Дисертації: "CXCL2"

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Danilucci, Taís Marolato [UNESP]. "CXCL12 estimula fibroblastos pulmonares a produzir CCL3, CXCL2, LTB4 e LTC4 via p38, MEK1/2, PI-3K e JNK." Universidade Estadual Paulista (UNESP), 2013. http://hdl.handle.net/11449/108908.

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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
A quimiocina C-X-X motif ligand 12 (CXCL12) e seu receptor de quimiocina 4 (CXCR4) desenvolvem um papel crítico na inflamação das vias aéreas. No entanto, os efeitos da ativação da via CXCL12/CXCR4 sobre fibroblastos pulmonares ainda são desconhecidos. Neste estudo, investigamos o efeito da via CXCL12/CXCR4 sobre a quimiocina (C-C motif) ligante 3 (CCL3) e (C-X-C motif) ligante 2 (CXCL2) e sobre os mediadores lipídicos leucotrienos B4 (LTB4) e C4 (LTC4) por fibroblastos pulmonares e a sinalização intracelular envolvida neste processo. CXCL12 foi capaz de induzir a produção de CCL3, CXCL2, LTB4 e LTC4; a produção de CCL3 não é dependente da produção de CXCL2, mas a produção de CXCL2 é dependente da produção de CCL3. A produção de LTB4 pode ser parcialmente regulada por CXCL2 e CCL3 e a produção de LTC4 é dependente da produção de CCL3 e CXCL2. Fibroblastos pulmonares constitutivamente expressam CXCR4 e a estimulação com CXCL12 induz sua expressão. Análises de Western blot mostraram que CXCL12 aumenta a expressão proteica de CXCR4 e induz a fosforilação da S339 do CXCR4. A expressão gênica constitutiva e induzida de CXCR4 foram inibidas pelo anticorpo anti-CXCL2. No entanto, o anticorpo anti-CCL3 e o inibidor farmacológico MK886 foram capazes de diminuir a expressão gênica induzida de CXCR4. Os fibroblastos pulmonares foram pré-tratados com MK886, dexametasona (Dexa) e/ou loratadina (Lor). MK886 e Lor promoveram a diminuição da produção de LTC4 e LTB4, mas não a de CCL3 e CXCL2. Dexa diminuiu níveis de CCL3, CXCL2, LTB4 e LTC4, e quando associado com Lor esta diminuição foi mais eficaz. Identificamos...
C-X-X motif ligand 12 (CXCL12) and its specific receptor Chemokine receptor 4 (CXCR4) play a critical role in airway inflammation. However, the effects of CXCL12/CXCR4 axis on pulmonary fibroblast activation are unknown. In this study, we investigated the effect of CXCL12/CXCR4 axis on chemokine (C-C motif) ligand 3 (CCL3), chemokine (C-X-C motif) ligand 2 (CXCL2), leukotrienes B4 (LTB4) and C4 (LTC4) production by pulmonary fibroblasts and the intracellular signaling involved in the process. CXCL12 induced CCL3, CXCL2, LTB4 and LTC4 production, and CCL3 production is not dependent on CXCL2; but CXCL2 production is dependent on CCL3 production. LTB4 production can be partially down-regulated by CXCL2 and CCL3 production and LTC4 production is dependent on CCL3 and CXCL2 production. Pulmonary fibroblasts constitutively expressed CXCR4, and CXCL12 stimulation up-regulated its expression. Western blot analysis showed that CXCL12 increased protein expression of CXCR4 and induced phosphorylation at S339 of CXCR4. Constitutive CXCR4 expression was decreased by anti-CCL3 antibody or MK 886. Inducible CXCR4 was inhibited by anti-CXCL2 antibody. Indeed pulmonary fibroblasts were pretreated with MK886, dexamethasone (Dexa) and loratadine (Lor). MK886 and loratadine was able to reduced LTB4 and LTC4 production but not CCL3 and CXCL2. Dexa decreased CCL3, CXCL2, LTB4 and LTC4 production, and when associated with Lor this decrease was more effective. We found that PI-3K and JNK intracellular signaling play a role in CCL3 production; p38, MEK1/2, PI-3K and JNK are involved in CXCL2 production and p38 and MEK1/2 pathways are involved in LTB4 production by...

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Danilucci, Taís Marolato. "CXCL12 estimula fibroblastos pulmonares a produzir CCL3, CXCL2, LTB4 e LTC4 via p38, MEK1/2, PI-3K e JNK /." Araçatuba, 2013. http://hdl.handle.net/11449/108908.

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Orientador: Sandra Helena Penha de Oliveira
Banca: Edson Antunes
Banca: Lucia Helena Faccioli
Resumo: A quimiocina C-X-X motif ligand 12 (CXCL12) e seu receptor de quimiocina 4 (CXCR4) desenvolvem um papel crítico na inflamação das vias aéreas. No entanto, os efeitos da ativação da via CXCL12/CXCR4 sobre fibroblastos pulmonares ainda são desconhecidos. Neste estudo, investigamos o efeito da via CXCL12/CXCR4 sobre a quimiocina (C-C motif) ligante 3 (CCL3) e (C-X-C motif) ligante 2 (CXCL2) e sobre os mediadores lipídicos leucotrienos B4 (LTB4) e C4 (LTC4) por fibroblastos pulmonares e a sinalização intracelular envolvida neste processo. CXCL12 foi capaz de induzir a produção de CCL3, CXCL2, LTB4 e LTC4; a produção de CCL3 não é dependente da produção de CXCL2, mas a produção de CXCL2 é dependente da produção de CCL3. A produção de LTB4 pode ser parcialmente regulada por CXCL2 e CCL3 e a produção de LTC4 é dependente da produção de CCL3 e CXCL2. Fibroblastos pulmonares constitutivamente expressam CXCR4 e a estimulação com CXCL12 induz sua expressão. Análises de Western blot mostraram que CXCL12 aumenta a expressão proteica de CXCR4 e induz a fosforilação da S339 do CXCR4. A expressão gênica constitutiva e induzida de CXCR4 foram inibidas pelo anticorpo anti-CXCL2. No entanto, o anticorpo anti-CCL3 e o inibidor farmacológico MK886 foram capazes de diminuir a expressão gênica induzida de CXCR4. Os fibroblastos pulmonares foram pré-tratados com MK886, dexametasona (Dexa) e/ou loratadina (Lor). MK886 e Lor promoveram a diminuição da produção de LTC4 e LTB4, mas não a de CCL3 e CXCL2. Dexa diminuiu níveis de CCL3, CXCL2, LTB4 e LTC4, e quando associado com Lor esta diminuição foi mais eficaz. Identificamos...
Abstract: C-X-X motif ligand 12 (CXCL12) and its specific receptor Chemokine receptor 4 (CXCR4) play a critical role in airway inflammation. However, the effects of CXCL12/CXCR4 axis on pulmonary fibroblast activation are unknown. In this study, we investigated the effect of CXCL12/CXCR4 axis on chemokine (C-C motif) ligand 3 (CCL3), chemokine (C-X-C motif) ligand 2 (CXCL2), leukotrienes B4 (LTB4) and C4 (LTC4) production by pulmonary fibroblasts and the intracellular signaling involved in the process. CXCL12 induced CCL3, CXCL2, LTB4 and LTC4 production, and CCL3 production is not dependent on CXCL2; but CXCL2 production is dependent on CCL3 production. LTB4 production can be partially down-regulated by CXCL2 and CCL3 production and LTC4 production is dependent on CCL3 and CXCL2 production. Pulmonary fibroblasts constitutively expressed CXCR4, and CXCL12 stimulation up-regulated its expression. Western blot analysis showed that CXCL12 increased protein expression of CXCR4 and induced phosphorylation at S339 of CXCR4. Constitutive CXCR4 expression was decreased by anti-CCL3 antibody or MK 886. Inducible CXCR4 was inhibited by anti-CXCL2 antibody. Indeed pulmonary fibroblasts were pretreated with MK886, dexamethasone (Dexa) and loratadine (Lor). MK886 and loratadine was able to reduced LTB4 and LTC4 production but not CCL3 and CXCL2. Dexa decreased CCL3, CXCL2, LTB4 and LTC4 production, and when associated with Lor this decrease was more effective. We found that PI-3K and JNK intracellular signaling play a role in CCL3 production; p38, MEK1/2, PI-3K and JNK are involved in CXCL2 production and p38 and MEK1/2 pathways are involved in LTB4 production by...
Mestre

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Di, Cesare Sebastian 1983. "The characterization of CXCL12, CXCL8, CXCL1 and HGF in five human uveal melanoma cell lines /." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112614.

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Uveal Melanoma is the most common primary intraocular tumor in adults. Despite the advances in numerous ophthalmic techniques leading to the increased accuracy of diagnosing this malignancy, the ten-year mortality rate for patients has remained unchanged at approximately fifty percent. Knowing this, further understanding of the specific steps that occur within the metastatic cascade of uveal melanoma is required.
Our laboratory utilizes five human uveal melanoma cell lines (92.1, SP6.5, MKT-BR, OCM-1, UW-1) of known proliferative, invasive, and metastatic potential. We used four methods to characterize the presence and roles of the chemotactic factors CXCL12, CXCL8, CXCL1 and HGF in these five cell lines. We also used a novel peptide inhibitor (TN14003) to block the biological action of CXCL12 on its receptor CXCR4.
With the results obtained from this thesis, we were able to establish the novel presence and importance of the four chosen factors for this malignancy. We were also able to display the positive effects TN14003 had on inhibiting uveal melanoma cell migration in vitro. This may lead to a future therapeutic target, which ultimately may delay or inhibit the metastatic process in uveal melanoma patients, improving the present unaffected ten-year mortality rate.

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Salim, Patrícia Hartstein. "Influência dos polimorfismos genéticos NFKB1, IL-10, CXCR2 E CXCL8 na esclerose sistêmica." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2013. http://hdl.handle.net/10183/76191.

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A esclerose sistêmica (ES) é uma doença difusa do tecido conjuntivo caracterizada por anormalidades fibróticas, imunológicas e vasculares. O fator nuclear-kB (NF-kB), como um fator de transcrição essencial envolvido na regulação de respostas imunitárias, parece ser um bom candidato para estudos sobre a patogênese de doenças autoimunes, bem como a interleucina-10 (IL-10) e as quimiocinas, CXCL8 e CXCR2. Vários estudos demonstram o envolvimento dos genes CXCR2 e IL-10 na patogênese das doenças autoimunes. Acredita-se que combinações desses genes possam ser favoráveis para o desenvolvimento da ES, podendo seu conhecimento ser benéfico para o entendimento da patogênese da ES. O objetivo deste estudo é investigar o polimorfismo dos genes IL-10, CXCR2, CXCL8 e NFKB1 em um grupo de pacientes com ES, incluindo a forma difusa e limitada da doença. Nossos resultados confirmam a associação do fenótipo de alta produção (GCC + / GCC +) com risco aumentado para ES, mas não encontrou nenhuma correlação com polimorfismos do NF-KB. Nossos achados também sugerem um papel protetor da CXCL8 (- 251) A nos genótipos TT e TC do gene CXCR2 (+1208) e um risco aumentado do CXCL8 (-251) A em associação com o genótipo CC do CXCR2 (+1208) em pacientes com ES. Nenhuma diferença estatística no polimorfismo dos genes IL-10, CXCR2, CXCL8 e NFKB1 foram encontradas entre a forma difusa e a forma limitada. Estes resultados indicam um potencial papel do gene IL-10 e da combinação CXCR2/CXCL8 na patogênese da ES.
Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrotic, immunological and vascular abnormalities. Nuclear factor-kB (NF-kB), as a key transcription factor involved in the regulation of immune responses, appears to be a good candidate for studies on the pathogenesis of autoimmune diseases, as well as the interleukin-10 (IL-10) polymorphism, and CXCL8 and CXCR2 chemokines. Several studies have demonstrated the involvement of genes CXCR2 and IL-10 in the pathogenesis of autoimmune diseases. It is believed that combinations of these genes may be favorable for the development of SSc, and this knowledge can contribute to the understanding of the pathogenesis of SSc. The objective of this study is to investigate the polymorphism of IL-10, CXCR2, CXCL8 and NFKB1 in a group of patients with SSc, including diffuse and limited subtypes of the disease. Our results confirm the association of high-producing phenotype (GCC/GCC) with increased risk for SSc, but found no correlation with NFKB1 polymorphisms. Our findings also suggest a protective role of CXCL8 (-251) A in the CXCR2 (+1208) TT and TC genotypes and an increased risk of CXCL8 (-251) A in association with the CXCR2 (+1208) CC genotype in SSc patients. No statistical difference in the polymorphism of IL-10, NFKB1, CXCR2 and CXCL8 were found between the diffuse and limited SSc. These results indicate a potential role of the IL-10 gene and the combination CXCR2/CXCL8 in the pathogenesis of SSc.

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Adlard, Nichola Jayne. "Expression of chemokines CXCL4 and CXCL7 in the synovium at an early stage of rheumatoid arthritis." Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/6600/.

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Identification of suitable biomarkers is growing increasingly important for the treatment of rheumatoid arthritis (RA). They can be measured in a number of different biological materials and can provide clinical information regarding prediction, diagnosis, and prognosis of disease, as well as response to therapeutics. In this thesis, I utilised synovial biopsies collected from patients enrolled in the Birmingham Early Inflammatory Arthritis Cohort (BEACON) to test the hypothesis that detection of expression of CXCL4 and CXCL 7 may be used to predict progression of early stage synovitis to RA. I found that these two chemokines, CXCL4 and CXCL 7, were predominantly expressed on macrophages within the synovium of patients presenting with early synovitis. Increased CXCL4 and CXCL 7 was observed in patients with early RA compared to those with a resolving disease course. However, this increase was transient as expression in treatment naive established RA patients ( > 12 weeks duration, < 3 years duration) was comparable to uninflamed controls. Moreover, I identified expression of a variant ofCXCL4, CXCL4Ll in the rheumatoid synovium. Expression of this potent inhibitor of angiogenesis was evident in the lining layer of the synovium. These data highlight CXCL4 and CXCL 7 as potential predictors of disease outcome in patients presenting with early synovitis.

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Ogawa, Ryotaro. "Loss of SMAD4 Promotes Colorectal Cancer Progression by Recruiting Tumor-Associated Neutrophils via the CXCL1/8-CXCR2 Axis." Kyoto University, 2019. http://hdl.handle.net/2433/245315.

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Denoyer, Alexandre. "Rôle des chimiokines CXCL12 et CXCL1 dans la physiopathologie du trabéculum et de la surface oculaire au cours du glaucome." Phd thesis, Université Pierre et Marie Curie - Paris VI, 2011. http://tel.archives-ouvertes.fr/tel-00824694.

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Le glaucome primitif à angle ouvert est une neuropathie optique rétinienne dont le premier facteur de risque, l'hypertonie intraoculaire, est causé par une dégénérescence du trabéculum dont les mécanismes demeurent inconnus. Ainsi, les traitements actuels ne ciblent pas la trabéculopathie originelle, ce qui pourrait expliquer leur inefficacité parfois observée. En outre, ces traitements contiennent un conservateur, le chlorure de benzalkonium (BAC), qui est responsable d'une inflammation iatrogène de la surface oculaire mise en cause dans l'inobservance thérapeutique. Les chimiokines, cytokines initialement décrites du fait de leurs propriétés chimioattractantes, sont également impliquées dans le contrôle de la viabilité cellulaire et du microenvironnement tissulaire. Dans cette thèse, nous démontrons l'existence d'une balance au niveau trabéculaire entre le système CXCL12/CXCR4 aux effets protecteurs et le système SDF-1(5-67)/CXCR3 proapoptotique. Nous rapportons de façon originale que l'utilisation in vivo d'un antagoniste non-peptidique spécifique de CXCR3 diminue la pression intraoculaire en restaurant la fonction trabéculaire dans un modèle animal de glaucome. En parallèle, nous révélons que les cellules épithéliales conjonctivales exposées au BAC attirent certaines populations leucocytaires via CX3CL1/CX3CR1, montrant ainsi que ce système est impliqué dans le trafic immunitaire au sein de la surface oculaire. De façon originale, les chimiokines apparaissent comme un système inédit de régulation de l'environnement trabéculaire et de la surface oculaire, constituant ainsi de nouvelles cibles thérapeutiques spécifiques

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Mateo, Lou. "Synthèse et évaluation de nouveaux antagonistes des récepteurs CXCR1-2 pour cibler conjointement l’angiogenèse et l’inflammation dans les pathologies cancéreuses." Thesis, Université Côte d'Azur, 2021. http://www.theses.fr/2021COAZ4006.

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L’angiogenèse et l’inflammation sont deux acteurs primordiaux dans le développement et la progression de nombreux cancers. Une meilleure connaissance des mécanismes cellulaires a permis l’essor des thérapies ciblées anti-angiogéniques. L’intérêt de ces thérapies ciblées anti-angiogéniques, est limité du fait de l’apparition de résistances. En parallèle de la voie du VEGF, il existe un second axe pro-angiogénique et pro-inflammatoire : la voie des CXCL-ELR+/CXCR, qui est particulièrement sollicitée dans le cancer et notamment dans le cancer du rein métastatique. Le but de cette thèse a été de développer de petites molécules originales capables d’inhiber l’interaction ligands/récepteurs (CXCL/CXCR1-2) afin d’avoir une action duale : à la fois anti-inflammatoire et anti-angiogénique. Le motif 2-aminobenzothiazinone a été choisi pour la préparation de trois familles d’inhibiteurs. Des stratégies de synthèse divergentes permettent d’obtenir les composés des deux premières familles, bien que les conditions opératoires aient nécessité une adaptation en fonction de la réactivité de chaque substrat. La dernière famille de molécules, est accessible selon une stratégie de synthèse linéaire qui comporte cependant des limitations lors de la dernière étape de cyclisation. Les évaluations biologiques des molécules obtenues ont mis en évidence un composé prometteur possédant une IC50 de 0.6 μM sur la lignée 786-O et inhibant la chimiotaxie des cellules exprimant les récepteurs CXCR1-2. Des études supplémentaires vont être effectuée pour confirmer ces résultats préliminaires encourageants afin d’envisager par la suite une campagne in vivo sur des poissons-zèbres, avec ce composé afin d’étudier sa capacité à entraver l’angiogenèse
Cancer is one of the main causes of death in the world. Angiogenesis and inflammation represent two essential hallmarks in the development and progression of tumors and are essential for the survival of the cancer cells. Better knowledge of cellular mechanisms has enabled the development of targeted anti-angiogenic therapies. However, the emergence of resistance constitutes the main limitation of these current anti-angiogenics targeted therapies, as you may know the anti-VEGF therapies. But in parallel to the VEGF pathway, another crucial pro-angiogenic and pro-inflammatory axis in cancers is required: the CXCL-ELR+/CXCR pathway, particularly in metastatic kidney cancer. The aim of this work was to develop original small organic molecules able to inhibit the ligand/receptor interaction (CXCL-ELR+ / CXCR1-2) in order to have both anti-inflammatory and anti-angiogenic activities. The 2-aminobenzothiazinone pattern was chosen for the preparation of 3 new classes of inhibitors. Divergent synthesis strategies were used to obtain the members of families 1 & 2, although the conditions have been adapted according to the reactivity of each substrate. The last family of molecules was prepared according to a linear synthesis. However, this latter strategy displayed some limitations during the cyclisation step. Thereafter, biological evaluations revealed a promising compound exhibiting an IC50 of 0.6 μM on the 786-O cell line compared with our reference molecule (IC50 = 2 μM). Other result highlighted that this compound also exerted an inhibition of the chemotaxis of cells expressing CXCR1-2 receptors. Further studies on zebrafish are planned with this compound in order to study its ability to interfere with the angiogenesis phenomenon in vivo

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Franz, Juliana Pires Marafon. "Estudo de polimorfismos dos genes CXCR2 e IL-8 em pacientes com câncer de próstata e grupo controle." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2015. http://hdl.handle.net/10183/139982.

