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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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RACCOSTA, LAURA. "Tumour-released Liver X Receptor ligands attract tumour promoting neutrophils in a CXCR2 dependent manner." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2012. http://hdl.handle.net/10281/28479.
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Tumour formation is the result of molecular alterations involving cellular regulators as well as the ability of tumor cells to affect the tumor microenvironment through smoldering inflammation, or even taking advantage of inflammation to grow and metastasize. Tumour microenvironment is composed of various cell types, among them neutrophils are recognized as playing an important pro-tumorigenic role, by promoting neoangiogenesis and/or by suppressing antitumor immune responses. We have recently shown that ligands of liver X receptors (LXRs), which are involved in cholesterol homeostasis and in modulating immune responses, are released by cancer cells and suppress antitumor immune responses by dampening dendritic cell migration to draining lymph nodes. Here, we report that natural and tumour-derived LXR ligands attract a subpopulation of bone marrow (BM)- derived cells in a LXR independent, CXCR2 dependent manner. These cells have phenotypic (CD11bhighGr1highLy6G+) and morphological features of neutrophils and favour initial tumour angiogenesis. Moreover, the in vivo inactivation of LXR ligands, the depletion of neutrophils, as well as the pharmacologic and genetic inactivation of CXCR2 inhibit neutrophil recruitment to the tumour and delay tumour growth. Our data reveal an unanticipated chemoattractant role for tumour-derived LXR ligands in promoting tumour growth that relies on the CXCR2-mediated recruitment of neutrophils, thus identifying a new therapeutic target for cancer patients.
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Padovani-Claudio, Dolly Ann. "Functional analysis of the chemokine receptor Cxcr2 in the normal and demyelinated adult central nervous system." Connect to text online, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=case1152193193.
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Padovani-Claudio, Dolly Ann. "FUNCTIONAL ANALYSES OF THE CHEMOKINE RECEPTOR CXCR2 IN THE NORMAL AND DEMYELINATED ADULT CENTRAL NERVOUS SYSTEM." Case Western Reserve University School of Graduate Studies / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=case1152193193.
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Russo, Remo de Castro. "Efeito da administração do antagonista de receptor CXCR2 no modelo de fibrose pulmonar induzida por bleomicina." Universidade Federal de Minas Gerais, 2005. http://hdl.handle.net/1843/UCSD-8FTN2Z.
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Pulmonary fibrosis is a disease characterized by progressive interstitial collagen deposition, which causes changes in the normal lung architecture and loss of function, which could lead to death. Acute pulmonary inflammatory processes and their chronification are associated with fibrotic phenomena acting as triggering events. The inflammation that precedes the emergence of pulmonary fibrosis is characterized by an increased cell influx, which culminates in the liberation of inflammatory mediators, which perpetuate the initial lesion. Therefore it is likely that the inhibition of the inflammatory response might be able to decrease the interstitial collagen deposition. The bleomycin-induced pulmonary fibrosis model is characterized by intense neutrophil influx concomitant with cytokine production, high levels of chemokines CXCL1-3/KC and CXCL1-2/MIP-2, followed by collagen deposition on the pulmonary parenchyma. In this study, we analyzed the effects of DF2162 administration, which is a CXCR2 chemokine receptor antagonist on bleomycin-induced pulmonary fibrosis model in mice. Our results show that the administration of 6 mg/kg of DF2162 twice a day significantly inhibited the neutrophilic influx peaks caused by intra-tracheal instillation of 0,125 U of bleomycin. However, DF2162 did not promote changes in the levels of modulatory cytokines such as IFN, IL-10 e VEGF, which are important for the inflammatory process. We did not observe changes in the levels of chemokines CXCL1-3/KC, CXCL1-2/MIP-2, CCL2/JE, CCL3/MIP-1 and CXCL10/IP-10 with the exception of CCL5/RANTES, whose production was inhibited and CXCL9/MIG, whose levels incresased during the early phase of DF2162 treatment. Furthermore, we observed pathological changes revealing less severe and reduced interstitial collagen deposition in the lungs of DF2162-treated animals. In spite of the observed improvement in all inflammatory aspects studied, the animals receiving DF2162 had a higher mortality (66.6%) than the animals in the control group, which showed only 25% lethality.These data suggest that the CXCR2 receptor exerts an important role in the regulation of the inflammatory process and pulmonary fibrosis induced by bleomycin. Notwithstanding, the increment in letality in the group of mice that received DF2162 treatment after bleomycin instillation is likely not associated with the fibrotic process itself, but depends on factors which shall be later studied.A fibrose pulmonar é uma doença caracterizada pela deposição intersticial progressiva de colágeno, que acarreta alterações na arquitetura normal pulmonar e perda da função, podendo levar ao óbito. As inflamações agudas pulmonares e a sua cronificação estão associadas a fenômenos fibróticos, sendo responsáveis por seu desencadeamento. A inflamação que precede a instalação da fibrose pulmonar é caracterizada pelo influxo de células inflamatórias, culminando na liberação de mediadores que perpetuam o dano inicial. Desta forma, é provável que a inibição da resposta inflamatória seja capaz de diminuir a deposição de colágeno intersticial. O modelo de fibrose pulmonar induzido por bleomicina é caracterizado por um intenso influxo de neutrófilos, concomitantemente com uma produção de citocinas, níveis elevados das quimiocinas CXCL1-3/KC e CXCL1-2/MIP-2, e posterior deposição de colágeno no parênquima pulmonar.No presente trabalho, estudamos os efeitos da administração do DF2162, um antagonista de receptores de quimiocinas CXCR2, no modelo experimental de fibrose pulmonar induzida por bleomicina em camundongos. Nossos dados mostram que a administração da dose de 6 mg/kg de DF2162, duas vezes ao dia, inibiu de forma significativa os picos de influxo neutrofílicos após administração de 0,125 U de bleomicina por via intra-traqueal. Entretanto, DF2162 não alterou os níveis das citocinas de caráter modulatório tais como IFN, IL-10 e VEGF, importantes para o processo inflamatório. As quimiocinas CXCL1-3/KC, CXCL1-2/MIP-2, CCL2/JE, CCL3/MIP-1 e CXCL10/IP-10 quantificadas também não apresentaram mudanças no seu perfil de produção, com exceção para CCL5/RANTES, que foi inibida, e CXCL9/MIG, que apresentou níveis elevados numa fase mais inicial, pelo tratamento com este antagonista. Além disso, foram verificadas alterações patológicas que revelaram uma inflamação menos severa e uma menor de deposição de colágeno intersticial no pulmão dos animais tratados com DF2162. Entretanto, apesar de uma melhora em todos os aspectos inflamatórios estudados, os animais que receberam DF2162 apresentaram um índice de letalidade de 66,6%; enquanto que no grupo controle foi observado a morte de apenas 25% dos animais.Estes dados em conjunto sugerem que o receptor CXCR2 exerça papel importante na regulação do processo inflamatório e fibrose pulmonar induzida por bleomicina. Apesar disso, o incremento na taxa de letalidade no grupo de animais que receberam tratamento com DF2162 após instilação de bleomicina provavelmente não está relacionado ao processo fibrótico em si, mas depende de outros fatores que serão investigados em estudos posteriores.
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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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Trevelin, Silvia Cellone. "Papel do receptor toll-like 9 na falência de migração dos neutrófilos na sepse." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/17/17133/tde-14082013-055722/.
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O recrutamento de neutrófilos para o sítio da infecção é um evento crucial para o combate aos microrganismos e sobrevivência na sepse. A migração destes polimorfonucleares é dirigida através de um gradiente quimiotático por meio do reconhecimento de quimiocinas por receptores acoplados a proteína G (GPCRs), os quais são regulados por quinases específicas (GRKs). Estudos prévios demonstraram que na sepse ocorre uma falência na migração de neutrófilos para o foco infeccioso em função da dessensibilização de receptores quimiotáticos via GRKs induzida pela ativação de receptores toll-like (TLRs), TLR2 e TLR4. Apesar de a ausência de TLR9 em células dendriticas ter sido relacionada a maior sobrevivência de camundongos sépticos, o papel do TLR9 atuando diretamente em neutrófilos não foi avaliado. Objetivando preencher esta lacuna, propôs-se avaliar o papel direto de TLR9 na falência de migração de neutrófilos na sepse. Os camundongos TLR9-/- apresentaram maior sobrevivência a sepse polimicrobiana avaliada por meio do modelo de ligadura e perfuração do ceco (CLP). A deficiência de TLR9 também acarretou em aumento na migração de neutrófilos para o foco da infecção, menor seqüestro de neutrófilos no pulmão, bem como, menor número de bactérias no lavado peritoneal e sangue. A ativação de TLR9 por oligodeoxinucleotídeo contendo o dinucleotídeo CpG não metilado (ODN CpG) nos neutrófilos reduziu a quimiotaxia destes em direção a quimiocina CXCL2 e expressão do receptor quimiotático CXCR2. Além disso, neutrófilos estimulados com ODN CpG apresentaram aumento na expressão da quinase tipo 2 relacionada a receptores acoplados a proteína G (GRK2). Dessa forma, a ativação de TLR9 em neutrófilos circulantes no sangue é prejudicial na sepse por reduzir a quimiotaxia destes para o foco da infecção ao induzir a dessensibilização de CXCR2 via GRK2.The recruitment of neutrophils to the site of infection is a crucial event for combating the microorganisms and survival on sepsis. The neutrophil migration is directed by a chemotactic gradient through the recognition of chemokines by G protein-coupled receptors (GPCRs), which are regulated by specific kinases (GRKs). Previous studies have shown a failure of neutrophil migration into infectious focus on sepsis due to chemotactic receptor desensitization via GRKs induced by activation of toll- like receptors (TLRs), TLR2 and TLR4. Despite the absence of activation of TLR9 in dendritic cells have been related to increase survival of septic mice, the role of TLR9 acting directly on neutrophils was not evaluated. We proposed to verify the direct role of TLR9 in the failure of neutrophil migration on sepsis. The TLR9 knockout mice (TLR9-/-) showed high survival to polymicrobial sepsis using cecal ligation and puncture model (CLP). TLR9-/- mice had high neutrophil migration to the focus of infection, low neutrophil sequestration in the lung, as well as, few bacteria in the peritoneal exudates and blood. The activation of TLR9 by oligodeoxinucleotide containing unmethylated dinucleotide CpG (CpG ODN) in neutrophils also reduced chemotaxis toward CXCL2 and the expression of chemokine receptor CXCR2. In addition, neutrophils stimulated with CpG ODN showed increased expression of kinase-related G protein-coupled receptor type 2 (GRK2). Thus, the activation of TLR9 in blood circulating neutrophils is harmful on sepsis by reducing their chemotaxis into the site of the infection by inducing CXCR2 desensitization via GRK2.
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Kiss, Debra Lois. "Regulation of the Chemokine Receptors CXCR4, CXCR7 , and the Androgen Receptor in Prostate Cancer." Thesis, Griffith University, 2013. http://hdl.handle.net/10072/367690.
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The chemokine receptor CXCR4 contributes to tumour cell migration and invasion during the progression of prostate cancer. In particular, this pathway is central to the metastasis of prostate cancer to the bone marrow. Limited therapeutic options exist for prostate cancer patients who have progressed to advanced metastatic disease, and pharmacological interference of the chemokine network may serve to control tumour cell dissemination and the establishment of metastasis. A more detailed knowledge of the mechanisms regulating chemokine receptors is required, in order to further characterise and explore the capacity and effectiveness of targeting these pathways for therapeutic intervention in prostate cancer.
