38 research outputs found
Modulation ROS/RNS dans le traitement de la sclérose systémique
No full textSeveral reports have suggested that reactive oxygen and nitrogen species are involved in SSc pathogenesis. SSc fibroblast from skin and internal organs overproduce ROS that trigger the proliferation of fibroblasts and the synthesis of type I collagen leading to the initiation and progresion of SSc. As in human SSc, skin fibroblasts from SSc mice constitutively produce large amounts of ROS. We have used this property to selectively induce apoptosis in the diseased fibroblast of SSc mice. Indeed, the organotelluride catalyst-(PHTE)2NQ and natural organosulfur compound – Dipropyltertrasulfide (DPTTS) are able of increasing ROS production by fibroblasts and inducing a lethal oxidative stress specificaly in SSc fibroblasts. This phenomenon has no impact on normal fibroblasts that present normal levels of ROS and a normal oxidant/antioxidant status. Many studies have also proved an importance of nitrogen species in the pathogenesis of SSc. In patients with SSc, the serum level of nitric oxide is significantly increased. Furthermore, NO can combine with other free radicals like superoxide anion (O•-2) to form the highly cytotoxic peroxynitrite (ONOO−) that contributes to inflammation, fibrosis and apoptosis of endothelial cells. Production of NO by endothelial cells or by fibroblasts can be stimulated by angiotensin II, the main peptide of the renin-angiotensin system (RAS). The level of angiotensin II is increased in SSc patients as well as in our HOCl mouse model and can promote proliferation of fibroblasts, fibrosis, and inflammation. These observations led us to test irbesartan, an angiotensin II type I receptor antagonist (AT1 RA) in the murine model of SSc. A new animal model based on chronic exposure to ROS and with many similarities to the human disease, allowed me to study new therapeutic approaches in SSc based on the cytotoxic action of pro-oxidative compounds - (PHTE)2NQ and DPTTS - and on the anti- nitrosative effect of irbesartan. These new therapeutic strategies open interesting perspectives in the treatment of SSc, where the therapeutic arsenal is currently still limited.Plusieurs rapports ont suggéré que les formes réactives de l'oxygène (FRO) et d'azote sont impliquées dans la pathogénèse de la ScS. Les fibroblastes ScS de la peau et des organes internes surproduisent des FRO qui déclenchent la prolifération des fibroblastes et la synthèse de collagène de type I, conduisant à l'initiation et à la progression de la ScS. Le laboratoire a mis au point un modèle de souris ScS, induite par injections itératives de HOCl. Comme dans la ScS humaine, les fibroblastes de la peau de souris ScS produisent de manière constitutive de grandes quantités de FRO. Nous avons utilisé cette propriété pour induire sélectivement l'apoptose de fibroblastes de souris ScS. Le catalyseur organotelluride-(PHTE) 2NQ et le composé naturel Dipropyltertrasulfide (DPTTS) sont capables d'augmenter specifiquement la production de FRO par les fibroblastes et d’induire un stress oxydatif létal dans les fibroblastes sclérodermiques. Ce phénomène n'a aucun impact sur les fibroblastes normaux qui présentent des taux de FRO basaux faible et un statut oxydant / antioxydant normal. De nombreuses études ont également prouvé l’importance des espèces azotées dans la l’induction de la ScS. Chez les patients atteints de SSc, le taux sérique de l'oxyde nitrique est considérablement accru. De plus, le NO peut se combiner avec d'autres radicaux libres comme l'anion superoxyde (O•-2) pour former le peroxynitrite (ONOO-) qui est hautement cytotoxique et contribue à l'inflammation, la fibrose et l'apoptose des cellules endothéliales. La production de NO par les cellules endothéliales ou les fibroblastes peut être stimulée par l'angiotensine II, principal peptide de la voie rénine-angiotensine (RAS). Comme chez les patients atteints de sclérodermie, les souris HOCl/ScS présentent des taux sériques d'angiotensine II élevés, ce qui est favorable à la prolifération des fibroblastes, à la fibrose, et à l'inflammation. Ces observations nous ont conduites à tester les effets de l'Irbésartan, un antagoniste des récepteurs de l’angiotensine II de type I (AT1 RA) dans le ScS modèle murin. Un nouveau modèle animal basé sur l'exposition chronique à des ROS et présentant de nombreuses similitudes avec la maladie humaine, m'a permis d'étudier de nouveaux traitements de la ScS. Ces nouvelles approches sont basées sur l'action cytotoxique de composés pro-oxydants - (PHTE) 2NQ et DPTTS - et sur les effets anti-nitrosatifs de molécules comme l'Irbésartan. Ces stratégies thérapeutiques originales ouvrent des perspectives intéressantes dans le traitement de la ScS, où l'arsenal thérapeutique est actuellement encore limité
Modulation ROS/RNS dans le traitement de la sclérose systémique
No full textPas de résumé en françaisPas de résumé en anglaisPARIS5-Bibliotheque electronique (751069902) / SudocSudocFranceF
