Mise en évidence de dysfonctions liées au développement de l'endométriose péritonéale : contributions angio-inflammatoires des cytokines et prostaglandines

L'endométriose est une maladie gynécologique, touchant les femmes en âge de procréer. Cette pathologie est caractérisée par la présence de tissu endométrial ectopique, c'est-à-dire en dehors de la cavité utérine. Des dysfonctions du système immunitaire sont de plus en plus souvent suspectées comme étant un des éléments responsables de la pathogenèse de cette maladie. L’objectif général de ce projet a donc été d’étudier les mécanismes cellulaires de molécules pro-inflammatoires aux propriétés variées et à l'expression anormalement élevée dans cette pathologie, que sont MIF et les prostaglandines PGE2 et PGF2α, dans les anomalies inflammatoires et invasives en cause dans cette pathologie. La première partie de nos travaux a porté sur l’étude d’un modèle murin de l’endométriose déficient du gène MIF. Le nombre et le volume des lésions collectées à partir des souris déficientes pour le gène MIF sont significativement inférieurs à ceux mesurés dans des souris sauvages utilisées comme contrôle. L’analyse par PCR des cellules isolées des lésions de souris déficientes du gène MIF a révélé une expression réprimée des protéines d’adhésion, d’inflammation et d’angiogenèse. Ces données démontrent pour la première fois que le MIF agit directement sur la croissance et la progression de lésions d’endométriose in vivo. Une partie de nos travaux a porté sur les molécules nécessaires au métabolisme de PGE2 et PGF2α dans l'endomètre eutopique des femmes normales et l'endomètre eutopique et ectopique des femmes atteintes d'endométriose. Selon nos données, l'expression de certains de ces facteurs est perturbée durant cette maladie, ce qui peut avoir des effets délétères sur la physiologie de la procréation. La stimulation des cellules ectopiques par PGF2α entraîne une libération accrue de VEGF et CXCL-8, ceci via l'induction de COX-2 et des deux variants d’épissage du récepteur FP. De plus, la PKC joue un rôle dans ce phénomène, dépendamment et indépendamment de la PLC. Par son effet inducteur sur la libération de VEGF et CXCL-8, PGF2α pourrait favoriser l'aspect inflammatoire et le développement ectopique des lésions d'endométriose, notamment par des phénomènes d’angiogenèse et de prolifération cellulaire accrus. L'effet de PGF2α sur la libération de VEGF et CXCL-8 par les cellules endométriales ectopiques pourrait également expliquer les quantités élevées de ces cytokines dans le liquide péritonéal des femmes atteintes d'endométriose, un phénomène suspecté dans l'infertilité et les douleurs associées à cette maladie. Nos derniers résultats obtenus à partir du liquide péritonéal montrent un profil cytokinique en faveur de l’angiogenèse et la prolifération des lésions d’endométriose, avec une forte augmentation des facteurs suivants : EGF, FGF-2, IL-1α, MIP-1β, TGFα, PDGF-AA, PDGF-BB, MCP-3, sCD40L, Gro Pan, IL-17α, MDC et Rantes, confortant nos observations préalables redéfinissant la maladie comme étant d’origine angio-inflammatoire. L'endométriose et ses symptômes sont des phénomènes complexes ayant probablement plus qu'une seule origine. Parmi les nombreux facteurs à l'expression altérée dans l'endométriose, notre étude montre que MIF, PGE2 et PGF2α, ainsi qu’une pléthore de facteurs pro-angiogéniques pourraient être de ceux jouant un rôle dans l'infertilité et les douleurs reliées à cette maladie.Endometriosis is a menstrual disorders, is mainly diagnosed in the peritoneal cavity by the presence of lesions, which are thought to originate from the endometrium. Little is known about the causes of endometriosis and no targeted treatment is available. Our studies were the first to show functional defects involving the immune system in the endometrium, i.e. before this tissue migrates and grows into abnormal locations. Our current main hypothesis is that endometriosis development requires a combination of immune dysfunction involving factors, such as MIF, PGE2 and PGF2α. Using a mouse model where MIF-knock out (KO) mice received intra-peritoneal injection of endometrial tissue from MIF-KO or syngenic wild type (WT) mice and vice versa, we first revealed that MIF genetic depletion resulted in a marked reduction ectopic endometrial tissue growth, a disrupted tissue structure and a significant downregulation of the expression of major inflammatory, cell adhesion, survival and angiogenic factors relevant to endometriosis pathogenesis, whereas MIF add-back to MIF-KO mice significantly restored endometriosis-like lesions number and size. This study provides compelling evidence for the role of MIF in endometriosis development and its possible interest for a targeted treatment of endometriosis. We then revealed for the first time multiple defects in PG biosynthesis and receptivity pathways, which differ between eutopic intrauterine and ectopic endometrial tissues and may, owing to the wide spectrum of PG properties, contribute to the initial steps of endometrial tissue growth and development and have an important role to play in the pathogenesis and symptoms of this disease. Afterward, we focussed on PGF2α which markedly up-regulated PGE2, CXCL-8 and VEGF secretion in endometriotic cells, through COX-2 activation. Such an effect was abolished by AL8810, a specific FP antagonist, and significantly down-regulated after specific inhibition of FP different variants signalling pathways. PGF2α enhanced angiogenesis through endothelial tubal formation and proliferation processes. These results show for the first time that PGF2α exerts an indirect angiogenic effects by interacting with ectopic stromal cells and induces the secretion of major angiogenic factors via FP signalling pathways. This study provides evidence for a new mechanism underlying endometriosis development and pathophysiology. As our last data showed distinct patterns of peritoneal fluid cytokine concentrations in endometriotic women most notably a marked increase in EGF, FGF-2, IL-1α, MIP-1β, TGFα, PDGF-AA, PDGF-BB, MCP-3, sCD40L, Gro Pan, IL-17α, MDC and Rantes. These changes may exacerbate the local peritoneal angiogenic and proliferative reaction observed in women with endometriosis, and contributes to its pathophysiology. Inflammation is a major hallmark of endometriosis and angiogenesis is crucial to ectopic endometrial tissue growth. Once viewed as archetypical mediators of inflammation and pain, prostaglandins and angiogenic cytokines should be now regarded major promoters of endometriotic lesions growth

