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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 | New therapeutic opportunities for Hepatitis C based on small RNA显示文摘Hepatitis C virus (HCV) infection is one of the major causes of chronic liver disease, including cirrhosis and liver cancer and is therefore, the most common indication for liver transplantation. Conventional antiviral drugs such as pegylated interferon-alpha, taken in combination with ribavirin, represent a milestone in the therapy of this disease. However, due to different viral and host factors, clinical success can be achieved only in approximately half of patients, making urgent the requirement of exploiting alternative approaches for HCV therapy. Fortunately, recent advances in the understanding of HCV viral replication and host cell interactions have opened new possibilities for therapeutic intervention. The most recent technologies, such as small interference RNA mediated gene-silencing, anti-sense oligonucleotides (ASO), or viral vector based gene delivery systems, have paved the way to develop novel therapeutic modalities for HCV. In this review, we outline the application of these technologies in the context of HCV therapy. In particular, we will focus on the newly defined role of cellular microRNA (miR-122) in viral replication and discuss its potential for HCV molecular therapy. | Qiu-wei Pan Scot D Henry Bob J Scholte Hugo W Tilanus Harry LA Janssen Luc JW van der Laan | 2007 | World Journal of Gastroenterology2007，13，33： | 4 |
| 3 | Infection by porcine endogenous retrovirus after islet xenotransplantation in SCID mice显示文摘 | Luc JW Vander L Christopher L | 2000 | Nature2000，407，： | 1 |
| 4 | Infection by porcine endngenous retrovirus after islet xenotransplantation in SCID mice, 显示文摘 | Luc JW Vander L Christopher L | 2000 | Nature2000，407，： | 1 |
| 5 | Infection by porcine endogenous retrovirus after islet xenotransplantation in SCID mice显示文摘 | Luc JW Vander L Lockey C | 2000 | Nature2000，407，： | 1 |
| 6 | Infection by porcine endogenous retrovirus after islet xenotransplantation in SCID mice显示文摘 | Vander L Lockey C | 2000 | Nature2000，407，6800： | 1 |
| 7 | Interaction of immunosuppressants with HCV antivirals daclatasvir and asunaprevir: combined effects with mycophenolic acid显示文摘AIM To investigate the specific effects of immunosuppressants on the antiviral action of daclatasvir and asunaprevir.METHODS The antiviral activity of daclatasvir(DCV) and asunaprevir(ASV) combined with immunosuppressants was tested using two in vitro models for hepatitis C virus(HCV) infection.RESULTS Tacrolimus, rapamycin and cyclosporine did not negatively affect the antiviral action of DCV or ASV. Mycophenolic acid(MPA) showed additive antiviral effects combined with these direct acting antivirals(DAAs). MPA induces interferon-stimulated genes(ISGs) and is a potent GTP synthesis inhibitor. DCV or ASV did not induce ISGs expression nor affected ISG induction by MPA. Rather, the combined antiviral effect of MPA with DCV and ASV was partly mediated via inhibition of GTP synthesis.CONCLUSION Immunosuppressants do not negatively affect the antiviral activity of DAAs. MPA has additive effect on the antiviral action of DCV and ASV. This combined benefit needs to be confirmed in prospective clinical trials. | Petra E de Ruiter Yashna Gadjradj Robert J de Knegt Herold J Metselaar Jan NM Ijzermans Luc JW van der Laan | 2018 | World Journal of Transplantation2018，8，5： | 0 |
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