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A Interleucina 8 (IL-8) é uma quimiocina CXC angiogênica que tem papel importante no desenvolvimento e progressão de vários tumores malignos, incluindo o câncer de próstata (CaP). O polimorfismo de nucleotídeo único (SNP) -251 T/A da região promotora do gene da IL-8, relativo ao local de início da transcrição deste gene, está associado com a produção desta citocina. O efeito da IL-8 é mediado através de dois receptores de alta afinidade, CXCR1 e CXCR2. O presente estudo investigou a influência da variação dos genes IL-8 e CXCR2 na susceptibilidade e nas características clinicopatológicas do CaP em um grupo de brasileiros. Duzentos e um pacientes e 185 controles saudáveis foram selecionados neste estudo casocontrole. Amostras de sangue foram coletadas para extração de DNA; a tipagem da IL-8 -251 T/A e CXCR2 +1208 C/T foi realizada através da reação em cadeia da polimerase com sequência específica de primers (PCR-SSP), seguida pela eletroforese em gel de agarose. O risco associado entre os genótipos, a susceptibilidade do CaP e as características do tumor, foi estimado pelo odds ratio (OR), com intervalo de confiança de 95%, usando análise de regressão logística e ajustando para idade ao diagnóstico. Encontramos uma associação estatisticamente significativa entre o genótipo heterozigoto CT do gene CXCR2 +1208 e CaP. Este genótipo foi significativamente menos frequente em pacientes com estádio clínico T3-T4 comparado com T1-T2 (56.7% versus 80.5%). Nossos achados sugerem que os portadores do genótipo CT CXCR2 +1208 tiveram um efeito protetor para estádio avançado de CaP (CT versus CC: OR ajustado = 0.25; P = 0.02). Não foi encontrada associação significativa entre o polimorfismo -251 T/A da IL-8 e os parâmetros clinicopatológicos do CaP. Estes resultados indicam que o genótipo CT do CXCR2 +1208 é menos frequente em estádios avançado de CaP, sugerindo que este receptor de quimiocina tenha um papel na patogênese desta doença.
Interleukin-8 (IL-8) is an angiogenic CXC chemokine that plays an important role in both the development and progression of several human malignancies including prostate cancer (PC). A single nucleotide polymorphism (SNP) at -251 upstream of the transcriptional start site of the IL-8 gene has been shown to influence its production. The effects of IL-8 are mediated by two highly related chemokine receptors, CXCR1 and CXCR2. The present study investigated the influence of the IL-8 and CXCR2 gene variation on susceptibility and clinicopathological characteristics of PC in a group of Brazilian subjects. Two hundred and one patients and 185 healthy controls were enrolled in a case-control study. Blood was collected for DNA extraction; typing of IL-8 -251 T/A and CXCR2 +1208 C/T genes was performed by polymerase chain reaction with sequence-specific primers (PCR-SSP), followed by agarose gel electrophoresis. Risk association between the genotypes, PC susceptibility and tumor characteristics was estimated by odds ratio (OR) and 95% confidence intervals (95% CI) using logistic regression analysis, after adjusting for age at diagnosis. A significant association was found between the heterozygous CXCR2 +1208 CT genotype and PC. The CXCR2 +1208 CT genotype was significantly less frequent in patients with clinical stage T3-T4 compared to T1-T2 (56.7 versus 80.5%). Our findings suggest that carriers of the CXCR2 +1208 CT genotype had a protective effect for advanced PC (CT versus CC: adjusted OR = 0.25; P = 0.02). No association was observed between the SNP for IL-8 -251 T/A and clinicopathological parameters of PC. These results indicated that the CXCR2 +1208 CT genotype is less frequent in advanced stages of PC, suggesting that this chemokine receptor plays a role in the pathogenesis of this disease.

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Desurmont, Thibault. "Etude de l'implication des chimiokines et de leurs récepteurs dans la survenue d'une rechute métastatique chez des patients atteints d'un cancer du côlon métastatique et traités par chirurgie hépatique avec ou sans chimiothérapie néoadjuvante." Thesis, Lille 2, 2015. http://www.theses.fr/2015LIL2S042/document.

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Notre objectif était d’analyser l’implication potentielle des voies associées aux récepteurs de chimiokines CXCR2 et CXCR4 dans le cancer colorectal métastatique au foie. Les niveaux d’expression de CXCR2, CXCR4 et de leurs chimiokines étaient évalués dans les métastases hépatiques de cancers colorectaux dans le but d’étudier leurs corrélations avec la survie globale et la survie sans récidive de patients ayant reçu, ou non, une chimiothérapie néoadjuvante. Des analyses d’expression pour RT-PCR quantitative et immunohistochimie étaient réalisées en utilisant des prélèvements humains de métastases hépatiques de cancers colorectaux. Les niveaux d’expression de CXCR2, CXCR4 et de leurs ligands étaient statistiquement analysés en fonction des traitements par chimiothérapie néoadjuvante administrés ou non, et en fonction du suivi des patients. Des modèles murins de xénogreffes sous-cutanées et orthotopiques intracaecales ont été mis au point et utilisés pour étudier l’expression de CXCR2, CXCR4 et CXCL7 en relation avec le traitement des souris par chimiothérapie.Nous avons montré que la surexpression de CXCR2 et CXCL7 était corrélée à de plus courtes survies globales et sans récidive de nos patients. En analyse multivariée, l’expression de CXCR2 et de CXCL7 étaient des facteurs indépendants de survie globale et sans récidive. La chimiothérapie néoadjuvante augmentait significativement l’expression de CXCR2, et de CXCL7 de façon proche de la significativité. Les résultats de nos modèles murins ont montré une tendance à la surexpression de nos gènes d’intérêts dans les tissus tumoraux des souris traités. En conclusion, ces résultats suggèrent l’implication de la voie de signalisation CXCL7/CXCR2 comme facteur prédictif de mauvais pronostic dans le cancer colorectal métastatique. Les chimiothérapies à base de 5 Fluoro-uracile augmentent l’expression de ces gènes dans les métastases hépatiques, fournissant une explication sur l’agressivité des tumeurs métastatiques en échappement thérapeutique. Un blocage sélectif de l’axe CXCR2/CXL7 pourrait fournir de nouvelles opportunités thérapeutiques
Our aim was to analyze the potential role of chemokine receptors CXCR2 and CXCR4 signalling pathways in liver metastatic colorectal cancer (CRC) relapse. Expression levels of CXCR2, CXCR4, and their chemokine ligands were evaluated in liver metastases of colorectal cancer in order to study their correlation with overall and disease-free survival of patients having received, or not received, a neoadjuvant chemotherapy regimen.Quantitative RT-PCR and CXCR2 immunohistochemical staining were carried out using human CRC liver metastasis samples. Expression levels of CXCR2, CXCR4, and their ligands were statistically analyzed according to treatment with neoadjuvant chemotherapy and patients ' outcome. Murine models of subcutaneous and orthotopic intracaecal xenografts have been developed and used to study the expression of CXCR2, CXCR4 and CXCL7 in connection with the treatment of mice with chemotherapy.We showed that CXCR2 and CXCL7 overexpression are correlated to patient’s shorter overall and disease-free survival. By multivariate analysis, CXCR2 and CXCL7 expressions are independent factors of overall and disease-free survival. Neoadjuvant chemotherapy increases significantly the expression of CXCR2 and CXCL7 was overexpressed close to significance. Results of our mouse models have shown a trend over-expression of our interest genes in tumor tissues of the treated mice.In conclusion, we show the involvement of CXCL7/CXCR2 signalling pathways as a predictive factor of poor outcome in metastatic CRC. 5-Fluorouracil-based chemotherapy regimens increase the expression of these genes in liver metastasis, providing one explanation for aggressiveness of relapsed drug-resistant tumors. Selective blockage of CXCR2/CXCL7 signalling pathways could provide new potential therapeutic opportunities

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GIANNICE, RAFFAELLA. "Il microambiente peritumorale nel carcinoma dell'endometrio." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2012. http://hdl.handle.net/10281/31294.

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INTRODUZIONE Sempre maggiori evidenze scientifiche confermano che il microambiente peri tumorale gioca un ruolo importante nello sviluppo e nel comportamento dei tumori solidi. Nelle ultime decadi la correlazione tra tumore e risposta infiammatoria peritumorale è stata ampiamente accettata indicando il ruolo centrale del sistema immunitario nella progressione tumorale e nella prognosi. Obiettivo primario dello studio è stato analizzare l’espressione dell’mRNA di alcune citochine, chemochine e loro recettori e di alcuni fattori di crescita, estratti da campioni di carcinoma originato da endometrio umano e confrontarli con l’ mRNA estratto da campioni di tessuto endometriale normale omologo al fine di caratterizzare le variazioni del microambiente tumorale del carcinoma endometriale rispetto al tessuto endometriale sano. L’obiettivo secondario è stato evidenziare i fattori più interessanti presenti nell’ambiente peritumorale del carcinoma endometriale per programmare uno studio prospettico con una casistica maggiore. MATERIALE E METODO. Presso l’istituto Clinico di Ricerca a Carattere Scientifico IRCCS Humanitas di Rozzano, da pazienti sottoposte a chirurgia primaria per carcinoma dell’endometrio, sono stati prelevati: un campione di carcinoma endometriale (A) e un campione da tessuto endometriale sano della stessa paziente (B) trattati con RNA later e conservati a –80°C. I parametri clinici e chirurgici sono stati raccolti. L’RNA è stato estratto, quantificato, retrotrascritto in cDNA ed infine quantificato mediante una RQ-PCR. RISULTATI. Dodici pazienti con carcinoma endometriale sono state arruolate nello studio. Nel tessuto tumorale endometriale umano, rispetto al tessuto di controllo sano, sono state osservate i risultati statisticamente significativi che seguono. Un’inibizione del CXCL12 mRNA nelle pazienti con infiltrazione del miometrio > 50% (P= .003). Il CXCL12 era direttamente correlato a quello del CXCR7 nel 100% dei casi (P=0.000). L’mRNA del TNF è risultato down-regolato nel 67% dei casi, ed in particolare, nel 100% delle pazienti in cui l’invasione miometriale era > 50% versus il 50% delle pazienti con infiltrazione del miometrio < 50% (P<.09) . Un basso livello di espressione dell’mRNA dell’ IL6 è stato evidenziato nel 100% degli stadi avanzati versus il 45% degli stadi iniziali nel tessuto tumorale rispetto al tessuto sano, (P< .05). Il MIF mRNA aveva un’ aumentata espressione nel 100% dei casi, (P<.001). L’up-regolazione del MIF mRNA era indirettamente proporzionale a quella del TGFb (P<.05). CONCLUSIONI. In base ai risultati di questo studio, tutti i fattori dell’ambiente peritumorale del carcinoma endometriale esaminati hanno dimostrato livelli di espressione interessanti e meritevoli di approfondimento. Tutti potrebbero essere presi in considerazione quali nuovi target di terapia antitumorale per prolungare l’intervallo libero da malattia o addirittura portare alla guarigione, mediante l’utilizzo di farmaci o anticorpi bloccanti soprattutto nei pazienti a rischio medio-alto ma con stadio del tumore ancora precoce. Il dosaggio dei fattori di crescita, citochine e chemochine esaminati nel nostro studio potrebbe essere utilizzato anchecome fattore prognostico per il tipo di terapia adiuvante, soprattutto negli stadi iniziali. Questi risultati, anche se devono essere confermati in una popolazione piu’ ampia e con un FU maggiore, forniscono un evidenza scientifica che individua nuovi obiettivi per la terapia anti-tumorale per il futuro.

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12

Petenuci, Diego Lima. "Análise dos polimorfismos genéticos de CXCL12 e CXCR4 e níveis plasmáticos de CXCL12 na leucemia linfoide aguda infantojuvenil." Universidade Estadual de Londrina. Centro de Ciências Biológicas. Programa de Pós-Graduação em Patologia Experimental, 2016. http://www.bibliotecadigital.uel.br/document/?code=vtls000205200.

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A leucemia linfoide aguda (LLA) é uma doença maligna originada a partir de uma série de alterações genéticas e/ou epigenéticas em um único precursor hematopoiético que adquire características de malignidade. No processo de desenvolvimento da doença, há um acúmulo inicial de leucócitos malignos na medula óssea com tendência de evasão para a corrente sanguínea e invasão para outros órgãos. Embora de etiologia desconhecida, acredita-se que a leucemogênese ocorre a partir de uma complexa rede de interações entre fatores ambientais e genéticos que favorecem as modificações celulares. Estudos de associação genética e suscetibilidade ao câncer, incluindo a LLA, têm avaliado polimorfismos de nucleotídeo único (SNP) em genes que regulam a hematopoiese e outros processos imunológicos importantes. A quimiocina CXCL12 e seu receptor CXCR4 desempenham uma função essencial no homing de células tronco hematopoiéticas e a ativação deste eixo serve de suporte para eventos malignos em células leucêmicas, além de desempenhar um importante papel na invasão extramedular em crianças com LLA. O gene que codifica a quimiocina CXCL12 apresenta um polimorfismo no segmento conservado da região 3'UTR (rs1801157) (G/A), o qual foi relacionado com o aumento de sua expressão, podendo facilitar a metástase e a mobilização de células leucêmicas. Da mesma forma, foi descrito no gene CXCR4 um polimorfismo de base única (C/T) no códon 138 (rs2228014) que vem sendo associado a diferentes neoplasias. Neste contexto, no presente estudo, investigouse a associação destes polimorfismos e os níveis plasmáticos de CXCL12, com a suscetibilidade da doença, risco de recidiva, fase clínica dos pacientes e risco de óbito. A análise dos polimorfismos foi realizada pelo método de reação em cadeia da polimerase seguido da avaliação do tamanho dos fragmentos de restrição (PCRRFLP), a partir de amostras de sangue periférico de 94 pacientes com LLA e 137 indivíduos livres de neoplasia; os níveis plasmáticos de CXCL12 foram determinados por ensaio de imunoadsorção ligado à enzima (ELISA) (grupo LLA n=62 e grupo controle n= 59). Não foram observadas associações entre os polimorfismos rs1801157 e rs2228014 com a suscetibilidade ou risco de recidiva da LLA; no entanto, foi observada uma forte associação do polimorfismo do CXCL12 com o risco de morte em pacientes com o genótipo AA comparado com os outros genótipos (p=0,014). Diferentemente, os níveis plasmáticos da quimiocina não demonstraram diferenças significativas entre pacientes com LLA e grupo controle, nem quanto ao risco de recidiva. No entanto, foi notado um significativo aumento de CXCL12 em pacientes (p=0,004) e controles (p=0,04) portadores do alelo A para o polimorfismo rs1801157. Este estudo sugere que o polimorfismo no gene CXCL12 pode alterar a sua expressão, e indica um possível envolvimento do polimorfismo do CXCL12 e o risco de morte em pacientes com LLA.
Acute lymphoblastic leukemia (ALL) is a malignant disorder that originates from the accumulation of genetic and/or epigenetic alterations in one single hematopoietic precursor that acquire malignant characteristics. In disease development, there is an initial accumulation of malignant leukocytes in the bone marrow with evasion tendency into the bloodstream and invasion to other organs. Although etiology is unknown, it is believed that the leukemogenesis occurs from complex interactions between genetic and environmental factors. Genetic and susceptibility association study to cancer, including ALL, have evaluated single nucleotide polymorphisms in genes regulating hematopoiesis and other important immunological processes. The chemokine CXCL12 and its receptor CXCR4 play an important role in the homing of hematopoietic stem cells, and activation of this axis acts as a support for malignant events in leukemic cells, moreover it plays an important role in extramedullary invasion in pediatric ALL. CXCL12 coding gene has a polymorphism in the 3'untranslated region (rs1801157) (G/A) which has been suggested to involve an upregulation of CXCL12 and can facilitate the mobilization and metastasis of leukemic cells. CXCR4 has revealed single nucleotide polymorphisms (C/T) at codon 138 (rs2228014) that has been associated with different cancers. In this context, this study aimed to investigate the association of polymorphisms in CXCL12 (rs1801157) and CXCR4 (rs2228014) genes, and plasma levels of CXCL12, with susceptibility, risk of relapse treatment phase and risk of death. The polymorphism analyses was carried out by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method from peripheral blood samples of 94 patients with ALL and 137 individuals free of neoplasia; CXCL12 plasma levels were quantified by enzyme linked immuno sorbent assay (ELISA) (ALL group n=62 and control group n=59). There were no associations between rs1801157 and rs2228014 with ALL susceptibility or risk of relapse; however, a strong association of CXCL12 polymorphism with risk of death was observed in individuals with AA genotype compared to other genotypes (p=0.014). Chemokine plasma levels did not show significant differences between patients and control group and risk of relapse. Although no differences were observed for CXCR4 polymorphism, a significant increase of CXCL12 was noted in patients (p=0.004) and controls (p=0.04) carrying A allele for rs1801157 polymorphism. This study suggests that variations in CXCL12 gene could change its expression, and it indicates a possible involvement of CXCL12 polymorphism in the risk of death in ALL patients.

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Wilson, Shirley Risk. "Oligomerisation of chemokine receptors CXCR1 and CXCR2." Thesis, University of Glasgow, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.418346.

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Daubeuf, Francois. "Neutraligands de la chimiokine CXCL12 dans l'asthme." Thesis, Strasbourg, 2013. http://www.theses.fr/2013STRAJ112/document.

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La liaison de CXCL12 à ses récepteurs CXCR4 et CXCR7 peut-être bloquée par un neutraligand de CXCL12, la chalcone 4, qui présente une activité anti-inflammatoire dans un modèle d’asthme chez la souris. Notre travail a consisté à proposer des stratégies permettant le développement de molécules biodisponibles et actives localement, et d’étudier le mécanisme d'action in vivo des neutraligands de CXCL12. Nous avons développé un modèle court et reproductible d'asthme allergique chez la souris, adapté à une évaluation rapide de l’activité anti-inflammatoire des nouveaux composés et un développement raisonné des stratégies envisagées. Nous avons synthétisé trois prodrogues solubles, adaptées à une administration locale, inactives et rapidement clivées en chalcone 4 active. In vivo, les prodrogues sont anti-inflammatoires à des doses susceptibles de limiter les effets indésirables. Pour favoriser davantage l'action anti-inflammatoire locale du neutraligand de CXCL12, nous avons synthétisé une ante-drogue, la carbonitrile-chalcone 4, active in vivo par administration locale et rapidement dégradée en deux composés inactifs avant sa distribution dans l'organisme. Enfin, l'étude de la chalcone 4 a mis en évidence une activité antiasthmatique significative, liée à l'élimination rapide de la chimiokine CXCL12 du poumon. La capture de CXCL12 par le neutraligand réduit la différenciation des macrophages M1 et leur libération de cytokines pro-inflammatoires, ainsi que le recrutement des éosinophiles et des lymphocytes CXCR4+. En conclusion, nos travaux ont permis de conforter les rôles de la chimiokine CXCL12 dans l'asthme et présenter deux stratégies aptes à limiter les effets indésirables
The binding of the chemokine CXCL12 to its receptors CXCR4 and CXCR7 may be prevent by a CXCL12 neutraligand, chalcone 4, having an anti -inflammatory activity in a mouse model of allergic asthma. Our work consisted in proposing strategies for the development of active and bioavailable molecules, able to promote local action, and to study the in vivo mechanism of action of the CXCL12 neutraligands. We initially developed a short and reproducible mouse model of allergic asthma, suitable for a rapid assessment of the anti -inflammatory activity of new compounds, in order to ensure rational development of the proposed strategies. We developped three soluble prodrugs, adapted to local administration, inactive but rapidly cleaved in active chalcone 4. In vivo, the prodrugs have an anti-inflammatory activity at suitable doses to minimize side effects. To promote the benefit of local anti-inflammatory action of CXCL12 neutraligand, we synthesized an antedrug, carbonitrile-chalcone 4, active locally in vivo after local administration and rapidly degraded before its distribution in the body.Finally, the study of chalcone 4 allowed us to highlight a significant asthma activity. An activity related to the rapid elimination of the CXCL12 chemokine from the lung. The trapping of CXCL12 by the neutraligand reduced M1 macrophage activation and their release of pro inflammatory cytokines, as decreases the recruitment of CXCR4+ eosinophils and lymphocytes. In conclusion, our work provided mechanistic elements related to the roles of the chemokine CXCL12 in asthma, and present two interesting strategies adapted to local administration to limit adverse effects

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Mikami, Sakae. "Blockade of CXCL12/CXCR4 axis ameliorates murine experimental colitis." Kyoto University, 2009. http://hdl.handle.net/2433/124258.

