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Huusko, T. (Tuija). "Genetic and molecular background of ascending aortic aneurysms." Doctoral thesis, Oulun yliopisto, 2013. http://urn.fi/urn:isbn:9789526201269.
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Abstract Thoracic aortic aneurysms (TAAs) are a significant source of morbidity and mortality. Classical risk factors for TAAs are hypertension, atherosclerosis, male gender, smoking, age, high body mass index, family history and chronic obstructive pulmonary disease. In addition, in certain cases of TAAs, i.e., ascending aortic aneurysms (AscAA), genetic factors are highly prominent. Matrix metalloproteinases are in a major role in the destruction of the aortic wall and the imbalance between matrix metalloproteinases, and their inhibitors are involved in the formation of aneurysms. In addition, osteopontin is a potent regulator of matrix metalloproteinases and it is widely expressed in injured arteries. Recently, telomere shortening has been shown to be involved in the development of abdominal aortic aneurysms (AAA). In this aneurysm type, atherosclerosis has a major role. Since atherosclerosis is frequently absent in the case of TAAs, the length of telomeres was measured in the blood samples of TAA patients. The purpose of this thesis was to study the genetic background of TAAs of the ascending aorta and furthermore, the molecular background of this disease. The first study was done with families with TAAs, and dissections and one chromosomal locus (5q13-14) of the studied seven loci showed a significant genetic linkage for TAAs. Two other studies were done exploiting our TAA case-control material. Study II showed elevated levels of osteopontin, matrix metalloproteinase type 2 and 9 in the plasma and tissue samples of TAA patients compared with controls. In the third study, longer blood leukocyte telomeres were found in the DNA samples of TAA patients compared with controls; furthermore, the elevation of telomere lengthening protein telomerase expression was found in the tissue samples of TAA patients. This thesis presents region 5q13-14 as a potential genetic regulator for TAAs in Finnish families. In addition, elevated levels of osteopontin, matrix metalloproteinase type 2 and 9 can be considered as a plasma biomarker for aneurysmal disease. Furthermore, longer blood leukocytes were found to be a significant risk factor for developing TAAsTiivistelmä Rinta-aortan aneurysmat ovat merkittävä sairastumisiin ja kuolemiin johtava tekijä. Perinteisinä riskitekijöinä aneurysmille on pidetty korkeaa verenpainetta, ateroskleroosia, miessukupuolta, tupakointia, ikää, ylipainoa, suvussa esiintyneitä aneurysmatapauksia ja keuhkoahtaumatautia. Näiden lisäksi erityisesti nousevan rinta-aortan alueella esiintyvissä aneurysmissa myös perinnöllisillä tekijöillä on korostunut merkitys. Matriksimetalloproteinaaseilla ja niiden estäjillä on merkittävä rooli, kun aortan seinämää hajotetaan. Tasapainon järkkyminen kyseisten proteiinien keskinäisessä suhteessa voi johtaa aneurysman muodostumiseen. Myös osteopontiinin tiedetään olevan tehokas matriksimetalloproteinaasien säätelijä, ja sitä tuotetaankin yleisesti vahingoittuneessa verisuonessa. Telomeerien lyhentyminen on vastikään yhdistetty vatsa-aortan alueella esiintyviin aneurysmiin, joissa ateroskleroosilla on yleensä merkittävä rooli. Koska ateroskleroosi on vain harvoin nousevan rinta-aortan alueen aneurysmien taustalla, rinta-aortan aneurysmapotilaiden valkosolujen telomeerien suhteelliset pituudet määritettiin. Väitöskirjan ensimmäisessä osatyössä keskityttiin löytämään geneettinen kytkentä rinta-aortan aneurysmien ja jonkin seitsemän tutkitun kromosomialueen välille. Geneettinen kytkentä löydettiin kromosomialueelta 5q13-14. Osatöissä 2 ja 3 hyödynnettiin rinta-aortan aneurysmien potilas- ja verrokkiaineistoja. Osatyö 2 osoitti, että matriksimetalloproteinaasien (2 ja 9) määrät ovat kohonneet rinta-aortan aneurysmapotilaiden näytteissä verrokkeihin verrattuna. Osatyössä 3 telomeerien suhteelliset pituudet veren valkosoluissa olivat pidemmät nousevan rinta-aortan aneurysmapotilaiden näytteissä verrokkihenkilöiden näytteisiin verrattuna. Myös telomeraasin tuotto oli lisääntynyt rinta-aortan aneurysmapotilaiden aorttakudosnäytteissä. Väitöskirjassa esitetään tuloksena kromosomialue 5q13-14 geneettisenä säätelijänä suomalaisissa suvuittain esiintyvissä rinta-aortan aneurysmatapauksissa. Kohonneita matriksimetalloproteinaasien ja osteopontiinin tasoja voidaan lisäksi pitää biomarkkereina rinta-aortan aneurysmien sairastavuudelle. Veren valkosolujen pidemmät telomeerit näyttävät myös olevan yhteydessä rinta-aortan aneurysmien sairastavuuteen
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Luukkonen, J. (Jani). "Osteopontin and osteoclasts in rheumatoid arthritis and osteoarthritis." Doctoral thesis, Oulun yliopisto, 2019. http://urn.fi/urn:isbn:9789526223643.
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Abstract Rheumatoid arthritis and osteoarthritis are two chronic joint diseases, which cause two of the largest socioeconomical burdens among all joint diseases according to the World Health Organization. Both diseases are associated with changes in bone structure and bone cell, especially osteoclast, function. The etiology or pathogenesis of these diseases are not completely understood. Traditionally, osteoarthritis is seen as a disease resulting from mechanical wear of cartilage and bone, and rheumatoid arthritis as an autoinflammatory disease of synovial tissue. However, also in osteoarthritis chronic inflammation is present in synovial tissue, and in rheumatoid arthritis large changes in bone structure are seen. The field of study focusing on this connection between inflammation and bone is called osteoimmunology and it can explain many features of these chronic diseases linking joint health to disturbances in bone homeostasis. Here, the study focused on the function of osteoclasts in normal and pathological environments, and on the factors that have an effect on bone resorption, with a special emphasis on the protein osteopontin. Samples of synovial fluid and serum from rheumatoid arthritis and osteoarthritis patients were analyzed for factors affecting osteoclasts, and in vitro cell cultures of human derived osteoclasts were used to analyze osteoclast function in normal and pathological environment. The phosphorylation of osteopontin was found to be increased in rheumatoid arthritis, along with multiple other inflammatory factors that also affect osteoclasts, such as IL-6, IL-8 and VEGF. Osteoclast cell cultures showed how the use of different patient samples significantly affected osteoclastogenesis, due to so-called inflammatory osteoclastogenesis. Additionally, we show that osteoclasts deposit osteopontin into the resorption lacunae during bone resorption. Based on the results, the inflammatory component present in both osteoarthritis and rheumatoid arthritis significantly affects osteoclast function, and its further study in the future may reveal new therapeutic possibilities. Especially the new discoveries of osteopontin’s role in normal osteoclast function and its changes seen between osteoarthritis and rheumatoid arthritis may prove to have therapeutic potentialTiivistelmä Nivelreuma ja nivelrikko ovat kroonisia nivelsairauksia, jotka Maailman terveysjärjestön (WHO) mukaan aiheuttavat eniten sosioekonomista haittaa. Molemmissa sairauksissa luiden rakenteessa ja luusolujen, erityisesti osteoklastien, toiminnassa tapahtuu muutoksia. Kummankaan taudin etiologiaa tai patogeneesiä ei täysin tunneta. Perinteisesti ajatellaan, että nivelrikko johtuu rusto- ja luukudoksen mekaanisesta kulumisesta ja nivelreuma nivelkalvon autoinflammatoorisesta tulehduksesta. Kuitenkin nivelrikossa nähdään myös selkeä nivelkalvon krooninen tulehdus ja nivelreumassa suuria luun rakenteen muutoksia. Tutkimusala, joka tutkii tulehduksen ja luun yhteyttä, on nimeltään osteoimmunologia. Tässä väitöskirjassa tutkitaan osteoklastien toimintaa ja niihin vaikuttavia tekijöitä, erityisesti proteiini osteopontiinia, normaalissa ja tautiympäristössä. Analysoin osteoklasteihin vaikuttavia tekijöitä nivelrikko- ja nivelreumapotilaiden näytteistä sekä osteoklastien toimintaa soluviljelmissä. Soluviljelmissä käytettiin nivelreuma- ja nivelrikkopotilaiden näytteitä mahdollisimman totuudenmukaisen ympäristön luomiseksi osteoklasteille. Tutkimuksessa osoitettiin, kuinka osteopontiinin fosforylaatio on lisääntynyt nivelreumapotilaiden nivelnesteessä. Myös useiden muiden osteoklasteihin vaikuttavien tekijöiden, kuten IL-6:n, IL-8:n ja VEGF:n, havaittiin lisääntyneen nivelreumassa. Osteoklastien soluviljelmissä havaittiin selkeät erot siinä, miten eri potilasnäytteet vaikuttavat osteoklasteihin ja erityisesti tulehduksen aiheuttamaan osteoklastien syntyyn. Osoitan myös, miten osteoklastit erittävät osteopontiinia luunhajotuskuoppaan luun hajotuksen aikana. Tutkimustulosten mukaan krooninen tulehdustila nivelrikossa ja nivelreumassa vaikuttaa huomattavasti osteoklastien toimintaan. Uskon, että lisätutkimukset tällä saralla voivat paljastaa uusia hoidollisia mahdollisuuksia. Erityisesti uudet löydökset osteopontiinin roolista osteoklastien toiminnassa sekä muutoksista nivelrikossa ja nivelreumassa vaativat jatkotutkimuksia, jotta proteiinin kliininen merkittävyys saadaan selvitettyä
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Teixeira, Lucas Novaes 1981. "Estudo da expressão de osteopontina em sistemas de coculturas de células osteoblásticas e epiteliais neoplásicas humanas e seus efeitos sobre o fenótipo neoplásico e a ativação osteoclástica." [s.n.], 2015. http://repositorio.unicamp.br/jspui/handle/REPOSIP/288466.
