miR-199a-5p Is Upregulated during Fibrogenic Response to Tissue Injury and Mediates TGFbeta-Induced Lung Fibroblast Activation by Targeting Caveolin-1

As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic lung diseases, especially the idiopathic form (IPF), remains poorly understood. Given the poor response rate of IPF patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop lung fibrosis after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in IPF patients (94 IPF versus 83 controls). In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with IPF. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon TGFβ exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of TGFβ signaling in lung fibroblasts by regulating CAV1, a critical mediator of pulmonary fibrosis. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of kidney fibrosis, as well as in both bile duct ligation and CCl4-induced mouse models of liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue fibrosis with therapeutic potency to treat fibroproliferative diseases. © 2013 Lino Cardenas et al

Identification of Keratinocyte Growth Factor as a Target of microRNA-155 in Lung Fibroblasts: Implication in Epithelial-Mesenchymal Interactions

International audienceBACKGROUND: Epithelial-mesenchymal interactions are critical in regulating many aspects of vertebrate embryo development, and for the maintenance of homeostatic equilibrium in adult tissues. The interactions between epithelium and mesenchyme are believed to be mediated by paracrine signals such as cytokines and extracellular matrix components secreted from fibroblasts that affect adjacent epithelia. In this study, we sought to identify the repertoire of microRNAs (miRNAs) in normal lung human fibroblasts and their potential regulation by the cytokines TNF-alpha, IL-1beta and TGF-beta. METHODOLOGY/PRINCIPAL FINDINGS: MiR-155 was significantly induced by inflammatory cytokines TNF-alpha and IL-1beta while it was down-regulated by TGF-beta. Ectopic expression of miR-155 in human fibroblasts induced modulation of a large set of genes related to "cell to cell signalling", "cell morphology" and "cellular movement". This was consistent with an induction of caspase-3 activity and with an increase in cell migration in fibroblasts tranfected with miR-155. Using different miRNA bioinformatic target prediction tools, we found a specific enrichment for miR-155 predicted targets among the population of down-regulated transcripts. Among fibroblast-selective targets, one interesting hit was keratinocyte growth factor (KGF, FGF-7), a member of the fibroblast growth factor (FGF) family, which owns two potential binding sites for miR-155 in its 3'-UTR. Luciferase assays experimentally validated that miR-155 can efficiently target KGF 3'-UTR. Site-directed mutagenesis revealed that only one out of the 2 potential sites was truly functional. Functional in vitro assays experimentally validated that miR-155 can efficiently target KGF 3'-UTR. Furthermore, in vivo experiments using a mouse model of lung fibrosis showed that miR-155 expression level was correlated with the degree of lung fibrosis. CONCLUSIONS/SIGNIFICANCE: Our results strongly suggest a physiological function of miR-155 in lung fibroblasts. Altogether, this study implicates this miRNA in the regulation by mesenchymal cells of surrounding lung epithelium, making it a potential key player during tissue injury

Amyloid and tau pathology associations with personality traits, neuropsychiatric symptoms, and cognitive lifestyle in the preclinical phases of sporadic and autosomal dominant Alzheimer’s disease

Background Major prevention trials for Alzheimer’s disease (AD) are now focusing on multidomain lifestyle interventions. However, the exact combination of behavioral factors related to AD pathology remains unclear. In 2 cohorts of cognitively unimpaired individuals at risk of AD, we examined which combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle (years of education or lifetime cognitive activity) related to the pathological hallmarks of AD, amyloid-β, and tau deposits. Methods A total of 115 older adults with a parental or multiple-sibling family history of sporadic AD (PREVENT-AD [PRe-symptomatic EValuation of Experimental or Novel Treatments for AD] cohort) underwent amyloid and tau positron emission tomography and answered several questionnaires related to behavioral attributes. Separately, we studied 117 mutation carriers from the DIAN (Dominant Inherited Alzheimer Network) study group cohort with amyloid positron emission tomography and behavioral data. Using partial least squares analysis, we identified latent variables relating amyloid or tau pathology with combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle. Results In PREVENT-AD, lower neuroticism, neuropsychiatric burden, and higher education were associated with less amyloid deposition (p = .014). Lower neuroticism and neuropsychiatric features, along with higher measures of openness and extraversion, were related to less tau deposition (p = .006). In DIAN, lower neuropsychiatric burden and higher education were also associated with less amyloid (p = .005). The combination of these factors accounted for up to 14% of AD pathology. Conclusions In the preclinical phase of both sporadic and autosomal dominant AD, multiple behavioral features were associated with AD pathology. These results may suggest potential pathways by which multidomain interventions might help delay AD onset or progression

Chemical profile identification of fugitive and confined particle emissions from an integrated iron and steelmaking plant

