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Betz, Christine [Verfasser], and Oliver [Akademischer Betreuer] Einsle. "Structural characterization of the metal-binding ligands S100A8/S100A9 and S100B of the receptor for advanced glycation end products = Strukturelle Charakterisierung der metallbindenden Liganden S100A8/S100A9 und S100B des Rezeptors für Advanced Glycation End Products." Freiburg : Universität, 2013. http://d-nb.info/1115813455/34.
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Leukert, Nadja. "Molekulare Charakterisierung verschiedener Komplexformen der Calcium-bindenden Proteine S100A8 und S100A9." [S.l. : s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=967777062.
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van, Hummel Annika Elise. "The Roles of S100A8 and S100A9 in Cartilage: Degradation and Formation." Thesis, The University of Sydney, 2014. http://hdl.handle.net/2123/11521.
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Osteoarthritis (OA) is a debilitating joint disease that increases in prevalence with age, with latest figures show that around 2.4 million Australians suffer from OA. There are currently no disease-modifying drugs available and due to poor management options, the number of joint replacement surgeries is increasing by nearly 10% per annum in Australia. S100A8 and S100A9 calcium-binding proteins are expressed by immune cells, and are involved in inflammatory situations, including inflammatory diseases such as rheumatoid arthritis, where there is an increase in circulating and local (synovial fluid) levels of S100A8 and S100A9. They are present in the body preferentially as a heterodimer (S100A8/S100A9) or less commonly as homodimers. Recently, S100A8 and S100A9 were found in bone and cartilage cells; however their roles in these tissues are still unknown. The aim of this research therefore was to determine the role(s) of S100A8 and S100A9 in cartilage degeneration and OA. The results presented in this thesis have provided insight into the role(s) of S100A8 and S100A9 in cartilage and in OA. S100A8 and S100A9 act as primers of cartilage degradation, through TLR4 and MAPK signalling pathways, but require a second messenger in order to achieve full biochemical breakdown. S100A8 is abundant in chondrocytes of human OA joints, but does not appear to be involved in non-inflammatory mouse models. S100A8, and to a lesser degree S100A9, are also abundant at joint margins and in osteophytes from human OA patients, and may play a role in chondrogenesis. The results presented in this thesis have determined some of the mechanisms of action of S100A8 and S100A9 in cartilage, however, the exact role of S100A8 and S100A9 in OA remain unclear, and further work will need to be performed to fully determine the significance of S100A8 and S100A9 in OA.
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Raquil, Marie-Astrid. "Études des rôles pro-inflammatoires et prolifératifs des protéines S100A8 et S100A9." Thesis, Université Laval, 2008. http://www.theses.ulaval.ca/2008/25415/25415.pdf.
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Sikora, Kristin [Verfasser]. "RAGE-abhängige S100A8- und S100A9-Expression in humanen THP-1 Zellen / Kristin Sikora." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2009. http://d-nb.info/1023749920/34.
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Dubois, Christelle. "Confirmation de biomarqueurs pour le pronostic du sepsis et développement de tests rapides High plasma level of S100A8/S100A9 and S100A12 at admission indicates a higher risk of death in septic shock patients Top-down and bottom-up proteomics of circulating S100A8/S100A9 complexes in plasma of septic shock patients." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS521.
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Le sepsis est la 3eme cause de mortalité dans les pays occidentaux, avec un taux de mortalité entre 20 et 50% selon la sévérité. La « prédiction » du devenir clinique du patient est essentielle pour établir le traitement le plus adéquat. Quelques protéines marqueurs de l'inflammation ou d'une infection (CRP, procalcitonine) sont citées pour le suivi des patients en clinique mais manquent de spécificité pour le sepsis. D'autre part, les études « omiques » ont permis de générer des listes de biomarqueurs potentiels du pronostic vital du sepsis. En revanche, aucun n'a encore été validé et/ou confirmé en fonction de la gravité du sepsis et du devenir du patient. Il faut pour cela accéder non seulement à des cohortes de patients parfaitement caractérisées et également disposer de méthodes quantitatives robustes et validées. La spectrométrie de masse apporte une capacité de spécificité et de multiplexage à haut niveau qui permettait de confirmer l'intérêt d'une ou plusieurs de ces protéines dans le cas du pronostic du sepsis. Les dosages immunologiques apportent quant à eux en plus de la sensibilité et de la spécificité, une mise en œuvre en routine clinique simple et rapide. Dans un premier temps, une liste de biomarqueurs identifiés avec des cohortes de patients a été établie d’après la littérature. Puis, des méthodes de quantification de ces biomarqueurs ont été développées. Nous nous sommes intéressés d’une part à quantifier les calgranulines dans le plasma en développant des ELISA et des méthodes de spectrométrie de masse par des approches bottom-up et top-down. D’autre part, deux méthodes de quantification multiplexes ont été développées par spectrométrie de masse avec et sans étape d’immunopurification en fonction des concentrations des protéines présentes dans le plasma afin de vérifier la pertinence de la liste de biomarqueurs potentiels. Toutes ces méthodes ont été appliquées à une cohorte de 49 patients atteints de choc septiqueSepsis is the 3rd leading cause of death in Western countries, with a mortality rate between 20 and 50% depending on the severity. The 'prediction' of the patient's clinical outcome is essential to establish the most appropriate treatment. Some inflammation or infection markers protein (CRP, procalcitonin) are cited for clinical follow-up of patients but lack specificity for sepsis. On the other hand, "omics" studies have generated lists of potential biomarkers of sepsis prognosis. However, none have yet been validated and/or confirmed based on the severity of the sepsis and the patient's fate. This requires access not only to fully characterized patient cohorts but also to robust and validated quantitative methods. Mass spectrometry provides a high level of specificity and high multiplex capacity and that would allow to confirm the interest of one or more of these proteins for sepsis prognosis. Immunological assays provide, in addition to sensitivity and specificity, a simple and rapid routine clinical implementation. First, a list of biomarkers identified with patient cohorts was established from the literature. Then, methods to quantify these candidate biomarkers were developed. On the one hand, we have been interested in quantifying calgranulins in plasma by developing ELISAs and mass spectrometry methods using bottom-up and top-down approaches. On the other hand, two multiplex quantification methods by mass spectrometry with and without immunopurification step according to protein concentrations have been developed to verify the relevance of the list of potential biomarkers. All these methods were applied to a cohort of 49 patients with septic shock
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Zwicker, Stephanie. "Psoriasin (S100A7) and koebnerisin (S100A15) in the model of inflammation." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-185702.
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Ludwig, Stefan [Verfasser]. "Die S100-Proteine S100A8 und S100A9 sowie der Heterodimerkomplex S100A8/A9 im Serum und Plasma als Marker des Prostatakarzinoms : Untersuchungen zu präanalytischen Einflussfaktoren und zur diagnostischen Differenzierung zwischen benigner Prostatahyperplasie und Prostatakarzinom / Stefan Ludwig." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2008. http://d-nb.info/1023022486/34.
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Belot, Nathalie. "Caractérisation du rôle des protéines S100A4 et S100A6 dans la migration de cellules gliales tumorales." Doctoral thesis, Universite Libre de Bruxelles, 2004. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/211198.
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Laouedj, Malika. "Effets des protéines S100A8 et S100A9 dans la différenciation cellulaire dans la leucémie myéloïde aiguë." Doctoral thesis, Université Laval, 2017. http://hdl.handle.net/20.500.11794/27761.
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Tableau d’honneur de la Faculté des études supérieures et postdoctorales, 2016-2017Les leucémies myéloïdes aiguës (LMA) sont des hémopathies rares, mais très agressives. Elles résultent d’un dérèglement du processus d’hématopoïèse qui se caractérise par une prolifération incontrôlée de cellules sanguines immatures engagées dans la lignée myéloïde. En dépit des traitements actuels qui reposent sur l’utilisation d’agents chimiothérapeutiques ciblant les cellules en prolifération, le pronostic des patients souffrants de LMA est très sombre. En effet, seuls 30% des patients souffrants de LMA survivent au-delà de 5 ans suivant la prise en charge thérapeutique. L’identification des acteurs participant au développement et au maintien des LMA est donc cruciale pour l’élaboration d’une stratégie thérapeutique efficace et ciblée. S100A8 et S100A9 sont des protéines fixatrices de calcium exprimées par les neutrophiles et les monocytes. Ce sont des alarmines jouant des rôles clés dans l’inflammation et dans des pathologies causées par une inflammation excessive. Les protéines S100A8 et S100A9 exercent également de multiples fonctions dans divers tumeurs solides. Elles favorisent la formation de niche pré-métastasique et inhibe la réponse immunitaire antitumorale. Une analyse du génome par séquençage a mis en évidence que S100A8 et S100A9 sont fortement exprimées chez les patients atteints de LMA. De plus, l’expression de la protéine S100A8 chez les patients souffrants de LMA serait corrélée avec un faible taux de survie. Principalement étudiées dans les tumeurs solides, les fonctions des protéines S100A8 et S100A9 dans les néoplasies hématologiques telles que les leucémies sont très peu documentées. Dans ces travaux de thèse, nous nous sommes donc intéressés aux rôles exercés par les protéines S100A8 et S100A9 dans les leucémies myéloïdes aiguës. À l’aide d’un modèle murin de LMA induit par la surexpression des facteurs HOXA9 et MEIS1 dans des cellules souches/progénitrices hématopoïétiques, nous avons démontré l’existence d’une fraction de cellules exprimant les protéines S100A8 et S100A9. Celle-ci est également retrouvée chez les patients atteints de leucémies aiguës myélomonocytaires et monocytaires (M4-M5 d’après la classification FAB). Les études menées in vivo et in vitro révèlent que la protéine S100A9 induit la différenciation des cellules leucémiques, tandis que la protéine S100A8, préviens l’effet de S100A9 permettant de maintenir ainsi le phénotype immature des cellules LMA. Le traitement par la protéine recombinante S100A9 permet d’accroitre la maturation des cellules LMA, diminue leur prolifération et prolonge la survie des souris LMA. De la même façon le traitement par les anticorps anti-S100A8 provoque un effet similaire au traitement par la protéine S100A9. Nos résultats suggèrent que de forts ratios de S100A9 sur S100A8 sont requis pour induire la différenciation des cellules LMA. Le mécanisme intracellulaire par lequel S100A9 induit la différenciation des cellules leucémiques a également été étudié dans le cadre de cette thèse. Nous avons identifié que S100A9 via la liaison au récepteur TLR (Toll-like receptor) active les voies de signalisations Mitogen Activated Protein Kinase p38, Jun N-terminal Kinase et extracellular signal-regulated kinases 1 et 2 et provoque la différenciation des cellules leucémiques. Les essais menés sur des cellules primaires de patients malades ont permis de confirmer la capacité de S100A9 et de S100A8 à réguler la différenciation des cellules leucémiques. En somme, les données présentées dans cette thèse contribuent à une meilleure compréhension des rôles des protéines S100A8 et S100A9 dans la différenciation des cellules myéloïdes. Par ailleurs, nos données permettent également d’entrevoir les bénéfices thérapeutiques liés au blocage de S100A8 ou à l’augmentation de S100A9 dans les LMA.
