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Interaction of IFNL3 with insulin resistance,steatosis and lipid metabolism in chronic hepatitis C virus infection

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World Journal of Gastroenterology 2013年第41期19卷 7055-7061页

作者： Mohammed Eslam David R Booth Jacob George Golo Ahlenstiel Storr Liver Unit Westmead Millennium Institute and Westmead HospitalUniversity of SydneySydneyNSW 2145Australia Institute for Immunology and Allergy Research Westmead Millennium InstituteUniversity of SydneySydneyNSW 2145Australia

Metabolic changes are inextricably linked to chronic hepatitis C(CHC).Recently polymorphisms in the IFNL3(IL28B)region have been shown to be strongly associated with spontaneous and treatment induced recovery from hepatitis C virus(HCV)***,circumstantial evidence suggests a link between IFNL3single nucleotide polymorphisms and lipid metabolism,steatosis and insulin resistance in *** emerging picture suggests that the responder genotypes of IFNL3polymorphisms are associated with a higher serum lipid profile,and less frequent steatosis and insulin *** review analyzes the current data regarding this interaction and its meaning for HCV pathogenesis and disease progression.

关键词： IFNL3 Chronic hepatitis C Insulin resistance Lipids

A humanized mouse model to study human immune response in xenotransplantation

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Hepatobiliary & Pancreatic Diseases International 2012年第5期11卷 494-498页

作者： Peta Phillips Center for Transplant and Renal Research Westmead Millennium InstituteWestmead HospitalWestmeadNSW Sydney 2145Australia

BACKGROUND: A major barrier to the clinical application of xenotransplantation as a treatment option for patients is T cell-mediated rejection. Studies based on experimental rodent models of xenograft tolerance or rejection in vivo have provided useful information about the role of T cell immune response in xenotransplantation. However not all observations seen in rodents faithfully recapitulate the human situation This study aimed to establish a humanized mouse model of xenotransplantation, which mimics xenograft rejection in the context of the human immune system. METHODS: NOD-SCID IL2rγ -/- mice were transplanted with neonatal porcine islet cell clusters (NICC) followed by reconstitution of human peripheral blood mononuclear cells (PBMC). Human leukocyte engraftment and islet xenograft rejection were confirmed by flow cytometric and histological analyses. RESULTS: In the absence of human PBMC, porcine NICC transplanted into NOD-SCID IL2rγ -/- mice revealed excellent graft integrity and endocrine function. Human PBMC demonstrated a high level of engraftment in NOD-SCID IL2rγ -/- mice. Reconstitution of NICC recipient NOD-SCID IL2rγ -/- mice with human PBMC led to the rapid destruction of NICC xenografts in a PBMC number-dependent manner. CONCLUSIONS: Human PBMC-reconstituted NOD-SCID IL2rγ -/- mice provide an ideal model to study human immune responses in xenotransplantation. Studies based on this humanized mouse model will provide insight for improving the outcomes of clinical xenotransplantation.

关键词： humanized mice xenotransplantation neonatal porcine islet cell cluster xenorejection tolerance

Dendritic cells in hepatitis C virus infection:Key players in the IFNL3-genotype response

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World Journal of Gastroenterology 2014年第47期20卷 17830-17838页

作者： Kate S O'Connor Jacob George David Booth Golo Ahlenstiel Institute for Immunology and Allergy Research Westmead Millennium InstituteUniversity of SydneySydneyNSW 2145Australia Storr Liver Unit Westmead Millennium Institute and Westmead HospitalUniversity of SydneySydneyNSW 2145Australia

Recently,single nucleotide polymorphisms,in the vicinity of the interferon lambda 3(IFNL3)gene have been identified as the strongest predictor of spontaneous and treatment induced clearance of hepatitis C virus(HCV)*** then,increasing evidence has implicated the innate immune response in mediating the IFNL3 genotype *** cells(DCs)are key to the host immune response in HCV infection and their vital role in the IFNL3 genotype effect is *** have identified subclasses of DCs,particularly myeloid DC2s and potentially plasmacytoid DCs as the major producers of IFNL3 in the setting of HCV *** the complexities of dendritic cell biology and the conflicting current available data,this review aims to summarize what is currently known regarding the role of dendritic cells in HCV infection and to placeit into context of what is know about lambda interferons and dendritic cells in general.