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Orientador: Paulo Tambasco de OliveiraTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
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Resumo: O carcinoma espinocelular (CEC) oral representa a neoplasia maligna mais prevalente das estruturas bucais, podendo invadir o tecido ósseo e promover sua reabsorção em até 56% dos casos. A expressão da proteína matricelular osteopontina (OPN) tem sido relacionada a uma maior agressividade de neoplasias malignas, incluindo o CEC oral. No tecido ósseo, a OPN representa a proteína mais abundante da matriz não colágena, concentrada nas interfaces ósseas, i.e. lâminas limitantes, linhas de cimentação e reversas, sendo essencial para adesão e funções de osteoblastos e osteoclastos. Apesar de no microambiente tumoral a OPN estar associada a um fenótipo neoplásico mais agressivo, ainda não está estabelecido o papel da OPN secretada por osteoblastos sobre células neoplásicas derivadas de CEC oral e o impacto sobre osteoclastos. O presente estudo teve como objetivos avaliar a expressão de OPN em sistemas de coculturas de células osteoblásticas e epiteliais neoplásicas malignas humanas e os efeitos da expressão de OPN secretada por osteoblastos sobre o fenótipo neoplásico in vitro. Adicionalmente, avaliou-se o efeito das coculturas sobre a atividade osteoclástica. Células epiteliais neoplásicas malignas derivadas de CEC oral (SCC9) foram plaqueadas sobre membranas de Transwell®, recobertas ou não por uma camada fina e uniforme de Matrigel, e cocultivadas com células osteoblásticas (SAOS-2) durante seu pico de expressão de OPN (10o dia de cultura). Células SCC9 expostas a culturas SAOS-2 silenciadas para OPN por RNA de interferência (RNAi) e células SCC9 cultivadas isoladamente foram usadas como controles. Após 24 h de cocultivo, células SCC9 foram avaliadas, quantitativamente, para adesão, proliferação, migração e invasão de Matrigel. A atividade de osteoclastos derivados de células monocíticas U-937 foi avaliada, quantitativamente, por meio dos ensaios de reabsorção de fosfato cálcio e de dosagem de citocinas em eluentes obtidos de células SCC9 e SAOS-2 após o cocultivo durante o pico de OPN ou com o seu silenciamento. A análise estatística foi realizada pelo teste não-paramétrico de Kruskal-Wallis (p < 0,05). Os resultados indicaram indução recíproca na expressão de OPN em SAOS-2 e SCC9 em cocultura. A OPN secretada por células SAOS-2 afetou o fenótipo de culturas SCC9, promovendo a adesão e a proliferação celulares e a invasão de Matrigel, a qual também estava aumentada, mas em menor intensidade, com o silenciamento para OPN. A migração celular não foi afetada. O cocultivo com SAOS-2, principalmente durante o pico de OPN, resultou na sobre-expressão das citocinas IL 6 e IL 8 pelas células SCC9, aumentando a capacidade de células osteoclásticas em reabsorver fosfato de cálcio. Conjuntamente, esses resultados sugerem que a OPN derivada de osteoblastos afeta as interações entre células epiteliais neoplásicas malignas, osteoblastos e osteoclastos, possivelmente contribuindo para a progressão de lesões ósseas do CEC oral
Abstract: The oral squamous cell carcinoma (OSCC) is the most prevalent malignant neoplasm of the oral structures. It may invade bone in up to 56% of the cases and promote osteoclast-mediated bone extracellular matrix (ECM) resorption. Expression of the matricellular protein osteopontin (OPN) in malignant neoplasms, including OSCC, has been positively correlated with aggressive tumor behavior. OPN is the most abundant non collagenous ECM protein in bone, where it preferentially accumulates at interfaces, including cement lines, laminae limitantes and reversal lines, being essential for the adhesion and function of osteoblasts and osteoclasts. Despite the importance attributed to OPN in the tumor microenvironment, indicative of more aggressive neoplastic phenotypes, the effects of osteoblast-derived OPN on OSCC cells and on OSCC-induced osteoclast activity are still not fully understood. The present in vitro study aimed to evaluate temporal expression of OPN in cocultures of human osteoblastic cells and malignant neoplastic epithelial cells and the effects of osteoblast-derived OPN on the neoplastic cell phenotype. Additionally, the effects of cocultures on osteoclastic activity were evaluated. Human OSCC-derived epithelial cells (SCC9 cell line) were plated on Transwell® membranes coated or not by a thin uniform layer of Matrigel and cocultured with human osteoblastic cells (SAOS-2 cell line) during its peak of OPN expression (day 10 of SAOS-2 culture). SCC9 cells exposed to OPN-silenced SAOS-2 cultures by means of interference RNA and SCC9 cells cultured alone were used as controls. At 24 h of coculture, SCC9 cells were quantitatively evaluated for cell adhesion, proliferation, migration and invasion of Matrigel. The impact of coculturing SCC9 and SAOS-2 cells either during the OPN peak expression or under the silencing of OPN was quantitatively evaluated in terms of calcium phosphate resorption by U-937-derived osteoclastic cells and expression of cytokines in the culture medium by ELISA assay. The statistical analyses were carried out using the non-parametric Kruskal-Wallis test (p < 0.05). The results showed a reciprocal induction of SAOS-2 and SCC9 cells in terms of OPN expression over the coculture interval. SAOS-2-secreted OPN altered the SCC9 cell phenotype, leading to enhanced cell adhesion and proliferation and higher Matrigel invasion, which was also enhanced, but to a lesser degree, by SAOS-2 cultures silenced for OPN. Cell migration was not affected. Cocultures with SAOS-2, mainly during the peak expression of OPN, resulted in overexpression of IL 6 and IL 8 by SCC9 cells, which corresponded with an enhanced resorptive capacity of osteoclastic cells. Taken together, the results suggest that osteoblast-derived OPN affects the interactions among malignant neoplastic epithelial cells, osteoblasts and osteoclasts, likely contributing to the progression of bone lesions in OSCC
Doutorado
Patologia
Doutor em Estomatopatologia
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Marques, Erika Afonso Costa Cortez. "Estudo da expressão e participação de osteopontina durante a interação taquizoíto de Toxoplasma gondii célula hospedeira." Universidade do Estado do Rio de Janeiro, 2007. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=2266.
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Toxoplasma gondii é um parasito do filo Apicomplexa que infecta uma grande variedade de hospedeiros, incluindo os humanos. O parasito invade a célula hospedeira por penetração ativa, com a participação das proteínas de suas organelas secretoras durante esse processo. Até o momento, somente um número limitado de proteínas secretoras tem sido descoberto, além disso, as moléculas efetoras envolvidas na invasão e sobrevivência do parasito não estão completamente compreendidas. A osteopontina (OPN) é uma glicofosfoproteína adesiva secretada, multifuncional, que contém o domínio arginina-glicina-ácido aspártico (RGD) de ligação à integrina, que está envolvida em uma variedade de eventos fisiológicos e patológicos, incluindo sinalização e sobrevivência celular. Pela primeira vez, nós demonstramos pelas técnicas de imunofluorescência e imunocitoquímica ultraestrutural que há uma intensa marcação para uma proteína OPN-like nos grânulos densos de taquizoítos de T. gondii extracelulares. O western blotting e o RT-PRC confirmaram a expressão de OPN-like nos taquizoítos. Nossos resultados também mostram que após a invasão dos macrófagos, a proteína OPN-like está localizada na membrana do vacúolo parasitóforo. Esses dados sugerem que os grânulos densos secretam uma proteína OPN-like, e nós podemos especular que essa proteína participa durante o processo de interação do parasito com as células hospedeiras.
.Toxoplasma gondii is an apicomplexan parasite infecting a broad host range, including humans. The parasite invades host cell by active penetration with the participation of its secretory organelles proteins during this process. Until now, only a limited number of secretory proteins have been discovered, and the effectors molecules involved in parasite invasion and survival are not well understood. Osteopontin (OPN) is a multifunctional secreted adhesive glycophosphoprotein containing the arginine-glycine-aspartic acid (RGD) integrin-binding domain, which is involved in various physiological and pathological events including cell signaling and survival. For the first time we demonstrated by immunofluorescence and immunoelectron microscopy approaches that there is an intense labeling for an OPN-like protein in the dense granules of extracellular T. gondii tachyzoites. Western blotting and RTPCR confirmed this protein expression in tachyzoites. Our results also showed that after macrophage invasion the OPN-like protein is localized at the parasitophorous vacuole membrane. These data suggest that dense granules secrete an OPN-like protein, and we can speculate that this protein participates during the parasite interaction process with host cells.
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Rothbarth, Claudia Pires. "Efeito do alendronato de sódio em molares de rato em formação após luxação lateral." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/23/23140/tde-19122013-153054/.
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Os bisfosfonatos são drogas capazes de inibir a reabsorção óssea por meio de seu efeito direto sobre as células ósseas, interferindo na dinâmica dos tecidos mineralizados. O alendronato (ALN), um tipo de bisfosfonato nitrogenado, foi utilizado com o objetivo de investigar os seus efeitos sobre os tecidos dentários e periodontais após luxação lateral de molares com as raízes em desenvolvimento. Ratos Wistar com 21 dias de idade tiveram os segundos molares superiores luxados lateralmente. Doses diárias de 2,5 mg / kg de ALN começaram no dia seguinte à luxação; os controles receberam solução salina estéril. As maxilas foram fixadas, descalcificadas e incluídas em parafina ou em resina Spurr 7, 14 e 21 dias pós-luxação. Os cortes foram corados com H & E, incubados por histoquímica TRAP e imuno marcados para osteopontina (OPN), bem como para análise ultraestrutural. Após 21 dias, o ápice dos molares luxados sem ALN estava aberto e desorganizado, coberto por uma camada irregular de cemento celular. Os molares luxados dos animais tratados com ALN apresentaram alguns locais de anquilose, bem como lacunas de reabsorção na superfície do cemento. Os osteoclastos TRAP positivos foram mais numerosos no grupo ALN, apesar de sua aparência latente e sua localização, afastados das trabéculas ósseas, em relação aos controles, achado que foi confirmado com a análise ultraestrutural. A imunomarcação de OPN revelou uma linha grossa imunopositiva na dentina, que deve ter surgido a partir do momento da luxação, enquanto que as amostras tratadas com ALN não apresentaram alterações na dentina. Os resultados indicam que o alendronato inibe algumas alterações na dentina e na formação do cemento, induzidas pelo trauma dental de luxação.Bisphosphonates are drugs that inhibit bone resorption through its direct effect on bone cells, interfering with the dynamics of mineralized tissues. Alendronate (ALN), a nitrogenated bisphosphonate, was used in order to investigate their effects on dental and periodontal tissues after lateral dislocation of molars with developing roots. Twenty one days old Wistar rats had their second molars laterally l. Daily doses of 2.5 mg / kg ALN started the day following the dislocation, while controls received saline solution. The maxillae were fixed, decalcified and embedded in paraffin or in Spurr resin after 7, 14 and 21 days post-dislocation. The sections were stained with H & E, incubated for TRAP, immunolabeled for osteopontin (OPN), and ultrastructurally analyzed by transmission electron microscopy. After 21 days, the apex of the luxated molar without ALN was open and disorganized, covered by an irregular layer of cellular cementum. The luxated molar from ALN-treated animals showed some areas of ankylosis and resorption lacunae on the cementum surface. TRAP-positive osteoclasts were more numerous in the ALN group, despite their latent appearance compared to controls, a finding that was ultrastructurally confirmed. OPN immunostaining revealed a thick immunopositive line in dentin, which must be resultant from the moment of dislocation, while the samples treated with ALN showed no changes in dentin. The results indicate that alendronate inhibits some changes in dentin and cementum formation induced by dental trauma of lateral luxation.
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Smith, Laura Lee. "Osteopontin structure and function /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/6322.
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Barbosa, Ana Claudia da Silva. "Estudo das proteínas ósseas não colágenas no processo de reparação óssea alveolar em ratos idosos." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/10/10132/tde-21112013-103224/.
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O trabalho teve como objetivo avaliar e quantificar o tecido ósseo neoformado, a distribuição e a importância das proteínas não colágenas (osteocalcina, osteopontina e osteonectina) no processo de reparação tecidual do alvéolo dental de ratos Wistar idosos após exodontia. Para sua realização, foram utilizados 80 Rattus Norvegicus albinus, linhagem Wistar, machos. Os animais foram distribuídos em dois grupos: Grupo Controle, correspondente a animais com 60 dias de vida; e Grupo Experimental correspondente aos animais com 2 anos de vida (700 dias em média). Cada grupo foi dividido em 4 subgrupos de 10 animais em cada grupo. Os animais foram submetidos à exodontia do incisivo superior direito e foram sacrificados com 05, 15, 21 e 28 dias de pós-operatório. Após a dissecção, 5 amostras foram submetidas à análise por microscopia convencional com coloração por Hematoxilina e Eosina e análise da imunohistoquímica e 5 amostras para análise por RT-PCR. Os resultados mostraram que o processo de envelhecimento não alterou a cronologia do reparo ósseo alveolar e não promoveu maior remodelação do alvéolo dental. A osteocalcina não apresentou atuação importante nos períodos pós-operatórios estudados. A osteonectina apresentou-se importante no processo de reparo, não sofrendo alterações no início da reparação óssea, apresentando marcação mais intensa durante a maturação óssea entre 21 e 28 dias de pós-operatório no grupo controle e diminuição da marcação no grupo experimental aos 28 dias de pósoperatório. O envelhecimento proporcionou uma diminuição da imunomarcação da osteonectina e demonstrou marcações positivas principalmente em osteoblastos e matriz mineralizada. A osteopontina apresentou-se importante no processo de reparo ósseo durante todos os períodos pós-operatório, apresentando marcações em osteoblastos, matriz osteóide, osteócitos e matriz mineralizada, apresentando maior marcação dos tipos celulares do no grupo experimental aos 28 de pós-operatório. Apesar desses achados, novos estudos são necessários para o melhor entendimento do processo de reparo ósseo alveolar em ratos adultos e idosos.The aim of the present study was to evaluate and quantify the newly formed bone tissue, as well as the distribution and the importance of non-collagen proteins (osteocalcin, osteopontin and osteonectin) in the process of dental alveolar repair in Wistar aged rats submitted to tooth extraction. To perform that, about 80 male Rattus Norvegicus albinus, Wistar strain, were randomly distributed into two groups: Control Group corresponding to 60 days old rats; and Experimental Group corresponding to 2 years old animals (about 700 days old). Both groups were later subdivided into 4 subgroups consisting of 10 animals each. All animals were submitted to the upright incisive tooth extraction and were euthanized 05, 15, 21 and 28 days after the tooth extraction surgery. After the dissection, five samples from each subgroup underwent conventional microscopy analysis by hematoxylin-eosin stain as well as immunohistochemistry. Bone tissue from other five samples of each groups were subjected to Real Time RT-PCR analysis of non-collagen proteins expression The results obtained suggest that aging process was not able to change either the chronology of alveolar bone repair or the remodeling of dental alveolus. Osteocalcin did not present any important action in the post-operation periods evaluated. On the other hand, osteonectin showed an important role during the repair process, since its expression was increased in the control group and decreased in comparison to the experimental group at 28 days. Osteopontin was important in the bone repair in all times evaluated, since it was present in osteoblasts, osteiod matrix, osteocytes and mineralized matrix, being even more stained at 21 days after the surgery. Finally, besides the results obtained in the present work, other studies are necessary to better understand the alveolar bone repair in adult and aged rats.
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Leitão, Glauber Moreira. "Osteopontina como marcador de resposta à radioterapia e quimioterapia em pacientes com câncer de cabeça e pescoço localmente avançado." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/5/5155/tde-12012009-162533/.
