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| 1 | Molecular determinants of the antitumor effects of trichostatin A in pancreatic cancer cells显示文摘AIM:To gain molecular insights into the action of the histone deacetylase inhibitor(HDACI) trichostatin-A(TSA) in pancreatic cancer(PC) cells.METHODS:Three PC cell lines,BxPC-3,AsPC-1 and CAPAN-1,were treated with various concentrations of TSA for def ined periods of time.DNA synthesis was assessed by measuring the incorporation of 5-bromo-2'deoxyuridine.Gene expression at the level of mRNA was quantif ied by real-time polymerase chain reaction.Expression and phosphorylation of proteins was monitored by immunoblotting,applying an infrared imaging technology.To study the role of p38 MAP kinase,the specif ic enzyme inhibitor SB202190 and an inactive control substance,SB202474,were employed.RESULTS:TSA most eff iciently inhibited BrdU incorporation in BxPC-3 cells,while CAPAN-1 cells displayed the lowest and AsPC-1 cells an intermediate sensitivity.The biological response of the cell lines correlated with the increase of histone H3 acetylation after TSA application.In BxPC-3 cells(which are wild-type for KRAS),TSA strongly inhibited phosphorylation of ERK 1/2 and AKT.In contrast,activities of ERK and AKT in AsPC-1 and CAPAN-1 cells(both expressing oncogenic KRAS) were not or were only modestly affected by TSA treatment.In all three cell lines,but most pronounced in BxPC-3 cells,TSA exposure induced an activation of the MAP kinase p38.Inhibition of p38 by SB202190 slightly but signif icantly diminished the antiproliferative effect of TSA in BxPC-3 cells.Interestingly,only BxPC-3 cells responded to TSA treatment by a signif icant increase of the mRNA levels of bax,a pro-apoptotic member of the BCL gene family.Finally,in BxPC-3 and AsPC-1 cells,but not in the cell line CAPAN-1,signif icantly higher levels of the cell cycle inhibitor protein p21Waf1 were observed after TSA application.CONCLUSION:The biological effect of TSA in PC cells correlates with the increase of acetyl-H3,p21Waf1,phospho-p38 and bax levels,and the decrease of phosphoERK 1/2 and phospho-AKT. | Elisabeth Emonds Brit Fitzner Robert Jaster | 2010 | World Journal of Gastroenterology2010，16，16： | 5 |
| 2 | Bone marrow-derived pancreatic stellate cells in rats显示文摘胰腺的星形的房间(PSC ) 在前,在期间并且在胰腺的损害以后的起源和命运是争论的一件事。在胰腺的纤维变性的致病的 PSC 的关键角色通常被接受。然而,房间的周转仍然保持阴暗。现在的学习处理了潜在的骨头髓(BM ) 的问题 PSC 的起源。我们由 grafting 使用了稳定的造血的 chimerism 的一个模型在领受人老鼠的照耀以后表示 BM 房间的提高的绿荧光蛋白质(eGFP ) 。Chimerism 被 eGFP 积极的房间的 FACS 分析在外部血检测。Dibutyltin 二氯化物(DBTC ) 被用来超过 4 个星期与随后的恢复导致尖锐胰腺的发炎。调查集中于孤立的房间检测休息 PSC 人口。从妄想的老鼠的胰获得的 eGFP 积极的 PSC 的发生在健康胰腺的织物是约 7% 并且 4 个星期在导致 DBTC 的尖锐发炎以后在恢复的胰显著地增加了到 18% 的一个平均数。我们的结果建议导出 BM 的祖先房间在胰代表可更新的星形的房间的来源。在新生以后放松 PSC 的增加的数字在导致发炎的激活以后向导出 BM 的房间的提高的招募指向一个静止状态的胰或重新获得。 | Gisela Sparmann Marie-Luise Kruse Nicole Hofmeister-Mielke Dirk Koczan Robert Jaster Stefan Liebe Daniel Wolff Joerg Emmrich | 2010 | Cell Research2010，20，3： | 4 |
