bluuebunny/crossref_metadata_2025 huggingface dataset:
Norcantharidin Inhibits Lymphangiogenesis by Downregulating the Expression of VEGF-C and VEGF-D in Human Dermal Lymphatic Endothelial Cells in vitro
Authors: Yuan Xiaojian , Chen Yi , Li Xianming , Zhang Gongnian , Jin Donghui , Zhao Hengfei , Su Zhiwei , Fan Yuezu
Published: January 2015

Aims: To investigate the effects of norcantharidin on the growth and migration of human dermal lymphatic endothelial cells (HDLECs) and further characterize its effect on lymphangiogenesis. Methods: A 3-dimensional fibrin gel lymphangiogenesis model was built. Flow cytometry was used to analyze the rate of apoptosis and necrosis. RT-PCR, immunohistochemistry and immunoblotting assays were used to examine the effect of norcantharidin on vascular endothelial growth factor C (VEGF-C), VEGF-D and VEGF receptor 3 during in vitro lymphangiogenesis. Results: Norcantharidin caused a marked dose and time-dependent inhibition of the growth of HDLECs with an IC50 of 40 nmol/l. The apoptotic rate of HDLECs was 13.21 ± 1.60% 24 h after treatment with 7.5 nmol/l norcantharidin and 42.34 ± 3.80% with 90 nmol/l norcantharidin (p < 0.01 vs. controls in both). Fibrin gel assays showed that norcantharidin (15 nmol/l) reduced the number of tubular structures from 68.4 ± 5.2 in untreated controls to 10.9 ± 2.3 (p = 0.000). RT-PCR, immunohistochemistry and immunoblotting assays showed norcantharidin markedly reduced the expression of VEGF-C and VEGF-D. Conclusion: Norcantharidin inhibits lymphangiogenesis by downregulating the expression of VEGF-C and VEGF-D, suggesting that norcantharidin could be an effective agent for targeting neolymphangiogenesis.
XAGE-1b Cancer/Testis Antigen Is a Potential Target for Immunotherapy in Prostate Cancer
Authors: Xie Chong , Wang Guomin
Published: January 2015

Introduction: Gene-modified cell vaccines are now considered to be the best way to achieve immunotherapy for a variety of cancers including prostate cancer (PCa). XAGE-1b is a member of the cancer/testis antigen family which has demonstrated strong immunogenicity. We investigated whether XAGE-1b is an ideal target for PCa immunotherapy. Materials and Methods: The recombinant eukaryotic expression vector pDisplay-XAGE-1b was constructed. Then the recombinant vector was transfected into Myc-CaP cells and its immunogenicity in vitro was studied. After transfection, the Myc-CaP-XAGE-1b cells were injected into FVB mice subcutaneously. Tumor growth was periodically observed and the anti-tumor effect and mechanism in vivo were further studied. Results: The recombinant vector was correctly constructed by DNA sequencing and restriction endonuclease digestion. Myc-CaP cells were successfully transfected with XAGE-1b gene by immunofluorescence staining and Western blot. The transfected cells exhibited increased IFN-γ secretion, decreased IL-6 secretion and enhanced killing activity. Tumor grew slower in XAGE-1b-modified FVB mice than in wild-type FVB mice. High dendritic cell expression and low myeloid-derived suppressor cell expression were observed in tumor tissues expressed with XAGE-1b. Conclusions: XAGE-1b gene transfection could significantly enhance the immunogenicity of Myc-CaP cells. Therefore, XAGE-1b may be an attractive target for antigen-specific immunotherapy in PCa.
Expression and Functional Activity of the Bitter Taste Receptors TAS2R1 and TAS2R38 in Human Keratinocytes
Authors: Wölfle Ute , Elsholz Floriana A. , Kersten Astrid , Haarhaus Birgit , Müller Walter E. , Schempp Christoph M.
Published: January 2015

Recent studies have shown that human bitter taste receptors (TAS2Rs) are not only expressed in mucous epithelial cells of the tongue, but also in epithelial cells of the colon, stomach and upper respiratory tract. These cell types come in close contact with external bitter compounds by ingestion or breathing. In the present work we addressed the question whether bitter taste receptors might also be expressed in cornified epithelial cells of the skin. Here, we show for the first time the expression of TAS2R1 and TAS2R38 in human skin. Double staining of HaCaT cells and primary keratinocytes demonstrated the colocalization of TAS2R1 and TAS2R38 with the adaptor protein α-gustducin that is essential for signal transduction upon ligand binding. To test if TAS2Rs in keratinocytes are functional, we stimulated HaCaT cells with diphenidol, a clinically used bitter-tasting antiemetic, or amarogentin, the bitterest plant substance, that binds TAS2Rs, including TAS2R1 and TAS2R38. Diphenidol and amarogentin induced calcium influx. Furthermore, in keratinocytes diphenidol and amarogentin stimulated the expression of the differentiation markers keratin 10, involucrin and transglutaminase. Therefore, apart from the known role in mucous membranes of the gastrointestinal tract, TAS2Rs are expressed in the epidermis and might play a role in keratinocyte differentiation.
Local Breast Cancer Recurrence after Mastectomy and Breast-Conserving Surgery for Paget's Disease: A Meta-Analysis
Authors: Li Yu-Jie , Huang Xiao-E , Zhou Xiao-Dong
Published: January 2015