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INTRODUÇÃO: Osteopontina (OPN) é uma glicoproteína presente em tecidos e fluidos orgânicos e envolvida em vários processos patológicos que incluem inflamação, proliferação celular, invasão da matriz extracelular, progressão tumoral e metástase. Em pacientes (pts) portadores de carcinoma epidermóide de cabeça e pescoço (CECCP), OPN tem sido associada a uma maior agressividade tumoral e empregada como marcador prognóstico. Nós investigamos o valor prognóstico e preditivo da OPN sérica em pacientes portadores de CECCP tratados de forma uniforme. MÉTODOS: Estudo longitudinal prospectivo de 47 pts portadores de CECCP localmente avançado e irressecável submetidos à quimioterapia e radioterapia. OPN sérica foi determinada pelo método ELISA (kit 1 com17 pts e kit 2 com 30 pts) com coleta realizada antes e após o término do tratamento e estudada a relação entre OPN, categorizada como alta ou baixa em relação ao valor mediano, e as características clínico-patológicas, resposta ao tratamento, sobrevida global (SG) e sobrevida livre de progressão (SLP). RESULTADOS: A OPN sérica mediana dos pacientes determinada pelo kit 1 (em ng/ml) foi de 2,1 e 1,9 pré e pós-tratamento, respectivamente; no kit 2 (em ng/ml) foi de 69,5 e 87,9 pré e pós-tratamento, respectivamente. Pacientes portadores de tumores de orofaringe foram mais freqüentemente associados a baixos níveis séricos de OPN pós-tratamento, em comparação com outros sub-sítios (p=0,03). Observada tendência à associação entre os valores séricos baixos de osteopontina pós-tratamento e a resposta tratamento (p=0,06). Houve associação entre os valores elevados da osteopontina pós-tratamento e menor SLP (p=0,09, log rank), com medianas de 11,9 meses e 14,5 meses, conforme valores séricos de OPN pós-tratamento altos e baixos, respectivamente. Não houve associação dos valores séricos de OPN pré e pós-tratamento e a SG (p=0,19 e p= 0,10, respectivamente). CONCLUSÃO: Neste grupo de pacientes portadores de CECCP, sugere-se que OPN sérica baixa após a quimioradioterapia associa-se à resposta ao tratamento e melhor SLP.INTRODUCTION: Osteopontin (OPN) is a glycoprotein present in tissues and body fluids involved in several pathological processes that include inflammation, cell proliferation, invasion of the extracellular matrix, tumor progression and metastasis. In head and neck squamous cell carcinoma (HNSCC) patients, OPN has been associated with greater tumor aggressiveness and used as a prognostic marker. We investigated the prognostic and predictive value of plasma OPN in homogeneously treated (HNSCC) patients. METHODS: Longitudinal prospective study of 47 patients with locally advanced and inoperable HNSCC treated with exclusive platin based concomitant chemoradiotherapy. Plasma OPN was determined by ELISA (n=14 kit I, n=32 kit II) pre and postreatment and correlated with tumor response, overall survival (OS) and progression-free survival (PFS). RESULTS: Median OPN levels in ng/ml were 2,1 and 1,9 pre and postreatment, respectively, by kit I and 69,5 and 87,9 by kit II. Patients were categorized as OPN low or high, using the median as a cut-off point. Patients with oropharynx tumors, as compared to other subsites, were more frequently categorized as low OPN (p = 0,03). A low postreatment OPN level was associated with tumor response (p = 0,06) and a high postreatment OPN level was associated with poor PFS, 11.9 vs. 14.5 months (p=0.09, log rank). Mean OS was 16.2 and 13.7 months in low and high postreatment OPN pts, respectively (p=0.10, log rank). CONCLUSIONS: In this group of HNSCC patients, it is suggested that a low plasma OPN after chemoradiotherapy is associated with a lower response rate and a worse PFS.
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Pereira, Thiago de Almeida. "Participação da via do Hedgehog na fibrose hepática da esquistossomose mansoni humana e murina experimental." reponame:Repositório Institucional da FIOCRUZ, 2015. https://www.arca.fiocruz.br/handle/icict/14002.
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Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil
INTRODUÇÃO/OBJETIVO: A esquistossomose mansonica é causa importante de fibrose hepática e hipertensão porta em regiões tropicais, e a patogênese da fibrose não está bem esclarecida. Como a via do hedgehog e um dos seus genes alvos, a osteopontina, estão envolvidos em fibroses hepáticas de outras etiologias o objetivo foi investigar a ativação destas vias na esquIsitossomose humana e murina experimental, no intuito de verificar o seu envolvimento no desenvolvimento da forma hepatoesplênica da esquistossomose mansonica (FHE). MATERIAL E MÉTODOS: 87 biópsias em cunha de fígados de pacientes com FHE submetidos a cirurgia e fragmentos de fígado de camundongos suiços infectados com Schistosoma mansoni foram submetidos a métodos imunohistoquímicos e de biologia molecular para avaliar a expressão de ligantes hedgehog (Ihh, Shh), receptor Patched, fatores de transcrição Gli 1 e 2 e osteopontina. Osteopontina sérica e ligante Shh do hedgehog foram avaliados em camundongos suíços infectados e os de osteopontina em camundongos CBA/J infectados e em pacientes com FHE e forma hepatointestinal da esquistossomose. In vitro foi avaliado o efeito de antígeno solúvel do ovo (SEA) em células de Kuppfer, células estreladas, macrófagos, colangiócitos e células endoteliais sinusoidais hepáticas. A relação com a via da IL-13 foi avaliada em camundongos geneticamente deficientes ou hiperexpressando a citocina. Foi avaliado in vitro se a IL-13 induz ligantes hedghog ou ativação da via em células de Kuppfer. RESULTADOS: Os resultados mostraram: (a) aumento expressão de ligantes Ihh, de fatores de transcrição Gli2 e de osteopontina no fígado de camundongos suíços infectados com Schistosoma mansoni, aumento de shh e osteopontina no plasma de camundongos suíços e de osteopontina no plasma de camundongos CBA/J infectados com S. mansoni; (b) aumento na expressão de Ihh, Shh, Gli1 e 2, receptor Patched e de osteopontina no fígado de pacientes com esquistossomose e aumento da osteopontina sérica em pacientes com a FHE; (c) A expressão de ligantes hedgehog e de Gli2 foi observada em macrófagos, células estreladas, ductos biliares e células endoteliais, e a de osteoponina em ductos biliares, macrófagos e células estreladas/miofibroblastos; (d) correlação positiva entre ativação do hedgehog (Gli2 e osteopontina) e fibrose, no modelo murino experimental e nos pacientes; nestes a correlação também foi observada com o grau de fibrose classificada pelo ultrassom e com a hipertensão porta; (e) Inibição in vitro do hedgehog com ciclopamina e vismodegib ou por nocauteamento condicional de receptor Smoothened bloqueou a ativação alternativa de macrófagos e inibiu a angiogênese a partir de células endoteliais sinusoidais hepáticas; (f) que o bloqueio da via da IL-13 reduziu e a hiperexpressão aumentou a ativação da via do hedgehog e IL-13 diretamente induziu, in vitro, produção de ihh em células de Kupffer de camundongos e de humanos, demonstrando a inter-relação das duas vias. CONCLUSÃO: Pode-se concluir que a via do hedgehog tem participação importante na patogênese da fibrose hepática esquistossomótica, atuando através de estímulos à fibrogênese e à angiogênese e que a osteopontina é candidata a ser um biomarcador de intensidade da fibrose e da hipertensão porta na doença.
BACKGROUND AND AIMS: Schistosomiasis is a major cause of liver fibrosis and portal hypertension in tropical regions, and the pathogenesis of fibrosis is not well established. As hedgehog pathway and one of its target genes, osteopontin, are involved in liver fibrosis of other etiologies our aims were to investigate the activation of these pathways in human and experimental murine schistosomiasis, in an attempt to verify their involvement in the development of hepatosplenic schistosomiasis mansoni (HS). METHODS: 87 wedge liver biopsies of patients with HS submitted to surgery and liver fragments Swiss mice infected with Schistosoma mansoni were submitted to immunohistochemistry and molecular biology methods to evaluate the expression of hedgehog ligands (Ihh, Shh), patched receptor , Gli transcription factors and osteopontin. Serum osteopontin and Shh were evaluated in infected Swiss mice and osteopontin was evaluated in serum of infected CBA/J mice and plasma from patients with hepatointestinal and HS forms of schistosomiasis. The effect of soluble egg antigen (SEA) on Kuppfer cells, stellate cells, macrophages, cholangiocytes and liver sinusoidal endothelial cells was evaluated in vitro. Relationship with IL-13 pathway was evaluated in mice genetically deficient or with hyperexpression of this cytokine. Whether IL-13 induces production of ligands and/or activation of the hedgehog pathway in Kuppfer cells was evaluated in vitro. RESULTS: Results demonstrated: (a) increased expression of Ihh, transcription factor Gli2 and osteopontin in the livers of Swiss mice infected with S. mansoni, increased plasma levels of shh and osteopontin in infected Swiss mice and increased osteopontin in plasma of S. mansoni infected CBA/J mice; (b) increased expression of ihh, shh, Gli1 and 2, patched and osteopontin receptor in the liver of patients with schistosomiasis and increased serum osteopontin in patients with HS; (c) expression of hedgehog ligands and Gli2 was observed in macrophages, stellate cells, endothelial cells and bile duct and expression of osteopontin was detected in macrophages and stellate/myofibroblast cells; (d) positive correlation between activation of the hedgehog (Gli2 and osteopontin) and fibrosis in experimental murine model and in patients; these correlation was also observed with the degree of fibrosis classified by ultrasound and with portal hypertension; (e) in vitro inhibition of hedgehog pathway with cyclopamine or vismogedib or by conditional knockout of Smoothened co-receptor blocked the alternative activation of macrophage and inhibited angiogenesis in liver sinusoidal endothelial cells; (f) reduction of IL-13 pathway or IL-13 over-expression respectively reduced or increased the activation of the hedgehog pathway and IL-13 directly induced in vitro ihh production in Kupffer cells from mice and human, demonstrating a cross-talk between the two pathways. CONCLUSION: In conclusion the hedgehog pathway plays an important role in the pathogenesis of liver fibrosis in schistosomiasis mansoni, acting through stimulation of angiogenesis and fibrogenesis and osteopontin is a putative candidate to be a biomarker of intensity of fibrosis and portal hypertension in the disease.
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Myers, Daniel. "The Role of Osteopontin in Vascular Remodeling." Fogler Library, University of Maine, 2004. http://www.library.umaine.edu/theses/pdf/MyersDL2004.pdf.
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Garrido, Eduardo [UNESP]. "Determinação dos valores plasmáticos de osteopontina em cães com tumores mamários metastáticos ou não: correlações clínicas e anatomopatológicas." Universidade Estadual Paulista (UNESP), 2011. http://hdl.handle.net/11449/95960.
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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
A osteopontina (OPN) é uma proteína produzida por diversas células e tem grande implicação com o desenvolvimento de tumores mamários e na disseminação de metástases em humanos. Em cães há poucos estudos envolvendo neoplasias e OPN. Neste trabalho objetiva-se determinar as concentrações de OPN sérica em cães sem a presença de tumores mamários (GC) ou com presença de carcinoma mamário ou carcinoma em tumor misto, com e sem metástase macro ou microscopicamente evidente. Utilizou-se o Ensaio Imunoenzimático Enzyme Linked Immunosorbent Assay (ELISA), a partir do plasma colhido antes e após a ressecção cirúrgica do tumor, em animais com neoplasia, e apenas em um momento (basal) nos animais sadios. As informações do ensaio, assim como os dados histopatológicos, hematológico e de bioquímica sérica foram confrontadas e analisadas por análise de variância e teste de Tukey. Os cães do GC obtiveram média de OPN de 2499 ± 1159 ng/d, com amplitude de referência entre 4770 e 227 ng/dL. Os cães com presença de tumor, quando em um único grande grupo, obtiveram uma diminuição significativa nos níveis plasmáticos de OPN, quando avaliado a densidade óptica. Quando o grupo se subdivide, em função do tipo histológico e/ ou presença de metástases, os resultados não evidenciam diferenças significativas nos níveis plasmáticos de OPN entre os animais sadios e os animais com neoplasias metastáticas ou não. A análise de correlação também não apresentou nenhum resultado significativo com os dados hematológicos ou de bioquímica sérica. Nas condições de realização deste ensaio, infere-se que, ao contrário...
The osteopontin (OPN) is a protein produced by several cells and has extensive involvement with the development of mammary tumors and its spread through metastases in humans. In dogs there are no studies involving cancer and OPN. This study aimed to determine serum concentrations of OPN in dogs without the presence of mammary tumors (GC) and presence of carcinoma in breast or carcinoma in mixed tumor with or without metastasis macro or microscopically evident. We used immunoenzymatic assay Enzyme Linked Immunosorbent Assay (ELISA) from plasma collected before and after surgical resection of the tumor, in animals with cancer, and only at a time (baseline) in healthy animals. The information of the test, and histopathological data, hematology and serum biochemistry were compared and analyzed by ANOVA and Tukey test. Dogs GC got an average of OPN in 2499 ± 1159 ng / d, with reference range between 227 and 4770 ng / dL. Dogs with the presence of tumor, when one large group, had a significant decrease in plasma levels of OPN, when determined by optical density. When the group is subdivided, according to the histological type and / or metastasis, the results showed no significant differences in serum levels of OPN between healthy animals and animals with metastases or not. The correlation analysis did not show any significant result with hematological or serum 4 biochemistry. We conclude that, contrarily to what is observed in humans, OPN does not appear important in the diagnosis or prognosis of breast neoplasm in dogs
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Aristizábal, Viviana Helena Vallejo. "Efeitos da osteopontina no sêmen sexado bovino." Botucatu, 2018. http://hdl.handle.net/11449/155876.
