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Cancer Biology
LncRNA-AF113014 promotes the expression of Egr2 by interaction with miR-20a to inhibit proliferation of hepatocellular carcinoma cells
May 25, 2017   PloS One
Zeng T, Wang D, Chen J, Tian Y, Cai X, Peng H, Zhu L, Huang A, Tang H
LncRNA-AF113014 promotes the expression of Egr2 by interaction with miR-20a to inhibit proliferation of hepatocellular carcinoma cells
May 25, 2017
PloS One
Long non-coding RNAs (lncRNAs), tentatively identified as non-protein coding RNA, are transcripts more than 200nt in length and accounting for 98% of the whole genome of human being. Accumulating evidence showed aberrant expressions of lncRNAs are strongly correlated to the development of cancers. In this study, AF113014 is a new lncRNA identified from Microarray. We found AF113014 is differentially expressed between HCC cell lines and normal hepatocytes. Functionally, AF113014 inhibited proliferation of HCC cells both in vitro and in vivo, whereas the opposite effect was observed when AF113014 knockdown. Moreover, we identified that Egr2, a tumor suppressor gene, was a downstream target gene of AF113014. Furthermore, we discovered that AF113014 up-regulated Egr2 expression through interacting with miR-20a by using dual-luciferase reporter assay, qRT-PCR and Western blotting analysis. Our data provides a new insight for understanding the mechanisms of HCC.
Survival and prognostic factors for patients with advanced hepatocellular carcinoma after stereotactic ablative radiotherapy
May 25, 2017   PloS One
Lo CH, Yang JF, Liu MY, Jen YM, Lin CS, Chao HL, Huang WY
Survival and prognostic factors for patients with advanced hepatocellular carcinoma after stereotactic ablative radiotherapy
May 25, 2017
PloS One
To evaluate the survival outcomes and prognostic factors of patients with advanced hepatocellular carcinoma (HCC) who underwent stereotactic ablative radiotherapy (SABR). This retrospective study evaluated patients with advanced HCC who underwent SABR between December 2007 and July 2015. All patients had Barcelona Clinic Liver Cancer stage C disease and Child-Turcotte-Pugh (CTP) class A-B function. In-field control (IFC), overall survival (OS), prognostic factors, and toxicity were evaluated. In this study of 89 patients, the 3-year IFC rate was 78.1%, and the 1-year and 3-year OS rates were 45.9% and 24.3%, respectively. The multivariate analysis revealed that CTP class, the presence of main portal vein tumor thrombosis, and the presence of extrahepatic spread were independent predictors of OS. The expected median OS values among patients with ≥2, 1, and 0 predictors were 4.2, 8.6, and 26.4 months, respectively (p
DEK protein level is a biomarker of CD138positive normal and malignant plasma cells
May 30, 2017   PloS One
Çalışkaner ZO, Çakar T, Özçelik E, Özdilek A, Kim AS, Doğan Ö, Bosompem A, Grosveld G, Saka B, Kandilci A
DEK protein level is a biomarker of CD138positive normal and malignant plasma cells
May 30, 2017
PloS One
Overexpression of DEK oncogene is associated with increased proliferation of carcinoma cells and it is observed in several solid tumors due to the amplification of the 6p22.3 chromosomal region where DEK locates. Although the same chromosomal amplification occurs in multiple myeloma (MM), a plasma cell neoplasm, whether the expression and the copy number of the DEK gene are affected in MM remains elusive. We show that despite the increased copy number in CD138positive MM cells (4 out of 41 MM samples), DEK mRNA expression was down-regulated compared with that in CD138negative bone marrow (BM) cells of the same patients (P
Inhibition of chronic prostate inflammation by hyaluronic acid through an immortalized human prostate stromal cell line model
May 30, 2017   PloS One
Liu MC, Chen WH, Chiou CS, Lo WC, Dubey NK, Chen YC, Lai WT, Yeh SD, Chiang HS, Deng WP
Inhibition of chronic prostate inflammation by hyaluronic acid through an immortalized human prostate stromal cell line model
May 30, 2017
PloS One
Benign prostatic hyperplasia (BPH) is the most common urologic disease among elderly men. A well-established in vitro cell model is required to determine the therapeutic mechanism of BPH inflammation. In this study, we attempted to establish an immortalized human prostate stromal cell line by transfecting with HPV-16 E6/E7 and designated as ihPSC. No significant difference was found in fibroblast-like morphology between primary hPSC and ihPSC. The ihPSC possessed a significantly higher cell proliferation rate than primary hPSC. The prostate-specific markers and proteins including cytoskeleton (α-SMA and vimentin) and smooth muscle (calponin), especially the androgen receptor (AR) were also examined in ihPSC, almost identical to the primary hPSC. To create an in vitro model featuring chronic prostatic inflammation, ihPSC was stimulated with IFN-γ+IL-17 and then treated with the high molecular weight hyaluronic acid hylan G-F 20 as an alternative strategy for inhibiting BPH inflammation. Hylan G-F 20 could dose-dependently diminish the inflammation-induced proliferation in ihPSC. The enhanced expressions of inflammatory molecules including IL-1β, IL-6, IL-8, cyclooxygenase 2 (COX2), inducible nitrogen oxide synthase (iNOS), and Toll-like receptor 4 (TLR4) were all abolished by hylan G-F 20. For inflammatory signaling, hylan G-F 20 can also diminish the IFN-γ+IL-17-increased expression of iNOS and p65 in ihPSC. These findings suggest that ihPSC could provide a mechanism-based platform for investigating prostate inflammation. The hylan G-F 20 showed strong anti-inflammatory effects by decreasing inflammatory cytokines and signalings in the ihPSC, indicating its therapeutic potentials in BPH treatment in the future.
