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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 | Deceleration capacity of heart rate as a predictor of mortality after myocardial infarction: cohort study显示文摘 | Axel Bauer Jan W Kantelhardt Petra Barthel Raphael Schneider Timo M?kikallio Kurt Ulm Katerina Hnatkova Albert Sch?mig Heikki Huikuri Armin Bunde Marek Malik Georg Schmidt | 2006 | The Lancet2006，，9523： | 3 |
| 3 | Primary structure and biochemical characterization of yeast GTPase-activating proteins with substrate preference for the transport GTPase Ypt7p 显示文摘 | Petra V Elke W Dietrich S | 1999 | Eur J Biochem1999，260，1： | 1 |
| 4 | Effects of exercise training on vascularfunctionin obese children显示文摘 | Katie W Petra B Aris S | 2004 | J Pediatrics2004，144，5： | 1 |
| 5 | Decleration capacity of heart rate as a prelictor of mortality after myocardial infarction~ cohort study 显示文摘 | Axel B Jan W K Petra B | 2006 | Lancet2006，367，9523： | 1 |
| 6 | Rapid quantification of Yersinia enterocolitica in pork samples by a novel sample preparation method , flotation, prior to Real-Time PCR显示文摘 | Petra W Rickard K | 2004 | J Clin Microbiol2004，42，： | 1 |
| 7 | Accumulation and metabolism of the anticancer flavonoid 5, -dimdthoxyflavone compared to its unmethylated analog chrysin in the Atlantic killifish显示文摘 | Petra A T Richard N W Thomas W | 2006 | Chem Biol Interact2006，164，4： | 1 |
| 8 | Enzymatic degradation and electrospray tandem mass spectrometry as tools for determi- ning the structure of cationic starches prepared by wet and dry methods 显示文摘 | Wiebke T Kerstin W Petra M | 2004 | Carbohydrate Research2004，339，3： | 1 |
| 9 | The fluorescence of ellagic acid and broax complex显示文摘 | OTTO S W PETRA H | 1986 | Monatshefte Fur Chemie1986，117，： | 1 |
| 10 | Subcellular FIH-1 expression patterns in invasive breast cancer in relation to HIF-1αexpression显示文摘 | Agon H Petra G Elsken W | 2011 | Cellular oncology2011，34，6： | 1 |
| 11 | Real-time nucleic acid sequence-based amplification is more convenient than real-time PCR for quantification of plasmodium falciparum显示文摘 | Petra S Liselotte W Gerard S | 2005 | Journal of clinical microbiology2005，43，1： | 1 |
| 12 | Morphology and properties of blends with different thermoplastic polyurethanes and polyolefines 显示文摘 | Petra P Katrin W Holger F | 1997 | Journal of Applied Polymer Science1997，64，： | 1 |
| 13 | Bleeding complications in pediatric ABO-incompatible kidney transplantation显示文摘 | Betti Schaefer Burkhard T?nshoff Jan Schmidt Mohammad Golriz Arianeb Mehrabi Petra Gombos Christian Morath Elke Wühl Franz Schaefer Claus Peter Schmitt | 2013 | Pediatric Nephrology2013，，2： | 1 |
| 14 | Suppression of interleukin-12 production by human monocytes after preincubation with lipopolysaccharide显示文摘 | Miriam W Vivi-ann L Petra S | | 0，，： | 1 |
| 15 | A causal role for E-cadherin in the transition from adenoma to carcinoma 显示文摘 | Anne-karina P Petra W Ulf D | 1998 | Nature1998，392，6672： | 1 |
| 16 | Antibody Response to the tumor-associated Inhibitor of apoptosis protein Survivin in cancer patients显示文摘 | Jacques R Petra D Bernd W | 2000 | Cancer Res2000，160，4： | 1 |
| 17 | Deceleration capacity of heart rate as a predictor of mortality after myocardial infarction:cohort study显示文摘 | Axel Bauer Jan W Kantelhardt Petra Barthel | 2006 | Lancet2006，367，： | 1 |
| 18 | Cometabolism of a nongrowth substrate: L-serine utilization by Corynebacterium glutamicum 显示文摘 | Roman N Petra P W Lothar E | 2004 | Appl Environ Microbiol2004，70，12： | 1 |
| 19 | Antithrombotic action of the kava pyrone (+)-kavain prepared from Piper methysticum on human platelets显示文摘 | Johannes G Anne B Petra W | 1997 | Planta Medica1997，63，1： | 1 |
| 20 | Long-term effec- tiveness of four pulpotomy techniques : 3-year randomized controlled trial 显示文摘 | Huth KC Niran HK Petra W | 2011 | Clin oral Invest2011，16，： | 1 |
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