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| 1 | Role of interleukin-1 and its antagonism of hepatic stellate cell proliferation and liver fibrosis in the Abcb4^(-/-) mouse model显示文摘AIM: To study the interleukin-1(IL-1) pathway as a therapeutic target for liver fibrosis in vitro and in vivo using the ATP-binding cassette transporter b4^(-/-)(Abcb4^(-/-)) mouse model.METHODS: Female and male Abcb4^(-/-) mice from 6 to 13 mo of age were analysed for the degree of cholestasis(liver serum tests), extent of liver fibrosis(hydroxyproline content and Sirius red staining) and tissue-specific activation of signalling pathways such as the IL-1 pathway [quantitative polymerase chain reaction(q PCR)]. For in vivo experiments, murine hepatic stellate cells(HSCs) were isolated via pronasecollagenase perfusion followed by density gradient centrifugation using female mice. Murine HSCs were stimulated with up to 1 ng/m L IL-1β with or without 2.5 μg/m L Anakinra, an IL-1 receptor antagonist, respectively. The proliferation of murine HSCs was assessed via the Brd U assay. The toxicity of Anakinra was evaluated via the fluorescein diacetate hydrolysis(FDH) assay. In vivo 8-wk-old Abcb4^(-/-) mice with an already fully established hepatic phenotype were treated with Anakinra(1 mg/kg body-weight daily intraperitoneally) or vehicle and liver injury and liver fibrosis were evaluated via serum tests, q PCR, hydroxyproline content and Sirius red staining. RESULTS: Liver fibrosis was less pronounced in males than in female Abcb4^(-/-) animals as defined by a lower hydroxyproline content(274 ± 64 μg/g vs 436 ± 80 μg/g liver, respectively; n = 13-15; P < 0.001; MannWhitney U-test) and lower m RNA expression of the profibrogenic tissue inhibitor of metalloproteinase-1(TIMP)(1 ± 0.41 vs 0.66 ± 0.33 fold, respectively; n = 13-15; P < 0.05; Mann-Whitney U-test). Reduced liver fibrosis was associated with significantly lower levels of F4/80 m RNA expression(1 ± 0.28 vs 0.71 ± 0.41 fold, respectively; n = 12-15; P < 0.05; Mann-Whitney U-test) and significantly lower IL-1β m RNA expression levels(1 ± 0.38 vs 0.44 ± 0.26 fold, respectively; n = 13-15; P < 0.001; Mann-Whitney U-test). No gender differences in the serum liver parameters [bilirubin; alanine aminotransferase(ALT); aspartate aminotransferase and alkaline phosphatase(AP)] were found. In vitro, the administration of IL-1β resulted in a significant increase in HSC proliferation [0.94 ± 0.72 arbitrary units(A.U.) in untreated controls, 1.12 ± 0.80 A.U. at an IL-1β concentration of 0.1 ng/m L and 1.18 ± 0.73 A.U. at an IL-1β concentration of 1 ng/m L in samples from n = 6 donor animals; P < 0.001; analyses of variance(ANOVA)]. Proliferation was reduced significantly by the addition of 2.5 μg/m L Anakinra(0.81 ± 0.60 A.U. in untreated controls, 0.92 ± 0.68 A.U. at an IL-1β concentration of 0.1 ng/m L, and 0.91 ± 0.69 A.U. at an IL-1β concentration of 1 ng/m L; in samples from n = 6 donor animals; P < 0.001; ANOVA) suggesting an anti-proliferative effect of this clinically approved IL-1 receptor antagonist. The FDH assay showed this dose to be non-toxic in HSCs. In vivo, Anakinra had no effect on the hepatic hydroxyprolinecontent, liver serum tests(ALT and AP) and profibrotic(collagen 1α1, collagen 1α2, transforming growth factor-β, and TIMP-1) and anti-fibrotic [matrix metalloproteinase 2(MMP2), MMP9 and MMP13 ] gene expression after 4 wk of treatment. Furthermore, the hepatic IL-1β and F4/80 m RNA expression levels were unaffected by Anakinra treatment.CONCLUSION: IL-1β expression is associated with the degree of liver fibrosis in Abcb4^(-/-) mice and promotes HSC proliferation. IL-1 antagonism shows antifibrotic effects in vitro but not in Abcb4^(-/-) mice. | Florian P Reiter Ralf Wimmer Lena Wottke Renate Artmann Jutta M Nagel Manuel O Carranza Doris Mayr Christian Rust Peter Fickert Michael Trauner Alexander L Gerbes Simon Hohenester Gerald U Denk | 2016 | World Journal of Hepatology2016，8，8： | 3 |