Acute myeloid leukemias (AMLs) are rare but still aggressive hematological diseases. They are the result of a perturbed hematopoietic process characterized by an uncontrolled proliferation of hematopoietic cells committed to the myeloid lineage. Despite current therapy based on chemotherapeutic agents, aimed at killing proliferating cells, prognosis of AML patients is dismal and only 30 % of patients survived beyond 5 years. Identification of actors involved in the initiation and sustaining LMA is crucial to the development of efficient and targeted therapy strategy. S100A8 and S100A9 are calcium-binding proteins predominantly expressed by neutrophils and monocytes, and play key roles in both normal and pathological inflammation. Recently, both proteins were found to promote tumor progression through the establishment of pre-metastatic niches and to inhibit antitumor immune responses. Although S100A8 and S100A9 have been studied in solid cancers, their functions in hematological malignancies remain poorly understood. However, S100A8 and S100A9 are highly expressed in acute myeloid leukemia (AML), and S100A8 expression has been linked to a poor prognosis in AML. Although the roles of these proteins were studies in solid tumor, little is known in their functions in hematological malignancies. We studied in this thesis the role of S100A8 and S100A9 in acute myeloid leukemia. Using AML mouse model of AML surexpressing HOXA9 and MEIS1 in hematopoietic stem and progenitor cells, we identified a small subpopulation of cells expressing S100A8 and S100A9. This subpopulation was consistently found in AML samples from patients with myelomonocytic and monocytic leukemias (M4 and M5 according FAB classification). In vitro and in vivo analyses revealed that S100A9 induces AML cell differentiation, whereas S100A8 prevents differentiation induced by S100A9 activity and maintains AML immature phenotype. Treatment with recombinant S100A9 proteins increased AML cell maturation, induced growth arrest, and prolonged survival in an AML mouse model. Interestingly, anti-S100A8 antibody treatment had effects similar to S100A9 therapy in vivo, suggesting that high ratios of S100A9 over S100A8 are required to induce differentiation. In this thesis, the mechanism of S100A9 leading to differentiation of leukemic cells was also study. Our in vitro studies on the mechanisms/pathways involved in leukemic cell differentiation revealed that binding of S100A9 to toll-like receptor 4 (TLR4) promotes activation of p38 mitogen-activated protein kinase, extracellular signal-regulated kinases 1 and 2, and Jun N-terminal kinase signaling pathways, leading to myelomonocytic and monocytic AML cell differentiation. Overall, our findings indicate that S100A8 and S100A9 are regulators of myeloid differentiation in leukemia and have therapeutic potential in myelomonocytic and monocytic AMLs.
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Defrêne, Joan. "Fonctions des protéines S100A8 et S100A9 dans la réponse inflammatoire associée aux maladies auto-immunes." Doctoral thesis, Université Laval, 2020. http://hdl.handle.net/20.500.11794/66869.
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De nos jours, les maladies auto-immunes concernent une part grandissante de la population mondiale et s’accompagnent d’une comorbidité importante, mais aussi d’un lourd fardeau économique. Parmi ces maladies les plus courantes, on distingue l'arthrite rhumatoïde et le psoriasis affectant respectivement les articulations et la peau et qui ne possèdent toujours pas de traitements curatifs. Dans la pathogenèse de ces maladies, une forte réponse inflammatoire est notamment générée et entretenue, contribuant ainsi à la dégradation des tissus ciblés. De nombreux marqueurs de l’inflammation sont sécrétés dans ces tissus, dont les protéines S100A8 et S100A9 qui sont deux motifs moléculaires associés aux dommages cellulaires. Ces deux protéines sont majoritairement exprimées par les neutrophiles et les cellules myéloïdes activées ainsi que les kératinocytes. Plusieurs études démontrent des propriétés pro-inflammatoires pour S100A8 et S100A9. S100A9 stimule la sécrétion de cytokines pro-inflammatoires par les neutrophiles et les monocytes. La protéineS100A8 est chimiotactique pour les neutrophiles et les monocytes et sa neutralisation in vivo diminue le recrutement de leucocytes dans l’inflammation aiguë. En revanche, des études suggèrent des fonctions anti inflammatoires pour S100A8. Son expression est notamment induite par l’interleukine 10 et les glucocorticoïdes. De plus, S100A8 est sensible à l’oxydation et sa forme oxydée possède des fonctions anti inflammatoires. Cependant, les fonctions de ces deux protéines dans le développement de l’inflammation associées aux maladies auto-immunes sont peu connues. Nous avons effectué la première caractérisation des souris déficientes pour S100a8 et démontré que la protéine S100A8 contrôle la différenciation des cellules myéloïdes et leur capacité à moduler la réponse inflammatoire. À l’aide du modèle d’arthrite induite par le collagène, nous avons démontré que S100A8 est anti-inflammatoire. Elle diminue l’infiltration de neutrophiles et la sécrétion de cytokines pro-inflammatoires dans les pattes. Également, nous avons démontré que S100A8 atténue l’activité des ostéoclastes in vitro et invivo. Le traitement avec un anticorps contre la protéine S100A8 nous a permis de démontrer que les fonctions anti-inflammatoires de S100A8 sont principalement extra cellulaires. En comparant les souris déficientes pour S100a8 et S100a9, nous avons étudié le rôle de S100A8 et S100A9 dans le psoriasis induit par l’imiquimod chez la souris. Dans ce modèle, S100A8 et S100A9 amoindrissent l’hyperplasie et l’inflammation de la peau. Ces travaux ont montré que S100A8 contrôle la différenciation et la prolifération des kératinocytes. Aussi, S100A8 et S100A9 contrôlent l’infiltration de neutrophiles dans le derme ainsi que la réponse des lymphocytes T producteurs d’IL-17 dans les ganglions lymphatiques et le derme.Les travaux de cette thèse démontrent que S100A8 est anti-inflammatoire dans l’arthrite et le psoriasis, mais que S100A9 possède des fonctions différentes dans l’inflammation dépendamment du type de réaction inflammatoire. Par ailleurs, nous avons révélé que deux alarmines peuvent étonnamment exercer des fonctions anti-inflammatoires. La compréhension de ces nouveaux rôles de modulation de l’inflammation pourrait contribuer au développement de nouvelles thérapies.
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Chapeton, Montes Julie Andrea. "Caractérisation des voies alternatives de sécrétion des protéines S100A8/A9 et S100A12 par les neutrophiles humains." Master's thesis, Université Laval, 2015. http://hdl.handle.net/20.500.11794/26156.
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Bien que les protéines S100A8/A9 et S100A12 exprimées par les neutrophiles ne possèdent pas de peptide signal, elles sont retrouvées dans le sérum de patients souffrant de diverses maladies inflammatoires. Les mécanismes de sécrétion de ces protéines demeurent peu connus ainsi que les agonistes qui favorisent leur sécrétion. Nous avons donc émis l´hypothèse que plusieurs voies de sécrétion alternative ainsi que plusieurs agonistes des neutrophiles pourraient participer à la libération de ces protéines. Dans un premier temps, nous avons étudié les stimuli capables de provoquer la sécrétion de la calprotectine et/ou de la S100A12. Dans une deuxième partie, nous nous sommes intéressés aux signaux et mécanismes alternatifs de sécrétion impliqués dans le relargage de ces protéines. L’ensemble de ces travaux montre la complexité des voies de sécrétion alternatives impliquées dans la sécrétion des protéines S100 et comment ces voies sont influencées par l’activation des neutrophiles par différents agonistes.Although S100A8/A9 (calprotectin) and S100A12 proteins expressed by neutrophils lack a signal peptide, they are found in the serum of patients with various inflammatory diseases. However, the mechanisms of secretion and the agonists that promote their secretion are still unknown. We hypothesized that several alternative secretory pathways and several agonists of neutrophils may participate in the release of S100A8/A9 and S100A12 protein. Initially, we studied the stimuli inducing the secretion of calprotectin and / or S100A12. In a second part, we were interested in signals and alternative mechanisms of secretion involved in the release of the calprotectin and S100A12. In conclusion, this study shows the complexity of alternative secretion pathways involved in S100 secretion and that these pathways are influenced by the activation of neutrophils by various agonists.
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Okada, Kouki. "CD68 on rat macrophages binds tightly to S100A8 and S100A9 and helps to regulate the cells’ immune functions." 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225517.
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Goyette, Jesse Davis Medical Sciences Faculty of Medicine UNSW. "The extracellular functions of S100A12." Publisher:University of New South Wales. Medical Sciences, 2008. http://handle.unsw.edu.au/1959.4/41302.
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The S100s comprise a group of Ca2+-binding proteins of the EF-hand superfamily with varied functions. Within this family, three inflammatory-related proteins - S100A8, S100A9 and S100A12 - form a subcluster known as the 'calgranulins'. S100A12 levels are elevated in sera from patients with inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. S100A12 is constitutively expressed in neutrophils and induced in monocytes by LPS and TNFα, and in macrophages by IL-6. S100A12 is a potent monocyte and mast cell chemoattractant and its potentiation of mast cell activation by IgE cross-linking indicates an important role in allergic inflammation. Importantly, mast cell-dependent activation of acute inflammatory responses and monocyte recruitment is provoked by S100A12 administration in vivo. S100A12 may also influence adhesion molecule expression on endothelial cells, stimulate IL 1β and TNFinduced in monocytes production in BV 2 microglial cells, and stimulate IL 2 secretion by T lymphocytes via ligation of the receptor for advanced glycation end-products (RAGE). To date, the only extracellular receptor characterised for S100A12 is RAGE, although additional/alternate receptors are indicated. In particular, recent studies indicate that chemotaxis and mast cell activation by S100A12 are likely mediated by other receptors. The studies presented here investigated some extracellular functions of S100A12, factors influencing these functions and suggest mechanisms that may be involved. In addition to Ca2+, S100A12 binds Zn2+. Chapter 3 explores the relevance Zn2+ binding to S100A12 structure and function. Zn2+ induced formation of complexes, principally hexamers, and this was not influenced by Ca2+. S100A12 inhibited the gelatinolytic activities of matrix metalloproteinase (MMP)-2 and 9 by chelating Zn2+ from their active sites. MMPs are important in processes leading to plaque rupture. An antibody that specifically recognised Zn2+-induced complexes was generated and immunohistochemical studies demonstrated S100A12, the hexameric complex, and MMP 2 and 9 co-localisation in human atheroma. These results suggest that hexameric S100A12 may form in vivo and may implicate S100A12 in regulating plaque rupture by inhibiting MMP activity. Interestingly S100A12 synergised with LPS to induce MMP 3 and 13 expression in vitamin D3-differentiated THP 1 macrophages (THP 1 macs). S100A12 regulation of MMP expression and activity indicates that it may be involved in a self-regulatory loop, which depends on relative levels of Zn2+ and on other stimuli (eg LPS) in the inflammatory milieu. Chapter 4 describes the development of tools and methods for assessing interactions of S100A12 with cell surface receptors. To assay surface binding, an alkaline phosphatase fusion protein, a biotinylated hinge peptide and biotinylated recombinant S100A12 were generated; only S100A12 b proved useful. Surface binding of S100A12 was detected on several monocytoid/macrophage and mast cells using flow cytometry and immunocytochemistry. Some cells contained intracytoplasmic granular structures that were S100A12-positive. Unexpectedly, a subpopulation of cells in murine bone marrow-derived mast cell cultures that expressed low levels of c-kit, a marker of mature mast cells, bound high levels of S100A12. These may represent haematopoietic stem cells, which express low levels of c kit, and S100A12-mediated functional changes of these cells is worthy of characterisation. Unlike interactions of S100A8/A9 with endothelial cells, pre-incubation of S100A12 with Zn2+ or heparin had no effect on surface binding to THP 1 macs, indicating that Zn2+-induced structural changes were unlikely to alter receptor interactions. Heparan sulfate moieties are unlikely to mediate surface binding of S100A12 even though S100A12 bound heparin with relatively high affinity. Chapter 5 focussed on mechanisms involved in some S100A12 extracellular functions. Based on experiments studying effects of bovine S100A12 on BV-2 murine microglial cells, S100A12 is proposed to induce pro-inflammatory cytokine in monocytes via RAGE. Human peripheral blood mononuclear cells or human THP 1 macs activated with S100A12 did not increase cytokine induction at the mRNA or protein levels, indicating that the 'S100/RAGE pro-inflammatory axis' theory should be re-evaluated. In an attempt to provide insights into a novel receptor, mechanisms involved in S100A12-provoked THP 1 chemotaxis were investigated. This activity was sensitive to pertussis toxin, but not to an ERK1/2 pathway inhibitor, suggesting involvement of a G protein-coupled receptor. Although some RAGE ligands also bind and activate Toll-like receptors (TLRs) antibodies to TLR2 and TLR4 did not block S100A12 binding to THP 1 macs. Affinity enrichment and separation of proteins by SDS PAGE and peptide mapping by mass spectrometry identified the α and γ subunits of F1 ATP synthase, implicating ATP synthase as a putative receptor. Although primarily mitochondrial, this complex is expressed on the surface of several cell types and was confirmed on THP 1 cells and mast cells by flow cytometry. By modulating surface F1 ATP synthase activity, and thereby extracellular ATP/ADP concentrations, S100A12 may mediate its pro-inflammatory functions through G-protein coupled purinergic receptors. This work has generated new directions for studying mechanisms by which S100A12 influences monocyte/macrophage and mast cell functions that are relevant to important inflammatory diseases, such as atherosclerosis and allergic inflammation.
