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Jia-Xin Jiang Karen J. Aitken Chris Sotiropolous Tyler Kirwan Trupti Panchal Nicole Zhang Shuye Pu Shoshana Wodak Cornelia Tolg Darius J. B?gli 《PloS one》2013,8(8)
Extracellular matrix changes are often crucial inciting events for fibroproliferative disease. Epigenetic changes, specifically DNA methylation, are critical factors underlying differentiated phenotypes. We examined the dependency of matrix-induced fibroproliferation and SMC phenotype on DNA methyltransferases. The cooperativity of matrix with growth factors, cell density and hypoxia was also examined. Primary rat visceral SMC of early passage (0–2) were plated on native collagen or damaged/heat-denatured collagen. Hypoxia was induced with 3% O2 (balanced 5% CO2 and 95% N2) over 48 hours. Inhibitors were applied 2–3 hours after cells were plated on matrix, or immediately before hypoxia. Cells were fixed and stained for DNMT3A and smooth muscle actin (SMA) or smooth muscle myosin heavy chain. Illumina 450 K array of CpG sites was performed on bisulfite-converted DNA from smooth muscle cells on damaged matrix vs native collagen. Matrix exquisitely regulates DNMT3A localization and expression, and influences differentiation in SMCs exposed to denatured matrix +/− hypoxia. Analysis of DNA methylation signatures showed that Matrix caused significant DNA methylation alterations in a discrete number of CpG sites proximal to genes related to SMC differentiation. Matrix has a profound effect on the regulation of SMC phenotype, which is associated with altered expression, localization of DNMTs and discrete changes DNA methylation. 相似文献
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Ran Liu Miao Yang Yanli Meng Juan Liao Jingyi Sheng Yuepu Pu Lihong Yin Sun Jung Kim 《PloS one》2013,8(10)
Recent studies have demonstrated the possible function of miR-139-5p in tumorigenesis. However, the exact mechanism of miR-139-5p in cancer remains unclear. In this study, the association of miR-139-5p expression with esophageal squamous cell carcinoma (ESCC) was evaluated in 106 pairs of esophageal cancer and adjacent non-cancerous tissue from ESCC patients. The tumor suppressive features of miR-139-5p were measured by evaluating cell proliferation and cell cycle state, migratory activity and invasion capability, as well as apoptosis. Luciferase reporter assay and Western blot analysis were performed to determine the target gene regulated by miR-139-5p. The mRNA level of NR5A2, the target gene of miR-139-5p, was determined in ESCC patients. Results showed that reduced miR-139-5p level was associated with lymph node metastases of ESCC. MiR-139-5p was investigated to induce cell cycle arrest in the G0/G1 phase and to suppress the invasive capability of esophageal carcinoma cells by targeting the 3′UTR of oncogenic NR5A2. Cyclin E1 and MMP9 were confirmed to participate in cell cycle arrest and invasive suppression induced by NR5A2, respectively. Pearson correlation analysis further confirmed the significantly negative correlation between miR-139-5p and NR5A2 expression. The results suggest that miR-139-5p exerts a growth- and invasiveness-suppressing function in human ESCCs, which demonstrates that miR-139-5p is a potential biomarker for early diagnosis and prognosis and is a therapeutic target for ESCC. 相似文献
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Kuo-How Huang Kuan-Lin Kuo I-Lin Ho Hong-Chiang Chang Yuan-Ting Chuang Wei-Chou Lin Ping-Yi Lee Shih-Chen Chang Chih-Kang Chiang Yeong-Shiau Pu Chien-Tso Chou Chen-Hsun Hsu Shing-Hwa Liu 《PloS one》2013,8(12)
Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, can elicit anti-tumor effects in various malignancies. Here, we sought to clarify the role of autophagy in celecoxib-induced cytotoxicity in human urothelial carcinoma (UC) cells. The results shows celecoxib induced cellular stress response such as endoplasmic reticulum (ER) stress, phosopho-SAPK/JNK, and phosopho-c-Jun as well as autophagosome formation in UC cells. Inhibition of autophagy by 3-methyladenine (3-MA), bafilomycin A1 or ATG7 knockdown potentiated celecoxib-induced apoptosis. Up-regulation of autophagy by rapamycin or GFP-LC3B-transfection alleviated celecoxib-induced cytotoxicity in UC cells. Taken together, the inhibition of autophagy enhances therapeutic efficacy of celecoxib in UC cells, suggesting a novel therapeutic strategy against UC. 相似文献
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Objectives
We investigated the effect of a nationwide educational program following surviving sepsis campaign (SSC) guidelines. Physicians’ clinical practice in sepsis care and patient mortality rate for severe sepsis were analyzed using a nationally representative cohort.Methods
Hospitalizations for severe sepsis with organ failure from 1997 to 2008 were extracted from Taiwan’s National Health Insurance Research Database (NHIRD), and trends in sepsis incidence and mortality rates were analyzed. A before-and-after study design was used to evaluate changes in the utilization rates of SSC items and changes in severe sepsis mortality rates occurred after a national education program conducted by the Joint Taiwan Critical Care Medicine Committee since 2004. A total of 39,706 hospitalizations were analyzed, which consisted of a pre-intervention cohort of 14,848 individuals (2000-2003) and a post-intervention cohort of 24,858 individuals (2005-2008).Results
The incidence rate of severe sepsis increased from 1.88 per 1,000 individuals in 1997 to 5.07 per 1,000 individuals in 2008. The cumulative mortality rate decreased slightly from 48.2% for the pre-intervention cohort to 45.9% for the post-intervention cohort. The utilization rates of almost all SSC items changed significantly between the pre-intervention and post-intervention cohorts. These changes of utilization rates were found to be associated with mild reduction in mortality rate.Conclusion
The nationwide education program through a national professional society has a significant impact on physicians’ clinical practice and resulted in a slight but significant reduction of severe sepsis mortality rate. 相似文献78.
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Herein, we found that salidroside suppressed hypoxia-inducible factor 1 alpha (HIF-1α) and lysyl oxidase-like protein 2 (LOXL2) within human pancreatic cancer BxPC-3 cells cultured both under normoxia and hypoxia condition. To investigate the effect of salidroside on tumorigenesis of BxPC-3 cells and whether HIF-1α and LXCL2 were involved in this process, cells transfected with or without LOXL2 overexpression vector, were treated with 50 μg/mL of salidroside or 50 μM of KC7F2 (a HIF-1α inhibitor) under hypoxia. Cell viability and invasion were assessed using CCK-8 and Transwell chamber assay, respectively. Expression of E-cadherin and matrix metalloproteinase 2/9 (MMP 2/9) was determined, by Western blot analysis, to assess cell mobility at molecular levels. We confirmed that hypoxia increased LOXL2 and induced tumorigenesis of BxPC-3 cells, as evidenced by promoted cell proliferation and invasion, enhanced MMP2/9 while reduced E-cadherin. Interestingly, hypoxia-induced carcinogenesis was significantly retarded by both salidroside and KC7F2, however, enhanced with LOXL2 overexpression. Besides, salidroside and KC7F2 reduced LOXL2, and reversed the tumorigenesis of BxPC-3 cells induced by LOXL2 overexpression. Given the inhibitory effect of salidroside on HIF-1α expression, our data suggested that: (1) LOXL2 was the mechanism, whereby salidroside and KC7F2 showed inhibitory effect on cancer progression of BxPC-3 cells; (2) salidroside exerted its anticancer effect, most likely, by a HIF-1α/LOXL2 pathway. In conclusion, salidroside was a novel therapeutic drug in pancreatic cancer, and downregulation of HIF-1α and LXCL2 was the underlying mechanism. 相似文献
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