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SARCHIO, Seri Narti Edayu. "Antagonising the CXCL12 pathway with AMD3100 inhibits skin cancer." Thesis, The University of Sydney, 2013. http://hdl.handle.net/2123/10111.

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One way sunlight causes skin cancer is by suppressing the anti-tumor immune response. A major mechanism involves altering mast cell migration via the C-X-C motif chemokine receptor 4-C-X-C motif chemokine ligand 12 (CXCR4-CXCL12) chemokine pathway. I have discovered that pharmacologically blocking this pathway with the CXCR4 antagonist AMD3100 prevents both UV radiation-induced immune suppression and skin cancer. The majority of control mice receiving UV-alone developed histopathologically confirmed squamous cell carcinomas. In contrast, skin tumor incidence and burden was significantly lower in AMD3100-treated mice. Perhaps most striking was that AMD3100 completely prevented the outgrowth of latent tumors that occurred once UV irradiation ceased. AMD3100 protection from UV immunosuppression and skin cancer was associated with reduced mast cell infiltration into the skin, draining lymph nodes, and the tumor itself. Thus a major target of CXCR4 antagonism was the mast cell. The results presented in this thesis provide important evidence that the CXCR4-CXCL12 chemokine axis plays multiple roles in the development of UV-induced skin cancer. It makes a significant and unique contribution to our understanding of the effects of antagonising CXCR4 in chronic UV-induced skin damage, mast cell migration, UV- immune suppression and melanin production. These studies provide important pre-clinical proof of principle evidence that antagonising CXCR4 will be of therapeutic benefit to high risk, chronically sun-damaged patients.

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Silva, Milena da. "Produção de CXCL8 e óxido nítrico por neutrófilos humanos estimulados com 4 cimentos endodônticos." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/25/25147/tde-30012014-092652/.

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Um material obturador deve apresentar boas propriedades biológicas e físico-químicas, uma vez que ficará em íntimo contato com os tecidos periapicais. Sendo assim, não deve ser irritante aos tecidos adjacentes, possibilitando, ou mesmo favorecendo, o reparo da região periapical, para isso não devem alterar o processo inflamatório. O presente estudo avaliou a citotoxicidade dos cimentos AH Plus, Sealapex, MTA Fillapex e Sealepox em neutrófilos humanos. Neutrófilos humanos cultivados na presença ou ausência de LPS foram tratados com os cimentos em diferentes diluições (1:1, 1:4, 1:8, 1:16 e 1:32) e tempo de presa (24 e 48 horas) durante 24 horas. A viabilidade celular foi analisada por citometria de fluxo, a dosagem de CXCL8 pelo método de ELISA, e Óxido Nítrico na absorvância de 540nm. Os dados foram analisados com o auxílio do programa GraphPad Prism5 por ANOVA a 1 critério seguido pelo teste de Tukey, e os valores considerados significantes quando p<0,05. O cimento AH Plus interferiu apenas na síntese de NO, estimulando-a, tendo a diluição 1:16 melhor comportamento biológico, em ambos períodos experimentais. O Sealapex diminuiu a produção de NO, sendo significante para 1:32 em 48 horas. O MTA Fillapex induziu apoptose, a produção de CXCL8 (1:4 e 1:8 em 48 horas) e diminuiu a síntese de NO (1:32 em 48 horas). Sealepox diminuiu a apoptose (1:16 e 1:32 em 24 horas) e interferiu na produção de CXCL8, diminuindo-a (1:8 em 48 horas, e 1:16 em ambos os períodos). A citotoxicidade em ordem crescente dos cimentos foram: AH Plus, Sealapex, MTA Fillapex e Sealepox. Nosso estudo concluiu que os cimentos AH Plus e Sealapex foram os menos citotóxicos, que menos interferiram na viabilidade celular e na sua função (não indução de CXCL8 e na produção de NO), tanto em 24 horas como em 48 horas. MTA Fillapex e o Sealepox, apesar de causarem mais morte celular e interferirem na produção de NO e CXCL8, seus efeitos podem ser aceitáveis, uma vez que os níveis dessas alterações são, de tal maneira discretos, não agressivos.
A filling material must have good biological and physicochemical, since you\'ll be in close contact with the periapical tissues. Thus it should not be irritating to the surrounding tissues, allowing, or even encouraging, the repair of the periapical region, for it must not alter the inflammatory process. The present study evaluated the cytotoxicity of AH Plus, Sealapex, MTA and Fillapex Sealepox in human neutrophils. Human neutrophils cultured in the presence or absence of LPS cements were treated with different dilutions (1:1, 1:4, 1:8 , 1:16, 1:32) and setting time (24 and 48 hours) for 24 hours. Cell viability was analyzed by flow cytometry, the dosage of CXCL8 by ELISA and nitric oxide in absorbance at 540 nm. Data were analyzed with the aid of GraphPad Prism5 ANOVA for the first criterion followed by Tukey test, and values considered significant when p < 0.05. The AH Plus sealer interfered only in NO synthesis , stimulating it , having a 1:16 dilution better biological behavior , in both experimental periods . The Sealapex decreased production of NO, with 1:32 significant to within 48 hours. The MTA Fillapex induced apoptosis, production of CXCL8 (1:4 to 1:8 within 48 hours) and reduced NO synthesis (1:32 in 48 hours). Sealepox decreased apoptosis (1:16 and 1:32 in 24 hours) and interfere with the production of CXCL8, reducing it (1:8 in 48 hours, and 1:16 in both periods). The cytotoxicity of the cements in ascending order were: AH Plus, Sealapex, MTA and Fillapex Sealepox. We conclude that AH Plus and Sealapex cements were less cytotoxic than less interfered with cell viability and function ( CXCL8 and noninduced NO production ) both in 24 hours and in 48 hours. MTA and Fillapex Sealepox, although most causing cell death and interferes the production of NO and CXCL8, their effects may be acceptable, since the levels of these changes are so mild, non-aggressive.

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Luo, Lingjie. "Etude in vivo et in vitro du rôle biologique des interactions de CXCL 12 et CXCL 13 avec les protéoglycanes." Sorbonne Paris Cité, 2015. http://www.theses.fr/2015USPCC267.

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Pour accomplir leurs fonctions essentielles, les chimiokines activent des récepteurs couples aux protéines G heterotrimeriques exprimés à la surface des leucocytes. Au-delà de cette interaction fondamentale avec leurs récepteurs, les chimiokines se lient de manière non covalente aux moities glycaniques (glycosaminoglycanes, gags) des protéoglycanes. De l'affinité des interactions avec les gags dépendent leur immobilisation tissulaire et la formation de gradients qui gouvernent les mécanismes de chimiotaxie et d'haptotaxie. L'intégrité de ces mécanismes pourrait être essentielle pour que les chimiokines puissent accomplir pleinement leurs fonctions biologiques, aussi bien en homéostasie que dans des situations physiopathologiques. Mon travail de thèse de doctorat s'inscrit dans une recherche pionnière initiée par mon laboratoire d'accueil. Il est axe sur l'étude du rôle in vivo des interactions des chimiokines CXCL12, chimiokine essentielle, et CXCL13 dans la régulation des réponses immunitaires, en particulier de la réponse humorale, dans laquelle CXCL13 et CXCL12 coopèrent positivement à son homéostasie. Les objectifs spécifiques du travail sont : i) la recherche du fonctionnement des centres germinatifs (CGS) des organes lymphoïdes secondaires chez des animaux portant une invalidation sélective de la fonction d'interaction des isoformes de CXCL12 avec les gags. Ii) l'identification et la caractérisation biochimique et fonctionnelle des déterminants moléculaires de CXCL13 complétée par une analyse structurelle de la protéine. Les données de mon travail montrent que chez les animaux mutants CXCL12gagtm/ gagtm il existe une très forte proportion de cgs configures de manière anormale, ou les compartiments DZ et LZ du CG ne sont pas bien délimités. Chez les animaux mutants, des cellules lz de grande taille sont fréquemment observees et expriment des marqueurs témoignant d'une activité mitotique. Ces cellules pourraient correspondre à des cellules du compartiment dz (centroblastes) ectopiquement localisées dans LZ comme conséquence de la disruption du gradient de CXCL12. Chez les animaux mutants on observe une diminution des mutations somatiques dans les gènes des immunoglobulines des cellules des cgs et post-cgs, qui s'accompagne de la diminution des anticorps de haute affinité produits en réponse à l'immunogène np. Nous concluons que les anomalies structurelles et fonctionnelles (cause et conséquence) dérivent de l'absence d'immobilisation de CXCL12. Chez l'animal mute, lorsque CXCL12 n'est pas fdœee à des surfaces cellulaires ou extracellulaires, la migration et localisation aberrante des cellules dz entraine un disfonctionnement de la production et la sélection des cellules b productrices des anticorps de haute affinité. L'abolition de l'interaction de CXCL12 avec les gags dans le cg serait ainsi à l'origine de la réponse immunitaire humorale sous-optimale observée chez les animaux CXCL12 gagtm/gagtm. Nous avons systématiquement effectue une mutagenèse CXCL13 murin et identifie d'abord les mutants qui conservaient une expression intacte dans les cellules eucaryotes. Puis, nous avons procédé a l'analyse fonctionnelle de chaque mutant avec, en parallèle, une évaluation de leurs interactions avec des gags immobilises soit in vitro (surface plasmonic résonance), soit in cellulo, à l'aide des cellules qui diffèrent génétiquement par leur expression des gags. Nos résultats montrent que deux déterminants moléculaires de CXCL13 coopèrent positivement dans la liaison sélective aux gags de type heparan sulphates (HSS). En outre, les mutants ainsi génères ont des expressions et des fonctions de Signalisation préservées via cxcr5. L'analyse structurale de la protéine CXCL13 montre aussi que les mutations dans les déterminants impliques dans la liaison aux HSS, n'affectent pas la structure générale de la chimiokine. Dans leur ensemble, ces résultats prouvent que l'invalidation par mutagenèse des Interactions du CXCL13 murin avec les hss est compatible avec une préservation de son expression et de ses fonctions biologiques. Ceci est une condition sine qua non pour développer une souris modifiée génétiquement permettant d'analyser sans biais le rôle in vivo de l'immobilisation de CXCL13 sur les protéoglycanes. La combinaison de deux mutations sur les deux gènes CXCL12 et CXCL13 devrait permettre la génération d'animaux viables. S'agissant des mutations affectant sélectivement l'interaction avec les protéoglycanes, sans diminution des pouvoirs agonistes de deux chimiokines, le modèle devrait permettre l'élucidation sans biais du rôle de l'immobilisation tissulaire de CXCL12 et CXCL13 sur leurs fonctions biologiques
To fulfill their core functions, chemokines activate receptors coupled to heterotrimeric g proteins expressed on the surface of leukocytes. Beyond this fundamental interaction with their receptors, chemokines also bind non-covalently to the glycan moieties (glycosaminoglycans, gags) of proteoglycans. Gags dependent tissue immobilization and formation of chemokine gradients that govern chemotaxis and haptotactic mechanisms largely relies in the affinity of gag/chemokine interactions. The integrity of these mechanisms might be essential for chemokines to fully perform their biological functions in homeostasis as well as in pathophysiological situations. My phd studies pursue a pioneer research initiated by my host laboratory. It focuses on the study of the role played in vivo by the interactions of the chemokines CXCL12, the only essential chemokine, and CXCL13 in the regulation of immune responses, and in particular, of the anamnestic b cell response wherein CXCL13 and CXCL12 positively cooperate to maintain the homeostasis of humoral immunity. Specific objectives of this work are: i) to study the structure and function of secondary lymphoid organs, and in particular of germinal centers (gc), in an animal model carrying a selective genetic invalidation of CXCL12/gags interactions; ii) to assess the capacity of CXCL13 to interact with gags and eventually to identify the molecular determinants accounting for and characterize the structure/function relationships of CXCL13/gags interactions. Our findingsshow that in the mutant animals CXCL12gagtm / gagtm there is a very high proportion of abnormally configured gcs, where dark zone (dz) and light zone (lz) compartment of the gc are not well defined. In mutant animals, large lz cells are commonly seen and express markers indicating mitotic activity. These cells might would correspond to centroblasts, that typically localizes in the dz compartment, ectopically settled in the lz as a consequence of the disruption of CXCL12 gradient. In mutant animals, a decrease is observed in the number of somatic mutations in gc- and post-gc-cell immunoglobulin genes, together with the reduction of high-affinity antibodies produced in response to the immunogen np. We conclude that the structural and functional abnormalities (cause and effect) derive from the absence of immobilization of CXCL12 in the dz compartment where this chemokines has been shown to accumulate preferentially in the gc structure. Mutant animals show aberrant migration and localization of dz cells which causes a dysfunction of both the production and selection of b cells expressing high affinity antibodies. The abolition of the interaction of CXCL12 with gags in the gc causes a Suboptimal humoral immune response in CXCL12gagtm/gagtmanimals. We have systematically performed a murine CXCL13 mutagenesis and first identified mutants that retained an intact expression in eukaryotic cells. Then we conducted functional analysis of each mutant together with an assessment of their interactions with immobilized gags either in vitro (surface plasmonic resonance) or in cellulo, using cells that differ genetically by their expression of gags. Our results show that two molecular determinants of CXCL13 positively cooperate to enable a selective, high-binding affinity of the chemokine to gags type heparan sulphates (hs). Furthermore, the mutant chemokines disabled of hs-binding capacity, exhibited a fully preserved, as compared to the wild type counterpart, cell-signaling functions via cxcr5. Structural analysis of the CXCL13 protein shows that mutations in the determinants involved in binding to hs do not affect the overall structure of the chemokine. Taken together, these results prove that the invalidation by mutagenesis of murine CXCL13 interactions with hs is compatible with the preservation of both expression and biological functions. This is a mandatory prerequisite for developing a genetically modified mouse, which would enable the study of the role played in vivo by the immobilization of CXCL13 on cell/tissue proteoglycans and makes conceivable the generation of viable animals encoding CXCL12 and CXCL13 genes. An animal model encompassing mutated CXCL12 and CXCL13 genes selectively disabled to complex with gags but expressing chemokines with intact agonist properties, would be an invaluable tool to perform an unbiased and complete study of the contribution of proteoglycan-anchoring to the biological roles of these important chemokines

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19

Uptaite, Migle. "Expression und Regulation von CD90 (Thy-1) auf makrovaskulären Endothelzellen." Doctoral thesis, Universitätsbibliothek Leipzig, 2013. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-116506.

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Das humane CD90 (Thy-1), ein membrangebundenes Glykoprotein, wird auf der Oberfläche von aktivierten mikrovaskulären Endothelzellen (EC), Fibroblasten, Nervenzellen und einer Subpopulation von CD34+ hämatopoetischen Stammzellen exprimiert. CD90 fungiert als Adhäsionsmolekül auf aktivierten mikrovaskulären EC, indem es die Bindung von Leukozyten über die Interaktion mit dem Integrin alfambeta2 (Mac-1, CD11b/CD18) oder dem Adhäsions-GPCR CD97 an das Endothel vermittelt. Die Expression von CD90 auf mikrovaskulären EC wurde sowohl in-vitro als auch in-vivo nachgewiesen. Zur Expression von CD90 auf makrovaskulären EC gibt es nur wenige und sich zum Teil widersprechende in-vitro Daten. In-situ konnte die Expression von CD90 auf diesen Zellen bisher nicht gezeigt werden. Die Atherosklerose ist ein stufenweise verlaufendes chronisch-entzündliches Geschehen in den arteriellen Gefäßen. In der vorliegenden Arbeit wurde in atherosklerotisch-veränderten Gefäßen die Expression von CD90 auf humanen makrovaskulären EC in-situ demonstriert. Dabei wurden neben Operationspräparaten von Patienten mit einer Stenose der A. carotis interna, die entsprechend der American Heart Association Klassifikation die höchsten Atherosklerosestadien zeigen, auch Gefäßtransplantate von Organspendern, die meist nur eine geringe Ausprägung der Atherosklerose aufwiesen, untersucht. CD90 wurde in jedem Atherosklerosestadium auf EC nachgewiesen. Eine signifikante Zunahme der CD90 Expression in höheren Atherosklerosestadien konnte gezeigt werden. Die histologischen Merkmale der Plaque, wie Verkalkung, Blutung, Plaqueruptur oder Thrombusformation korrelieren nicht mit der CD90 Expression. Ein statistisch signifikanter Zusammenhang zwischen symptomatischer und asymptomatischer A.carotis interna-Stenose konnte bezüglich der CD90 Expression auf makrovaskulären EC ebenfalls nicht nachgewiesen werden. Weiterhin sollte mittels Stimulationsversuchen in-vitro geklärt werden, wie die CD90 Expression auf makrovaskulären EC im Rahmen der Atherosklerose auf den makrovaskulären EC reguliert wird. Denkbar ist, dass Zytokine, die eine Rolle im atherosklerotischen Prozess spielen, einen Einfluss auf die CD90 Expression ausüben. Deshalb wurde die Expression von CD90 auf makrovaskulären EC nach Stimulation mit proinflammatorischen Zytokinen untersucht. Die Expression von CD90 konnte in-vitro durch pro-inflammatorische Zytokine tendenziell erhöht werden. Die Stimulation mit CXCL12, einem bedeutsamen Trigger der Mobilisation der endothelialen Vorläuferzellen, der in atherosklerotischen, aber nicht in gesunden Gefäßen nachweisbar ist, bewirkte einen signifikanten Anstieg der CD90 Expression. Durch die Stimulation mit den lipid-beladenen Schaumzellen, die zahlreich in atherosklerotischen Läsionen vorhanden sind, konnte die CD90 Expression eher reduziert werden. Da Diabetes mellitus mit einem früheren Auftreten einer Atherosklerose assoziiert ist, wurden die makrovaskulären EC auch mit D-Glukose inkubiert. Dies führte ebenfalls zur tendenziellen Reduktion der CD90 Expression. Zusammenfassend konnte in der vorliegenden Arbeit die CD90-Expression auf den makrovaskulären EC in-situ eindeutig demonstriert werden. Im Rahmen der Atherosklerose nimmt CD90-Expression auf den makrovaskulären EC in den höheren Atherosklerosestadien zu. Eine tendenzielle Zunahme der CD90 Expression nach Stimulation mit proinflammatorischen Zytokinen, die an der Atheroskleroseentwicklung beteiligt sind, sowie eine signifikante Hochregulation der CD90 Expression nach Stimulation mit einem Trigger der EPC-Migration, dem CXCL12, konnte in dieser Arbeit gezeigt werden. Die Ergebnisse deuten auf eine wichtige Rolle des CD90 auf makrovaskulären EC in dem atherosklerotischen Prozess hin. Die publizierten Daten zeigen, dass CD90 in die Leukozytenmigration durch das aktivierte mikrovaskuläre Endothel involviert ist. In der vorliegenden Arbeit konnte jedoch nicht eindeutig nachgewiesen werden, welche Funktion das CD90 auf makrovaskulären EC besitzt. Hierbei ergaben sich zusammenfassend zwei an sich unterschiedliche Hypothesen. Zum einen zeigt die tendenzielle Zunahme der CD90-Expression nach Stimulation mit proinflammatorischen Zytokinen, dass CD90 an der Migration der neutrophilen Granulozyten und somit z.B. durch die Freisetzung von MMP-9 an der Destruktion der Plaque beteiligt sein kann. Zum anderen könnte man behaupten, dass die signifikante Hochregulation der CD90-Expression nach Stimulation mit dem CXCL12 auf die Beteiligung des CD90 an der EPC-Migration hindeutet. Somit könnte CD90 durch die EPC-Migration sowie z.B. zusätzlich durch die eingewanderten neutrophilen Granulozyten, welche den Zelldebris phagozytieren, in die Neointimaformation involviert sein. Um eine sichere Aussage diesbezüglich treffen zu können sind weitere Untersuchungen notwendig.

