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| 1 | Neuroprotective role of(Val^8)GLP-1-Glu-PAL in an in vitro model of Parkinson's disease显示文摘The growth factor glucagon-like peptide-1(GLP-1) is neuroprotective in several animal models of neurodegeneration. Here, we analyzed the neuroprotective effects of a novel protease-resistant GLP-1 analogue,(Val^8)GLP-1-Glu-PAL, which has advantages over older analogues, such as improvement of hippocampal neurogenesis, glucose homeostasis, and insulin secretion. We established an in vitro model of Parkinson's disease using the mitochondrial stressor rotenone in primary cultured mouse neurons pretreated with(Val^8)GLP-1-Glu-PAL.(Val^8)GLP-1-Glu-PAL alone did not affect neuronal viability, but prevented the rotenone-induced reduction in cell viability in a dose-dependent manner. In addition,(Val^8)GLP-1-Glu-PAL pretreatment prevented rotenone-induced proapoptotic changes manifesting as downregulation of procaspase-3 and Bcl-2 and upregulation of cleaved caspase-3. These results demonstrate that the novel agent(Val^8)GLP-1-GluPAL shows promise as a drug treatment for Parkinson's disease. | Lin Li Ke Liu Juan Zhao Christian Holscher Guang-lai Li Yue-ze Liu | 2016 | Neural Regeneration Research2016，11，2： | 6 |
| 2 | GLP-1/GIP/Gcg三受体激动剂改善阿尔茨海默病三转基因小鼠的认知行为显示文摘阿尔茨海默病(Alzheimer’s disease,AD)是一种严重威胁人类健康的进行性神经退行性疾病,目前为止仍然缺乏有效的治疗方法。最新研究表明,2型糖尿病(type 2 diabetes mellitus,T2DM)是AD发生的一个重要危险因素,T2DM的治疗药物对AD也显示出一定的神经保护效应。胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)/葡萄糖依赖性促胰岛素多肽(glucose-dependent insulinotropic polypeptide,GIP)/胰高血糖素(glucagon,Gcg)三受体激动剂(Triagonist)是在GLP-1/Gcg双受体激动剂关键序列基础上,融入GIP部分氨基酸序列后,改造而成的一种新的、同等程度激活GLP-1/GIP/Gcg受体的单分子多肽。最近Triagonist已在啮齿类动物肥胖模型上被证实具有良好的控制血糖效应。本研究利用多种行为学手段首次观察了慢性腹腔注射Triagonist对三转AD(3xTg-AD)小鼠学习记忆认知行为的改善作用,并利用ELISA和Western blot技术探讨了可能的分子机制。结果显示,Triagonist慢性处理明显逆转了3xTg-AD小鼠的工作记忆损伤,Y迷宫自发交替实验正确率明显上升;Triagonist还改善了3xTg-AD小鼠的长时程空间学习记忆能力,使经典Morris水迷宫测试中的逃避潜伏期明显缩短、目标象限游泳时间延长、对位水迷宫再学习的可塑性增强。ELISA和Western blot实验结果显示,Triagonist上调了3xTg-AD小鼠海马内的cAMP、PKA和p-CREB水平。这些结果表明,GLP-1/GIP/Gcg三受体激动剂可以改善3xTg-AD小鼠的认知行为,c AMP/PKA/CREB信号通路的上调可能介导了其神经保护作用,提示GLP-1/GIP/Gcg三受体激动剂有望成为预防或治疗AD的一种新策略。 | 焦娟娟 HOLSCHER Christian 李甜 董雪帆 曲雪松 曹越 武美娜 王昭君 祁金顺 | 2017 | 生理学报2017，69，2： | 5 |
| 3 | 抗糖尿病新药(D-Ser2)Oxm拮抗淀粉样β蛋白细胞毒性的神经保护效应观察显示文摘淀粉样β蛋白(amyloidβ-protein,Aβ)在脑内的沉积及其神经毒性是阿尔茨海默病(Alzheimer’s disease,AD)的主要原因之一,目前仍缺乏拮抗Aβ的有效药物。最新报道表明,一种新的抗糖尿病药物(D-Ser2)Oxm不仅可以改善2型糖尿病(T2DM)大鼠的血糖和胰岛素水平,也具有促进皮层和海马神经元及其突触发生的效应。然而,(D-Ser2)Oxm是否能拮抗AD时Aβ所致的细胞损伤仍缺乏实验依据。本研究在培养原代大鼠海马神经细胞基础上,通过细胞活性和早期凋亡测定、细胞内钙成像以及线粒体膜电位检测,研究了(D-Ser2)Oxm对Aβ1-42所致细胞毒性的拮抗效应。结果显示,与单独给予Aβ1-42处理的细胞相比,(D-Ser2)Oxm+Aβ1-42处理组的细胞活力明显提高,而加入GLP-1受体抑制剂exendin(9-39)后,细胞活力则显著下降;(D-Ser2)Oxm可有效拮抗Aβ1-42导致的细胞凋亡,并使凋亡相关蛋白caspase3含量显著降低;(D-Ser2)Oxm处理还有效阻止了Aβ1-42引起的海马细胞内钙水平升高、线粒体膜电位去极化以及糖原合成酶激酶-3β(glycogen synthase kinase-3β,GSK-3β)(Y216)的活化。以上结果表明,(D-Ser2)Oxm可能是通过激动GLP-1受体对抗Aβ1-42的神经毒性,并且这种保护效应可能与细胞内钙稳态调节和线粒体膜电位稳定有关。 | 韩宇飞 HOLSCHER Christian 王昭君 张军 原丽 仝嘉庆 王丹丹 武美娜 祁金顺 | 2016 | 生理学报2016，68，3： | 3 |