Update on biomarkers in systemic sclerosis: tools for diagnosis and treatment
No full textSystemic sclerosis (SSc) is a complex autoimmune disease in which immune activation, vasculopathy, and extensive fibrosis of the skin and internal organs are among the principal features. SSc is a heterogeneous disease with varying manifestations and clinical outcomes. Currently, patients' clinical evaluation often relies on subjective measures, non-quantitative methods, or requires invasive procedures as markers able to predict disease trajectory or response to therapy are lacking. Therefore, current research is focusing on the discovery of useful biomarkers reflecting ongoing inflammatory or fibrotic activity in the skin and internal organs, as well as being predictive of future disease course. Recently, remarkable progress has been made towards a better understanding of numerous mechanisms involved in the pathogenesis of SSc. This has opened new possibilities for the development of novel biomarkers and therapy. However, current proposed biomarkers that could reliably describe various aspects of SSc still require further investigation. This review will summarize studies describing the commonly used and validated biomarkers, the newly emerging and promising SSc biomarkers identified to date, and consideration of future directions in this field
Armenia: An Uneasy Choice Between Russia's New Initiatives And The Eu Eastern Partnership
No full textThe article studies the problems of foreign policy orientations of the Republic of Armenia, first of all those concerning "Russian" and "European" integration processes. Particularly, the main stages and peculiarities of Armenia's cooperation with the EU are presented. The author reflects upon the issue of the essence of the status and perspectives of associated membership in the EU. Revealing the difficulties within the EU and on the CIS territory, the author analyzes the capabilities of Armenia to combine, on the one hand, economic integration with the West and, on the other, military-political integration with the East. The article identifies the reasons of "freezing" Armenian-Russian relations in early 2013. Examining the perspectives of the Association Agreement with the EU and of membership in the Customs Union and taking into account the complex geopolitical situation in the region, analyzing all the facets of Armenia's economic and political collaboration both with the EU and RF, the author comes to the conclusion that Yerevan's choice of September 35 3,2013 is expedient and justified. Deepened strategic cooperation with Moscow, first of all, provides military and energy security of Armenia, although the economic factor shouldn't be underestimated. The author draws attention to the fact that Armenia's involvement in the Customs Union avails it the opportunity to keep collaborating with the European Union, however, from a more powerful position, which we have already witnessed through the alterations in the tone of some European officials
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Computer-based learning in German.
No full textFor many students, the most difficult part of learning a language is learning vocabulary. Even after grammar concepts are learned, a student of a language must still learn thousands of words to become fluent in the language. This IQP work presents a PC-based computer program to assist in the memorization of vocabulary that was written. The programming language is Sun Java v. 1.4.2. The program uses several original features and ideas developed by the author in order to help the student learn vocabulary more efficiently. These features are discussed in detail in the text. Also, the structure of the program and the associated documentation or "the user manual" are thoroughly described. The program runs on an ordinary PC with any operating system, such as Windows or GNU/Linux, to name a few, since Java is a portable programming language
Dendritic cells in systemic sclerosis: Advances from human and mice studies
No full textSystemic sclerosis (SSc) is a complex heterogeneous fibrotic autoimmune disease with an unknown exact etiology, and characterized by three hallmarks: fibrosis, vasculopathy, and immune dysfunction. Dendritic cells (DCs) are specialized cells in pathogen sensing with high potency of antigen presentation and capable of releasing mediators to shape the immune response. Altered DCs distributions and their impaired functions may account for their role in breaking the immune tolerance and driving inflammation in SSc, and the direct contribution of DCs in promoting endothelial dysfunction and fibrotic process has only begun to be understood. Plasmacytoid dendritic cells in particular have been implicated due to their high production of type I interferon as well as other cytokines and chemokines, including the pro-inflammatory and anti-angiogenic CXCL4. Furthermore, a deeper understanding of human and mouse DC biology has clarified their identification and function in different tissues, and novel DC subsets have only recently been discovered. In this review, we highlight key findings and recent advances exploring DC role in the pathogenesis of SSc and other related autoimmune diseases, and consideration of their potential use as targeted therapy in SSc