Systematyczne podejście do zrównoważonego rozwoju systemów rolno-spożywczych – przykład Republiki Sacha (Jakucja) i Arktyki

The relevance of the study is conditioned by the need to apply a systematic approach to the investigation of agricultural production features as a complex dynamic structure that functions in an unstable market environment and depends on the influence of natural changes. In this regard, this study aims to identify socio-economic, natural, and environmental factors that affect the sustainable development of agricultural sectors, as well as predict the impact of material, technological, and climatic factors on the health and stability of the entire system. The leading method for studying this problem is the method of a systematic approach, which allows investigating agricultural production as a complex dynamic structure that functions in an unstable market environment and depends on the influence of natural factors. In addition, this study involved the following research methods: the method of structural analysis, comparative, statistical, and deduction methods, classification method. The study presents the factors directly or indirectly influencing the development of northern agriculture, predicts the impact of these factors on the stability of the system, and shows possible ways to overcome the negative impact. The regional management system directly affected the level of food self-sufficiency of the Sakha Republic. To improve the current situation, it is necessary to review the mechanisms of interaction between state institutions and agricultural producers. Furthermore, there is an entire list of factors that negatively affect the functioning of the agricultural sector of Yakutia. The situation requires an immediate design of a policy for the development of rural areas through the socio-economic development of villages in the region. The research materials are of practical value for the governing bodies of the agro-industrial complex of the Republic of Sakha (Yakutia), as well as teachers and students studying the issues of sustainable development of agriculture.Trafność badań uwarunkowana jest koniecznością zastosowania systematycznego podejścia do badania cech produkcji rolnej jako złożonej struktury dynamicznej, funkcjonującej w niestabilnym otoczeniu rynkowym i zależnej od wpływu zmian naturalnych. W tym zakresie niniejsze opracowanie ma na celu identyfikację czynników społeczno-ekonomicznych, przyrodniczych i środowiskowych wpływających na zrównoważony rozwój sektorów rolnictwa, a także prognozę wpływu czynników materiałowych, technologicznych i klimatycznych na zdrowotność i stabilność całego systemu. Wiodącą metodą badania tego problemu jest metoda podejścia systemowego, która pozwala badać produkcję rolniczą jako złożoną strukturę dynamiczną, funkcjonującą w niestabilnym otoczeniu rynkowym i zależną od wpływu czynników naturalnych. Ponadto w pracy wykorzystano następujące metody badawcze: metodę analizy strukturalnej, metodę porównawczą, statystyczną i dedukcyjną, metodę klasyfikacyjną. W opracowaniu przedstawiono czynniki wpływające bezpośrednio lub pośrednio na rozwój rolnictwa północnego, przewiduje się wpływ tych czynników na stabilność systemu oraz wskazuje możliwe sposoby przezwyciężenia negatywnego wpływu. Regionalny system zarządzania bezpośrednio wpłynął na poziom samowystarczalności żywnościowej Republiki Sacha. Dla poprawy obecnej sytuacji konieczny jest przegląd mechanizmów interakcji między instytucjami państwowymi a producentami rolnymi. Ponadto istnieje cała lista czynników, które negatywnie wpływają na funkcjonowanie sektora rolnego Jakucji. Sytuacja wymaga pilnego zaprojektowania polityki rozwoju obszarów wiejskich poprzez społeczno-gospodarczy rozwój wsi w regionie. Materiały badawcze mają wartość praktyczną dla władz kompleksu rolno-przemysłowego Republiki Sacha (Jakucja), a także dla nauczycieli i studentów studiujących problematykę zrównoważonego rozwoju rolnictwa