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Dyer, Douglas Philip. "Tumour necrosis factor-stimulated gene-6 (TSG-6) binds to the pro-inflammatory chemokine CXCL8 and modulates its activity." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/tumour-necrosis-factorstimulated-gene6-tsg6-binds-to-the-proinflammatory-chemokine-cxcl8-and-modulates-its-activity(d7ee8a1f-ebd2-44e2-aa9f-cff6d0cf26ab).html.

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Tumour necrosis factor stimulated gene 6 (TSG-6) is a protein present in a range of tissues and is produced by a wide range of cell types in response to a number of inflammatory stimuli, where this protein is thought to mediate protection against excessive inflammation. TSG-6 is expressed in response to inflammation and has been implicated as an endogenous protector of tissues, e.g. in the context of inflammatory arthritis. TSG-6 has also been shown to reduce inflammatory damage in animal models of both myocardial infarction and corneal injury. Our earlier studies demonstrated that TSG-6 is a potent inhibitor of neutrophil migration, which likely contributes to these protective activities. Here we investigated the effect of TSG-6 on CXCL8-mediated pro-inflammatory processes. The interaction of TSG-6 with CXCL8, and how this influences the binding of CXCL8 to heparin, was investigated using solid-phase assays and surface plasmon resonance (SPR). The ability of this interaction to inhibit the interaction between CXCL8 and one of its receptors CXCR2 was investigated using murine pre-B cells expressing this receptor, in flow cytometry experiments. The effects of TSG-6 on CXCL8's pro-inflammatory activities were assessed using a neutrophil cell line (differentiated HL60 cells) in a trans-endothelial migration assay and gelatin zymography to measure secretion of MMPs by the endothelial cell (EC) line EA.hy 926. TSG-6 expression in EA.hy 926 and HL-60 cells was assessed using qRT-PCR, immunofluorescence and western blotting of cell lysates and culture media. We have shown that TSG-6 binds to CXCL8 via its Link module domain (Link_TSG6) and inhibits the interaction of CXCL8 with heparin. Analysis of culture media from EA.hy 926 cells revealed that both full-length TSG-6 and Link_TSG6 abolished CXCL8-mediated up-regulation of MMP-2 secretion. In transmigration assays, TSG-6 and Link_TSG6 were found to inhibit CXCL8-induced migration of neutrophils across an EC monolayer and also inhibited the interaction between CXCL8 and CXCR2; this effect was enhanced in mutants of Link_TSG6 with reduced heparin-binding functions. Very limited TSG-6 expression was observed in EA.hy 926 and HL-60 cells, where stimulation with pro-inflammatory mediators had little effect on expression. Here we have shown that TSG-6 binds directly to CXCL8 and inhibits its interaction with heparin, its interaction with CXCR2 and its enhancement of MMP-2 secretion by ECs; these effects are mediated via the Link module of TSG-6. Furthermore, Link_TSG6 inhibits trans-endothelial migration of neutrophils in a dose dependent manner; this could be due in part to reduced association of CXCL8 with EC glycosaminoglycans or with its receptors on neutrophils, thereby limiting its pro-migratory activity. Inhibition of MMP production by ECs could also limit neutrophil trans-migration as well as tissue damage and angiogenesis. Thus, the modulation of CXCL8 activity represents one way in which TSG-6 might protect tissues from the damaging effects of inflammation.

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Pandey, Shubham. "Identification of Interleukin 4 - CXCL12 supportive loop in follicular lymphoma." Thesis, Rennes 1, 2016. http://www.theses.fr/2016REN1B031/document.

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Le lymphome folliculaire (FL) est le lymphome B indolent le plus fréquent. Outre des altérations géniques récurrentes, le micro-environnement tumoral, et notamment les cellules stromales lymphoides,joue un rôle majeur dans le développement de ce cancer. Cependant, la caractérisation in-situ des cellules stromales lymphoïdes chez l'homme tout comme les facteurs menant à la polarisation du stroma en un stroma protumoral ont été peu étudiés. Dans cette thèse, nous avons montré, que les cellules stromales présentes dans les ganglions et la moelle osseuse envahis des patients atteints de FL surexpriment fortement la chimiokine CXCL12. Nous avons ensuite tenté de comprendre les mécanismes responsables de cette induction. Alors que les cellules B tumorales induisent une surexpression de la chimiokine CCL2 dans les cellules stromales de façon dépendante de leur synthèse de TNF, elles ne contribuent pas à l'induction de CXCL12. A l'inverse, le principal compartiment TCD4 impliqué dans la croissance tumorale du FL, les cellules T follicular helper (TFH), augmentent l'expression de CXCL12 dans les cellules stromales. Le taux d'IL-4, la principale cytokine produite par les TFH de FL, est d'ailleurs corrélé à celui de CXCL12 au sein de ma niche tumorale du FL. De plus, à l’aide d'un modèle de différenciation en stroma lymphoide, nous avons démontré que l’IL4 induit l’expression de CXCL12 par les cellules stromale in vitro. Cette production est augmentée quand les cellules stromales sont déjà engagées vers la voie de différentiation lymphoide par un traitement TNF/LT qui favorise l'activation de STAT6 par l'IL-4. Nous avons validé ces résultats dans un modèle de formation d'organe lymphoide ectopique chez la souris. Enfin, CXCL12 induit la migration et l'adhésion au stroma des B de FL via l'activation de cascades de signalisations qui peuvent être abrogées par l'utilisation d'un inhibiteur de Btk utilisé en clinique, l'Ibrutinib. Ces résultats sont en faveur de l'intérêt de considérer la boucle IL-4/CXCL12 pour développer de nouvelles stratégies thérapeutiques dans cette pathologie constamment fatale
Follicular lymphoma (FL) is the most frequent indolent B-cell lymphoma. Beside recurrent genetic alterations, tumor microenvironment, including lymphoid stromal cells, has been shown to play a key role in FL development. However, in situ characterization of lymphoid stromal cells is still lacking in humans and there are very few studies focusing on the factors that could lead to stroma polarization in normal and pathological context. In this thesis, we showed first that in FL, lymph node (LN) and bone marrow (BM) infiltrating stromal cells highly express the chemokine CXCL12. We next focused on the mechanisms underlying this upregulation. Interestingly, whereas malignant FL B cells induced overexpression of CCL2 in stromal cells in a TNF-dependent manner, they did not contribute to CXCL12 induction. Conversely, FL-infiltrating follicular helper T cells (FL-TFH), the key FL-supportive T-cell subset could trigger CXCL12 expression in stromal cells. IL-4 is the main FL-TFH-derived cytokine and showed a positive correlation with CXCL12 expression inside FL cell niches. Moreover, based on our in vitro lymphoid stroma differentiation model, we demonstrated that IL-4 promoted CXCL12 expression in stromal cells, together with a phenotype close to that identified in situ within FL cell niche. Such IL4 dependent CXCL12 regulation is more pronounced in stromal cells already committed towards lymphoid stromal cells by a prestimulation by TNF/LT in association with an increased STAT6 activation. These data were validated in a model of ectopic lymphoid organ formation in mice. Finally, CXCL12 induced FL B-cell migration, and adhesion to stromal cells through the activation of a signaling pathway that could be abrogated by the Btk inhibitor Ibrutinib. These data argue for considering IL-4/CXCL12 axis as a potential therapeutic target to disrupt FL protective cell niche in this still fatal malignancy

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Ramos, Edneia Amancio de Souza. "Hipermetilação de ilhas de CpG dos genes CXCL12 e ESR1." reponame:Repositório Institucional da UFPR, 2009. http://hdl.handle.net/1884/18637.

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Romanini, Juliana. "Envolvimento dos receptores CXCR2 para quimiocinas no carcinoma espinocelular oral." Pontifícia Universidade Católica do Rio Grande do Sul, 2010. http://hdl.handle.net/10923/462.

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The present study has evaluated the relevance of CXCR2 chemokine receptors in the oral squamous cell carcinoma, by means of in vitro and in vivo approaches. The in vitro incubation of the selective and non-peptide CXCR2 receptor antagonist SB225002 (25 to 3200 nM) produced a time- and concentration-dependent inhibition of viability of the cell lines SCC158 e HN30, from rat and human origin, respectively. On the other hand, this antagonist failed to significantly affect the viability of the normal keratinocyte lineage HaCaT. The role of CXCR2 receptors was further confirmed by testing the effects of the selective human and rat agonists, IL-8 (1 to 100 ng/ml) and CINC-1 (1 to 10 nM), respectively. This series of results revealed a concentration-dependent increase of HN30 and SCC158 cell proliferation, respectively. The sub-mucosal injection of SCC158 cells (5 x 106 cells per site), into the tongue of Fischer 344 rats, induced tumor development, which displayed typical clinical features. The tumor growth was evident as early as seven days following cell inoculation, being maximal at 40 days.After this period, the lesion length did not allow continuing experiments. Of high interest, the immunohistochemical analysis of rat tongue biopsies revealed a marked increase of CXCR2 receptor expression in the tumor groups, independent on the time of evaluation. The up-regulation of CXCR2 receptors was accompanied by an expressive augmentation in the expression of the molecular markers of angiogenesis and apoptosis, VEGF and caspase-3, respectively. Our data suggests an important role for CXCR2 receptors in oral squamous cell carcinoma. Additional studies are needed to determine the effects of treatment with the selective CXCR2 chemokine receptor antagonist SB225002, on in vivo tongue carcinoma growth.
O presente estudo avaliou o envolvimento dos receptores CXCR2 para quimiocinas, no carcinoma espinocelular oral, através de ensaios in vitro e in vivo. A incubação in vitro do antagonista seletivo não-peptídico dos receptores CXCR2, SB225002 (25 a 3200 nM), produziu uma inibição dependente do tempo e da concentração, da viabilidade das linhagens SCC158 e HN30, de carcinoma oral de células escamosas de ratos e humanos, respectivamente. Por outro lado, a incubação com este antagonista não produziu alteração significativa da viabilidade da linhagem HaCaT de queratinócitos humanos normais. O papel dos receptores CXCR2 foi ainda avaliado através da utilização dos agonistas seletivos para estes receptores em humanos (IL-8) e em ratos (CINC-1). Esta série de resultados demonstrou que a incubação de IL-8 (1 a 100 ng/ml) ou de CINC-1 (1 a 10 nM) produziu um aumento concentração-dependente da proliferação das linhagens celulares HN30 de humanos e SCC158 de ratos, respectivamente. A injeção submucosa de células SCC158 (5 x 106 células/sítio), na língua de ratos Fischer 344, induziu o desenvolvimento de carcinoma espinocelular oral, com características lembrando àquelas observadas clinicamente em humanos. O aumento tumoral foi evidente após sete dias da inoculação das células, sendo máximo em 40 dias. Depois desse período de tempo, o tamanho da lesão impediu que fossem continuados os experimentos. De forma interessante, a análise por imunoistoquímica demonstrou um aumento marcante da expressão dos receptores CXCR2 na língua de ratos com tumor, independente do tempo de avaliação. O aumento da expressão dos receptores CXCR2 foi acompanhado de um aumento dos marcadores de angiogênese e apoptose, VEGF e caspase-3, respectivamente. Os dados do presente estudo sugerem um importante papel para os receptores CXCR2 no carcinoma oral de células escamosas.Estudos adicionais precisam ser realizados a fim de determinar o efeito do tratamento com o antagonista seletivo dos receptores CXCR2, SB225002, no desenvolvimento tumoral in vivo.

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Shayan, Raheleh. "CXCL12/CXCR4 in embryonic lymphatic vasculature and lymph node formation." Thesis, Aix-Marseille, 2019. http://www.theses.fr/2019AIXM0304.

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Nous avons étudié le rôle de l’axe CXCL12 / CXCR4 dans la période initiale de formation de LN, de E12.5 à E14.5. Nous avons utilisé le modèle rapporteur Cxcl12DsRed et généré des embryons de KO généraux à l'aide de Cxcl12DsRed, ce qui nous a permis d'étudier les effets de cette suppression sur les embryons. Il en résultait beaucoup moins de cellules dans le LN anlagen cervical et mandibulaire, ce qui se reflétait dans la quantité totale de LTi4 dans l'embryon. Nous avons également éliminé Cxcr4 de manière conditionnelle sur les CSH en utilisant des souris Vavicre croisées avec des souris Cxcr4flox. Il en résultait moins de cellules LTi dans le LN anlagen mandibulaire. Pour déterminer si l'endothélium des vaisseaux sang est la source de CXCL12 impliquée dans l'initiation de la formation de LN, nous avons utilisé Cxcl12Tie2KO, qui n'a cependant eu aucun effet sur la formation de LN. Pour supprimer Cxcl12 de l'autre source au sein de LN anlagen, les cellules mésenchymateuses, nous avons utilisé NestinCre pour entraîner Cxcl12flox. Dans ce modèle, nous avons observé une diminution modeste du nombre de cellules LTi dans le LN anlagen mandibulaire, mais pas de reflet du Cxcl12 KO complet. Pour établir que CXCL12 est impliqué dans la rétention des cellules LTi au sein du LN anlagen, nous avons bloqué la signalisation CXCR4 juste avant l'isolement des embryons à E13.5 à l'aide de Plerixafor ou AMD31000. Nous avons observé que les cellules LTi ont commencé à sortir du LN anlagen et à former du LN anlagen en vrac et plus étendu. Par conséquent, nous avons conclu que CXCL12 / CXCR4 était impliqué dans la rétention des cellules LTi au sein du LN anlagenuins
We investigated the role of the CXCL12/CXCR4 axis in the initial period of LN formation, from E12.5 until E14.5. We used the Cxcl12DsRed reporter model and generated general KO embryos using Cxcl12DsRed, which allowed us to investigate the effects of this deletion on embryos. It caused significantly less cells in the cervical and mandibular LN anlagen which was reflected in the total amount of LTi4 in the embryo. Also, we conditionally knocked out Cxcr4 on HSCs using Vavicre mice crossed with Cxcr4flox mice. This resulted in less LTi cells in the mandibular LN anlagen. To establish if the blood vessel endothelium is the source of CXCL12 involved in initiation of LN formation, we used Cxcl12Tie2KO, which, however, had no effect on the LN formation. To delete Cxcl12 from the other source within the LN anlagen, the mesenchymal cells, we used NestinCre to drive Cxcl12flox. In this model, we observed a modest decrease in the number of LTi cells in the mandibular LN anlagen but no reflection of the complete Cxcl12 KO. To establish that CXCL12 is involved in retention of LTi cells within the LN anlagen, we blocked CXCR4 signaling just before isolation of the embryos at E13.5 using Plerixafor or AMD31000. We observed that the LTi cells started to move out from the LN anlagen and form loose and more spread LN anlagen. Therefore, we concluded that CXCL12/CXCR4 was involved in retaining the LTi cells within the LN anlagen

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Manjavachi, Marianne Neves. "Participação da quimiocina CXCL1 em modelos experimentais de dor crônica." reponame:Repositório Institucional da UFSC, 2015. https://repositorio.ufsc.br/xmlui/handle/123456789/169571.

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Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas. Programa de Pós-Graduação em Farmacologia, Florianópolis, 2015.
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A dor crônica é um problema de saúde grave, que afeta milhões de pessoas por todo o mundo. No entanto, não há terapia farmacológica disponível para o tratamento adequado de pacientes com dor crônica. Estudos recentes fornecem evidências convincentes de que a neuroinflamação desempenha um papel fundamental na patogênese dador crônica. O objetivo deste estudo foi avaliar o possível envolvimento da quimioquina CXCL1 na patogênese da dor neuropática, utilizando para isso diferentes modelos experimentais. A injeção intraneural (i.n.)de CXCL1 em camundongos causou hiperalgesia mecânica e térmica (ao calor) de longa duração, associada com migração de neutrófilos para o local da injeção no nervo ciático. A depleção destas células, após o tratamento dos animais com vimblastina, reduziu a hiperalgesia mecânica induzida pela quimiocina. A administração da CXCL1 no nervo ciático de camundongos aumentou os níveis teciduais da interleucina 1?? (IL-1??), interleucina 6 (IL-6) e da quimiocina CCL2, mas não do fator de necrose tumoral ?? (TNF-??). A participação da CXCL1 no modelo de ligação parcial do nervo ciático (LPNC) também foi evidenciada, uma vez que após a lesão os níveis teciduais e a expressão do RNAm para a CXCL1 encontraram-se aumentados tantono nervo ciático quanto na medula espinhal de camundongos. Otratamento com anticorpo anti-CXCL1 no momento, ou 4 dias após aLPNC reduziu de maneira significante tanto a hiperalgesia mecânica como a térmica (ao calor). Além disso, a administração intratecal (i.t.)do anticorpo anti-CXCL1 foi eficaz em inibir a hiperalgesia mecânica induzida pela LPNC, sugerindo a participação central desta quimiocinano desenvolvimento da dor neuropática. Estendendo os resultados anteriores, foi demonstrado que a participação da CXCL1 nos mecanimos envolvidos na LPNC depende da migração de neutrófilos, bem como da liberação de mediadores inflamatórios, especialmente daIL-1?? e IL-6. Finalmente, avaliou-se o possível envolvimento da quimiocina CXCL1 em um modelo de dor neuropática não relacionadoa lesão direta de nervos, a neuropatia periférica induzida pelo paclitaxel (PTX), um quimioterápico de amplo uso clínico. A administração repetida de PTX induziu o aumento significativo da expressão do RNAm para CXCL1 tanto no GRD como na medula espinhal, bem como aumentou os níveis teciduais desta quimiocina na medula espinal. O tratamento sistêmico com o anticorpo anti-CXCL1, mas não o com antagonista do receptor CXCR2, reduziu a hiperalgesia mecânica instalada induzida pelo PTX. De modo relevante, o tratamento preventivo destas drogas quando administrados pela via intratecal inibiram de maneira significativa a hiperalgesia mecânica induzida pelo PTX. Estes resultados sugerem a participação da quimiocina CXCL1 e do seu receptor expressos na medula espinhal no desenvolvimento da neuropatia induzida pelo PTX. Ainda os mecanismos centrais envolvidos na hiperalgesia mecânica induzida pelo PTX parecem depender da ativação da via de sinalização PI3K/AKT, e não das enzimas PLC e PKC. Os resultados do presente estudo demonstraram que a quimiocina participa dos mecanismos envolvidos no estabelecimento e manutenção da dor crônica em modelos experimentais. Desta maneira, estratégias que contribuam para inibir a ação e/ou a liberação desta quimiocina poderiam constituir ferramentas terapêuticas importantes para o tratamento da dor neuropática em seres humanos.