Background: Paget's disease (PD) of the breast is a rare presentation of breast malignancy. Mastectomy has been considered the standard of care, but several studies have shown that breast-conserving surgery (BCS) with radiotherapy is an alternative option. According to the literature, the total recurrence rate is as high as 20-40%. In an effort to enable a rational therapy decision, we compiled and analyzed the available data on PD. Methods: Pubmed, Web of Knowledge, and China Journal Net were searched for studies concerning treatment for PD between 1990 and 2013. A meta-analysis was performed to compare the effect of different treatments. Results: 7 studies with a total of 685 patients were included. The cumulative local recurrence rate was 7.6%, 5.6% among women undergoing mastectomy and 13.2% among those treated with BCS. Compared to the BCS group, mastectomy showed significant differences in terms of local recurrence (odds ratio = 0.38, 95% confidence interval 0.21-0.69; p = 0.001). Conclusion: Since not all currently available diagnostic and therapeutic options (magnetic resonance imaging, radiotherapy, tamoxifen) were systematically used in the studies included in this meta-analysis, it may be presumptuous to suggest that mastectomy is the right choice for all patients with PD in a modern interdisciplinary setting. Rather we can conclude that all efforts should be undertaken to assure local control since BCS is not equivalent to mastectomy in the treatment of PD.
Cognitive and Behavioral Determinants of Psychotic Symptoms in Alzheimer's Disease
Authors: Quaranta Davide , Vita Maria Gabriella , Bizzarro Alessandra , Masullo Carlo , Piccininni Chiara , Gainotti Guido , Marra Camillo
Published: January 2015

Aims: To investigate the relationship between psychotic symptoms and cognitive impairment in Alzheimer's disease (AD). Methods: A total of 108 subjects affected by AD were subdivided into subjects without delusions (ND), subjects with paranoid delusions (PD), subjects with delusional misidentifications (DM), subjects with both DM and PD (DM+PD), subjects with visual hallucinations (v-HALL), and subjects without visual hallucinations (N-HALL). Results: PD and ND subjects performed similarly on neuropsychological tests, while DM patients performed significantly worse than PD and ND patients. v-HALL patients performed worse than N-HALL patients on memory, visuospatial, and executive functions. As for behavioral features, DM and v-HALL subjects reported higher scores on the abnormal motor behavior subscale of the neuropsychiatric inventory (NPI); PD subjects reported higher scores on the disinhibition subscale of the NPI. The severity of PD was predicted by the severity of disinhibition (B = 0.514; p = 0.016) but not by neuropsychological performances. The severity of DM was predicted by age (B = 0.099; p = 0.048) and MMSE (B = -0.233; p = 0.001). The severity of v-HALL was predicted by age (B = 0.052; p = 0.037) and scores on an immediate visual memory task (B = -0.135; p = 0.007). Conclusions: The occurrence of PD may require the relative sparing of cognitive functions and be favored by frontal lobe dysfunction, while DM is associated with the overall level of cognitive impairment. Finally, v-HALL are associated with the impairment of visuospatial abilities.
Epidemiology of Rett Syndrome in Serbia: Prevalence, Incidence and Survival
Authors: Sarajlija Adrijan , Kisic-Tepavcevic Darija , Nikolic Zorana , Savic Pavicevic Dusanka , Obradovic Slobodan , Djuric Milena , Pekmezovic Tatjana
Published: January 2015

Background: Rett syndrome (RTT) is a severe neurodevelopmental disorder that represents the second most common cause of mental retardation in females. However, incidence and prevalence of RTT are scarcely reported. Methods: A retrospective study included all patients with RTT diagnosed between 1981 and 2012 in Serbia. Estimation of incidence and prevalence was calculated on the basis of vital statistics reported by Statistical Office of Republic of Serbia. Results: From 1981 to 2012, RTT has been diagnosed in 102 girls in Serbia. Incidence of RTT in Serbia is estimated at 0.586:10,000 female live births. We estimated the prevalence of RTT in population of females younger than 19 years at 1:8,439. Death occurred in 19 patients (18.63%), with pneumonia as the most common cause. The lethal outcome by the age of 12 years could be expected for 11% of patients. The mean age at diagnosis was 3.5 years and we have confirmed a significant trend towards earlier dianosis during studied period. Conclusions: Rett syndrome incidence in Serbia is in accordance with reports from other countries. Serbian RTT patients have increased risk for early death when compared to patients in more developed countries, most commonly due to pneumonia. There was significant trend towards early diagnosis of RTT in Serbia over recent decades.
The OPN Gene Polymorphism Confers the Susceptibility and Response to Ara-C Based Chemotherapy in Chinese AML Patients
Authors: Zhang Rong , Yang Wei , Li Ying Chun , Zhang Guo Jun , Yao Kun , Hu Rong , Wu Bin
Published: January 2015

Aim: To investigate the possible association between the Osteopontin (OPN) gene polymorphisms and the susceptibility and chemotherapy response of acute myeloid leukemia patients. Methods: A total of 381 patients with de nova AML and 430 healthy controls were enrolled. All patients received Ara-C-based standard induction chemotherapy regimens, and the treatment response was evaluated. Several polymorphisms in the human OPN encoding gene have been identified. The OPN) gene polymorphisms at 3 loci, namely, -156 GG>G, -443 C>T and -66T>G were determined. Results: We identified that the -443C>T polymorphism was the only one which is closely related to AML. Compared with the -443TT carriers, our data showed that the -443CC genotype carriers were significantly related to a higher risk for AML. The -443CC genotype was also more prevalent in poor response groups than in good response group. The -443CC carriers are more likely to have poor response to AML treatment. Cellular assay indicated that the leukemic cell lines receiving the OPN -443C transfection have a significantly lower apoptosis rate to Ara-C treatment compared to cell lines transfected with -443T. Conclusion: The findings of this study suggest OPN-443C>T gene polymorphism may be sued as a molecular for susceptibility and chemotherapy response of AML.
Modulation of FoxO1 Expression by miR-21 to Promote Growth of Pancreatic Ductal Adenocarcinoma
Authors: Song Weifeng , Li Qi , Wang Lei , Wang Liwei
Published: January 2015