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Mossel, Dieuwertje M. [Verfasser], and Julia [Akademischer Betreuer] Kzhyshkowska. "Epigenetic regulation of S100A9 and S100A12 expression in monocytes-macrophage system in hyperglycemic conditions / Dieuwertje Marije Mossel ; Betreuer: Julia Kzhyshkowska." Heidelberg : Universitätsbibliothek Heidelberg, 2020. http://d-nb.info/1219303100/34.
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Mossel, Dieuwertje Marije [Verfasser], and Julia [Akademischer Betreuer] Kzhyshkowska. "Epigenetic regulation of S100A9 and S100A12 expression in monocytes-macrophage system in hyperglycemic conditions / Dieuwertje Marije Mossel ; Betreuer: Julia Kzhyshkowska." Heidelberg : Universitätsbibliothek Heidelberg, 2020. http://d-nb.info/1219303100/34.
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Turnier, Jessica L. M. D. "Urine S100 Proteins as Potential Biomarkers of Lupus Nephritis Activity." University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1491308278173071.
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Eggers, Kai. "S100A8-S100A9 abhängige Akivierung der RAGE-MAPK-NF-kB-Signaltransduktionssequenz [RAGE-MAPK-NF-kappa-B-Signaltransduktionssequenz] ein neues Modell der chronischen Inflammation am humanen Endothel /." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=974453455.
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Baillet, Athan. "Régulation de l'activité de la NADPH oxydase des neutrophiles par des enzymes du métabolisme du glucose et l'hétérocomplexe S100A8/S100A9 : application à la polyarthrite rhumatoïde." Phd thesis, Université de Grenoble, 2011. http://tel.archives-ouvertes.fr/tel-00680093.
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La Polyarthrite Rhumatoïde est caractérisée par une synovite à l'origine de lésions progressives ostéo-articulaires induites par les formes réactives de l'oxygène (ROS) produites par la NADPH oxydase des polynucléaires neutrophiles (PMN). La NADPH oxydase des phagocytes, est formée d'un centre catalytique membranaire, le cytochrome b558, sur lequel vient s'associer des protéines cytosoliques régulatrices (p67phox, p47phox, p40phox et Rac1/2). Nous avons étudié la spécificité de l'interaction entre la (6-phosphofructokinase 2) et de la 6PGDH (6-phosphogluconate déshydrogénase) et la NADPH oxydase des PMN. D'autre part, nous avons caractérisé les domaines de l'hétérocomplexe S100A8/A9 impliqués dans l'activation de la NADPH oxydase phagocytaire. Par ailleurs, une étude de la signature protéique dans le liquide synovial a été menée afin de rechercher l'empreinte de l'activation du PMN dans la PR.Après stimulation par le PMA, la 6PGDH et la PFK2 co-imunoprécipitent avec les facteurs cytosoliques p67phox, p47phox and p40phox. Les expériences de microscopie confocale suggèrent une co-localisation de ces deux enzymes du métabolisme du glucose avec la NADPH oxydase, dans des micro-domaines membranaires : les radeaux lipidiques. La 6PGDH est impliquée dans l'activation de la NADPH oxydase phagocytaire en élevant la concentration du NADPH cytosolique mais également en augmentant l'affinité de cette enzyme pour son substrat, le NADPH. PFK2 est l'enzyme majeure de la régulation de la glycolyse, voie est essentielle pour la production d'ATP du PMN. L'utilisation du complexe S100A8/A9 et de protéines chimères de fusion nous a permis de révéler que la partie C-terminale de S100A8 est impliquée dans la liaison avec le cytochrome b558 et l'activation de la NADPH oxydase phagocytaire. In vivo, le profil protéique du liquide articulaire de PR a révélé l'empreinte de l'activation du PMN dans cette pathologie avec une surexpression des protéines S100A8 et S100A9. Une production ectopique de S100A8/A9 par les synoviocytes de type fibroblastique a été mise en évidence.En conclusion, la 6PGDH, la PFK2 et l'hétérodimère S100A8/A9 sont de nouveaux partenaires d'activation de la NADPH oxydase des phagocytes. Dans la PR, l'activation des PMNs conduit à la sécrétion de S100A8/A9 qui semblent constituer à la fois des biomarqueurs pertinents, mais également des cibles thérapeutiques potentielles.
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Baker, Jonathan Richard. "S100A8 in development." Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/1444146/.
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S100 proteins are a family of Ca2+ binding EF-hand proteins. S100A8 is a cytosolic protein expressed in myeloid cells and epithelia where it forms a stable heterodimer with another S100 protein family member, S100A9. The S100A9 null mouse is viable and has no gross defect whereas the S100A8 null mouse is embryonic lethal. It was originally proposed that the S100A8 null mouse is lethal at E 9.0 in development due to lack of expression at E 6.5 in ectoplacental cone cells. This thesis shows that the S100A8 null phenotype is more complex than originally thought. S100A8 has a role in preimplantation development, which is previously unstudied. A small number of S100A8 null embryos survive to blastocyst but none survive implantation showing fatal compromise of S100A8 null embryos early in development. This thesis presents evidence that this lethality presents between fertilisation and E 2.5 of development. S100A8 also has a role in the murine decidua after implantation possibly key to normal murine development. S100A8 mRNA is highly expressed in maternal decidua yet S100A8 protein is not highly expressed. Foetal yolk sac cells do not express S100A8 mRNA yet they do stain positively for S100A8 protein. This thesis proposes that S100A8 protein is generated in the murine decidua and exported to the foetus where haematopoietic cells present the protein. The S100A8 protein has been shown to be expressed and stable independently of its myeloid partner, S100A9. These observations explain the discrepancy between the two SI00 null mouse phenotypes and add new insight to the S100A8 null phenotype.
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Zwicker, Stephanie [Verfasser], and Ronald [Akademischer Betreuer] Wolf. "Psoriasin (S100A7) and koebnerisin (S100A15) in the model of inflammation : functional characterization in the inflammation cascade / Stephanie Zwicker. Betreuer: Ronald Wolf." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2014. http://d-nb.info/1075456991/34.
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Herwig, Nadine. "Der RAGE-Ligand S100A4." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-214035.
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Das maligne Melanom zählt zu den aggressivsten und behandlungsresistentesten aller Krebsarten. In den letzten 20 Jahren hat sich die Rate der Melanom-Erkrankungen innerhalb der weißen Bevölkerung verdreifacht.
Mittlerweile liegen eine Reihe von Untersuchungen zu den molekularbiologischen Mechanismen der Entwicklung und Progression des malignen Melanoms vor. Aktuelle Forschungsvorhaben beschäftigen sich vor allem mit der Identifizierung Melanom-spezifischer Biomarker, die diagnostische und prognostische Informationen liefern sowie die Entwicklung einer zielgerichteten, kombinierten und individualisierten Therapie des metastasierenden Melanoms ermöglichen. In diesem Kontext soll die vorliegende Arbeit einen weiteren Beitrag zum Verständnis der Metastasierungskaskade und der daran beteiligten Proteine leisten.
Aufgrund der Überexpression in einer Reihe von Tumoren und seiner geringen Molmasse von lediglich 11,5 kDa bietet sich das S100A4-Protein als Marker mit hoher prognostischer Signifikanz für verschiedene Tumorentitäten an. Jedoch ist die Beteiligung von S100A4 bei der Ausbildung des invasiven Tumorphänotyps noch nicht vollständig aufgeklärt. S100A4 besitzt zahlreiche intra- und extrazelluläre Bindungspartner, wobei die Metastasierung scheinbar ausschließlich durch das extrazelluläre Protein beeinflusst wird. S100A4 wechselwirkt extrazellulär beispielsweise mit dem Rezeptor für fortgeschrittene Glykierungsendprodukte (RAGE). Ziel dieser Arbeit war es, speziell die Bedeutung von S100A4 und seiner Interaktion mit RAGE für das prometastatische Verhalten von Melanomzellen in vitro und in vivo näher zu charakterisieren. Darüber hinaus sollte die Beteiligung von S100A4 bei der Gehirn-Metastasierung untersucht werden, wobei insbesondere die Regulierung der Endothelzell-Permeabilität und der transendothelialen Migration der Melanomzellen im Vordergrund stand.
Im Rahmen dieser Arbeit wurde gezeigt, dass S100A4 und die Interaktion mit RAGE die prometastatischen Eigenschaften der A375-Melanomzellen förderte. Zudem verringerte extrazelluläres S100A4 die Zell-Integrität von Gehirn-Endothelzellen und erleichterte somit die Durchdringung der Blut-Hirn-Schranke. Diese Erkenntnis lässt sich möglicherweise auf andere Blut-Gewebe-Schranken übertragen. Die In-vivo-Orientierungsstudie zeigte, dass S100A4- und RAGE-überexprimierende Zellen zu einer verstärkten disseminierten Metastasierung führten, wobei sich zwei unterschiedliche Verteilungsmuster ergaben. Darüber hinaus führten beide Zelllinien vereinzelt zur Bildung von Gehirnmetastasen, wodurch sich die intrakardiale Injektion durchaus als Modell für weitere Therapiestudien mit dem Augenmerk der S100A4-RAGE-stimulierten Metastasierung eignet. Die genauere Kenntnis regulativer Mechanismen bei der Synthese und Sekretion von S100A4 sowie die pathophysiologische Differenzierung der S100A4-Interaktion mit RAGE eröffnen neue Wege, die S100A4-vermittelten Effekte therapeutisch zu beeinflussen. Daraus lassen sich möglicherweise neue zielgerichtete Radionuklid-basierte Therapieansätze für das metastasierende Melanom ableiten.
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Moroz, Olga. "Structural studies on human S100A12." Thesis, University of York, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.403963.
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Müller, Irene [Verfasser], Carsten [Akademischer Betreuer] Tschöpe, Sophie Van [Akademischer Betreuer] Linthout, Jens [Gutachter] Kurreck, Roland [Gutachter] Lauster, Carsten [Gutachter] Tschöpe, and Sophie Van [Gutachter] Linthout. "Role of NOD2 and S100A8/S100A9 in the pathogenesis of Coxsackievirus B3-induced myocarditis / Irene Müller ; Gutachter: Jens Kurreck, Roland Lauster, Carsten Tschöpe, Sophie Van Linthout ; Carsten Tschöpe, Sophie Van Linthout." Berlin : Technische Universität Berlin, 2017. http://d-nb.info/1156013542/34.
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Endoh, Yasumi Medical Sciences Faculty of Medicine UNSW. "New mechanisms modulating S100A8 gene expression." Publisher:University of New South Wales. Medical Sciences, 2008. http://handle.unsw.edu.au/1959.4/42942.
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S100A8 is a highly-expressed calcium-binding protein in neutrophils and activated macrophages, and has proposed roles in myeloid cell differentiation and host defense. Functions of S100A8 are not fully understood, partly because of difficulties in generating S100A8 knockout mice. Attempts to silence S100A8 gene expression in activated macrophages and fibroblasts using RNA interference (RNAi) technology were unsuccessful. Despite establishing validated small interfering RNA (siRNA) systems, enzymaticallysynthesized siRNA targeted to S100A8 suppressed mRNA levels by only 40% in fibroblasts activated with FGF-2+heparin, whereas chemically-synthesized siRNAs suppressed S100A8 driven by an S100A8-expression vector by ~75% in fibroblasts. Suppression of the gene in activated macrophages/fibroblasts was low, and some enzymatically-synthesized siRNAs to S100A8, and unrelated siRNA to GAPDH, induced/enhanced S100A8 expression in macrophages. This indicated that S100A8 may be upregulated by type-1 interferon (IFN). IFN-β enhanced expression, but did not directly induce S100A8. Poly (I:C), a synthetic dsRNA, directly induced S100A8 through IL-10 and IFN-dependent pathways. Induction by dsRNA was dependent on RNA-dependent protein kinase (PKR), but not cyclooxygenase-2, suggesting divergent pathways in LPS- and dsRNA-induced responses. New mechanisms of S100A8 gene regulation are presented, that suggest functions in anti-viral defense. S100A8 expression was confirmed in lungs from influenza virus-infected mice and from a patient with severe acute respiratory syndrome (SARS). Multiple pathways via mitochondria mediated S100A8 induction in LPS-activated macrophages; Generation of reactive oxygen species via the mitochondrial electron transport chain and de novo synthesis of ATP may be involved. This pathway also regulated IL-10 production, possibly via PKR. Extracellular ATP and its metabolites enhanced S100A8 induction. Results support involvement of cell stress, such as transfection, in S100A8 expression. A breast tumor cell line (MCF-7) in which the S100A8 gene was silenced, was established using micro RNA technology; S100A8 induction by oncostatin M was reduced by >90% in stably-transfected cells. This did not alter MCF-7 growth. The new approach to investigate the role of S100A8 in a human tumor cell line may assist in exploring its functions and lead to new studies concerning its role in cancer.
