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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 | Rearing condition and plasma cortisol in rhesus monkey infants 显示文摘 | SHANNON C CHAMPOUX M SUOMI S J | 1998 | American Journal of Primatology1998，46，： | 1 |
| 3 | Self-directed strength training:its effect on leg strength in men with mental retardation显示文摘 | Suomi R | 1998 | Archives of Physical Medicine and Rehabilitation1998，79，3： | 1 |
| 4 | Prepmation of atarch betainate: a novd cationic atarch derivative 显示文摘 | Grano H Yli - Kauhahxmm J Suomi T | 2000 | Carbohydrate Polymers2000，41，3： | 1 |
| 5 | Larger testes and higher inhibin B levels in Finnish than in Danish newborn boys 显示文摘 | Main KM Toppari J Suomi AM | 2006 | J Clin Endocrinol Metab2006，91，7： | 1 |
| 6 | Dietary preferences of weaned piglets offered diets containing organic acids显示文摘 | Partanen K Siljander-Rasi H Suomi K | 2002 | Agricul- tural and Food Science in Finland2002，11，： | 1 |
| 7 | hTe radiation balance of Earth from a satellite显示文摘 | Suomi V. E | | 0，，： | 1 |
| 8 | Analysis of satellite infrared radiation measurements on a synoptic scale显示文摘 | Weinstein M Suomi V E | | 0，，11： | 1 |
| 9 | Satellite observation of the Earth's radiation budget显示文摘 | Vonder Haar Suomi V E | | 0，，： | 1 |
| 10 | From thought to therapy: Lessons from a primate laboratory显示文摘 | Harlow H F Harlow M K Suomi S J | 1971 | American Scientist1971，59，： | 1 |
| 11 | Effects of arthritis exercise programs on functionai fitness and perceived activities of daily living measures in older adults with arthritis 显示文摘 | Suomi R Collier D | 2003 | Arch Phys Med Rehabil2003，84，11： | 1 |
| 12 | DRD1 5′UTR variation,sex and early infant stress influence ethanol consumption in rhesus macaques显示文摘 | Newman TK Parker CC Suomi SJ Goldman D Barr CS Higley JD | | 0，，06： | 1 |
| 13 | Early experience and serotonin transporter gene variation interact to influence primate CNS function显示文摘 | Bennett A J Lesch K P Heils A Long J C Lorenz J G Shoal S E Champoux M Suomi S J Linnoila M V Higley J D | 2002 | Molecular Psychiatry2002，7，1： | 1 |
| 14 | Monoamine oxidase A gene promoter variation and rearing experience influences aggressive behavior in rhesus monkeys显示文摘 | Timothy K. Newman Yana V. Syagailo Christina S. Barr Jens R. Wendland Maribeth Champoux Markus Graessle Stephen J. Suomi J. Dee Higley Klaus-Peter Lesch | 2005 | Biological Psychiatry2005，，2： | 1 |
| 15 | Current status of modem analytical luminescence mthods显示文摘 | Kulmala S Suomi J | 2003 | Anal Chim Acta2003，500，： | 1 |
| 16 | Impact of stro- real cell composition on BMP-induced chondrogenic differentia- tion of mouse bone marrow derived mesenchymal ceils显示文摘 | Taipaleenmaki H Suomi S Hentunen T | 2008 | Exp Cell Res2008，314，13： | 1 |
| 17 | Review: Current status of modern analytical luminescence methods 显示文摘 | Kulmala S Suomi J | 2003 | Anal Chim Acta2003，500，1： | 1 |
| 18 | Effect of betaine supple-mentation of low methionine diet for growing pigs 显示文摘 | Alaviuhkola T Suomi K | 1990 | Annals Agriculture Fenniae1990，29，2： | 1 |
| 19 | Hereditary aspects of endometrial adenecarcinoma 显示文摘 | Suomi R Pietila THA Leminen A | 1995 | Int J Cancer1995，62，： | 1 |
| 20 | Utilization of information resources for business success: The knowledge sharing model显示文摘 | Widen-Wulff G Suomi R | 2007 | Information Resources Manage- ment Journal2007，20，1： | 1 |
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