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal primary tumors in humans, with undetermined tumorigenesis. Although previous work by us, and by others, has clearly demonstrated an involvement of miR-21 in the growth of PDAC, the underlying mechanism has not been clarified. Methods: Here we analyzed the regulation of FoxO1 by miR-21 in vitro and in vivo, using luciferase-reporter assay and pancreatic intraductal infusion of antisense of miR-21, respectively. Results: We found that overexpression of miR-21 in PDAC cells decreased FoxO1 protein levels, whereas inhibition of miR-21 increased FoxO1 levels. Further, miR-21 bound to FoxO1 mRNA to prevent its translation through its 3'UTR. Moreover, administration of antisense of miR-21 through an intraductal infusion system significantly decreased miR-21 levels and increased FoxO1 levels in implanted PDAC, resulting in a significant decrease in PDAC growth. Conclusion: Taken together, our data highlight miR-21/FoxO1 axis as a novel therapeutic target for inhibiting the growth of PDAC.
MiR-301a Promotes Colorectal Cancer Cell Growth and Invasion by Directly Targeting SOCS6
Authors: Fang Yantian , Sun Bo , Xiang Jianbin , Chen Zongyou
Published: January 2015

Background/Aims: Colorectal cancer (CRC) is one of the most common malignancies worldwide, and microRNAs play a crucial role in CRC biology. The purpose of this study was to investigate the exact functions and potential mechanisms of action of miR-301a in CRC. Methods: Quantitative real-time PCR was conducted to assess the expression of miR-301a. Cell proliferation was detected using MTT and colony formation assay, and cell invasion and migration were evaluated using Transwell assay. Luciferase reporter assay was used to identify the direct regulation of suppressor of cytokine signaling 6 (SOCS6) by miR-301a. Results: We first confirmed the upregulation of miR-301a in CRC tissues and cell lines. Gain-of-function and loss-of-function studies in the human CRC cell lines, SW480 and SW620, showed that miR-301a acts as an oncogene by increasing cell proliferation, migration and invasion as well as tumor growth. Furthermore, SOCS6 was identified as a target gene of miR-301a. Reintroduction of SOCS6 partially abrogated miR-301a-induced cell proliferation, migration and invasion. Conclusion: These data suggest that miR-301a promotes CRC progression by directly downregulating SOCS6 expression, and miR-301a may represent a novel biomarker for the prevention and treatment of CRC.
Genetic Association of MiR-146a with Multiple Sclerosis Susceptibility in the Chinese Population
Authors: Li You , Du Chen , Wang Wei , Ma Guoda , Cui Lili , Zhou Haihong , Tao Hua , Yao Lifen , Zhao Bin , Li Keshen
Published: January 2015

Background: miR-146a polymorphisms have been involved in susceptibility to multiple diseases. The aim of the present study was to analyze the potential association between two functional miR-146a polymorphisms (rs2910164 and rs57095329) and multiple sclerosis (MS) in the Han Chinese population. Methods: A cohort of 525 patients and 568 healthy controls were genotyped to detect the two polymorphisms by SNaPshot. Results: No significant differences were detected in the distribution of the two miR-146a polymorphisms between the patients and controls (P > 0.05). However, stratification by gender showed a statistically significant difference in the frequency of the genotype rs2910164 between MS patients and control females (P=0.009). Further stratification analysis by subgroup revealed that the miR-146a rs2910164 C allele conferred a higher risk of developing relapsing-remitting MS (RRMS) (P=0.018). In addition, the rs2910164 C allele was significantly associated with increased expression of miR-146a in patients with RRMS (P=0.025). Moreover, patients with the rs2910164 C allele released more TNF-α and IFN-γ, but not IL-1β, compared with individuals carrying the homozygous GG genotype (P < 0.05). Conclusions: Our results provide evidence that rs2910164 may play a role in MS susceptibility in females. The rs2910164 G>C variation may affect the expression of miR-146a and the release of proinflammatory cytokines.
Electrophysiological Characteristics of Embryonic Stem Cell-Derived Cardiomyocytes are Cell Line-Dependent
Authors: Hannes Tobias , Wolff Marie , Doss Michael Xavier , Pfannkuche Kurt , Haustein Moritz , Müller-Ehmsen Jochen , Sachinidis Agapios , Hescheler Jürgen , Khalil Markus , Halbach Marcel
Published: January 2015

Background: Modelling of cardiac development, physiology and pharmacology by differentiation of embryonic stem cells (ESCs) requires comparability of cardiac differentiation between different ESC lines. To investigate whether the outcome of cardiac differentiation is consistent between different ESC lines, we compared electrophysiological properties of ESC-derived cardiomyocytes (ESC-CMs) of different murine ESC lines. Methods: Two wild-type (D3 and R1) and two transgenic ESC lines (D3/aPIG44 and CGR8/AMPIGX-7) were differentiated under identical culture conditions. The transgenic cell lines expressed enhanced green fluorescent protein (eGFP) and puromycin-N-acetyltransferase under control of the cardiac specific α-myosin heavy chain (αMHC) promoter. Action potentials (APs) were recorded using sharp electrodes and multielectrode arrays in beating clusters of ESC-CMs. Results: Spontaneous AP frequency and AP duration (APD) as well as maximal upstroke velocity differed markedly between unpurified CMs of the four ESC lines. APD heterogeneity was negligible in D3/aPIG44, moderate in D3 and R1 and extensive in CGR8/AMPIGX-7. Interspike intervals calculated from long-term recordings showed a high degree of variability within and between recordings in CGR8/AMPIGX-7, but not in D3/aPIG44. Purification of the αMHC+ population by puromycin treatment posed only minor changes to APD in D3/aPIG44, but significantly shortened APD in CGR8/AMPIGX-7. Conclusion: Electrophysiological properties of ESC-CMs are strongly cell line-dependent and can be influenced by purification of cardiomyocytes by antibiotic selection. Thus, conclusions on cardiac development, physiology and pharmacology derived from single stem cell lines have to be interpreted carefully.
Ezrin/Exocyst Complex Regulates Mucin 5AC Secretion Induced by Neutrophil Elastase in Human Airway Epithelial Cells
Authors: Li Qi , Li Na , Liu Chun-Yi , Xu Rui , Kolosov Victor P. , Perelman Juliy M. , Zhou Xiang-Dong
Published: January 2015