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McNeill, Eileen. "Neutrophil function in S100A9 null mice." Thesis, University College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.423552.
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Mondet, Julie. "Impacts cliniques et physiopathologiques de l'équilibre redox et de la protéine S100A8 extracellulaire dans les leucémies aiguës myéloïdes de novo de l'adulte (hors LAM3)." Thesis, Université Grenoble Alpes (ComUE), 2018. http://www.theses.fr/2018GREAS007/document.
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Les leucémies aigues myéloïdes (LAM) sont caractérisées par une expansion clonale de cellule(s) souche(s) leucémique(s) bloquée à un stade précoce de maturation. Malgré les avancées thérapeutiques, leur pronostic reste sombre et des progrès thérapeutiques doivent encore être réalisés. Dans les LAM, les espèces réactives de l’oxygène (ROS) sont considérées comme, d’une part, participant à la leucémogenèse et, d’autre part, comme hautement impliquées dans la sensibilité aux chimiothérapies conventionnelles. Par ailleurs, l’équilibre redox qui participe aux dérégulations métaboliques associées au processus leucémique, dépend de nombreux régulateurs, dont la protéine S100A8, protéine connue pour son action stimulatrice sur la NADPH oxydase et sa valeur pronostique dans les LAM.Ce travail s’est donc intéressé à la caractérisation des désordres oxydatifs dans les LAM afin d’évaluer leur impact clinico-biologique, et d’autre part au rôle de la sécrétion de la S100A8 dans le microenvironnement médullaire. De plus, à partir de lignées leucémiques, nous avons étudié l’impact de la S100A8 exogène sur la production de ROS, la respiration mitochondriale et le métabolome des cellules blastiques.A partir d’une cohorte de 84 patients atteints de LAM de novo au diagnostic, nous avons mis en évidence des désordres de l’équilibre redox à la fois dans les cellules leucémiques, dans les cellules normales de l’environnement médullaire ainsi que sur les systèmes régulateurs antioxydants (SOD, GPX, glutathion…). De plus, nous avons montré que la production des ROS observée en réponse à des modulateurs de la mitochondrie, qui reflète indirectement la fonctionnalité mitochondriale, joue un rôle pronostique indépendant des facteurs pronostiques habituels. L’analyse de la S100A8 dans les plasmas médullaires montre une expression augmentée dans les LAM, d’origine monocytaire majoritairement et est associée à des anomalies moléculaires de bon pronostic (inv(16), NPM1) ou un sous-groupe de patients FLT3-ITD mutés présentant une meilleure survie. Enfin, l’étude de la S100A8 sur les lignées leucémiques a permis de mettre en évidence la diversité de ses effets sur la croissance cellulaire, l’apoptose, la production de ROS ainsi qu’une variation métabolique de la phosphocholine dont les mécanismes restent à explorer.En conclusion, mon travail apporte des éléments originaux sur les particularités de l’équilibre bio-énergétique dans les LAM. Il souligne, que l’impact de ses dérégulations sur le pronostic des patients résulte de la combinaison d’un ensemble de facteurs métaboliques, qui doivent être appréhender dans leur globalité pour une meilleure efficacité thérapeutiqueAcute myeloid leukemia (AML) is characterized by clonal expansion of leukemic(s) cell(s) blocked at an early stage of maturation. Despite therapeutic advances, their prognosis remains poor and therapeutic improvements are needed. In AML, reactive oxygen species (ROS) are considered to contribute to leukemogenesis and, on the opposite, standard chemotherapies exert cytotoxicity via ROS. In addition, the redox balance acts on metabolic dysregulation in AML and depends on many regulators, such as S100A8 protein, associated with worst prognostic in AML and known to stimulate NADPH oxidase.In this context, this work focuses on oxidative disorders, and S100A8 expression in bone marrow microenvironment according to clinical-biological characteristics and evaluate their prognostic impact in AML. In addition, we investigated the impact of exogenous S100A8 on ROS production, mitochondrial respiration, and metabolism in leukemia cell lines.In a cohort of 84 de novo AML at diagnosis, we demonstrate the existence of redox balance disorders on leukemic cells, on normal cells from bone marrow microenvironment, and on antioxidant systems (SOD, GPX, glutathione ...). In addition, ROS production observed in response to mitochondrial modulators indirectly reflects mitochondrial functionality plays a prognostic role independent of the current prognostic factors. The analysis of S100A8 in bone marrow plasmas shows a higher expression in AML than in healthy controls or other hematological neoplasms. This hyperexpression is predominantly of monocytic origin and is associated with molecular abnormalities of good prognosis such as (inv (16), NPM1) or with a subgroup of mutated FLT3-ITD patients with better survival. Finally, the study of S100A8 on leukemia cell lines highlights its heterogeneous effect on cell growth, apoptosis, ROS production and on NOX regulation. Furthermore, we observe a S100A8-phosphocholine change which remains to be explored.In conclusion, this work provides original information on bio-energetic balance in AML and their prognostic impacts, emphasizing that these metabolic alterations impact AML prognosis through complex interactions
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Raponi, Eric. "L'expression séquentielle des calciprotéines S100A1 et S100B dans les cellules gliales du système nerveux central caractérise différents stades développementaux en relation avec leurs potentialités de différenciation." Université Joseph Fourier (Grenoble), 2005. https://tel.archives-ouvertes.fr/tel-00178904.
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Les précurseurs neuraux adultes possèdent une plasticité cellulaire suggérant un role dans l'apparition de pathologies mais aussi un potentiel curratif inespéré. Cependant, l'emploi clinique de ces cellules nécessite une connaissance des mécanismes biologiques contrôlant leur prolifération, maturation ou spécification cellulaire. Dans cette thèse nous avons étudié l'expression des protéines 8100 A1 et B dans les cellules progénitrices d'oligodendrocytes (OPC) et les cellules souches astrocytaires. Nous avons démontré que 1) toutes les cellules gliales expriment précocement la 8100A1 alors que la 8100B est liée à leur maturation 2) la 8100B régule la maturation des OPC 3) les cellules souches astrocytaires adultes sont maintenues dans un stade de développement immature (8100B-) grâce à l'EGF, afin de conserver leurs propriétés germinales. Ces résultats démontrent un lien entre les protéines 8100A1/B, la maturation des cellules gliales et leurs propriétés de différenciation cellulaireAdult neural precursors possess a cellular plasticity reflecting their possible role in disease and for treating neurological illness. However, we need to truly understand the biological mecanisms governing these cells in order to use them in futur cellular therapy. Ln this thesis, we have studied the 8100 A1 and B expression pattern both in oligodendrocyte progenitor calls and in astrocytic neural stem cells. We demonstrate that 1) ail glial cells precociously express 81 OOA 1 whereas 81 OOB appearence is only linked to their maturation step 2) 8100B is a molecular actor regulating OPC maturation 3) in adult brain, astrocytic neural stem cells are maintained in a 8100Bimmature developmental stage to preserve their potential via an EGF microenvironnemental pathway. Altogether, these results hightlight a link beetween 8100A1/B proteins, glial cells maturation and cellular plasticity
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Nogueira, Thiago de Oliveira. "Efeito antinociceptivo induzido pelo glicogênio em ratos submetidos ao modelo de pressão de pata: relação com a migração neutrofílica e a expressão da proteína S100A9." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/10/10133/tde-08102012-151355/.
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A peritonite neutrofílica induzida por glicogênio acarreta antinocicepção em camundongos submetidos ao teste de contorção abdominal, a qual é mediada por uma proteína ligante de cálcio, com peso molecular de 14 kDa, denominada S100A9. O objetivo do presente trabalho foi aprofundar o estudo sobre o envolvimento dos neutrófilos na antinocicepção induzida pelo glicogênio em ratos submetidos ao teste de pressão de pata e avaliar a expressão da proteína S100A9 nos tempos onde foi detectado esse efeito. O glicogênio induz antinocicepção em ratos entre 2 e 12 horas após sua injeção intraplantar. O pré-tratamento dos animais com fucoidina, um inibidor de selectinas, não só reverte o efeito antinociceptivo observado como também induz hiperalgesia entre 2 e 6 horas após a injeção do glicogênio. Após 8 horas do tratamento com glicogênio, a fucoidina apenas inibiu a antinocicepção induzida pelo agente inflamatório. A análise histológica demonstrou um aumento na migração de células polimorfonucleares entre 2 e 8 horas após a administração de glicogênio, a qual foi inibida pelo pré-tratamento com fucoidina. Tanto a injeção subcutânea como intraplantar de naloxona, um inibidor inespecífico de receptores opioides, não interferiram no efeito antinociceptivo induzido pelo glicogênio, em nenhum dos tempos avaliados. Quanto à expressão da S100A9, analisada por "Western Blotting", foi observado que as amostras obtidas do coxim plantar dos animais injetados com o glicogênio, entre 2 e 12 horas, apresentaram uma banda com peso molecular aproximado de 14 kDa, o qual equivale ao peso da proteína S100A9. A quantificação das bandas marcadas com o anticorpo anti-S100A9, nos tempos entre 2 e 12 horas, demonstrou um aumento significativo da expressão dessa proteína nas amostras obtidas dos animais tratados com glicogênio, em comparação com os tratados com salina. A injeção intraperitoneal de glicogênio induziu um aumento significativo no número total de células presentes na cavidade abdominal dos animais entre a 2º e a 12º hora após o tratamento, representado pelo aumento do número de células polimorfonucleares migradas. Os sobrenadantes obtidos do exsudato peritoneal entre 2 e 12 horas após a injeção de glicogênio, administrados via intraplantar, não só reverteram a hiperalgesia induzida pela carragenina (Cg) como induziram efeito antinociceptivo. Já, o sobrenadante obtido após 24 horas da injeção de glicogênio reverteu apenas parcialmente o efeito hiperalgésico induzido pela Cg. O tratamento do sobrenadante obtido 4 horas após a injeção do glicogênio com o anticorpo anti-S100A9 aboliu totalmente o efeito antinociceptivo observado com esse sobrenadante sobre a hiperalgesia induzida pela Cg. Esses dados sugerem que a antinocicepção acarretada pelo glicogênio em ratos submetidos ao modelo de pressão de pata é dependente da migração neutrofílica, não está relacionado à liberação de peptídeos opioides, mas possivelmente à secreção da proteína S100A9 por essas células. Ainda, os resultados obtidos com os sobrenadantes do exsudato peritoneal após a injeção do glicogênio, demonstram que durante a peritonite neutrofílica é secretada uma molécula capaz tanto de inibir a hiperalgesia acarretada pela carragenina quanto induzir antinocicepção, a qual possivelmente é a proteína S100A9.Neutrophilic peritonitis induced by glycogen causes antinociception in mice subjected to the writhing test, which is médiated by a calcium-binding protein with a molecular mass of 14 kDa, named S100A9. The purpose of this study was to deepen the study on the involvement of neutrophils in glycogen-induced antinociception in rats subjected to the paw pressure test and evaluate the expression of S100A9 protein in time periods when this effect was detected. Glycogen induces antinociception in rats between 2 and 12 hours after intraplantar injection. Pretreatment of animals with fucoidan, a selectin inhibitor, not only reversed the antinociceptive effect, but also induces hyperalgesia between 2 and 6 hours after glycogen injection. Eight hours after treatment with glycogen, fucoidan only inhibited the antinociception induced by the inflammatory agent. Histological analysis showed an increased migration of polymorphonuclear cells between 2 and 8 hours after glycogen administration, which was inhibited by pretreatment with fucoidan. Both intraplantar and subcutaneous injection of naloxone, a nonspecific inhibitor of opioid receptors, did not affect the antinociceptive effect induced by glycogen at all evaluated times. In relation to the expression of S100A9 analyzed by Western blotting, it was observed that the samples obtained from the footpad injected with glycogen, between 2 and 12 hours, had a band with a molecular weight of 14 kDa, which is similar to molecular weight of S100A9. Relative quantification of the bands marked with anti-S100A9 in the time periods between 2 and 12 hours showed a significant increase in protein expression in samples obtained from animals treated with glycogen, compared with those treated with saline. Intraperitoneal injection of glycogen induced a significant increase in the total number of cells in the abdominal cavity of animals between 2 and 12 hours after treatment, represented by increased numbers of migrated polymorphonuclear cells. The supernatants obtained from peritoneal exudate between 2 and 12 hours after injection of glycogen, administered intraplantarly, not only reversed the hyperalgesia induced by carrageenan (Cg) but also induced antinociceptive effect. Already, the supernatant obtained 24 hours after injection of glycogen only partially reversed the hyperalgesic effect induced by Cg. The treatment of the supernatant obtained 4 hours after injection of glycogen with anti-S100A9 abolished the antinociceptive effect observed with the supernatant on hyperalgesia induced by Cg. These data suggest that antinociception entailed by glycogen in rats submitted to the paw pressure is dependent on neutrophil migration. Moreover, this effect is not related to the release of opioid peptides but possibly to the S100A9 protein secretion by these cells. In addition, the results obtained with the supernatants of peritoneal exudate after glycogen injection show that during neutrophilic peritonitis a molecule able to inhibit carrageenan-induced hyperalgesia is secreted and induce antinociception entailed by glycogen, which is possibly the S100A9 protein.
