cell lung cancer. iMVD significantly increased with increasing VEGF expression. CONCLUSION: There is VEGF expression in lung cancer. VEGF expression is significantly associated with iMVD, but there is no association between iMVD or VEGF expression and PCNA expression. There is no association between VEGF expression and histological classification and clinical stages.

Adult↗
PubMed2001

[Imaging diagnosis of intestinal tuberculosis].

OBJECTIVE: To assess significance and limitation of CT and radiological gastrointestinal examination in the diagnosis of the intestinal tuberculosis. METHODS: 22 cases of intestinal tuberculosis proven pathologically were analyzed. CT scans and radiological examination were performed (barium meal examination in 18 cases, intestinal or colonic double contrast examination in 10 cases and hypotonic duodenography in 3 cases). RESULTS: Sensitivity and specificity of diagnosing the intestinal tuberculosis with CT were inferior than that with radiological examination. Lesions in small intestine (not including ileocecal region) were not easily identified by CT scan. However, CT scan was more preferable in identifying abdominal tuberculosis other than intestinal tuberculosis, especially typical tuberculous lymphadenopathy. Intestinal radiological examination was of great significance for the assessment of the status of intestinal tuberculosis by demonstrating mucosal alterations, morphologic appearance of ulcer, bowel deformation, and the involvement of lesion and fissures. CONCLUSIONS: Gastrointestinal radiological examination and CT scans possess their diagnostic value, but have limitation in diagnosis of intestinal tuberculosis. CT scans combined with gastrointestinal radiological examination further improve the accuracy of diagnosis.

Adult↗
PubMed2001

Association of HIF-1alpha expression and cell apoptosis after traumatic brain injury in the rat.

OBJECTIVE: To explore the expression of hypoxia inducible factor-1alpha (HIF-1alpha) and the correlation between HIF-1alpha and apoptosis after traumatic brain injury. METHODS: Using experimental traumatic brain injury in the rats, the expression of HIF-1alpha was studied by immunohistochemistry in cerebral tissue, apoptotic cell death was evaluated with TUNEL (transferase-mediated X-dUTP nick end labeling), and double-labeled immunohistochemistry and TUNEL methods were used to investigate the relationship between HIF-1alpha and apoptosis. RESULTS: There was remarkable difference in the expression of H IF-1alpha between the experimental groups and the control groups (P<0.01), in the experimental groups, the expression of HIF-1alpha at 48 hours was highest; the evidence of apoptotic cell death after experimental traumatic brain injury was found by TUNEL; the apoptotic percentage increased or decreased according to the changes of the positive expression of HIF-1alpha (r=0.99). CONCLUSIONS: The results suggest that secondary brain ischemia plays a crucial role in apoptotic cell death after traumatic brain injury; HIF-1alpha can prompt apoptotic cell death after experimental traumatic brain injury.

Animals↗
PubMed2001

[The combination of cyclosporin A and androgen in the treatment of chronic aplastic anemia].

OBJECTIVE: To explore the therapeutic effectiveness of combination of cyclosporin A (CsA) and androgen in the treatment of chronic aplastic anemia (CAA). METHOD: Androgen alone or combined with CsA for the treatment of CAA was compared by a randomized controlled clinical trial. RESULT: The efficacy of androgen combined with CsA (87.9%) was higher than that of androgen alone (57.1%). Therapeutic effectiveness of the combination treatment between the patients with positive and negative peripheral blood mononuclear cells (PBMNCs) inhibiting normal colony formation unit-granulocyte and macrophage (CFU-GM) test showed a significant difference (P < 0.005). CONCLUSION: Androgen combined with CsA had a much better efficacy than that of androgen alone in the treatment of CAA. The patients' PBMNCs inhibiting normal CFU-GM growth test can be used as an index of the treatment outcome. The side effects of the combination therapy are low and tolerable.

Adolescent↗
PubMed2001

Drug properties of second-generation antisense oligonucleotides: how do they measure up to their predecessors?

Antisense technology has progressed beyond the point of using only phosphorothioate oligodeoxynucleotides as therapeutic agents to looking at antisense molecules that contain additional chemical modifications as the next generation of therapeutic agents. These modifications are intended to improve the overall therapeutic properties by increasing potency, optimizing pharmacokinetic properties and improving the safety profile. This review will focus on the non-clinical pharmacokinetic and safety properties of 2'-O-methoxyethyl-modified oligonucleotides. Implications on the convenience and safe use of these compounds as therapeutic agents will be discussed.

Animals↗
PubMed2000

Activation of mitogen-activated protein kinase pathways induces antioxidant response element-mediated gene expression via a Nrf2-dependent mechanism.