关键词： Hepatitis C virus Interferon lambda 3 Dendritic cells Plasmacytoid dendritic cells Myeloid dendritic cells Innate immunity

Interaction between cyclooxygenase-2,Snail,and E-cadherin in gastric cancer cells

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World Journal of Gastroenterology 2013年第37期19卷 6265-6271页

作者： Xiao-Jun Liu Zhao-Feng Chen Hai-Long Li Ze-Nan Hu Min Liu Ai-Ping Tian Da Zhao Jing Wu Yong-Ning Zhou Liang Qiao The First hospital of Lanzhou University Key Laboratory for Gastrointestinal Disease of Gansu Province Beijing Shijitan hospital Storr Liver Unit Westmead Millennium InstituteWestern Clinical School of the Faculty of Medicine at Westmead Hospital

AIM:To investigate the mechanisms of how cyclooxygenase-2(COX-2)regulates E-cadherin in gastric cancer ***:COX-2 expression in human gastric cancer cell lines SGC-7901,BGC-823,MGC-803 and AGS were measured at the mRNA and protein ***-2 rich cell line SGC-7901 was chosen for subsequent *** mediated gene knockdown was used to investigate the impact of COX-2 on nuclear factor-κB (NF-κB),Snail,and E-cadherin in gastric cancer *** expression was determined by Western blot and real-time polymerase chain *** analyze whether NF-κB inhibition could interrupt the modulatory effect of COX-2 or prostaglandin E2(PGE2)on E-cadherin,gastric cancer cells were treated with celecoxib or PGE2,in the presence of NF-κB specific ***:Highest expression level of COX-2 was found in SGC-7901 cells,both at mRNA and protein *** mediated down-regulation of COX-2 led to a reduced expression of NF-κB and Snail,but an increased expression of E-cadherin in SGC-7901 *** mediated down-regulation of NF-κB also led to a reduced expression of E-cadherin and Snail in SGC-7901 ***,COX-2 expression did not alter after cells were treated with NF-κB specific siRNA in SGC-7901 *** of SGC-7901 cells with celecoxib led to a reduced expression of Snail but an increased expression of *** contrast,treatment of SGC-7901 cells with PGE2 led to an increased Snail and a decreased ***,siRNAmediated knockdown of NF-κB partially abolished the effect of celecoxib and PGE2 on the regulation of E-cadherin and Snail in SGC-7901 ***:COX-2 likely functions upstream of NF-κB and regulates the expression of E-cadherin via NF-κB/Snail signaling pathway in gastric cancer cells.

关键词： Cyclooxygenase-2 E-cadherin celecoxib Prostaglandin E2 Gastric cancer

Increased expression of cyclooxygenase-2 in first-degree relatives of gastric cancer patients

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World Journal of Gastroenterology 2005年第31期11卷 4918-4922页

作者： Jin-Ting Zhang ing-Wei Wang, Zhen-Long Zhu Xiao-Hui Huo Jian-Kun Chu Dong-Sheng Cui Liang Qiao Jun Yu Department of Medicine the First Affiliated Hospital of Hebei Medical UniversityShijiazhuang 050017 Hebei Province China Westmead millennium Institute University of Sydney at Westmead Hospital NSW 2145Sydney Australia

AIM: To study the expression of cyclooxygenase-2 (COX-2)in human gastric cancer tissues and their paired adjacent mucosa, as well as mucosa from gastric antrum and corpus of the first-degree relatives of the recruited cancer ***: The expression of COX-2 mRNA in 38 patients with gastric cancer and their 29 first-degree relatives and 18 healthy controls was assessed by the real time *** expression of COX-2 protein was determined by Western ***: A marked increase in COX-2 mRNA expression was found in 20 of 37 (54%) cancerous tissues compared to their respective paired normal mucosa (P＜0.001).Interestingly, increased COX-2 mRNA expression was also found in mucosa of the corpus (6/29) and antrum (13/29)of their first-degree relatives. Increased COX-2 mRNA expression was more frequently observed in the antrum biopsies from cancer patients than in the antrum biopsies from healthy controls (P＜0.05). In addition, 3 of 23 (13%)patients with atrophic mucosa and 6 of 35 (17%) patients with intestinal metaplasia showed increased COX-2 mRNA expression. Furthermore, COX-2 expression increased in H pylori-positive tissues, especially in antrum ***: Increased COX-2 expression is involved in gastric carcinogenesis, and may be necessary for maintenance of the malignant phenotype and contribute to Helicobacterpylori-associated malignant transformation.

关键词： Gastric cancer First-degree relatives COX-2 H pylori

Effects of resveratrol in experimental and clinical non-alcoholic fatty liver disease

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World Journal of Hepatology 2014年第4期6卷 188-198页

作者： Sara Heebll Karen Louise Thomsen Steen B Pedersen Hendrik Vilstrup Jacob George Henning Grnbk Department of Hepatology and Gastroenterology Aarhus University Hospital Department of Endocrinology Aarhus University Hospital Storr Liver Unit Westmead Millennium InstituteWestmead Hospital and University of Sydney