Overexpression of the human DEK oncogene reprograms cellular metabolism and promotes glycolysis
May 30, 2017   PloS One
Matrka MC, Watanabe M, Muraleedharan R, Lambert PF, Lane AN, Romick-Rosendale LE, Wells SI
Overexpression of the human DEK oncogene reprograms cellular metabolism and promotes glycolysis
May 30, 2017
PloS One
The DEK oncogene is overexpressed in many human malignancies including at early tumor stages. Our reported in vitro and in vivo models of squamous cell carcinoma have demonstrated that DEK contributes functionally to cellular and tumor survival and to proliferation. However, the underlying molecular mechanisms remain poorly understood. Based on recent RNA sequencing experiments, DEK expression was necessary for the transcription of several metabolic enzymes involved in anabolic pathways. This identified a possible mechanism whereby DEK may drive cellular metabolism to enable cell proliferation. Functional metabolic Seahorse analysis demonstrated increased baseline and maximum extracellular acidification rates, a readout of glycolysis, in DEK-overexpressing keratinocytes and squamous cell carcinoma cells. DEK overexpression also increased the maximum rate of oxygen consumption and therefore increased the potential for oxidative phosphorylation (OxPhos). To detect small metabolites that participate in glycolysis and the tricarboxylic acid cycle (TCA) that supplies substrate for OxPhos, we carried out NMR-based metabolomics studies. We found that high levels of DEK significantly reprogrammed cellular metabolism and altered the abundances of amino acids, TCA cycle intermediates and the glycolytic end products lactate, alanine and NAD+. Taken together, these data support a scenario whereby overexpression of the human DEK oncogene reprograms keratinocyte metabolism to fulfill energy and macromolecule demands required to enable and sustain cancer cell growth.
The clinical significance of accompanying NME on preoperative MR imaging in breast cancer patients
May 30, 2017   PloS One
Gweon HM, Jeong J, Son EJ, Youk JH, Kim JA, Ko KH
The clinical significance of accompanying NME on preoperative MR imaging in breast cancer patients
May 30, 2017
PloS One
To investigate the significance of accompanying NME in invasive ductal carcinoma (IDC) on preoperative MR imaging and assess the factors affecting the significance. Between January 2015 and February 2016, 163 consecutive patients with IDC who underwent preoperative MR imaging and subsequent surgery were enrolled and reviewed. Index cancer mass size and total extent with accompanying NME on MR images was measured and compared with pathologic size. Positive NME was defined as pathological result of IDC or DCIS. To identify affecting factors associated with frequency of accompanying NME on MR and positive pathologic result, clinicopathologic features were compared between breast cancers with NME and without NME, and between breast cancers with positive NME and negative NME using the Student t-test or Chi-square test. Of the 163 invasive breast cancers, 123(75.5%) cancers presented as only mass feature and 40(24.5%) cancers had accompanying NME around the index mass. Of the 40 accompanying NME, 22 (55%) had positive pathologic results and 18 (45%) had negative results. The HER2 positive status was significantly associated with positive pathologic results of accompanying NME (P = .016). Accompanying NME on preoperative MR imaging showed malignant pathologic results in 55%. The HER2 positive IDC was more frequently accompanied by malignant NME.
The pathogenic role of interleukin-22 and its receptor during UVB-induced skin inflammation
May 30, 2017   PloS One
Kim Y, Lee J, Kim J, Choi CW, Hwang YI, Kang JS, Lee WJ
The pathogenic role of interleukin-22 and its receptor during UVB-induced skin inflammation
May 30, 2017
PloS One
Recent studies show that IL-22, a cytokine produced by activated CD4+ T cells and NK cells, plays a pathogenic role in acute and chronic skin diseases. While IL-22 is produced by immune cells, the expression of IL-22Rα, the functional subunit of IL-22R, is mostly restricted to non-hematopoietic cells in organs such as the skin and pancreas. Although it is well known that ultraviolet B (UVB) radiation induces skin inflammation, there have been no reports regarding the effect of UVB on the expression of IL-22Rα. This study investigated IL-22Rα expression and IL-22-mediated proliferation and pro-inflammatory cytokine production by UVB-irradiated keratinocytes. IL-22Rα was increased in HaCaT and primary human keratinocytes after UVB irradiation through the translocation of IL-22Rα from the cytosol to the membrane. This increase in the expression of IL-22Rα was mediated by the PI3K/Akt pathway. Moreover, the suppression of keratinocyte proliferation by UVB irradiation was inhibited by treatment with IL-22. At the same time, IL-22 increased the production of IL-1α, IL-6, and IL-18 in UVB-irradiated HaCaT cells and primary human keratinocytes. Finally, IL-22Rα expression was increased in UVB-irradiated human and mouse skin by immunohistochemistry. The increased expression of IL-22Rα therefore promotes keratinocyte proliferation and pro-inflammatory cytokine production during UVB-induced skin inflammation, suggesting that UVB facilitates skin inflammation by increasing the responsiveness of keratinocytes to IL-22. This study provides a new insight into UVB-induced skin inflammation and the regulation of related inflammatory skin diseases.