Antioxidant response element (ARE) regulates the induction of a number of cellular antioxidant and detoxifying enzymes. However, the signaling pathways that lead to ARE activation remain unknown. Here, we report that the expression of mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase kinase kinase 1 (MEKK1), transforming growth factor-beta-activated kinase (TAK1), and apoptosis signal-regulating kinase (ASK1) in HepG2 cells activated the ARE reporter gene, whereas the expression of their dominant-negative mutants impaired ARE activation by the chemicals sodium arsenite and mercury chloride. Coexpression of downstream kinases, MAP kinase kinase 4, MAP kinase kinase 6, and c-Jun NH(2)-terminal kinase-1, but not MAP kinase kinase 3 and p38, augmented ARE activation by MEKK1, TAK1, and ASK1. The coexpression of a basic leucine zipper transcription factor Nrf2 but not c-Jun also greatly enhanced the activation of reporter gene by MEKK1, TAK1, and ASK1; however, a dominant-negative mutant of Nrf2 (NF-E2-related factor 2) blocked this event. Furthermore, when overexpressed, MEKK1, TAK1, and ASK1 induced the expression of heme oxygenase-1, a gene regulated by ARE, and the cotransfection with the dominant-negative mutant of Nrf2 abolished the induction. Taken together, these results suggest that MAP kinase pathways that are activated by MEKK1, TAK1, and ASK1 may link chemical signals to Nrf2, leading to the activation of ARE-dependent genes.

Antioxidants↗
PubMed2000

Pituitary tumor transforming gene causes aneuploidy and p53-dependent and p53-independent apoptosis.

The pituitary tumor transforming gene, PTTG, is abundantly expressed in several neoplasms. We recently showed that PTTG overexpression is associated with apoptosis and therefore have now studied the role of p53 in this process. In MCF-7 breast cancer cells that express wild type p53, PTTG overexpression caused apoptosis. p53 was translocated to the nuclei in cells expressing PTTG. Overexpression of p53, along with PTTG, augmented apoptosis, whereas expression of the human papillomavirus E6 protein inhibited PTTG-induced apoptosis. In MG-63 osteosarcoma cells that are deficient in p53, PTTG caused cell cycle arrest and subsequent apoptosis that was inhibited by caspase inhibitors. A proteasome inhibitor augmented PTTG expression in stable PTTG transfectants, suggesting that down-regulated PTTG expression is required for cell survival. Finally, MG-63 cells expressing PTTG showed signs of aneuploidy including the presence of micronuclei and multiple nuclei. These results indicate that PTTG overexpression causes p53-dependent and p53-independent apoptosis. In the absence of p53, PTTG causes aneuploidy. These results may provide a mechanism for PTTG-induced tumorigenesis whereby PTTG mediates aneuploidy and subsequent cell transformation.

Aneuploidy↗
PubMed2000

Polymorphisms of the DNA repair gene XRCC1 and risk of gastric cancer in a Chinese population.

Gastric cancer remains the leading cause of cancer death in China and other countries in eastern Asia. Studies of gastric cancer have revealed that it is a disease of complex etiology involving dietary, infectious, environmental, occupational and genetic factors. DNA repair capacity has been suggested as a genetic factor contributing to variation in susceptibility to cancer. In the present study, we described an association between 2 polymorphisms of the DNA repair gene XRCC1 and risk of gastric cancer in a Chinese population. We used a polymerase chain reaction-based assay to detect Pvu II and Nci I restriction fragment length polymorphisms (XRCC1 26304 C-->T and XRCC1 28152 G-->A, respectively) in 188 patients with gastric cancer and 166 healthy controls. The XRCC1 26304 T allele (194Trp) frequency (34.6%) was higher and the XRCC1 28152 A allele (399Gln) frequency (25.6%) was lower in healthy Chinese controls than previously reported healthy U.S. Caucasian controls (7.2% and 34.1%, respectively). Multivariate logistic regression analysis revealed that the putative high-risk genotypes XRCC1 26304 CC and XRCC1 28152 GA/AA were associated with a non-significant increased risk for gastric cancer (adjusted odds ratio [OR]=1.45, 95% confidence interval [CI]= 0.93-2.25 and OR=1.53, 95% CI= 0.98-2.39, respectively) compared with other genotypes. However, the XRCC1 26304 CC genotype was associated with a significantly increased risk for gastric cardia cancer (adjusted OR=1.86, 95% CI=1.09-3.20). Individuals with both putative high-risk genotypes (CC and GA/AA) had a significantly higher risk (adjusted OR=1.73, 95% CI=1.12-2.69), particularly for gastric cardia cancer (adjusted OR=2.18, 95% CI=1.21-3.94) than individuals with other genotypes. These findings support the hypothesis that these 2 XRCC1 variants may contribute to the risk of developing gastric cancer, particularly gastric cardia cancer.

Adult↗
PubMed2000

Capsaicin protects against ethanol-induced oxidative injury in the gastric mucosa of rats.