Abstract : Chronic pain is a rising health problem that is predicted to affect millions of people worldwide. However, there are so far no available pharmacotherapies providing satisfactory pain relief for patients with persistent pain. Recent studies provide compelling evidence that neuroinflammation plays a key role in the pathogenesis of chronic pain. In this study we sought to evaluate the involvement of chemokine CXCL1 in the pathogenesis of neuropathic pain in different experimental models. Intraneural injection (i.n.) of CXCL1 induced thermal and mechanical hyperalgesia in mice and caused neutrophil migration into the mouse sciatic nerve. Depletion of these cells in animals pre-treated with vinblastine significantly reduced the mechanical hyperalgesia induced by the chemokine. Administration of CXCL1 in the sciatic nerve of mice increased tissue levels of interleukin1ß (IL-1ß), interleukin 6 (IL-6) and chemokine CCL2, but not the tumor necrosis factor a (TNF-a). CXCL1 role in the partial ligation of the sciatic nerve (PLSN) model was also demonstrated since after surgery their tissue levels and CXCL1 mRNA expression increased in the sciatic nerve and spinal cord tissues. Treatment with anti-CXCL1 antibody at the moment or 4 days after surgery reduced mechanical and thermal hyperalgesia induced by PLSN. Furthermore, the intratecal (i.t.) injection of anti-CXCL1 antibody also inhibited mechanical hyperalgesia induced by PLSN, suggesting the central involvement of this chemokine in the development of neuropathic pain. The participation of the CXCL1 in the PLSN model also depends on neutrophils migration and release of inflammatory mediators such as IL-1ß and IL-6. Finally we evaluated the involvement of CXCL1 chemokine in a neuropathic pain model that was not dependent on direct nerve injuries, the neuropathic pain model induced by the chemotherapy paclitaxel (PTX). Repeated administration of PTX induced a significant increase in expression of CXCL1 mRNA in spinal cord and DRG, as well as increased the tissue levels of this chemokine in the spinal cord. Systemic treatment with anti-CXCL1 antibody, but not the CXCR2 receptor antagonist, reduced the installed mechanical hyperalgesia induced by PTX. Preventive treatment of these drugs when administered by intratecal route significantly inhibited the mechanical hyperalgesia induced by PTX. These results suggest the involvement of CXCL1 chemokine and its receptor expressed in the spinal cord in the development of neuropathy induced by PTX. Furthermore, central mechanisms involved in the mechanical hyperalgesia induced PTX appear to depend on activation of the PI3K/AKT signaling pathway, and independent of PLC and PKC enzymes activation. The results of this study demonstrated the role of CXCL1 in the establishment and maintenance of chronic pain in experimental models. Thus, strategies to inhibit the action and/or the release of this chemokine might be an important therapeutic tool for the treatment of neuropathic pain inhumans.

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Teixeira, Maraiza Alves. "Papel de receptores CXCR2 na mucusite intestinal induzida por irinotecano." reponame:Repositório Institucional da UFC, 2015. http://www.repositorio.ufc.br/handle/riufc/15664.

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TEIXEIRA, Maraiza Alves. Papel de receptores CXCR2 na mucusite intestinal induzida por irinotecano. 2015. 94 f. Dissertação (Mestrado em Farmacologia) - Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, 2015.
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Introduction: Irinotecan is an anticancer agent used in first and second line treatment protocols for colorectal cancer. However, a major side effect associated with irinotecan, intestinal mucositis, has negatively impacted on patient’s quality of life and limiting the therapeutic outcome. The literature reports the involvement of several inflammatory mediators in the pathogenesis of intestinal mucositis, including IL-1, IL-18, IL-33, nitric oxide and several others, whose pharmacological inhibition prevents neutrophil infiltration and leads to mucositis improvement. However, the role of chemokine receptors that are important to neutrophil recruitment, such as CXCR2, in intestinal mucositis is unknown. Aims: To study the role of CXCR2 receptors in the pathogenesis of irinotecan-induced intestinal mucositis. Methods: Male C57BL/6 mice (n = 6) were divided into groups and injected with either saline (5ml / kg, ip) or irinotecan (75, 90, 105 or 120 mg/kg ip) for 4 days. The dose of 120 mg/kg reproduced the inflammatory condition of mucositis, so it was used in association with SB225002, a CXCR2 antagonist. Body mass variation, diarrhea scores and leukocyte count were recorded. Following euthanasia, intestinal samples were collected for histopathological analysis, mieloperoxidase activity (MPO), IL-1β, KC and IFN-γ levels. In addition, the length of the small intestine was measured so was the weight of its solid contents. Bacteremia was further carried out. Additionally, we measured the expression of CXCR2 and CCR2 receptors on neutrophils surface. We also performed the in vitro chemotaxis assay, using neutrophils isolated from bone marrow of mice treated with IRI or IRI + SB225002 (Study approval number: 58/14). Results: IRI produced a significant (P <0.05) weight loss and leukopenia in all doses tested. However, only the doses of 105 and 120 mg/kg reduced (P<0.05) the villus/crypt ratio and increased (P<0.05) neutrophil infiltration (MPO assay). None of the doses promoted diarrhea. The dose of 120 mg/kg was the best in reproducing the typical histopathological damage seen during intestinal mucositis, thus this dose was chosen for further analysis. The treatment with SB225002 did not protect the animals from the weight loss, leukopenia, histopathological damage (measured by the villus/crypt ratio), reduction of the small intestine length or weight reduction of the small intestine content induced by IRI. There was no difference between IRI or IRI + SB225002 groups in regard to these parameters. In regard to neutrophil infiltration, SB225002 prevented the increase in MPO activity as early as 24 hours post 1st dose of IRI (P<0.05) vs IRI group, but failed to do so in late mucositis. In addition, IRI led to CXCR2 internalization followed by an increased expression of CCR2 receptor on neutrophils harvested from IRI-treated mice. Accordingly, in vitro neutrophil migration towards MIP-2, a CXCR2 ligand, was reduced. We also observed that mice injected with IRI or SB225002+IRI showed bacteremia when compared to the saline group. Conclusion: CXCR2 receptors only participate in the early phases of intestinal mucositis, likely due to the downregulation of these receptors, which are replaced by CCR2 on the surface of neutrophils.
Introdução: O irinotecano é um antineoplásico usado no tratamento de primeira e segunda linha do câncer colorretal. No entanto, um importante efeito colateral associado ao irinotecano, a mucosite intestinal, tem impactado negativamente na qualidade de vida dos pacientes e no sucesso terapêutico. Trabalhos anteriores demonstraram que na patogênese da mucosite intestinal há a participação de mediadores pró-inflamatórios, como IL-1, IL-18, IL-33, óxido nítrico dentre outros, cuja modulação leva à redução do infiltrado neutrofílico no intestino e melhora do dano tecidual. Entretanto, o papel de receptores de quimiocinas, como o CXCR2, importantes no recrutamento de neutrófilos, ainda não foram investigados no contexto da mucosite. Objetivos: Avaliar o papel de receptores CXCR2 na mucosite intestinal induzida pelo Irinotecano. Métodos: Camundongos C57BL/6 machos, 18-25g, foram divididos em grupos (n=6), administrados por 4 dias com salina (5mL/kg, i.p) ou com irinotecano (75, 90, 105 ou 120 mg/kg, i.p). A dose de 120 mg/kg foi a que melhor reproduziu o quadro inflamatório característico da mucosite, sendo então utilizada nos ensaios posteriores em associação ao SB225002, um antagonista de receptores CXCR2. Os animais foram analisados quanto ao peso corpóreo, escores de diarreia, contagem de leucócitos. Após a eutanásia, uma amostra de intestino foi coletada para análise histopatológica e morfométrica, dosagem de mieloperoxidase e níveis de IL-1β, IFN-γ e KC. Além disso, o comprimento do intestino delgado foi mensurado, bem como o peso do conteúdo sólido. Avaliou-se também a bacteremia. Adicionalmente, realizou-se a quantificação dos receptores CXCR2 e CCR2, além do ensaio de quimiotaxia in vitro de neutrófilos isolados de camundongos tratados com IRI ou com IRI+SB225002. (Protocolo CEPA 58/14). Resultados: O IRI em todas as doses avaliadas promoveu uma significativa (P<0,05) perda ponderal e leucopenia. Sendo que, apenas as doses de 105 e 120 mg/kg foram capazes de reduzir de forma significativa (P<0,05) a razão vilo/cripta e de aumentar (P<0,05) o infiltrado neutrofílico (ensaio de MPO). Nenhuma das doses avaliadas promoveu diarreia nos camundongos desse experimento. A dose de 120 mg/kg foi que a melhor reproduziu o dano histopatológico típico da mucosite intestinal, sendo a dose escolhida para as demais análises. O uso do antagonista dos receptores CXCR2, o SB225002, associado ao IRI não protegeu os animais da perda de peso, da leucopenia, do dano histopatológico (mensurado pela razão vilo/cripta), da redução do comprimento do intestino delgado nem da redução do peso do conteúdo do delgado. Todos esses parâmetros apresentaram-se de forma semelhante nos animais tratados apenas com IRI ou em associação IRI+SB225002. Quanto ao infiltrado neutrofílico, observamos que o uso do SB225002 no D2, 24h após a 1ª administração do IRI, foi capaz de reduzir a atividade da MPO (P<0,05). Tal redução não foi observada nos tempos subsequentes. Observou-se que o tratamento com irinotecano levou à internalização de CXCR2 e aumento da expressão do CCR2 nos neutrófilos de animais tratados com o antineoplásico. Houve, ainda, uma redução da migração de neutrófilos do quinto para o sétimo dia após a injeção do IRI. Corroborando com esse dado, houve redução da migração dos neutrófilos (isolados da medula óssea de camundongos tratados com irinotecano) ao MIP-2, um ligante de CXCR2. Observamos, ainda, que os camundongos injetados com IRI apresentaram bacteremia, quando comparados ao grupo salina. Conclusão: O receptor CXCR2 participa somente da fase precoce da mucosite intestinal, provavelmente devido a uma internalização deste receptor, o qual é substituído pelo CCR2 na superfície dos neutrófilos.

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Hamon, Morgan. "La liaison de SDF-1/CXCL au Syndécane-4." Paris 13, 2004. http://www.theses.fr/2004PA132029.

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Le but de ce travail a été de montrer que SDF-1 ne se lie pas seulement à son récepteur actuellement identifié, CXRA, mais également à d'autres ligands membranaires. Nos expèriences nous ont permis de montrer, dans un premier temps, l'existence de deux classes de sites de liaison de SDF-1/CXCL12 à la surface de macrophages et de lymphocytes en culture primaire, et de cellule HeLa en lignée. Nous avons ensuite observé que SDF-1/CXCL12 se lie, non seulement à son récepteur couplé à une protéine G, CXCRA, mais également, à un protéoglycanne : le syndécane-4. Cette liaison, GAG-dépendante, faciliterait la fixation de SDF-1 à CXCRA exprimé à la surface des macrophages. Nous avons également montré que le syndécane-4 est co-associé, en l'absence de SDF-1, à CXCRA. De plus, la liaison de SDF-1 au syndécane-4 induit une transduction de signal ainsi qu'une homo- ou hétéro-oligomérisation du syndécane-4 et de CXCR4.

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Steele, Colin W. "Investigating the role of CXCR2 signalling in pancreatic inflammation and cancer." Thesis, University of Glasgow, 2014. http://theses.gla.ac.uk/5809/.

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C-X-C motif receptor 2 (CXCR2) is a G-protein coupled receptor normally expressed on granulocytes, in particular CD11b +, Gr1+, Ly6G+ bone marrow derived suppressor cells (BMDCs) and once differentiated neutrophils.

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Fox, James Martin. "Characterisation of CXCL4 and CCL1 interactions with their respective chemokine receptors." Thesis, Imperial College London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.430464.

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Mellor, Paul. "Disruption of CXCL12/CXCR4 interactions : a role in breast cancer therapy?" Thesis, University of Newcastle Upon Tyne, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433130.

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Callewaere, Céline. "Interaction de la chimiokine SDF-1α/CXCL12 avec le système vasopressinergique". Paris 5, 2007. http://www.theses.fr/2007PA05P620.

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La chimiokine SDF-1α (CXCL12) et son récepteur CXCR4 co-localisent avec l’hormone antidiurétique, l’arginine vasopressine (AVP) dans l’hypothalamus et la neurohypophyse. Au cours de nos études, nous avons établi que : 1) le SDF-1α et l’AVP présentent une distribution cellulaire spécifique dans les neurones des noyaux magnocellulaires hypothalamiques et sont localisés dans les mêmes vésicules neurosécrétoires de la neurohypophyse ; 2) le SDF-1α, par l’intermédiaire du CXCR4, module l’activité électrique du système à AVP et la libération plasmatique d’AVP; 3) l’expression du couple SDF-1α/CXCR4 est régulée lors de changements dans l’équilibre hydrique suite à une déshydratation ou chez des animaux Brattleboro ; animaux déficients en synthèse centrale d’ AVP. Les données originales obtenues au cours de ce travail ouvrent un axe de recherche novateur dans l’implication des chimiokines dans la régulation hydrique et plus généralement dans la régulation des fonctions neuroendocriniennes
The chemokine SDF-1α (CXCL12) and its receptor CXCR4 are co-localized with the antidiuretic hormone arginine vasopressin (AVP) in the hypothalamus and in the posterior pituitary. During our studies we demonstrated that: 1) SDF-1α and AVP present a selective cellular distribution inside the neuronal cell and can be found in the same dense core vesicles in the nerve terminals in the posterior pituitary; 2) SDF-1α can modulate, through CXCR4, the electrical activity of AVP neurons and plasma AVP release; 3) the expression of SDF-1α/CXCR4 is regulated when the hydro-osmotic balance is disturbed as in case of dehydration or in Brattleboro rats ; an endogenous knock-out model for brain AVP deficiency. The original data obtained during this work open new avenues in the implication of chemokines in the water balance regulation and more generally in neuroendocrine functions

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Williams, Mark Anthony. "DISPARATE REGULATION OF NEUTROPHIL PRO-INFLAMMATORY FUNCTIONING BY CXCR2-SELECTIVE CHEMOKINES." University of Cincinnati / OhioLINK, 2000. http://rave.ohiolink.edu/etdc/view?acc_num=ucin971879221.

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Öhnstedt, Emelie. "Accelerated wound healing by on-site production and delivery of CXCL12." Licentiate thesis, Uppsala universitet, Institutionen för medicinsk cellbiologi, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-442088.

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Non-healing wounds is a growing medical problem, often associated with pathological conditions such as diabetes and peripheral ischemia. A non-healing wound entails a large amount of suffering for the patient, and demands extensive health care resources. In this thesis, a new drug treatment paradigm for wound healing was developed by transforming Limosilactobacillus reuteri R2LC with a plasmid encoding CXCL12 (LB_CXCL12). The drug candidate was tested for safety and biological effects following topical administration to full thickness wounds in both mice and minipigs. In parallel, different techniques, including 2D and 3D measurements, planimetry, and ultrasound, for assessing wound healing were developed and evaluated. Murine wounds treated with LB_CXCL12 demonstrated increased proliferation of dermal cells, and an increased density of macrophages of which a larger fraction expressed TGF-β. If macrophages were depleted prior to wounding, the accelerated effect on healing was abolished demonstrating a macrophage-dependent mechanism of action. Importantly, the LB_CXCL12 treatment also accelerated wound healing in mice with impaired healing as a result of hyperglycemia or peripheral ischemia, conditions that in humans are associated with development of non-healing wounds. Wounds in minipigs treated with the freeze-dried formulation of LB_CXCL12, upon resuscitation referred to as ILP100, showed accelerated healing both by increased granulation tissue formation and accelerated re-epithelialization. The treatment with ILP100 was well tolerated with no treatment-related deviations in haematology, urinalysis, and histopathology. Further, we found improved detection of thin layers if newly formed epithelial using planimetry and ultrasound compared to 2D photographs, whereas 3D scans accounting for surface curvatures yielded larger wound areas than 2D photographs of the same wounds. Development of topical treatments for non-healing wounds are limited by the proteolytic environment of the wound that cause degradation of applied molecules. Our developed technology, a new-in-class candidate, overcomes this by continuous on-site delivery and increased bioavailability of CXCL12, resulting in prolonged instruction of local immune cells to stimulate wound healing.

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Rial, Nathaniel S. "The Adenomatous Polyposis Coli Tumor Suppressor Gene Suppresses Deoxycholic Acid Induction of the Chemotactic Cytokine CXCL8 in Human Colorectal Cancer." Diss., The University of Arizona, 2007. http://hdl.handle.net/10150/194449.

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Elevated deoxycholic acid (DCA) and mutations in the Adenomatous Polyposis Coli (APC) tumor suppressor gene have been associated with increased risk of colorectal cancer (CRC). Chronic inflammation has also been associated with increased risk of CRC. It is unclear if DCA mediates inflammation in the normal or transformed colonic mucosa. The status of APC was manipulated in human CRC cell lines to study the role of DCA mediated inflammation. The chemotactic cytokine, CXCL8, was used as a marker of inflammation. Addition of DCA to the HT29-parental cell line with mutant-APC increased the steady state mRNA and protein levels of CXCL8. Conversely, addition of DCA to the HT29-APC cell line with wild type-APC was protective for increased steady state RNA and protein levels of CXCL8. DCA activated transcription factors which had binding regions in the CXCL8 5’-promoter. To elucidate the mechanism of induction, the 5’-promoter of CXCL8 was investigated. DCA increased promoter-reporter activity of the CXCL8 gene in HT29-parental cell line but wild type-APC blocked this effect. Chromatin immunoprecipitation (ChIP) revealed that DCA activated transcription factors, AP-1 and NF-κB were bound to the 5’-promoter of CXCL8. The transcription factor, β-catenin, was also bound to the 5’-promoter of CXCL8. Phenotypic effects were measured. Increased CXCL8 lead to matrix metalloproteinase-2 (MMP-2) production and increased invasion by HT29-parental cells on laminin coated filters. The DCA-mediated invasion was blocked by antibody directed against CXCL8 and wild type- APC. Therefore DCA-mediated inflammation occurs in transformed colonic epithelium and increases the invasive phenotype of CRC cells by CXCL8.

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Cavalcante, Galyléia Menezes. "Estudo da imunoexpressão dos sistemas CXCR4-CXCL12/SDF-1, CCR7-CCL21 e KI-67 no carcinoma de células escamosas oral e sua associação com indicadores clínicopatológicos, metástase linfonodal e sobrevida." reponame:Repositório Institucional da UFC, 2013. http://www.repositorio.ufc.br/handle/riufc/8455.