| 2 | Th1 cytokines promote T-cell binding to antigen-presenting cells via enhanced hyaluronan production and accumulation at the immune synapse显示文摘Hyaluronan(HA)production by dendritic cells(DCs)is known to promote antigen presentation and to augment T-cell activation and proliferation.We hypothesized that pericellular HA can function as intercellular‘glue’directly mediating T cell–DC binding.Using primary human cells,we observed HA-dependent binding between T cells and DCs,which was abrogated upon pre-treatment of the DCs with 4-methylumbelliferone(4-MU),an agent which blocks HA synthesis.Furthermore,T cells regulate HA production by DCs via T cell-derived cytokines in a T helper(Th)subset-specific manner,as demonstrated by the observation that cell-culture supernatants from Th1 but not Th2 clones promote HA production.Similar effects were seen upon the addition of exogenous Th1 cytokines,IL-2,interferon c(IFN-c)and tumor necrosis factor a(TNF-a).The critical factors which determined the extent of DC–T cell binding in this system were the nature of the pre-treatment the DCs received and their capacity to synthesize HA,as T-cell clones which were pre-treated with monensin,added to block cytokine secretion,bound equivalently irrespective of their Th subset.These data support the existence of a feedforward loop wherein T-cell cytokines influence DC production of HA,which in turn affects the extent of DC–T cell binding.We also document the presence of focal deposits of HA at the immune synapse between T-cells and APC and on dendritic processes thought to be important in antigen presentation.These data point to a pivotal role for HA in DC–T cell interactions at the IS. | Paul L Bollyky Stephen P Evanko Rebecca P Wu Susan Potter-Perigo S Alice Long Brian Kinsella Helena Reijonen Kelly Guebtner Brandon Teng Christina K Chan Kathy R Braun John A Gebe Gerald T Nepom Thomas N Wight | 2010 | Cellular & Molecular Immunology2010，7，3： | 3 |
| 3 | Bovine immunoglobulin protein isolates for the nutritional management of enteropathy显示文摘The gastrointestinal tract is responsible for a multitude of digestive and immune functions which depend upon the balanced interaction of the intestinal microbiota, diet, gut barrier function, and mucosal immune response. Disruptions in one or more of these factors can lead to intestinal disorders or enteropathies which are characterized by intestinal inflammation, increased gut permeability, and reduced capacity to absorb nutrients. Enteropathy is frequently associated with human immunodeficiency virus(HIV) infection, inflammatory bowel disease, autoimmune enteropathy, radiation enteritis, and irritable bowel syndrome(IBS), where pathologic changes in the intestinal tract lead to abdominal discomfort, bloating, abnormal bowel function(e.g., diarrhea, urgency, constipation and malabsorption). Unfortunately, effective therapies for the management ofenteropathy and restoring intestinal health are still not available. An accumulating body of preclinical studies has demonstrated that oral administration of plasmaor serum-derived protein concentrates containing high levels of immunoglobulins can improve weight, normalize gut barrier function, and reduce the severity of enteropathy in animal models. Recent studies in humans, using serum-derived bovine immunoglobulin/protein isolate, demonstrate that such protein preparations are safe and improve symptoms, nutritional status, and various biomarkers associated with enteropathy. Benefits have been shown in patients with HIV infection or diarrhea-predominant IBS. This review summarizes preclinical and clinical studies with plasma/serum protein concentrates and describes the effects on host nutrition, intestinal function, and markers of intestinal inflammation. It supports the concept that immunoglobulin-containing protein preparations may offer a new strategy for restoring functional homeostasis in the intestinal tract of patients with enteropathy. | Bryon W Petschow Anthony T Blikslager Eric M Weaver Joy M Campbell Javier Polo Audrey L Shaw Bruce P Burnett Gerald L Klein J Marc Rhoads | 2014 | World Journal of Gastroenterology2014，20，33： | 2 |
| 4 | Age at diagnosis of type 2 diabetes and cardiovascular risk factor profile:A pooled analysis显示文摘BACKGROUND The diagnosis of type 2 diabetes(T2D)in younger adults,an increasingly common public health issue,is associated with a higher risk of cardiovascular complications and mortality,which may be due to a more adverse cardiovascular risk profile in individuals diagnosed at a younger age.AIM To investigate the association between age at diagnosis and the cardiovascular risk profile in adults with T2D.METHODS A pooled dataset was used,comprised of data from five previous studies of adults with T2D,including 1409 participants of whom 196 were diagnosed with T2D under the age of 40 years.Anthropometric and blood biomarker measurements included body weight,body mass index(BMI),waist circumference,body fat percentage,glycaemic control(HbA1c),lipid profile and blood pressure.Univariable and multivariable linear regression models,adjusted for diabetes duration,sex,ethnicity and smoking status,were used to investigate the association between age at diagnosis and each cardiovascular risk factor.RESULTS A higher proportion of participants diagnosed