Background/Aim: Increased mucin secretion is a characteristic feature of many chronic airway diseases, particularly during periods of exacerbation; however, the exact mechanism of mucin secretion remains unclear. Ezrin, which is a specific marker of apical membranes, is predominantly concentrated in exocyst-rich cell surface structures, crosslinking the actin cytoskeleton with the plasma membrane. In the present study, we examined whether Ezrin is involved in mucin 5AC (MUC5AC) secretion after neutrophil elastase (NE) attack, and we investigated the role of the exocyst complex docking protein Sec3 in this process. Methods: NE was used as a stimulator in a 16HBE14o- cell culture model. The expression and location of Ezrin and Sec3 were investigated, and the interaction between Ezrin and Sec3 in 16HBE14o-cells was assayed after treatment with NE, Ezrin siRNA, Sec3 siRNA, neomycin or PIP2-Ab. Results: We found that Ezrin was highly expressed in the bronchi of humans with chronic airway diseases. NE induced robust MUC5AC protein secretion. The Ezrin siRNA, Sec3 siRNA, and neomycin treatments led to impaired MUC5AC secretion in cells. Both Ezrin and Sec3 were recruited primarily to the cytoplasmic membrane after NE stimulation, and the neomycin and PIP2-Ab treatments abrogated this effect. Immunoprecipitation analysis revealed that Ezrin and Sec3 combined to form complexes; however, these complexes could not be detected in Ezrin∆1-333 mutant-transfected cells, even when PIP2 was added. Conclusions: These results demonstrate that Ezrin/Sec3 complexes are essential for MUC5AC secretion in NE-stimulated airway epithelial cells and that PIP2 is of critical importance in the formation of these complexes.
Effects of Moderate Exercise on the Biochemical, Physiological, Morphological and Functional Parameters of the Aorta in the Presence of Estrogen Deprivation and Dyslipidemia: an Experimental Model
Authors: Marchon Claudia , de Marco Ornelas Elisabete , da Silva Viegas Katia Aparecida , Lacchini Silvia , de Souza Romeu Rodrigues , Fonseca Fernando Luiz Affonso , Maifrino Laura Beatriz Mesiano
Published: January 2015

Background: The estrogen deficiency, abnormal lipid profile, weight gain and a sedentary lifestyle are factors associated with the increased prevalence of cardiovascular disease in menopausal women. However, physical exercise practice reduces some of these risk factors. Moreover, it has been shown that exercise has an impact on inflammation, in sympathetic activity and improves endothelial function. Aims: The present study aims to evaluate the effects of moderate aerobic training on biochemical, morphological and physiological parameters in LDL Knockout mice with estrogen deprivation, evaluating the components of the ascending aortic wall. Methods: The animals were randomly divided into six groups (n=5): sedentary control (SC), sedentary control ovariectomized (SCO), trained control ovariectomized (TCO), LDL-Knockout sedentary (KS), LDL-Knockout sedentary ovariectomized (KOS) and LDL-Knockout trained ovariectomized (KOT). The trained groups underwent a protocol of moderate training for 4 weeks on a treadmill with speed and progressive load. After training, blood samples were collected for biochemical assessments and the aorta was removed for dissection and histological morphometry study. In addition, the expression of angiotensin-converting enzyme (ACE) and angiotensin II proteins were examined by immunohistochemistry in all groups of animals. Results: Changes of expressions of ACE and angiotensin II were found when the group was subjected to exercise. The concentrations of cholesterol and triglycerides were lower in the groups of animals with estrogen deprivation and dyslipidemia. In animals that performed exercises we found significant increase (p<0.05) in Vv[lam]; decrease in Vv[col] and CWT, and a tendency for decrease both in TS and IMT when compared to the SC groups. The histological morphometry findings showed consistency in the results of the aorta study when the ovariectomized group underwent the exercise protocol. Conclusion: We conclude that physical training contributed to reducing vessel rigidity and to improvements in vascular compliance, with the increase in volume density of elastic lamellae in the estrogen-deprived groups who had normal cholesterol levels.
Gene Expression Profile in the Early Stage of Angiotensin II-induced Cardiac Remodeling: a Time Series Microarray Study in a Mouse Model
Authors: Dang Meng-Qiu , Zhao Xue-Chen , Lai Song , Wang Xia , Wang Lei , Zhang Yun-Long , Liu Yang , Yu Xiao-Hong , Liu Ying , Li Hui-Hua , Xia Yun-Long
Published: January 2015

Background/Aims: Angiotensin II (Ang II) plays a critical role in the cardiac remodeling contributing to heart failure. However, the gene expression profiles induced by Ang II in the early stage of cardiac remodeling remain unknown. Methods: Wild-type male mice (C57BL/6 background, 10-weeek-old) were infused with Ang II (1500 ng/kg/min) for 7 days. Blood pressure was measured. Cardiac function and remodeling were examined by echocardiography, H&E and Masson staining. The time series microarrays were then conducted to detected gene expression profiles. Results: Microarray results identified that 1,489 genes were differentially expressed in the hearts at day 1, 3 and 7 of Ang II injection. These genes were further classified into 26 profiles by hierarchical cluster analysis. Of them, 4 profiles were significant (No. 19, 8, 21 and 22) and contained 904 genes. Gene Ontology showed that these genes mainly participate in metabolic process, oxidation-reduction process, extracellular matrix organization, apoptotic process, immune response, and others. Significant pathways included focal adhesion, ECM-receptor interaction, cytokine-cytokine receptor interaction, MAPK and insulin signaling pathways, which were known to play important roles in Ang II-induced cardiac remodeling. Moreover, gene co-expression networks analysis suggested that serine/cysteine peptidase inhibitor, member 1 (Serpine1, also known as PAI-1) localized in the core of the network. Conclusions: Our results indicate that many genes are mainly involved in metabolism, inflammation, cardiac fibrosis and hypertrophy. Serpine1 may play a central role in the development of Ang II-induced cardiac remodeling at the early stage.
Curcumin Treatment Suppresses CCR7 Expression and the Differentiation and Migration of Human Circulating Fibrocytes
Authors: Fu Xu-yan , Zhang Dong-wei , Li Ya-dong , Zhao Pi-wen , Tang Yu-qing , Niu Jian-zhao , Li Yu
Published: January 2015