Here, the regulation of CXCR4 protein expression and function was investigated in relation to androgens and the extracellular matrix. Accumulating evidence of CXCR4 regulation by androgens and the androgen receptor have indicated that androgens not only promote the growth and development of prostate cancer, but may actively contribute to the metastatic progression of prostate through modulation of the chemokine network. In the current study, the endogenous protein expression and functionality of the androgen receptor were firstly characterised in the androgen-insensitive prostate cancer cell lines DU145 and PC3, using the androgen-sensitive LNCaP cells as a basis for comparison. Investigations were performed using two-dimensional culture in conjunction with the more physiologically relevant three-dimensional in vitro culture model.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
Eskitis Institute for Cell and Molecular Therapies
Science, Environment, Engineering and Technology
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Bento, Allisson Freire. "Efeito do SB225002, antagonista seletivo do receptor para quimiocinas CXCR2, no modelo de colite induzida pelo ácido 2,4,6-trinitrobenzeno sulfônico (TNBS) em camundongos." reponame:Repositório Institucional da UFSC, 2012. http://repositorio.ufsc.br/xmlui/handle/123456789/92097.
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Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pos-Graduação em Farmacologia, Florianópolis, 2008.Made available in DSpace on 2012-10-24T05:44:12Z (GMT). No. of bitstreams: 1 271599.pdf: 9768628 bytes, checksum: ac3442843a34970b9d196ca07b9b8959 (MD5)
Os neutrófilos são células importantes para a eliminação de patógenos, no entanto, o recrutamento excessivo dessas células pode levar a lesão tecidual. Essa migração é mediada pelas quimiocinas CXC, e seus receptores, CXCR1 e CXCR2 presentes nos neutrófilos. Dessa forma, a redução do influxo de células durante o processo inflamatório, através da inibição desses receptores, pode ser uma alternativa terapêutica apropriada para o tratamento de inúmeras doenças inflamatórias, como as doenças inflamatórias intestinais (IBD). O presente estudo buscou avaliar se o tratamento sistêmico curativo com antagonista seletivo para o receptor CXCR2, SB225002, era capaz de reduzir a inflamação intestinal, no modelo de colite induzida pelo TNBS em camundongos. O SB225002 (SB) ou dexametasona (DEX) (controle positivo) foram administrados 24 h após a indução da colite, de 12 em 12 horas por três dias. No terceiro dia após a indução da colite, os animais foram sacrificados e diferentes parâmetros inflamatórios foram avaliados. A administração do TNBS induziu danos macro e microscópicos no cólon dos animais, encurtamento e edema desse tecido, além de aumento do peso do baço, causando, em muitos casos, a morte dos animais. Os tratamentos com SB ou DEX reduziram de forma significativa todos os parâmetros analisados, demonstrando uma melhoria no quadro inflamatório. Alguns dos mecanismos envolvidos nos efeitos do SB também foram analisados. O tratamento sistêmico reduziu o influxo de neutrófilos, a atividade da enzima MPO, os níveis de IL-1ß e KC além da expressão das proteínas VEGF, iNOS e COX-2, no cólon dos animais. Adicionalmente, os níveis das citocinas antiinflamatórias IL-4 e IL-10 estavam aumentados no cólon de animais que receberam SB. Dessa forma, nossos resultados demonstraram que o bloqueio seletivo do receptor CXCR2, através da ação do antagonista SB, se mostrou eficaz em reduzir a inflamação colonica no modelo de colite induzida por TNBS, sugerindo que o SB é um potencial agente terapêutico para o tratamento das doenças inflamatórias intestinais.
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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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McDonagh, Ellen Mary. "The molecular mechanisms governing the regulation of chemokine receptors CXCR3 and CXCR6." Thesis, Imperial College London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.523747.
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Filho, Décio Abdo. ""Avaliação da expressão dos receptores de interleucina-8, CXCR1 e CXCR2, e da atividade proliferativa em fibroblastos de quelóide e de pele normal"." Universidade de São Paulo, 2006. http://www.teses.usp.br/teses/disponiveis/5/5132/tde-16102006-171640/.
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O quelóide é um tumor fibroso benigno que ocorre durante a cicatrização da pele em indivíduos geneticamente predispostos. A cicatrização é um processo biológico complexo e depende da interação de diferentes estruturas teciduais e de um grande número de tipos celulares residentes e infiltrativos, que produzem citocinas. A interleucina 8 (IL-8), citocina pró-inflamatória, é super-expressa pelos fibroblastos durante o desenvolvimento do tecido de granulação, acelerando o processo de cicatrização. Como o quelóide resulta de uma reparação tecidual anormal após lesão da pele, o presente estudo teve por objetivo determinar a expressão dos receptores da IL-8, CXCR1 e CXCR2, e a capacidade proliferativa, pelo ciclo celular, dos fibroblastos queloideanos cultivados e extraídos ex vivo, por citometria de fluxo. Fibroblastos de cicatriz queloideana e de pele normal foram obtidos de 21 pacientes da raça negra, com idade variando entre 10 e 40 anos, de lesões com até 2 anos de evolução. Em nosso estudo constatamos expressão reduzida dos receptores para a IL-8, CXCR1(35,7%±11,2) e CXCR2 (27,8%±11,3), em fibroblastos de cicatriz queloideana cultivados, comparando com a pele normal (44,1±16,2 e 46,3±27,1 respectivamente). Entretanto, essa diferença só foi significante para o receptor CXCR2. A baixa expressão desses receptores poderia ser decorrente da atividade de metaloproteinases, que regulam a expressão de proteínas da superfície celular, através de clivagem enzimática, ou a capacidade reduzida de internalização e a reciclagem de receptores, mantida por filamentos de actina do citoesqueleto, que nos fibroblastos do quelóide estão diminuídos. Em relação ao ciclo celular de fibroblastos cultivados do quelóide e da pele normal, verificamos diferenças não significantes da capacidade de replicação (fase S do ciclo celular) e de apoptose. No quelóide observamos significante aumento de células na fase G2/M, indicando aumento da velocidade de divisão celular. Para confirmar esses achados estudamos o ciclo celular de fibroblastos extraídos ex vivo, da porção periférica e central do quelóide e da pele normal. Os fibroblastos da porção periférica apresentaram porcentagem significantemente maior de células com capacidade replicativa, fase S do ciclo (22,9% ± 11,6), em relação à porção central (4,7% ± 2,9) e à pele normal (6,8% ± 4,9), e maior velocidade de divisão celular, fase G2/M (18,6 ± 12,0), em relação à porção central (35,6 ± 7,0) e pele normal (32,3 ± 6,9). Verificamos que a porção central apresentou maior porcentagem de células em apoptose (7,0% ± 2,1), comparado à porção periférica (4,9% ± 1,9) e pele normal (2,0% ± 0,86). Esses dados indicam que as células da porção periférica do quelóide parecem ser responsáveis pela elevada taxa de proliferação, justificando o crescimento expansivo a partir das margens da cicatriz queloideana, com desenvolvimento de lesão semelhante a tumor, bem como a porção central ser responsável pela fibrose, contendo células quiescentes e apoptóticas. Esses resultados sugerem modulação diferencial das reações celulares através das vias de sinalização para proliferação ou morte celular programada. Neste sentido, a baixa expressão dos receptores da IL-8, CXCR1 e principalmente de CXCR2, nos fibroblastos do quelóide sugere capacidade reduzida da IL-8 em promover cicatrização acelerada. A baixa atividade da IL-8 sobre os fibroblastos queloideanos estaria promovendo desregulação da resposta inflamatória e com isso atraindo novas células inflamatórias para o local e produzindo sinais alterados, como grande produção da citocina TGFβ. Essa desregulação do processo de cicatrização, com alteração de citocinas e da matriz extracelular, poderia ser responsável pelas duas populações de fibroblastos, uma proliferativa na periferia e outra quiescente e apoptótica na porção central. Finalizando, podemos concluir que nossos resultados correspondem às alterações histológicas e clínicas do quelóide que se expande nos limites da lesão.A keloid is a benign fibrous tumor that occurs during wound healing in genetically predisposed individuals. Healing is a complex biological process and depends on the interaction of different tissue structures and a great number of resident and infiltrative cell types. The interleukin-8 (IL-8), a proinflammatory chemokine, showed higher expression in fibroblasts during the development of the granulation tissue, promoting more rapid tissue maturation. Since keloids result from abnormal wound healing, the objective of the present study was to determine the expression of CXCR1 and CXCR2, IL-8 receptors, and the proliferation capacity, throughout the cell cycle, of the keloid fibroblasts extracted ex vivo and those submitted to in vitro cultivation. Normal skin and keloid scar fibroblasts were obtained from 21 African-Brazilian patients, aged from 10 to 40 years, whose lesions had evolved for no longer than 2 years. Expression of receptors and the cell cycle was assessed by flow cytometry. We showed lower expression of the CXCR1 (35,7% ± 11,2) and CXCR2 (27,8%±11,3) in keloid fibroblasts, when compared with normal skin (44,1 ± 16,2 e 46,3 ± 27,1 respectively), but the difference was not significant for the CXCR1 receptor. This lower expression of IL-8 receptors in keloid fibroblasts could be due to the action of metalloproteinases, which regulate the surface protein enzymatically, or fibroblastic cytoskeleton conditions, which influence receptor internalization and recycling. The distribution assessment of cell cycle phases of fibroblasts cultivated from keloid scars and normal skin did not show significant difference in replication capacity and apoptosis. The keloid fibroblasts presented a significantly higher proportion of cells in the G2/M phase, suggesting higher rate of cell division. To confirm these results we studied the cell cycle of fibroblasts extracted ex vivo, now separated by central and peripheral portions of keloid and normal skin. The peripheral fibroblasts showed significant high cell proportions in phase S (22,9% ± 11,6), compared with the central portion (4,7% ± 2,9) and normal skin (6,8% ± 4,9), and higher cells in division phase G2/M (18,6% ± 12,0), compared with the central portion (35,6% ± 7,0) and normal skin (32,3% ± 6,9). The central portion showed higher proportion of apoptosis (7,0% ± 2,1), compared with the peripheral portion (4,9% ± 1,9) and normal skin (2,0% ± 0,86). These results suggest that the keloid peripheral cells could be responsible for the proliferation rate, justifying the expansive keloid growth at the borders of the keloid scar, in a similar fashion to tumor development and the central portion being responsible for fibrosis, with quiescent and apoptotic cells. These results suggest a differentiated modulation of cell reactions by signal pathways for programmed cellular proliferation or death. In this sense, the low expression of the IL-8 receptors CXCR1 and CXCR2 in keloid fibroblasts suggests a diminished capacity of IL-8 to promote accelerated healing. This low expression of IL-8 receptors in keloid fibroblasts could promote the dysregulation of the inflammatory response and thus attract more inflammatory cells to the site, producing different signals, such as a high production of the TGFβ cytokine. This dysregulation of the healing process, with changed cytokine and extracellular matrix expression, could be responsible for two different cell populations of fibroblasts, one proliferation at the periphery and the other fibrotic at the center of the lesion, with apoptotic and quiescent cells. Finally, we conclude that our results correspond to the histological and clinical changes of keloids that grow beyond the wound boundaries.
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Melo, Rita de Cássia Carvalho 1988. "Expressão e função de CXCR7 em sídromes mielodisplásicas e leucemias." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311982.