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Orientador: José Antônio Dell'aqua JuniorResumo: Tem sido relatado que altas concentrações de osteopontina (OPN) no plasma seminal de diversar espécies esta correlacionada com animais de alta fertilidade, identificando-a como bio marcador reprodutivo. De igual maneira estudos mostram uma maior taxa de fertilização in vitro quando é implementada nos meios para fertilização. Visto que a OPN pode ter funções antagônicas, o presente estudo visou identificar se suas funções são dose dependente, adicionando 4 diferentes concentrações de OPN sobre o sêmen sexado bovino por 30 minutos e avaliar por (i) citometria de fluxo a viabilidade, integridade de membrana e capacitação espermática; (ii) teste de ligação a células epiteliais da tuba uterina bovina (BOECs), para quantificar o numero de espermatozoides ligados às células epiteliais, formando o que seria in vivo o reservatório espermático e (iii) avaliar a produção de embriões in vitro. Na avaliação por citometria não foi observada uma interação da adição de OPN com os espermatozoides sexados e não sexados, diferente dos outros dois testes onde se evidenciou que independente da dose a OPN diminuiu a ligação dos espermatozoides às BOECs e a concentração de 0.5g/1x106 espermatozoides aumento a taxa de clivagem e formação de blastocistos. Isto ratifica o poder capacitante da OPN de 60KDa sobre os espermatozoides e confirma que esta, pode ter associações diretas com ambos gametos, gerando melhores taxas de fertilização in vitro e, por tanto, melhor desenvolvimento embrionário nos bovi... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: It has been reported that high concentrations of osteopontin (OPN) in the seminal plasma of diverse species is correlated with high fertility animals, identifying it as a bio-reproductive marker. Likewise studies show a higher rate of in vitro fertilization when it´s implemented in fertilization media. Since OPN may have antagonistic functions, the present study aimed to identify if its functions are dose-dependent, adding four different concentrations of OPN on the sex-sorted and non-sorted bovine sperm for 30 minutes. The samples were evaluated by means of (i) flow cytometry the viability, membrane integrity and sperm capacitation; (ii) sperm-binding assay to BOECs, to quantify the number of sperm attached to the epithelial cells, forming what would be in vivo the spermatic reservoir and (iii) to evaluate the in vitro embryo production. In flow cytometry an interaction of the addition of OPN with the sex-sorted and non-sorted sperm was not observed, different from the other two tests where it was evidenced that regardless of the dose, the OPN decreased the sperm binding to the BOECs and the concentration of 0.5 µg /1 x 106 spermatozoa increased the rate of cleavage and formation of blastocysts. This corroborates the capacitive power of the OPN of 60KDa on the spermatozoa, and confirm that it can have direct associations with both gametes, generating better rates of in vitro fertilization and, therefore, better embryonic development in cattle. However, from the results obtai... (Complete abstract click electronic access below)
Doutor
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Moye, Victoria Ellen. "Mode of action of metastasis-inducing-DNAs in the upregulation of OPN expression." Thesis, University of Liverpool, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250383.
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Paula, Fernanda Oliveira de. "Avaliação da imunoexpressão de vimentina e de osteopontina no reparo ósseo precoce de defeitos preenchidos com enxerto bovino associado à terapia laser de baixa intensidade." Universidade Federal de Juiz de Fora (UFJF), 2010. https://repositorio.ufjf.br/jspui/handle/ufjf/2638.
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O objetivo deste estudo foi avaliar, pelo método de imunoistoquímica, a expressão de vimentina e osteopontina durante as fases iniciais de reparo de defeitos ósseos criados em fêmures de ratos Wistar albinus tratados com enxerto ósseo bovino orgânico Gen-ox® em associação com terapia laser de baixa intensidade. Foram selecionadas de forma aleatória 24 amostras emblocadas de arquivo provenientes de trabalho experimental desenvolvido anteriormente, no qual foram efetuadas análises histológicas e histomorfométricas de fêmures de cinquenta ratos. Obtiveram-se lâminas histológicas dos blocos de diferentes animais, os quais estavam previamente divididos, de acordo com o tratamento realizado, da seguinte forma: grupo I (controle), grupo II (Gen-Ox®) e grupo III (LLLT e Gen-Ox®). Foram elaboradas quatro lâminas para cada um dos tempos experimentais de 3, 5, 7 e 15 dias para cada grupo. Duas lâminas foram utilizadas para analisar a expressão da osteopontina e duas para vimentina, totalizando 48 lâminas. Em cada lâmina considerou-se dois campos para análise, sendo um campo na região da interface osso-defeito e o outro próximo ao periósteo, em um total de 96 campos. Para realização da reação imunoistoquímica anti-vimentina e anti-osteopontina utilizou-se o método clássico do complexo avidina-biotina peroxidase anti-peroxidase. A marcação positiva foi determinada pela identificação de coloração castanha intracitoplasmática nas reações com ambos os anticorpos. Os cortes foram analisados em microscópio Zeiss em aumentos de 200x, 400x e 1000x, em toda extensão, por dois diferentes observadores. Determinou-se, por método de contagem semiquantitativo, a média de intensidade de células positivas marcadas nos campos dos tratamentos propostos em cada período, o qual foi classificado pelo sistema de escore de acordo com os seguintes parâmetros: 0 = ausência de marcação; + = marcação leve (até 1/3 de células positivas); ++ = marcação moderada (até 2/3 de células positivas); e +++ = marcação intensa (acima de 2/3 de células marcadas). Os resultados mostraram que todos os grupos apresentaram marcação para vimentina e para osteopontina em todos os períodos do experimento. Observou-se marcação celular mais acentuada para vimentina no período cicatricial inicial no grupo III. Não foram verificadas diferenças na marcação para osteopontina nos animais submetidos à terapia laser de baixa intensidade associada ao enxerto quando comparado aos outros grupos.
The aim of this study was to evaluate, by immunohistochemistry, the expression of vimentin and osteopontin during the early stages of repair of bone defects created in femurs of Wistar albinus rats treated with organic bovine bone graft Gen-ox® and associated with low level laser therapy. Twenty four embedded samples were randomly selected from the file of a previous experimental work, in which histological analysis and histomorphometry of the femurs of fifty rats was performed. Histological slides were obtained from blocks of different animals which were divided in accordance to previous treatment as follow: group I (control), group II (Gen-Ox ® ) and group III (LLLT and Gen-Ox ®). Four slides were prepared for each of the experimental time of 3, 5, 7 and 15 days for each group. Of the four slides, two were assessed for the expression of osteopontin and two of vimentin, in a total of 48 slides. On each slide two fields were considered for analysis: one in the bone-defect interface and the other near the periosteum, in a total of 96 fields. To perform the immunohistochemistry anti-vimentin and anti-osteopontin, we used the classical avidin-biotin peroxidase anti-peroxidase method. The positive staining was determined by identification of intracytoplasmic brown color in the reactions with both antibodies. The sections were analyzed in Zeiss microscope at a magnification of 200x, 400x and 1000x by two different observers. The average intensity of positive cells stained in the fields in each period was determined by a semiquantitative counting method which was classified by a scoring system as follow: 0 = no marking; + = mild labeling (up to one third of positive cells); + + = moderate labeling (up to two thirds of positive cells) and + + + = intense labeling (over two thirds of labeled cells). The results showed that all groups had marked for vimentin and osteopontin in all periods of the experiment. We observed a stronger cell labeling for vimentin in the initial healing period in group III. There were no differences in cell labeling for osteopontin in animals subjected to low level laser therapy associated with graft as compared to other groups.
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Kitagori, Koji. "Cleaved Form of Osteopontin in Urine as a Clinical Marker of Lupus Nephritis." 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225495.
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Wahl, Vincent. "Wirkung von Osteopontin auf die osmotische Volumenregulation von Müller- und Bipolarzellen der Rattennetzhaut." Doctoral thesis, Universitätsbibliothek Leipzig, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-198550.
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Die Arbeit befasst sich mit dem Anschwellen von Neuronen und Gliazellen der Netzhaut, was einen wichtigen pathogenetischen Faktor des Netzhautödems darstellt.
Osteopontin ist ein neuroprotektiver Faktor, der durch GDNF-Stimulation (glial cell line-derived neurotrophic factor) aus Müllerzellen ausgeschüttet wird. Die durch Osteopontin vermittelte Inhibition der osmotischen Zellschwellung von Müllerzellen der Ratte in Anwesenheit von Bariumionen oder H2O2 wird beschrieben und es wird dargestellt, dass Osteopontin keinen Einfluss auf die osmotische Zellschwellung der Bipolarzellen hat. Der für Müllerzellen beschriebene Effekt war dosisabhängig mit einer mittleren effektiven Konzentration von ca. 0,6 ng/ml.
Durch den Einsatz pharmakologischer Rezeptor- oder Enzymblocker bzw. Antikörper werden die Schritte der Osteopontinwirkung identifiziert. Osteopontin induziert die Freisetzung von VEGF, Glutamat, ATP und Adenosin aus Müllerzellen. Die Osteopontinwirkung wurde verhindert durch die Blockade von spannungsabhängigen Natriumkanälen, T-Typ Calciumkanälen, Kalium- und Chloridkanälen. Der Effekt ist außerdem abhängig von einem intrazellulären Calciumsignal, der Aktivierung der Phospholipase C und der Proteinkinase C und der vesikulären Exozytose von Glutamat.
Die Arbeit kommt zu dem Schluss, dass der neuroprotektive Effekt von Osteopontin teilweise durch das Verhindern eines Anschwellens der Müllerzellen und durch die Induktion einer Freisetzung von VEGF und Adenosin vermittelt wird.
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Altalhi, Wafa. "Biological Effects of Osteopontin on Endothelial Progenitor Cells." Thèse, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/20280.
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Endothelial Progenitor Cells (EPCs) are thought to participate in the healing of injured vascular endothelium by incorporating into the defect sites to mediate endothelial recovery. Recently, osteopontin (OPN) was shown to be fundamental in accelerating estrogen-dependent healing of injured blood vessels. Here, we are investigating the effect OPN has on EPC behavior. Late outgrowth human EPCs (LEPCs) were derived from circulating monocytes isolated by leukophoresis, and grown in culture until passage six. L-EPCs were then assayed for adhesion, spreading, chemotaxis, and haptotaxis, as well as resistance to detachment by flow electric cellsubstrate
impedance sensing (ECIS). The results of standard and ECIS methods showed both dose and time dependent responses in cell adhesion and spreading. In addition, OPN promoted haptotactic migration of EPCs in Boyden chamber assays. LEPCs seeded onto 10μM OPN substrates and exposed to laminar flow had grater survival and higher resistance to detachment than OPN/static and flow only conditions. CD44 and !1 integrins were only responsible for approximately 50% of LEPCs
adhesion to OPN compared to the unblocked condition. Western blots showed that Rho GTPases were activated in L-EPCs seeded on OPN. However, this activation could not be completely blocked by either CD44 or !1 integrin antagonists. These data confirm the direct effects of OPN on EPCs adhesion, and suggest that OPN works by mediating cell adhesion during vascular injury.
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Mansouri, Ahmad. "Computational modeling of osteopontin peptide binding to hydroxyapatite." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=104546.
