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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 | Regulation of C-C chemokine production by routine T cells by CD28/B7 costimulation显示文摘 | Herold KC Lu J Rulifson I | 1997 | J Immunol1997，159，： | 1 |
| 3 | A new approach to high-speed protection for transmission line based on transient signal analysis using wavelets显示文摘 | Shang L Herold G Jaeger J | 2001 | Developments in Power System Protection IEE 20012001，，： | 1 |
| 4 | Steroid and benzyl alcohol diffusion through tissue breast implants显示文摘 | Berman DE Lettieri J Herold DA | 1991 | Ann Plast Surg1991，27，3： | 1 |
| 5 | Fruit Contact Pressure Distributions Equipment 显示文摘 | Herold B Geyer M Studman C J | 2001 | Computers and Electronics in Agriculture2001，32，3： | 1 |
| 6 | A highly immunogenic and protective middle east respiratory syndrome coro- navirus vaccine based on a recombinant measles virus vaccine platform显示文摘 | Malczyk A H Kupke A Prufer S Scheuplein V A Hutzler S Kreuz D Beissert T Bauer S Hubich Rau S Tondera C Eldin H S Schmidt J Vergara-Alert J Suzer Y Seifried J Hanschmann K M Kalinke U Herold S Sahin U Cichutek K Waibler Z Eickmann M Becker S Muhlebach M D | 2015 | J Virol2015，89，11： | 1 |
| 7 | The sue of remote sensing and landscape metrics to describe structures and changes in urban land uses显示文摘 | Herold M J Sceph K Clarke | 2002 | Environment and Planning A2002，34，8： | 1 |
| 8 | Effects of Vitamin E on Susceptibility of Low-Density Lipoprotein and Low-Density Lipoprotein Subfractions to Oxidation and on Protein Glycationin NIDDM显示文摘 | Reaven P D Herold D A Bamett J | 1995 | Diabetes Care1995，18，： | 1 |
| 9 | Poliovirus requires a precise 5' end for efficient positive-strand RNA synthesis显示文摘 | Herold J Andino R | 2000 | J Virol2000，74，14： | 1 |
| 10 | Infectious RNA transcribed in vitro from a cDNA copy of the human coronavirus genome cloned in vaccinia virus显示文摘 | Thiel V Herold J Schelle B | 2001 | J Gen Virol2001，82，6： | 1 |
| 11 | Severe left ventricular failure after double lung transplantation: pathophysiology and management 显示文摘 | KamlerM Herold U Piotrowski J | 2004 | J Heart Lung Transplant2004，23，1： | 1 |
| 12 | P, educed expression of the mevalonate pathway enzyme farnesy/ pyrophosphate synthase unveils recognition of tumor cells by VgammagVdelta2 T cells显示文摘 | Li J Herold MJ Kimmel B | 2009 | J Immunol2009，182，12： | 1 |
| 13 | Comparison of grey matter vol- ume and thickness for analysing cortical changes in chronic schizo- phrenia: a matter of surface area, grey/white matter intensity con- trast, and curvature显示文摘 | Kong L Herold C J Zollner F | 2015 | Psychiatry Res2015，231，： | 1 |
| 14 | Non-destructive tests on the prediction of apple fruit flesh firmness and soluble solids content on tree and in shelf life显示文摘 | ZUDE M HEROLD B ROGER J M | 2006 | Journal of Food Engineering2006，77，2： | 1 |
| 15 | Assessment of pulmonary airway reactivity with high-resolution CT显示文摘 | Herold C J Brown R H Mitzner W | | 0，，02： | 1 |
| 16 | Activation of human T cells by FcR nonbinding anti-CD3 mAb,hOKT3gammal (AlaAla)显示文摘 | Herold K C Burton J B Francois F | 2003 | J Clin Invest2003，111，3： | 1 |
| 17 | Glucocorti - coids in T cell a popt osis and function 显示文摘 | Herold M J Mc Pherson KG Reichardt HM | 2006 | Cell Mol Life Sci2006，63，： | 1 |
| 18 | Fungal and bacterial denitrification are differently affected by longterm pH amendment and cultivation of arable soil显示文摘 | HEROLD M B BAGGS E M DANIELL T J | 2012 | Soil Biol Biochem2012，54，1： | 1 |
| 19 | Isolation and quantitative determination of ergos terol peroxide in various edible mushroom species 显示文摘 | Krzyczkowski W Malinowska E Suchocki P Kleps J Olejnik M Herold F | 2009 | Food Chemistry2009，113，： | 1 |
| 20 | A machine learning approach to automatic stroke segmentation 显示文摘 | Herold J Stahovich T F | 2014 | Computer & Graphics (S0097-8493)2014，38，2： | 1 |
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