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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 | Real time optimal interruptible tariff mechanism incorporatiog utility-custormer interactions显示文摘 | Math H J Bollen Jaap E Daalder | 2000 | IEEE Transactions on Power Systems2000，15，2： | 1 |
| 3 | Morbidity of handassisted laparoscopic splenectomy compared toconventional laparoscopic splenectomy: a 6-year review显示文摘 | Altaf AM Ellsmere J Jaap Bonjer H | 2012 | Can J Sur2012，55，4： | 1 |
| 4 | OFDM channel estimation by singular value decomposition 显示文摘 | Ore E Sandell M Jaap J | 1998 | IEEE Transactions on Communications1998，46，7： | 1 |
| 5 | The atherogenie lipoprotein phenotype and vascular endothelial dysfunetion显示文摘 | Sattar N Petrie JR Jaap A J | 1998 | Atherosderosis1998，138，： | 1 |
| 6 | Clinical Pharmaeokinetics of unbound docetaxel: Role of Polysorbate 80 and Serum Proteins显示文摘 | Waiter J Loos Sharyn D Baker Jaap Verweij MD | 2003 | Clinical Pharmacology & Therapeutics2003，74，： | 1 |
| 7 | Treat ment of space-occupying cerebral infarction显示文摘 | Hofeijer J Bart van der Worp H Jaap Kappetle L | 2003 | Crit Care Med2003，，31： | 1 |
| 8 | Genetic changes in the bacterial community structure associated with protistan grazers显示文摘 | van Hannen E J Veninga M Jaap B | 1999 | Arch Hydrobiol1999，145，1： | 1 |
| 9 | Modulation of camptothecin analogs in the treatment of cancer: a review显示文摘 | Diederik FS Kehrer Otto Soepenberg Walter J Loos Jaap Verweij Alex Sparreboom | 2001 | Anti-Cancer Drugs2001，，2： | 1 |
| 10 | Denitrification in concentration recirculating systems:Theory and applications显示文摘 | Jaap Van Rijn Yossi Tal Harold J Schreier | 2006 | Aquacultural Engineering2006，34，： | 1 |
| 11 | Direct Stenting with TAXUS StentsSeems to be as Safe and Effective as withPredilatation显示文摘 | Sigmund Silber Jaap Hamburger Eberhard Grube Matthias Pfisterer Jorge Belardi John Webb Krzysztof Zmudka Christoph Nienaber Karl Hauptman Wolfgang Rutsch Keith Dawkins Janusz Drzewiecki J?rg Koglin Antonio Colombo | 2004 | Herz2004，，： | 1 |
| 12 | Morbidity of hand-assisted laparoscopic splenectomy compared to conventional laparoscopic splenectomy: a 6-year review显示文摘 | Altaf AM Ellsmere J Jaap Bonjer H | 2012 | Can J Surg2012，55，4： | 1 |
| 13 | Characterisation of a unique ‘asphalt’ sample from the early 19th century Hafkenscheid painting materials collection by analytical pyrolysis MS and GC/MS显示文摘 | Georgiana M Languri Jerre van der Horst Jaap J Boon | 2002 | Journal of Analytical and Applied Pyrolysis2002，，1： | 1 |
| 14 | Treatment of spaceoccupying cerebral infarction显示文摘 | Hofeijer J Bart van der Worp H Jaap Kappelle L | 2003 | Crit Care Med2003，2，31： | 1 |
| 15 | Antisense inhibition of hyaluronan synthase-2 in human articular chondrocytes inhibits proteoglycan retention and matrix assembly显示文摘 | Yoshihiro Nishida Cheryl B Knudson J Jaap Nietfeld | 1999 | The Journal of Biological Chemistry1999，274，21： | 1 |
| 16 | Specific energy consumption of membrane bioreaetor (MBR) for sewage treatment显示文摘 | Krzeminski P Jaap H J M van der Graaf Jules B van Li er | 2012 | Water Sci Technol2012，65，2： | 1 |
| 17 | Pore size, shape and connectivity in tills and their relationship to deformation processes显示文摘 | KILFEATHERA A A VAN D M JAAP J M | 2008 | Quaternary Science Reviews2008，27，34： | 1 |
| 18 | Plasma levels of arginine vasopressin elevated in patients with major depression 显示文摘 | Liesbeth VL Jaap GG Godfried M J | 1997 | Neuropsychopharmacology1997，17，： | 1 |
| 19 | Clinical pharmaeokineties and metabolism of irinoteean (CPT-11)显示文摘 | Ron HJ Mathijssen Robbert J van Alphen Jaap Verweij | 2001 | Clin Cane Res2001，7，8： | 1 |
| 20 | Exploration of lipase-catalyzed direct amidation of free carboxylic acids with ammonia in organic solvents显示文摘 | MIKE J J ADRIE J J JAAP A J | 1999 | Tetrahedron1999，55，12： | 1 |
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