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Osteopontin (OPN), a secreted, noncollagenous, acidic, and mineral-binding phosphoprotein, is composed of 314 amino acids (in humans), mostly composed of glutamate, aspartate and serine. It is prominently associated with biominerals and has a regulatory effect on hydroxyapatite (HAP) crystal growth, the mineral phase of bones and teeth. Recent studies have revealed that OPN contains an acidic, serine- and aspartate-rich motif (ASARM), which potently inhibits mineralization of osteoblast cultures in a phosphate-dependent manner. ASARM peptides accumulate in hypophosphatemia patients whose distinguishing clinical feature is soft bones (osteomalacia). To understand the mechanism of how OPN and the acidic and negatively charged peptides from OPN inhibit the mineralization process by adsorbing to HAP crystal surfaces, we modeled the binding by computational studies. Computational simulations allow for assessing the mechanism by which polyelectrolytes, such as OPN and its peptides, can inhibit mineralization. We used the RosettaSurface protocol to examine human OPN-ASARM peptide (DDSHQSDESHHSDESDEL) binding to flat surfaces of HAP mineral and determined binding affinities, specificities, and structure for ASARM-Sp0 (without phosphoserine) and two phosphorylated forms of ASARM (ASARM-Sp3 and ASARM-Sp5, with 3 and 5 phosphoserines, respectively). Our simulations show an increase in adsorption of ASARM to HAP when the peptide is phosphorylated. Moreover, ASARM and its phosphorylated counterparts show preferential adsorption to the (100) and (010) crystallographic orientations of HAP compared to the (001) orientation.Beside the "flat" surfaces of the HAP crystal, "active sites" such as steps, kinks, and vacancies play deterministic roles in adsorption of foreign molecules and ultimately affect the process of crystal growth. We examined phosphorylated ASARM (DDSpHQSDESHHSpDESpDEL / ASARM-Sp3) binding to HAP mineral with and without vacancies to determine the following: the changes in binding affinity attributable to the phosphate vacancies, the effect of vacancies' geometry in adsorption of the peptide, and the structural changes of ASARM-Sp3 upon adsorption to these surfaces. Our results suggest that the presence of phosphate vacancies on (100) surface increases the adsorption energies of ASARM-Sp3 more than two-fold, and the increase in adsorption energies is related to the number of vacancies available on the surface. The adsorption on the surfaces was mostly mediated through ASARM-Sp3 phosphate groups, which were oriented towards the phosphate vacancies of the crystal surface. In addition, different geometry of the phosphate vacancies was shown to have influence in changing the adsorption energies of ASARM-Sp3. These results indicate that "active sites" present on the surface of a growing crystal can influence the adsorption of biological molecules. More specifically, peptides such as ASARM-Sp3 have side chains (phosphate groups) that can fill the vacancies (phosphate vacancies), driving their adsorption.L'ostéopontine (OPN), une phosphoprotéine acide secrétée non collagénique, est composée de 314 acides aminés (chez les humains). Elle est constituée principalement de glutamate, l'aspartate et de serine. L'ostéopontine est associée avec des biominéraux et a un effet régulateur sur la croissance de cristaux hydroxyapatite (HAP), la phase minérale des os et des dents. De récentes recherches ont révélé que l'OPN contient un motif acide, riche en sérine et en aspartate (ASARM), qui peut fortement inhiber la minéralisation des cultures d'ostéoblastes en dépendance de phosphates. Les peptides ASARM s'accumulent dans les patients souffrant d'hypophosphatémie, ayant comme symptôme des os souples (ostéomalacie). Afin de comprendre le mécanisme par lequel l'OPN et les peptides charges négativement de l'OPN inhibe le processus de minéralisation par l'adsorption aux surfaces cristallines HAP, nous avons modélisé les liaisons par une étude de simulations computationnelles. Ces simulations nous permettent de déterminer le mécanisme par lequel les poly électrolytes (OPN et ses peptides) inhibent le processus de minéralisation. Nous avons utilise le protocole RosettaSurface pour examiner la liaison du peptide OPN-ASARM (DDSHQSDESHHSDESDEL) aux surfaces planes d'un minéral HAP. Plus précisément, nous avons observe les affinités, les spécificités de liaison ainsi que la structure de ASARM-Sp0 (sans phosphosérine) et deux formes phosphorylées de ASARM (ASARM-SP3 et ASARM-SP5, possédant 3 et 5 phosphosérines respectivement). Nous simulations indiques une augmentation de l'adsorption d'ASARM pour le HAP lorsque le peptide est phosphorylé. De plus, ASARM et ses versionsivphosphorylées montres une adsorption préférentielle aux orientations cristallographiques de HAP (100) et (010) comparé à l'orientation (001). Mis à part la surface plane du cristal HAP, des « sites d'activité », tels que des paliers, des crevasses ainsi que des vides jouent un rôle critique dans l'adsorption de molécules étrangères, affectant le processus de croissance des cristaux. Nous avons examine la liaisons entre un ASARM phosphorylé (DDSpHQSDESHHSpDESpDEL / ASARM-Sp3) et un minéral HAP avec et sans vide. Nous en avons déterminé les changements dans l'affinité de liaison attribuables au manque de phosphate, les effets des vides dans la géométrie pour l'adsorption du peptide ainsi que les changements de structure de l'ASARM-Sp3 lors de l'adsorption à ces surfaces. Nos résultats suggèrent que la présence de vides sur la surface (100) augmente l'énergie d'adsorption d'ASARM-Sp3 par plus de deux fois, et l'augmentation de l'énergie d'adsorption est lie au nombre de vides disponibles sur la surface. L'adsorption sur ces surfaces est assurée a traves les groupes phosphate d'ASARM-Sp3, orientes vers les vides phosphates de la surface du cristal. De plus, différentes géométries des vides de phosphate semblent avoir une influence sur le changement de l'énergie d'adsorption de ASARM-Sp3. Ces résultats indiquent que les sites actifs présents sur la surface d'un cristal en croissance peut influencer l'adsorption de molécules biologiques. Plus précisément, des peptides tels que ASARM-Sp3 ont des chaines secondaires (groupes phosphates) qui peuvent combler les vides (vides phosphates), entrainant leur adsorption.
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Galler, Karolina. "Osteopontin: A Bone Matrix Protein for Adhesion Assay." Master's thesis, Temple University Libraries, 2010. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/99994.
Full textAbstract:
BioengineeringM.S.
Skeletal development is a tightly regulated homeostatic process that requires proper functioning of osteoblasts, the bone forming cells, and osteoclasts, the bone resorbing cells. Improper functioning of either of these cell types results in diseases such as osteoporosis, osteogenesis imperfecta as well as Paget's disease. Crucial for the proper maintenance of the skeleton is the bone matrix, which encompasses both organic and inorganic components. Osteopontin (Opn) is an example of a major non-collagenous protein present in bone. Its expression is crucial for bone remodeling since it functions in recruiting osteoclasts for bone resorption and facilitates their adhesion to the bone matrix. Osteopontin is expressed in variety of cells and functions in facilitating signal transduction upon engagement of integrin. Osteopontin binds to the αvß3 (vitronectin receptor) the major integrin expressed on osteoclasts thereby mediating cell adhesion and migration. As a model to study osteopontin-mediated adhesion we have employed commercially available osteopontin and the HEK 293 cells that stably overexpress the vitronectin receptor (Vnr cells). We studied the ability of the Vnr cells to adhere to different extracellular matrices including osteopontin.
Temple University--Theses
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Casals, Soler Gemma. "Investigación de la osteopontina y la integrina αvβ3 como marcadores de receptividad endometrial para la implantación embrionaria." Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/301774.
Full textAbstract:
El estudio del endometrio y de su estado de receptividad para la implantación embrionaria es crucial en la evaluación de la fertilidad de la mujer. No obstante, se ha demostrado que el estudio histológico clásico carece de utilidad clínica práctica para valorar la adecuada capacidad del endometrio para implantar embriones. Por tanto, la búsqueda de nuevos marcadores de receptividad endometrial constituye una línea de investigación de gran interés. Se ha descrito que tanto la integrina αvβ3 como la osteopontina presentan unos patrones de expresión temporales y espaciales específicos en los diferentes tipos celulares del endometrio, que definirían la fase de receptividad endometrial para la implantación embrionaria o "ventana de implantación".
En base a lo anterior, nuestra hipótesis de trabajo es que la identificación y estudio de la osteopontina y la integrina αvβ3 como marcadores endometriales de implantación embrionaria en diferentes situaciones clínicas, debería permitir ir más allá de los simples criterios clásicos morfo-histológicos valorados por microscopia óptica y de esta forma poder definir de una manera más precisa y objetiva el grado de receptividad endometrial para la implantación embrionaria.
Para ello, se han realizado 3 estudios, publicados en revistas del primer cuartil de la especialidad:
I. “Osteopontin and αvβ3 integrin expression in the endometrium of infertile and fertile women”
Casals G, Ordi J, Creus M, Fábregues F, Casamitjana R, Quinto L, Campo E, Balasch J.
Reprod Biomed Online, 2008;16(6):808-816
II. “Osteopontin and αvβ3 integrin as markers of endometrial receptivity: the effect of different hormone therapies”
Casals G, Ordi J, Creus M, Fábregues F, Carmona F, Casamitjana R, Balasch J.
Reprod Biomed Online, 2010;21(3):349-359
III. “Expression pattern of osteopontin and αvβ3 integrin during the implantation window in infertile patients with early stages of endometriosis”
Casals G, Ordi J, Creus M, Fábregues F, Carmona F, Casamitjana R, Balasch J.
Hum Reprod, 2012;27(3):805-813
Según los datos obtenidos en estos estudios, podemos afirmar que no existe una relación causa-efecto entre la presencia o ausencia de estos dos marcadores endometriales (osteopontina e integrina αvβ3) durante la denominada "ventana de implantación" y la esterilidad de la mujer asociada o no a la presencia de endometriosis. Por otra parte, la administración de diferentes hormonas con efectos probados sobre el endometrio modifica la expresión de osteopontina e integrina αvβ3 sólo en tanto en cuanto son capaces de influir sobre el estado de maduración histológica de la mucosa endometrial. Por tanto, el interés de su uso rutinario en la valoración de la paciente estéril no puede confirmarse de acuerdo con los resultados de esta Tesis Doctoral.The study of the human endometrium as a fertility-determining factor and understanding the factors that contribute to a receptive endometrium are, at present, important areas of research. Investigation of endometrial function has traditionally been assessed by morphological criteria. However, the relationship between histological changes and endometrial receptivity has been seriously questioned in recent years and, consequently, a number of new biomarkers of endometrial receptivity have been described. The study of integrin αvβ3 and osteopontin (OPN) has been proposed as a means of distinguishing receptive from non-receptive endometrium in clinical practice and as a new method to investigate the impaired endometrial receptivity in certain groups of infertile patients. Both glycoproteins have been found to be coordinately expressed in the human endometrium across the menstrual cycle and maximally expressed at the time of the implantation window. According to these findings, we have developed and subsequently published the following studies: I. “Osteopontin and αvβ3 integrin expression in the endometrium of infertile and fertile women” Casals G, Ordi J, Creus M, Fábregues F, Casamitjana R, Quinto L, Campo E, Balasch J. Reprod Biomed Online, 2008;16(6):808-816 II. “Osteopontin and αvβ3 integrin as markers of endometrial receptivity: the effect of different hormone therapies” Casals G, Ordi J, Creus M, Fábregues F, Carmona F, Casamitjana R, Balasch J. Reprod Biomed Online, 2010;21(3):349-359 III. “Expression pattern of osteopontin and αvβ3 integrin during the implantation window in infertile patients with early stages of endometriosis” Casals G, Ordi J, Creus M, Fábregues F, Carmona F, Casamitjana R, Balasch J. Hum Reprod, 2012;27(3):805-813 The results of these studies indicate that although the expression of the OPN:αvβ3 integrin complex is closely correlated with histological maturation of endometrium evaluated by histological dating, neither OPN nor αvβ3 alone or in combination are useful markers of endometrial functional receptivity: there were no differences in expression or coexpression of these two markers between fertile controls and infertile patients. On the other hand, endometrial OPN and αvβ3 integrin expression or co-expression during the window of implantation are not impaired in patients with stage I–II endometriosis. Finally, OPN and alphavbeta3 integrin expression was closely related to endometrial maturation and this was irrespective of the hormonal treatment received. In conclusion, the results of our studies do not support the routine use of these markers in the clinical practice.
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Saker, Mirna. "Identification de l'ostéopontine comme facteur libéré par les cellules vasculaires sénescentes et son implication dans l'hypertension pulmonaire." Thesis, Paris Est, 2015. http://www.theses.fr/2015PESC0047.