The prevalence of obesity and related conditions like non-alcoholic fatty liver disease(NAFLD) is increasing worldwide and therapeutic options are *** treatment options are therefore intensively sought *** interesting candidate is the natural polyphenol resveratrol(RSV) that activates adenosinmonophosphate-activated protein kinase(AMPK) and silent information regulation-2 homolog 1(SIRT1).In addition,RSV has known anti-oxidant and anti-inflammatory ***,we review the current evidence for RSVmediated effects on NAFLD and address the different aspects of NAFLD and non-alcoholic steatohepatitis(NASH) pathogenesis with respect to free fatty acid(FFA) flux from adipose tissue,hepatic de novo lipogenesis,inadequate FFA β-oxidation and additional intra- and extrahepatic inflammatory and oxidant *** review the in vivo evidence from animal studies and clinical *** abundance of animal studies reports a decrease in hepatic triglyceride accumulation,liver weight and a general improvement in histological fatty liver changes,along with a reduction in circulating insulin,glucose and lipid *** studies document AMPK or SIRT1 activation,and modulation of relevant markers of hepatic lipogenesis,inflammation and oxidation ***,AMPK/SIRT1-independent actions are also *** trials are scarce and have primarily been performed with a focus on overweight/obese participants without a focus on NAFLD/NASH and histological liver *** clinical studies with appropriate design are needed to clarify the true impact of RSV treatment in NAFLD/NASH patients.

关键词： Non-alcoholic fatty liver disease Nonalcoholic steatohepatitis Steatosis Resveratrol AMPactivated protein kinase Silent information regulation-2 homolog 1 Anti-oxidants Anti-inflammatory agents Animal studies Clinical trial

Clinical features of nonalcoholic fatty liver disease-associated hepatocellular carcinoma

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Hepatobiliary & Pancreatic Diseases International 2012年第1期11卷 18-27页

作者： Xiao-Yan Duan, Liang Qiao and Jian-Gao Fan Department of Gastroenterology, Xinhua hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China Storr Liver Unit at the Westmead millennium Institute, the University of Sydney at Westmead hospital, Westmead, NSW 2145, Australia Department of Gastroenterology Xinhua Hospital Shanghai Jiaotong University School of Medicine Shanghai 200092 China Storr Liver Unit at the Westmead millennium Institute the University of Sydney at Westmead Hospital Westmead NSW 2145 Australia

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis, is a recognized risk factor for hepatocellular carcinoma (HCC). However, detailed analysis of the clinical features in patients with NAFLD and their association with HCC is lacking. This study aimed to update the clinical features of patients with NAFLD-associated HCC. DATA SOURCES: The clinical data of patients with NAFLD- associated HCC from 25 studies published between 1990 and 2010 in the Pubmed database were comprehensively reviewed. RESULTS: In a total of 169 patients with NAFLD-associated HCC, 72.8% were male. The median age at abnormal liver function tests and diagnosis of NAFLD and HCC was 60, 64 and 67 years, respectively. Most patients were obese (75%) and diabetic (59.8%), 32.3% had dyslipidemia, and 53% had hypertension. Nearly all patients (98.6%, 71/72) were complicated with at least one metabolic disorder. The majority (76%) of the HCC patients had a solitary tumor nodule, with the tumor size ranging from 0.8 to 20 cm in diameter (mean 3.4 cm). Most (61.1%) of the patients had moderately-differentiated HCC. In 40.2% of the patients, HCC occurred in the absence of cirrhosis. Among 130 patients, 57.7% underwent hepatectomy and 14.6% received liver transplantation. The mean follow-up of the treated patients for 25 months showed that 32.4% (24/74) died and 18.8% (9/48) had recurrence. CONCLUSIONS: Patients with NAFLD-associated HCC are usually accompanied with metabolic disorders. Regular surveillance in patients with NAFLD for HCC is necessary, especially for elderly men with metabolic syndrome.

关键词： obesity diabetes mellitus dyslipidemia nonalcoholic fatty liver disease nonalcoholic steatohepatitis hepatocellular carcinoma

Resistin mediates the hepatic stellate cell phenotype

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World Journal of Gastroenterology 2013年第28期19卷 4475-4485页

作者： Zhi-Xia Dong Lin Su Joanne Brymora Claire Bird Qing Xie Jacob George Jian-Hua Wang Department of Infectious Disease Rui jin Hospital Shanghai Jiao Tong University School of Medicine Storr Liver Unit Westmead Millennium Institute and Westmead Hospital University of Sydney Westmead NSW 2145 Australia