A Lightweight Treatment of Inexact Dates
No full textThis paper presents a lightweight approach to representing inexact dates on the semantic web, in that it imposes minimal ontological commitments on the ontology author and provides data that can be queried using standard approaches. The approach is presented in the context of a significant need to represent inexact dates but the heavyweight nature of existing proposals which can handle such information. Approaches to querying the represented information and an example user interface for creating such information are presented
Low RUNX3 expression alters dendritic cell function in patients with systemic sclerosis and contributes to enhanced fibrosis
No full textObjectives Systemic sclerosis (SSc) is an autoimmune disease with unknown pathogenesis manifested by inflammation, vasculopathy and fibrosis in skin and internal organs. Type I interferon signature found in SSc propelled us to study plasmacytoid dendritic cells (pDCs) in this disease. We aimed to identify candidate pathways underlying pDC aberrancies in SSc and to validate its function on pDC biology.Methods In total, 1193 patients with SSc were compared with 1387 healthy donors and 8 patients with localised scleroderma. PCR-based transcription factor profiling and methylation status analyses, single nucleotide polymorphism genotyping by sequencing and flow cytometry analysis were performed in pDCs isolated from the circulation of healthy controls or patients with SSc. pDCs were also cultured under hypoxia, inhibitors of methylation and hypoxia-inducible factors and runt-related transcription factor 3 (RUNX3) levels were determined. To study Runx3 function, Itgax-Cre: Runx3(f/f) mice were used in in vitro functional assay and bleomycin-induced SSc skin inflammation and fibrosis model.Results Here, we show downregulation of transcription factor RUNX3 in SSc pDCs. A higher methylation status of the RUNX3 gene, which is associated with polymorphism rs6672420, correlates with lower RUNX3 expression and SSc susceptibility. Hypoxia is another factor that decreases RUNX3 level in pDC. Mouse pDCs deficient of Runx3 show enhanced maturation markers on CpG stimulation. In vivo, deletion of Runx3 in dendritic cell leads to spontaneous induction of skin fibrosis in untreated mice and increased severity of bleomycin-induced skin fibrosis.Conclusions We show at least two pathways potentially causing low RUNX3 level in SSc pDCs, and we demonstrate the detrimental effect of loss of Runx3 in SSc model further underscoring the role of pDCs in this disease
The microplastic-crisis: Role of bacteria in fighting microplastic-effects in the digestive system /
No full textPlastic particles smaller than 5 mm, referred to as Microplastics, pose health risks, like metabolic, immunological, neurological, reproductive, and carcinogenic effects, after being ingested. Smaller plastic particles are more likely to be absorbed by human cells, with nanoplastics showing higher potential for cellular damage, including DNA fragmentation and altered protein functions. Micro- and nanoplastics (MNPs) affect the gastrointestinal tract by altering the microbial composition, they could influence digestive enzymes, and possibly disrupt mucus layers. In the stomach, they potentially interfere with digestion and barrier functions, while in the intestines, they could increase permeability via inflammation and tissue disruption. MNPs can lead to microbial dysbiosis, leading to gastrointestinal symptoms. By activating inflammatory pathways, altering T cell functions and affecting dendritic cells and macrophages, immune system homeostasis could possibly be disrupted. Probiotics offer potential strategies to alleviate plastic effects, by either degrading plastic particles or directly countering health effects. We compared genetic sequences of probiotics to the genome of known plastic degraders and concluded that no probiotic bacteria could serve the role of plastic degradation. However, probiotics could directly mitigate MNP-health effects. They can restore microbial diversity, enhance the gut barrier, regulate bile acid metabolism, reduce inflammation, regulate insulin balance, and counteract metabolic disruptions. Antioxidative properties protect against lipid peroxidation and MNP-related reproductive system damage. Probiotics can also bind and degrade toxins, like heavy metals and bisphenol A. Additionally, bacteria could be used to aggregate MNPs and reduce their impact. Therefore, probiotics offer a variety of strategies to counter MNP-induced health effects
