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41.
Ihara E Akiho H Nakamura K Turner SR Macdonald JA 《World journal of gastrointestinal pathophysiology》2011,2(2):19-25
The number of patients suffering from symptoms associated with gastrointestinal(GI) motility disorders is on the rise. GI motility disorders are accompanied by alteration of gastrointestinal smooth muscle functions. Currently available drugs,which can directly affect gastrointestinal smooth muscle and restore altered smooth muscle contractility to normal,are not satisfactory for treating patients with GI motility disorders. We have recently shown that ERK1/2 and p38MAPK signaling pathways play an important role in the contractile response not only of normal intestinal smooth muscle but also of inflamed intestinal smooth muscle. Here we discuss the possibility that ERK1/2 and p38MAPK signaling pathways represent ideal targets for generation of novel therapeutics for patients with GI motility disorders. 相似文献
42.
To date, most studies of Shc family of signaling adaptor proteins have been focused on the near-ubiquitously expressed ShcA, indicating its relevance to age-related diseases and longevity. Although the role of the neuronal ShcC protein is much less investigated, accumulated evidence suggests its importance for neuroprotection against such aging-associated conditions as brain ischemia and oxidative stress. Here, we summarize more than decade of studies on the ShcC expression and function in normal brain, age-related brain pathologies and immune disorders with a focus on the interactions of ShcC with signaling proteins/pathways, and the possible implications of these interactions for changes associated with aging. 相似文献
43.
目的:观察活血解毒方对糖尿病大鼠视网膜血管形态的影响并探讨其可能的作用机制。方法:一次性腹腔注射链脲佐菌素(Streptozotocin,STZ,65 mg/kg)诱导糖尿病大鼠模型,造模后随机分为模型组和活血解毒方组。另设正常对照组。药物干预12周后,应用视网膜消化铺片法观察视网膜血管形态;应用Western blot法检测视网膜VEGF蛋白的表达,应用Real-Time PCR法检测视网膜VEGF、Ras、Raf-1与ERK mRNA的表达。结果:模型组视网膜毛细血管面积密度及内皮细胞/周细胞比例与较正常组升高(P<0.001),VEGF蛋白及VEGF、Ras、ERKmRNA表达升高(P<0.05),Raf-1mRNA表达升高(P>0.05)。与模型组比较,活血解毒方组视网膜毛细血管面积密度和内皮细胞/周细胞比例降低(P<0.01和P<0.001),VEGF蛋白与VEGF、Ras、Raf-1、ERK mRNA表达下降(P<0.05)。结论:活血解毒方能明显抑制视网膜毛细血管和内皮细胞的增生,其机制可能是通过干预Ras/Raf-1/ERK信号转导通路,下调VEGF在视网膜中的表达,抑制血管新生,从而改善DR。 相似文献
44.
丝裂原活化蛋白激酶1/2(ERK1/2)通路是第一个被发现的细胞信号转导通路,由Ras、Raf、MEK1/2和ERK1/2组成。ERK1/2通路激活后可以将细胞外信号从细胞膜转到细胞核,参与了细胞的多种生理病理功能,如细胞的生长、增殖、分化和凋亡等,并且与多种疾病的发病有关,包括多发性硬化(MS)和实验性自身免疫性脑脊髓炎(EAE)。ERK1/2通路的激活可以引起星形胶质细胞、MG、T细胞、巨噬细胞等活化,释放多种炎性因子,引起髓鞘损伤,导致MS/EAE的发病。多项研究表明,通过抑制ERK1/2通路可以减少炎性因子的释放,减轻髓鞘损伤,改善MS/EAE的病情,为治疗MS药物的开发提供了重要的靶点。 相似文献
45.
