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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 | Changes in phototaxis during the larval life of the eyed hawk moth显示文摘 | DE Ruiter VAN DER Horn I J | 1957 | Nature1957，179，： | 1 |
| 3 | Direct control of the Forkhead transcription factor AFX by protein kinase B显示文摘 | Kops G J de Ruiter ND de Vries-Smits AM | 1999 | Nature1999，398，6728： | 1 |
| 4 | Management of ob- structive sleep apnea in edentulous patients: an overview of the literature显示文摘 | Heidsieck DS de Ruiter MH de Lange J | 2016 | Sleep Breath2016，20，1： | 1 |
| 5 | RNA interference by expression of short interfering RNAs and hairpin RNAs in mammalian cells 显示文摘 | Yu J Y De Ruiter S L Turner D L | 2002 | Proc Natl Acad Sci USA2002，99，9： | 1 |
| 6 | Treatmenl of complexbillaD' stones by eholangioseopy laser litho/ripsy in 10 patients显示文摘 | Verdonk RC de Ruiter A J Weersma RK | 2010 | Ned TijdschrGeneeskd2010，154，： | 1 |
| 7 | Collagens are functional, high affinity ligands for the inhibitory immune receptor LAIR-1 显示文摘 | Lebbink R J de Ruiter T Adelmeijer J | 2006 | J Exp Med2006，203，6： | 1 |
| 8 | Isotopic evidence for dietary variability in the early Hominin Paranthropus robustus显示文摘 | Sponheimer M Passey B H de Ruiter D J | 2006 | Science2006，314，10： | 1 |
| 9 | Developing a geographic information system(GIS)for mapping and analyzing fossil deposits at Swartkrans,Gauteng Province,South Africa显示文摘 | NIGROB J D UNGARB P S RUITER DE D J | 2003 | Journal of Archaeological Science2003，30，3： | 1 |
| 10 | Hominins, sedges, and termites : New carbon isotope data from the Sterkfontein valley and Kruger National Park 显示文摘 | Sponheimer M Lee-Thorp J de Ruiter D | 2005 | Journal of Human Evolution2005，48，： | 1 |
| 11 | British HIV Association and Children's HIV Association guidelines for the management of HIV infection in pregnant women 2008显示文摘 | De Ruiter A Mercey D Anderson J | 2008 | HIV Medicine2008，9，7： | 1 |
| 12 | Collagens are functional, high affinity ligands for the inhibitory immune receptor LAIR 1 显示文摘 | Lebbink RJ de Ruiter T Adelmeijer J | 2006 | J ExpMed2006，203，： | 1 |
| 13 | Com- puter modeling of ocelusal surfaces of posterior teeth with the CICERO CAD/CAM system 显示文摘 | Ohhof L W van Der Zel J M de Ruiter W J | 2000 | J Prosthet Dent2000，8，2： | 1 |
| 14 | The CICERO system for CAD/CAM fabrieation of full ceram- ic crowns 显示文摘 | vail der Zel J M Vlasr S de Ruiter W J | 2001 | Prosthet Dent2001，85，3： | 1 |
| 15 | The epidemiology of intra-abdominal flora in critically ill patients with secondary and tertiary abdominal sepsis 显示文摘 | de RUITER J WEEL J MANUSAMA E | 2009 | Infection2009，37，： | 1 |
| 16 | Osteoinductive ceramics as a synthetic alternative to autologous bone grafting 显示文摘 | Yuan H Fernandes H Habibovic P de Boer J Barradas A M de Ruiter A | 2010 | Proc Natl Acad Sci U S A2010，107，13： | 1 |
| 17 | Mechanisms of androgen receptor activation and function显示文摘 | Brinkmann A O Blok L J de Ruiter P E | 1999 | J Steroid Biochem Mol Biol1999，69，16： | 1 |
| 18 | British HIV Association and children' s HIV Association guidelines for the management of HIV in- fection in pregnant women 2008 显示文摘 | De Ruiter A Memey D Anderson J | 2008 | HIV Medicine2008，9，7： | 1 |
| 19 | Collagens are functional, high affinity ligands for the inhibitory immune receptor LAIR-l显示文摘 | Lehbiuk R J de Ruiter T Adelmeijer J | 2006 | The Journal of Experimental Medicine2006，203，6： | 1 |
| 20 | RNA interference by expression of short - interfering RNAs and hairpin RNAs in mammalian cells 显示文摘 | Yu J Y De Ruiter S L Turner D L | 2002 | Proc Natl Acad Sci2002，99，9： | 1 |
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