Antimicrobial peptides (AMPs) are mucosal defense effectors of the human innate immune response. In the intestine, AMPs are produced and secreted by epithelial cells to protect the host against ...pathogens and to support homeostasis with commensals. The inducible nature of AMPs suggests that potent inducers could be used to increase their endogenous expression for the prevention or treatment of diseases. Here we aimed at identifying molecules from the natural pharmacopoeia that induce expression of human β-defensin-3 (HBD3), one of the most efficient AMPs, without modifying the production of proinflammatory cytokines. By screening, we identified three molecules isolated from medicinal plants, andrographolide, oridonin, and isoliquiritigenin, which induced HBD3 production in human colonic epithelial cells. This effect was observed without activation of the NF-κB pathway or the expression of associated proinflammatory cytokines. We identified the EGF receptor as the target of these compounds and characterized the downstream-activated MAPK pathways. At the chromatin level, molecules increased phosphorylation of histone H3 on serine S10 and recruitment of the c-Fos, c-Jun, and Elk1 or c-Myc transcription factors at the HBD3 promoter. Interestingly, stimulating cells with a combination of andrographolide and isoliquiritigenin synergistically enhanced HBD3 induction 10-fold more than observed with each molecule alone. Finally, we investigated the molecular basis governing the synergistic effect, confirmed our findings in human colonic primary cells, and demonstrated that synergism increased cellular antimicrobial activity. This work shows the capability of small molecules to achieve induction of epithelial antimicrobial defenses while simultaneously avoiding the deleterious risks of an inflammatory response.
La crise Covid-19 a mis en évidence le besoin d’anticipation des crises sanitaires. L’ANRS I Maladies Infectieuses Émergentes, agence issue de la fusion de l’ANRS (Agence Nationale de Recherche sur ...le SIDA) et du consortium REACTing (REsearch and ACTion targeting emerging infectious diseases), a été créée dans ce contexte. C’est une agence autonome de l’Inserm qui anime, évalue, coordonne et finance la recherche sur le VIH/sida, les hépatites virales, les infections sexuellement transmissibles, la tuberculose et les maladies infectieuses émergentes et ré-émergentes. La stratégie de l’agence s’intègre dans un large cadre d’initiatives structurantes mises en place au niveau national et international, allant de la recherche fondamentale au développement et à la bioproduction, pour améliorer la préparation et la réponse aux épidémies. Les aspects liés à l’innovation, aux enjeux sociétaux, ainsi qu’à la collaboration internationale sont particulièrement renforcés pour répondre à ces objectifs.
Abstract
The burden of ticks and the pathogens they carry is increasing worldwide. Powassan virus (POWV; Flaviviridae: Flavivirus), the only known North American tick-borne flavivirus, is of ...particular concern due to rising cases and the severe morbidity of POWV encephalitis. Here, we use a multifaceted approach to evaluate the emergence of the II POWV lineage, known as deer tick virus (DTV), in parts of North America where human cases occur. We detected DTV-positive ticks from eight of twenty locations in the Northeast USA with an average infection rate of 1.4 per cent. High-depth, whole-genome sequencing of eighty-four POWV and DTV samples allowed us to assess geographic and temporal phylodynamics. We observed both stable infection in the Northeast USA and patterns of geographic dispersal within and between regions. A Bayesian skyline analysis demonstrated DTV population expansion over the last 50 years. This is concordant with the documented expansion of Ixodes scapularis tick populations and suggests an increasing risk of human exposure as the vector spreads. Finally, we isolated sixteen novel viruses in cell culture and demonstrated limited genetic change after passage, a valuable resource for future studies investigating this emerging virus.
Over 40 years ago the historic Kerner Commission Report declared that America was undergoing an urban crisis whose effects were disproportionately felt by underclass populations. In America's Urban ...Crisis and the Advent of Color-blind Politics, Curtis Ivery and Joshua Bassett explore the persistence of this crisis today, despite public beliefs that America has become a "post-racial" nation after the election of Barack Obama to the presidency. Ivery and Bassett combine their own experience in the fields of civil rights and education with the knowledge of more than 20 experts in the field of urban studies to provide an accessible overview of the theories of the urban underclass and how they affect America's urban crisis. This engaging look into the still-present racial politics in America's cities adds significantly to the existing scholarship on the urban underclass by discussing the role of the prison-industrial complex in sustaining the urban crisis as well as the importance of the concept of multiracial democracy to the future of American politics and society. America's Urban Crisis and the Advent of Color-blind Politics encourages the reader not only to be aware of persisting racial inequalities, but to actively engage in efforts to respond to them.
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