Background/Aim: Recent studies have demonstrated that circulating fibrocytes contribute to the formation and development of fibrosis. Curcumin, a polyphenolic compound isolated from turmeric, has been shown to have anti-fibrotic effects in various organs. We and others have demonstrated that curcumin beneficially affects the development of fibrosis. However the effect of curcumin on circulating fibrocytes has not been reported. Methods: Human circulating fibrocytes were isolated from leukocyte concentrates of healthy human donors and identified based on the expression of CD34, CD45, collagen I (COLI), and chemokine receptor CCR7 (CCR7) via flow cytometry. Cell Counting Kit-8 was used to evaluate cell viability. The effect of curcumin on the differentiation and migration of human circulating fibrocytes was evaluated by immunofluorescence staining, flow cytometry and a transwell migration assay. Transforming growth factor (TGF)-β1 secretion was examined by ELISA. Results: Curcumin treatment (72 h; 20 μM) significantly decreased the expression of COL I, α-SMA and CCR7, as well as TGF-βl secretion, in human circulating fibrocytes. The inhibitory effect of curcumin on the differentiation and migration of human circulating fibrocytes is likely via regulating the CCR7/CCL21 signaling pathway, in particular by reducing CCR7 expression. These observed effects may be beneficial in resolving fibrosis by suppressing TGF-β1 secretion. Conclusion: Our results suggest that curcumin has the potential to suppress the differentiation and migration of circulating fibrocytes, which would provide new explanation for curcumin's application in the development of fibrosis in various organs.
MicroRNA-149 Suppresses Colorectal Cancer Cell Migration and Invasion by Directly Targeting Forkhead Box Transcription Factor FOXM1
Authors: Xu Kai , Liu Xiaobei , Mao Xiaobei , Xue Lijun , Wang Rui , Chen Longbang , Chu Xiaoyuan
Published: January 2015

Background/Aims: The aim of this study is to investigate the clinicopathological and prognostic values of miR-149 expression and its roles in colorectal cancer (CRC) progression. Methods: qRT-PCR was performed to detect miR-149 expression in CRC cell lines or tissues. Also, the clinical significance of miR-149 expression was investigated. The study further explored whether miR-149 inhibits migration and invasion of CRC cells by targeting the mammalian Forkhead Box M1 (FOXM1). Results: miR-149 was significantly downregulated in CRC tissues, and low miR-149 expression was observed to be significantly correlated with lymph node or distant metastasis and advanced TNM stage of CRC patients. Patients with low miR-149 expression showed poorer prognosis than those with high miR-149 expression, and multivariate analyses indicated that status of miR-149 expression might be an independent prognostic factor. Gain- and loss - of - function assays indicated that miR-149 significantly inhibited growth, migration and invasion of CRC cells by targeting FOXM1. Furthermore, FOXM1 was significantly uiregulated in CRC tissues and inversely correlated with miR-149 expression. Conclusions: mR-149 was an independent prognostic factor and could inhibit migration and invasion of CRC cells, at least partially by targeting FOXM1.
Protective Effects of Millettia Pulchra Flavonoids on Myocardial Ischemia In Vitro and In Vivo
Authors: Huang Jianchun , Zhang Xudong , Qin Feizhang , Li Yingxin , Duan Xiaoqun , Jian Jie , Li Yongwen , Chen Jian , Huang Renbin
Published: January 2015

Background: Previous studies have demonstrated that Millettia pulchra flavonoids (MPF) exhibit protective effects on myocardial ischemia reperfusion injury (MI/RI) in isolated rat hearts and show anti-oxidative, anti-hypoxic and anti-stress properties. Methods: In this study, the cardioprotective effects of MPF on myocardial ischemia and its underlying mechanisms were investigated by a hypoxia/ reoxygenation (H/R) injury model in vitro and a rat MI/RI model in vivo. Results: We found that the lactate dehydrogenase (LDH) and inducible nitric oxide synthase (iNOS) activities were decreased in the MPF pretreatment group, whereas the activities of constructional nitric oxide synthase (cNOS), total nitric oxide synthase (tNOS), Na+-K+-ATPase and Ca2+-Mg2+-ATPase were significantly increased. In addition, the cardiocytes were denser in the MPF groups than in the control group. The mortality rate and apoptosis rate of cardiocytes were significantly decreased. Furthermore, pretreatment with MPF in vivo significantly improved the hemodynamics, decreased malondialdehyde (MDA) abundance, increased the activities of plasma superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decreased the expression of the Bax protein and ratio Bax/Bc1-2 ration. Conclusions: These results suggest that MPF is an attractive protective substance in myocardial ischemia due to its negative effects on heart rate and ionotropy, reduction of myocardial oxidative damage and modulation of gene expression associated with apoptosis.
Modified-Release Calcifediol Effectively Controls Secondary Hyperparathyroidism Associated with Vitamin D Insufficiency in Chronic Kidney Disease
Authors: Sprague Stuart M. , Silva Arnold L. , Al-Saghir Fahd , Damle Radhika , Tabash Samir P. , Petkovich Martin , Messner Eric J. , White Jay A. , Melnick Joel Z. , Bishop Charles W.
Published: January 2015