| 4 | Dual-Targeting of Arabidopsis 6-Phosphogluconolactonase 3 (PGL3)to Chloroplasts and Peroxisomes Involves Interaction with Trx m2 in the Cytosol显示文摘 | Christian Holscher Tanja Meyer Antje von Schaewen | 2014 | Molecular Plant2014，7，1： | 2 |
| 5 | Glucocorticoid receptor and protein/RNA synthesis-dependent mechanisms underlie the control of synaptic plasticity by stress显示文摘 | Xu L Holscher C Anwyl R Rowan M J | 1998 | Proc Natl Acad USA1998，95，： | 1 |
| 6 | Towards genetic prediction of radiation responses: ESTRO's GENEPI project 显示文摘 | Baumann M Holscher T Begg AC | 2003 | Radiother Oncol2003，69，2： | 1 |
| 7 | The IL-27 receptor chain WSX2-1 differentially regulates antibacterial immunity and survival during experimental tuberculosis显示文摘 | Holscher C Holscher A Rückerl D | 2005 | J Immunol2005，174，： | 1 |
| 8 | Evaluation of the symptomatic treatment of residual neu- rological symptoms in Wilson Disease显示文摘 | HOLSCHER S LEINWEBER B HEFTER H | 2010 | Eur Neurol2010，64，： | 1 |
| 9 | Tissue factor activity is increased in a combined platelet and microparticle sample from cancer patients显示文摘 | Tilley RE Holscher T Belani R | 2008 | Thromb Res2008，122，5： | 1 |
| 10 | Tern perature dependence of point contact friction on sili con显示文摘 | Schirmeisen A Jansen L Holscher H Fuchs H | 2006 | Applied Physics Letters2006，88，12： | 1 |
| 11 | Rainfall parti- tioning in relation to forest structure in differently man- aged montane forest stands in Central Sulawesi, Indonesia 显示文摘 | Dietz J Holscher D Leusehner C | 2006 | Forest Eeology and Management2006，237，1： | 1 |
| 12 | MR imaging of edemaaccompanying benign and malignant bone tumors显示文摘 | Kroon HM Bloem JL Holscher HC | 1994 | SkeletalRadiol1994，23，4： | 1 |
| 13 | Intraoperative ultrasonographic detection of occult liver metastases in colorectal cancer 显示文摘 | Stadler J Holscher AH Adolf J | 1991 | Surg Endosc1991，5，1： | 1 |
| 14 | Time, spaoe and Mppocampal functions显示文摘 | Holscher C | 2003 | Rev Neurosic2003，14，3： | 1 |
| 15 | No inhibition of IL-27 signaling by soluble gp130显示文摘 | SCHUSTER B HOLSCHER C | 2005 | Biochem Biophys Res Commun2005，326，4： | 1 |
| 16 | Prion protein contains a second endoplasmic reticulum targeting signal sequence located at its C terminus 显示文摘 | Holscher C Bach U C Dobberstein B | 2001 | J Biol Chem2001，276，13： | 1 |
| 17 | Real-time cerebral angiography:sensitivity of a new contrast-specific ultra-sound technique 显示文摘 | Holscher T Sattin J A Raman R | 2007 | AJNR Am J Neuroradiol2007，28，4： | 1 |
| 18 | Hepcidin treatment modulates the expression of divalent metal transporter-1,ceruloplasmin,and ferroportin-1 in the rat cerebral cortex and hippocampus显示文摘 | Li L Holscher C Chen BB | | 0，，03： | 1 |
| 19 | Cardia cancer: at- tempt at a therapeutically relevant classification 显示文摘 | Siewert JR Holscher AH Becker K | 1987 | Chirurg1987，58，1： | 1 |
| 20 | Multimodal treatment of esophageal cancer显示文摘 | Lordick F Holscher AH Haustermans K | 2013 | Langenbecks Arch Surg2013，398，2： | 1 |
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