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Les cellules musculaires lisses de l'artère pulmonaire (PA-PSM) peuvent contribuer à la pathogenèse de l'hypertension pulmonaire (PH) en produisant des facteurs sécrétés.Objectif: explorer le rôle de PH de protéines de la matrice extracellulaire libéré par Les cellules musculaires lisses de l'artère pulmonaire sénescentes (PA-PSM)Méthodes et résultats:L'analyse Microarray de l'ADN de PA-CML humaine subir à la sénescence réplicative révélé une régulation positive de l'ostéopontine, qui médie l'effet stimulateur ,du médium et de la matrice de l'AP-SMC de sénescentes, sur la croissance et de la migration des cellules musculaires lisses de l'artère pulmonaire. Osteopontin était régulé à la hausse dans les poumons de patients atteints de BPCO et de patients hypertension artérielle pulmonaire idiopathique (HAPi). Prominent ostéopontine immunocoloration a été noté dans le PA-SMC qui a également colorée pour p16 dans les sites de l'hypertrophie vasculaireet les niveaux de l'ostéopontine pulmonaire étalaient étroitement corrélée avec l'âge. Comparativement aux jeunes souris avec des souris ont 1 an affiche des niveaux plus élevés d'ostéopontine du poumon, et la pression systolique ventriculaire droite (de RVSP), et la muscularisation vasculaires pulmonaires, et le nombre de PA-CML colorée pour p16 ou p21 et aussi pour l'ostéopontine.Aucun de ces changements avec l'âge étaient observée dans les souris ostéopontine - / -, qui a développé atténués PH pendant l'hypoxie.Comparé de culture PA-CML, les PA-CML de souris ont 1 ans qui proliféraient plus rapide que PA-CML de jeunes souris. Avec un taux de croissance rapide a été observée avec PA-CML de jeunes souris stimulées par matrice ou médium issu de les PA-CML de souris âgées. Différences entre les anciens jeune souris / PA-SMC taux de croissance étaient supprimée par des anticorps anti-ostéopontine.culture de la PA-CML de souris ostéopontine - / - a augmenté de plus lente que fait chez PA-SMC de souris sauvage et ces cellules ont été stimulés par le medium et la matrice de PA-CML de type sauvage et cet effet était plus fort avec PA-CML de souris âgés par apport de souris jeunes.Conclusion: Osteopontin est un médiateur clé libéré par PA-SMC sénescente et contribuer à la progression de la HTAPRationale: Senescent pulmonary artery smooth muscle cells (PA-SMCs) may contribute tothe pathogenesis of pulmonary hypertension (PH) by producing secreted factors.Objective: To explore the role in PH of extracellular matrix proteins released by senescentPA-SMCsMethods and results: Microarray analysis of human PA-SMCs undergoing replicativesenescence revealed osteopontin upregulation, which mediated the stimulatory effect ofsenescent PA-SMC media and matrix on PA-SMC growth and migration. Osteopontin wasupregulated in lungs from patients with COPD or idiopathic pulmonary arterial hypertension(PAH). Prominent osteopontin immunostaining was noted in PA-SMCs that also stained forp16 at sites of vascular hypertrophy, and lung osteopontin levels correlated closely with age.Compared to younger mice, 1-year-old mice displayed higher lung osteopontin levels, rightventricular systolic pressure (RVSP), pulmonary vessel muscularization, and numbers ofPA-SMCs stained for p16 or p21 and also for osteopontin. No such changes with age wereobserved in osteopontin-/- mice, which developed attenuated PH during hypoxia. Comparedto cultured PA-SMCs from young mice, PA-SMCs from 1-year-old mice grew faster; asimilar fast growth rate was seen with PA-SMCs from young mice stimulated by matrix ormedia from old mice. Differences between old/young mouse PA-SMC growth rates weresuppressed by anti-osteopontin antibodies. PA-SMCs from osteopontin-/- mice grew moreslowly than did wild-type PA-SMCs; they were stimulated by wild-type PA-SMCs mediaand matrix, and this effect was stronger with PA-SMCs from older vs. younger mice.Conclusion: Osteopontin is a key mediator released by senescent PA-SMCs andcontributing to PH progression
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Brunialti, Karen Cristina de Sant'Anna. "Correlação entre osteopontina sérica e polimorfismos nos genes GSTT1, GSTP1, ERCC1(118), XPD (751) com prognóstico e sobrevida em pacientes com carcinoma epidermóide de cabeça e pescoço." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/5/5155/tde-03022010-151704/.
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INTRODUÇÃO: A resposta ao tratamento no carcinoma epidermóide de cabeça e pescoço (CECCP) varia significantemente em diferentes casos e muitos pacientes não respondem ao tratamento e são expostos aos seus efeitos. A cisplatina é o quimioterápico mais utilizado no tratamento de CECCP e a quimioradioterapia é o método terapêutico usado nos carcinomas localmente avançado. Neste trabalho foram estudados possíveis marcadores de resposta a quimioradioterapia e sobrevida em pacientes portadores de CECCP, dentre eles a osteopontina (OPN) que tem sido associada à agressividade tumoral em vários cânceres e também tem sido relacionada a sobrevida, formam estudados também alguns polimorfismos em genes que estão relacionados com a cisplatina, seja na detoxificação deste fármaco, Glutationas S transferase (GSTP1, GSTT1 e GSTM1), seja no reparo dos danos causados no DNA pela via de excisão de nucleotídeos (XPD -751 e ERCC 118). CASUÍSTICA E MÉTODOS: Amostras de 69 pacientes localmente avançados submetidos à quimioterapia adjuvante ou exclusiva com cisplatina tiveram a sua OPN dosada pelo imunoensaio elisa em coletas realizadas antes e depois do término do tratamento. Para a análise dos polimorfismos, amostras de 95 pacientes localmente avançados tratados com quimioradioterapia com cisplatina exclusiva foram analisadas por PCR RFLP. RESULTADOS: Com relação à OPN, dos 69 pacientes estudados, a concentração da OPN antes do início da quimioradioterapia no grupo como um todo, foi de 102,5 ng/mL com uma mediana de 82,1 ng/mL. O correspondente valor da OPN após o tratamento n=46 foi de 104,0 ng/mL e mediana de 92,9 ng/mL. A OPN se mostrou mais elevada nos pacientes com maior tamanho tumoral, p=0,009 (ANOVA). Em análises correlacionado reposta ao tratamento e concentração de OPN, observamos que os pacientes que obtiveram resposta completa apresentaram menores níveis de OPN do que aqueles que não responderam ao tratamento. Quando realizamos uma análise multivariada notamos correlação entre baixa OPN antes do tratamento e uma melhor sobrevida global. Na análise dos polimorfismos (n=95), observamos que para os genes de reparo de DNA, XPD e ERCC, o genótipo mais freqüente foi C/T (n=43) e A/A (n=44), respectivamente. Para a GSTP1 a maior freqüência foi de A/G (47,4%) e para a GSTT1 e M1, vimos que a maioria dos pacientes, 83,2% mostrou ter GSTT1 funcional, enquanto 58,9% tiveram GSTM1 não funcional. Neste grupo de pacientes, não notamos nenhuma associação significante entre os genótipos dos pacientes e a resposta a quimioradioterapia, assim como não foi possível uma correlação entre a sobrevida global e os genótipos. CONCLUSÃO: Em síntese, a OPN após o término do tratamento pareceu estar associada com a resposta ao tratamento e com uma melhor sobrevida no grupo estudado e em relação aos polimorfismos, um aumento do número de amostras possa talvez mostrar alguma associação com resposta ao tratamento e a sobrevida global em pacientes com CECCP localmente avançados.INTRODUCTION: The response to treatment in head and neck squamous cell carcinoma (HNSCC) varies significantly in different cases and many patients do not respond to treatment and are exposed collateral effects. Cisplatin is a chemotherapeutic used to treat HNSCC and chemoradioterapy is the major strategy used in locally advanced carcinomas. In this work, we studied potential markers for chemoradioterapy response and survival in HNSCC patients, such as osteopontin (OPN), which has been associated with tumor aggressiveness and survival. Furthermore, it was studied some genetic polymorphisms related to cisplatin detoxification (glutathione - S transferase, subtypes GSTP1, GSTT1 and GSTM1), as well genes involved in the repair of DNA damage by nucleotide excision (ERCC and XPD -751 - 118). METHODS: Plasmatic OPN levels, before and end of treatment, were measured in 69 patients with locally advanced tumors submitted to adjuvant chemotherapy with cisplatin only by ELISA. For polymorphism analysis, samples from 95 patients with locally advanced tumors treated with cisplatin alone were analyzed by PCR - RFLP. RESULTS: The OPN levels before the chemoradioterapy in the group (n=69) was 102.5 ng/mL with a median of 82.1 ng/mL. The corresponding value of OPN after treatment (n= 46) was 104.0 ng/mL and a median of 92.9 ng/mL. The OPN was higher in patients with larger tumor size, p = 0.009 (ANOVA). In tests correlated to treatment response and concentration of OPN, we observed that patients who achieved complete response had lower levels of OPN than those who did not respond to treatment. The multivariate analysis revealed that lower OPN levels before treatment significant a better overall survival. In the analysis of the polymorphisms (n = 95) the frequency of genotype for the DNA repair genes (XPD and ERCC), was C / T (n = 43) and A / A (n = 44), respectively. The most frequent genotype for GSTP1 was A/ G (47.4%), in 83.2% of the patients, the GSTT1 was functional, while in 58.9% of patients presented GSTM1 non-functional. In this group of patients, there was no any significant association between the genotypes and chemoradiotherapy response nor overall survival. CONCLUSION: In summary, plasmatic OPN levels after treatment cisplatin seemed to be associated with treatment response and better survival. However, larger sample size would be demonstrating some association with treatment response and overall survival in patients with locally advanced HNSCC.
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Vandor, Douglas. "Characterization of human recombinant osteopontin from transfected renal cells." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=29406.
Full textAbstract:
This project will attempt to characterize the OPN secreted from our human embryonic kidney cells. Since we believe that tissue-specific post-translational modifications, such as phosphorylation and glycosylation, play a crucial role in the physiological properties of OPN with regards to its function, the focus will be to obtain some insight into the post-translational modifications occurring to OPN in our renal expression system. We believe that these modifications are comparable to what is occurring to OPN in vivo.Some of these post-translational modifications, namely phosphorylation, appear to influence the activity of OPN as an inhibitor of nucleation, growth and aggregation of crystals. Therefore in addition to characterizing OPN, an attempt will be made to look at some of the hormones which could potentially play a role in regulating the post-translational processes occurring to this protein. Kidney stone disease being a calcium dependent process, this project will focus on two hormones, PTH and 1,25(OH)2D3, because of their involvement in calcium regulation in the body.
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Zohar, Ron. "Intracellular osteopontin, relationship to osteogenic differentiation and cell migration." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ35388.pdf.
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Hallack, Stefanie. "Nachweis von Osteopontin in der extrazellulären Matrix der Rinderplazenta." Giessen : VVB Laufersweiler, 2007. http://d-nb.info/988006723/04.
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Mamazhakypov, Argen [Verfasser]. "Role of Osteopontin in Right Ventricular Remodeling / Argen Mamazhakypov." Gießen : Universitätsbibliothek, 2020. http://d-nb.info/1210444364/34.
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Alsarkhi, Lamyaa. "Do Anti-Osteopontin Auto-Antibodies Arise in Cancer Patients?" University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1491560735600409.
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Oates, Adam John. "The identification of metastasis-related gene products in a rodent mammary tumour model." Thesis, University of Liverpool, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283448.
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Banerjee, Atrayee. "Osteopontin-mediated neutrophilic infiltration and higher liver injury in a female rodent alcoholic steatohepatitis model." [College Station, Tex. : Texas A&M University, 2008. http://hdl.handle.net/1969.1/ETD-TAMU-2836.
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Souza, Fabio Ricardo Pablos de. "Polimorfismos dos genes MUC1 e Osteopontina em novilhas da raça Nelore (Bos taurus indicus)." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/17/17135/tde-14082007-090840/.
Full textAbstract:
A MUC1 (MUC1) e a osteopontina (SPP1) são glicoproteínas expressas na superfície luminal uterina com funções na proteção e adesão celular. A MUC1 possui função antiadesiva, enquanto a osteopontina desempenha função adesiva. A expressão de ambas é regulada pelo hormônio esteróide progesterona. Durante a fase receptiva do útero, a MUC1 é inibida por este hormônio, enquanto a osteopontina é estimulada. O objetivo deste trabalho é caracterizar o polimorfismo genético destas moléculas e analisar a associação entre o polimorfismo, o diagnóstico de gestação e as diferenças esperadas na progênie (DEP) de várias características em novilhas da raça Nelore (Bos taurus indicus). A amostra foi constituída por 309 novilhas procedentes de duas fazendas participantes do Programa de Melhoramento Genético da Raça Nelore (PMGRN). A amostra da primeira fazenda incluiu 56 novilhas prenhas e foi utilizada para caracterização do polimorfismo e da estrutura do número variável de repetições em tandem (VNTR) MUC1 na raça Nelore. A segunda amostra foi constituída por 76 novilhas com resultado positivo de gestação e 156 com resultado negativo de gestação e foi utilizada para caracterização do polimorfismo dos genes MUC1 e SPP1 na raça Nelore, assim como para análise da associação entre os polimorfismos e os fenótipos. O gene MUC1 apresentou 5 alelos constituídos por um VNTR formado por uma seqüência de 60 nucleotídeos. A seqüência da repetição consensus foi idêntica às seqüências descritas em caprinos e em Bos taurus taurus. Descrevemos a seqüência de uma terceira repetição consensu na raça Nelore. O alelo 1 apresentou 10 repetições, o alelo 2 apresentou 12 repetições, o alelo 3 apresentou 15 repetições, o alelo 4 foi formado por 18 repetições, e o alelo 5 apresentou 24 repetições. O alelo com menor número de repetições apresentou a maior freqüência, sendo 0,70 na amostra do 1º grupo e 0,80 na amostra do 2º grupo. Os alelos 2, e 3 tiveram a segunda e terceira maior freqüência, sendo seguidos pelos alelos 4 e 5. A análise estatística não evidenciou associação entre o polimorfismo do gene MUC1 e o diagnóstico de gestação e entre o polimorfismo e os valores das diferenças esperadas na progênie das características consideradas economicamente importantes. Na amostra referente às novilhas da segunda fazenda, não identificamos o polimorfismo de nucleotídeo simples no íntron 4 (T/C) do gene SPP1 da osteopontina, como descrito na raça Holandesa. Sugerimos que a ausência deste polimorfismo possa constituir uma característica específica em Bos taurus indicus. Porém, dada a associação já descrita entre polimorfismo do gene SPP1 e características de crescimento, não descartamos a hipótese de que, assim como o MUC1, tenha ocorrido uma seleção indireta devido aos critérios aplicados pelo Programa de Melhoramento Genético da Raça Nelore.MUC1 (MUC1) and osteopontin (SPP1) are glycoproteins expressed in the uterine luminal surface with predict functions in protection and cell adhesion. MUC1 has anti-adhesive role and osteopontin has adhesive role. The expression of both molecules is regulated by the steroid hormone, progesterone. During the receptive period for embryo implantation in the uterus, MUC1 is inhibited by progesterone and the osteopontin is stimulated. The objective of this work is to characterize the genetic polymorphism of these molecules, and to characterize associations between the polymorphisms, gestation rate and the expected progeny difference (EPD) in the Nelore breed (Bos taurus indicus). The study group comprised 309 heifers derived from two participating farms of the Nelore Cattle Breeding Program (PMGRN). The first farm provided 56 fertile female for the study for the characterization of the MUC1 polymorphism and the variable number of tandem repeats (VNTR) genomic structure in the Nelore breed. The second farm contributed 76 heifers with confirmed gestation and 156 no-pregnant female that were used to characterize both gene polymorphisms and to analyze the association between the MUC1 and SPP1 polymorphisms and the phenotypes. The MUC1 gene presented five alleles caused by length differences generated by a VNTR of 60 nucleotides. The consensus repeat sequence was identical to the caprine and Bos taurus taurus sequence. In this study we described the sequence of the third consensus repeat in the Nelore breed. Allele 1 presented with 10 repeats, allele 2 presented with 12 repeats, allele 3 presented with 15 repeats, allele 4 had 18 repeats and allele 5 had 24 repeats. Allele 1 had the smallest size and was the most frequent (0.70) in the group 1 and 0.80 in the group 2. Alleles 2 and 3 were the next most frequent followed by alleles 4 and 5. The ?2 test showed that the polymorphism was not significantly associated with the diagnostic of gestation and the EPD values. In this Nelore study group it was not possible to identify the single nucleotide polymorphism (T/C) of the SPP1 gene previously described in Holstein breed. The absence of this polymorphism could be specific to the Nelore cattle. However, considering the correlation between the SPP1 polymorphism and growth parameters, an indirect selection could happen due to the established criteria within the Nelore Cattle Breeding Program.