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Orientadores: Sara Teresinha Olalla Saad, Carolina Louzão BigarellaDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: A medula óssea é constituída por microambientes específicos denominados "nichos". O fator SDF-1 (Stromal derived factor-1) foi identificado como um importante fator quimioatrativo produzido por células estromais da medula óssea. Sua ação sobre seu receptor CXCR4 desempenha função primordial na migração, retenção e desenvolvimento dos progenitores hematopoiéticos na medula óssea. Células leucêmicas mielóides e linfóides expressam CXCR4 e aproveitam-se disso para acessar nichos medulares normalmente restritos ás células progenitoras, passando a residir em microambientes que propiciam sobrevivência e proliferação. Recentemente foi descoberto que o receptor CXCR7 é capaz de se ligar ao SDF-1. Ele é expresso em várias linhagens tumorais, mas em células hematopoiéticas seu papel é ainda pouco explorado. Em vista da escassez de dados na literatura o objetivo deste trabalho foi investigar a expressão e função de CXCR7 em síndromes mielodisplásicas e leucemias agudas. Neste estudo, foi mostrado que a expressão gênica de CXCR7 foi significativamente maior em leucemia linfoblástica aguda (LLA) em comparação com sindrome mielodisplásica (SMD), leucemia mielóide aguda (LMA) e indivíduos controles (p<0.0001, Mann-Whitney). A proteína CXCR7 também foi mais expressa em linhagens celulares linfoblástica T (Molt-4 e Jurkat) em comparação com linhagens mielóides. Em células linfoblásticas T, a localização subcelular de CXCR7 e CXCR4 por microscopia confocal e citometria de fluxo evidenciou CXCR7 mais próximo à membrana das células Molt-4 e mais frequentemente no citoplasma de células Jurkat enquanto CXCR4 está na membrana de ambas as linhas celulares. Curiosamente, notamos também que, depois da indução de SDF-1, células Molt-4 têm maior capacidade migratória comparada com Jurkat (mediana Molt 4 = 52,0 ± 5 vs Jurkat = 24,1 ± 3, p = 0,0079, teste de Mann-Whitney), que pode estar relacionado com a disponibilidade de membrana de CXCR7. Além disso, a inibição da CXCR7 ou CXCR4 resultou em mudanças significativas na resposta migratória de Molt4 e Jurkat (p<0,05 Mann-Whitney), no entanto, a inibição de ambos, CXCR7 e CXCR4 resultou em uma redução mais significativa na migração celular (p = 0.0079/Molt-4; p = 0.0043/Jurkat, Mann-Whitney). Uma vez que é bem estabelecido que células CD34+ de pacientes com SMD não são atraídas pelo gradiente de SDF-1, apesar de terem expressão normal de CXCR4, nos interessou investigar qual a localização de CXCR4 nas células SMD e se esta irresponsividade estava associada a CXCR7. Linhagens mielóides P39 e U937 foram usadas como modelo de SMD e LMA, respectivamente. Foram encontrados níveis similares de expressão de CXCR4 e CXCR7 em ambas as linhagens celulares, no entanto encontramos que CXCR4 está localizado no citoplasma de células P39 enquanto ele está na membrana das células U937. Uma vez que a proteína quinase C isotipo zeta (PKC'dzeta' está relacionada com a sinalização SDF-1/CXCR4 aumentando a expressão de CXCR4 e sua disponibilidade na membrana, resolvemos trabalhar também com células P39 hiperexpressando PKC'dzeta' (PKC'dzeta'wt). Este procedimento resultou na translocação de CXCR4 para a membrana de células P39, mas não alterou a localização subcelular de CXCR7. Ensaios de migração por tranwell mostraram que células P39 PKC'dzeta'wt apresentam maior capacidade de migração em relação a SDF-1 em comparação com células P39 controle (aumento de 35 vezes pcDNA3 PKC-'dzeta'-HA vs pcDNA3 transfectadas células P39, p = 0,0032, Mann-Whitney), sugerindo que a PKC'dzeta' restaura a capacidade quimiotática de células P39. Aumento da expressão de CXCR7, como aqui observado em células leucemicas linfoblásticas, é um fenômeno já descrito em uma variedade de linhagens de células tumorais sólidas, tais como cérebro, próstata e pulmão. Em tumores sólidos, CXCR7 principalmente aumenta a proliferação de células malignas. Estes resultados sugerem que a função biológica de CXCR7 depende tecido e órgãos que ele está localizado e que, na leucemia linfoblástica aguda pode ter um papel na migração de células, potencializando a resposta de CXCR4 a SDF-1 e, portanto, poderia contribuir para o recrutamente de células leucêmicas para nichos uma vez já ocupados por células-tronco hematopoéticas normais. Além disso, nossos resultados levam a crer que um defeito na via PKC'dzeta'/CXCR4 está envolvido com a irresponsividade de células SMD a SDF-1, gerando uma hematopoese ineficaz. E confirma dados que sugerem que PKC'dzeta' é uma proteína central na via de sinalização SDF-1/CXCR4, muito importante para a migração de células hematopoéticas malignas
Abstract: Bone marrow is constituted of specific microenvironments called "niches". The factor SDF-1 (stromal derived factor-1) was identified as an important chemoattractant factor produced by bone marrow cells. SDF-1 acts on its receptor CXCR4 and plays primordial function in migration, retention and development of hematopoietic progenitors in bone marrow. CXCR4 is expressed in leukemic cells and enables them to access marrow niches that normally are restricted to quiescent stem cells, thereby ensuring its protection from cell death resulting in a worse prognosis. Recently, CXCR7 was identified as another SDF-1-binding receptor, but its contribution to SDF-1 - mediated effects in hematopoietic cells is still poorly explored, even though the CXCR7 relationship with tumor progression in non-hematopoietic malignancies is well established. Given that there is little information regarding CXCR7 we investigated its function and expression in MDS and acute leukemias. This work, was showed that CXCR7 is significantly higher expressed in ALL compared to MDS, AML and control subjects (p<0.0001, Mann-Whitney test). CXCR7 protein is also higher expressed in lymphoblastic cell lines (Molt-4 and Jurkat) compared with myeloid cells. In lymphoblastic cell lines, the subcellular location of CXCR7 and CXCR4 by confocal microscopy and flow cytometry evidenced CXCR7 closer in the membrane of Molt-4 cells and more frequently in the cytoplasm of Jurkat cells whereas CXCR4 was in the membrane of both cell lines. Interestingly, we also noticed that, after SDF-1 induction, Molt-4 cells have higher chemotactic ability compared with Jurkat (median Molt 4=52.0 ± 5 vs Jurkat=24.1 ± 3, p=0.0079, Mann-Whitney test) which may be related with the membrane availability of CXCR7. In addition, the inhibition of CXCR7 or CXCR4 resulted in significant changes in Molt4 and Jurkat chemotactic response (p<0,05, Mann-Whitney test), however, the inhibition of both CXCR7 and CXCR4 resulted in a more significant reduction in cell migration (p=0.0079/Molt-4; p=0.0043/Jurkat, Mann-Whitney test). Since it is well established that CD34 + progenitor cells from patients with myelodysplastic syndromes (MDS) are not attracted by gradient of SDF-1 despite of having CXCR4 normal expression, we addressed if MDS cells have an abnormal localization of CXCR4 or association with CXCR7. P39 and U937 cell line were used as a model of MDS and AML, respectively. Similar expression levels of CXCR4 and CXCR7 in both cell lines however we found, by confocal microscopy and flow cytometry, that CXCR4 was localized in the cytoplasm of P39 cells while it was in the membrane of U937 cells. Since the protein quinase C (PKC'dzeta') is related to the SDF-1/CXCR4 signaling by increasing CXCR4 expression and its membrane availability, we decided to work with cells P39 overexpressing PKC'dzeta' (PKC'dzeta'wt). This procedure resulted in translocation of CXCR4 to the membrane of P39 cells but did not change the CXCR7 subcellular localization. Transwell chemotaxis assay showed that P39 cells overexpressing PKC'dzeta' displayed higher chemotactic ability upon SDF-1 treatment compared with control P39 (35 fold increase pcDNA3-PKC'dzeta'-HA vs pcDNA3-HA transfected P39 cells, p=0.0032; Mann-Whitney), suggesting that PKC'dzeta' restored the chemotactic capacity of P39 cells. Increased expression of CXCR7, as here observed in lymphoblastic leukemia cells, is a phenomenon already described in a variety of solid tumor cell lines such as brain, prostate and lung. In solid tumors, CXCR7 mainly increases the proliferation of malignant cells. These results suggest that the biological function of CXCR7 depends on its tissue and organ localization and that, in acute lymphoblastic leukemia may have a role in cell chemotaxis, potentiating CXCR4 response to SDF-1 and thus, could contribute for leukemia initiating cell recruitment to niches once occupied by normal hematopoietic stem cells. Furthermore, our results lead us to believe that a defect in the PKC'dzeta'/CXCR4 pathway is involved with the unresponsiveness of MDS cells to SDF-1, generating an ineffective hematopoiesis. It confirms data that suggest that PKC'dzeta' is a central protein in the SDF-1/CXCR4 signaling pathway, important for the migration of malignant hematoietic cells
Mestrado
Fisiopatologia Médica
Mestre em Ciências
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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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000749985.pdf: 1413898 bytes, checksum: 7421bc33cc6d75478dcb676de29021bd (MD5)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 OliveiraBanca: 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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Khan, Abid. "CXCR4 chemokine receptor antagonists : new metallodrugs." Thesis, University of Hull, 2009. http://hydra.hull.ac.uk/resources/hull:10418.
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Chemokine receptors are a target of growing interest for new therapeutic drugs, as their role in multiple disease states has been demonstrated. The CXCR4/ CXCL12 pairing has been implicated in HIV and cancer, as well as chronic inflammatory diseases, including asthma and rheumatoid arthritis. HIV uses CXCR4 or CCR5 receptors in the key binding step of the infection process, leading to the idea that drugs could be developed to block this interaction. Cancer metastasis has also been linked to cellular communication via the chemokine pathways and hence, receptor antagonists could potentially inhibit this important pathway of disease progression. Small synthetic CXCR4 antagonists exist including AMD3100 (Mozobil®/Plerixafor), which has been identified as a potent CXCR4 antagonist exhibiting anti-HIV, anti-inflammatory and anti-tumour activity. Configurationally restricted analogues of AMD3100 complexed to metal ions have improved binding characteristics compared to AMD3100 and its metal complexes. Herein we report the binding of a new class of cyclen, cyclam and tris-cyclam based complexes in vitro. Compounds competed effectively in anti-CXCR4 competition assays with the tricyclam linear complex displaying improved binding characteristics. The difference in activity of the compounds is discussed in relation to the different possible binding interactions that are occurring. Furthermore, a monocyclam derivative conjugated to biotin competed effectively in competition with a CXCR4 mAb, however could not directly be detected via a fluorescent conjugated streptavidin molecule. Our most potent compound to date, copper(II) cross-bridged bicyclam was found to have a significant higher relative residence time in CXCR4 compared to AMD3100 and copper(II) AMD3100 in vitro. Moreover, copper(II) cross-bridged bicyclam was able to totally block CXCL12 induced and partially block serum induced, invasion of CXCR4 positive cancer cells with a higher potency than AMD3100 and copper(II) AMD3100. This shows the potential of using such a drug in the clinic. Using CXCR4 mutants, it has been shown that CXCR4 defective degradation and recycling increases invasion in breast cancer cells. Moreover the development of a multicellular tumour spheroid (MTS) is reported that could be used as a preclinical model in the evaluation of the anti-cancer activity of CXCR4 antagonists.