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Liu, Yidong. "Design, synthesis and evaluation of S100A4 protein inhibitors." Thesis, University of Nottingham, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.738338.
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S100A4 is a 101-amino acid protein belong to a largest sub group of EF-hand calcium binding proteins, and has been described as having both intracellular and extracellular functions. Human S100A4 is the best characterized member of the S100 protein family in terms of its role in cancer and metastasis formation. Overexpression of S100A4 has been observed in several metastatic cancers. It is recognized that an increased level of S100A4 expression correlates with a high incidence of metastasis and poor prognosis for cancer patients. Therefore S100A4 is regarded as a practical target for cancer treatment. The work of investigating S100A4 inhibitors is presented in this thesis. Using the fluorescence resonance energy transfer (FRET) method, a biochemistry assay for monitoring the binding between S100A4 and two of its targets, annexin A2 and myosin IIA, was successfully established. By using this FRET assay, 89 3-hydroxy-1H-pyrrol-2(51-1)-one compounds were screened against the binding of S 100A4 to an annexin A2 (1-14) peptide. 68 compounds were found to be active to inhibit the interaction, exhibiting a different degree of potency. A structure activity relationship (SAR) of all active compounds was established, supported by the predicted binding poses from docking studies. Guided by these SAR conclusions, 13 novel compounds were designed and synthesized based on the 3-hydroxy-1H-pyrrol-2(5H)-one scaffold in order to find better S100A4 inhibitors as well as to further confirm the SAR study. Activities of these new chemicals against both S100A4-annexin A2 complex and S100A10-annexin A2 complex were examined showing very interesting results of different potencies against the two different targets. Docking studies revealed an alternative binding pose, which could be used to explain the potencies and selectivity of novel 3-hydroxy-1H-pyrrol-2(51)-one inhibitors. Two compounds with high S100A4 selectivity were capable of inhibiting the interaction of S100A4 with surface annexin A2 of MDA-231 breast cancer cells In conclusion, this work for the first time identified a series of 3- hydroxy-1H-pyrrol-2(5H)-one compounds as S100A4-annexin A2 inhibitors. The effectiveness of inhibiting S100A4-annexin A2 interaction on cell surface has been proved by selected compounds. As S100A4 plays an important role in cancer metastasis, the results described in this thesis, including the screening method, compounds synthesizing and docking studies, are very meaningful and important to fully understand the specific role of S100A4 in cancer progression in future. This could be a promising start for the development of new cancer treatments.
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Sack, Ulrike. "New insights into S100A4-induced colon cancer metastasis." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2011. http://dx.doi.org/10.18452/16313.
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S100A4 spielt eine zentrale Rolle für die Metastasierung des Dickdarmkrebses. Die Hemmung der S100A4 Expression stellt damit einen vielversprechenden therapeutischen Ansatz dar. Die vorliegende Arbeit präsentiert Niklosamid und Calcimycin als neue Inhibitoren der S100A4 Transkription. In Kolonkarzinomzellen, die mit einem der beiden Inhibitoren behandelt wurden, wurde die S100A4 Expression konzentrations- und zeitabhängig unterdrückt. Des Weiteren war die Zellmigration und -invasion in Abhängigkeit von S100A4 in behandelten Zellen vermindert. Niklosamid und Calcimycin Behandlung verhinderten die Zellproliferation und die Koloniebildung von Kolonkarzinomzellen. Beide Inhibitoren hemmten den konstitutiv aktiven Wnt Pathway von Kolonkarzinomzellen. Calcimycin Behandlung verminderte die Expression von beta-catenin. Niklosamid hemmte die Bildung des beta-catenin/TCF Komplexes und unterband damit die Expression von Wnt Pathway Genen, wie z.B. S100A4. Im Rahmen dieser Arbeit wurde ein in vivo Tiermodell entwickelt, mit dem die S100A4-induzierte Metastasierung mit Hilfe von nicht-invasivem Biolumineszenz Imaging visualisiert werden konnte. In diesem Model konnte gezeigt werden, dass Niklosamid signifikant die S100A4 Expression im Tumor vermindert und damit die Metastasierung hemmt. Des Weiteren zeigt diese Arbeit, dass S100A4 die Expression des Wnt Pathway Antagonisten DKK-1 in Kolonkarzinomzellen hemmt. DKK-1 selbst konnte als endogener Inhibitor der S100A4 Expression identifiziert werden. Zusammenfassend beschreibt die vorliegende Arbeit einen neuen regulativen Mechanismus im Wnt Pathway, der die S100A4 Expression im Kolonkarzinom fördert. Diese Beobachtung verdeutlicht die Notwendigkeit für wirksame S100A4 Inhibitoren, wie Niklosamid und Calcimycin, die das Potenzial haben, in einer klinischen Anwendung die Metastasierung von Kolonkarzinompatienten mit erhöhter S100A4 Expression zu hemmen und damit deren Überlebenschance wesentlich zu verbessern.S100A4 promotes metastasis in colon cancer patients thereby reducing their five-year survival chances to less than 10%. Consequently, inhibition of S100A4 expression is a promising strategy for anti-metastatic treatment of colon cancer patients. The present study characterizes the small molecules niclosamide and calcimycin as transcriptional inhibitors of S100A4 which reduced S100A4 expression concentration- and time-dependently. Niclosamide and calcimycin treatment restricted cell migration, invasion and wound healing capabilities in a S100A4-specific manner, and inhibited cell proliferation and colony formation of colon cancer cells. Both small molecule inhibitors interfere with the constitutively active Wnt pathway. Targeting β-catenin expression by calcimycin or interfering with the β-catenin/TCF transcription activating complex by niclosamide resulted in reduced Wnt target gene transcription, among them S100A4. The study further presents a human colon cancer xenograft mouse model for monitoring S100A4-induced metastasis formation via non-invasive bioluminescence imaging. Treatment of xenograft mice with niclosamide resulted in a significant reduction of the S100A4 mRNA level in the tumor accompanied by inhibition of metastasis formation. Moreover, this study presents evidence that S100A4 is an inhibitor of DKK-1 expression. In colon cancer cells DKK-1 and S100A4 expression was negatively correlated. Ectopic S100A4 overexpression inhibited DKK-1 expression. Targeting S100A4 via shRNA recovered the repressed DKK-1 expression and vice versa. In summary, the study describes a novel positive feedback loop in the Wnt pathway regulation formed by S100A4 repressing its antagonist DKK-1. This novel mechanism further strengthens the need for S100A4 inhibitors such as niclosamide or calcimycin. Consequently, such small molecules provide immense potential for the treatment of colon cancer patients who are at high risk for S100A4-induced colon cancer metastasis.
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Garcia, Assuero Faria. "Estudo da estabilidade estrutural de uma proteína recombinante ligante de zinco e cálcio - Calgranulina C (S100A12) porcina." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/76/76132/tde-30042007-141038/.
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S100A12 porcina é um membro da família das proteínas S100, um grupo de pequenas proteínas ligantes de cálcio caracterizado pela presença de dois motivos EF-hand. Estas proteínas estão envolvidas em diversos eventos celulares, como a regulação da fosforilação protéica, atividade enzimática, tamponamento de Ca+2, processos inflamatórios e a polimerização de filamentos intermediários. Adicionalmente, algumas dessas proteínas podem ligar Zn+2, o qual pode afetar a ligação do íon Ca+2, particularmente para as proteínas S100. Neste trabalho, a seqüência gênica que codifica a proteína S100A12 porcina foi obtida por meio da construção de um gene sintético usando códons preferenciais para E.coli, permitindo a produção recombinante de grandes quantidades da proteína. Um estudo termodinâmico da estabilidade estrutural foi realizado, assim como a interação da proteína recombinante com íons divalentes usando técnicas de dicroísmo circular (CD) e fluorescência extrínseca. A desnaturação e renaturação induzidas por uréia ou temperatura indicam que se trata de um processo reversível e que a ligação dos íons Zn+2 e ou Ca+2 à rS100A12 aumenta sua estabilidade. A interação da sonda ANS com a proteína na presença de seus ligantes expõe superfícies hidrofóbicas podendo assim facilitar sua interação com macromoléculas alvo. Analisados em conjunto, os resultados obtidos indicam que S100A12 porcina é capaz de assumir diferentes conformações as quais podem estar correlacionadas com sua função fisiológica.Porcine S100A12 is a member of S100 family, a small acidic calcium-binding proteins group characterized by the presence of two EF-hand motifs. These proteins are involved in many cellular events as the regulation of protein phosphorylation, enzymatic activity, Ca+2 homeostasis, inflammatory processes and intermediate filament polymerization. In addition, some of these proteins can bind Zn+2, which can affect the binding of Ca+2 particularly to S100 proteins. In this study, the gene sequence encoding S100A12 was obtained by the synthetic gene approach using E. coli codon bias allowing the recombinant production of large amounts of the protein. We report here a thermodynamic study on the structural stability of this recombinant protein and its interaction with divalent ions using circular dichroism and extrinsic fluorescence. The folding/unfolding induced by urea or temperature indicated a reversible process and the binding of Zn+2 or Zn+2 and Ca+2 to S100A12 increasing its stability. The interaction of the ANS probe with the protein in the ligant presence can lead to exposition of hydrofobic regions allowing its interaction with target macromolecules. Taken together, the results indicated that porcine S100A12 may assume different conformations that could be correlated to its physiological function.
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Wache, Christina. "Rolle von S100A8/A9 in der Immunpathogenese der Pneumokokkenmeningitis." Diss., Ludwig-Maximilians-Universität München, 2015. http://nbn-resolving.de/urn:nbn:de:bvb:19-179585.
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Jervis, T. J. "Crystallisation and structural studies of bifunctional enzyme and S100A4." Thesis, Keele University, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267460.
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Melo, Bruno Marcel Silva de. "Alarmina S100A9: um mediador crítico no desenvolvimento da psoríase." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/17/17147/tde-06042018-094810/.