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Nourkami-Tutdibi, Nasenien [Verfasser], and Norbert [Akademischer Betreuer] Graf. "Osteopontin im Kindesalter bei Kindern mit und ohne Tumorerkrankung : Erstellung altersspezifischer Referenzweerte für Osteopontin in Liquor und Blutplasma / Nasenien Nourkami-Tutdibi. Betreuer: Norbert Graf." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2015. http://d-nb.info/1074404610/34.
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Schwendinger, Nina [Verfasser]. "The influence of host-derived osteopontin on glioma / Nina Schwendinger." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2020. http://d-nb.info/1218078065/34.
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Martin, Stephanie M. "Characterization and analysis of osteopontin-immobilized poly(2-hydroxyethyl methacrylate) /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/8109.
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De, Mello Natalie Victoria. "Characterisation of osteopontin and CD44 in endometrium of infertile women." Thesis, Swansea University, 2013. https://cronfa.swan.ac.uk/Record/cronfa42761.
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Cell adhesion proteins osteopontin, CD44 and integrin alphaVbeta3 interact to form an adhesion complex between the embryo and endometrial surface forming an attachment that can lead to implantation. Whilst receptivity has been investigated extensively, the expression of this adhesion complex has yet to be studied simultaneously in the endometrium. This thesis establishes the expression of the adhesion complex in fertile and infertile endometrium. In addition the regulation of the adhesion complex components by distinct signalling pathways and the key regulators estrogen receptor, nuclear factor kappa B and signal transducer and activator of transcription 1 have been investigated in endometrial cell lines. Objectives: To establish the expression profile of adhesion complex components in samples obtained from fertile and infertile women. To model in vitro hormonal regulation of adhesion complex components to mimic estrogen and progesterone stimulus in the menstrual cycle. To determine if adverse environments common to poly cystic ovarian syndrome and endometriosis affect uterine expression of the adhesion complex via high glucose and pro-inflammatory cytokines. To investigate the direct regulation of Osteopontin and CD44 by estrogen and cytokine signalling through estrogen receptor ?, nuclear factor kappa B and signal transducer and activator of transcription 1. Methodology: Investigation of human biopsies and cell line models by immunohistochemistry, quantitative polymerase chain reaction, chromatin immunoprecipitation and enzyme linked immunosorbent assay. Conclusions: Adverse uterine environments including high glucose and pro-inflammatory cytokines may regulate the expression of the adhesion complex, and contribute to a lack of endometrial receptivity in endometriosis and poly cystic ovarian patients. CD44, ITGAV and ITGB3 levels may be used as markers for loss of receptivity in unexplained infertility.
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Souza, Vinícus Carolino de. "Associação da osteopontina com densidade mineral óssea em indivíduos muito idosos." reponame:Repositório Institucional da UnB, 2012. http://repositorio.unb.br/handle/10482/12325.
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Dissertação (mestrado)—Universidade de Brasília, Faculdade de Ciências da Saúde, Programa de Pós-Graduação em Ciências da Saúde, 2012.Submitted by Albânia Cézar de Melo (albania@bce.unb.br) on 2013-02-19T13:46:12Z No. of bitstreams: 1 2012_ViniciusCarolinoSouza.pdf: 1039449 bytes, checksum: 7297d2fe0ffb51b5643264faf585bff2 (MD5)
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Introdução e objetivo: Dado que a concentração sérica de osteopontina (OPN) constitui promessa de marcador para o diagnóstico precoce de doenças ósseas, tecemos a hipótese de que um polimorfismo em seu gene poderia explicar níveis séricos diferenciais do mediador e, em sequencia, os escores de densidade óssea entre adultos muito idosos no Brasil. Métodos: homens e mulheres (80 anos ou mais) residentes no Distrito Federal brasileiro foram submetidos a avaliação por densitometria óssea de raio-X de dupla energia para determinação da densidade mineral óssea (DMO) das regiões do colo do fêmur, cabeça do fêmur e lombosacral (L1 a S5). Exame clínico foi realizado para avaliar outras características físicas e para excluir co-morbidades (cardiovasculares, autoimunidade, infecções ou doenças neoplásicas). As concentrações séricas de OPN foram determinadas por ensaio imunoenzimático, enquanto o polimorfismo A7385G (rs1126772) foi determinada por sequenciamento direto dos produtos de reação em cadeia da polimerase. Resultados: Entre os duzentos e dez sujeitos envolvidos, não foram observados níveis diferenciais de densidade mineral óssea entre os genótipos, mas um teor circulatório aumentado de OPN foi encontrado entre os portadores do alelo A (P ≤ 0,05) mesmo após os ajustes. Os níveis séricos de OPN foram negativamente correlacionados com a densidade do colo do fêmur (P = 0,050 para a DMO; P = 0,032 para T-score), mas não os níveis de outras regiões investigadas. As análises com a amostra dicotomizada para idade e massa corporal revelou que esta associação foi perceptível apenas entre os sujeitos pertencentes à faixa etária mais avançada e aos com peso corporal dentro do intervalo inferior. Conclusão: Nossos achados apontam para níveis circulantes elevados de osteopontina entre pacientes com densidade mineral óssea diminuída, consistente com uma modesta contribuição de uma variação alélica OPN para a expressão do mediador. Atestar relevância clínica destes achados exige estudos futuros. ______________________________________________________________________________ ABSTRACT
Introduction and objective: Given that serum osteopontin (OPN) concentrations may be a promising marker for early diagnosis of bone disorders, we hypothesized that a polymorphism in its gene might account to differential serum levels of the mediator and thus to the bone density scores among very-old adults in Brazil. Methods: Men and women (80 years or older) living in the Brazilian Federal District underwent assessments with dual energy X-ray absorptiometry for bone mineral density (BMD) of the femoral neck, femoral head and lumbarsacral (L1 to S5) regions. Clinical inspection was performed to assess other physical traits and to exclude co-morbidities (cardiovascular, autoimmunity, infections or neoplastic diseases). Serum concentrations of OPN were determined with an enzyme-linked immunosorbent assay, whereas the A7385G polymorphism (rs1126772) was determined by direct sequencing of a polymerase chain reaction product. Results: Among the two hundred and ten subjects enrolled, no differential scores for bone mineral density could be observed across genotypes, but a greater content of circulating OPN was found among carriers of the A allele (P ≤ 0.05) even after adjustments. Serum OPN levels were negatively correlated with the femoral neck density (P = 0.050 for BMD; P = 0.032 for T-scores) but not with scores of the other regions investigated. Analyses with the sample dichotomized to age and body mass revealed that this inverse relationship was noticeable only among those aged within the highest and weighed within the lowest intervals. Conclusion: Our findings indicate elevated circulating osteopontin levels in patients with decreased bone mineral density, consistent with a modest contribution of an OPN allelic variation to its expression. Attesting clinical relevance of our findings demands forthcoming studies.
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Ravindranath, Amod. "Tcf-4 regulates osteopontin-mediated malignant transformation in human breast cancer." Thesis, Queen's University Belfast, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.534602.
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Singh, Mahipal, Cerrone R. Foster, Suman Dalal, and Krishna Singh. "Osteopontin: Role in Extracellular Matrix Deposition and Myocardial Remodeling Post-MI." Digital Commons @ East Tennessee State University, 2010. https://dc.etsu.edu/etsu-works/8576.
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Remodeling after myocardial infarction (MI) associates with left ventricular (LV) dilation, decreased cardiac function and increased mortality. The dynamic synthesis and breakdown of extracellular matrix (ECM) proteins play a significant role in myocardial remodeling post-MI. Expression of osteopontin (OPN) increases in the heart post-MI. Evidence has been provided that lack of OPN induces LV dilation which associates with decreased collagen synthesis and deposition. Inhibition of matrix metalloproteinases, key players in ECM remodeling process post-MI, increased ECM deposition (fibrosis) and improved LV function in mice lacking OPN after MI. This review summarizes — 1) signaling pathways leading to increased expression of OPN in the heart; 2) the alterations in the structure and function of the heart post-MI in mice lacking OPN; and 3) mechanisms involved in OPN-mediated ECM remodeling post-MI.
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Marsh, Barnaby C. L. "The Role of Osteopontin in the Peripheral and Central Nervous Systems." Thesis, University of Bristol, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.486122.
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The glycoprotein osteopontin (OPN) is a secreted and heavily phosphorylated peptide that plays a role in a variety of cellular processes from cell adhesion to apoptosis. These actions are principally thought to be mediated via interactions with CD44.and integrins. OPN is expressed in a wide variety of tissues including the peripheral and central nervous systems (PNS and CNS respectively), although its exact function in these tissues remains unclear. We identified OPN as a putative axotomy response gene from a previously generated dorsal root ganglia (DRG) subtractive cDNA library. Immunohistochemical ,staining demonstrated that OPN protein colocalises with neurofilament but not other nociceptive markers. Mechanosensory thresholds in osteopontin knockout (OPN KO) animals are significantly increased compared to wild-type (WT) controls, although there are no differences in allodynia between genotypes after a spared nerve injury (SNI) model of neuropathic pain. Moreover, exogenous recombinant OPN has no effect on neurite outgrowth from adult WT sensory neurons, and no differences in neurite outgrowth were observed in OPN KO animals compared to WT controls. Within the CNS, previous studies have demonstrated that OPN expression increases in a number of cell types after injury, although its precise function is equivocal. Here, I demonstrate that organotypic hippocampal OPN KO cultures display increased apoptosis following glutamate induced cell death compared to WT controls. Moreover, exogenous recombinant OPN is neuroprotective to OPN KO and WT cultures. This neuroprotective effect is integrin mediated and involves activation ofthe Akt and ERK pathways. In summary, these studies further extend our understanding of the neuroprotective and possible cell survival roles played by OPN in the nervous system. Further studies are now warranted to extend those presented here and define the mechanisms that underlie the observed effects thus far delineated.
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Shanmugam, Vijayalakshmi. "Characterization of osteopontin in RSV transformed rat-1 cells and its role in cell transformation." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0005/NQ37025.pdf.
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Nemir, Mohamed. "Inhibition of osteopontin expression in mammary epithelial cells alters mammary gland morphogenesis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0020/NQ44529.pdf.
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Andrews, Stuart. "The inflammatory response and effect of osteopontin suppression within murine postsurgical adhesions." Thesis, University of Bristol, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.573930.