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Memi, F. "The role of the chemokine SDF-1 and its receptors CXCR4 and CXCR7 in the migration of GnRH neurons." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1388706/.
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Reproduction in mammals is initiated and maintained by a small population of cells called Gonadotropin-releasing hormone (GnRH) neurons, scattered throughout the preoptic area and anterior hypothalamus. These neurons originate in the nasal placode, and migrate across the nasal compartment in association with olfactory, vomeronasal and terminal nerves to reach their targets in the hypothalamus. In humans, defective GnRH neuron migration results in gonadal dysfunction and subsequent infertility. As mutated genes identified so far in patients account for only 30% of the cases, many unknown genes involved in GnRH neuron development still need to be discovered. One of the molecules required for their early migration is the chemokine SDF-1 which is expressed in the embryonic nasal mesenchyme in an increasing rostral to caudal gradient, presumably guiding CXCR4-expressing GnRH neurons towards the forebrain. Mice lacking CXCR4, the receptor for SDF-1, exhibit defective GnRH neuron migration along with a significant reduction in number. This thesis focuses on the role of the more recently identified second SDF-1 receptor, CXCR7, in GnRH neuron development. A detailed analysis of the expression pattern of CXCR7 in the nasal region and comparison to that of its agonist (SDF-1) as well as CXCR4, was elucidated for the first time. CXCR7 was found to be expressed along the migratory path of GnRH neurons in the nasal region, but not by GnRH neurons or their guiding axons. The role of CXCR7 in GnRH neuron migration in vivo was assessed using transgenic mice deficient for this receptor. This analysis revealed that in these mice, many GnRH cells remained in the nasal compartment, clustering or found ectopically in the olfactory epithelium. Interestingly, CXCR4 was downregulated in CXCR7 defective mice, suggesting that CXCR7 affects GnRH migration indirectly, by regulating CXCR4 in a non-cell autonomous manner.
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Weigold, Florian [Verfasser]. "Antibodies against chemokine receptors CXCR3 and CXCR4 predict progressive deterioration of lung function in patients with systemic sclerosis / Florian Weigold." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2018. http://d-nb.info/1176633147/34.
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Murphy, Brendan John. "The sequelae of CXCR4 engagement." Thesis, Queen Mary, University of London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.251823.
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Bianco, André de Macedo. "Expressão de CXCR7 e CXCR4 em em astrocitomas iniltrativos em relação ao tecido cerebral não neoplásico e sua interação com HIF1alfa e IDH1." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5138/tde-01112013-122908/.
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Introdução: Existem dados suficientes disponíveis demonstrando a importância da quimiocina CXCL12 e seu receptor CXCR4 na progressão tumoral e angiogênese dos gliomas. O CXCR4 é regulado positivamente pelo HIF1alfa. Recentemente um novo receptor com maior afinidade à CXCL12 foi identificado, o receptor órfão RDC1, agora denominado CXCR7. O objetivo deste estudo é investigar a expressão de mRNA CXCR7 em tecidos astrocitomas difusos e avaliar suas interações com expressão CXCR4 e HIF1alfa, bem como analisar sua relação com mutação do IDH1. Métodos: A expressão do CXCR7, CXCR4, IDH1 e HIF1alfa foram avaliadas por PCR quantitativo em tempo real (qRT-PCR) em 129 amostras congeladas de astrocitomas (25 astrocitoma difuso - AGII, 18 de astrocitoma anaplásico - AGIII e 86 glioblastoma - GBM) e 22 amostras de tecido cerebral não neoplásico (NN) obtidos de cirurgia de epilepsia. A mutação do IDH1 previamente determinada foi analisada em relação aos níveis de expressões de mRNA do CXCR7, CXCR4 e HIF1alfa, combinado com os parâmetros clínico-patológicos e sobrevida global. Adicionalmente, a expressão proteica do CXCR7 foi analisada por imuno-histoquímica em astrocitomas de diferentes graus e em linhagem celular de glioma (U87MG) por microscopia confocal. Resultados: Houve diferença significativa nos níveis de expressão dos genes estudados entre astrocitomas e NN (p < 0,001). Na análise da expressão gênica associada nos AGII não se observou correlação entre os níveis de expressão de CXCR7/HIF1alfa (p = 0,548); observou-se correlação significativa entre CXCR7/IDH1 (p < 0,001) e CXCR7/CXCR4 (p = 0,042). Nos GBM houve correlação significativa entre CXCR7/CXCR4 (p = 0,002), CXCR7/IDH1 (p < 0,001) e CXCR7/HIF1alfa (p = 0,008). Hiperexpressão do HIF1alfa foi associado com maior expressão do CXCR7 e CXCR4 (p = 0,001), enquanto a presença de IDH1 mutado foi associada a menor expressão de mRNA do CXCR7 e CXCR4 (p = 0,009). A expressão proteica de CXCR7 foi identificada em todas as amostras estudadas, e aumentou com malignidade. A proteína CXCR7, na linha celular U87MG, foi localizada principalmente na membrana celular. Conclusão: O CXCR7 é um gene diferencialmente expresso em astrocitomas difusamente infiltrativos em relação tecido cerebral não neoplásico. O nível de expressão do CXCR7 correlacionou-se significativamente com os níveis de expressão do CXCR4 e IDH1 nos AGII e com CXCR4, IDH1 e HIF-1alfa nos GBM. O nível de expressão elevado do CXCR7 e CXCR4 correlacionou-se com nível elevado de expressão de HIF-1a, enquanto a presença da mutação do IDH1 associou-se a níveis reduzidos de CXCR7 e CXCR4. Não se observou associação significativa entre os níveis de expressão de CXCR7 e CXCR4 com os dados de sobrevidaIntroduction: There is abundant evidence showing that chemokine CXCL12 and its receptor CXCR4 are involved in glioma progression and angiogenesis. CXCR4 is upregulated by HIF1alfa. The CXCR7, a recent additional receptor for CXCL12 with higher affinity than CXCR4 has raised key issues on glioma cell migration. The aim of this study is to investigate the CXCR7 mRNA expression in diffuse astrocytoma tissues and to evaluate its interactions with CXCR4 and HIF1alfa expression and IDH1 mutation. Methods: CXCR7, CXCR4, IDH1 and HIF1alfa expressions were evaluated by quantitative real-time PCR (qRT-PCR) in 129 frozen samples of astrocytoma (25 diffuse astrocytomas - AGII, 18 anaplastic astrocytomas - AGIII and 86 glioblastomas - GBM) and 22 samples of non-neoplastic tissue cerebral (NN) from epilepsy surgery. IDH1 mutation status was analyzed with CXCR7, CXCR4 e HIF1alfa mRNA expressions, matched with clinicopathological parameters and overall survival time. Furthermore, CXCR7 protein expression was analyzed by immunohistochemistry in different grades of astrocytoma and in glioma cell line (U87MG) by confocal microscopy. Results: There was significant difference in the expression levels of the genes studied between astrocytomas and NN (p < 0.001). The analysis of associated gene expressions in AGII showed no significant correlation between CXCR7/HIF1alfa (p = 0.548); there was significant correlation between CXCR7/CXCR4 (p = 0.042) and CXCR7/IDH1 (p = 0.008). In GBM, there were significant correlations between CXCR7/CXCR4 (p = 0.002), CXCR7/IDH1 (p < 0.001) and CXCR7/HIF1alfa (p = 0.008). HIF1alfa overexpression was associated with higher expressions of CXCR7 and CXCR4 (p = 0.001), while presence of IDH1 mutation was associated with lower CXCR7 and CXCR4 mRNA expressions (p = 0.009). Protein expression was identified in all samples studied, and it increased with malignancy. CXCR7 protein, in U87MG cell line, was mainly localized in the cellular membrane. Conclusion: CXCR7 was overexpressed in astrocytoma of different grades of malignancy compared to non-neoplastic brain tissue. CXCR7 expression levels correlates with CXCR4 and IDH1 in AGII and CXCR4, IDH1 and HIF1alfa in GBM. Overexpression HIF1alfa was related with higher expressions of CXCR7 and CXCR4, otherwise presence of IDH1 mutation related with lower expression of both genes. Protein expression level was associated with the degree of malignancy. The results revealed no significant association between CXCR7 and CXCR4 expression and survival data
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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 thérapeutiquesOur 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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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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license.txt: 581 bytes, checksum: 44ea52f0b7567232681c6e3d72285adc (MD5)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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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.Submitted by denise santos (denise.santos@ufc.br) on 2016-03-22T13:35:18Z No. of bitstreams: 1 2015_dis_mateixeira.pdf: 2275440 bytes, checksum: 14899bf8302a4a676758288d6cf00415 (MD5)
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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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Reinecke, Bethany A. "Development of Bivalent Ligands Targeting the Putative Mu Opioid Receptor and Chemokine Receptor CXCR4 Heterodimer." VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/5754.
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Human immunodeficiency virus (HIV) and opioid abuse have been described as synergistic epidemics. Pharmacologically, it has been found that opioids have the capacity to enhance HIV infection and replication. Research has shown that activation of the mu-opioid receptor (MOR) elevates the expression of the HIV-1 entry co-receptor CXCR4 on T-lymphocytes in the peripheral nervous system, thus allowing for enhanced viral entry and invasion. Although the exact mechanism for opioid modulation of CXCR4 expression and subsequent exacerbation of HIV is unknown, several hypotheses exist. One hypothesis is that MOR and CXCR4 are functionally interacting through the formation of a heterodimer. This hypothesis is supported by studies substantiating the ability for MOR and CXCR4 to form heterodimers with other GPCRs, and the finding that MOR and CXCR4 were co-expressed in several central and peripheral regions including immune cells. To test this hypothesis, a series of bivalent ligands containing both a mu opioid receptor (MOR) antagonist and a CXCR4 antagonist pharmacophore was designed and synthesized to understand the pharmacological role of the putative CXCR4-MOR heterodimer in opioid exacerbated HIV progression.
These bivalent ligands were evaluated for their binding and functional activities in radioligand binding, antibody binding, [35S]GTPγS, and calcium mobilization assays. In these assays, the bivalent ligands were shown to maintain binding and functional activities in both MOR and CXCR4 monoclonal cell lines. In addition, these bivalent ligands were evaluated for their ability to block HIV entry in a reverse transcriptase assay, and for their ability to inhibit morphine exacerbated HIV invasion in an LTR-luciferase assay. In these assays, the bivalent ligands were shown to inhibit HIV entry in a dose dependent manner. However, due to experimental limitations in our morphine exacerbated reporter system, the ability for the bivalent ligands to inhibit viral entry upon morphine co-exposure was not fully validated. Finally, molecular modeling approaches were utilized to visualize the putative binding modes of the bivalent ligands in a constructed MOR-CXCR4 heterodimer model.
Overall, these studies have provided a solid basis for the utility of bivalent ligands in studying MOR-CXCR4 interactions and their involvement in opioid potentiated HIV progression. Further studies are ongoing to optimize the bivalent ligands construct and explore new analyses to evaluate their ability to block opioid modulation of the virus.