Targeting resilient lentil genotypes with an adding value of nutritional quality by using AMMI and GGE biplots analysis

The current study aims to assess the impact of different genotypes, environmental conditions, and their interactions (G×E) on lentil yield and nutritive traits in various agro-ecological locations across Morocco. To achieve this, two analysis methods, Analysis of Main Additive Effects and Multiplicative Interaction (AMMI), and Genotype and Genotype by Environment (GGE) were used. The study involved evaluating sixty-four lentil genotypes in six diverse environments during the 2017–2018 and 2019–2020 seasons. Results from the analysis of variance revealed that environmental variation significantly influenced grain yield (75.7%), zinc (48.4%), and magnesium (73.3%). In contrast, genotype by environment interaction (G×E) played a more substantial role in determining protein (45.7%), iron (53.2%), and manganese (49.6%) content. The first two components explained 69.2%, 78.3%, 90.5%, 79.3%, 71.4%, and 74.3% of the variation in grain yield, protein content, iron, zinc, manganese, and magnesium, respectively. The GGE biplot analysis identified specific environments (E3 and E5) as representative and discriminative for yield, zinc, and manganese. Similarly, E3 and E4 were discriminative for iron and protein and magnesium, respectively. Seventeen lentil genotypes exhibited high performance, combining yield and nutritional quality. Notably, genotypes LN34 and VR28 performed well in the Marchouch 2019-2020 environment, while genotype LN54 excelled in the Douyet and Sidi el Aydi environments during 2019-2020. Furthermore, three advanced lines (LN34, LN58 and LN64) expressed stability in yield and most nutrient traits, outperforming released lentil varieties. These promising lines hold potential for developing novel, resilient lentil varieties with both high yield and nutritive quality

Reflections from Our Library Visit in Kazakhstan, Heart of Central Asia

Bu okuyucu mektubu, iki Türk akademisyenin Kazakistan’a gerçekleştirmiş oldukları akademik seyahat sırasında iki Kazak akademisyen ile birlikte Astana’da bulunan Kazakistan Cumhuriyeti Ulusal Akademik Kütüphanesi ziyaretine ilişkin yansımaları ele almaktadır. This reader letter addresses the reflections of two Turkish academicians regarding their visit to National Academic Library of the Republic of Kazakhstan in Astana during their academic travel to Kazakhstan

Genetic polymorphism of CYP1A2 but not total or free teriflunomide concentrations is associated with leflunomide cessation in rheumatoid arthritis