A promoter-proximal transcript targeted by genetic polymorphism controls E-cadherin silencing in human cancers
May 30, 2017   Nature Communications
Pisignano G, Napoli S, Magistri M, Mapelli SN, Pastori C,   . . . . . .   , Chiorino G, Garcia-Escudero R, Varani G, Carbone GM, Catapano CV
A promoter-proximal transcript targeted by genetic polymorphism controls E-cadherin silencing in human cancers
May 30, 2017
Nature Communications
Long noncoding RNAs are emerging players in the epigenetic machinery with key roles in development and diseases. Here we uncover a complex network comprising a promoter-associated noncoding RNA (paRNA), microRNA and epigenetic regulators that controls transcription of the tumour suppressor E-cadherin in epithelial cancers. E-cadherin silencing relies on the formation of a complex between the paRNA and microRNA-guided Argonaute 1 that, together, recruit SUV39H1 and induce repressive chromatin modifications in the gene promoter. A single nucleotide polymorphism (rs16260) linked to increased cancer risk alters the secondary structure of the paRNA, with the risk allele facilitating the assembly of the microRNA-guided Argonaute 1 complex and gene silencing. Collectively, these data demonstrate the role of a paRNA in E-cadherin regulation and the impact of a noncoding genetic variant on its function. Deregulation of paRNA-based epigenetic networks may contribute to cancer and other diseases making them promising targets for drug discovery.
Purification and characterization of a bioactive alpha-fetoprotein produced by HEK-293 cells
May 30, 2017   Protein Expression And Purification
Lin B, Peng G, Feng H, Li W, Dong X, Chen Y, Lu Y, Wang Q, Xie X, Zhu M, Li M
Purification and characterization of a bioactive alpha-fetoprotein produced by HEK-293 cells
May 30, 2017
Protein Expression And Purification
Alpha-fetoprotein (AFP) is a biomarker that is used to diagnose hepatocellular carcinoma (HCC) and can promote malignancy in HCC. AFP is an important target in the treatment of liver cancer. To obtain enough AFP to screen for AFP inhibitors, we expressed and purified AFP in HEK-293 cells. In the present study, we produced AFP in the cells and harvested highly pure rAFP (or recombinant expression AFP in HEK-293 cells). We also analysed the bioactivity of rAFP and found that rAFP promoted growth of the human HCC cells, antagonize paclitaxel inhibition of HCC cell proliferation, suppress expression of active caspase-3, and promote expression of Ras and survivin. This study provides a method to produce significant amounts of AFP for use in biochemical assays and functional studies and to screen AFP inhibitors for use in HCC therapy. Copyright © 2017 Elsevier Inc. All rights reserved.
Long Non-coding RNA UCA1 Targets miR-122 to Promote Proliferation, Migration, and Invasion of Glioma Cells
May 26, 2017   Oncology Research
Sun Y, Jin JG, Mi WY, Wu H, Zhang SR, Meng Q, Zhang ST
Long Non-coding RNA UCA1 Targets miR-122 to Promote Proliferation, Migration, and Invasion of Glioma Cells
May 26, 2017
Oncology Research
Glioma is the most common and lethal intracranial malignant tumor. Long non-coding RNAs (lncRNAs) have been identifiedas pivotal regulators in the tumorigenesis of glioma. However, the role of lncRNA urothelial carcinoma-associated 1 (UCA1) in the gliomagenesis is still unknown. The purpose of this study is to investigate the underlying function of UCA1 on glioma genesis. Results demonstrated that UCA1 was up-regulated in glioma tissue and indicated the poor prognosis. UCA1 knockdown induced by si-UCA1 significantly suppressed the proliferative, migrative and invasive activity of glioma cell lines (U87 and U251). Bioinformatics analysis and luciferase reporter assay verified the complementary binding within UCA1 and miR-122 at 3'-UTR. Functional experiments revealed that UCA1 acted as miR-122 'sponge' to modulate glioma cell proliferation, migration and invasion via downregulating miR-122. Overall, the present study demonstrated that lncRNA UCA1 acts as endogenous sponge of miR-122 to promote glioma cells proliferation, migration and invasion, which provides a novel insight and therapeutic targets for the tumorigenesis of glioma.
Proteomics investigation of OSCC-specific salivary biomarkers in a Hungarian population highlights the importance of identification of population-tailored biomarkers
May 25, 2017   PloS One
Csősz É, Lábiscsák P, Kalló G, Márkus B, Emri M, Szabó A, Tar I, Tőzsér J, Kiss C, Márton I
Proteomics investigation of OSCC-specific salivary biomarkers in a Hungarian population highlights the importance of identification of population-tailored biomarkers
May 25, 2017
PloS One
Oral squamous cell carcinoma (OSCC) accounting for about 90% of malignant oral lesions is the 6th most common malignancy worldwide. Diagnostic delay may contribute to dismal survival rate therefore, there is a need for developing specific and sensitive biomarkers to improve early detection. Hungarian population occupies the top places of statistics regarding OSCC incidence and mortality figures therefore, we aimed at finding potential salivary protein biomarkers suitable for the Hungarian population. In this study we investigated 14 proteins which were previously reported as significantly elevated in saliva of patients with OSCC. In case of IL-1α, IL-1β, IL-6, IL-8, TNF-α and VEGF a Luminex-based multiplex kit was utilized and the salivary concentrations were determined. In case of catalase, profilin-1, S100A9, CD59, galectin-3-bindig protein, CD44, thioredoxin and keratin-19, SRM-based targeted proteomic method was developed and the relative amount of the proteins was determined in the saliva of patients with OSCC and controls. After several rounds of optimization and using stable isotope-containing peptides, we developed an SRM-based method for rapid salivary protein detection. The validation of the selected potential biomarkers by ELISA revealed salivary protein S100A9 and IL-6 as useful protein biomarkers for OSCC detection improving the diagnostic accuracy for OSCC in the Hungarian population.A noninvasive diagnostic method to detect biomarkers useful for the early diagnosis of OSCC was developed. This can be an attractive strategy in screening saliva samples collected in a nation-wide multi-centric study in order to decrease morbidity, mortality, to enhance survival rate and to improve quality of life. The heterogeneity of protein biomarkers found in different ethnic groups presented in the literature highlights the importance of identification of population-tailored protein biomarkers.