International audienceThe aim of this study is to obtain the characteristic inorganic chemical profile of important particle sources identified in the integrated iron and steel process: sintering, blast furnace, steelmaking and desulfurization slag processing. A complete chemical and physical characterization program was developed: particle size distribution, chemical analysis, XRD, SEM-EDX and TGA/DTA. The sample collected from the sinter stack showed high levels of K and Cl(-), followed by Fe, NH4(+), Ca, Na and Pb. The profile of the dust samples taken from the sinter cake discharge zone was quite different, showing higher amounts of Fe, Ca and Al, and lower amounts of K, Cl(-), Na and Pb. Dust samples collected from the blast furnace (BF) and steelmaking cast house may be distinguished from each other based on the higher levels of Fe (hematite and magnetite) and lower levels of Ca, Zn and C (graphite) found in BF dust. High levels of Ca and Fe were found in samples taken from the desulfurization slag processing area. Such information can be useful for source apportionment studies at receptor sites that could be influenced by iron and steelmaking plant emissions

Chemical characterization of industrial- and road traffic-influenced fine particles (PM0.3-2.5) and impact on xenobiotic metabolizing enzymes gene expression in human reconstituted airway epithelium

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Utilisation des Éléments Potentiellement Toxiques pour le traçage des poussières sédimentables industrielles dans les sols (Nord, France)

International audienceAt the vicinity of metallurgical and steel activities, notable contamination of Potentially Toxic Elements (PTE) is measured in discrete environmental compartments (soils, biosphere, atmosphere). The main question addressed in this study pertains to the influence of industrial dust fallout on PTE concentrations in soils. The study was conducted near the seaport of Dunkerque, belonging to one of the most industrialised and dust-emitting sites of France.A composite sample of dust fallout was collected over a 4-month-period in urban areas downwind of nearby industries. SEM-EDS and ICP-AES/MS analyses were conducted on this sample to identify metallurgical particles and highlight the main tracer elements of industrial activities. Then, a comprehensive characterization of soils was conducted to map the spatial distribution of metallic pollution levels in the study area. Nearby soil parameters analysis (grain-size distribution, pH, CEC, SOM, calcium carbonates and water contents), the soil chemical composition was identified using XRF and ICP-AES/MS analyses.We quantified the proportion of particles of industrial origin in the composite dust sample at 88% of the total fraction, stressing the importance of metallurgical activities near the seaport of Dunkerque. This dust sample shows particularly high enrichment factors (EF) for Cd, Cr, Ni, and Mo with values of 235, 108, 78 and 169 respectively. The use of different pollution assessment indexes evidences that Mo-Cr-Ni associations appear particularly interesting to trace the incorporation of metallurgical sedimentable dusts into soils. Thus, we identified the presence of distinct high-PTE patches related to industrial dust deposition in the studied soils, with a parallel decrease in their quality index (i.e. Mo Geo Accumulation Index indicating moderate to heavy contamination).Our study revealed that the soils located close to the industrial area are the most affected by industrial dust deposition. Several factors explaining the spatial distribution of the soil contamination levels are examined, and it seems that distance from emission sources is not necessarily the most relevant. The study suggests that distribution of plant cover or buildings may act as barriers preventing soils from being exposed to dust deposits

Fast magic angle spinning solid-state

Catalysts V2O5 supported on TiO2 (anatase) with different contents (between 8% and 1% wt V2O5) have been studied by fast magic angle spinning solid-state 51V NMR. Two commercial supports are used (Rhône-Poulenc and Tioxide). In both samples containing 8% and 3% wt V2O5, two vanadium species in a distorted octahedral environment are observed. In the case of the smallest content (1% wt V2O5), octahedral species are always present in one support (Rhône-Poulenc), but on the other (Tioxide), a tetrahedral vanadium species appears

Pseudo-nitzschia sp. diversity and seasonality in the southern North Sea, domoic acid levels and associated phytoplankton communities

The diversity, toxicity and seasonality of Pseudo-nitzschia sp. were investigated from February to November 2012 in the southern Bight of the North Sea (SBNS) along the French coast. The identification of Pseudo-nitzschia species in this area was addressed for the first time in this study. Our results revealed a low species richness (3 distinct species) in association with moderate (102 pg mL−1) to high (263 pg mL−1) domoic acid (DA) levels in autumn and spring, respectively. Pseudo-nitzschia succession corresponded to the dominance of P. delicatissima in April–May (86% of total diatoms) as a co-occurring species of the Phaeocystis globosa bloom. Following the Phaeocystis bloom (May–September), P. pungens dominated markedly over P. fraudulenta and P. delicatissima and was the only species present in autumn, although at low abundance (<1000 cell L−1). The results of this study support the idea that Pseudo-nitzschia seasonality in the SBNS relies principally on temperature and nutrient availability (DIN and silicates), which, in turn, depend on locally fluctuating environmental conditions (rainfalls and winds). This study highlights the potential for the SBNS to be a potential risk area in regard to the possible impacts of DA on marine resources and the DA transfer through marine food webs. This is of particular concern since DA concentration in seawater was not systematically correlated to potentially toxic Pseudo-nitzschia abundance

Urban soils exposed to industrial dust deposition: bioavailability of dust-borne metals and ecotoxicity of soil matrices

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