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CAVALCANTE, Galyléia Menezes. Estudo da imunoexpressão dos sistemas CXCR4-CXC112/SDF-1, CCR7-CCl21 e KI-67 no carcinoma de células escamosas oral e sua associação com indicadores clínicopatológicos, metástase linfonodal e sobrevida. 2013. 57 f. Dissertação (Mestrado em Odontologia) - Universidade Federal do Ceará. Faculdade de Farmácia, Odontologia e Enfermagem, Fortaleza, 2013.
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Chemokines are responsible for the directed migration of leukocyte chemotactic cytokines, coordinating cell movement during inflammation and the transport of hematopoietic cells. In addition to leukocytes, chemokine receptors are also found in neoplastic cells and tumors associated with stromal cells. Among chemokines, and the CXCR4/CXCL12 CCR7/CCL21 systems have been shown the involvement of lymph node metastases or distant metastases in different cancers. Thus, aim of this study was to evaluate the expression of CXCR4, CXCL12, CCR7, CCL21 and Ki-67 in oral squamous cell carcinoma (SCC) and to correlate these markers with clinicopathological indicators, lymph node metastasis and survival. We conducted a survey of reports and paraffin blocks of excisional biopsies of patients with SCC treated at the Hospital Haroldo Juaçaba (2001-2009). Data on anatomic location of the lesion, sex, age, patient survival, degree of histological differentiation of the tumor, tumor stage and presence or absence of lymph node metastasis, lymphovascular and perineural invasion, nuclear grade and depth of invasion were collected. For immunohistochemical analysis, followed by the technique of streptavidin-biotin-peroxidase using the anti-CXCR4, anti-CXCL12, anti-CCR7, anti-CCL21 and Ki-67 antibody. Histological sections were photomicrographed in 10 fields chosen randomly and measured for the number of labeled tumor cells and determined the percentage of each labeling antibody. The marking of CXCR4 was detected in the cytoplasm and nucleus, CXCL12, CCR7 and CCL21 were only cytoplasmic, their expression was observed in 18 (60%) 8 (22.66%) 16 (53.3%) and 3 (12%) cases, respectively. We found a significant positive association between lymphovascular invasion and immunostaining of CXCR4 (p = 0.007) and CCR7 (P = 0.01) and among these cases metastasis was present in 62.5% and 37.5%, respectively. When in combination with Ki67, we found a significant positive correlation between CXCR4 (p = 0.0086), CXCL12 (p = 0.036) and CCR7 (p = 0:04). Among patients CXCR4 + over 111 months, only 38.4% were alive (p = 0.845), whereas both patients CCR7 + (p = 0.398) as well as CXCR4 +, and CCR7 + (p = 0.441) after 62 months, everyone had already died. We conclude that these chemokines are associated with lymphovascular invasion and cell proliferation, perhaps favoring the development of metastasis and poor prognosis.
As quimiocinas são citocinas quimiotáticas responsáveis pela migração direcionada de leucócitos, coordenando o movimento celular durante a inflamação e o transporte de células hematopoiéticas. Além dos leucócitos, os receptores de quimiocinas também são encontrados em células neoplásicas e em tumores associados com células estromais. Dentre as quimiocinas, os sistemas CXCR4/CXCL12 e CCR7/CCL21 têm sido demonstrado no envolvimento de metástases linfonodais ou à distância em diferentes tipos de câncer. Dessa forma, foi objetivo desse trabalho avaliar a expressão de CXCR4, CXCL12, CCR7, CCL21 e Ki-67 em carcinoma de células escamosas orais (CEC) e correlacionar estes marcadores com indicadores clínicopatológicos, metástase linfonodal e sobrevida. Realizou-se um levantamento de laudos e blocos parafinados de biopsias excisionais de pacientes portadores de CEC tratados no Hospital Haroldo Juaçaba (2001 a 2009). Foram coletados dados sobre localização anatômica da lesão, sexo, idade, sobrevida do paciente, grau de diferenciação histopatológica do tumor, estadiamento tumoral e presença ou ausência de metástase linfonodal, invasão linfovascular e perineural, grau nuclear e profundidade de invasão. Para reação de imunohistoquímica, seguiu-se a técnica da estreptavidina-biotina-peroxidase, utilizando os anticorpos anti-CXCR4, anti-CXCL12, anti-CCR7, anti-CCL21 e Ki-67. As secções histológicas foram fotomicrografadas em 10 campos escolhidos aleatoriamente e quantificadas quanto ao número de células tumorais marcadas e determinado o percentual de marcação de cada anticorpo. A marcação de CXCR4 foi detectada em citoplasma e núcleo, CXCL12, CCR7 e CCL21 tiveram marcação apenas citoplasmática, sendo observada suas expressões em 18 (60%), 8 (22,66%), 16 (53,3%) e 3 (12%) casos, respectivamente. Encontrou-se uma associação significativa positiva entre a invasão linfovascular e a imunomarcação do CXCR4 (p=0.007) e CCR7 (p=0.01) e dentre esses casos a metástase esteve presente em 62,5% e 37,5%, respectivamente. Quando em associação com o Ki67, encontrou-se uma correlação positiva significante entre o CXCR4 (p=0.0086), CXCL12 (p=0.036) e CCR7 (p=0.04). Dentre os pacientes CXCR4+, ao longo de 111 meses, apenas 38,4% estavam vivos (p=0.845), ao passo que tanto para pacientes CCR7+ (p = 0.398), quanto CXCR4+ e CCR7+ (p = 0.441), após 62 meses, todos haviam ido a óbito. Conclui-se que essas quimiocinas estão associadas com a invasão linfovascular e proliferação celular, talvez favorecendo o desenvolvimento de metástases e um pior prognóstico.

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Fujita, Thiago Cezar. "Análise do polimorfismo CXCL12 rs1801157 e envolvimento dos inibidores de tirosina quinase na expressão da quimiocina humana CXCL12 e do seu receptor CXCR4 em leucemia mielóide crônica." Universidade Estadual de Londrina. Centro de Ciências Biológicas. Programa de Pós-Graduação em Patologia Experimental, 2011. http://www.bibliotecadigital.uel.br/document/?code=vtls000167955.

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As leucemias são doenças particularmente heterogêneas e complexas, tanto do aspecto morfológico quanto biológico. A leucemia mieloide crônica (LMC) é uma doença proliferativa do sistema hematopoiético caracterizada por uma superprodução de células da linhagem granulocítica, especialmente neutrófilos e ocasionalmente monócitos, resultando em acentuada esplenomegalia e elevada leucometria. Cerca de 90% dos pacientes diagnosticados com LMC apresentam um marcador denominado cromossomo Filadélfia (Ph), produto de uma translocação entre os cromossomos 9 e 22, caracterizando uma oncoproteína denominada BCR/ABL. O tratamento para LMC, Ph positivo, inclui diferentes estratégias, que vão desde o simples controle na contagem de leucócitos, eliminação das células Ph positivas por substituição de células alogênicas ou por supressão não-específica do clone neoplásico. Dentre as drogas descritas para o tratamento de LMC na fase crônica são o Bussulfan e a Hidroxiuréia; transplante alogênico de células tronco hematopoiéticas, Interferon-_ e inibidores do domínio tirosina quinase do BCR/ABL. Ultimamente têm-se discutido o papel das quimiocinas e o seu envolvimento nas neoplasias. O fator-1 derivado do estroma da medula óssea (SDF-1/CXCL12) é uma quimiocina que ao se ligar ao receptor (CXCR4), desenvolve importantes funções na migração, retenção e desenvolvimento de progenitores hematopoiéticos na medula óssea. Além disso, o sistema CXCL12/CXCR4 está envolvido na quimiotaxia de células cancerosas e na metástase tumoral. Observou-se que as células leucêmicas escapam da apoptose in vitro quando entram em contato com as células produtoras de CXCL12. Foi descrito um polimorfismo do CXCL12 designado rs1801157 na região 3 UTR da quimiocina CXCL12 relacionada com um possível aumento da expressão dessa quimiocina. Portanto, o presente trabalho investigou a relação do polimorfismo rs1801157 CXCL12 na expressão de CXCL12 e CXCR4 em pacientes com LMC comparado a indivíduos saudáveis. No presente estudo, não foi encontrado relação entre a presença do polimorfismo 3A para o CXCL12 e os pacientes acometidos por Leucemia Mielóide Crônica. Além disso, não houve associação entre a expressão de CXCL12 e a expressão de CXCR4, teste de correlação de Sperman não significante (p = 0,621). Entretanto, foi detectada uma maior expressão de CXCR4 (1,946 vezes maior) nos pacientes com Leucemia Mielóide Crônica (p = 0,009) comparados aos indivíduos saudáveis. Além disso, nesse trabalho, os diferentes aspectos da terapia na LMC também foram considerados para análise. Nessa população, há uma inferência entro o tempo de tratamento com o mesmo quimioterápico e a expressão de CXCR4 (p = 0,036) nos pacientes com LMC. Curiosamente, sete pacientes analisados que possuem tempo de tratamento por um período igual ou superior a 20 meses, demonstraram aumento acentuado na expressão de CXCR4, sendo que esse aumento foi em média três vezes maior aos pacientes com tempo de tratamento inferior a 10 meses (p = 0,043). Os aspectos moleculares desse trabalho podem auxiliar no diagnóstico, monitoramento e prognóstico das leucemias. Podem proporcionar também uma melhor compreensão dos mecanismos moleculares envolvidos na patogênese assim como outros alvos e alternativas terapêuticas para a Leucemia Mielóide Crônica.
Leukemias are particularly heterogeneous and complex, both the morphological and biological aspects. The chronic myeloid leukemia (CML) is a proliferative disease of hematopoietic system characterized by an overproduction of cells of granulocytic lineage, particularly neutrophils and monocytes occasionally resulting in marked splenomegaly and elevated WBC (White Blood Cells) count. About 90% of patients diagnosed with CML have a "marker" called Filadélfia chromosome (Ph), the product of a translocation between chromosomes 9 and 22, featuring an oncoprotein called BCR/ABL. The treatment for CML, Ph positive, including different strategies, ranging from the simple control of leukocyte count, elimination of Ph positive cells for cell replacement or allogeneic non-specific suppression of neoplastic clone. Among the drugs described for the treatment of CML in chronic phase are busulfan and hydroxyurea; allogeneic hematopoietic stem cell, interferon-_ and inhibitors of tyrosine kinase domain of BCR/ABL. A major cause of treatment failure and death of cancer patients is metastasis to secondary organs. Lately have been discussing the role of chemokines and their involvement in malignancies. Bone Marrow Stromal Derived Factor-1 (SDF-1/CXCL12) is a chemokine that through the binding to its receptor (CXCR4), has major roles in the migration, retention and development of hematopoietic progenitors in bone marrow. It was observed that the leukemic cells escape from apoptosis in vitro when in contact with CXCL12-producing cells. Described a polymorphism of CXCL12 designated rs181157 in the 3UTR of the chemokine CXCL12 in relation to a possible increase in expression of this chemokine. Therefore, this study investigated the relationship of the polymorphism rs181157 in the expression of CXCL12 and CXCR4 in patients of CML compared to healthy subjects. In this study, no relationship was found between the presence of polymorphism for CXCL12 3A and patients suffering from CML. Furthermore, no association between the expression of CXCL12 and CXCR4 by Sperman correlation test was not significant (p = 0,621). However, we detect a higher expression of CXCR4 (1.946 more) in patients with CML (p = 0,009) compared to healthy subjects. Moreover, in this work, the different aspects of therapy in CML were also considered for analysis. In this population, there is an inference from the time get of treatment with same chemotherapy and the expression of CXCR4 (p = 0,036) in patients with CML. Interestingly, seven patients have time to treatment for a period equal to or greater than 20 months, showed marked increased in the expression of CXCR4, and this increase was on average three times higher than patients with treatment time of less than 10 months (p=0,043). The molecular aspects of this work may help in diagnosis, monitoring and prognosis of leukemia. They can also provide a better understanding of the molecular mechanisms involved in the pathogenesis as well as other targets and alternative therapias for chronic myeloid leukemia.

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Albrecht, Ulrike. "Anti-angiogenetische Therapie beim humanen Pankreaskarzinom durch CXCR2-Inhibition im orthotopen Nacktmausmodell." Diss., kostenfrei, 2008. http://edoc.ub.uni-muenchen.de/8566/.

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Karatt, Vellatt Aneesh. "Investigating the potential of antibody and peptide blockade of CXCL12/CXCR4 signalling." Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708501.

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39

Khurram, Syed Ali. "The chemokine receptors XCR1, CXCR1 and CXCR2 regulate oral epithelial cell behaviour." Thesis, University of Sheffield, 2008. http://etheses.whiterose.ac.uk/10311/.

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Chemokines are chemoattractant cytokines which act on specific receptors and play an important role in tumour biology. The aim of this project was to determine whether the chemokine receptors XCRl, CXCRl and CXCR2 and their respective ligands lymphotactin, IL-8 (CXCRl&2) and GRO-a regulate the behaviour of normal and malignant oral epithelial cells. XCRl, CXCRl and CXCR2 mRNA and surface protein expression was detected in normal and oral cancer cell lines. Lymphotactin, IL-8 and GRO-a facilitated intracellular activation of ERK1/2 signaling pathway and stimulated migration, invasion and proliferation of all cells. These effects were mediated through XCRl for lymphotactin, CXCRl and CXCR2 for IL-8 and CXCR2 for GRO-a. The cancer cells showed a greater response than normal cells and a direct relationship between receptor expression and migration, invasion and proliferation was observed. XCRl but not lymphotactin was expressed by epithelial cells in normal oral mucosa in vivo and both were expressed and upregulated in inflammation and cancer. Constitutive expression of both XCRl and lymphotactin was found in regional lymph nodes and on metastatic tumours. Lymphotactin mRNA al}d constitutive intracellular protein was detected in normal and cancerous oral cells. Exposure of normal cells to lymphotactin resulted in increased adhesion to fibronectin but not collagen and stimulated MMP-2 and -9 release whereas exposure of cancer cells resulted in increased adhesion to both collagen and fibronectin and stimulated MMP-2, 9 and MMP-7 release. These findings show for the first time that XCRl and its ligand lymphotactin are expressed by epithelial cells in a range of oral conditions and strongly suggest that they play an important role in regulating the behaviour of normal and malignant epithelial cells. Similarly CXCRl and CXCR2 are upregulated on malignant oral cells in vitro and may be important in the biology of oral cancer.

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Elvas, Filipa Catarina Bernardino D'. "Papel da quimiocina CXCL12 no Acidente Vascular Cerebral Isquémico: revisão da literatura." Master's thesis, Universidade da Beira Interior, 2013. http://hdl.handle.net/10400.6/1643.

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Este documento encontra-se dividido em dois capítulos: o primeiro capítulo incide sob a vertente de investigação e o segundo aponta para a experiencia profissionalizante relativa ao estágio realizado na vertente de Farmácia Comunitária, que cessa o plano curricular do Mestrado Integrado em Ciências Farmacêuticas. O Acidente Vascular Cerebral (AVC) assume-se, ainda, como a primeira causa de mortalidade e uma das causas primordiais de incapacidade em Portugal. Este problema grave de saúde pública está provido de um enorme impacto pessoal, familiar e social, tornando-o numa doença com elevados custos económicos. A quimiocina CXCL12, originalmente chamada de fator 1 derivado das células do estroma, é um membro da subfamília CXC e encontra-se expressa em todos os tipos de células do Sistema Nervoso Central. Está documentado que após a ocorrência de um AVC Isquémico, os recetores desta quimiocina, portanto o CXCR4 e o CXCR7, estão sobreregulados no cérebro. A quimiocina abordada demonstrou desempenhar um papel significativo em modelos animais de Acidente Vascular Cerebral Isquémico, contudo o seu papel no Acidente Vascular Cerebral humano é incerto. Investigações neste âmbito, efetuadas em seres humanos, são escassas e apresentam declarações antagónicas acerca de uma quimiocina que parece prometer avanços na clínica da patologia tão fatal nos dias de hoje, que é o AVC. Esta foi a principal motivação para a escolha deste tema para o meu projeto de investigação. Sendo assim, o objetivo do presente trabalho consistiu na realização de uma revisão da literatura relativa ao papel da quimiocina no Acidente Vascular Isquémico. Para tal, procedeu-se á consulta de várias bases de dados, tais como: Pubmed, Medline, B-on, Web of Science e Web of Knowledge, e jornais como o ―Stroke‖. Neste contexto, foi passível apurar que os níveis plasmáticos da quimiocina em causa no presente trabalho podem representar um novo biomarcador de um Acidente Vascular Cerebral futuro. No entanto, para além da contribuição da quimiocina CXCL12 para desencadeamento desta patologia, a CXCL12 também é pensada ser um regulador chave na reparação do AVC, onde conceções mais divergentes são aludidas. Por um lado parece desempenhar um papel benéfico de neuroproteção, neurogénese, regeneração neuronal, remielinização, remodelação vascular e angiogénese, que são pré-requisitos importantes para a reparação e regeneração do SNC após a isquémia. Por outro lado é inferido que a quimiocina CXCL12 se encontra associada com a infiltração de leucócitos nas áreas de lesão isquémica e medeia potencialmente a patogénese do AVC isquémico. A correlacção entre a extensão da lesão procedente no AVC isquémico e os níveis da quimiocina CXCL12 também não é consensual. Portanto, são propostas algumas questões passíveis de serem fruto de uma investigação futura a fim de procurar saber qual o papel exato desta quimiocina e possivelmente envergar por estratégias farmacológicas nesse sentido. Quem sabe se este poderá ser um alvo para intervenção farmacológica no futuro? No que diz respeito ao estágio realizado em Farmácia Comunitária, este decorreu com o objetivo de conhecer a realidade da prática profissional do farmacêutico, bem como possibilitar a aplicação dos conhecimentos adquiridos ao longo do Mestrado Integrado em Ciências Farmacêuticas. No capítulo II deste documento estão descritas as atividades desenvolvidas no dia a dia da Farmácia Comunitária, bem como a experiência advinda deste estágio.
This document is divided into two chapters: the first chapter focuses on the research side and the second point to the professional experience in the Community Pharmacy Internship, which finishes the curriculum of the Master in Pharmaceutical Sciences. The Cerebral Vascular Accident (CVA) is still assumed as the first cause of mortality and one of the leading causes of disability in Portugal. This serious problem of public health is provided with a huge personal, family and social impact, making it a disease with high economic costs. The chemokine CXCL12, originally called chemokine stromal-derived factor 1 is a member of the CXC subfamily and is expressed in all cell types of the central nervous system. It is documented that after the occurrence of ischemic stroke, this chemokine receptors, CXCR4 and CXCR7, are upregulated in the brain. This chemokine demonstrated plays a significant role in animal models of ischemic stroke; however its role in human stroke is uncertain. Investigations in this area, in humans, is scarce and present conflicting statements about a chemokine that seems promising advances in clinical pathology as fatal, which is stroke . This was the main motivation for choosing this topic for my research project. Thus, the aim of this study consisted of a literature review on the role of chemokine in Ischemic Stroke. To achieve this, we will be consulting various databases, such as PubMed, Medline, B-on, Web of Science and Web of Knowledge and newspapers as the "Stroke". In this context, it was likely established that plasma levels of the chemokine in the present study may represent a new biomarker of a future stroke. However, in addition to the contribution of the chemokine CXCL12 trigger for this disease, the CXCL12 is also thought to be a key regulator in repairing strokes, which are different conceptions, alluded to. On the one hand, it appears to play a beneficial role in neuroprotection, neurogenesis, neuronal regeneration, remyelination, vascular remodeling and angiogenesis, which are important pre-requisites for the repair and regeneration after CNS ischemia. On the other hand, it is inferred that the CXCL12 chemokine is associated with the infiltration of leukocytes in the ischemic areas and potentially mediate the pathogenesis of ischemic stroke. The correlation between the extent of the injury and levels of the chemokine CXCL12 is not a consensus. Therefore, we propose some questions for future research in order to find out what the exact role of this chemokine and possibly wear pharmacological strategies accordingly. Who knows if this can be a target for pharmacological intervention in the future? With regard to the internship in Community Pharmacy, this took place in order to know the reality of the practice of pharmacy, and to enable the application of the knowledge acquired during the Master in Pharmaceutical Sciences. In Chapter II of this paper there are descriptions of the activities related to the Community Pharmacy, and the experience arising from this internship.

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Botton, Thomas. "Étude des effets anti-mélanome des thiazolidinediones : implication de la chimiokine CXCL1." Nice, 2010. http://www.theses.fr/2010NICE4028.

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Les thiazolidinediones (TZD) sont utilisés dans le traitement du diabète de type 2. Cependant, des études ont montré que les TZD inhibent la croissance de nombreuses cellules tumorales. Nous avons donc testé les effets des TZD dans la lutte contre le mélanome, un cancer très agressif contre lequel on ne dispose d’aucun traitement efficace au stade métastatique. Nous avons montré qu’un TZD, la ciglitazone, inhibe la prolifération des cellules de mélanome mais pas celle des mélanocytes. A de faibles doses, la ciglitazone induit un arrêt du cycle alors qu’à de fortes doses elle entraine une apoptose. Les effets antinéoplasiques de la ciglitazone ont été confirmés dans un modèle murin de xénogreffe de mélanome. Nous avons alors montré que les effets biologiques de la ciglitazone sont précédés par une forte diminution de CXCL1, une chimiokine oncogénique surexprimée durant la mélanomagenèse. Cette diminution de CXCL1 est associée à une diminution de MITF, un facteur de transcription contrôlant à la fois la différenciation mélanocytaire et la progression tumorale des cellules de mélanome. Des expériences de xénogreffe ont confirmé que la diminution du potentiel tumoral des cellules de mélanome est associée à une inhibition de l’expression de MITF et du taux sérique de CXCL1 dans les souris traitées à la ciglitazone. Nos travaux suggèrent donc que la ciglitazone pourrait être un candidat intéressant pour la mise en place d’un test clinique. Ils démontrent également l’existence d’un axe MITF/CXCL1 qui semble jouer un rôle clé dans la tumorogénicité des cellules de mélanome. Cet axe pourrait constituer une cible thérapeutique intéressante dans la lutte contre le mélanome
Thiazolidinediones (TZD) are commonly used in the treatment of type 2 diabetes. However, studies on various cancer types have shown that TZD inhibit tumor growth. Thus, we have tested the effects of TZD in the struggle against melanoma, a very aggressive cancer for which there is no hitherto efficient therapeutics when it is metastatic. We have shown in vitro that ciglitazone, a member of the TZD family, is able to inhibit proliferation of melanoma cells but not of melanocytes. At low concentrations, ciglitazone effects on melanoma cells are mediated by a cell cycle arrest while higher concentrations induce cell death by apoptosis. Then, antineoplastic effects of ciglitazone have been confirmed in a xenograft model. Next, we have shown that the biological effects of ciglitazone are preceded by a dramatic decrease in CXCL1. This chemokine overexpressed in melanoma contributes to tumorigenicity. Interestingly, ciglitazone-induced CXCL1 decrease is mediated by the downregulation of microphthalmia-associated transcription factor, MITF, the master gene in melanocyte differentiation and involved in melanoma development. Additional xenograft experiments have emphasized that dramatic decrease in melanoma tumor potential was associated with an inhibition of MITF and a decrease in serum CXCL1 levels of ciglitazone-treated mice. Thus, our results suggest that ciglitazone might be an interesting candidate for clinical trial in melanoma treatment. They also demonstrate existence of a MITF/CXCL1 axis and highlight the key role of this specific pathway in melanoma malignancy. This axis could be a potential interesting therapeutic target in the future of the struggle against melanoma

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42

Asagoe, Kosuke. "Down-Regulation of CXCR2 Expression on Human Polymorphonuclear Leukocytes by TNF-α". Kyoto University, 1998. http://hdl.handle.net/2433/182261.