In this study, we investigated the protective effects of capsaicin on gastric mucosal oxidative damage induced by ethanol. Sprague Dawley rats intragastrically received 0.5-10 mg/kg, BW capsaicin or vehicle; 30 min later gastric lesions were induced by intragastric administration of absolute ethanol. Lipid peroxidation was estimated by measuring thiobarbituric acid reactive substances in gastric mucosa. Myeloperoxidase activity, a marker enzyme of polymorphonuclear leukocytes for tissue inflammation, was also measured in the gastric mucosa. The expression level of cyclooxygenase-2, which increases in inflammatory region, was determined by Western blot analysis. Capsaicin significantly suppressed gastric haemorrhagic erosions induced by ethanol. Capsaicin inhibited lipid peroxidation and myeloperoxidase activity in ethanol-induced gastric mucosal lesion in a dose-dependent manner. Capsaicin also inhibited the expression of cyclooxygenase-2 in the gastric mucosal lesion. The gastroprotective activity of capsaicin on the ethanol-induced oxidative damage may be important for chemoprevention.

Animals↗
PubMed2000

Activation of caspase-3 and c-Jun NH2-terminal kinase-1 signaling pathways in tamoxifen-induced apoptosis of human breast cancer cells.

Tamoxifen (TAM) is widely used in the treatment of breast cancer. The cytostatic effects of TAM have been attributed to the antagonism of estrogen receptor (ER) and inhibition of estrogen-dependent proliferative events. However, the mechanism by which TAM is also effective against certain ER-negative breast tumors remains to be elucidated. Here we report that TAM induced the activity of caspase-3-like proteases in ER-negative breast cancer cell lines MDA-MB-231 and BT-20, as evidenced by the cleavage of fluorogenic tetrapeptide substrate and of poly(ADP-ribose) polymerase. The activation of caspase-3-like proteases preceded TAM-induced chromatin condensation and nuclear fragmentation, the typical apoptotic morphologies. Pretreatment of cells with a specific inhibitor of caspase-3, acetyl-Asp-Glu-Val-Asp-aldehyde, or with a general inhibitor of caspases, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, prevented TAM-induced apoptosis. TAM also stimulated c-Jun NH2-terminal kinase (JNK) 1 activity, and interfering with the JNK pathway by over-expressing a DN JNK1 mutant attenuated TAM-induced apoptosis. In addition, treatment of cells with a lipid-soluble antioxidant vitamin E blocked TAM-induced caspase-3 and JNK1 activation as well as apoptosis, whereas water-soluble antioxidants N-acetyl L-cysteine and glutathione had little effect. Thus, this study demonstrates that TAM induces apoptosis in ER-negative breast cancer cells through caspase-3 and JNK1 pathways, which are probably initiated at the cell membrane by an oxidative mechanism.

Amino Acid Chloromethyl Ketones↗
PubMed2000

Rapid turnover of calcium in the endoplasmic reticulum during signaling. Studies with cameleon calcium indicators.

HEK293 cells expressing the thyrotropin-releasing hormone (TRH) receptor were transfected with cameleon Ca(2+) indicators designed to measure the free Ca(2+) concentration in the cytoplasm, [Ca(2+)](cyt), and the endoplasmic reticulum (ER), [Ca(2+)](er). Basal [Ca(2+)](cyt) was about 50 nm; thyrotropin-releasing hormone (TRH) or other agonists increased [Ca(2+)](cyt) to 1 micrometer or higher. Basal [Ca(2+)](er) averaged 500 micrometer and fell to 50-100 micrometer over 10 min in the presence of thapsigargin. TRH consistently decreased [Ca(2+)](er) to 100 micrometer, independent of extracellular Ca(2+), whereas agonists for endogenous receptors generally caused a smaller decline. When added with thapsigargin, all agonists rapidly decreased [Ca(2+)](er) to 5-10 micrometer, indicating that there is substantial store refilling during signaling. TRH increased [Ca(2+)](cyt) and decreased [Ca(2+)](er) if applied after other agonists, whereas other agonists did not alter [Ca(2+)](cyt) or [Ca(2+)](er) if added after TRH. When Ca(2+) was added back to cells that had been incubated with TRH in Ca(2+)-free medium, [Ca(2+)](cyt) and [Ca(2+)](er) increased rapidly. The increase in [Ca(2+)](er) was only partially blocked by thapsigargin but was completely blocked if cells were loaded with 1, 2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. In conclusion, these new Ca(2+) indicators showed that basal [Ca(2+)](er) is approximately 500 micrometer, that [Ca(2+)](er) has to be >100 micrometer to support an increase in [Ca(2+)](cyt) by agonists, and that during signaling, intracellular Ca(2+) stores are continuously refilled with cytoplasmic Ca(2+) by the sarcoendoplasmic reticulum Ca(2+)-ATPase pump.

Animals↗