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| 1 | m TOR signaling in liver regeneration: Rapamycin combined with growth factor treatment显示文摘AIM: To investigate the effects of mammalian target of rapamycin(mT OR) inhibition on liver regeneration and autophagy in a surgical resection model.METHODS: C57BL/6 mice were subjected to a 70% partial hepatectomy(PH) and treated intraperitoneally every 24 h with a combination of the m TOR inhibitor rapamycin(2.5 mg/kg per day) and the steroid dexamethasone(2.0 mg/kg per day) in phosphate bufferedsaline(PBS) or with PBS alone as vehicle control. In the immunosuppressant group, part of the group was treated subcutaneously 4 h prior to and 24 h after PH with a combination of human recombinant interleukin 6(IL-6; 500 μg/kg per day) and hepatocyte growth factor(HGF; 100 μg/kg per day) in PBS. Animals were sacrificed 2, 3 or 5 d after PH and liver tissue and blood were collected for further analysis. Immunohistochemical staining for 5-Bromo-2'-deoxyuridine(Brd U) was used to quantify hepatocyte proliferation. Western blotting was used to detect hepatic microtubule-associated protein 1 light chain 3(LC3)-Ⅱ protein expression as a marker for autophagy. Hepatic gene expression levels of proliferation-, inflammation- and angiogenesisrelated genes were examined by real-time reverse transcription-polymerase chain reaction and serum bilirubin and transaminase levels were analyzed at the clinical chemical core facility of the Erasmus MC-University Medical Center.RESULTS: m TOR inhibition significantly suppressed regeneration, shown by decreased hepatocyte proliferation(2% vs 12% Brd U positive hepatocyte nuclei at day 2, P < 0.01; 0.8% vs 1.4% at day 5, P = 0.02) and liver weight reconstitution(63% vs 76% of initial total liver weight at day 3, P = 0.04), and furthermore increased serum transaminase levels(aspartate aminotransferase 641 U/L vs 185 U/L at day 2, P = 0.02). Expression of the autophagy marker LC3-Ⅱ, which was reduced during normal liver regeneration, increased after mT OR inhibition(46% increase at day 2, P = 0.04). Hepatic gene expression showed an increased inflammation-related response [tumor necrosis factor(TNF)-α 3.2-fold upregulation at day 2, P = 0.03; IL-1Ra 6.0-fold upregulation at day 2 and 42.3-fold upregulation at day 5, P < 0.01] and a reduced expression of cell cycle progression and angiogenesis-related factors(HGF 40% reduction at day 2; vascular endothelial growth factor receptor 2 50% reduction at days 2 and 5; angiopoietin 1 60% reduction at day 2, all P ≤ 0.01). Treatmentwith the regeneration stimulating cytokine IL-6 and growth factor HGF could overcome the inhibitory effect on liver weight(75% of initial total liver weight at day 3, P = 0.02 vs immunosuppression alone and P = 0.90 vs controls) and partially reversed gene expression changes caused by rapamycin(TNF-α and IL-1Ra levels at day 2 were restored to control levels). However, no significant changes in hepatocyte proliferation, serum injury markers or autophagy were found.CONCLUSION: mT OR inhibition severely impairs liver regeneration and increases autophagy after PH. These effects are partly reversed by stimulation of the IL-6 and HGF pathways. | Suomi MG Fouraschen Petra E de Ruiter Jaap Kwekkeboom Ron WF de Bruin Geert Kazemier Herold J Metselaar Hugo W Tilanus Luc JW van der Laan Jeroen de Jonge | 2013 | World Journal of Transplantation2013，3，3： | 6 |
| 2 | A rough sets based characteristic relation approach for dynamic attribute generalization in data mining显示文摘 | LI Tian-rui DA Ruan Geert W | 2007 | Knowledge-Based Systems2007，20，5： | 1 |
| 3 | Endoge nous cellutases in animals: isolation of β-1, 4-endoglucanase genes from two species of plant parasitic cyst nemtodes显示文摘 | GEERT S JACK P W G STOKKERMAN S | 1998 | Proc Natl Acad Sci USA1998，95，9： | 1 |
| 4 | Enrich- ment and characterization of marine anammox bacteria asso- ciated with global nitrogen gas production 显示文摘 | Van de Vossenberg J Rattray J E Geerts W | 2008 | Environmental Microbiology2008，10，11： | 1 |
| 5 | Prevention of venous thromboembolism:American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)显示文摘 | Geerts W H Bergqvist D Pineo G F | | 0，，6： | 1 |
| 6 | Prevention of venous thromboembolism:The seventh ACCPconference on antithrombotic and thronbolytic therapy显示文摘 | Geerts W Pineo G Heir J | 2004 | Chest2004，126，： | 1 |
| 7 | A prospective study of venous thromboembolism after major trauma显示文摘 | Geerts W H Code K I Jay R M | 1994 | N Engl J Med1994，331，24： | 1 |
| 8 | A rough sets based characteristic relation approach for dynamic attribute generalization in data mining显示文摘 | LI Tian-rui RUAN D GEERT W | 2007 | Knowledge-based Systems2007，20，5： | 1 |
| 9 | A prospective study of venous thromboembolism aftermajor trauma显示文摘 | GEERTS W H CODE K I JAY R M | 1994 | N Engl J Med1994，331，24： | 1 |
| 10 | Prevention of venous thromboembolism after total hip and knee arthroplasty显示文摘 | Lieberman J R Geerts W H | 1994 | J Bone Joint Surg Am1994，76，8： | 1 |
| 11 | Prevention of venous thromboembolism in high-risk patients 显示文摘 | Geerts W H | 2006 | Hematology Am Soc Hematol Educ Pro-gram2006，2006，1： | 1 |
| 12 | Prevention of v m: American college of chest physicians evidence based clinical practice guidelines (8th edition) 显示文摘 | Geerts W H Bergqvist D Pinco G F | 2008 | Chest2008，133，： | 1 |
| 13 | Prevention of venous thromboembolism in the ICU 显示文摘 | GEERTS W SELBY R | 2003 | CHEST Journal2003，124，6： | 1 |
| 14 | A rough sets based charac- teristic relation approach for dynamic attribute generalization in data mining 显示文摘 | Li Tian-rui Ruan Da Geert W | 2007 | Knowledge-Based Systems2007，20，5： | 1 |
| 15 | Prevention of venous thromboembolism: American College of Chest Physicians Evidence- Based Clinical Practice Guidelines(8th Edition)显示文摘 | GEERTS W H BERGQVIST D PINEO G F | 2008 | Chest2008，133，6： | 1 |
| 16 | Prevention of venous thromboembolism显示文摘 | CLAGETT G P ANDERSON F A Jr GEERTS W | 1998 | Chest1998，114，： | 1 |
| 17 | Vena caval filters: current knowledge, uncertainties and practical approaches 显示文摘 | INGBER S GEERTS W H | 2009 | Curr Opin Hematol2009，16，5： | 1 |
| 18 | Thrombophilia and new anticoagulant drugs显示文摘 | Weitz J I Middeldorp S Geerts W | | 0，，： | 1 |
| 19 | Practial management of venous thromboembolism following pelvic fractures显示文摘 | Montgomery K D Geerts W H Potter H G | 1997 | Orthop Clin North Am1997，28，3： | 1 |
| 20 | Prevention of thromboembolism 显示文摘 | Clagett G Andersen F Geerts W | 1998 | Chest1998，114，： | 1 |
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