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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 | ROC analysis of noninvasive tests for peripheral arterial disease 显示文摘 | Lijmer JG Hunink MG van den Dungen JJ | 1996 | Ultrasound Med Biol1996，22，： | 1 |
| 3 | Mouse models for Type 1 Diabetes 显示文摘 | Van Bellea TL Taylora P Von Herrath MG | 2009 | Drug Discovery Today: Disease Models2009，6，2： | 1 |
| 4 | Intestinal barrier dysfunction in a randomized trial of a specific probiotic composition in acute pancreatitis 显示文摘 | Besselink MG van Santvoort HC Renooij W | 2009 | Ann Surg2009，250，5： | 1 |
| 5 | A step-up proach or open necrosectomy for necrotizing pan- creatitis显示文摘 | Van Santvoort HC Bessel ink MG Bakker OJ | 2010 | N Engl J Med2010，362，16： | 1 |
| 6 | Bone seeking radiopharma- ceuticals for palliation of pain in cancer patients with osseous me- tastases显示文摘 | Lam MG de Klerk JM van Rijk PP | 2007 | Anticancer Agents Med Chem2007，714，： | 1 |
| 7 | Laparo scopic staging and subsequent palliation in patients with peripan creatic carcinoma显示文摘 | Nieveen van Dijkum EJ Romijn MG Terwee CB | 2003 | Ann Surg2003，237，1： | 1 |
| 8 | Early en- doscopic retrograde cholangiopancreatography versus conservative mangement in acute biliary pancreatitis without chloangitisa: Met- a-analysis of randomized trials显示文摘 | Petrov MS Van Santvoort HC Besselink MG | 2008 | Ann Surg2008，247，2： | 1 |
| 9 | Predictive value of tumor load in breast cancer sentinel lymphnodes for second echelon lymph node metastases 显示文摘 | Van Deurzen CH van Hillegersberg R Hobbelink MG | 2007 | CellOncol2007，29，6： | 1 |
| 10 | Intestinal barrier dysfunction in a randomized trial of a specific probiofic composition in acute pancreatitis显示文摘 | Besselink MG van Santvoort HC Renooij W | | 0，，05： | 1 |
| 11 | Zidovudine/ lamivudine but not nevirapine in combination with lopina- vir/ritonavir decreases subcutaneous adipose tissue mito- chondrial DNA显示文摘 | Feeney ER Van Vonderen MG Wit F | 2012 | AIDS2012，26，17： | 1 |
| 12 | Genetics of alkane oxidation by Pseudomonas oleovorans 显示文摘 | Van Beilen JB Wubbolts MG Witholt B | 1994 | Biodegradation1994，5，34： | 1 |
| 13 | A Step- up approach or open necrosectomy for necrotizing pancreatitis 显示文摘 | van Santvoort HC Besselink MG Bakker OJ | 2010 | N Engl J Med2010，362，16： | 1 |
| 14 | Man-agement of Severe acute pancreatitis:it's all about timing显示文摘 | Besselink MG Van Santoort HC Witteman BJ | 2007 | Curr Opin Crit Care2007，13，2： | 1 |
| 15 | Vaccination against CD99 inhibits atherogenesis in low-density lipoprotein receptor-deficient mice显示文摘 | van Wanrooij E J de Vos P Bixel MG | 2008 | Cardiovasc Res2008，78，3： | 1 |
| 16 | Tumor recurrence in liver grafts:two animal models显示文摘 | Schotman SN van Ijken MG Marquet RL | 1998 | Transplant Proc1998，30，4： | 1 |
| 17 | The toll-like receptor 4 Asp299Gly variant and tuberculosis susceptibility in HIV-infected patients in Tanzania 显示文摘 | Ferwerda B Kibiki GS Netea MG Dolmans WM van der Ven AJ | 2007 | AIDS2007，21，10： | 1 |
| 18 | Cardiovascular and gastrointestinal outcomes in clopidogrel users on proton pump inhibitors: results of a large dutch cohort study显示文摘 | van Boxel OS van Oijen MG Hagenaars MP | 2010 | Am J Gastroenterol2010，105，11： | 1 |
| 19 | Apolipoprotein A-V:a novel apolipoprotein associated with an early phase of liver regeneration显示文摘 | Van der Vliet HN Sammelsm MG Leegwater AC Levels JH Reitsma PH Boers W | 2001 | J Biol Chem2001，276，44： | 1 |
| 20 | Measurement of the metal complexing ability of exudates of marine macroalgae显示文摘 | SUEUR S VAN DEN BERG C MG RILEY J P | 1982 | Limnology and Oceanography1982，27，3： | 1 |
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