Background/Aims: Vitamin D insufficiency drives secondary hyperparathyroidism (SHPT) and is associated with increased cardiovascular mortality in patients with chronic kidney disease (CKD). SHPT is poorly addressed by current vitamin D repletion options. The present study evaluated a novel investigational vitamin D repletion therapy: a modified-release (MR) formulation of calcifediol designed to raise serum 25-hydroxyvitamin D in a gradual manner to minimize the induction of CYP24 and, thereby, improve the SHPT control. Methods: This randomized, double-blind, placebo-controlled trial evaluated MR calcifediol in CKD subjects (n = 78) with plasma intact parathyroid hormone (iPTH) >70 pg/ml and serum total 25-hydroxyvitamin D <30 ng/ml. Subjects received daily treatment for six weeks with oral MR calcifediol (30, 60 or 90 µg) or a placebo. Results: More than 90% of subjects treated with MR calcifediol achieved serum 25-hydroxyvitamin D levels ≥30 ng/ml versus 3% of subjects treated with placebo (p < 0.0001). Mean plasma iPTH decreased from baseline (140.3 pg/ml) by 20.9 ± 6.2% (SE), 32.8 ± 5.7 and 39.3 ± 4.3% in the 30, 60 and 90 µg dose groups, respectively, and increased 17.2 ± 7.8% in the pooled placebo group (p < 0.005). No clinically significant safety concerns arose during MR calcifediol treatment. Conclusion: Oral MR calcifediol appears safe and highly effective in treating SHPT associated with vitamin D insufficiency in CKD.
Protein Intake in Infancy and Carotid Intima Media Thickness at 5 Years - A Secondary Analysis from a Randomized Trial
Authors: Gruszfeld Dariusz , Weber Martina , Nowakowska-Rysz Monika , Janas Roman , Kozlik-Feldmann Rainer , Xhonneux Annick , Carlier Clotilde , Riva Enrica , Verduci Elvira , Closa-Monasterolo Ricardo , Escribano Joaquin , Dobrzanska Anna , Koletzko Berthold ,   for the European Childhood Obesity Study Group
Published: January 2015

Background: Nutrition in childhood has an influence on the cardiovascular function later on in life. European Childhood Obesity Project is a multicenter, randomized clinical intervention trial examining the effect of early protein intake on later health outcomes, particularly adiposity and related disorders. The aim of the study was to examine the effect of nutritional intervention - different protein intake in infancy on carotid intima-media thickness (cIMT) at 5 years. The association of cardiovascular risk factors with cIMT was also assessed. Methods: Healthy term formula-fed infants in five European countries were enrolled either to the higher (HP) or to the lower (LP) protein group. Observational group consisted of breastfed infants. Plasma insulin, glucose, lipid profile, IGF-1, apolipoprotein A1 and B were measured as well as anthropometric parameters of parents and a child, blood pressure and physical activity. Results: No difference in cIMT between HP and LP group was observed. Insulin, HOMA-IR index and total IGF-1 were positively associated with cIMT but after adjustment for confounders only an inverse association between ApoA1 and positive between ApoB/ApoA1 and cIMT were significant. Conclusion: High versus low protein intake in infancy does not influence cIMT at 5 years. cIMT in healthy children at 5 years is associated with their apolipoprotein profile.
Central Centrifugal Cicatricial Alopecia Presenting with Irregular Patchy Alopecia on the Lateral and Posterior Scalp
Authors: Miteva Mariya , Tosti Antonella
Published: January 2015

Background: Central centrifugal cicatricial alopecia (CCCA) is the most common cause of scarring alopecia among women of African descent which affects the central scalp and spreads centrifugally but spares the lateral and posterior scalp. Objectives: The objective of this study is to report on a new clinical variety of CCCA presenting with patchy alopecia involving the lateral and posterior scalp in addition to the central scalp. Materials and Methods: We reviewed the medical records and the clinical, dermatoscopic and pathologic data of 14 African-American women with CCCA presenting with patchy alopecia. Results: Two patients had individual well-delineated patches of hair loss, and 12 patients had multiple irregular patches of hair loss. In all cases, the alopecia affected the lateral and posterior scalp in addition to the central scalp. Four patients had a history of traumatic hairstyles, and 10 patients were also affected by marginal traction alopecia. On dermatoscopy, the patches showed peripilar white-gray halos and broken hairs. The pathologic diagnosis of CCCA was based on the following features: follicular dropout, absent or only focally preserved sebaceous glands, premature desquamation of the inner root sheath and perifollicular fibrosis with mild inflammatory infiltrate. Conclusion: CCCA can present with patches of hair loss involving the parietal and posterior scalp in addition to the central scalp. Without dermatoscopy and pathology, this variety can be easily misdiagnosed as traction alopecia.
Receptor-Interacting Protein Kinase 3 Contributes to Abdominal Aortic Aneurysms via Smooth Muscle Cell Necrosis and Inflammation
Authors: Wang Qiwei , Liu Zhenjie , Ren Jun , Morgan Stephanie , Assa Carmel , Liu Bo
Published: January 2015

Rationale:

Depletion of medial smooth muscle cell (SMC) is a major pathological characteristic of abdominal aortic aneurysm (AAA), although the mechanism by which these cells are eliminated remains incompletely understood. We reasoned that necroptosis, a recently described form of necrosis mediated by receptor-interacting protein kinase 3 (RIP3), may contribute to AAA pathology through the induction of SMC death and the significant production of inflammatory cytokines.

Objective:

To test the hypothesis that RIP3-mediated necroptosis is actively involved in aneurysm pathogenesis.

Methods and Results:

RIP3 and RIP1 levels were found to be elevated in human AAAs, most noticeably in SMCs. Elevations of RIP3 and SMC necrosis were also observed in the elastase-induced mouse model of AAAs. Deletion of one or both copies of
Rip3
prevented AAA formation. By transplanting
Rip3
+/−
aortae to
Rip3
+/+
mice, we demonstrated that reduced
Rip3
expression in arterial wall was the primary cause of aneurysm resistance. In vitro, adenoviral overexpression of RIP3 was sufficient to trigger SMC necroptosis. Protein kinase C-delta contributed to tumor necrosis factor-α–induced SMC necroptosis by regulating
Rip3
expression. Furthermore,
Rip3
deficiency impaired tumor necrosis factor-α–induced inflammatory gene expression in aortic SMCs, which was at least in part because of attenuation of p65 Ser536 phosphorylation. In vivo, the lack of RIP3 diminished activation of p65 in SMCs, implicating a necrosis independent function of RIP3 in aneurysms.

