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| 1 | Proteasome inhibition-induces endoplasmic reticulum dysfunction and cell death of human cholangiocarcinoma cells显示文摘AIM: To determine if proteasome inhibition induces apoptosis in human cholangiocarcinoma cells, and if so, to elucidate the cellular mechanisms. METHODS: Studies were performed in the human KMCH, KMBC, and Mz-ChA-1 cholangiocarcinoma, and normal rat cell lines. MG132, a peptide aldehyde, which inhibits the chymotrypsin-like activity of the proteaosome was employed for this study. Apoptosis was assessed morphologically by 4'-6-Diamidino-2-phenylindole (DAPI) nuclear staining and fluorescence microscopy. Mitochondrial membrane potential was examined using a fluorescent unquenching assay. Ultrastructural changes during cell death were examined using transmission electron microscopy (TEM). Caspase 3/7 activity was assessed using an enzymatic-based fluorescent assay. Cytosolic-free calcium concentrations were measured using Fura-2 and digitized fluorescent microscopy. RESULTS: MG132, a proteasome inhibitor, induced apoptosis in all the cholangiocarcinoma cell lines examined. In contrast, minimal cytotoxicity was observed in normal rat cholangiocytes. Apoptosis was time-and -concentration-dependent. There was no change in the mitochondrial membrane potential between treated and untreated cells. Ultrastructural examination by transmission electron microscopy displayed the classic features of apoptosis, but in addition, there was also dramatic vacuolization of the endoplasmic reticulum (ER). Unexpectedly, no increase in caspase 3/7 activity was observed in MG132 treated cells, nor did the pancaspase inhibitor, Q-VD-OPh prevent cell death. The protein synthesis inhibitor, cycloheximide, blocked apoptosis induced by proteosome inhibitor indicating that ER dysfunction was dependent upon the formation of new proteins. CONCLUSION: Proteosome inhibition induces ERdysfunction and caspase-independent cell death selectively in human cholangiocarcinoma cells. Proteasome inhibitors warrant evaluation as anticancer agents for the treatment of human cholangiocarcinoma. | Yucel Ustundag Steven F Bronk Gregory J Gores | 2007 | World Journal of Gastroenterology2007，13，6： | 9 |
| 2 | Constitutive androstane receptor agonist, TCPOBOP,attenuates steatohepatitis in the methionine choline-deficientdiet-fed mouse显示文摘AIM:To ascertain whether constitutive androstane receptor(CAR)activation by 1,4-bis-2-(3,5,-dichloropyridyloxy)benzene(TCPOBOP)modulates steatohepatitis in the methionine choline-deficient(MCD)diet-fed animal.METHODS:C57/BL6 wild-type mice were fed the MCD or standard diet for 2 wk and were treated with either the CAR agonist,TCPOBOP,or the CAR inverse agonist,androstanol.RESULTS:Expression of CYP2B10 and CYP3A11,known CAR target genes,increased 30-fold and 45-fold,respectively,in TCPOBOP-treated mice fed the MCD diet.TCPOBOP treatment reduced hepatic steatosis(44.6 ± 5.4% vs 30.4 ± 4.5%,P < 0.05)and serum triglyceride levels(48 ± 8 vs 20 ± 1 mg/dL,P < 0.05)in MCD diet-fed mice as compared with the standard diet-fed mice.This reduction in hepatic steatosis was accompanied by an increase in enzymes involved in fatty acid microsomal ω-oxidation and peroxisomal β-oxidation,namely CYP4A10,LPBE,and 3-ketoacyl-CoA thiolase.The reduction in steatosis was also accompanied by a reduction in liver cell apoptosis and inflammation.In contrast,androstanol was without effect on any of the above parameters.CONCLUSION:CAR activation stimulates induction of genes involved in fatty acid oxidation,and ameliorates hepatic steatosis,apoptosis and inflammation. | Edwina S Baskin-Bey Akira Anan Hajime Isomoto Steven F Bronk Gregory J Gores | 2007 | World Journal of Gastroenterology2007，13，42： | 3 |