AIM(S): Leflunomide, via its active metabolite teriflunomide, is used in rheumatoid arthritis (RA) treatment, yet approximately 20 to 40% of patients cease due to toxicity. The aim was to develop a time-to-event model describing leflunomide cessation due to toxicity within a clinical cohort and to investigate potential predictors of cessation such as total and free teriflunomide exposure and pharmacogenetic influences. METHODS: This study included individuals enrolled in the Early Arthritis inception cohort at the Royal Adelaide Hospital between 2000 and 2013 who received leflunomide. A time-to-event model in NONMEM was used to describe the time until leflunomide cessation and the influence of teriflunomide exposure and pharmacogenetic variants. Random censoring of individuals was simultaneously described. The clinical relevance of significant covariates was visualised via simulation. RESULTS: Data from 105 patients was analysed, with 34 ceasing due to toxicity. The baseline dropout hazard and baseline random censoring hazard were best described by step functions changing over discrete time intervals. No statistically significant associations with teriflunomide exposure metrics were identified. Of the screened covariates, carriers of the C allele of CYP1A2 rs762551 had a 2.29 fold increase in cessation hazard compared to non-carriers (95% CI 2.24 - 2.34, p = 0.016). CONCLUSIONS: A time-to-event model described the time between leflunomide initiation and cessation due to side effects. The C allele of CYP1A2 rs762551 was linked to increased leflunomide toxicity, while no association with teriflunomide exposure was identified. Future research should continue to investigate exposure-toxicity relationships, as well as potentially toxic metabolites. This article is protected by copyright. All rights reserved.Ashley M. Hopkins, Michael D. Wiese, Susanna M. Proudman, Catherine E. O'Doherty, Richard N. Upton, David J. R. Foste

Estrogen- and Progesterone (P4)-Mediated Epigenetic Modifications of Endometrial Stromal Cells (EnSCs) and/or Mesenchymal Stem/Stromal Cells (MSCs) in the Etiopathogenesis of Endometriosis

Endometriosis is a common chronic inflammatory condition in which endometrial tissue appears outside the uterine cavity. Because ectopic endometriosis cells express both estrogen and progesterone (P4) receptors, they grow and undergo cyclic proliferation and breakdown similar to the endometrium. This debilitating gynecological disease affects up to 15% of reproductive aged women. Despite many years of research, the etiopathogenesis of endometrial lesions remains unclear. Retrograde transport of the viable menstrual endometrial cells with retained ability for attachment within the pelvic cavity, proliferation, differentiation and subsequent invasion into the surrounding tissue constitutes the rationale for widely accepted implantation theory. Accordingly, the most abundant cells in the endometrium are endometrial stromal cells (EnSCs). These cells constitute a particular population with clonogenic activity that resembles properties of mesenchymal stem/stromal cells (MSCs). Thus, a significant role of stem cell-based dysfunction in formation of the initial endometrial lesions is suspected. There is increasing evidence that the role of epigenetic mechanisms and processes in endometriosis have been underestimated. The importance of excess estrogen exposure and P4 resistance in epigenetic homeostasis failure in the endometrial/endometriotic tissue are crucial. Epigenetic alterations regarding transcription factors of estrogen and P4 signaling pathways in MSCs are robust in endometriotic tissue. Thus, perspectives for the future may include MSCs and EnSCs as the targets of epigenetic therapies in the prevention and treatment of endometriosis. Here, we reviewed the current known changes in the epigenetic background of EnSCs and MSCs due to estrogen/P4 imbalances in the context of etiopathogenesis of endometriosis

Particular solutions of generalized Euler-Poisson-Darboux equation

In this article we consider the generalized Euler-Poisson-Darboux equation $${u}_{tt}+\frac{2\gamma }{t}{{u}_{t}}={u}_{xx}+{u}_{yy} +\frac{2\alpha }{x}{{u}_{x}}+\frac{2\beta }{y}{{u}_y},\quad x>0,\;y>0,\;t>0.$$ We construct particular solutions in an explicit form expressed by the Lauricella hypergeometric function of three variables. Properties of each constructed solutions have been investigated in sections of surfaces of the characteristic cone. Precisely, we prove that found solutions have singularity $1/r$ at $r\to 0$, where ${{r}^2}={{( x-{{x}_0})}^2}+{{( y-{{y}_0})}^2}-{{( t-{{t}_0})}^2}$