with T2D under the age of 40 were female,current smokers and treated with glucose-lowering medications,compared to participants diagnosed later in life.Participants diagnosed with T2D under the age of 40 also had higher body weight,BMI,waist circumference and body fat percentage,in addition to a more adverse lipid profile,compared to participants diagnosed at an older age.Modelling results showed that each one year reduction in age at diagnosis was significantly associated with 0.67 kg higher body weight[95%confidence interval(CI):0.52-0.82 kg],0.18 kg/m^(2) higher BMI(95%CI:0.10-0.25)and 0.32 cm higher waist circumference(95%CI:0.14-0.49),after adjustment for duration of diabetes and other confounders.Younger age at diagnosis was also significantly associated with higher HbA1c,total cholesterol,low-density lipoprotein cholesterol and triglycerides.CONCLUSION The diagnosis of T2D earlier in life is associated with a worse cardiovascular risk factor profile,compared to those diagnosed later in life. | Mary M Barker Francesco Zaccardi Emer M Brady Gaurav S Gulsin Andrew P Hall Joseph Henson Zin ZinHtike Kamlesh Khunti Gerald P McCann Emma L Redman David R Webb Emma G Wilmot Tom Yates Jian Yeo Melanie J Davies Jack A Sargeant | 2022 | World Journal of Diabetes2022，13，3： | 2 |
| 5 | Higher differentiation among subspecies of the house mouse(Mus muscu/us )in genomic regions with low recombination显示文摘 | GERALDES A BASSET P SMITH K L | 2011 | Molecular Ecology2011，20，22： | 1 |
| 6 | Membrane binding protein for baetericidal/permeability-increasing protein signaling pathways in retinal pigment epithelial cells显示文摘 | Geraldes P Yamagata M Rook S L | 2007 | Invest Ophthalmol Vis Sci2007，18，12： | 1 |
| 7 | Does Perceived Organizational Support Mediate the Relationship between Procedural Justice and Behavior? 显示文摘 | Robert H M Gerald L B Brian P N | 1998 | Academy of Organizational Citizenship Management Journal1998，41，3： | 1 |
| 8 | HVOF-spray technology poised for growth显示文摘 | DANIEL W P GERALD L K | 1991 | Advanced Materials and Processes1991，，4： | 1 |
| 9 | Reference genome sequence of the model plant Setaria显示文摘 | Jeffrey L Bennetzen Jeremy Schmutz Hao Wang RyanPercifield Jennifer Hawkins Ana C Pontaroli Matt Estep Liang Feng Justin N Vaughn Jane Grimwood JerryJenkins Kerrie Barry Erika Lindquist Uffe Hellsten Shweta Deshpande Xuewen Wang Xiaomei Wu ThereseMitros Jimmy Triplett Xiaohan Yang Chu-Yu Ye Margarita Mauro-Her-rera Lin Wang Pinghua Li ManojSharma Rita Sharma Pamela C Ronald Olivier Panaud Elizabeth A Kellogg Thomas P Brutnell Andrew NDoust Gerald A Tuskan Daniel Rokhsar Katrien MDevos | 2012 | Nature Biotechnology2012，，30： | 1 |
| 10 | A constitutive model for themechanical behavior of a 3D C-C composite 显示文摘 | Jerome P Gerald C Jacques L | 2002 | Mechanics ofMaterials2002，34，： | 1 |
| 11 | Activation of protein kinase C isoforms and its impact on diabetic complications显示文摘 | Geraldes P Kinh G L | 2010 | Circ Res2010，106，8： | 1 |
| 12 | The development of a standard method for determining oxidation induction times of hydrocarbon liquids by PDSC 显示文摘 | Pamela L S Gerald H P Alan T R | 1994 | Thermochimica Acta1994，，243： | 1 |
| 13 | Fundamentals of dry powder blending for metal matrix composites显示文摘 | Gerald P J Jayashree L Hani H | 1993 | The International Journal of Powder Metallurgy1993，29，4： | 1 |
| 14 | The Effect of Economic Similarity-Dissimilarity as Determinants of Attraction显示文摘 | BYRNE D E GERALD L C J WORCHEL P | 1966 | Journal of Personality and Social Psychology1966，4，2： | 1 |
| 15 | Room temperature molten salts as lithium battery electrolyte 显示文摘 | BEATRICE G SERGE L GERALD P | 2004 | Electrochimica Acta2004，49，： | 1 |
| 16 | A Comparison of Long-Term Functional Outcome After 2 Middle Cerebral Artery Occlusion Models in Rats显示文摘 | Robin L Gerald P Xiaodan Ren | 2001 | Stroke2001，32，： | 1 |
| 17 | Extraction Coupled with Liquid Chromatography/Electrospray Ionization Mass Spectrometry for the Simplified Determination of Imidazolinone Herbicides and Their Metabolites in Plant Tissue显示文摘 | STEVEN J S ADRIAN RD GERALD L P | 1996 | Journal of Agricultural and Food Chemistry1996，44，： | 1 |
| 18 | HVOF-spray technology poised for growth 显示文摘 | Daniel W P Gerald L K | 1991 | Advanced Materials and Processes1991，，4： | 1 |
| 19 | Room temperature molten salts lithium battery electrolyte显示文摘 | BEATRICE G SERGE L GERALD P | 2004 | Electrochimica Acta2004，49，26： | 1 |
| 20 | Long-term results of implantation of phakic posterior chamber intraocular lenses显示文摘 | Birgit L Stefan P Gerald S | 2004 | J Cataract Refract Surg2004，30，： | 1 |
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