Melanie F. Weingart Jacquelyn J. Roth Marianne Hutt-Cabezas Tracy M. Busse Harpreet Kaur Antoinette Price Rachael Maynard Jeffrey Rubens Isabella Taylor Xing-gang Mao Jingying Xu Yasumichi Kuwahara Sariah J. Allen Anat Erdreich-Epstein Bernard E. Weissman Brent A. Orr Charles G. Eberhart Jaclyn A. Biegel Eric H. Raabe 《Oncotarget》2015,6(5):3165-3177
Atypical teratoid rhabdoid tumor (AT/RT) is among the most fatal of all pediatric brain tumors. Aside from loss of function mutations in the SMARCB1 (BAF47/INI1/SNF5) chromatin remodeling gene, little is known of other molecular drivers of AT/RT. LIN28A and LIN28B are stem cell factors that regulate thousands of RNAs and are expressed in aggressive cancers. We identified high-levels of LIN28A and LIN28B in AT/RT primary tumors and cell lines, with corresponding low levels of the LIN28-regulated microRNAs of the let-7 family. Knockdown of LIN28A by lentiviral shRNA in the AT/RT cell lines CHLA-06-ATRT and BT37 inhibited growth, cell proliferation and colony formation and induced apoptosis. Suppression of LIN28A in orthotopic xenograft models led to a more than doubling of median survival compared to empty vector controls (48 vs 115 days). LIN28A knockdown led to increased expression of let-7b and let-7g microRNAs and a down-regulation of KRAS mRNA. AT/RT primary tumors expressed increased mitogen activated protein (MAP) kinase pathway activity, and the MEK inhibitor selumetinib (AZD6244) decreased AT/RT growth and increased apoptosis. These data implicate LIN28/RAS/MAP kinase as key drivers of AT/RT tumorigenesis and indicate that targeting this pathway may be a therapeutic option in this aggressive pediatric malignancy. 相似文献
46.
Eun-Joo Shin Yoon Hee Chung Hoang-Lan Thi Le Ji Hoon Jeong Duy-Khanh Dang Yunsung Nam Myung Bok Wie Seung-Yeol Nah Yo-Ichi Nabeshima Toshitaka Nabeshima Hyoung-Chun Kim 《The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)》2015,18(6)
Background:
We demonstrated that oxidative stress plays a crucial role in cognitive impairment in klotho mutant mice, a genetic model of aging. Since down-regulation of melatonin due to aging is well documented, we used this genetic model to determine whether the antioxidant property of melatonin affects memory impairment.Methods:
First, we examined the effects of melatonin on hippocampal oxidative parameters and the glutathione/oxidized glutathione (GSH/GSSG) ratio and memory dysfunction of klotho mutant mice. Second, we investigated whether a specific melatonin receptor is involved in the melatonin-mediated pharmacological response by application with melatonin receptor antagonists. Third, we examined phospho-extracellular-signal-regulated kinase (ERK) expression, nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, Nrf2 DNA binding activity, and glutamate-cysteine ligase (GCL) mRNA expression. Finally, we examined effects of the ERK inhibitor SL327 in response to antioxidant efficacy and memory enhancement mediated by melatonin.Results:
Treatment with melatonin resulted in significant attenuations of oxidative damage, a decrease in the GSH/GSSG ratio, and a significant amelioration of memory impairment in this aging model. These effects of melatonin were significantly counteracted by the selective MT2 receptor antagonist 4-P-PDOT. Importantly, 4-P-PDOT or SL327 also counteracted melatonin-mediated attenuation in response to the decreases in phospho-ERK expression, Nrf2 nuclear translocation, Nrf2 DNA-binding activity, and GCL mRNA expression in the hippocampi of klotho mutant mice. SL327 also counteracted the up-regulation of the GSH/GSSG ratio and the memory enhancement mediated by melatonin in klotho mutant mice.Conclusions:
Melatonin attenuates oxidative stress and the associated memory impairment induced by klotho deficiency via signaling interaction between the MT2 receptor and ERK- and Nrf2-related antioxidant potential. 相似文献47.
Pb2+ induced IL‐8 gene expression by extracellular signal‐regulated kinases and the transcription factor,activator protein 1, in human gastric carcinoma cells 下载免费PDF全文
48.
Pb2+ induces gastrin gene expression by extracellular signal‐regulated kinases 1/2 and transcription factor activator protein 1 in human gastric carcinoma cells 下载免费PDF全文
49.
Han Li Guo-feng Pan Zhen-zhou Jiang Jing Yang Li-xin Sun Lu-yong Zhang 《Acta pharmacologica Sinica》2015,36(5):606-613