Conclusions:

Enhanced RIP3 signaling in aneurysmal tissues contributes to AAA progression by causing SMC necroptosis, as well as stimulating vascular inflammation, and therefore may serve as a novel therapeutic target for AAA treatment.
Aldosterone Promotes Cardiac Endothelial Cell Proliferation In Vivo
Authors: Gravez Basile , Tarjus Antoine , Pelloux Véronique , Ouvrard‐Pascaud Antoine , Delcayre Claude , Samuel Janelise , Clément Karine , Farman Nicolette , Jaisser Fréderic , Messaoudi Smail
Published: January 2015

Background

Experimentally, aldosterone in association with NaCl induces cardiac fibrosis, oxidative stress, and inflammation through mineralocorticoid receptor activation; however, the biological processes regulated by aldosterone alone in the heart remain to be identified.

Methods and Results

Mice were treated for 7 days with aldosterone, and then cardiac transcriptome was analyzed. Aldosterone regulated 60 transcripts (51 upregulated and 9 downregulated) in the heart (fold change ≥1.5, false discovery rate <0.01). To identify the biological processes modulated by aldosterone, a gene ontology analysis was performed. The majority of aldosterone‐regulated genes were involved in cell division. The cardiac Ki‐67 index (an index of proliferation) of aldosterone‐treated mice was higher than that of nontreated mice, confirming microarray predictions. Costaining of Ki‐67 with vinculin,
CD
68, α‐smooth muscle actin,
CD
31, or caveolin 1 revealed that the cycling cells were essentially endothelial cells. Aldosterone‐induced mineralocorticoid receptor–dependent proliferation was confirmed ex vivo in human endothelial cells. Moreover, pharmacological‐specific blockade of mineralocorticoid receptor by eplerenone inhibited endothelial cell proliferation in a preclinical model of heart failure (transverse aortic constriction).

Conclusions

Aldosterone modulates cardiac gene expression and induces the proliferation of cardiac endothelial cells in vivo.
Lower Mortality Rate in Elderly Patients With Community‐Onset Pneumonia on Treatment With Aspirin
Authors: Falcone Marco , Russo Alessandro , Cangemi Roberto , Farcomeni Alessio , Calvieri Camilla , Barillà Francesco , Scarpellini Maria Gabriella , Bertazzoni Giuliano , Palange Paolo , Taliani Gloria , Venditti Mario , Violi Francesco
Published: January 2015

Background

Pneumonia is complicated by high rate of mortality and cardiovascular events (CVEs). The potential benefit of aspirin, which lowers platelet aggregation by inhibition of thromboxane A2 production, is still unclear. The aim of the study was to assess the impact of aspirin on mortality in patients with pneumonia.

Methods and Results

Consecutive patients admitted to the University‐Hospital Policlinico Umberto I (Rome, Italy) with community‐onset pneumonia were recruited and prospectively followed up until discharge or death. The primary end point was the occurrence of death up to 30 days after admission; the secondary end point was the intrahospital incidence of nonfatal myocardial infarction and ischemic stroke. One thousand and five patients (age, 74.7±15.1 years) were included in the study: 390 were receiving aspirin (100 mg/day) at the time of hospitalization, whereas 615 patients were aspirin free. During the follow‐up, 16.2% of patients died; among these, 19 (4.9%) were aspirin users and 144 (23.4%;
P
<0.001) were aspirin nonusers. Overall, nonfatal CVEs occurred in 7% of patients, 8.3% in nonaspirin users, and 4.9% in aspirin users (odds ratio, 1.77; 95% confidence interval, 1.03 to 3.04;
P
=0.040). The Cox regression analysis showed that pneumonia severity index (
PSI
), severe sepsis, pleural effusion, and PaO
2
/FiO
2
ratio <300 negatively influenced survival, whereas aspirin therapy was associated with improved survival. Compared to patients receiving aspirin, the propensity score adjusted analysis confirmed that patients not taking aspirin had a hazard ratio of 2.07 (1.08 to 3.98;
P
=0.029) for total mortality.

Conclusions

This study shows that chronic aspirin use is associated with lower mortality rate within 30 days after hospital admission in a large cohort of patients with pneumonia.
Job Strain and the Risk of Stroke
Authors: Fransson Eleonor I. , Nyberg Solja T. , Heikkilä Katriina , Alfredsson Lars , Bjorner Jakob B. , Borritz Marianne , Burr Hermann , Dragano Nico , Geuskens Goedele A. , Goldberg Marcel , Hamer Mark , Hooftman Wendela E. , Houtman Irene L. , Joensuu Matti , Jokela Markus , Knutsson Anders , Koskenvuo Markku , Koskinen Aki , Kumari Meena , Leineweber Constanze , Lunau Thorsten , Madsen Ida E.H. , Hanson Linda L. Magnusson , Nielsen Martin L. , Nordin Maria , Oksanen Tuula , Pentti Jaana , Pejtersen Jan H. , Rugulies Reiner , Salo Paula , Shipley Martin J. , Steptoe Andrew , Suominen Sakari B. , Theorell Töres , Toppinen-Tanner Salla , Vahtera Jussi , Virtanen Marianna , Väänänen Ari , Westerholm Peter J.M. , Westerlund Hugo , Zins Marie , Britton Annie , Brunner Eric J. , Singh-Manoux Archana , Batty G. David , Kivimäki Mika
Published: January 2015

Background and Purpose—

Psychosocial stress at work has been proposed to be a risk factor for cardiovascular disease. However, its role as a risk factor for stroke is uncertain.