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Ueda, Satoshi. "Synthetic studies on chemokine receptor CXCR4 and its specific antagonists." 京都大学 (Kyoto University), 2007. http://hdl.handle.net/2433/137117.
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Petit, Sarah Joanna. "Molecular Characterisation of the Chemokine CXCL16 and its Receptor CXCR6." Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.495432.
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The chemokine CXCL16 is selectively expressed by antigen presenting cells and unli ke most chemokines, is attached to the cell surface by means of a mucin stalk. This allows CXCL16 to function as an adhesion molecule, binding leukocytes such as T-cells which display the cognate receptor, CXCR6. Cleavage of CXCL16 by metalloproteinases can also release a soluble form of CXCLI6 which can induce the migration of CXCR6 expressing cells. In addition, membrane-bound CXCL16 can also ftinction as a scavenger receptor for a variety of ligands, including oxidised low density lipoprotein. Collectively, these functions support a role for both CXCL16 and CXCR6 in the process of atherosclerosis. The CXCL16:CXCR6 relationship appears to be monogamous and the nature of this interaction was investigated by a programme of mutagenesis used to examine CXCR6 function in vitro, assessed by adhesion, chemotaxis and ligand binding assays. CXCL16 function was also examined, in particular, the effects of a single nucleotide polymorphism associated with disease. In a third arm of the project, recombinant CXCL16 was produced in E. Coli using two different systems and subjected to assays of biological function. In contrast to other chemokine receptors, mutation of the CXCR6 N-terminus and inhibition of post-translational modifications were without effect on function. Likewise, N-terminal extension of CXCL16 by 24 amino-acids resulted in a protein with decent potency and efficacy in chemotaxis and not as anticipated, a CXCR6 antagonist. Cells expressing the CXCR6 mutants Asp-176-Asn and Glu274- Gln were unable to interact with soluble CXCLI6, suggesting that these residues are critical for ligand binding. Intriguingly, although unable to interact with soluble CXCL16, the Glu-274-Gln mutant was able ·to promote robust adhesion to membrane-anchored CXCL16, suggesting that the soluble and membrane-bound forms of CXCL16 possess distinct conformations. Glycosylation of CXCL16 was found to be critical for cell-cell adhesion function, and a Ala-181-Val polymorphic variant of CXCL16 was found to have no capacity for mediating cell-cell adhesion, suggesting a potential relevance of this mutation in disease. Collectively, the data suggests that the CXCL16:CXCR6 interaction is distinct from other chemokine-chemokine interactions described in the literature, and that current models for chemokine receptor activation, in which the chemokine N-terminus ligand protrudes into an intrahelical pocket, do not apply to the CXCR6:CXCLI6 interaction. This may have implications for successful antagonism of the receptor by small molecules.
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Hosogi, Hisahiro. "Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes." Kyoto University, 2008. http://hdl.handle.net/2433/135806.
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Dornelles, Fabiana Noronha. "Participação dos receptores CXCR2 e TRPV1 na cistite induzida por ciclofosfamida em ratos." reponame:Repositório Institucional da UFSC, 2013. https://repositorio.ufsc.br/xmlui/handle/123456789/122946.
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Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia, Florianópolis, 2013.Made available in DSpace on 2014-08-06T17:35:15Z (GMT). No. of bitstreams: 1 324637.pdf: 1897248 bytes, checksum: b9dbb12df301eef47b15a90504d1db3d (MD5) Previous issue date: 2013
A proposta do presente estudo foi avaliar a participação dos receptores CXCR2 e TRPV1 na cistite induzida por ciclofosfamida (CYP) em ratos. A CYP é um quimioterápico cujo principal efeito adverso é a urotoxicidade, caracterizada pelo desenvolvimento de cistite hemorrágica e fibrose da bexiga urinária. A administração sistêmica de CYP causou inflamação da bexiga urinária, disfunção do processo de micção e comportamento de dor visceral. A cistite induzida por CYP foi caracterizada por aumento do peso úmido da bexiga urinária, edema, hemorragia, infiltração de neutrófilos e dano urotelial. Além disso, ocorreu um aumento nos níveis de citocinas inflamatórias como a IL-1ß e o TNF-a. A presença de dor visceral foi evidenciada através do aumento do comportamento nociceptivo, bem como pela presença de hipersensibilidade mecânica referida avaliada na pata e na região abdominal A cistite induzida por CYP alterou os parâmetros urodinâmicos do processo de micção. Ainda, a cistite induzida por CYP induziu aumento nos níveis do RNAm dos receptores CXCR2 e TRPV1 na bexiga urinária. Ensaios de imunofluorescência revelaram um aumento na expressão dos receptores CXCR2 e TRPV1 na bexiga urinária, em especial no urotélio e fibras nervosas, e nos neurônios do GRD (gânglio da raiz dorsal) após o tratamento com CYP. O pré-tratamento dos animais com os antagonistas seletivos dos receptores CXCR2 (SB225002) e TRPV1 (SB366791) reduziu o edema e a hemorragia, o peso úmido, a infiltração de neutrófilos determinada através dos níveis de atividade da enzima mieloperoxidase (MPO), bem como os níveis das citocinas IL-1ß e TNF-a na inflamação da bexiga urinária. Curiosamente, os antagonistas SB225002 e SB366791, ou a combinação de ambos, reduziu significativamente os escores comportamentais nociceptivos e a hipersensibilidade mecânica na pata e na região abdominal, causados pela CYP. Além disso, o aumento dos níveis de RNAm dos receptores CXCR2 e TRPV1 na bexiga após a administração de CYP, foi inibido pelo pré-tratamento com o SB225002, SB366791 ou pela combinação de ambos os antagonistas. A disfunção da bexiga urinária, avaliada através de cistometria, foi evidenciada pelo aumento do número de contrações não associadas à micção (CNMs) e nas pressões vesicais e também pela redução da capacidade da bexiga, do volume de urina eliminado e da eficiência de esvaziamento vesical. O pré-tratamento com o antagonista SB225002 ou a sua combinação com SB366791, reduziu as pressões vesicais, enquanto que os antagonistas SB225002 e SB366791, administrados isoladamente ou a combinação de ambos, causaram um aumento da capacidade da bexiga, do volume eliminado e da eficiência de esvaziamento da bexiga urinária, além de reduzir o número de CNMs. Tomados em conjunto os resultados obtidos no presente estudo sugerem um potencial efeito benéfico dos antagonistas seletivos dos receptores CXCR2 e TRPV1 na inflamação, na dor e nas alterações funcionais da bexiga urinária após a cistite induzida pela CYP.
Abstract : The purpose of this study was to evaluate the role of CXCR2 and TRPV1 receptors in the rat model of cyclophosphamide (CYP) induced cystitis. CYP is a chemotherapeutic agent that induces urotoxicity characterized by the development of hemorrhagic cystitis and urinary bladder fibrosis. Systemic administration of CYP induced bladder inflammation, voiding dysfunction and visceral pain behavior. CYP-induced cystitis was characterized by edema, hemorrhage, increased neutrophil infiltration, urothelial damage, increased bladder wet weight. Furthermore, there was an increase in the levels of inflammatory cytokines such as IL-1ß and TNF-a. Visceral pain was determined by the increase in the nociceptive behavior as well as mechanical hypersensitivity measured by von Frey filaments applied in the paw and abdominal area. CYP-induced cystitis altered bladder contractility and urodynamic parameters involved in voiding function. Also, CYP-induced cystitis increased the mRNA levels of CXCR2 and TRPV1 receptors in the urinary bladder. Immunofluorescence assays revealed an increase in the expression of CXCR2 and TRPV1 receptors in the urinary bladder, particular in the urothelium, and in DRG neurons (dorsal root ganglia) after CYP treatment. Pretreatment of animals with selective antagonists of CXCR2 (SB225002) and TRPV1 (SB366791) receptors significantly reduced the edema and hemorrhage, the bladder wet weight, neutrophil infiltration, myeloperoxidase activity (MPO) and the cytokines levels in the urinary bladder. Interestingly, the administration of the antagonists, SB225002 and SB36679, or the combination of both, significantly reduced the behavioral nociceptive scores and the mechanical hypersensitivity in the paw and in the abdominal area, caused by CYP. In addition, increased levels of CXCR2 and TRPV1 mRNA in the bladder after CYP administration, was inhibited by the pre-treatment with SB225002, SB366791 or the combination of both antagonists. The urinary bladder dysfunction was assessed by cystometry and determined by an increase in the number of non-voiding contractions (NVCs) and in bladder pressure and also by the reduction in bladder capacity, voided volume and bladder efficiency. Of note, the pretreatment with the antagonist SB225002 or its combination with SB366791 significantly reduced the bladder pressure, whereas the antagonists SB225002 and SB366791, administered alone or in combination resulted in an increased bladder capacity, voided volume and bladder efficiency, and reduced the number of NVCs. Taken together, these results indicate a potential role for CXCR2 and TRPV1 receptors antagonists in inflammation, pain and functional alterations in the bladder after CYP -induced cystitis.
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Campofiorito, Cristina Maria Meireles. "Correlação dos ligantes de quimiocinas e de seus respectivos receptores em relação à invasão de linfonodos nos carcinomas epidermóides em cabeça e pescoço." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/5/5155/tde-27042007-135738/.
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Tanto a invasão local como o comprometimento de linfonodos cervicais tem grande impacto na sobrevida de pacientes portadores de carcinomas epidermóides de cabeça e pescoço. Em nosso trabalho nós primeiramente determinamos a expressão dos receptores de quimiocinas de CXCR1 a CXCR5, além de CCR7 e CX3CR1 pelo método do ensaio de proteção à ribonuclease (RPA) em 98 fragmentos de tumores primários, 91 fragmentos de mucosas adjacentes e 26 linfonodos comprometidos e correlacionamos estes dados com parâmetros anátomo-patológicos e sobrevida. CXCL12 ligante do receptor CXCR4 e CCL19 e CCL21 ambos ligantes de CCR7 foram determinados em 38 fragmentos de tumores, 33 mucosas adjacentes e 25 linfonodos comprometidos pela técnica de real-time PCR. Os tumores primários apresentam expressão aumentada do mRNA de CXCR1 (P=0.013), CXCR3 (P=0.008) e CXCR4 (P=0.025). Não observamos correlações entre status linfonodal ou tamanho de tumor. Os linfonodos comprometidos expressam mais mRNA dos receptores de quimiocinas CXCR4, CXCR5, CCR7 e CX3CR1 (todos com P<0.0001) em comparação aos tumores comprometidos. Observamos um aumento de sobrevida (P=0.048) e uma tendência a aumento de sobrevida livre de doença (P=0.074) nos pacientes negativos para a expressão de CX3CR1 (n=17) em comparação aos pacientes positivos (n=21) somente no subgrupo de pacientes portadores de carcinomas da cavidade oral. O mesmo foi observado com os pacientes CCR7 negativos também no subgrupo de pacientes portadores de carcinomas da cavidade oral, tanto em sobrevida global (P=0.024) como para sobrevida livre de doença (P=0.049). Em relação aos ligantes de quimiocinas observamos um aumento do mRNA de CCL21 em linfonodos comprometidos em relação aos tumores primários (P=0.059). Concluímos que a interação quimiotática entre CCR7 e de seu ligante CCL21, poderia ser um mecanismo de atração de células tumorais para os linfonodos em tumores de cavidade oral, além disso a negatividade da expressão do mRNA de CCR7 e CX3CR1 são candidatos marcadores de uma melhor sobrevida em carcinomas epidermóides de cavidade oral.Local invasion and lymph nodal spread impact in the outcome of Head and Neck squamous cell carcinoma (HNSCC) patients (pts). We determined CXCR1-5, CCR7 and CX3CR1 mRNA expression by means of RNAse protection assay in 98 HNSCC primary tumors and 91 adjacent mucosa and 26 metastatic lymph nodes, correlating this data with outcome. CXCL12 and CCL19/CCL21, ligands for CXCR4 and CCR7, were determined in 38 tumor fragments, 33 adjacent mucosas and 25 de metastatic lymph nodes, by means of Quantitative Real-Time PCR. Tumors presented higher CXCR1 (P=0.013), CXCR3 (P=0.008) and CXCR4 mRNA (P=0.025) expression as compared to mucosa. No correlations are observed neither lymph nodal status nor tumor size impacted on chemokine receptor expression. Metastatic lymph nodes expressed more CXCR4, CXCR5, CCR7 and CX3CR1 (P<0.0001) as compared to matched tumors. We found a longer overall survival (OS) (P=0.048) and a trend toward longer disease free survival (DFS) (P=0.074) in CX3CR1 negative (n=17) as compared to positive pts (n=21) only in oral subgroup. The same occurred for CCR7 negative oral SCC, in terms of OS (P=0.024) and DFS (P=0.049). We conclude that, of the chemokine receptors here studied, CCR7 and CX3CR1 mRNA expression seems to better reflect outcome in oral subsite only. In addition, CCL21, a CCR7 ligand mRNAs is more expressed in metastatic lymph nodes than tumors (P=0.059). Further studies are warranted to confirm these results.