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A psoríase (Ps) é uma doença inflamatória crônica-imunomediada da pele, caracterizada por proliferação acentuada e diferenciação anormal de queratinócitos e aumento do infiltrado de células inflamatórias na derme. S100A9 é um alarmina que é produzida por queratinócitos e células mielóides em condições inflamatórias. No entanto, o papel desta molécula no desenvolvimento e manutenção da resposta inflamatória da Ps permanece desconhecida. Nesso objeitvo foi investigar o papel de S100A9 no desenvolvimento da psoríase. Análises de bioinformática de um banco de dados disponível on-line contendo valores de expressão de gênica de humanos mostrou que a expressão de S100A9 está aumentada pele lesionada de pacientes com Ps. Esses dados foram confirmados por imunofluorescência e Western blot onde foi observado um aumento na expressão de S100A9 na pele lesionada de pacientes com Ps, em comparação com amostras de pele não lesionada desses mesmo pacientes. Estes níveis de S100A9 foram positivamente correlacionados com a expressão de queratina-17, um marcador de ativação de queratinócitos. Para investigar o papel do S100A9 no desenvolvimento de Ps, autilizamos o modelo de Ps induzido por aplicação tópica de imiquimode (IMQ) nas costas de de camundongos WT, S100A9 - / - ou camundonos previamente tratados com paquinimod (10mg / kg, vo ), um quelante de S100A9. A exposição ao IMQ induziu o aumento da expresão gênica de S100a9 e proteica de forma rápida e dependente do tempo na pele e nos linfonodos drenantes da pele, e esse aumento permaneceu elevado até o final do experimento (6º dia). Notavelmente, a inflamação, e espessura da pele foram significativamente reduzidas em camundongos tratados com PAQ ou camundongos S100A9 -/- em comparação com camundongos WT. Os parâmetros histológicos confirmam a redução da espessura da epiderme, mostrada por seções histológicas coradas com HE. Para determinar quais células produtoras de S100A9 contribuem para o desenvolvimento de Ps, realizamos uma quimera e mostramos que ambos os queratinócitos e células mieloides são importantes para a produção de s100a9 e contribuem para o desenvolvimento da psoríase. No entanto os queratinócitos parecem ser mais importantes no aumento da espessua e na lesão da pele. Além disso, a expressão de Il23, na pele de animais S100A9 -/- ou tratados com PAQ foi reduzida, o que poderia explicar a redução das linfócitos T gamma-delta IL-17 nos linfonodos desses mesmos camundongos. Nosso trabalho mostrou que o alarmina S100A9 desempenha um papel importante no desenvolvimento da psoríase. Assim, S100A9 poderia ser uma estratégia futura para o tratamento farmacológico da psoríase. Além disso essa proteína poderia ser usada como marcador da atividade da doençaPsoriasis (Ps) is an immune-mediated chronic inflammatory skin disease, characterized by accentuated proliferation and abnormal differentiation of keratinocytes and infiltration of inflammatory cells in the dermis. S100A9 is an alarmin that is produced by keratinocytes and myeloid cells in inflammatory conditions. However, the role of this molecule in the development and maintenance of the inflammatory response in Ps remains not well understood. Herein, we investigated the role of S100A9 in the development of psoriasis. Bioinformatical analysis of an online database containing human gene expression information showed that the s100a9 is overexpressed in lesional skin from Ps patients. These data were confirmed by immunofluorescence and western blot that showed an overexpression of s100a9 in the lesional skin from Ps patients compared with paired samples of nonlesional psoriatic skin. These levels of s100a9 were positively correlated with the expression of keratin-17, a keratinocyte activation marker. To investigate the role of S100A9 in the development of Ps, psoriasis-like skin inflammation was induced by topical application of imiquimod (IMQ) on the back skin of S100A9-deficient mice (S100A9-/-) or paquinimod (10mg/kg, v.o) pretreated mice. IMQ exposure induced s100a9 mRNA and S100A9 protein expression in a rapid and time-dependent manner in the skin and lymph node of mice and remained elevated until the end of the experiment (6th day). Notably, inflammation, assessed by epidermal thickness measurement and H&E-stained histological sections, was significantly reduced in S100A9-/- or paquinimod treated-mice compared with wild-type (WT) control mice. To determine which S100A9- producing cell contributes to the Ps development we performed a chimera and showed that both keratinocytes and myeloid cells are important for the production of s100a9 and contribute to the development of psoriasis. However keratinocytes seems to be most important to development of lesion skin. Moreover, the expression of IL-23, in the skin, was reduced, which might explain the reduction of IL-17-producing gamma-delta T cells in the lymph nodes of S100A9-/- or paquinimod-treated mice. We showed that the alarmin S100a9 plays an important role in the development of psoriasis. Thus, targeting S100A9 could be a future strategy for pharmacological treatment of psoriasis and this protein can be used as a marker of disease activity.
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Otterbein, Ludovic R. "Etudes cristallographiques de l'actine et de la S100A6 humaine." Aix-Marseille 1, 2002. http://www.theses.fr/2002AIX11018.
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Dans la cellule eucaryote, l'actine est une protéine impliquée dans de nombreuses fonctions biologiques où elle joue un rôle dans la mobilité, la modification de l'aspect des cellules et dans la contraction musculaire. Nous avons déterminé la structure cristallographique de l'actine monomérique sous forme ADP à la résolution de 1,54 Å. Cette structure montre des changements conformationnels de la protéine lors de la libération du Pi du site catalytique. De plus, l'utilisation de la tétraméthylrhodamine-5-maléimide pour bloquer la polymérisation de l'actine permet dorénavant d'envisager la co-cristallisation de complexes de l'actine avec de nombreuses protéines qui interagissent avec celle-ci, mais qui contrairement à toutes celles étudiées jusqu'à présent ne permettent pas de prévenir sa polymérisation. Dans le muscle lisse, caldesmon, une protéine liant l'actine, joue un rôle important dans la régulation de la contraction musculaire. Cette protéine est régulée par des protéines liant le calcium, telles que la calmoduline et la S100A6. Nous avons déterminé les structures de la S100A6 avec et sans calcium. La liaison du calcium induit un large changement conformationnel ainsi qu'une modification des charges du dimère de S100A6 aboutissant à l'exposition de deux sites de liaison de cibles naturelles diamétralement opposés. Ces résultats permettent de classer la S100A6 et de manière plus globale les protéines S100 dans la famille des protéines "sensor" du calcium. La libération d'actine dans le flux sanguin peut être létal. Les structures de la "Vitamin D-binding protein" et de son complexe avec l'actine déterminées ici, apportent des informations importantes sur le rôle de l'actine dans le système de protection appelé "Actin-Scavenger System".
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Moraes, Natassja Foizer. "O C-terminal da proteína S100A9 murina modula os eventos envolvidos na angiogênese e na progressão tumoral em modelos in vitro." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/10/10133/tde-09122015-114330/.
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As proteínas S100A8/A9 são expressas em diferentes tipos celulares e quando sozinhas ou complexadas e em baixas concentrações, promoveram proliferação, migração celular e formação de estruturas capilares. Por outro lado, quando em altas concentrações, esse complexo inibe o crescimento de diversos tipos de células tumorais murinas e humanas. Ainda, tanto a proteína S100A9 humana, quanto um peptídeo sintético idêntico a porção C-terminal da proteína S100A9 murina (pS100A9m) possuem efeitos antinociceptivo e imunorregulatório. Apesar dessas evidencias, até o momento não foi investigado o efeito do pS100A9m sobre a angiogênese e a tumorigênese. Portanto, o objetivo do presente estudo foi investigar, in vitro, o efeito do pS100A9m sobre os eventos fundamentais envolvidos com a angiogênese e o desenvolvimento tumoral. Para tanto, a fim de avaliar o efeito do pS100A9m sobre a angiogênese foi utilizada a linhagem de células endoteliais tímicas murinas (tEnd.1) nos ensaios de proliferação, migração da célula endotelial em meio de cultura, avaliada nos modelos de wound healing e transwell ou migração em meio condicionado, obtido de células tumorais LLC WRC256, avaliada no modelo de transwell, ensaio de adesão (aos componentes de matriz, tais como o colágeno tipo I, fibronectina e laminina) e formação de tubos em matrigel tridimensional (3D). Para os estudos sobre o efeito do pS100A9m sobre as células tumorais, foi utilizada a linhagem de células LLC WRC256 para realização dos ensaios funcionais de proliferação, migração (wound healing) e adesão (sobre os componentes da matriz extracelular). Os resultados obtidos demonstraram que o pS100A9m inibe a proliferação, migração, adesão sobre os componentes de matriz e, consequentemente, a formação de estruturas capilares em matriz 3D. Em relação às células tumorais LLC WRC256, foi observada, novamente, a ação inibitória do pS100A9m sobre os eventos de proliferação e migração. Em relação à adesão, o peptídeo aumentou a capacidade de adesão das células tumorais sobre o colágeno tipo I e fibronectina, porém inibiu a adesão dessas células sobre laminina. Em conclusão, os dados aqui obtidos demonstram que o pS100A9m inibe in vitro os eventos fundamentais envolvidos com a angiogênese e com a progressão tumoral. Desta forma, o peptídeo da porção C-terminal da proteína S100A9 pode ser considerado uma nova ferramenta para o estudo da angiogênese e tumorigênese, além apresentar potencial para uma possível aplicação terapêutica nesses processosThe S100A8/A9 proteins are expressed in different cell types and alone or when complexed, and at low concentrations promoted proliferation, cell migration and formation of capillary structures. On the other hand, at higher concentrations, this compound inhibits the growth of many types of murine and human tumor cells. Moreover, both human S100A9 protein and a synthetic peptide identical to the C-terminal portion of murine S100A9 (mS100A9p) present antinociceptive and immunomodulatory effects. Despite these evidences, the effect of mS100A9p on angiogenesis and tumorigenesis has not been investigated. Therefore, the aim of this study was to investigate the in vitro effect of mS100A9p on crucial events involved in angiogenesis and tumor development. For this, in order to evaluate the effect of mS100A9p on angiogenesis was used the murine endothelial cell line derived from thymus hemangioma (tEnd.1) for proliferation assays, endothelial cell migration in the presence of culture medium (scratch wound healing and chemotaxis assays) or in conditioned medium prevenient from LLC WRC256 tumor cells (chemotaxis assays), adhesion assay (on extracellular matrix components, such as type I collagen, fibronectin and laminin) and tube like-structure formation in 3D matrix. For the analyzes of the effect of mS100A9p on tumor cells, the cell line LLC WRC256 was used to perform functional assays such as proliferation, migration (scratch wound healing model) and adhesion (on components of the extracellular matrix). The results showed that the mS100A9p inhibits the proliferation, migration and adhesion of endothelial cells to the matrix components and consequently the formation of capillary structures in 3D matrix. Regarding LLC WRC256 tumor cells, it was observed again the inhibitory action of the mS100A9p on proliferation and migration events. In relation to cellular adhesion, this peptide increased this parameter of tumor cells on type I collagen and fibronectin. However mS100A9p inhibited the adhesion of these cells on laminin. In conclusion, the data obtained show that the mS100A9p inhibits in vitro crucial events involved in angiogenesis and tumor progression. Thus, the C-terminal portion of murine S100A9 protein may be considered as a new tool for the study of tumorigenesis and angiogenesis besides presenting potential to a possible therapeutic application in these processes
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Hemmelmayr, Vera, Karl Doerner, Richard F. Hartl, and Stefan Rath. "A heuristic solution method for node routing based solid waste collection problems." Springer US, 2013. http://dx.doi.org/10.1007/s10732-011-9188-9.
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This paper considers a real world waste collection problem in which glass, metal, plastics, or paper is brought to certain waste collection points by the citizens of a certain region. The collection of this waste from the collection points is therefore a node routing problem. The waste is delivered to special sites, so called intermediate facilities (IF), that are typically not identical with the vehicle depot. Since most waste collection points need not be visited every day, a planning period of several days has to be considered. In this context three related planning problems are considered. First, the periodic vehicle routing problem with intermediate facilities (PVRP-IF) is considered and an exact problem formulation is proposed. A set of benchmark instances is developed and an efficient hybrid solution method based on variable neighborhood search and dynamic programming is presented. Second, in a real world application the PVRP-IF is modified by permitting the return of partly loaded vehicles to the depots and by considering capacity limits at the IF. An average improvement of 25% in the routing cost is obtained compared to the current solution. Finally, a different but related problem, the so called multi-depot vehicle routing problem with inter-depot routes (MDVRPI) is considered. In this problem class just a single day is considered and the depots can act as an intermediate facility only at the end of a tour. For this problem several instances and benchmark solutions are available. It is shown that the algorithm outperforms all previously published metaheuristics for this problem class and finds the best solutions for all available benchmark instances.
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Baranowska-Rataj, Anna, Anna Matysiak, and Monika Mynarska. "Does Lone Motherhood Decrease Women's Happiness? Evidence from Qualitative and Quantitative Research." Springer Nature, 2014. http://dx.doi.org/10.1007/s10902-013-9486-z.