AIM: To describe the role of resistin in liver fibrosis. METHODS: For the in vivo animal study, Sprague Dawley rats were subjected to bile duct ligation (BDL) for 4 wk. Rat liver, adipose tissue (epididymal fat) and serum were analyzed for resistin expression. For the in vitro experiment, rat primary hepatic stellate cells (HSCs) and Kupffer cells (KCs) were used. HSCs were exposed to recombinant resistin, and collagenⅠ, transforming growth factor β1, α smooth muscle actin, tissue inhibitor of metalloproteinase 1 and connective tissue growth factor expression were analyzed. Resistin gene and protein expression was quantified as was the expression of pro-inflammatory cytokines including tumor necrosis factor α (TNFα), interleukin (IL)-1, IL-6, IL-8 and monocyte chemotactic protein-1 (MCP-1). The effects of resistin on HSC proliferation, migration and apoptosis were determined. The effects of resistin on KCs were also investigated. RESULTS: Following BDL, rat epididymal fat and serum rather than liver showed higher resistin expression compared to control rats. In liver, resistin was expressed in quiescent HSCs and KCs. Resistin treatment resulted in enhancement of TNFα , IL-6 , IL-8 and MCP-1 gene expression and increased IL-6 and MCP-1 protein in HSCs. Resistin activated HSC phospho-MAPK/p38, and p38 inhibition diminished IL-6 and MCP-1 expression. Furthermore, resistin facilitated HSC proliferation and migration, but decreased apoptosis which was via an IL-6 and MCP-1 mechanism. Finally, resistin-induced transforming growth factor β1 from KCs enhanced HSC collagenⅠexpression. CONCLUSION: Resistin directly and indirectly modulates HSC behavior towards a more pro-fibrogenic phenotype.

关键词： Resistin Hepatic stellate cell Kupffer cell Liver fibrosis Monocyte chemotactic protein-1

Notch2 regulates matrix metallopeptidase 9 via PI3K/AKT signaling in human gastric carcinoma cell MKN-45

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World Journal of Gastroenterology 2012年第48期18卷 7262-7270页

作者： Ling-Yun Guo Yu-Min Li Liang Qiao Tao Liu Yuan-Yuan Du Jun-Qiang Zhang Wen-Ting He Yong-Xun Zhao Dong-Qiang He the Second Clinical Medical School of Lanzhou University the Second Hospital of Lanzhou University Key Laboratory of Digestive System Tumors Department of General Surgerythe Second Hospital of Lanzhou University Storr Liver Unit at the Westmead millennium Institute the University of Sydney at Westmead Hospital Key Laboratory of Digestive System Tumors the Second Hospital of Lanzhou University Department of Oncological Surgery the First Hospital of Lanzhou University

AIM：To clarify the role of activated Notch2 in the invasiveness of gastric ***：To investigate the invasiveness of silencing Notch2 gene expression,we established a Notch2small interfering RNA（siRNA） transfected cell line using the MKN-45 gastric cancer cell *** the successful transfection confirmed by real-time reverse transcription-polymerase chain reaction（RT-PCR） and Western blotting,migration and invasion assays were employed to evaluate the aggressiveness of the gastric ***-PCR and Western blottings were employed to confirm the down-regulation of Notch2 and to evaluate the expression of epithelial mesenchymal transition-related gene matrix metallopeptidase 9（MMP9）,Akt,*** confirm the relationship between PI3KAkt and MMP9,the PI3K inhibitor LY294002 was used to treat MKN-45 ***：Notch2 expression was dramatically decreased after Notch2 siRNA transfection（100.00% ± 9.74% vs 11.61% ± 3.85%,P 〈 0.01 by qRT-PCR）.There was also a marked reduction of Notch target gene Hes1（100.00% ± 4.74% vs 61.61% ± 3.58%,P 〈 0.05） at the mRNA,indicating an inhibition of Notch *** of Notch signaling was also confirmed by the marked reduction of Notch2 intracellular domain at the protein levels（100.00% ± 9.74% vs 65.61% ± 7.58%,P 〈 0.05）.Down-regulation of Notch2 by siRNA enhanced tumor cell invasion（100.00% ± 21.64% vs 162.22% ± 16.84%,P 〈 0.05） and expression of MMP9（1.56 fold,P 〈 0.05）,and activated the pro-MMP9 protein to its active form（1.48 fold,P 〈 0.05）.There was no significant difference in the protein levels of Akt between the two groups（100.00% ± 10.87% vs 96.61% ± 7.33%,P 〉 0.05）,while down-regulation of Notch2 elevated p-Akt expression（100.00% ± 9.87% vs 154.61% ± 13.10%,P 〈 0.05）.Furthermore,p-Akt and MMP9 was down-regulated in response to the inhibitor LY294002（p-Akt 100.00% ± 8.87% vs 58.27% ± 5.01%,P 〈 0.05;MMP9 100.00% ± 9.17% vs 50.03% ± 4.88%,P 〈 0.05）.CONCLUSION：Notch2 may negatively regulate cell invasion by

关键词： Notch2 Stomach Cancer Invasion Epithelial mesenchymal transition Matrix metallopeptidase 9 RNA interference