| 3 | Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study显示文摘 | Pierre Fenaux Ghulam J Mufti Eva Hellstrom-Lindberg Valeria Santini Carlo Finelli Aristoteles Giagounidis Robert Schoch Norbert Gattermann Guillermo Sanz Alan List Steven D Gore John F Seymour John M Bennett John Byrd Jay Backstrom Linda Zimmerman David M | 2009 | Lancet Oncology2009，，： | 2 |
| 4 | DUSP1 is a novel target for enhancing pancreatic cancer cell sensitivity to gemc- itabine显示文摘 | Liu F Gore AJ Wilson JL | 2014 | PLoS One2014，9，84： | 1 |
| 5 | Use of Sertoli Cell Transplants to Provide Local Immunoprotection for Tissue Grafts显示文摘 | Halberstadt C Emerich D F Gores P | 2004 | Expert Opin Biol Ther2004，4，6： | 1 |
| 6 | Association of prediabetes by fasting glucose and/or haemoglobin Ale levels with subclinical atherosclerosis and impaired renal function: observations from the Dallas Heart Study显示文摘 | Xing F Y Neeland I J Gore M O | 2014 | Diab Vase Dis Res2014，11，1： | 1 |
| 7 | High-temperature mechanical behavior and hot rolling of AA705X显示文摘 | HARNISH S F PADILLA H A DANTZIG J A BEAUDOIN A J GORE B E ROBERTSON I M | 2005 | Metallurgical and Materials Transactions A2005，36，： | 1 |
| 8 | The proline--rich,extensin-like receptor kinase-1 (PPERK4)gene is rapidly induced by wounding 显示文摘 | Silva N F Goring D R | 2002 | Plant Mol Biol2002，50，： | 1 |
| 9 | Effect of mercerization on the crystallite size and crystallinity index in cellulose from different sources显示文摘 | Revol J F Dietrich A Goring D A I | 1987 | Canadian Journal of Chemistry1987，65，8： | 1 |
| 10 | Optimal combinations of systematic sextant and laterally directed biopsies for the detection of prostate cancer显示文摘 | GORE J L SHARIAT S F MILES B J | 2001 | J Urol2001，165，5： | 1 |
| 11 | A review of acute stress reactions a-mong victims of violence:implications for early intervention显示文摘 | Gore F Gill M Koopman C | 1999 | Ag-gression and Violent Behavior1999，4，3： | 1 |
| 12 | Cell death by apoptosis: basic concepts and disease relevance for the gastroenterologist 显示文摘 | Que F G Gores G | 1996 | Gastroenterology1996，110，4： | 1 |
| 13 | Mad3 Negatively Regulates B Cell Dif- ferentiation in the Spleen by Inducing Id2 Expression 显示文摘 | Gore Y Lantner F Hart G | 2010 | Mol Biol Cell2010，21，11： | 1 |
| 14 | Biochemical and genetic studies on yeast flocculation显示文摘 | Stewart G G Garrison I F Goring T E | 1976 | Kemia-Kemi(S0355-1628)1976，3，5： | 1 |
| 15 | Mechanisms of self-incompatibilityin flowering plants 显示文摘 | SILVA N F GORING D R | 2001 | Cell Mol Life Science2001，58，： | 1 |
| 16 | Biliary tract cancers显示文摘 | De Groen P C Gores G J LaRusso N F | 1999 | N Engl J Med1999，341，： | 1 |
| 17 | Lactic acidosis during sep- sis is related to inereased pyruvate production, not deficits in tissue oxygen availability显示文摘 | Gore DC Jahoor F Hibhert JM | 1996 | Ann Surg1996，224，1： | 1 |
| 18 | Mechanisms of self-incompatibility in flowering plants 显示文摘 | SILVA N F GORING D R | 2001 | Cell Mol Life Sci2001，58，： | 1 |
| 19 | Can large rivers be restored显示文摘 | Gore J A Shields F D | 1995 | Bioscience1995，，45： | 1 |
| 20 | The utility of CA 19-9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis显示文摘 | Anand H Patel Denise M Harnois George G Klee Nicholas F LaRusso Gregory J Gores | 2000 | The American Journal of Gastroenterology2000，，1： | 1 |
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