Predictive factors of right paraesophageal lymph node metastasis in papillary thyroid carcinoma: Single center experience and meta-analysis
May 25, 2017   PloS One
Park YM, Lee SM, Kim DW, Shin SC, Lee BJ
Predictive factors of right paraesophageal lymph node metastasis in papillary thyroid carcinoma: Single center experience and meta-analysis
May 25, 2017
PloS One
We performed this retrospective study to identify predictors of right paraesophageal lymph node metastasis, and reviewed previous studies related to this topic. Between June 2005 and March 2015, 1107 patients were diagnosed with papillary thyroid carcinoma and underwent surgery at Pusan National University Hospital. Right paraesophageal lymph node metastasis was observed in 171 (15.4%) patients. Multivariate analyses showed that the risk of right paraesophageal metastasis was significantly associated with tumor size, location, a higher number of metastatic central lymph nodes, and lateral lymph node metastasis. In a meta-analysis of the eligible studies, tumor size, number of metastatic central lymph nodes, and lateral lymph node metastasis showed significant relationships with the risk of right paraesophageal metastasis. In patients with risk factors such as those identified in our study, the possibility of right paraesophageal metastasis should be kept in mind, and careful inspection and dissection are required.
SiGNet: A signaling network data simulator to enable signaling network inference
May 25, 2017   PloS One
Coker EA, Mitsopoulos C, Workman P, Al-Lazikani B
SiGNet: A signaling network data simulator to enable signaling network inference
May 25, 2017
PloS One
Network models are widely used to describe complex signaling systems. Cellular wiring varies in different cellular contexts and numerous inference techniques have been developed to infer the structure of a network from experimental data of the network's behavior. To objectively identify which inference strategy is best suited to a specific network, a gold standard network and dataset are required. However, suitable datasets for benchmarking are difficult to find. Numerous tools exist that can simulate data for transcriptional networks, but these are of limited use for the study of signaling networks. Here, we describe SiGNet (Signal Generator for Networks): a Cytoscape app that simulates experimental data for a signaling network of known structure. SiGNet has been developed and tested against published experimental data, incorporating information on network architecture, and the directionality and strength of interactions to create biological data in silico. SiGNet is the first tool to simulate biological signaling data, enabling an accurate and systematic assessment of inference strategies. SiGNet can also be used to produce preliminary models of key biological pathways following perturbation.
Effects of histatin-1 peptide on human corneal epithelial cells
May 25, 2017   PloS One
Shah D, Ali M, Shukla D, Jain S, Aakalu VK
Effects of histatin-1 peptide on human corneal epithelial cells
May 25, 2017
PloS One
Ocular surface and corneal epithelial wounds are common and potentially debilitating problems. Ideal treatments for these injuries would promote epithelial healing without inflammation, infection and scarring. In addition the best treatments would be cost-efficient, effective, non-toxic and easily applied. Histatin-1 peptides have been shown to be safe and effective enhancers of epithelial wound healing in other model systems. We sought to determine whether histatin-1 peptides could enhance human corneal epithelial wound healing in vitro. Histatin-1 peptides were applied to human corneal epithelial cells and compared over useful dose ranges in scratch assays using time-lapse microscopy. In addition, path finding analysis, cell spreading assays, toxicity and proliferation assays were performed to further characterize the effects of histatin-1 peptide on human corneal limbal epithelial (HCLE). Histatin-1 enhanced human corneal epithelial wound healing in typical wound healing models. There was minimal toxicity and no significant enhancement of proliferation of corneal epithelium in response to histatin-1 application. Corneal epithelial spreading and pathfinding appeared to be enhanced by the application of histatin-1 peptides. Histatin -1 peptide may enhance migration of HCLE cells and wound healing in vitro. These peptides may have benefit in corneal epithelial wounds and need to be investigated further.