| 3 | Cis-hydroxyproline-induced inhibition of pancreatic cancer cell growth is mediated by endoplasmic reticulum stress显示文摘瞄准:在老鼠上调查 cis-hydroxyproline (CHP ) 的生物效果,并且检验内在的分子的机制胰腺的癌房间线 DSL6A。方法:DSL6A 房间增长上的 CHP 的效果被使用 BrdU 加入估计。焦点的粘附激酶(FAK ) 的表示被西方的弄污和免疫荧光描绘。endoplasmic 感应(嗯) 应力被使用 RT-PCR 并且为葡萄糖相关的 protein-78 (GRP78 ) 和生长拘捕和 DNA 的西方的弄污调查可诱导的基因(GADD153 ) 。房间生存能力通过基于 DSL6A 房间的减小潜力测量新陈代谢的活动被决定。Apoptosis 被 caspase-3 激活的察觉和多形核白细胞(自动数据处理核糖) 的劈开分析象 DNA laddering 一样的聚合酶(PARP ) 。结果:除了增长的抑制,有 CHP 的孵化从焦点的粘附导致了 FAK 的解朊的劈开和酶的 delocalisation,由房间坚持的损失列在后面。同时,我们能显示出 GRP78 和 GADD153 的增加的表情,显示在 DSL6A 房间线的 ER 压力串联的调停 CHP 的激活。有 CHP 的 DSL6A 房间的延长孵化最后导致了 apoptotic 细胞死亡。在 L 脯氨酸旁边,由一个广谱朊酶禁止者的增加的细胞内部的解朊作用的抑制能在细胞的功能和分子的过程上废除 CHP 的效果。相反,阻碍执行 apoptosis caspases 的活动没在调停 CHP 的房间损坏上有影响。结论:我们的数据建议开始嗯由 CHP 的压力机械导致细胞内部的解朊的进程的激活包括 caspase 独立的 FAK 降级,导致损坏胰腺的癌房间。 | Christoph Mueller Joerg Emmrich Robert Jaster Dagmar Braun Stefan Liebe Gisela Sparmann | 2006 | World Journal of Gastroenterology2006，12，10： | 3 |
| 4 | Antifibrogenic effects of vitamin D derivatives on mouse pancreatic stellate cells显示文摘AIM To study the molecular effects of three different D-vitamins, vitamin D2, vitamin D3 and calcipotriol, in pancreatic stellate cells(PSCs).METHODS Quiescent PSCs were isolated from mouse pancreas and activated in vitro by seeding on plastic surfaces. The cells were exposed to D-vitamins as primary cultures(early-activated PSCs) and upon re-culturing(fullyactivated cells). Exhibition of vitamin A-containing lipid droplets was visualized by oil-red staining. Expression of α-smooth muscle actin(α-SMA), a marker of PSC activation, was monitored by immunofluorescence and immunoblot analysis. The rate of DNA synthesis was quantified by 5-bromo-2'-deoxyuridine(Brd U) incorporation assays. Real-time PCR was employed to monitor gene expression, and protein levels of interleukin-6(IL-6) were measured by ELISA. Uptake of proline was determined using 18 F-proline.RESULTS Sustained culture of originally quiescent PSCs inducedcell proliferation, loss of lipid droplets and exhibition of stress fibers, indicating cell activation. When added to PSCs in primary culture, all three D-vitamins diminished expression of α-SMA(to 32%-39% of the level of control cells; P < 0.05) and increased the storage of lipids(scores from 1.97-2.15 on a scale from 0-3; controls: 1.49; P < 0.05). No such effects were observed when D-vitamins were added to fully-activated cells, while incorporation of Brd U remained unaffected under both experimental conditions. Treatment of re-cultured PSCs with D-vitamins was associated with lower expression of IL-6(-42% to-49%; P < 0.05; also confirmed at the protein level) and increased expression of the vitamin D receptor gene(209%-321% vs controls; P < 0.05). There was no effect of D-vitamins on the expression of transforming growth factor-β1 and collagen type 1(chain α1). The lowest uptake of proline, a main component of collagen, was observed in calcipotriol-treated PSCs.CONCLUSION The three D-vitamins inhibit, with similar efficiencies, activation of PSCs in vitro, but cannot reverse the phenotype once the cells are fully activated. | Peter Wallbaum Sarah Rohde Luise Ehlers Falko Lange Alexander Hohn Carina Bergner Sarah Marie Schwarzenbock Bernd Joachim Krause Robert Jaster | 2018 | World Journal of Gastroenterology2018，24，2： | 3 |