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This paper contributes to the discussion on the effects of single motherhood on
happiness. We use a mixed-method approach. First, based on indepth interviews with
mothers who gave birth while single, we explore mechanisms through which children may
influence mothers' happiness. In a second step, we analyze panel survey data to quantify
this influence. Our results leave no doubt that, while raising a child outside of marriage
poses many challenges, parenthood has some positive influence on a lone mother's life.
Our qualitative evidence shows that children are a central point in an unmarried woman's
life, and that many life decisions are taken with consideration of the child's welfare,
including escaping from pathological relationships. Our quantitative evidence shows that,
although the general level of happiness among unmarried women is lower than among their
married counterparts, raising a child does not have a negative impact on their happiness.
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Deol, Yadwinder S. "ROLE OF PSORIASIN (S100A7) IN ESTROGEN RECEPTOR POSITIVE BREAST CANCERS." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338359283.
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Pietas, Agnieszka. "Identification of the tumour-associated gene S100A14 and analysis of its regulation." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2005. http://dx.doi.org/10.18452/15196.
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Durch Analyse der Subtraktion-cDNA Bibliothek einer humanen Lungentumor Zelllinie haben wir ein neues Mitglied der S100 Genfamilie identifiziert und charakterisiert, welches S100A14 benannt wurde. Die vollständige cDNA hat eine Länge von 1067 bp und kodiert für ein Protein von 104 Aminosäuren, welches die S100-spezifische Kalzium-bindende Domäne enthält. Das Gen wird in normalen humanen Epithelien ubiquitär exprimiert, zeigt jedoch Expressionsverluste in vielen Tumorzelllinien. Im Gegensatz zu Tumorzelllinien ist S100A14 auf mRNA- und Proteinebene in vielen humanen Primärtumoren stärker exprimiert, unter anderem in Lungen- und Brustkarzinomen. Um den Mechanismus der erhöhten S100A14 Expression in Lungen- und Brustkarzinomen zu verstehen, haben wir die Effekte des EGF (epidermal growth factor) und des TGF-alpha (transforming growth factor-alpha) untersucht. Beide Faktoren sind Liganden des ERBB Rezeptors und induzieren in der immortalisierten bronchialen Epithelzelllinie S100A14 Expression. Unter Verwendung spezifischer Inhibitoren konnte gezeigt werden, dass für die EGF-vermittelte transkriptionelle Induktion der ERK1/2 Signalweg (extracellular signal-regulated kinase) verantwortlich ist und eine de novo Proteinsynthese erfordert. Diese Ergebnisse unterstützend konnte immunhistologisch eine signifikante Korrelation zwischen der Überexpression von ERBB2 und S100A14 in primären Brustkarzinomen nachgewiesen werden. Phorbolester-12-Myristat-13-Acetat (PMA) verstärkte gleichfalls die S100A14 mRNA Expression in 9442 Zellen, was eine Regulation durch die Protein Kinase C (PKC) vermuten lässt. Die PMA-induzierte Expression von S100A14 wird ebenso wie die TGF-alpha/EGF-Induktion durch die Aktivierung des ERK1/2 Signalweges vermittelt. In Anbetracht der großen Bedeutung der ERK1/2 und PKC Signalwege in der Tumorentstehung und Tumorprogression ist zu vermuten, dass S100A14 über die aberrante Regulation dieser Signalwege an die maligne Transformation gekoppelt ist.By analysing a human lung tumour cell line subtraction cDNA library, we have identified and characterized a novel member of the human S100 gene family that we designated S100A14. The full-length cDNA is 1067 bp and encodes a putative protein of 104 amino acids. The predicted protein contains the S100-specific EF-hand calcium-binding domain. The gene is ubiquitously expressed in normal human tissues of epithelial origin. S100A14 transcript was found to be down-regulated in many immortalized and tumour cell lines from diverse tissues. In contrast to the tumour cell lines, S100A14 shows up-regulation at the mRNA and protein level in many human primary tumours, including lung and breast carcinomas. To elucidate mechanisms whereby S100A14 expression is enhanced in lung and breast tumours, we studied the effects of epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) on its expression. Both are ligands of ERBB receptor and induced S100A14 expression in the immortalized bronchial epithelial cells. By use of specific inhibitors, we found that EGF-mediated transcriptional induction of S100A14 involves extracellular signal-regulated kinase (ERK1/2) signalling and requires de novo protein synthesis. In support of these findings, we demonstrated by immunohistochemistry a significant correlation between ERBB2 and S100A14 protein overexpression in primary breast carcinomas. Our studies showed that the phorbol ester 12-myristate 13-acetate (PMA) increases S100A14 mRNA expression in immortalized bronchial epithelial cells suggesting regulation by protein kinase C (PKC). Similar to TGF-alpha/EGF induction, the PMA-induced S100A14 expression was also mediated by activation of the ERK1/2 signalling cascade. Considering the importance of the ERK1/2 and PKC signalling pathways in tumour development and progression we suggest that it is the aberrant regulation of these signalling cascades that couples S100A14 to malignant transformation.
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Guerra, Maria Cristina Azambuja Barea da Silveira. "Efeito do LPS e de anti-inflamatórios sobre a secreção de S100B em cultura de astrócitos." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2014. http://hdl.handle.net/10183/109488.
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As respostas inflamatórias no cérebro são mediadas principalmente pela microglia, mas evidências crescentes sugerem uma importância crucial dos astrócitos. A S100B, uma proteína ligante de cálcio e secretada por astrócitos, tem propriedades neurotróficas e de citocina inflamatória. No entanto, não se sabe se sinais primários que ocorrem durante a indução de uma resposta inflamatória como, por exemplo, lipopolissacarídeo (LPS) modulam diretamente a S100B. A neuroinflamação está implicada na patogênese ou na progressão de uma variedade de distúrbios neurodegenerativos e muitos estudos procuram uma conexão entre S100B e doenças degenerativas, incluindo a doença de Alzheimer e esquizofrenia. O uso terapêutico de fármacos anti-inflamatórios não-esteroidais (AINEs) para estas doenças tem aumentado. No entanto, existem poucos estudos sobre o efeito desses fármacos em relação à proteína S100B. Neste trabalho, nós avaliamos se os níveis de S100B no líquido cefalorraquidiano (LCR) e soro de ratos Wistar são afetados por injeção de LPS administrado por via intraperitoneal (IP) ou intracerebroventricular (ICV), bem como se as culturas primárias de astrócitos respondem diretamente ao LPS. Além disso, nós avaliamos o conteúdo e a secreção de S100B medido por ELISA (bem como o conteúdo de GFAP e secreção de TNF-α) em culturas primárias de astrócitos expostos a dexametasona e quatro classes químicas diferentes de AINEs (ácido acetilsalicílico, ibuprofeno, diclofenaco e nimesulida) durante 24 h. Os nossos dados sugerem que a secreção de S100B no tecido cerebral é estimulada rapidamente e persistentemente (durante pelo menos 24 h) por administração ICV de LPS. Este aumento da S100B no LCR foi transitório quando o LPS foi administrado IP. Em contraste com estes resultados de S100B, observou-se um aumento nos níveis de TNF-α no soro, mas não no LCR, após a administração IP de LPS. Em astrócitos isolados e em fatias de hipocampo frescas, observou-se uma estimulação direta da secreção de S100B por LPS numa concentração de 10 ug/ml. Um envolvimento de TLR4 foi confirmado pelo uso de antagonistas específicos deste receptor. No entanto, baixas concentrações de LPS em culturas de astrócitos foram capazes de induzir uma diminuição na secreção de S100B após 24 h, sem alteração significativa no conteúdo intracelular de S100B. Além disso, após 24 horas de exposição ao LPS, observou-se um decréscimo na glutationa e um aumento na proteína ácida fibrilar glial. Também foi observado que os AINEs apresentam diferentes efeitos sobre parâmetros gliais. O ácido acetilsalicílico e o diclofenaco foram capazes de aumentar a GFAP, enquanto que a nimesulida, um inibidor seletivo de COX-2, e a dexametasona diminuiram a secreção de S100B. No entanto, todos os AINEs reduziram os níveis de PGE2. Juntos, esses dados contribuem para a compreensão dos efeitos de LPS em astrócitos, especialmente sobre a secreção de S100B, e nos ajuda a interpretar mudanças nesta proteína no LCR e soro em doenças neuroinflamatórias. Além disso, tecidos periféricos que expressam S100B talvez devam ser regulados diferentemente, uma vez que a administração IP de LPS não foi capaz de aumentar os níveis séricos de S100B. Em relação aos AINEs, a PGE2 parece estar envolvida no mecanismo de secreção de S100B, mas vias adicionais, não claras neste momento, necessitam de uma maior caracterização. O papel inflamatório de S100B em doenças degenerativas, onde também são observados níveis elevados da COX-2 e PGE2, poderia ser atenuado por inibidores de COX-2.Inflammatory responses in brain are primarily mediated by microglia, but growing evidence suggests a crucial importance of astrocytes. S100B, a calciumbinding protein secreted by astrocytes, may act as a neurotrophic or an inflammatory cytokine. However, it is not known whether primary signals occurring during induction of an inflammatory response (e.g. lipopolysaccharide, LPS) directly modulate S100B. Neuroinflammation has been implicated in the pathogenesis or progression of a variety of neurodegenerative disorders and several studies have looked for a connection of S100B, and degenerative diseases including Alzheimer’s disease and schizophrenia. The therapeutic use of non-steroid anti-inflammatory drugs (NSAID) to these diseases has growth up. However, there are few reports about the effect of these drugs on S100B. In this work, we evaluated whether S100B levels in cerebrospinal fluid (CSF) and serum of Wistar rats are affected by LPS administered by intraperitoneal (IP) or intracerebroventricular (ICV) injection, as well as whether primary astrocyte cultures respond directly to lipopolysaccharide. Moreover we evaluated S100B content and secretion measured by ELISA (as well as GFAP content and TNF-α secretion) in primary astrocyte cultures exposed to dexamethasone and 4 different chemical classes of NSAID (acetyl salicylic acid, ibuprofen, diclofenac and nimesulide) for 24 h. Our data suggest that S100B secretion in brain tissue is stimulated rapidly and persistently (for at least 24 h) by ICV LPS administration. This increase in CSF S100B was transient when LPS was IP administered. In contrast to these S100B results, we observed an increase in in TNFα levels in serum, but not in CSF, after IP administration of LPS. In isolated astrocytes and in acute hippocampal slices, we observed a direct stimulation of S100B secretion by LPS at a concentration of 10 μg/mL. An involvement of TLR4 was confirmed by use of specific inhibitors. However, lower levels of LPS in astrocyte cultures were able to induce a decrease in S100B secretion after 24 h, without significant change in intracellular content of S100B. In addition, after 24 h exposure to LPS, we observed a decrease in astrocytic glutathione and an increase in astrocytic glial fibrillary acidic protein. We also observe that NSAIDs have distinct effects on glial parameters. ASA and diclofenac are able to increase GFAP, while nimesulide, a selective COX-2 inhibitor, and dexamethasone were able to decrease S100B secretion. However, all anti-inflammatories were able to reduce levels of PGE2. Together, these data contribute to the understanding of the effects of LPS on astrocytes, particularly on S100B secretion, and help us to interpret cerebrospinal fluid and serum changes for this protein in neuroinflammatory diseases. Moreover, non-brain S100B-expressing tissues may be differentially regulated, since LPS administration did not lead to increased serum levels of S100. With respect to NSAIDs, PGE2 is possibly involved in the mechanism of S100B secretion but additional pathways, unclear at this moment, demand further characterization. The inflammatory role of S100B in degenerative diseases, where also is observed elevated levels of COX-2 and PGE2, could be attenuated by COX-2 inhibitors in which elevated levels of COX-2.
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Paccola, Carina Cicconi. "Avaliação de possíveis mecanismos envolvidos no efeito antinociceptivo do C-terminal da S100A9 murina sobre a dor neuropática experimental." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/10/10133/tde-11042008-102039/.