Polymorphism of TLR5 rs5744174 is associated with disease progression in Chinese patients with chronic HBV infection
May 25, 2017   APMIS : Acta Pathologica, Microbiologica, Et Immunologica Scandinavica
Cao L, Zhang T, Zhu J, Li A, Zheng K, Zhang N, Su B, Xia W, Wu H, Li N, He Q
Polymorphism of TLR5 rs5744174 is associated with disease progression in Chinese patients with chronic HBV infection
May 25, 2017
APMIS : Acta Pathologica, Microbiologica, Et Immunologica Scandinavica
Toll-like receptors (TLRs) play a crucial role in innate and adaptive immunity, protecting the host from viral pathogens. Studies have implicated that TLR5 is associated with various diseases such as autoimmune and inflammation related diseases. However, little is known about the relationship between TLR5 and hepatitis B virus (HBV) infection. We studied the effect of TLR5 gene polymorphisms on susceptibility to and disease progression of chronic hepatitis B (CHB) infection in Chinese. Blood samples were taken from 636 patients with CHB, HBV-related liver cirrhosis (LC) or hepatocellular carcinoma (HCC) and 273 controls. Polymorphisms of TLR5 (1775A>G rs2072493 and 1846T>C rs5744174) were analyzed by PCR-based sequencing. No difference in genotypic and allelic frequencies of TLR5 rs2072493 and rs5744174 was observed between patients and controls. Significant difference was found in frequency of TLR5 rs5744174 TT genotype between men with CHB and LC (p = 0.035). Frequency of TT genotype of TLR5 rs5744174 in patients positive for HBeAg was increased from 53.2% in patients with CHB to 74.1% in those with HCC (p = 0.024). Our results indicate that in Chinese genetic variation of TLR5 may be not a determinant of susceptibility to HBV-related diseases but may play a role in development of HBV-related severe liver diseases. © 2017 APMIS. Published by John Wiley & Sons Ltd.
Evaluation of connectivity map-discovered celastrol as a radiosensitizing agent in a murine lung carcinoma model: Feasibility study of diffusion-weighted magnetic resonance imaging
May 25, 2017   PloS One
Jun HY, Kim TH, Choi JW, Lee YH, Lee KK, Yoon KH
Evaluation of connectivity map-discovered celastrol as a radiosensitizing agent in a murine lung carcinoma model: Feasibility study of diffusion-weighted magnetic resonance imaging
May 25, 2017
PloS One
This study was designed to identify potential radiosensitizing (RS) agents for combined radio- and chemotherapy in a murine model of human lung carcinoma, and to evaluate the in vivo effect of the RS agents using diffusion-weighted magnetic resonance imaging (DW-MRI). Radioresistance-associated genes in A549 and H460 cells were isolated on the basis of their gene expression profiles. Celastrol was selected as a candidate RS by using connectivity mapping, and its efficacy in lung cancer radiotherapy was tested. Mice inoculated with A549 carcinoma cells were treated with single ionizing radiation (SIR), single celastrol (SC), or celastrol-combined ionizing radiation (CCIR). Changes in radiosensitization over time were assessed using DW-MRI before and at 3, 6, and 12 days after therapy initiation. The tumors were stained with hematoxylin and eosin at 6 and 12 days after therapy. The percentage change in the apparent diffusion coefficient (ADC) value in the CCIR group was significantly higher than that in the SC and SIR group on the 12th day (Mann-Whitney U-test, p = 0.05; Kruskal-Wallis test, p < 0.05). A significant correlation (Spearman's rho correlation coefficient of 0.713, p = 0.001) was observed between the mean percentage tumor necrotic area and the mean ADC values after therapy initiation. These results suggest that the novel radiosensitizing agent celastrol has therapeutic effects when combined with ionizing radiation (IR), thereby maximizing the therapeutic effect of radiation in non-small cell lung carcinoma. In addition, DW-MRI is a useful noninvasive tool to monitor the effects of RS agents by assessing cellularity changes and sequential therapeutic responses.
Impaired functional capacity of fetal endothelial cells in preeclampsia
May 25, 2017   PloS One
Brodowski L, Burlakov J, Hass S, von Kaisenberg C, von Versen-Höynck F
Impaired functional capacity of fetal endothelial cells in preeclampsia
May 25, 2017
PloS One
Preeclampsia is one of the main contributers to maternal and fetal morbidity and mortality during pregnancy. A history of preeclampsia puts mother and offspring at an increased cardiovascular risk in later life. We hypothesized that at the time of birth functional impairments of fetal endothelial cells can be detected in pregnancies complicated by preeclampsia and that a therapeutic intervention using 1,25 (OH)2 vitamin D3 can reverse the adverse effects of preeclampsia on cell function. Human umbilical vein endothelial cells (HUVEC) were isolated from umbilical cords obtained from preeclamptic (N = 12) and uncomplicated pregnancies (N = 13, control). Placental villous tissue fragments from uncomplicated term pregnancies were incubated in explant culture for 48 h at 2% (hypoxia), 8% or 21% O2. Explant conditioned media (CM) was collected and pooled according to oxygen level. We compared the ability of preeclampsia vs. control HUVEC to migrate, proliferate, and form tubule-like networks in a Matrigel assay, in the presence/absence of CM and 1,25(OH)2 vitamin D3. HUVEC from preeclamptic pregnancies showed reduced migration (P = 0.04) and tubule formation (P = 0.04), but no change in proliferation (P = 0.16) compared to healthy pregnancies. Placental villous explant CM derived from 2% O2 incubations significantly reduced HUVEC migration, when compared to non-CM (P = 0.04). Vitamin D3 improved HUVEC function in neither of the groups. There was no significant difference in VEGF gene expression between healthy and preeclamptic pregnancies and no effect of Vitamin D3 on VEGF expression. Reduced functional abilities of fetal endothelial cells from preeclamptic pregnancies suggests that disease pathways, possibly originating from the dysfunctional placenta, negatively impact fetal endothelium. The neutral effect of 1,25(OH)2 vitamin D3 contrasts with previous findings that vitamin D rescues the poor migration, proliferation and tubule formation exhibited by cord blood fetal endothelial progenitor cells from preeclamptic pregnancies. Further investigations to distinguish pathways by which offspring exposed to preeclampsia are at risk for cardiovascular disease are needed.