| 5 | Impact of hyperglycemia on autoimmune pancreatitis and regulatory T-cells显示文摘AIM To evaluate the influence of hyperglycemia on the progression of autoimmune pancreatitis.METHODS We induced hyperglycemia by repetitive intraperitoneal(ip) injection of 50 mg/kg streptozotocin in MRL/Mp J mice, which develop autoimmune pancreatitis due to a genetic predisposition. We compared the extent of inflammation(histological score, CD3^+ lymphocytes, CD8^+ T-cells, CD4^+ T-cells, Foxp3^+ T-helper cells) in the pancreas of hyperglycemic and normoglycemic mice. We also analyzed the number of leukocytes, lymphocytes, granulocytes and monocytes in the blood. In addition, we determined the percentage of CD3^+ lymphocytes, CD8^+ T-cells, CD4^+ T-cells, Foxp3^+ T-helper cells, Foxp3^+ CD25^+ T-helper and Foxp3^+T-helper cells in the spleen by flow cytometry.RESULTS Treatment with streptozotocin caused a strong induction of hyperglycemia and a reduction in body weight(P < 0.001). Severe hyperglycemia did not, however, lead to an aggravation, but rather to a slight attenuation of autoimmune pancreatitis. In the pancreas, both the histological score of the pancreas as well as the number of CD3+ lymphocytes(P < 0.053) were decreased by hyperglycemia. No major changes in the percentage of CD8^+ T-cells, CD4^+ T-cells, Foxp3^+ T-helper cells were observed between hyperglycemic and normoglycemic mice. Hyperglycemia increased the numbers of leukocytes(P < 0.001), lymphocytes(P = 0.016), granulocytes and monocytes(P = 0.001) in the blood. Hyperglycemia also moderately reduced the percentage of CD3^+ lymphocytes(P = 0.057), significantly increased the percentage of Foxp3^+ T-helper cells(P = 0.018) and Foxp3^+ CD25^+ T-helper cells(P = 0.021) and reduced the percentage of Foxp3^+T-helper cells(P = 0.034) in the spleen. CONCLUSION Hyperglycemia does not aggravate but moderately attenuates autoimmune pancreatitis, possibly by increasing the percentage of regulatory T-cells in the spleen. | Franz-Tassilo Müller-Graff Brit Fitzner Robert Jaster Brigitte Vollmar Dietmar Zechner | 2018 | World Journal of Gastroenterology2018，24，28： | 3 |
| 6 | Trametinib and dactolisib but not regorafenib exert antiproliferative effects on rat pancreatic stellate cells显示文摘BACKGROUND: Modulation of the stroma response is considered a promising approach for the treatment of chronic pancreatitis and pancreatic cancer. The aim of this study was to evaluate the effects of three clinically available small molecule kinase inhibitors,regorafenib,trametinib and dactolisib,on effector functions of activated pancreatic stellate cells(PSCs),which play a key role in pancreatic fibrosis.METHODS: Cultured rat PSCs were exposed to small molecule kinase inhibitors. Proliferation and cell death were assessed by measuring the incorporation of 5-bromo-2'-deoxyuridine and cytotoxicity,respectively. Levels of m RNA were determined by real-time PCR,while protein expression and phosphorylation were analyzed by immunoblotting. Interleukin-6 levels in culture supernatants were quantified by ELISA. Zymography assays were performed to monitor collagenase activity in culture supernatants.RESULTS: The MEK inhibitor trametinib and the dual phosphatidylinositol 3-kinase/m TOR inhibitor dactolisib,but not the multi-kinase inhibitor regorafenib,efficiently inhibited PSC proliferation. Trametinib as well as regorafenib suppressed the expression of two autocrine mediators of PSC activation,interleukin-6 and transforming growth factor-β1. Dactolisibtreated cells expressed less α1 type I collagen and lower levels of α-smooth muscle actin,a marker of the myofibroblastic PSC phenotype. Simultaneous application of dactolisib