Étude des rôles de la voie antioxydante Nrf2 et la voie anti-inflammatoire PPARγ dans le contrôle de l’inflammation lors d’infections sévères par l'influenza

Chaque année, la grippe provoque des centaines de milliers de décès dans le monde. Dans le cas d’infections sévères, il a été démontré que la génération excessive de molécules inflammatoires telles que les cytokines et les chimiokines, la sécrétion d’espèces réactives dérivées de l'oxygène ainsi que l’afflux massif de cellules immunitaires innées et adaptatives dans les voies respiratoires contribuent à la génération de dommages pulmonaires aigus et contribuent à l'immunopathologie reliée à l’infection. Tenant compte de ce fait, le défi actuel dans le traitement de la grippe est de contrôler la réponse inflammatoire tout en inhibant la réplication virale afin de permettre à l'organisme de se défendre contre les infections sévères à l'influenza. Des études récentes ont montré que l’activation du récepteur nucléaire PPARγ par ses ligands, tel que la 15d-PGJ[indice inférieur 2], diminuait l’inflammation pulmonaire et améliorait la survie des souris infectées avec des doses létales du virus influenza. Mis à part ses effets sur PPARγ, le ligand 15d-PGJ[indice inférieur 2] est aussi connu pour activer le facteur nucléaire antioxydant Nrf2. Il a été montré que Nrf2 réduit la réplication du virus influenza. Cependant, son mode d'action dans cette fonction nécessite une clarification. De manière intéressante, une étude a montré que Nrf2 réduit l’inflammation pulmonaire en régulant l’expression de PPARγ et ceci dans un modèle murin du syndrome de détresse respiratoire aigu. Les résultats de ces études précédentes mènent à l’hypothèse que les voies de PPARγ et Nrf2 interagissent fonctionnellement et qu'elles sont impliquées dans la réduction de l’inflammation induite lors d'infections sévères causées par l'influenza. L’objectif général de cette étude est donc de mieux comprendre les mécanismes protecteurs de PPARγ et Nrf2 dans la régulation de l’inflammation et la réplication virale suite à une infection par le virus influenza. Nos résultats ont démontré premièrement que le fait de cibler les deux voies moléculaires PPARγ et Nrf2, permet une inhibition significative de l’inflammation et de la morbidité liée à l’infection. Dans un deuxième temps, nos résultats dévoilent le mécanisme antiviral de Nrf2 et démontrent que l’activation de cette voie réduit la réplication du virus influenza d’une façon dépendante de l’expression de l’antiprotéase SLPI

Supporting information for "Bis-michael acceptors as novel probes to study the Keap1/Nrf2/ARE pathway"

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator that promotes the transcription of cytoprotective genes in response to oxidative/electrophilic stress. Various Michael-type compounds were designed and synthesized, and their potency to activate the Keap1/Nrf2/ARE pathway was evaluated. Compounds bearing two Michael-type acceptors proved to be the most active. Tether length and rigidity between the acceptors was crucial. This study will help to understand how this feature disrupts the interaction between Keap1 and Nrf2

Aryl hydrocarbon receptor deficiency causes the development of chronic obstructive pulmonary disease through the integration of multiple pathogenic mechanisms

Emphysema, a component of chronic obstructive pulmonary disease (COPD), is characterized by irreversible alveolar destruction that results in a progressive decline in lung function. This alveolar destruction is caused by cigarette smoke, the most important risk factor for COPD. Only 15%-20% of smokers develop COPD, suggesting that unknown factors contribute to disease pathogenesis. We postulate that the aryl hydrocarbon receptor (AHR), a receptor/transcription factor highly expressed in the lungs, may be a new susceptibility factor whose expression protects against COPD. Here, we report that Ahr-deficient mice chronically exposed to cigarette smoke develop airspace enlargement concomitant with a decline in lung function. Chronic cigarette smoke exposure also increased cleaved caspase-3, lowered SOD2 expression, and altered MMP9 and TIMP-1 levels in Ahr-deficient mice. We also show that people with COPD have reduced expression of pulmonary and systemic AHR, with systemic AHR mRNA levels positively correlating with lung function. Systemic AHR was also lower in never-smokers with COPD. Thus, AHR expression protects against the development of COPD by controlling interrelated mechanisms involved in the pathogenesis of this disease. This study identifies the AHR as a new, central player in the homeostatic maintenance of lung health, providing a foundation for the AHR as a novel therapeutic target and/or predictive biomarker in chronic lung disease