Fluvastatin inhibits AGE-induced cell proliferation and migration via an ERK5-dependent Nrf2 pathway in vascular smooth muscle cells
May 25, 2017   PloS One
Hwang AR, Han JH, Lim JH, Kang YJ, Woo CH
Fluvastatin inhibits AGE-induced cell proliferation and migration via an ERK5-dependent Nrf2 pathway in vascular smooth muscle cells
May 25, 2017
PloS One
Advanced glycation endproduct (AGE)-induced vascular smooth muscle cell (VSMC) proliferation and reactive oxygen species (ROS) production are emerging as important mechanisms of diabetic vasculopathy, but little is known about the molecular mechanism responsible for the antioxidative effects of statins on AGEs. It has been reported that statins exert pleiotropic effects on the cardiovascular system due to decreases in AGE-induced cell proliferation, migration, and vascular inflammation. Thus, in the present study, the authors investigated the molecular mechanism by which statins decrease AGE-induced cell proliferation and VSMC migration. In cultured VSMCs, statins upregulated Nrf2-related antioxidant gene, NQO1 and HO-1, via an ERK5-dependent Nrf2 pathway. Inhibition of ERK5 by siRNA or BIX02189 (a specific ERK5 inhibitor) reduced the statin-induced upregulations of Nrf2, NQO1, and HO-1. Furthermore, fluvastatin was found to significantly increase ARE promoter activity through ERK5 signaling, and to inhibit AGE-induced VSMC proliferation and migration as determined by MTT assay, cell counting, FACS analysis, a wound scratch assay, and a migration chamber assay. In addition, AGE-induced proliferation was diminished in the presence of Ad-CA-MEK5α encoding a constitutively active mutant form of MEK5α (an upstream kinase of ERK5), whereas depletion of Nrf2 restored statin-mediated reduction of AGE-induced cell proliferation. Moreover, fluvastatin suppressed the protein expressions of cyclin D1 and Cdk4, but induced p27, and blocked VSMC proliferation by regulating cell cycle. These results suggest statin-induced activation of an ERK5-dependent Nrf2 pathway reduces VSMC proliferation and migration induced by AGEs, and that the ERK5-Nrf2 signal module be viewed as a potential therapeutic target of vasculopathy in patients with diabetes and complications of the disease.
Robustness analysis of the detailed kinetic model of an ErbB signaling network by using dynamic sensitivity
May 25, 2017   PloS One
Masunaga H, Sugimoto Y, Magi S, Itasaki R, Okada-Hatakeyama M, Kurata H
Robustness analysis of the detailed kinetic model of an ErbB signaling network by using dynamic sensitivity
May 25, 2017
PloS One
The ErbB receptor signaling pathway plays an important role in the regulation of cellular proliferation, survival and differentiation, and dysregulation of the pathway is linked to various types of human cancer. Mathematical models have been developed as a practical complementary approach to deciphering the complexity of ErbB receptor signaling and elucidating how the pathways discriminate between ligands to induce different cell fates. In this study, we developed a simulator to accurately calculate the dynamic sensitivity of extracellular-signal-regulated kinase (ERK) activity (ERK*) and Akt activity (Akt*), downstream of the ErbB receptors stimulated with epidermal growth factor (EGF) and heregulin (HRG). To demonstrate the feasibility of this simulator, we estimated how the reactions critically responsible for ERK* and Akt* change with time and in response to different doses of EGF and HRG, and predicted that only a small number of reactions determine ERK* and Akt*. ERK* increased steeply with increasing HRG dose until saturation, while showing a gently rising response to EGF. Akt* had a gradual wide-range response to HRG and a blunt response to EGF. Akt* was sensitive to perturbations of intracellular kinetics, while ERK* was more robust due to multiple, negative feedback loops. Overall, the simulator predicted reactions that were critically responsible for ERK* and Akt* in response to the dose of EGF and HRG, illustrated the response characteristics of ERK* and Akt*, and estimated mechanisms for generating robustness in the ErbB signaling network.
A mutation in porcine pre-miR-15b alters the biogenesis of MiR-15b\16-1 cluster and strand selection of MiR-15b
May 25, 2017   PloS One
Sun W, Lan J, Chen L, Qiu J, Luo Z, Li M, Wang J, Zhao J, Zhang T, Long X, Chai J, Yan Z, Guo Z, Gun S
A mutation in porcine pre-miR-15b alters the biogenesis of MiR-15b\16-1 cluster and strand selection of MiR-15b
May 25, 2017
PloS One
MicroRNAs (miRNAs) are small non-coding RNAs that are involved in translational regulation of the messenger RNA molecules. Sequence variations in the genes encoding miRNAs could influence their biogenesis and function. MiR-15b plays an important role in cellular proliferation, apoptosis and the cell cycle. Here, we report the identification of a C58T mutation in porcine pre-miR-15b. Through in vitro and in vivo experiments, we determined that this mutation blocks the transition from pri-miRNA to pre-miRNA, alters the strand selection between miR-15b-5p and miR-15b-3p, and obstructs biogenesis of the downstream miR-16-1. These results serve to highlight the importance of miRNA mutations and their impacts on miRNA biogenesis.