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Frey, Susan Carol Stankewitz. "The role of CXCR4 in feline immunodeficiency virus cell entry /." Thesis, Connect to this title online; UW restricted, 2001. http://hdl.handle.net/1773/11487.
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Domínguez, Hernández Francisco. "Implicación de las quimoquinas IL-8, MCP-1, rantes, los receptores CXCR1, CXCR4, CCr2, CCr5 y el factor IGFBP-rP1 en la interfase materno-embrionaria." Doctoral thesis, Universitat de València, 2003. http://hdl.handle.net/10803/10135.
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La implantación embrionaria es la fijación del blastocisto al endometrio materno. El conocimiento de los factores moleculares implicados en su regulación es crucial para comprender los mecanismos que controlan la reproducción humana Las quimoquinas y sus receptores participan activamente en este proceso así como otros factores como IGFBP-rP1.Los objetivos principales de la tesis doctoral fueron los siguientes - Investigar la expresión y localización de la quimoquinas IL-8, MCP-1, RANTES y SDF-1 en el endometrio humano.- Estudiar la expresión y localización de los receptores de las quimoquinas antes citadas CXCR1, CCR2b, CCR5 y CXCR4 en el endometrio humano.- Determinar la presencia de dichos receptores en el blastocisto humano.- Analizar la expresión de qué genes están regulados en el endometrio durante la ventana de implantación y establecer su implicación en la receptividad endometrial humana.- Evaluar la expresión y localización de IGFBP-rP1 en el endometrio humano.Las conclusiones de la tesis doctoral fueron las siguientes- IL-8 y MCP-1 a nivel de proteína se localizan en el epitelio luminal y glandular así como en células endoteliales. RANTES fue localizada principalmente en células del estroma y endoteliales.- Los niveles de IL-8 y MCP-1 aumentaron debido a la administración de progesterona durante la fase receptiva del ciclo menstrual.- El blastocisto humano no produce cantidades medibles de IL-8, MCP-1 y RANTES, pero induce un aumento en el ARN mensajero de IL-8 en células epiteliales endometriales en cultivo.- Los receptores de quimoquinas CXCR1 (IL-8), CCR5 (RANTES) y CCR2b (MCP-1) a nivel de ARNm esta aumentado en el endometrio premenstrual, mientras que CXCR4 (SDF-1) se encontró aumentado ligeramente durante la ventana de implantación (fase secretora media). El blastocisto humano posee los receptores CCR5 (RANTES) y CCR2b (MCP-1) a nivel de proteína. - Las células endometriales epiteliales en cultivo poseen los receptores CXCR1 (IL-8), CCR5 (RANTES) y CCRb (MCP-1). El embrión humano induce una polarización de dichos receptores endometriales.- IGFBP-rP1 fue la segunda molécula más expresada tanto por el endometrio receptivo (LH+7) como en la línea celular RL95-A (receptiva) entre más de 375 genes analizados de citoquinas, quimoquinas, factores de crecimiento y sus receptores.- El ARN mensajero de IGFBP-rP1 aumentó unas 35 veces durante la fase receptiva comparado con el endometrio pre-receptivo, mostrando además un pico de expresión en la fase lútea tardía. La separación de estroma, y epitelio demostró que la expresión de IGFBP-rP1 aumentaba principalmente en células del estroma.- La localización del ARNm de IGFBP-rP1 por hibridación in situ confirmó la localización de dicha molécula en células del estroma aunque también se observó en epitelio y células endoteliales. La localización de la proteína se concentró en la superficie apical del endometrio, sugiriendo su posible función en la fisiología de la receptividad endometrial. Concluimos por todo ello que algunas quimoquinas secretadas por el endometrio de forma local como IL-8, RANTES, MCP-1 u otras pueden activar sus receptores en la superficie del blastocisto, lo que supondría su heterodimerización y con ello, se provocaría un fenotipo adhesivo en el blastocisto y su posterior implantación.Human implantation is the process of the adhesion of the blastocyst to the human endometrium. The knowledge of the biochemical factors involved in this process is crucial for the understanding of the mechanisms of the human reproduction.Chemokines, a subfamily of cytokines, and their receptors are actively implicated in this process. Another factor, IGFBP-rP1, is also related to the molecular basis of implantation. Our objectives in this doctoral thesis are: - To investigate the localization and expression of IL-8, MCP-1, RANTES and SDF-1 in the human endometrium. - To study the localization and expression of the chemokine receptors CXCR1, CCR2b, CCR5 and CXCR4 in the human endometrium. - To determine the presence of these receptors in the human blastocyst - To analyze the expression of genes expressed differentially in human receptive endometrium versus pre-receptive endometrium. - To evaluate the expression and localization of IGFBP-rP1 in the human endometrium. The major conclusions of this doctoral thesis are: - IL-8 and MCP-1 are localized in the luminal and glandular epithelium. RANTES was localized in stroma and endothelial cells. The levels of IL-8 and MCP-1 were up-regulated with the administration of progesterone. - The human blastocyst doesn't produce IL-8, MCP-1 nor RANTES, but induces an up-regulation of IL-8 mRNA in endometrial epithelial cells in culture. - The chemokine receptors CXCR1, CCR5, CCR2 are up-regulated in the premenstrual endometrium, whereas CXCR4 is up-regulated in the implantation window. The human blastocyst expresses the CCR5 and CCR2 receptors. - The epithelial endometrial cells in culture express the CXCR1, CCR5 and CCR2 receptors. The human blastocyst produces an up-regulation and polarization of these receptors in this culture. - IGFBP-rP1 was the second most up-regulated molecule in receptive endometrium and in RL95A (receptive) cell line, among more than 375 genes analyzed. - IGFBP-rP1 mRNA was up-regulated more than 35 times during receptive phase compared to pre-receptive one. Stromal cells were responsible for the expression of this molecule. mRNA of IGFBP-rP1 was localized by in situ hybridization in luminal and glandular epithelium and stromal cells. The protein was localized in the apical zone of the luminal epithelium, suggesting a possible role in endometrial receptivity.
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Cheuk, Tin-hoi, and 卓殿凱. "CXCR4 and FOXO3a expression in breast cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46632360.
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Valiathan, Rajeshwari Rajan. "Functional interactions of HIV-1 GAg with the cellular endocytic pathway /." Access full-text from WCMC, 2007. http://proquest.umi.com/pqdweb?did=1481666381&sid=16&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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Willox, Ian. "Role of the chemokine receptor CXCR3 in human mast cell degranulation and signalling." Thesis, University of Bath, 2009. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.518109.
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The chemokine receptor CXCR3, which has three known variants (CXCR3-A, CXCR3-B and CXCR3-Alt), has been implicated in the recruitment of mast cells to tissues in many different chronic diseases with its agonists found in elevated levels in many pulmonary diseases. All three variants of CXCR3 were detected in cord blood-derived mast cells at the mRNA level. Using an antibody that is unable to distinguish individual CXCR3 isoforms, we detected a marked down-regulation of intracellular protein during maturation from progenitor cells, with no concomitant changes in the modest surface expression of CXCR3. The known CXCR3 agonists CXCL9, CXCL10 and CXCL11 as well as the reported CXCR3-B agonist CXCL4, were able to induce Akt and ERK1/2 phosphorylation, as well as partial degranulation. Responses to all agonists were inhibited by pre-treatment with selective CXCR3 antagonists and pertussis toxin. Use of novel isoform-selective inhibitors indicates that the p110 isoform of PI3K is required for degranulation and signalling responses to CXCR3 agonists. Unexpectedly, dual (but not individual) isoform inhibition of the class I and isoforms substantially inhibited signalling and degranulation responses, indicating a hitherto unrecognised synergy between these isoforms, which provide a conduit for CXCR3 signalling in mast cells.
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Masuda, Ryo. "Development and Application of Imaging Probes for CXC Chemokine Receptor 4 (CXCR4)." 京都大学 (Kyoto University), 2012. http://hdl.handle.net/2433/157894.
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Rahimi, Massod. "The role of the chemokine receptor CXCR4 in EGFRvIII-expressing breast cancer." Connect to Electronic Thesis (CONTENTdm), 2009. http://worldcat.org/oclc/501000073/viewonline.
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Palmesino, Elena. "Signaling and structural properties required for function of the chemokine receptor CXCR4 /." Bern : [s.n.], 2005. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Costa, Kesiane Mayra da. "Participação dos receptores CXCR2 para quimiocinas na toxicidade induzida pelo paraquat em roedores." Pontifícia Universidade Católica do Rio Grande do Sul, 2014. http://hdl.handle.net/10923/5705.
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Previous issue date: 2014Paraquat (PQ) is an agrochemical agent commonly used worldwide, which is allied to potential risks of intoxication. This herbicide induces the formation of reactive oxygen species (ROS) that ends up compromising various organs, particularly the lungs (by the polyamine uptake system), and the brain (by dopaminergic neuronal cell loss). This study evaluated the deleterious effects of paraquat on the central nervous system (CNS) (changes in physiologic parameters, nociceptive responses, locomotor activity and motor coordination, and expression profile of some inflammatory markers), or peripherally (inflammatory cells in the blood and lungs), with special attempts to assess the putative protective effects of the selective CXCR2 receptor antagonist SB225002 on these parameters. PQ-toxicity was induced in male Wistar rats, in a total dose of 50 mg/kg, given by the intraperitoneal (i. p. ) route (10 mg/kg each three days). Control animals received saline solution (10 ml/kg) at the same schedule of administration. Separate groups of animals were treated with the selective CXCR2 antagonist SB225002 (1 or 3 mg/kg, i. p. ), administered 30 min before each paraquat injection. The major changes found in paraquat-treated animals were: decreased body weight and hypothermia, nociception behavior, impairment of locomotor and gait capabilities, enhanced TNF-α and IL-1β expression in the striatum, and cell migration to the lungs and blood. Some of these parameters were reversed when the antagonist SB225002 was administered, including recovery of physiological parameters, decreased nociception, improvement of gait abnormalities, modulation of striatal TNF-α and IL-1β expression, and decrease of neutrophil migration to the lungs and blood. Taken together, our results demonstrate that damage to the central and peripheral systems elicited by paraquat can be prevented by the pharmacological inhibition of CXCR2 chemokine receptors. The experimental evidence presented herein extends the comprehension on the toxicodynamic aspects of paraquat, and opens new avenues to treat intoxication induced by this herbicide.