Methods—

We conducted an individual-participant-data meta-analysis of 196 380 males and females from 14 European cohort studies to investigate the association between job strain, a measure of work-related stress, and incident stroke.

Results—

In 1.8 million person-years at risk (mean follow-up 9.2 years), 2023 first-time stroke events were recorded. The age- and sex-adjusted hazard ratio for job strain relative to no job strain was 1.24 (95% confidence interval, 1.05;1.47) for ischemic stroke, 1.01 (95% confidence interval, 0.75;1.36) for hemorrhagic stroke, and 1.09 (95% confidence interval, 0.94;1.26) for overall stroke. The association with ischemic stroke was robust to further adjustment for socioeconomic status.

Conclusion—

Job strain may be associated with an increased risk of ischemic stroke, but further research is needed to determine whether interventions targeting job strain would reduce stroke risk beyond existing preventive strategies.
Plaque Components in Symptomatic Moderately Stenosed Carotid Arteries Related to Cerebral Infarcts
Authors: de Rotte Alexandra A.J. , Truijman Martine T.B. , van Dijk Anouk C. , Liem Madieke I. , Schreuder Floris H.B.M. , van der Kolk Anja G. , de Kruijk Jelle R. , Daemen Matt J.A.P. , van der Steen Anton F.W. , de Borst Gert Jan , Luijten Peter R. , Nederkoorn Paul J. , Kooi Marianne Eline , van der Lugt Aad , Hendrikse Jeroen , Schreuder A.H.C.M.L. , Koudstaal P.J. , Limburg M. , Weisfelt M. , Korten A.G.G.C. , Saxena R. , van Oostenbrugge R.J. , Mess W.H. , van Orshoven N.P. , Tromp S.C. , Bakker S.L.M. , Kruyt N.D. , Meems B.J. , Verhey J.C.B. , Wijnhoud A.D.
Published: January 2015

Background and Purpose—

Carotid plaque composition is a major determinant of cerebrovascular events. In the present analysis, we evaluated the relationship between intraplaque hemorrhage (IPH) and a thin/ruptured fibrous cap (TRFC) in moderately stenosed carotid arteries and cerebral infarcts on MRI in the ipsilateral hemisphere.

Methods—

A total of 101 patients with a symptomatic 30% to 69% carotid artery stenosis underwent MRI of the carotid arteries and the brain, within a median time of 45 days from onset of symptoms. The presence of ipsilateral infarcts in patients with and without IPH and TRFC was evaluated.

Results—

IPH was seen in 40 of 101 plaques. TRFC was seen in 49 of 86 plaques (postcontrast series were not obtained in 15 patients). In total, 51 infarcts in the flow territory of the symptomatic carotid artery were found in 47 patients. Twenty nine of these infarcts, found in 24 patients, were cortical infarcts. No significant relationship was found between IPH or TRFC and the presence of ipsilateral infarcts.

Conclusions—

MRI detected IPH and TRFC are not related to the presence of old and recent cortical and subcortical infarcts ipsilateral to a symptomatic carotid artery stenosis of 30% to 69%.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01208025.
God in the Public Domain
Authors: Gatwa Tharcisse
Published: January 2015

God has been very much present in public domain in the life of Rwandans. Every successful enterprise would lead Rwandans to pay tribute to God. At the end of every other failed try the Rwandan would say, ‘ahasigaye ni ah’Imana’ — I have done what I could, the rest belongs to God. His overwhelming presence was expressed in many ways including by theophoric names. This God celebrated by the triumphant ‘Christian kingdom’ came under fire attacks during the 1994 genocide against the Tutsi, many of them being slaughtered in churches and public buildings. Had God, the life Giver and the protector, become a cynical destroyer, an executioner, or simply a sleeper who didn’t care for his creatures? Irrespective to these unanswered questions, the post 1994 genocide Rwandan religious era was imbued with another form of triumphalism, in which God was called, celebrated, and inaugurated as the One who showed the way to new charismatic movements to bring about a spiritual revolution in the country, whilst traditional Christianity remained ambivalent towards the moral guidance they were expected to provide. Yet many survivors continue to tell of their deception about such a ‘silent and cynical’ God, or at the best they wonder if their fate was sealed with His consent and that of His heralds on earth. This paper takes the view that religious competition and triumphalism of the clergy over crowds that continue to fill in areas of worship, amplified the feeling that God is still a very marketable good in Rwanda. And yet he never ran away from the victims of the tragedies.
On a Long Neglected Player: The Religious Factor in Poverty Alleviation
Authors: Schliesser Christine
Published: January 2015

Much of poverty alleviation theory and practice fails to sufficiently consider the following crucial factor: the religious dimension. This paper elaborates this thesis by focusing on the African context and the valuable resources African religious communities and movements can provide in the struggle against poverty. One particularly influential streak of present-time African religiousness serves as a case study: the so-called ‘Prosperity Gospel’ as part of Pentecostal Christianity. The author first argues for the continuing formative influence of religion on African conceptions of self, other, and world. Secondly, she provides a critical assessment of the impact of Pentecostalism and the ‘Prosperity Gospel’ on poverty alleviation. In comparison with secular ngos, Pentecostal churches emerge as the more effective agents of change. A third part situates the insights gained into a wider perspective, seeking ways to integrate the religious factor into a more holistic conception of and engagement against poverty
Fan Pu (China): The Bible Interpreted through the Art of Paper Cutting
Authors: Hoekema Alle G.
Published: January 2015

In this article two major volumes with Chinese paper cut art by Fan Pu (Paula Fan) are reviewed. In her work it becomes clear how a traditional type of folk art can be transformed by using new techniques and material. By doing so, Fan Pu is able to make modern Christian art, which hopefully also appeals to present-day Chinese people. Herself being an evangelical Christian, she interestingly also uses sayings by pre-Christian Chinese sages like Confucius in her art; their wisdom can be seen as a kind of preparatio evangelica. The two works, analyzed here, together form a catalog of her work so far, from the nineteen seventies till now.