A Rho-associated coiled-coil containing kinases (ROCK) inhibitor, Y-27632, enhances adhesion, viability and differentiation of human term placenta-derived trophoblasts in vitro
May 25, 2017   PloS One
Motomura K, Okada N, Morita H, Hara M, Tamari M, Orimo K, Matsuda G, Imadome KI, Matsuda A, Nagamatsu T, Fujieda M, Sago H, Saito H, Matsumoto K
A Rho-associated coiled-coil containing kinases (ROCK) inhibitor, Y-27632, enhances adhesion, viability and differentiation of human term placenta-derived trophoblasts in vitro
May 25, 2017
PloS One
Although human term placenta-derived primary cytotrophoblasts (pCTBs) represent a good human syncytiotrophoblast (STB) model, in vitro culture of pCTBs is not always easily accomplished. Y-27632, a specific inhibitor of Rho-associated coiled-coil containing kinases (ROCK), reportedly prevented apoptosis and improved cell-to-substrate adhesion and culture stability of dissociated cultured human embryonic stem cells and human corneal endothelial cells. The Rho kinase pathway regulates various kinds of cell behavior, some of which are involved in pCTB adhesion and differentiation. In this study, we examined Y-27632's potential for enhancing pCTB adhesion, viability and differentiation. pCTBs were isolated from term, uncomplicated placentas by trypsin-DNase I-Dispase II treatment and purified by HLA class I-positive cell depletion. Purified pCTBs were cultured on uncoated plates in the presence of epidermal growth factor (10 ng/ml) and various concentrations of Y-27632. pCTB adhesion to the plates was evaluated by phase-contrast imaging, viability was measured by WST-8 assay, and differentiation was evaluated by immunofluorescence staining, expression of fusogenic genes and hCG-β production. Ras-related C3 botulinum toxin substrate 1 (Rac1; one of the effector proteins of the Rho family) and protein kinase A (PKA) involvement was evaluated by using their specific inhibitors, NSC-23766 and H-89. We found that Y-27632 treatment significantly enhanced pCTB adhesion to plates, viability, cell-to-cell fusion and hCG-β production, but showed no effects on pCTB proliferation or apoptosis. Furthermore, NSC-23766 and H-89 each blocked the effects of Y-27632, suggesting that Y-27632 significantly enhanced pCTB differentiation via Rac1 and PKA activation. Our findings suggest that Rac1 and PKA may be interactively involved in CTB differentiation, and addition of Y-27632 to cultures may be an effective method for creating a stable culture model for studying CTB and STB biology in vitro.
Simulating within-vector generation of the malaria parasite diversity
May 25, 2017   PloS One
Childs LM, Prosper OF
Simulating within-vector generation of the malaria parasite diversity
May 25, 2017
PloS One
Plasmodium falciparum, the most virulent human malaria parasite, undergoes asexual reproduction within the human host, but reproduces sexually within its vector host, the Anopheles mosquito. Consequently, the mosquito stage of the parasite life cycle provides an opportunity to create genetically novel parasites in multiply-infected mosquitoes, potentially increasing parasite population diversity. Despite the important implications for disease transmission and malaria control, a quantitative mapping of how parasite diversity entering a mosquito relates to diversity of the parasite exiting, has not been undertaken. To examine the role that vector biology plays in modulating parasite diversity, we develop a two-part model framework that estimates the diversity as a consequence of different bottlenecks and expansion events occurring during the vector-stage of the parasite life cycle. For the underlying framework, we develop the first stochastic model of within-vector P. falciparum parasite dynamics and go on to simulate the dynamics of two parasite subpopulations, emulating multiply infected mosquitoes. We show that incorporating stochasticity is essential to capture the extensive variation in parasite dynamics, particularly in the presence of multiple parasites. In particular, unlike deterministic models, which always predict the most fit parasites to produce the most sporozoites, we find that occasionally only parasites with lower fitness survive to the sporozoite stage. This has important implications for onward transmission. The second part of our framework includes a model of sequence diversity generation resulting from recombination and reassortment between parasites within a mosquito. Our two-part model framework shows that bottlenecks entering the oocyst stage decrease parasite diversity from what is present in the initial gametocyte population in a mosquito's blood meal. However, diversity increases with the possibility for recombination and proliferation in the formation of sporozoites. Furthermore, when we begin with two parasite subpopulations in the initial gametocyte population, the probability of transmitting more than two unique parasites from mosquito to human is over 50% for a wide range of initial gametocyte densities.