and trametinib displayed additive inhibitory effects on cell growth without statistically significant cytotoxicity. Activity of matrix metalloproteinase-2 was not affected by any of the drugs.CONCLUSION: We suggest the combination of two drugs,that specifically target two key signaling pathways in PSC,Ras-Raf-MEK-ERK(trametinib) and phosphatidylinositol 3-kinase-AKT-m TOR(dactolisib),as a concept to modulate the activation state of the cells in the context of fibrosis. | Laura Witteck Robert Jaster | 2015 | Hepatobiliary & Pancreatic Diseases International2015，14，6： | 3 |
| 7 | Distinct antifibrogenic effects of erlotinib,sunitinib and sorafenib on rat pancreatic stellate cells显示文摘AIM:To study if three clinically available small molecule kinase inhibitors(SMI),erlotinib,sunitinib and sorafenib,exert antifibrogenic effects on pancreatic stellate cells(PSC)and analyze the basis of their action.METHODS:Cultured rat PSC were exposed to SMI.Cell proliferation and viability were assessed employing 5-bromo-2’-deoxyuridine incorporation assay and flow cytometry,respectively.2-Deoxy-2-[18F]fluoroglucose(18F-FDG)uptake was measured to study metabolic activity.Exhibition of the myofibroblastic PSC phenotype was monitored by immunofluorescence analysis ofα-smooth muscle actin(α-SMA)expression.Levels of mRNA were determined by real-time PCR,while protein expression and phosphorylation were analyzed by immunoblotting.Transforming growth factor-β1 (TGF-β1)levels in culture supernatants were quantified by ELISA.RESULTS:All three SMI inhibited cell proliferation and18F-FDG uptake in a dose-dependent manner and without significant cytotoxic effects.Furthermore,additive effects of the drugs were observed.Immunoblot analysis showed that sorafenib and sunitib,but not erlotinib,efficiently blocked activation of the AKT pathway,while all three drugs displayed little effect on phosphorylation of ERK1/2.Cells treated with sorafenib or sunitinib expressed less interleukin-6 mRNA as well as less collagen type 1 mRNA and protein.Sorafenib was the only drug that also upregulated the expression of matrix metalloproteinase-2 and reduced the secretion of TGF-β1 protein.All three drugs showed insignificant or discordant effects on the mRNA and protein levels ofα-SMA.CONCLUSION:The tested SMI,especially sorafenib,exert inhibitory effects on activated PSC,which should be further evaluated in preclinical studies. | Anne Elsner Falko Lange Brit Fitzner Martin Heuschkel Bernd Joachim Krause Robert Jaster | 2014 | World Journal of Gastroenterology2014，20，24： | 2 |
| 8 | Different characteristics of chronic dibutyltin dichloride-induced pancreatitis and cholangitis in mouse and rat显示文摘Background:Current animal models of chronic pancreatitis(CP)often provide only limited pathophysio-logical insights since they incompletely reflect the human disease.CP induced by injection of dibutyltin dichloride(DBTC-pancreatitis)shares with human CP the important feature of extended fibrosis and would be an even more attractive model if it could be transferred from rats to mice,as recently sug-gested in the context of combined ethanol and DBTC application.This study aimed to evaluate the effects of DBTC in pancreas and liver of C57BL/6 mice,a strain commonly used to engineer genetic mouse mod-els.Methods:C57BL/6 mice and Lewis rats were