O paraquat (PQ) é um composto químico bastante utilizado no mundo, o qual é aliado a potenciais riscos de intoxicação. Este herbicida induz a formação de espécies reativas de oxigênio (ROS) que podem comprometer vários órgãos, especialmente os pulmões (através da recaptação de poliaminas), e o cérebro (pela perda de neurônios dopaminérgicos). Este trabalho avaliou os efeitos deletérios do paraquat frente ao Sistema Nervoso Central (SNC) (como mudanças nos parâmetros fisiológicos, respostas nociceptivas, atividade locomotora e coordenação motora, e o perfil de expressão de alguns marcadores moleculares de inflamação), e periférico (como células inflamatórias no sangue e pulmões), com o objetivo de avaliar o possível papel protetor do antagonista de receptores de quimiocinas CXCR2, o SB225002, nestes parâmetros. A toxicidade ao paraquat foi induzida em ratos machos Wistar, em uma dose total de 50 mg/kg, administrada intraperitonealmente (i. p. ) (10 mg/kg a cada três dias). Animais do grupo controle receberam solução salina (10 ml/kg) no mesmo protocolo de administração. Diferentes grupos de animais foram tratados com o antagonista SB225002 (1 ou 3 mg/kg, i. p. ), administrado 30 minutos antes de cada aplicação do paraquat. As prinicpais mudanças encontradas nos animais tratados com paraquat foram: diminuição do peso corporal e hipotermia, aumento da resposta nociceptiva, diminuição da capacidade de marcha e locomoção, aumento da expressão de TNF-α e IL-1β no estriado, e a migração de células inflamatórias no sangue e pulmões. Alguns destes parâmetros foram revertidos quando administrado o antagonista SB225002, como recuperação dos parâmetros fisiológicos, diminuição da nocicepção, melhora na atividade de marcha, modulação da expressão estriatal de TNF-α e IL-1β, e diminuição da migração neutrofílica para o sangue e pulmões. Em conjunto, nossos resultados demonstram que os danos causados pelo paraquat ao sistema central e periférico podem ser prevenidos através da inibição farmacológica dos receptores de quimiocinas CXCR2. A evidência experimental aqui apresentada extende a compreensão dos efeitos toxicodinâmicos do paraquat, e proporciona novas possibilidades para tratar a intoxicação causada por este herbicida.
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Rath, Dominik [Verfasser], and Tobias [Akademischer Betreuer] Geisler. "Expression of SDF-1 Receptors CXCR4 and CXCR7 on Circulating Platelets of Patients with Acute Coronary Syndrome and Association with Left Ventricular Functional Recovery / Dominik Rath ; Betreuer: Tobias Geisler." Tübingen : Universitätsbibliothek Tübingen, 2016. http://d-nb.info/1197694757/34.
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Collier, Jonathan Marc. "The role of the chemokine receptor CXCR4 in oral squamous cell carcinoma metastasis." Thesis, Queen Mary, University of London, 2010. http://qmro.qmul.ac.uk/xmlui/handle/123456789/454.
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Oral Squamous Cell Carcinoma (OSCC) is the sixth most common cancer worldwide. The greatest cause of mortality and surgical morbidity is due to the common spread of tumour cells from the primary lesion to the lymph nodes of the neck. This pathway is not unique to cancer: under physiological conditions, specific chemokine receptors on the surface of leukocytes mediate cell “homing” to tissues defined by gradients of complimentary chemotactic cytokines (chemokines). The chemokine receptors CXCR4 and CCR7 mediate leukocyte “homing” to secondary lymphoid tissue and have been demonstrated on the surface of a number of carcinomas of the aero-digestive tract. The aim of this project was to determine the role of chemokine receptor expression and function in OSCC metastasis. CXCR4 mRNA expression (microarrays and semi-quantitative RT-PCR) and surface protein production (flow cytometry and immunocytochemistry) was significantly increased in some (but not all) established OSCC cell lines compared with primary oral keratinocytes grown in culture. Examination of clinical samples using a novel, quantitative immunohistochemistry methodology demonstrated a positive association between CXCR4 staining of the cell membrane in primary OSCC lesions and histological evidence of lymph node metastases. CXCR4 over-expression in a constitutively low expressing OSCC cell line (H357) was produced using stable transfection with the CXCR4 insert. Stimulation of CXCR4-bearing OSCC cells with the ligand SDF was shown to mediate statistically significant increases in OSCC cell proliferation in-vitro using a number of complimentary techniques. No effect on apoptosis was demonstrated. The SDF/CXCR4 axis also mediated significant increases in tumour cell chemokinesis, chemotaxis and invasion as measured by a range of in-vitro assays. These results demonstrate a potential role for CXCR4 as part of a panel of prognostic markers for OSCC. Therapeutic strategies aimed at the SDF/CXCR4 axis may be clinically beneficial if the problems of systemic toxicity can be overcome.
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Archibald, Kyra Mhairi. "The chemokine receptor CXCR4 and the malignant transformation of the ovarian surface epithelium." Thesis, Queen Mary, University of London, 2010. http://qmro.qmul.ac.uk/xmlui/handle/123456789/621.
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Ovarian cancer is the most lethal gynaecological cancer in the Western world today. Mortality remains high, partly due to poor understanding of the pre-malignant changes that occur in ovarian cancers. This thesis describes the characterisation of cells derived from the ovarian surface epithelium that may represent an in vitro model of early malignancy. Cells derived from one of three hTERT immortalised human non-malignant ovarian surface epithelial (IOSE) cell lines with functional Rb and p53 acquired the ability to form colonies in soft agar. These transformed cells (TOSE) had increased senescence and nuclear p53 when compared with the parental IOSE25 cells. While they did not form tumours in nude mice, they fulfilled other hallmarks of transformation, such as loss of anchorage dependence, alterations in cell morphology, loss of contact inhibition and cytogenetic abnormalities. Cytogenetic changes were analysed using high-resolution SNP6.0 arrays, which showed a concise amplification of the chemokine receptor CXCR4 gene locus. CXCR4 is implicated in metastasis and higher levels are found in malignant and pre-malignant lesions than in normal cells. This genomic amplification was accompanied by increased functional CXCR4 protein as assessed by cell motility assays. TOSE cells also exhibited altered signalling downstream of CXCR4 when compared with parental IOSE25 cells. Abrogation of the CXCR4 receptor in TOSE cells reduced the number and the size of soft agar colonies and also reduced senescence, suggesting that CXCR4 is oncogenic. In parallel to amplified CXCR4, TOSE cells also contained epigentically silenced CXCL12, the ligand for CXCR4. This thesis argues that TOSE cells represent pre-malignant ovarian cancer and support an emerging model where pre-malignant cells disseminate down a chemokine gradient to sites of distant metastasis at organs expressing high levels of CXCL12. No CXCR4 amplification was observed in human ovarian cancer. However, hypermethylation of the CXCL12 gene promoter was observed in the ovarian cancer cell line SKOV3 and in three out of four borderline ovarian tumours.
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Désogère, Pauline. "Synthesis and studies of new optimised chelating agents for targeting chemokine receptor CXCR4." Thesis, Dijon, 2012. http://www.theses.fr/2012DIJOS047/document.
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L’objectif de ce travail de thèse était de développer des outils pour détecter et traiter le cancer àun stade précoce. Nous avons donc entrepris la synthèse de nouveaux radiopharmaceutiques ciblantspécifiquement le récepteur CXCR4, en utilisant le savoir-faire et l'expertise de notre groupe dans lasynthèse et la fonctionnalisation des polyazacycloalcanes. Nous avons travaillé simultanément surdeux aspects : l’agent chélatant et la molécule vectrice.Dans un premier temps, les travaux ont concerné la conception, la synthèse et la caractérisationde nouveaux macrocycles à fort potentiel pour la chélation du cuivre et du gallium. Nous avons toutd’abord développé une nouvelle voie de synthèse permettant d’accéder à des dérivés homocyclènesC-functionnalisés. Nous nous sommes ensuite intéressés aux dérivés du 1,4,7-triazacyclononane(TACN). En optimisant une voie de synthèse déjà développée au laboratoire, nous avons facilitél’accès à des dérivés TACN N- et C-fonctionnalisés. Nous avons ainsi préparé une série denouveaux agents chélatants bifonctionnels adaptés pour la complexation du cuivre ou du gallium, envariant la nature de la fonction de greffage et des bras coordinants. Nous avons également réalisé lasynthèse de nouveaux cryptands en série cyclène et nous avons étudié leur propriété decomplexation vis à vis du cuivre.Dans un second temps, nous avons développé une nouvelle famille d’agents imageants duCXCR4 en modifiant la structure des AMD3100 et AMD3465. Ce travail a tout d’abord nécessité lamise au point de nouvelles méthodes de fonctionnalisation de ces structures. Nous avons ainsi pupréparer de nouveaux synthons porteur d’une fonction de greffage dans les deux séries. Nous avonsensuite introduit différentes sondes imageantes, telles que des chélates adaptés pour la complexationdu cuivre, gallium et indium ainsi que des sondes fluorescentes de type bodipyThe objective of this thesis work was to develop CXCR4-targeted tools to localize and treat cancer at an early stage. In this line, we investigated the synthesis of new target-specific radiopharmaceuticals. The work focused on two main axes, i.e. the chelating agent and the carrier, by using the know-how and the expertise of our group in polyazacycloalkanes synthesis and functionalization. In the first part, we were interested in developing new macrocyclic scaffolds of high potential for copper and gallium chelation. We first focused on the development of a new powerful route towards selectively functionalized constrained homocyclens. The second part was based on C-functionalized 1,4,7-triazacyclononane (TACN) and its derivatives. From a synthetic route previously developed in our group, we were able to facilitate and optimize the synthesis of selectively N- and C-functionalized TACN. By varying the grafting functions and the pendant coordinating arms, we prepared several really promising bifunctional chelating agents for copper and gallium chelation. We also investigated the synthesis of new cryptands based on cyclen and we studied their properties towards copper complexation. In the second part of this thesis work, we were interested in generating a new family of imaging agents based on well-known CXCR4 antagonists, i.e. AMD3100 and AMD3465. The access towards these agents first required the preparation of original building blocks by modification of the AMD3100 and AMD3465 cores. The conjugation of such platforms onto the appropriate probe enabled the synthesis of various systems for optical and nuclear imaging. Thus, we were able to introduce a bodipy dye and several chelators adapted for gallium, copper and indium chelation
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Costa, Kesiane Mayra da. "Participa??o dos receptores CXCR2 para quimiocinas na toxicidade induzida pelo paraquat em roedores." Pontif?cia Universidade Cat?lica do Rio Grande do Sul, 2014. http://tede2.pucrs.br/tede2/handle/tede/1758.