Effect of hyperbaric oxygen on BDNF-release and neuroprotection: Investigations with human mesenchymal stem cells and genetically modified NIH3T3 fibroblasts as putative cell therapeutics
May 25, 2017   PloS One
Schulze J, Kaiser O, Paasche G, Lamm H, Pich A, Hoffmann A, Lenarz T, Warnecke A
Effect of hyperbaric oxygen on BDNF-release and neuroprotection: Investigations with human mesenchymal stem cells and genetically modified NIH3T3 fibroblasts as putative cell therapeutics
May 25, 2017
PloS One
Hyperbaric oxygen therapy (HBOT) is a noninvasive widely applied treatment that increases the oxygen pressure in tissues. In cochlear implant (CI) research, intracochlear application of neurotrophic factors (NTFs) is able to improve survival of spiral ganglion neurons (SGN) after deafness. Cell-based delivery of NTFs such as brain-derived neurotrophic factor (BDNF) may be realized by cell-coating of the surface of the CI electrode. Human mesenchymal stem cells (MSC) secrete a variety of different neurotrophic factors and may be used for the development of a biohybrid electrode in order to release endogenously-derived neuroprotective factors for the protection of residual SGN and for a guided outgrowth of dendrites in the direction of the CI electrode. HBOT could be used to influence cell behaviour after transplantation to the inner ear. The aim of this study was to investigate the effect of HBOT on the proliferation, BDNF-release and secretion of neuroprotective factors. Thus, model cells (an immortalized fibroblast cell line (NIH3T3)-native and genetically modified) and MSCs were repeatedly (3 x - 10 x) exposed to 100% oxygen at different pressures. The effects of HBO on cell proliferation were investigated in relation to normoxic and normobaric conditions (NOR). Moreover, the neuroprotective and neuroregenerative effects of HBO-treated cells were analysed by cultivation of SGN in conditioned medium. Both, the genetically modified NIH3T3/BDNF and native NIH3T3 fibroblasts, showed a highly significant increased proliferation after five days of HBOT in comparison to normoxic controls. By contrast, the number of MSCs was decreased in MSCs treated with 2.0 bar of HBO. Treating SGN cultures with supernatants of fibroblasts and MSCs significantly increased the survival rate of SGN. HBO treatment did not influence (increase / reduce) this effect. Secretome analysis showed that HBO treatment altered the protein expression pattern in MSCs.
Angelica Dahurica ethanolic extract improves impaired wound healing by activating angiogenesis in diabetes
May 25, 2017   PloS One
Zhang XN, Ma ZJ, Wang Y, Sun B, Guo X, Pan CQ, Chen LM
Angelica Dahurica ethanolic extract improves impaired wound healing by activating angiogenesis in diabetes
May 25, 2017
PloS One
Abnormal angiogenesis plays an important role in impaired wound healing and development of chronic wounds in diabetes mellitus. Angelica dahurica radix is a common traditional Chinese medicine with wide spectrum medicinal effects. In this study, we analyzed the potential roles of Angelica dahurica ethanolic extract (ADEE) in correcting impaired angiogenesis and delayed wound healing in diabetes by using streptozotocin-induced diabetic rats. ADEE treatment accelerated diabetic wound healing through inducing angiogenesis and granulation tissue formation. The angiogenic property of ADEE was subsequently verified ex vivo using aortic ring assays. Furthermore, we investigated the in vitro angiogenic activity of ADEE and its underlying mechanisms using human umbilical vein endothelial cells. ADEE treatment induced HUVECs proliferation, migration, and tube formation, which are typical phenomena of angiogenesis, in dose-dependent manners. These effects were associated with activation of angiogenic signal modulators, including extracellular signal-regulated kinase 1/2 (ERK1/2), Akt, endothelial nitric oxide synthase (eNOS) as well as increased NO production, and independent of affecting VEGF expression. ADEE-induced angiogenic events were inhibited by the MEK inhibitor PD98059, the PI3K inhibitor Wortmannin, and the eNOS inhibitor L-NAME. Our findings highlight an angiogenic role of ADEE and its ability to protect against impaired wound healing, which may be developed as a promising therapy for impaired angiogenesis and delayed wound healing in diabetes.
Diagnostic accuracy of gadoxetic acid-enhanced MR for small hypervascular hepatocellular carcinoma and the concordance rate of Liver Imaging Reporting and Data System (LI-RADS)
May 30, 2017   PloS One
Bae JS, Kim JH, Yu MH, Lee DH, Kim HC, Chung JW, Han JK
Diagnostic accuracy of gadoxetic acid-enhanced MR for small hypervascular hepatocellular carcinoma and the concordance rate of Liver Imaging Reporting and Data System (LI-RADS)
May 30, 2017
PloS One
To assess diagnostic accuracy of gadoxetic acid-enhanced MR for small hypervascular hepatocellular carcinoma (HCC) detected by C-arm CT and concordance rate of Liver Imaging Reporting and Data System (LI-RADS). In this retrospective study, we recruited 4,544 patients suspected of having HCC underwent C-arm CT from November 2008 to May 2013. Among these patients, gadoxetic acid-enhanced MR was performed in 167 patients with HCC (n = 379; 257 > 1 cm, 122 ≤ 1 cm). HCC was confirmed by MR, CT, or follow-up images. Two radiologists graded likelihood of HCC and assessed MR features. Jackknife alternative free-response receiver operating characteristic (JAFROC) analysis was performed. All HCCs were evaluated concordance rate of LI-RADS. Mean JAFROC figure of merit for large (>1-cm) HCC was 0.948, while that for small HCC was 0.787 with fair agreement (κ = 0.409). Mean sensitivity and positive predictive value (PPV) were 91% and 90% for large HCC versus 63.0% and 79% for small HCC, respectively. Seventeen of 122 small HCCs (13.9%) were not visible on MR. Among 379 HCCs, 99 met LR-5, and 259 met LR-4. Common features for small HCC included arterial enhancement (81.9%), hepatobiliary phase hypointensity (80.3%), and delayed washout (72.9%). Diagnostic accuracy of gadoxetic acid-enhanced MR imaging for small, hypervascular HCCs (Mean figure of merit = 0.787) was still low compared with large HCC (Mean figure of merit = 0.948). LR-5 and LR-4 covered 94% (358/379) of the HCCs.

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