Inhalation Toxicology of Vaping Products and Implications for Pulmonary Health

E-cigarettes have a liquid that may contain flavors, solvents, and nicotine. Heating this liquid generates an aerosol that is inhaled into the lungs in a process commonly referred to as vaping. E-cigarette devices can also contain cannabis-based products including tetrahydrocannabinol (THC), the psychoactive component of cannabis (marijuana). E-cigarette use has rapidly increased among current and former smokers as well as youth who have never smoked. The long-term health effects are unknown, and emerging preclinical and clinical studies suggest that e-cigarettes may not be harmless and can cause cellular alterations analogous to traditional tobacco smoke. Here, we review the historical context and the components of e-cigarettes and discuss toxicological similarities and differences between cigarette smoke and e-cigarette aerosol, with specific reference to adverse respiratory outcomes. Finally, we outline possible clinical disorders associated with vaping on pulmonary health and the recent escalation of acute lung injuries, which led to the declaration of the vaping product use-associated lung injury (EVALI) outbreak. It is clear there is much about vaping that is not understood. Consequently, until more is known about the health effects of vaping, individual factors that need to be taken into consideration include age, current and prior use of combustible tobacco products, and whether the user has preexisting lung conditions such as asthma and chronic obstructive pulmonary disease (COPD)

Inhaled Pollutants: The Molecular Scene behind Respiratory and Systemic Diseases Associated with Ultrafine Particulate Matter

Air pollution of anthropogenic origin is largely from the combustion of biomass (e.g., wood), fossil fuels (e.g., cars and trucks), incinerators, landfills, agricultural activities and tobacco smoke. Air pollution is a complex mixture that varies in space and time, and contains hundreds of compounds including volatile organic compounds (e.g., benzene), metals, sulphur and nitrogen oxides, ozone and particulate matter (PM). PM0.1 (ultrafine particles (UFP)), those particles with a diameter less than 100 nm (includes nanoparticles (NP)) are considered especially dangerous to human health and may contribute significantly to the development of numerous respiratory and cardiovascular diseases such as chronic obstructive pulmonary disease (COPD) and atherosclerosis. Some of the pathogenic mechanisms through which PM0.1 may contribute to chronic disease is their ability to induce inflammation, oxidative stress and cell death by molecular mechanisms that include transcription factors such as nuclear factor κB (NF-κB) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Epigenetic mechanisms including non-coding RNA (ncRNA) may also contribute towards the development of chronic disease associated with exposure to PM0.1. This paper highlights emerging molecular concepts associated with inhalational exposure to PM0.1 and their ability to contribute to chronic respiratory and systemic disease

Relation entre le facreur de transcription et de réparation TFIIH et le coactivateur Peroxisome Proliferator-Activated Receptor coactivator 1a (PGC-1a)

Des mutations dans la sous unité XPD du facteur de transcription IIH (TFIIH) conduit à des maladies génétiques rares incluant trichothiodystrophy TTD. Connaissant que la sous unité MAT1 de TFIIH est nécessaire pour une activité complète de l activateur proliferator activated receptor g coactivator 1a (PGC-1a), on a décidé de regarder l influence de la mutation R722W dans XPD sur l activité de PGC-1a dans les hépatocytes TTD. Nos résultats montrent que le facteur transcriptionnel TFIIH est nécessaire pour l activité hépatique du cofacteur PGC-1a dans la voie de la néoglucogenèse. En plus on montre que la mutation R722W dans la sous unité XPD du TFIIH perturbe l interaction du PGC-1a avec SIRT1, dérégulant par ca l activité du PGC-1a. Etant PGC-1a un régulateur important du métabolisme du glucose et des lipides, nos résultats permet donc de suggérer un lien entre les symptômes liés à un défaut du métabolisme observés chez les patients TTD et le dérèglement du comportement du PGC-1a. Des études ultérieures seront nécessaires pour mieux comprendre le mécanisme d activation du PGC-1a par TFIIH, surtout voir si ca implique un lien directe entre SIRT1 et TFIIH. Il est ainsi important d analyser si d autres voies du PGC-1a sont aussi affectées.Mutations in the subunit XPD of the transcription factor IIH (TFIIH) lead to genetic disorders including trichothiodystrophy TTD. Knowing that subunit MAT1 of TFIIH is required for the full function of the proliferator activated receptor g coactivator 1 a (PGC-1a), we decided to study the influence of the mutation R722W in XPD on PGC-1a activity. Using immortalized hepatocytes isolated from TTD mutant mice, we investigated the expression of PGC-1a target genes involved in gluconeogenesis. We observed that these genes are downregulated in TTD hepatocytes. Moreover, we found that XPD mutation disrupted the interaction between PGC-1a and the deacetylase Sirtuin1 (SIRT1) leading to reduced activation of PGC-1a. We also showed that PGC-1a and SIRT1 both interact with TFIIH. We thus established that TFIIH is required for full PGC-1a activity in the gluconeogenesis pathway, and more likely through modulation of SIRT1 activity. Therefore, our results suggest that the deregulation in TTD likely results from the inability of the mutated TFIIH to fully participate in recruitment of PGC-1a and/or SIRT1 to the DNA.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Coronary Access After TAVR With a Self-Expanding Bioprosthesis: Insights From Computed Tomography