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Previous issue date: 2014-01-02Paraquat (PQ) is an agrochemical agent commonly used worldwide, which is allied to potential risks of intoxication. This herbicide induces the formation of reactive oxygen species (ROS) that ends up compromising various organs, particularly the lungs (by the polyamine uptake system), and the brain (by dopaminergic neuronal cell loss). This study evaluated the deleterious effects of paraquat on the central nervous system (CNS) (changes in physiologic parameters, nociceptive responses, locomotor activity and motor coordination, and expression profile of some inflammatory markers), or peripherally (inflammatory cells in the blood and lungs), with special attempts to assess the putative protective effects of the selective CXCR2 receptor antagonist SB225002 on these parameters. PQ-toxicity was induced in male Wistar rats, in a total dose of 50 mg/kg, given by the intraperitoneal (i.p.) route (10 mg/kg each three days). Control animals received saline solution (10 ml/kg) at the same schedule of administration. Separate groups of animals were treated with the selective CXCR2 antagonist SB225002 (1 or 3 mg/kg, i.p.), administered 30 min before each paraquat injection. The major changes found in paraquat-treated animals were: decreased body weight and hypothermia, nociception behavior, impairment of locomotor and gait capabilities, enhanced TNF-α and IL-1β expression in the striatum, and cell migration to the lungs and blood. Some of these parameters were reversed when the antagonist SB225002 was administered, including recovery of physiological parameters, decreased nociception, improvement of gait abnormalities, modulation of striatal TNF-α and IL-1β expression, and decrease of neutrophil migration to the lungs and blood. Taken together, our results demonstrate that damage to the central and peripheral systems elicited by paraquat can be prevented by the pharmacological inhibition of CXCR2 chemokine receptors. The experimental evidence presented herein extends the comprehension on the toxicodynamic aspects of paraquat, and opens new avenues to treat intoxication induced by this herbicide.
O paraquat (PQ) ? um composto qu?mico bastante utilizado no mundo, o qual ? aliado a potenciais riscos de intoxica??o. Este herbicida induz a forma??o de esp?cies reativas de oxig?nio (ROS) que podem comprometer v?rios ?rg?os, especialmente os pulm?es (atrav?s da recapta??o de poliaminas), e o c?rebro (pela perda de neur?nios dopamin?rgicos). Este trabalho avaliou os efeitos delet?rios do paraquat frente ao Sistema Nervoso Central (SNC) (como mudan?as nos par?metros fisiol?gicos, respostas nociceptivas, atividade locomotora e coordena??o motora, e o perfil de express?o de alguns marcadores moleculares de inflama??o), e perif?rico (como c?lulas inflamat?rias no sangue e pulm?es), com o objetivo de avaliar o poss?vel papel protetor do antagonista de receptores de quimiocinas CXCR2, o SB225002, nestes par?metros. A toxicidade ao paraquat foi induzida em ratos machos Wistar, em uma dose total de 50 mg/kg, administrada intraperitonealmente (i.p.) (10 mg/kg a cada tr?s dias). Animais do grupo controle receberam solu??o salina (10 ml/kg) no mesmo protocolo de administra??o. Diferentes grupos de animais foram tratados com o antagonista SB225002 (1 ou 3 mg/kg, i.p.), administrado 30 minutos antes de cada aplica??o do paraquat. As prinicpais mudan?as encontradas nos animais tratados com paraquat foram: diminui??o do peso corporal e hipotermia, aumento da resposta nociceptiva, diminui??o da capacidade de marcha e locomo??o, aumento da express?o de TNF-α e IL-1β no estriado, e a migra??o de c?lulas inflamat?rias no sangue e pulm?es. Alguns destes par?metros foram revertidos quando administrado o antagonista SB225002, como recupera??o dos par?metros fisiol?gicos, diminui??o da nocicep??o, melhora na atividade de marcha, modula??o da express?o estriatal de TNF-α e IL-1β, e diminui??o da migra??o neutrof?lica para o sangue e pulm?es. Em conjunto, nossos resultados demonstram que os danos causados pelo paraquat ao sistema central e perif?rico podem ser prevenidos atrav?s da inibi??o farmacol?gica dos receptores de quimiocinas CXCR2. A evid?ncia experimental aqui apresentada extende a compreens?o dos efeitos toxicodin?micos do paraquat, e proporciona novas possibilidades para tratar a intoxica??o causada por este herbicida.
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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.Submitted by denise santos (denise.santos@ufc.br) on 2014-07-14T13:15:32Z No. of bitstreams: 1 2013_dis_gmcavalcante.pdf: 1293725 bytes, checksum: fa485fabd530db7d0d4df8d64c549656 (MD5)
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Made available in DSpace on 2014-07-14T13:16:38Z (GMT). No. of bitstreams: 1 2013_dis_gmcavalcante.pdf: 1293725 bytes, checksum: fa485fabd530db7d0d4df8d64c549656 (MD5) Previous issue date: 2013
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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Barbi, Joseph James. "The Importance of Inflammatory Chemokine Receptors in The Immune Response To Leishmania Infections." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1211566575.
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Qureishi, Amer Naveed. "Ribozymes against the chemokine receptors CCR5 and CXCR4 for inhibiting HIV-1." Thesis, King's College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408060.
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Rahman, Ishrat. "Functional analysis of the G-protein coupled chemokine receptor CXCR3-A and its ligands." Thesis, University of Reading, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.578079.
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CXCR3 is a G-protein coupled chemokine receptor. Chemokine receptors play a key part in orchestrating immune responses. CXCR3 in particular has attracted attention owing to its abundant expression in activated T-cells and its role in the trafficking of Thl cells to sites of inflammation, and thus may potentially be involved in the pathogenesis of many chronic inflammatory diseases, such as Multiple Sclerosis (MS) and Rheumatoid arthritis (RA). CXCR3 is known to exist as two functional variants; CXCR3-A and CXCR3-B, both associated with diverse signalling events and exert contrasting functional effects. This thesis explores the effect of T -cell activation on CXCR3 expression and compares the agonist induced CXCR3-A signalling events in CHO-CXCR3-A cells and activated T-cells. T -cell activation causes a two-phase mechanism of CXCR3 induction to occur in CD4+ T- cells. Transcriptional regulation of the CXCR3 gene occurs in naive CD4+ T -cells early in activation (days I to 4), to down-regulate CXCR3-B and up-regulate CXCR3-A mRNA. During mid-activation (days 4 to 8) these cells become high CXCR3-A expressing mature Thl effector cells (CD4+CXCR3-A+high T-cells) but become low in frequency. CD4+CXCR3-A+high T-cells may be implicated in the pathogenesis of Thl type chronic disorders as they constitutively express high levels of CXCR3-A, which is known to be a tissue homing chemokine receptor. A comparative study of the agonist induced pharmacological response of CXCR3-A in CHO-CXCR3-A transfected cells and in activated T -cells shows that T -cells may be a better system to study CXCR3-A signalling in and differences in signalling events seem to arise due to changes in cell environment.
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Korniejewska, Anna. "Characterisation of the chemokine receptor CXCR3 and its atypical variants in human T lymphocytes." Thesis, University of Bath, 2009. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.518106.
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The chemokine receptor CXCR3 and its agonists CXCL9/Mig, CXCL10/IP-10 and CXCL11/I-TAC are involved in a variety of inflammatory disorders including multiple sclerosis, rheumatoid arthritis, psoriasis and sarcoidosis. CXCL11 has also been reported to bind to an additional receptor, namely CXCR7, which also interacts with CXCL12. Two alternatively spliced variants of the human CXCR3 receptor have been described, namely CXCR3-B and CXCR3-alt. The human CXCR3-B has been found to bind CXCL9, CXCL10, CXCL11 as well as an additional agonist CXCL4/PF4. In contrast, CXCR3-alt only binds CXCL11. This work demonstrates that CXCL4 like the original CXCR3 agonists is capable of inducing biochemical signalling, namely intra-cellular calcium elevation, and activation of p44/p42 MAPK and PI3K/Akt pathways in activated human T lymphocytes. Phosphorylation of p44/p42 MAPK and Akt was inhibited by pertussis toxin, suggesting coupling to Gi protein. In contrast CXCR3 antagonists blocked CXCR3 agonists but not CXCL4-mediated responses. Surprisingly, stimulation of T cells with CXCL4 failed to elicit migratory responses of these cells and did not lead to loss of surface CXCR3 expression. Collectively our evidence shows that although CXCL4 is coupled to downstream biochemical machinery, its function in T cells is distinct from the function of CXCR3 agonists. The work presented in this thesis also indicates that despite considerably lower surface expression in comparison to the full length CXCR3, CXCR3-B and CXCR3-alt transduce biochemical signals in response to CXCL11 in transfected cells. According to previous reports the role of CXCR7 in signalling and chemotaxis in T cells could not be detected. In T cells and transfected cells system CXCR7 was localised at the plasma membrane and was efficiently internalized in response to CXCL11 and CXCL12. Studies of the involvement of methylation in T cell chemotaxis suggest that this modification may be required in this process as it was partially inhibited by methylation inhibitor- MTA. Moreover T cell co-stimulation caused increased levels of arginine mono-methylated proteins suggesting the importance of methylation in T lymphocyte signalling.
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Overbeck-Zubrzycka, Dorota. "FOXP3 regulates metastatic spread of breast cancer via control of expression of CXCR4 chemokine receptor." Thesis, University of Newcastle Upon Tyne, 2012. http://hdl.handle.net/10443/1465.
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The FOXP3 transcription factor can regulate T cell migration by inhibiting expression of CXCR4, the receptor for the chemokine CXCL12. The increased expression of CXCR4 by breast cancer cells can drive metastatic migration towards sites that express CXCL12. Intracellular trafficking of FOXP3 to the nucleus is required in order for this factor to function. The presence of alternative splicing forms, mutations and post-translationally modified forms may disrupt FOXP3 nuclear localization. We hypothesised that FOXP3 tumour suppressor is inactive in breast cancer causing an increase in CXCR4 expression and the development of metastasis. The expression of FOXP3 and CXCR4 were measured at mRNA and protein (immunohistochemistry, immunofluorescence, FACS) levels. FOXP3 DNA sequences of normal and cancer cells were analysed. Stable FOXP3 overexpressing breast cancer transfectants were used to investigate the potential of FOXP3 to regulate chemotaxis. Normal breast epithelial cells (both patient-derived tissues and laboratory cultured cell lines) expressed FOXP3 in their nuclei but did not express CXCR4. Breast cancer cells overexpressed CXCR4 (p<0.05), whereas FOXP3 expression was decreased (p<0.05) and confined to the cytoplasm with negligible nuclear expression. Metastases expressed less FOXP3 and more CXCR4 than primary cancers (p<0.05). FOXP3 sequencing in breast cancer cell lines did not reveal mutations. However, there were at least three bands on the PCR electrophoreses gel. The predominant form in breast cancer cells contained an insertion of 120bp within the forkhead domain. Transfection of breast cancer cells with wild-type FOXP3 restored its nuclear expression, reduced CXCR4 expression and inhibited cell migration. This study demonstrated failure of nuclear localisation of FOXP3 in breast cancer cells and an inverse correlation between this failure and CXCR4 expression. Disruption of FOXP3 nuclear localisation may be due to abnormal co-expression of FOXP3 splice variants leading to increased CXCR4 expression and acquisition of the capacity to metastasize.
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Nishizawa, Koji. "Fluorescent imaging of high grade bladder cancer using a specific antagonist for chemokine receptor CXCR4." Kyoto University, 2011. http://hdl.handle.net/2433/142547.
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