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Ma, Junjun. "Synthesis and Optimization of ‘Sugar tongs’ Lock Neutraligands of the Chemokine CXCL12." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS241.

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L’Héparane Sulfate (HS) est un polysaccharide linéaire hautement sulfaté largement présent à la surface des cellules ou dans la matrice extracellulaire des tissus animaux. L’HS est l'un des polymères les plus hétérogènes et présente une alternance de domaines fortement sulfatés (S) et faiblement sulfatés (A). L'exposition à la surface cellulaire de ces domaines SAS permet d'établir des interactions spécifiques avec des protéines basiques présentant des topologies de charges complémentaires, permettant la régulation de leurs activités biologiques. CXCL12, une protéine de la famille des chimiokines se liant aux chaînes d’HS, est l'unique ligand naturel du récepteur CXCR4. La signalisation CXCL12/CXCR4 est impliquée dans divers processus biologiques dont l'hématopoïèse, la réponse immunitaire et la migration des cellules cancéreuses et leur prolifération. La conception de glycoligands pouvant se lier spécifiquement à CXCL12 pourrait permettre de moduler son interaction avec son récepteur et donner accès à une substance thérapeutique innovante pour le traitement de plusieurs types de cancer. Nous avons ainsi imaginé la construction d’un ligand tridentate symétrique comportant une partie centrale de type fragment d’HS synthétique (dp4) dont les extrémités réductrice (ER) et non réductrice (ENR) seraient reliées à des ligands capables d'occuper une partie du site de liaison à CXCR4.Grâce à de précédents travaux sur l'IFN-γ, une cytokine se liant aux chaînes HS, notre laboratoire a déjà démontré que la préparation de mimes de SAS pouvait être obtenue en reliant deux fragments d’HS synthétiques (domaines S) par leur ER via des bras espaceurs de type PEG et de longueur différente pour mimer les domaines A. Afin d’adapter cette stratégie à la préparation de neutraligands de CXCL12 et d’une nouvelle génération de mimes de SAS, ce programme doctoral visait (i) à établir une stratégie générale de modification de l’ER et l’ENR de fragments d’HS, (ii) à établir des conditions efficaces de réactions de couplage pour (iii) synthétiser des ligands de CXCL12 ainsi que de nouveaux mimes de SAS. Nous avons sélectionné deux réactions orthogonales de couplage dans le panel de Chimie Click, à savoir la formation de triazole «CuAAC» et la «ligation oxime». Afin de déterminer la faisabilité de transformation des deux extrémités de fragments d’HS pour réaliser ces réactions de couplage, nous avons optimisé les conditions de ces modifications sur un disaccharide modèle dérivé du cellobiose. Tout d’abord, en utilisant la procédure de couplage thiol-ène décrite par notre équipe, nous avons introduit une amine sur l'ER de ce disaccharide et optimisé les conditions d’une séquence monotope transfert de diazo/CuAAC permettant la conversion sélective de cette amine en azoture puis son couplage avec des alcynes vrais. Cette séquence a également pu être appliquée à des acides aminés libres pour la préparation de dérivés organofluorés. Ensuite, l'installation d'un motif aldéhyde sur l’ENR du composé modèle a été obtenue par une séquence en trois étapes comportant une allylation décarboxylante de type Tsuji-Trost de la position O-4 de l'unité NR, une dihydroxylation de l’éther d’allyle obtenu et enfin une coupure oxydante du diol formé. En plus d'explorer la sélectivité de la coupure oxydante en faveur de diols vicinaux acycliques en présence de diols cycliques portés par le squelette saccharidique, nous avons également optimisé les conditions de la réaction de formation d’oximes pour obtenir une seconde procédure monotpe de coupure oxydante/formation d’oxime pour la modification rapide de l’ENR de fragments d’HS. Cette stratégie de fonctionnalisation sélective de l’ER et l’ENR d’oligosaccharides a été implémentée dans notre voie actuelle de synthèse de fragments d’HS : elle a été appliquée de manière représentative à un fragment tétrasaccharidique d’HS qui permettra la préparation de neutraligands de CXCL12 et de mimes de SAS
Heparan sulfate (HS) is a class of linear and highly sulfated polysaccharides widely present in animal tissues, onto the cell surface or into the extracellular matrix. HS is one of the most heterogeneous polymers and presents an alternation of highly sulfated domains (S domains) and weakly sulfated one (A domains). Exposition of those SAS domains at the cell surface permits the establishment of specific interactions with proteins displaying complementary charge topologies, leading to the regulation of their biological activities.CXCL12, a HS-binding protein, member of the chemokine family of pro-inflammatory mediators, is the unique natural ligand of CXCR4 receptor. CXCL12/CXCR4 signaling is involved in several biological processes, including hematopoiesis, immune response and cancer metastasis. The design of HS type ligands that could bind specifically to CXCL12 to block or modulate its interaction with its receptor should give access to therapeutic substance being able to modulate its activity and allow treatment of several cancer types. To this aim, we planed to construct a symmetric tridentate ligand of CXCL12 in which the reducing end (RE) and non-reducing end (NRE) of a short synthetic HS fragment (dp4) would be connected to ligands able to occupy part of the CXCR4 binding site. Thanks to previous investigation onto IFN-γ, a cytokine that binds tightly to HS chains, our lab already demonstrated that the preparation of SAS mimics should be reached by connecting two synthetic HS fragments (S domains) by their RE through a PEG-type spacer differing in length to mimic internal A domain. To adapt this strategy to the preparation of CXCL12 neutraligands and new type of SAS mimics, this PhD program aimed (i) to establish a general strategy of modification of the HS fragments RE and NRE, (ii) to setup efficient conditions of ligation reactions for (iii) the preparation of CXCL12 neutraligands as well as a second generation of SAS mimics. We selected our two orthogonal ligation reactions into the Click Chemistry panel: “the CuAAC” triazole formation and the “oxime ligation”. In order to setup the practicability of this strategy of transformation of the two HS fragments ends, we optimized reaction conditions onto model disaccharide derived from cellobiose. On one hand, by using thiol-ene coupling procedure reported by our lab, we introduced an amino group to the RE of this disaccharide and optimized reactions conditions of a one-pot diazotransfer reaction/CuAAC sequence, allowing the selective conversion of this amino group into azide and its coupling with alkyne derivatives. To demonstrate the robustness of this sequence, we applied it to the direct modification of free amino acids for the preparation of organofluorine derivatives. On the other hand, the installation of an aldehyde motif onto the NRE of the model compound was obtained via a three steps sequence involving a Tsuji-Trost decarboxylative allylation of the position O-4 of the NRE unit, dihydroxylation of the resulting allyl ether and finally oxidative cleavage of the formed diol. Besides exploring the possibility of the selectivity of the oxidative cleavage in favor of vicinal acyclic diols without affecting cyclic diols of the disaccharide backbone, we also optimized the reaction conditions of oxime ligation to obtain a second one-pot procedure of oxidative cleavage/oxime ligation for the rapid modification of the NRE of HS fragments. This strategy of functionalization of the RE and NRE of oligosaccharides was implemented into our current synthetic pathway of preparation of HS fragments: a tetrasaccharidic HS fragment was representatively modified using this strategy for the synthesis of CXCL12 neutraligands and SAS mimics

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Biajoux, Vincent. "Impact d’un gain de fonction de Cxcr4 sur le développement et la compartimentalisation périphérique des lymphocytes." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA114825/document.

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Le syndrome WHIM (SW) est un déficit immuno-hématologique rare causé principalement par des mutations autosomales dominantes du gène CXCR4 qui entrainent une troncation du domaine C-terminal (C-Ter) du récepteur. Les formes mutantes de CXCR4 associées au SW génèrent des altérations de la désensibilisation et de l’internalisation du récepteur en réponse à CXCL12, qui se traduisent par une hypersensibilité à l’action chimiotactique du ligand. CXCR4 est un récepteur de chimiokine exprimé sur les leucocytes dont le rôle dans l’hématopoïèse et le trafic leucocytaire à l’état basal suggère que la lympho-neutropénie des patients atteints du SW est due à des défauts de production et/ou de domiciliation périphérique des leucocytes causés par le gain de fonction de CXCR4. Néanmoins, la validation de cette hypothèse est difficile chez les patients. En générant une souche de souris (Cxcr4+/1013), porteuse d’une mutation rapportée chez une famille de patients par une stratégie de knock-in, nous avons mis en évidence le rôle du domaine C-Ter de Cxcr4 dans le développement, la domiciliation périphérique des lymphocytes et l’immunité adaptative à médiation humorale.Les principaux résultats issus de notre travail, obtenus en combinant des approches biochimiques, fonctionnelles, de reconstitution de l’hématopoïèse par compétition, de transferts adoptifs et d’injection d’anticorps anti-CD45 in vivo, sont : 1) La mutation Cxcr41013 tronquant le domaine C-Ter se comporte différemment en terme de signalisation, selon qu’elle soit présente à l’état hétérozygote ou homozygote, et perturbe respectivement les transitions double-négatif (DN) 2-DN3 et proB-preB de la lymphopoïèse dans le thymus et la moelle osseuse (MO). Au contraire, elle ne génère pas d’effets sur le développement des cellules NK et la myélopoïèse ; 2) La lymphopénie qui touche les lymphocytes B (LB) et T (LT) est un processus intrinsèque aux cellules porteuses de la mutation Cxcr41013 et suit un modèle allèle-dose-dépendant ; 3) Le défaut de désensibilisation de Cxcr41013 empêche le relargage des lymphocytes NK et B immatures de la MO et celui des LB et LT matures des ganglions lymphatiques dans le sang. A l’inverse, le gain de fonction exacerbe la migration des LB recirculants et LT matures et leur rétention dans le parenchyme médullaire ; et 4) malgré l’absence de follicules primaires dans les ganglions lymphatiques, les souris mutantes sont capables de mettre en place une réponse immunitaire humorale efficace et spécifique d’un antigène T-dépendant, comme en témoigne l’augmentation des LB du centre germinatif et des plasmocytes ayant effectué une commutation isotypique. En conclusion, nous démontrons que la signalisation fine médiée par Cxcr4 est nécessaire pour le développement, la compartimentalisation périphérique et la fonction des lymphocytes
The WHIM Syndrome (WS) is a rare combined immuno-hematological disorder caused by inherited heterozygous autosomal dominant mutations in CXCR4, which result in most cases in the distal truncation of the receptor’s Carboxyl-terminal tail (C-Tail). Mutants of CXCR4 associated with WS display impaired desensitization and internalization of the receptor upon CXCL12 exposure, leading to enhanced migratory response. Because CXCR4 is expressed on leukocytes, we hypothesized that circulating pan-leukopenia could arise from altered CXCR4-mediated signalling that would skew tissue distribution and differentiation of leukocytes. This assumption was obviously difficult to address in patients. By generating a knock-in mouse strain (Cxcr4+/1013) that harbors a WS-linked gain-of-Cxcr4-function mutation, we establish that the C-tail domain in Cxcr4-mediated signalling is a pivotal regulator of lymphocyte development, peripheral trafficking and humoral immunity. The essential findings of our work, obtained by combining biochemical, bone marrow (BM)-mixed chimeras, in vivo labelling, adoptive co-transfers and functional approaches, are: 1) the C-tail truncating Cxcr41013 mutation caused differential signalling capacities depending on its heterozygous versus homozygous status and inhibited double-negative (DN) 2-to-DN3 and pro-B-to-pre-B developmental transitions during lymphopoiesis. In contrast, it had no effect on NK lymphopoiesis and granulopoiesis; 2) the resulting circulating B and T lymphopenia was due to hematopoietic cell-intrinsic defects and followed a mutated allele dose-dependent pattern; 3) impaired Cxcr41013 desensitization prevented the release of immature BM NK and B cells and mature lymph node (LN) B and T lymphocytes into the blood. Conversely, it forced homing and retention of mature recirculating B and T cells in the BM parenchyma; and 4) despite the absence of primary B-cell follicles in LNs, mutant mice produced efficient humoral responses upon immunization as illustrated by increased antigen-specific germinal center B cells and isotype-switched plasma cells. Collectively, our findings demonstrate that fine-tuning of Cxcr4 signal strength is required for optimal trafficking, egress and fitness of lymphocytes

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Devignes, Claire-Sophie. "Hypoxia signaling in osteoblast lineage cells promotes Systemic breast cancer growth and metastasis." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC325.

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La formation de métastases osseuses implique de nombreuses interactions entre les cellules de cancer du sein et le microenvironnement osseux. Les gradients d’hypoxie et l’activation de HIF (hypoxia inducible factor) 1alpha sont essentiels au maintien de l’homéostasie osseuse. Le rôle de la signalisation HIF dans les ostéoblastes lors du processus métastatique n’a pourtant jamais été exploré. Dans cette étude, nous montrons que les cellules ostéoprogénitrices (OPC), se situent dans des niches hypoxique, et que l’activation de la signalisation HIF dans ces cellules augmente la masse osseuse et favorise les métastases osseuses du cancer sein. L’effet de la signalisation HIF dans les OPC n’est pas limité au squelette, en effet celle-ci stimule aussi la croissance des tumeurs mammaires et la dissémination tumorale dans les poumons et d’autres organes distants. Nous avons mis en évidence que la signalisation HIF dans les OPC induit l’augmentation de la concentration plasmatique de la chimiokine C-X-C motif ligand 12 (CXCL12), qui entraine une augmentation systémique de la prolifération et de la dissémination tumorale, via l’activation de son récepteur CXCR4 sur les cellules cancéreuses. Ainsi, nos résultats mettent en évidence le rôle protumorigénique de l’hypoxie dans le lignage ostéoblastique, lors de la formation de métastases osseuse, mais également par une action systémique sur les tumeurs mammaires et les métastases dans les tissus mous. Nous démontrons également que des altérations de l’anabolisme osseux peuvent affecter la progression du cancer du sein, révélant un nouveau rôle du squelette au sein du macroenvironnement tumoral
Bone metastasis involves dynamic interplay between tumor cells and thelocal stromal environment. In bones, local hypoxia and activation of the hypoxiainducible factor (HIF)-1alpha in osteoblasts are essential to maintain skeletalhomeostasis. However, the role of osteoblast-specific HIF signaling in cancermetastasis is unknown. Here we show that osteoprogenitor cells (OPC) are locatedin hypoxic niches in the bone marrow, and that activation of HIF signaling in thesecells increases bone mass and favors breast cancer metastasis to bone locally.Remarkably, HIF signaling in osteoblast lineage cells also promotes breast cancergrowth and dissemination remotely, in the lungs and in other tissues distant frombones. Mechanistically, we found that activation of HIF signaling in OPC increasesblood levels of the chemokine C-X-C motif ligand 12 (CXCL12), which leads to asystemic increase of breast cancer cell proliferation and dissemination, throughdirect activation of the CXCR4 receptor. Hence, our data reveal a previouslyunrecognized role of the hypoxic osteogenic niche in promoting tumorigenesisbeyond the local bone microenvironment. They also indicate that alterations inbone formation can affect breast cancer progression, and support the concept thatthe skeleton is an important regulator of the systemic tumor environment

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46

Meuris, Floriane. "L’axe de signalisation CXCL12/CXCR4 : un nouveau facteur de l’hôte impliqué dans la carcinogenèse induite par les papillomavirus humains." Thesis, Paris 11, 2015. http://www.theses.fr/2015PA114833.

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Les papillomavirus humains (HPV), dont on dénombre plus de 300 types différents, infectent spécifiquement les épithéliums. Ces infections sont communes et généralement asymptomatiques. Cependant, lorsqu’elles persistent, elles peuvent donner lieu à des lésions bénignes, telles que les verrues, ou cancéreuses, telles que le cancer du col de l’utérus. Les facteurs de l’hôte impliqués dans la persistance et la pathogénie des infections par les HPV restent largement méconnus. Les premières évidences du rôle de l’axe de signalisation CXCL12/CXCR4 dans la pathogénie virale proviennent d’observations faites dans le contexte d’un déficit immunitaire rare, le syndrome WHIM. En effet, ce syndrome est dû à des dysfonctions de l’axe CXCL12/CXCR4 − causées par des mutations de CXCR4 conduisant à un gain de fonction de l’axe CXCL12/CXCR4 − et est caractérisé par une susceptibilité sélective des patients à des infections sévères, persistantes et parfois malignes par les HPV. Au vu de cette susceptibilité, l’objectif de ma thèse a été d’approfondir cet éventuel lien causal entre les dysfonctions de l’axe CXCL12/CXCR4 et la pathogenèse associée aux infections par les HPV et de caractériser les mécanismes moléculaires en jeu.Afin de répondre à cette problématique, je me suis intéressée dans la première partie de mes travaux de thèse aux conséquences des dysfonctions de l’axe CXCL12/CXCR4 − à travers le gain de fonction de CXCR4 associé au syndrome WHIM − sur le cycle biologique d’HPV18 étudié dans des cultures organotypiques épithéliales tridimensionnelles. Ces travaux nous ont permis de mettre en évidence que les dysfonctions de CXCR4 limitaient la production virale au profit de la mise en place d’un processus de transformation cellulaire. Les mécanismes en jeu impliquent une augmentation de la prolifération cellulaire et un changement du profil d’expression des protéines virales en faveur des oncoprotéines et au détriment de celles impliquées dans la réplication virale.Dans la seconde partie de mes travaux, je me suis attachée à déterminer les effets du blocage de l’axe CXCL12/CXCR4 dans un modèle murin de néoplasie épithéliale induite par HPV16 (souris K14-HPV16). Le traitement de ces souris par l’AMD3100, un antagoniste sélectif de CXCR4, induit une tendance à la normalisation se manifestant par une diminution significative de l’hyperplasie induite par HPV16. Cet effet est associé à une réduction de l’hyperprolifération des kératinocytes et de l’infiltrat de cellules immunitaires dans le derme.En conclusion, ce travail de thèse identifie l’axe CXCL12/CXCR4 comme un facteur de l’hôte impliqué dans la carcinogenèse induite par les HPV, et révèle le bénéfice de stratégies thérapeutiques basées sur le blocage de cet axe
Human papillomaviruses (HPVs), which encompass almost 300 different types identified so far, specifically infect epitheliums. Most of the time, HPVs are associated with asymptomatic infections suggesting an efficient control by the host immune system. However, when these infections persist, HPVs can cause cutaneous warts but also mucosal lesions that can progress to dysplasia and cancer (e.g. cervical cancers). The host factors involved in HPV persistence and derived-pathogenesis remain quite obscure. The first evidence for a role of the CXCL12/CXCR4 signaling axis in HPV pathogenesis came from observations made in the context of a rare immunodeficiency disorder, the WHIM syndrome. This syndrome is caused by dysfunctions of the axis formed by the chemokine CXCL12 and its receptor CXCR4 – caused by inherited heterozygous mutations in CXCR4 leading to a gain-of-function of the CXCL12/CXCR4 axis – and featured by a high susceptibility to severe, persistent and sometimes malignant HPV infections. In light of this susceptibility, the aim of my thesis was to characterise the molecular mechanisms involved and to find out whether it extend to a more general interplay between the CXCL12/CXCR4 axis and HPV biological cycle and pathogenesis.In the first part of my work, I investigated the consequences of CXCL12/CXCR4 dysfunctions – through the CXCR4 gain-of-function – on the HPV18 life cycle in three-dimensional organotypic epithelial cultures. We found that CXCR4 dysfunctions limited the viral replication at the benefit of cell transformation. The mechanisms included an increased in cell proliferation and a change in viral protein expression profile in favour of oncoproteins and at the expense of proteins involved in viral replication.In the second part of my work, I determined the impact of the CXCL12/CXCR4 blockade on a murin model of HPV16-induced neoplasia (K14-HPV16 mice). Treatment of these mice by AMD3100, a selective antagonist of CXCR4, results in a normalisation of HPV-induced lesions manifested by a significant decrease of skin hyperplasia. This effect is associated with a reduction in keratinocyte hyperproliferation and immune cell infiltration in dermis.To conclude, this thesis work identifies the CXCL12/CXCR4 axis as a new host factor involved in human papillomavirus-induced carcinogenesis, and reveals the benefit of therapeutic strategies based on the blockade of this axis

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47

Hardy, David. "Le rôle clef de la chimiokine CXCL12/SDF1 au sein du couplage angiogenèse/myogenèse au cours de la régénérescence du muscle strié squelettique." Thesis, Paris Est, 2015. http://www.theses.fr/2015PESC0035.