exposed to variable doses of DBTC.After an investigation period of up to 4 weeks,laboratory findings and histopathological changes of pancreas and liver were evaluated.Results:Chronic DBTC-pancreatitis in rats was characterized by acinar cell damage,ductal changes,fi-brosis,and inflammatory cell infiltrates.Mice treated with DBTC at 6–8 mg/kg body weight,the standard doses in rats,showed transient increases of lipase activities but no morphological signs of chronic DBTC-pancreatitis 4 weeks after injection of the drug.Increased doses of 10–12 mg/kg DBTC were intolerable due to their high toxicity.In contrast,mice and rats presented with a similar histopathology of the liver that can be characterized as a chronic-proliferative DBTC-cholangitis with predominating damage and proliferation of the small bile ducts as well as secondary portal inflammatory cell infiltrates and a begin-ning portal fibrosis.Conclusions:The DBTC-model cannot be transferred from rats to C57BL/6 mice with respect to chronic DBTC-pancreatitis,but might be of interest to study DBTC-cholangitis in both species. | Friederike Lütt Luise Ehlers Horst Nizze Robert Jaster | 2020 | Hepatobiliary & Pancreatic Diseases International2020，19，2： | 2 |
| 9 | Hemicellulose monosaccharide composition and in vitro disappearance of orchard grass and alfalfa hay 显示文摘 | Wedig C L Jaster E H Moore K J | 1987 | Journal of Agricultural Food Chemistry1987，35，2： | 1 |
| 10 | Molecular regulation of pancreatic stellate cell function显示文摘 | Jaster R | 2004 | Mol Cancer2004，3，1： | 1 |
| 11 | Molecular regulation of pancreatic stellate cell function 显示文摘 | Jaster R | 2004 | Mol cancer2004，3，1： | 1 |
| 12 | Unexpected sudden death after lateral medullary infarction 显示文摘 | Jaster JH | 2001 | J Neurol Neurosurg Psychiatry2001，70，1： | 1 |
| 13 | ExtraceUular signal regulated kinases are key mediators of mitogenic signals in rat pancreatic stellate cells显示文摘 | Jaster R Sparmann G Emmrich J | 2002 | Gut2002，51，： | 1 |
| 14 | Pemxisome proliferator-aetivated receptor gamma overexpression inhibits profibrogenic activities of immortalised rat pancreatic stellate cells 显示文摘 | Jaster R Lichte P Fitzner B | 2007 | Cell Mol Med2007，9，3： | 1 |
| 15 | Evaluation of quality, quantity, and timing ofcolostrum feeding on immunoglobulin G1 absorption in Jerseycalves显示文摘 | Jaster E H | 2005 | J Dairy Sci2005，88，1： | 1 |
| 16 | Quality and fermentation of enzyme treated alfalfa silages at three moisture concentration显示文摘 | Jaster E H Moore K J | 1991 | An im Feed Sci Technol1991，31，： | 1 |
| 17 | Unexpected sudden death after lateral medullary infarction显示文摘 | Jaster J n | 2001 | J Neurol Neurosurg Psychiatry2001，70，： | 1 |
| 18 | Bivalirudin inhibits peripro- cedural platelet function and tissue factor expression of human smooth muscle ceils显示文摘 | Pepke W Eisenreich A Jaster M | 2013 | Cardiovasc Ther2013，31，2： | 1 |
| 19 | Regulation of pancreatic stellate cell function in vitro: biological and molecular effects of all-trans retinoic acid显示文摘 | Jaster R Hilgandorf I Fitzner B | 2003 | Biochem Pharmacol2003，66，4： | 1 |
| 20 | Bivalirudin inhibits periprocedural plateIet function and tissue factor expression of human smooth muscle cells显示文摘 | Pepke W Eisenreich A Jaster M | 2013 | Cardiovasc Ther2013，31，2： | 1 |
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