Objectives: The authors sought to estimate possible interference of the Medtronic Evolut R/Pro transcatheter heart valve (THV) frame with coronary access using multislice computed tomography (MSCT) data. Background: Lower-risk patients undergoing transcatheter aortic valve replacement (TAVR) endure a high cumulative risk of coronary events, but coronary access can be challenging. Methods: In 101 patients who received an Evolut R/Pro THV, post-TAVR MSCT (performed at a median of 30 days after TAVR) was used to assess possible interference of the elements of the THV frame with coronary access. Results: The closest cell of the THV frame vertically aligned with the coronary ostium was located opposite the ostium in 58% and 63%, below the ostium in 22% and 30%, or above the ostium in 20% and 7% of left and right coronary arteries, respectively. The free sinus of Valsalva space between the THV frame and the coronary ostium was 0.45 ± 0.17 cm and 0.44 ± 0.17 cm for the left and right coronary arteries, respectively, and showed a stepwise decrease with decreasing THV size (p < 0.001). Bioprosthetic valve commissures were antianatomic (i.e., not aligned with native commissures) in 45 patients (47%), and the commissural post was overlapping a coronary ostium in 15 patients (16%). Two patients (2.0%) had a possible interference of the paravalvular sealing skirt with coronary access. Conclusions: Using post-TAVR MSCT data, the main mechanism of potential interference of Evolut R/Pro frame with coronary access was an antianatomic commissural post overlapping the coronary ostium

The Aryl Hydrocarbon Receptor and the Maintenance of Lung Health

Much of what is known about the Aryl Hydrocarbon Receptor (AhR) centers on its ability to mediate the deleterious effects of the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin). However, the AhR is both ubiquitously-expressed and evolutionarily-conserved, suggesting that it evolved for purposes beyond strictly mediating responses to man-made environmental toxicants. There is growing evidence that the AhR is required for the maintenance of health, as it is implicated in physiological processes such as xenobiotic metabolism, organ development and immunity. Dysregulation of AhR expression and activity is also associated with a variety of disease states, particularly those at barrier organs such as the skin, gut and lungs. The lungs are particularly vulnerable to inhaled toxicants such as cigarette smoke. However, the role of the AhR in diseases such as chronic obstructive pulmonary disease (COPD)&#8212;a respiratory illness caused predominately by cigarette smoking&#8212;and lung cancer remains largely unexplored. This review will discuss the growing body of literature that provides evidence that the AhR protects the lungs against the damaging effects of cigarette smoke

Social networks serving web feeds

A web feed is a new kind of web services that was created in the past two decades to keep remote users updated with the latest news without having to crawl individual web sites. Currently, the existing web feed services get their information from one source (the website hosting the feed) in a standardized format that is normally structured as follows: title, description, link, image and date. In this paper, we propose a new method called NERVES (social Networks sERVing wEb feedS) that connects web feeds to a Social Networking Sites (SNS), and aims at (1) keeping users aware of the wider context taking into account both the source of the feed and the SNS. (2) Our approach enriches existing feeds with extra information harvested from the social web. We validated the efficiency and accuracy of our approach on public data and report on empirical results yielding an accuracy of 94%

Purely Inorganic Highly Efficient Ice Nucleating Particle

Air pollution of anthropogenic origin is largely from the combustion of biomass (e.g., wood), fossil fuels (e.g., cars and trucks), incinerators, landfills, agricultural activities and tobacco smoke. Air pollution is a complex mixture that varies in space and time, and contains hundreds of compounds including volatile organic compounds (e.g., benzene), metals, sulphur and nitrogen oxides, ozone and particulate matter (PM). PM0.1 (ultrafine particles (UFP)), those particles with a diameter less than 100 nm (includes nanoparticles (NP)) are considered especially dangerous to human health and may contribute significantly to the development of numerous respiratory and cardiovascular diseases such as chronic obstructive pulmonary disease (COPD) and atherosclerosis. [...] This paper highlights emerging molecular concepts associated with inhalational exposure to PM0.1 and their ability to contribute to chronic respiratory and systemic disease