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La régénération du muscle fait appel à des cellules souches spécialisées mais elle nécessite également une action coordonnée d'éléments et de cellules du stroma et des tissus de soutien. L'étude de la régénération musculaire ne peut se borner à la seule étude de l'activation, la prolifération et la différenciation des cellules souches musculaires. L'objectif de mon travail de thèse a été d'approcher les mécanismes qui participent à la régénération harmonieuse du muscle à côté des cellules satellites à savoir les différents éléments cellulaires des tissus de soutien et aussi le stroma au travers de l'étude de la chimiokine CXCL12 et de son ancrage à la matrice extra-cellulaire musculaire. Dans un premier temps, nous avons fait le constat que les modèles de lésions musculaires étaient nombreux et étaient utilisés de façon indistincte avec une méconnaissance de leurs spécificités propres. Ainsi, la première partie de ce travail de thèse a consisté en la comparaison des modèles les plus utilisés dans la littérature afin de connaître leurs cibles potentielles et de choisir le mieux adapté aux questions scientifiques posées. Dans un deuxième temps, nous avons utilisé un modèle d'animaux génétiquement invalidés pour l'ancrage de l'isoforme gamma de CXCL12 à la matrice pour étudier le muscle strié squelettique, son développement, les cellules souches et l'organisation de leur niche et enfin, sa réparation. Bien que dans tous les modèles la lésion du muscle évolue à terme vers une restitution ad integrum, les processus mis en oeuvre varient en fonction du type et de l'ampleur de l'atteinte. En outre, nous avons montré que les paramètres histologiques seuls ne sont pas entièrement suffisants pour affirmer que la régénération musculaire est achevée et qu'il faut savoir considérer chaque type cellulaire en détail ainsi que des paramètres fonctionnels qu'il conviendra de mesurer dans les suites de ce travail. Nous avons ensuite étudié l'influence de l'adhésion de la chimiokine CXCL12 aux glycosaminoglycanes dans sa capacité à réguler la réparation musculaire. Pour ce faire nous avons utilisé comme modèle d'étude la souris knock in CXCL12Gagtm/Gagtm, récemment développée au laboratoire et dans laquelle le gène CXCL12 a été muté dans la région du site contrôlant l'ancrage de la molécule CXCL12 aux HS. Chez cette souris, CXCL12 est présent mais incapable de se fixer aux HS de la matrice extracellulaire tout en gardant son activité via CXCR4. Dans ce cas précis CXCL12 est donc incapable de générer un gradient responsable de l'attraction, la rétention et la migration de cellules cibles.Même si cette mutation n'altère pas le bon développement de la souris et que le muscle à l'état basal est normal, nous avons montré un défaut de régénérescence musculaire chez ces souris mutées ayant subit l'agression musculaire la plus sévère avec la présence d'un tissus fibreux cicatriciel et une infiltration d'adipocytes. Nous avons montré que l'absence de gradient de CXCL12 aboutit à une dérégulation de l'angiogenèse dont certains stigmates sont visibles à l'état basal, mais dont la pleine anomalie ne se mesure qu'en conditions d'agression. Cette dérégulation pourrait s'expliquer par la présence de vaisseaux non stabilisés par des cellules murales (cellules musculaires lisses et péricytes). Le développement de ce modèle de fibrose ouvre la voie à différentes questions sur le déroulement de la fibrose en général, de la réparation musculaire, et des relations qu'entretient l'arbre vasculaire les cellules de soutien
Muscle regeneration needs specialized stem cells but it also requires coordinated action of stromal cells and supporting tissue. The study of muscle regeneration can not be only limited to the study of the activation, proliferation and differentiation of muscle stem cells. The aim of this thesis was to approach the mechanisms involved in the harmonious regeneration of the muscle beside satellite cells to know the different cellular elements of the supporting tissues and also the stroma through the study of CXCL12 chemokine and its anchorage to the GAG of the muscle extracellular matrix.First, we made the observation that muscle damage models were numerous and were used indistinctly with ignorance of their own specificities. Thus, the first part of this thesis consisted of comparing different injury models commonly used in the literature to determine their potential targets and choose the most adapted to scientific questions asked. secondarily, we used an animal model genetically invalidated for anchoring of CXCL12 gamma isoform to the matrix to study the skeletal muscle development, stem cells and the organization of their niche and finally, the repair.We showed initially that the initial choice of the injury model is important during pathophysiological studies. Although all muscle injury models lead to an ad integrum restitution, regeneration processes vary considerably and the impact on different cell types also varies widely. In addition, we have shown that the only histological parameters, are not entirely sufficient to say that muscle regeneration is complete and each cell type should be considering in detail as well as functional parameters that should be measured in perspectives of this work.We used as a study model, mice knock in CXCL12Gagtm/Gagtm recently developed in the laboratory and in which CXCL12 gene has been mutated for the region coding the controlling anchoring of CXCL12 to HS. In this mouse, CXCL12 is present but unable to bind to the extracellular matrix HS while keeping its activity via CXCR4. In this case CXCL12 is unable to generate a gradient responsible for the attraction, retention and migration of target cells.Although this change does not affect the development of the mouse and the muscle at basal state is normal, we have shown a lack of muscle regeneration in these mice with fibrosis and fat infiltartion.The muscle stem cell compartment seems not to be altered in the mutant mice in the basal state and during the regeneration of the muscle. We have shown that the absence of CXCL12 gradient leads to deregulated angiogenesis through vascular hyperproliferation at the basal state. This deregulation seems to be responsible of an altered vascular regeneration after injury with the presence of non-stabilized mural cells (smooth muscle cells and pericytes). This lack of vascular regeneration appears to be responsible for a muscle regeneration failure

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Bassand, Kévin. "Modulation du processus d’angiogenèse induite par la chimiokine CXCL12 (SDF-1α) : Implication du miR-126 et des Glycosaminoglycannes". Thesis, Paris 13, 2019. http://www.theses.fr/2019PA131070.

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Les pathologies ischémiques constituent l’une des principales causes de mortalité dans le monde. En situation ischémique, afin d’éviter une nécrose tissulaire, la stimulation de l’angiogenèse est permise par la synthèse de facteurs pro-angiogéniques comme des chimiokines ou des microARNs (miRs). CXCL12 (SDF-1α), est une chimiokine exprimée par les cellules endothéliales en situation d’ischémie. Le miR-126 (miR-126-3p et miR-126-5p) est impliqué dans l’angiogenèse en accélérant le recrutement de progéniteurs endothéliaux attiréspar CXCL12, en stimulant l’expression de ses récepteurs à la surface des cellules endothéliales. En revanche, le rôle de CXCL12 dans la régulation de l’expression des miR-126 et leur implication dans le processus angiogénique induite par cette dernière demeure inconnue. Durant ma thèse, je me suis intéressé à l’implication des miR-126 et des glycosaminoglycannes (GAGs) dans l’angiogenèse induite par CXCL12.Nos résultats montrent pour la première fois que CXCL12 induit l’expression du miR-126-3p in vitro dans les cellules HUVEC et ex vivo dans des aortes de rats. De plus, le miR-126-3p est nécessaire à la formation de réseaux vasculaires (in vitro et ex vivo) et au processus de migration des HUVEC induite par CXCL12. Par ailleurs, nous montrons que CXCL12 induit une diminution de l’expression protéique de SPRED-1 (une cible connue du miR-126-3p) et cette inhibition stimule de façon plus importante la formation de réseaux vasculaires induite par CXCL12. Enfin, nous montrons que les GAGs sont nécessaires à la formation de réseauxvasculaires (in vitro et ex vivo) induite par CXCL12
Ischemic diseases are one of the leading causes of death in the world. In ischemic tissue, in order to avoid tissue necrosis, angiogenesis is stimulated through pro-angiogenic factors synthesis such as chemokines or microRNAs (miRs). CXCL12 (SDF-1α), is a pro-angiogenic chemokine expressed by endothelial cells in ischemic conditions. miR-126 (miR-126-3p and miR-126-5p) is involved in angiogenesis by accelerating endothelial progenitor’s recruitment induced by CXCL12, by stimulating the expression of its receptors on the endothelial cells surface. On the other hand, the role of CXCL12 in miR-126 regulation and their involvement in angiogenic processes induced by CXCL12 remains unknown. During my thesis, I was interested in the involvement of miR-126 and glycosaminoglycans (GAGs) in CXCL12-induced angiogenesis. Our results showed for the first time that CXCL12 induces miR-126-3p expression in vitro in HUVEC and ex vivo in rat aorta. In addition, miR-126-3p is necessary for the formation of vascular networks (in vitro and ex vivo) and for CXCL12-induced HUVEC migration process. In addition, we showed that CXCL12 induces a decrease of SPRED-1 protein expression (aknown target of miR-126-3p) and this inhibition have stimulated the formation of vascular networks induced by CXCL12 more significantly. Finally, we showed that GAGs are necessary for the formation of vascular networks (in vitro and ex vivo) induced by CXCL12

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RIGHETTI, ALESSANDRA. "Pancreatic ductal adenocarcinoma: microenvironment and clinical finding." Doctoral thesis, Università Politecnica delle Marche, 2020. http://hdl.handle.net/11566/273675.

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Per poter comprendere i meccanismi alla base dei processi di sviluppo e progressione dell’AdenoCarcinoma dei Dotti Pancreatici (PDAC), particolare attenzione deve essere rivolta al ruolo del microambiente tumorale. Nel PDAC infatti, le cellule tumorali, piccola porzione della massa tumorale, sono avvolte da un denso stroma circostante che cambia con il progredire del tumore. Recentemente, si è scoperto che le cellule tumorali sono in costante interazione sia tra di loro sia con le diverse componenti del microambiente. Questo continuo scambio di informazioni favorisce la proliferazione, la migrazione e la resistenza ai farmaci chemioterapici delle cellule tumorali. Numerose sono le componenti del microambiente che favoriscono lo sviluppo di tali processi, in particolare il rilascio della chemochina CXCL12 da parte dei fibroblasti associati al tumore (CAF) e il rilascio degli esosomi da parte delle cellule tumorali sembrerebbero essere particolarmente coinvolti nella progressione di questo tumore. Al fine di individuare possibili bio-marcatori prognostici, in questo studio si è dapprima verificata l'esistenza di correlazioni tra le sottopopolazioni di esosomi rilasciate nel plasma di pazienti PDAC e le loro variabili cliniche. Successivamente si è cercato di determinare il ruolo specifico di ciascuna isoforma di CXCL12 nell’AdenoCarcinoma dei Dotti Pancreatici. In particolare, gli effetti pro-tumorali o anti-tumorali delle isoforme disponibili in commercio, CXCL12-α, CXCL12-β e CXCL12-γ, sono stati valutati sulla linea cellulare pre-tumorale h-Tert HPNE. Dall’analisi esosomiale è emerso che la proteina EpCAM potrebbe svolgere un ruolo importante come fattore prognostico per il cancro del pancreas. Infatti, alti livelli di espressione della proteina EpCAM, in seguito a chemioterapia, correlano con una migliore sopravvivenza dei pazienti. Infine, questo lavoro dimostra che sia CXCL12-α che CXCL12-β mostrano un effetto pro-tumorale sulla linea cellulare pre-tumorale pancreatica h-Tert HPNE, poiché inducono un'alterazione in alcuni percorsi coinvolti nei processi di tumorigenesi del carcinoma del pancreas.
In order to understand the mechanisms underlying the development and progression processes of Pancreatic Ductal AdenoCarcinoma (PDAC), particular attention must be paid to the role of the tumour microenvironment. In PDAC in fact, the tumour cells, a small portion of the tumour mass, are enveloped by a dense surrounding stroma that changes with the tumour progression. Recently, it has been discovered that cancer cells are in constant interaction both with each other and with the different components of the tumour microenvironment. This continuous exchange of information promotes the proliferation, migration and resistance of cancer cells to chemotherapy drugs. Several components of pancreatic tumour microenvironment favour the development of these processes, in particular the release of the chemokine CXCL12 by tumour-associated fibroblasts (CAF) and the release of exosomes by tumour cells seem to be particularly involved in the progression of this tumour. In order to identify possible prognostic bio-markers, this study first verified the existence of correlations between the subpopulations of exosomes released in the plasma of PDAC patients and their clinical variables. Subsequently an attempt was made to determine the specific role of each isoform of CXCL12 in the Pancreatic Ductal AdenoCarcinoma. In particular, the pro-tumour or anti-tumour effects of commercially available isoforms, CXCL12-α, CXCL12-β and CXCL12-γ, have been evaluated on the pre-tumour cell line h-Tert HPNE. Exosomal analysis has shown that the EpCAM protein could play an important role as a prognostic factor for pancreatic cancer. In fact, high EpCAM expression levels, following chemotherapy, correlate with improved patient survival. Finally, this work shows that both CXCL12-α and CXCL12-β show a pro-tumour effect on the pancreatic pre-tumour cell line h-Tert HPNE, since they induce an alteration in some pathways involved in pancreatic cancer tumorigenesis processes.

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Desnoyer, Aude. "Etude de l'impact clinique et immunologique d'un traitement par lénalidomide dans la maladie de Kaposi liée au VIH." Thesis, Université Paris-Saclay (ComUE), 2015. http://www.theses.fr/2015SACLS017/document.

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L'objectif de cette thèse menée dans le cadre de l'essai clinique ANRS 154 Lenakap a été d'étudier l'impact clinique et immunologique d'un traitement par lénalidomide dans la maladie de Kaposi liée au VIH (MK-VIH) et d'identifier de nouveaux biomarqueurs de la pathologie, notamment à travers l'étude du trio de chimiokine et récepteurs CXCL12/CXCR4-CXCR7. A l'heure actuelle aucun traitement curatif de la MK-VIH n'est disponible. Le lénalidomide, un immunomodulateur pléïotrope, ciblant différentes anomalies rencontrées dans la MK constitue une perspective thérapeutique dans cette indication. L'interprétation de la réponse clinique des patients au traitement au cours de l'essai clinique ANRS 154 Lenakap est difficile, notamment en raison de discordances entre les scores d'évaluation utilisés. Cependant, nos résultats ont montré une bonne tolérance du lénalidomide chez les patients inclus, infectés par le VIH et traités par antirétroviraux. Aucune interaction médicamenteuse pharmacologiquement ou cliniquement significative n'a été détectée chez les patients, ouvrant de nouvelles perspectives pour la prise en charge de ces derniers, y compris dans d'autres indications, tels que le myélome multiple et les syndromes myélodysplasiques. Nous avons également mis en évidence l'impact du TNF-α, de l'IFN-γ et de l'IL-10 dans la progression de la MK-VIH.L'ensemble des mécanismes physiopathologiques de la MK n'est pas encore élucidé et nous ne disposons actuellement d'aucun biomarqueur, de suivi d'évolution, ou de réponse au traitement dans cette indication. Des données de la littérature suggèrent une implication du trio CXCL12/CXCR4-CXCR7 dans la physiopathologie de la MK-VIH. Nos analyses immunohistochimiques et par immunofluorescence, couplées à la mise au point d'une technique de quantification sur lames numérisées ont permis de mettre en évidence la présence augmentée des protéines CXCL12/CXCR4-CXCR7 dans les lésions de MK. Les corrélations positives retrouvées entre les protéines du trio et la présence du virus sous forme latente, la prolifération cellulaire et à la présence du facteur de croissance VEGF, suggèrent de possibles effets autocrines et paracrines du trio à l'origine d'une propagation tissulaire du virus et d'effets prolifératif et pro-angiogénique dans le MK. Cette étude suggère pour la première fois le rôle de biomarqueur tissulaire, témoin du processus physiopathologique de la MK, pour le trio CXCL12/CXCR4-CXCR7. En revanche, CXCL12 ne semble pas être un biomarqueur plasmatique à la fois de la physiopathologie ou de la progression de la MK. Enfin, cette étude confirme l'état pro-inflammatoire des patients infectés par le VIH et rapporte une immunomodulation particulière chez les patients MK-VIH avec des taux plasmatiques de TNF-alpha, IL-6, IFN-gamma et IL-10 augmentés, peut-être à l'origine du développement et de la progression de la maladie
The objective of my PhD works, conducted as part of the clinical trial ANRS 154 Lenakap, was to evaluate the clinical and immunological impact of lenalidomide in patients with HIV-associated Kaposi's sarcoma (AIDS-KS) and to identify new biomarkers of disease, particularly through the study of the trio CXCL12/CXCR4-CXCR7 So far, no cure for the AIDS-KS is available. Lenalidomide, an oral immunomodulating agent targeting various anomalies observed in KS is a therapeutic perspective in this indication. Evaluation of clinical response to treatment in the ANRS 154 Lenakap clinical trial was difficult, especially because of discrepancies observed between assessments scores used to evaluate this parameter. However, lenalidomide was well tolerated in patients infected with HIV and treated with antiretroviral drugs. We detected no pharmacologically or clinically significant drug interactions between lénalidomide and antiretroviral drugs, opening new perspectives for the treatment of HIV-positive patients, including other indications such as multiple myeloma and myelodysplastic syndromes. We also highlighted the impact of TNF-alpha, IFN-gamma and IL-10 in the progression of AIDS-KS. All pathophysiological mechanisms of KS are not yet elucidated, and so far, no biomarker is available to monitor evolution, or response to treatment in this indication. Some data suggest an involvement of the trio CXCL12/CXCR4-CXCR7 in the pathophysiology of KS. Our immunohistochemical and immunofluorescence analysis, coupled to a technique for quantification of digitized slides, have allowed us to demonstrate the over-expression of CXCL12, CXCR4 and CXCR7 proteins in KS cutaneous lesions. Moreover, we reported for the first time the simultaneous in situ up-regulation of CXCL12, CXCR4 and CXCR7 in AIDS- and classic-KS. These deregulations correlated with lesion severity, latent viral load, proliferation and angiogenesis. This suggests a possible autocrine and paracrine effects of the trio leading to the virus propagation, the cells proliferation and the angiogenic process observed in KS. Our results further indicate that the trio could be used in KS rather as a histologic than a circulating biomarker. Finally, this study confirms the pro-inflammatory state of HIV-infected patients and highlights a specific immune modulation in AIDS-KS patients with increased TNF-α, IL-6, IFN-γ and IL-10 plasma levels. This microenvironment may participate in the disease progression

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Дисертації з теми "CXCL2"

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