Full textAbstract:
O peptídeo sintético idêntico ao C-terminal da proteína S100A9 murina (pS100A9m) possui efeito antinociceptivo em diferentes modelos de dor inflamatória aguda. No presente estudo, o efeito do pS100A9m foi avaliado sobre a dor neuropática induzida pela constrição crônica (CCI) do nervo ciático em ratos. Ainda, foram investigados os possíveis mecanismos envolvidos neste efeito. A nocicepção foi avaliada pelos testes de hiperalgesia, alodinia e dor espontânea. Os animais foram tratados com diferentes doses do pS100A9m pelas vias intraplantar, oral ou intratecal 14 dias após a CCI e a nocicepção avaliada após 1 hora. As três vias de administração bloquearam a hiperalgesia, a alodinia e a dor espontânea decorrentes da dor neuropática. A duração do efeito do pS100A9m varia de acordo com a via utilizada e com o fenômeno nociceptivo testado. Ainda, a injeção intraplantar do peptídeo, na pata contralateral à CCI, inibiu a hiperalgesia e a alodinia observadas após a constrição do nervo. Quando o pS100A9m foi administrado pela via intraplantar no 7° dia após a CCI, ele também induziu inibição da hiperalgesia inflamatória que é observada nesse período. Os prováveis mecanismos envolvidos no efeito antinociceptivo do pS100A9m foram investigados pela administração de antagonistas de receptores de serotonina, noradrenalina, GABA (A e B) e opióides. Os resultados obtidos demonstraram que apenas o antagonista de receptor GABAB reverteu completamente o efeito antinociceptivo do pS100A9m sobre a dor neuropática, detectada no 14º dia pós-cirúrgico. Além disso, foram avaliadas as expressões das proteínas Egr-1, Fos e TNFα na medula dos ratos submetidos à CCI e tratados com o peptídeo 7 ou 14 dias do procedimento cirúrgico. O aumento na expressão das proteínas Egr-1 e Fos foi evidenciado tanto no 7º como no 14º dia após a CCI, em animais que não receberam nenhum tratamento ou aqueles que foram tratados com o veículo do peptídeo. Por outro lado, o pS100A9m inibiu a expressão destas duas proteínas no lado ipsolateral à CCI no corno dorsal da medula espinhal dos animais. Com relação ao TNFα, apenas no 7º dia após a CCI foi detectado o aumento na expressão desta proteína. Ainda, foi neste período que o pS100A9m acarretou inibição da expressão do TNFα no corno ventral de animais submetidos ao procedimento cirúrgico. Estes resultados demonstram que o C-terminal da S100A9 murina inibe a dor neuropática experimental por uma ação dependente de receptores GABAB, sugerindo que este peptídeo possivelmente promova uma ativação dos mecanismos inibitórios espinhais, acarretando em redução da ativação de neurônios na medula. Desta forma, o pS100A9m demonstra um potencial terapêutico para o tratamento de dores persistentes.The synthetic peptide identical to the C-terminus of murine S100A9 protein (mS100A9p) has antinociceptive effect on different acute inflammatory pain models. In this study, the effect of mS100A9p was evaluated on neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve in rats, and the possible mechanisms involved in this effect were investigated. Hyperalgesia, allodynia, and spontaneous pain were assessed to evaluate nociception. Rats were treated with different doses of mS100A9p by intraplantar, oral, or intrathecal routes on day 14 after CCI, and nociception was evaluated 1 hour later. These three routes of administration blocked hyperalgesia, allodynia and spontaneous pain. The duration of mS100A9p effect depends on the route used and the phenomenon analyzed. Moreover, intraplantar injection of mS100A9p in the contralateral paw inhibited the hyperalgesia and allodynia induced by CCI. When mS100A9p was administered by intraplantar route on day 7 after CCI, it reversed the inflammatory hyperalgesia observed in this period. The mechanisms likely involved in the antinociceptive effect of mS100A9p were investigated by administration of antagonists of serotonin, norepinephrine, GABA (A and B) and opioid receptors. Only the GABAB receptor antagonist completely reversed the antinociceptive effect of mS100A9p on neuropathic pain on day 14 after CCI. Besides, the expression of Egr-1, Fos and TNFα proteins was evaluated in the spinal cord of rats submitted to CCI and treated with mS100A9p on days 7 or 14 after CCI. The expression of Egr-1 and Fos was increased in animals not treated or treated with vehicle on days 7 and 14 after CCI. On the other hand, mS100A9p inhibited the expression of these two proteins in the dorsal horn of spinal cord ipsilateral to CCI. The increase in TNFα expression was observed exclusively on day 7 after CCI. In the same time period, mS100A9p nhibited the expression of TNFα in the ventral horn of spinal cord of animals submitted to CCI. The results obtained herein demonstrate that the C-terminus of murine S100A9 protein inhibits the experimental neuropathic pain by a GABAB-dependent action, suggesting that this peptide promotes the activation of spinal inhibitory mechanisms leading to the reduction of activation of spinal neurons. Therefore, mS100A9p demonstrates a potential therapeutic use in persistent pain syndromes.
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Padilla, García Laura. "Estudi del valor terapèutic de la proteïna S100A7 en el desenvolupament tumoral." Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/286554.
Full textAbstract:
Els avenços en la recerca oncològica han obert la possibilitat d’introduir noves estratègies terapèutiques basades en un major enteniment dels mecanismes i processos subjacents al desenvolupament tumoral. Aquestes noves aproximacions han desviat el focus d’atenció de la cèl·lula tumoral, per actuar sobre aquells components de l’estroma que, mitjançant, entre d’altres, una comunicació paracrina on intervenen multitud de factors, donen suport al creixement de la cèl·lula maligna.
Entre aquests factors, ha cobrat protagonisme la família de proteïnes d’unió a calci S100, i, en concret, la proteïna S100A7. Està descrit que aquesta proteïna té funcions relacionades amb la mobilitat cel·lular, correlacionant la seva expressió amb un major creixement tumoral i una major capacitat metastàtica. A més, algunes dades clíniques han mostrat una relació directa entre la seva presència i un pitjor pronòstic per als pacients amb càncer de mama o amb càncer de cap i coll. Per últim, la S100A7 s’ha trobat en biofluids com la sang o l’orina de pacients amb càncer de pulmó, bufeta o melanoma, de manera que s’ha proposat com un possible biomarcador tumoral.
Aquest treball fa front a la necessitat existent d’aprofundir en el mecanisme d’acció de la S100A7, per tenir una visió integradora de la seva funció en els diferents compartiments cel·lulars dins el tumor. A més, l’absència d’inhibidors específics contra la proteïna obre l’oportunitat de desenvolupar anticossos monoclonals dirigits a bloquejar la seva funció extracel·lular, com una nova estratègia terapèutica per al tractament del càncer.
A nivell cel·lular, s’ha demostrat que la proteïna S100A7 indueix la migració de la cèl·lula endotelial, immune, fibroblàstica i tumoral, actua com a molècula d’adhesió i afavoreix la unió dels monòcits a l’endoteli, suportant el seu possible paper en el reclutament de les cèl·lules inflamatòries cap al tumor. A més, indueix la secreció de múltiples citoquines i factors de creixement que contribueixen, junt amb la pròpia S100A7, a la creació d’un microentorn proangiogènic i proinflamatori que afavoreix, en darrer terme, la progressió de la malaltia. Per últim, la proteïna participa en la formació del nínxol premetastàtic, augmentant la fibrosi del teixit.
Els anticossos monoclonals obtinguts són eficaços bloquejant la interacció de la S100A7 amb el seu receptor RAGE. A més, en estudis in vitro, inhibeixen la funció extracel·lular de la proteïna a nivell de migració cel·lular i de secreció de metal·loproteïnases. Per últim, en estudis d’eficàcia utilitzant un model subcutani de creixement tumoral, el tractament amb els anticossos seleccionats redueix significativament el volum tumoral, així com la seva vasculatura, provocant un augment de la necrosi dins del teixit. Aquests resultats demostren, per primer cop, la prova de principi de la teràpia antitumoral basada en anticossos monoclonals contra la S100A7.
D’altra banda, es va estudiar el valor diagnòstic de la proteïna, utilitzant mostres derivades de models animals, demostrant que pot ser considerada com un bon biomarcador sanguini de diagnòstic i de pronòstic.
Els resultats d’aquest treball demostren que la proteïna S100A7 extracel·lular té una funció important en el desenvolupament tumoral, de manera que el seu bloqueig, mitjançant els anticossos monoclonals obtinguts, pot ser una bona estratègia terapèutica pel tractament del càncer.The tumor microenvironment supports the malignant cells growth, secreting a wide variety of growth factors and cytokines. The identification and regulation of those key factors in this crosstalk has opened the opportunity to develop new therapeutic strategies that not only act on tumor cells, but also on the stroma. Among these factors, S100A7 protein has gained interest in the last years. It is described that this protein is related to cell mobility, correlating its expression with an increased tumor growth and metastatic potential. Furthermore, S100A7 is found in biofluids derived from some cancer patients, so that it has been proposed as a possible tumor biomarker. In this study we have deepened the mechanism of action of S100A7 protein on different cell lines, representative of each of the compartments within the tumor (endothelial, immune, fibroblast and tumor), demonstrating its role in cell migration and adhesion, as well as in creating a proangioganic and proinflammatory environment, that favors the disease progression. Also, due to the absence of protein inhibitors, we have obtained specific monoclonal antibodies, that have shown to be effective in blocking its extracellular function in several in vitro models. Furthermore, in an in vivo tumor growth model, the treatment with the selected monoclonal antibodies induced a decrease in disease progression, as well as a decrease in tumor vasculature and an increase in tumor necrosis. Finally, additional data were obtained on its role as a blood biomarker, using samples derived from animal models. The results of this study evidence that extracellular S100A7 protein has an important role in tumor development, so that blocking, by using specific monoclonal antibodies, could be a good therapeutic strategy for cancer treatment.
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Herbert, Christopher William. "The regulation of expression of S100A4 in normal and malignant pancreatic cells." Thesis, University of Liverpool, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268920.
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Allard, David John. "Transcriptional regulation of the human S100A4 gene in breast epithelial cell lines." Thesis, University of Liverpool, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366650.
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Zhang, Shu. "The identification of the functional domains of the metastasis-inducing protein S100A4." Thesis, University of Liverpool, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417175.
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Braumann, Simon [Verfasser], and Lucie [Akademischer Betreuer] Carrier. "S100A4 als Zielprotein der E3-Ligase Asb2β / Simon Braumann ; Betreuer: Lucie Carrier." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2016. http://d-nb.info/1122286449/34.
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Braumann, Simon Pascal [Verfasser], and Lucie [Akademischer Betreuer] Carrier. "S100A4 als Zielprotein der E3-Ligase Asb2β / Simon Braumann ; Betreuer: Lucie Carrier." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2016. http://d-nb.info/1122286449/34.
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Alkhateeb, Tuqa PharmD, Ajinkya MD Kumbhare, Isatou BS Bah, and Mohamed PhD Elgazzar. "S100A9 Sustains Myeloid-Derived Suppressor Expansion and Immunosuppression During Chronic Murine Sepsis." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/217.
Full textAbstract:
Myeloid-derived suppressor cells (MDSC) expand during sepsis, suppress both innate and adaptive immunity, and promote chronic immunosuppression, which characterizes the late/chronic phase of sepsis. We previously reported that the transcription factors Stat3 and C/EBPb synergize to induces the expression of microRNA (miR)-21 and miR-181b to promote MDSC expansion in a mouse model of polymicrobial sepsis that progresses from an early/acute proinflammatory phase to a late/chronic immunosuppressive stage. We also showed that Gr1+CD11b+ cells, the precursors of MDSCs, from mice genetically deficient in the inflammatory protein S100A9 lack miR-21 or miR-181b in late sepsis, and are not immunosuppressive. In the present study, we show that S100A9 induces miR-21 and miR-181b during the late sepsis phase. We find that S100A9 associates with and stabilizes the Stat3-C/EBPb protein complex that activates the miRNA promoters. Reconstituting Gr1+CD11b+ cells from the S100A9 knockout mice with late sepsis with S100A9 protein restores the Stat3-C/EBPb protein complex and miRNA expressions, and switches the Gr1+CD11b+ cells into the immunosuppressive, MDSC phenotype. Importantly, we find that this process requires IL-10 mediated signaling, which induces S100A9 translocation from the cytosol to the nucleus. These results demonstrate that S100A9 promotes MDSC expansion and immunosuppression in late/chronic sepsis by inducing the expression of miR-21 and miR-181b.