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Adhesions following abdominal surgery remain a significant unresolved clinical problem causing a great deal of post-operative morbidity. To date adhesion prevention strategies have proven of limited effectiveness. Osteopontin COPN) is a cytokine up-regulated in cell injury and tissue repair. Previous studies have shown that blocking OPN expression in the cutaneous wound demonstrates reduced granulation tissue and scarring without compromising healing. I hypothesise that it might be possible to produce a similar effect on inflammation associated fibrosis that leads to inter-loop bowel adhesions after intra-peritoneal surgery using a murine model. My experimental work on OPN suppression using mRNA blockade by delivering OPN antisense oligodeoxynucleotides on to the surface of injured juxtaposed small bowel supports this hypothesis. There was a significant reduction in granulation tissue and subsequent adhesion size. Also demonstrated was a significant reduction of leukocyte flux, alpha smooth muscle actin expression and collagen density within developing adhesions. There was no impact on mortality or delay in wound healing. Inflammation triggered by expression of OPN was not essential for healing of serosal injury to bowel within the peritoneal cavity. Blocking OPN expression is a very interesting target for anti-adhesion therapeutics.
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Uebele, Tanja [Verfasser]. "Die Expression von Osteopontin und seinen Rezeptoren bei allergischen Kontaktekzemen / Tanja Uebele." Ulm : Universität Ulm. Medizinische Fakultät, 2014. http://d-nb.info/1046623532/34.
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Lenton, Samuel. "Neutrons reveal the structure and dynamics of osteopontin phosphopeptides and nanocluster formation." Thesis, Keele University, 2017. http://eprints.keele.ac.uk/2916/.
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In bovine milk the highly phosphorylated cleavage fragment of osteopontin (OPN1-149) is capable of stabilising high concentrations of calcium phosphate ions by formation of calcium phosphate nanoclusters (CPN). Here OPN1-149 isolated from bovine milk is characterised by a range of biophysical techniques as adopting an intrinsically disordered conformation in solution. The transient ensemble of conformations sampled by OPN1-149 is characterised by small angle X-ray scattering (SAXS) in combination with the ensemble optimisation method. Formation of CPN by OPN1-149 is characterised using dynamic light scattering and small angle neutron scattering (SANS). The dynamics of the protein and the effects of sequestration on the molecular fluctuations are quantified on the nanosecond-angstrom resolution by elastic incoherent neutron scattering. The molecular fluctuations of the free phosphopeptide are found to represent a highly flexible protein. Upon sequestration of calcium phosphate, stiffening of OPN1-149 is reflected in molecular fluctuations more closely resembling those characteristic of globular proteins. The quantification of the effects provides a handle for future comparisons and classification of molecular fluctuations. The formed OPN1-149 calcium phosphate nanoclusters are characterised according to a core shell model using SANS and static light scattering. The structure of the core is probed using neutron and X-ray diffraction. The results bring insight into the modulation of the activity of OPN1-149 and phosphopeptides with a role in the control of biomineralisation. A recombinant human fragment (hOPN1-157) equivalent to OPN1-149 is produced and characterised in order to extend the work further towards the human regulatory system. The effects of phosphorylation, a key requirement for sequestration of calcium phosphate, on the structure and dynamics are determined using SAXS and elastic incoherent neutron scattering. The results indicate that phosphorylation of the protein has limited impact on both the structure and dynamics of hOPN1-157.
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Barbosa-Souza, Valéria. "Mediação da osteopontina na mionecrose e regeneração muscular após envenenamento por Bothrops lanceolatus." [s.n.], 2011. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310755.
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Orientador: Maria Alice da Cruz Hofling, Albetiza Lôbo de AraújoDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Os acidentes por serpentes venenosas podem causar alterações locais graves e de rápido desenvolvimento. O veneno de Bothrops lanceolatus (VBL) contém, dentre outras toxinas, metaloproteinases hemorrágicas e pouco hemorrágicas (SVMPI e SVMPIII) e atividade pró-trombina que causam inflamação (vias das ciclooxigenases-COX e lipoxigenases), alterações hemostáticas e degenerativas. O veneno de Bothrops lanceolatus (100 ?g/100 ?l) foi injetado no gastrocnêmio de ratos para investigar a patogênese da mionecrose (1,3,6,18 horas 1, 2 dias) e regeneração muscular (3,7,14 e 21 dias) ocasionada pelo envenenamento através de análise histológica quantitativa (medida do menor diâmetro 1 hora e 21 dias pós- VBL) e imunohistoquímica para a osteopontina (OPN), citocina inflamatória, quimiotática, com sítios de ligação para integrinas de matriz e células. A medida da expressão dos macrófagos residentes (CD68+) e dos macrófagos migrantes (CD163+), de myoD e miogenina, membros da família de fatores transcricionais miogênicos foi feita com o objetivo de correlacionar com a expressão da OPN nos diferentes estágios patológicos (n=6/período) ao longo do período experimental. Os grupos controles foram injetados com PBS (100 ?l). O envenenamento produziu hemorragia local, edema, infiltrado neutrofílico e macrofágico e desorganização das bainhas perimisiais de tecido conjuntivo, após 48 horas. As fibras mionecróticas apresentavam-se em número moderado. Aos 3 dias, havia focos de deposição de colágeno (tipo I) no meio dos quais se viam mioblastos. O número de macrófagos CD68+ atingiu o máximo às 24 horas, e manteve-se significativamente maior que nos grupos controles até aos sete dias. A expressão de OPN foi significativamente maior das 6 horas aos 3 dias e dos 7 aos 14 dias, sendo expressa em fibras musculares, macrófagos, mioblastos, miotubos e fibroblastos. Não foi obtida marcação para anti-myoD; a expressão de miogenina, que tipicamente é nuclear, foi observada também no citoplasma de mioblastos e miotubos até o 70 dia (pico), sendo sua expressão somente nuclear aos 14 dias. A retenção de miogenina no citoplasma tem sido interpretada como mecanismo de retardo na diferenciação, já que a presença no núcleo é necessária para o seu papel regulador transcricional. Aos 21 dias as fibras regeneradas, com núcleo central, não haviam atingido o tamanho das fibras maduras intactas (VBL) e dos controles. Considerando que as SVMPs e a enzima com atividade tipo trombina de VBL, podem aumentar a capacidade de ligação de sítios da OPN a integrinas de matriz e de superfícies de células, sugerimos que durante a patogênese da regeneração muscular post- VBL a OPN estaria criticamente envolvida no processo inflamatório agudo, e como tal atuaria primordialmente como citocina ativadora de células satélites quiescentes, seguida por atividade quimiotática e adesiva, favorecendo migração, proliferação de mioblastos e a diferenciação de miotubos. Segundo a literatura a OPN é profibrótica em certas doenças. Sugerimos que a fibrose intersticial observada, mais a presença tardia de macrófagos no local, mais a expressão citoplasmática da miogenina podem ter sido fatores relevantes que levaram ao atraso da regeneração das fibras musculares, como constatado pelo tamanho menor diâmetro das fibras. Sugere-se para a OPN um papel dual, isto é, tanto próregenerativo, como anti-regenerativo na patogênese das alterações causadas pelo veneno de B. lanceolatus
Abstract: Accident caused by venomous snakes can lead to local changes of serious and rapid development. Bothrops lanceolatus venom (BLV) contains, among other toxins, hemorrhagic metalloproteinases and non-hemorrhagic (SVMPI and SVMPIII) and prothrombin activity. As result, the venom causes hemostatic and inflammatory (via lipoxygenase and cyclooxygenase) and degenerative alterations. In this study, Bothrops lanceolatus venom (100 ?g/100?l) was injected into the gastrocnemius of rats to investigate the pathogenesis of myonecrosis (one, three, six, 18 hours and two days) and regeneration (three, seven, 14 and 21 days) by quantitative histological analysis (measurement of the small diameter one hour and 21 days post-BLV injection) and immunohistochemistry for osteopontin (OPN) protein, an inflammatory and chemotactic cytokines, with integrin binding sites to matrix proteins and cells. The number of macrophages CD68+ (resident macrophages), and CD163 (migrants macrophages), the expression of myoD and myogenin, members of the myogenic, both transcription factors family were correlated (n = 6/period). Control groups were injected with PBS (100?l). The envenomation produced local hemorrhage (initially massive), acute interstitial edema and myofibers, neutrophil and macrophage infiltration, and disruption of the perimysium sheath of connective tissue. These changes were observed up to 48 hours. The number of myonecrotic fibers was in moderate number. At 3 days, there were foci of collagen (type I) deposition surrounding groups of myoblasts. The number of macrophages (CD68 +) peaked at 24 hours, and remained significantly higher for seven days: there was no expression of CD163 macrophages. The OPN expression showed two steps, a significant increase in, from six hours to three days and seven to 14 days, and it was expressed in muscle fibers, macrophages, myoblasts, myotubes and fibroblasts. There was no MyoD imunolabeling. The myogenin expression, which is known to be typically nuclear, was also observed in the cytoplasm of myoblasts and myotubes until 7 days (peak). At 14 days, the myogenin expression became nuclear. The cytoplasmic retention of myogenin has been interpreted as a mechanism to delay myotube differentiation, since the presence in the nucleus is required for its transcriptional regulatory role. At 21 days, the regenerated fibers with central nucleus had not reached the size of intact fibers (VBL), nor that of controls. Whereas SVMPs and an enzyme with thrombin-like activity are known to increase the capacity of OPN binding to integrin of matrix and cell surfaces, we suggest that, during the pathogenesis of muscle regeneration post-VBL injection, OPN would be critically involved in an acute inflammatory process. OPN would act primarily as a cytokine activator of quiescent satellite cells and later play chemotactic and adhesive activities, promoting migration, proliferation of myoblasts, and formation and differentiation of myotubes. According to the literature, OPN is profibrotic in certain diseases. We suggest that the foci of interstitial fibrosis and the late presence of macrophages at the site of regeneration, as well as the cytoplasmic expression of myogenin may be relevant factors that lead to regeneration delay. It is suggested a pro-regenerative and anti-regenerative roles for OPN in the pathogenesis of alterations caused by B. lanceolatus venom
Mestrado
Farmacologia
Mestre em Farmacologia
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Hallack, Stefanie [Verfasser]. "Nachweis von Osteopontin in der extrazellulären Matrix der Rinderplazenta / eingereicht von Stefanie Hallack." Giessen : VVB Laufersweiler, 2007. http://d-nb.info/988757702/34.
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Höppner, Susanne-Katharina [Verfasser]. "Expression von Osteopontin im Rahmen der Entzündungsreaktion bei Psoriasis vulgaris / Susanne-Katharina Höppner." Ulm : Universität Ulm. Medizinische Fakultät, 2012. http://d-nb.info/1027536859/34.
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Swierzewska, Sylvia [Verfasser]. "Hypertrophe Kardiomyopathie und der Biomarker Osteopontin: Korrelation mit klinisch-diagnostischen Parametern / Sylvia Swierzewska." Kiel : Universitätsbibliothek Kiel, 2019. http://d-nb.info/1193994217/34.
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Thapar, Divya. "Osteopontin knockout abates high fat diet-induced insulin resistance and adipose tissue inflammation." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2008. http://wwwlib.umi.com/cr/ucsd/fullcit?p1459910.
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Thesis (M.S.)--University of California, San Diego, 2008.Title from first page of PDF file (viewed January 5, 2009). Available via ProQuest Digital Dissertations. Includes bibliographical references (p. 43-46).
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Terporten, Johannes Marius Dietmar [Verfasser]. "Prognostischer Stellenwert von Osteopontin für Patienten mit akuter Lungenembolie / Johannes Marius Dietmar Terporten." Mainz : Universitätsbibliothek der Johannes Gutenberg-Universität Mainz, 2021. http://d-nb.info/122704884X/34.
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Chan, Julie. "Osteopontin Expression During the Acute Immune Response Mediates Reactive Synaptogenesis and Adaptive Outcome." VCU Scholars Compass, 2013. http://scholarscompass.vcu.edu/etd/3207.
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Traumatic brain injury (TBI) is a worldwide epidemic as the number of victims living with the resulting cognitive and physical impairment continues to rise, principally due to limited treatment options which fail to address its multifaceted sequelae. By approaching TBI therapy from a molecular standpoint, we have the opportunity to develop a better understanding of the mechanisms which prevent effective recovery. With this information, we can move toward the identification of novel therapeutic treatments which target specific molecules to improve patient outcome following TBI. Here, we have focused on the therapeutic potential of osteopontin (OPN), an extracellular matrix (ECM) protein which is a substrate of several matrix metalloproteinases (MMPs), and capable of acting as both a cytokine and modulator of axonal outgrowth during synaptic recovery. The ECM and its components are of particular interest with respect to selecting novel TBI therapeutics since this network has been implicated in neuronal plasticity during both development and following central nervous system (CNS) insult. In this dissertation study, the temporal and spatial profile of OPN expression, its protein and transcript localization within reactive glia (IBA1 positive microglia or GFAP positive astroglia), and its interaction with the cytoarchitectural protein (microtubule associated protein 1B, MAP1B) after injury were each compared under conditions of deafferentation induced synaptogenesis. Two TBI models were employed: one exhibiting adaptive synaptic plasticity (unilateral entorhinal cortex lesion, UEC), and the other generating maladaptive synaptic plasticity (central fluid percussion injury followed by bilateral entorhinal cortex lesions, TBI+BEC), in each case targeting 1, 2, and 7d postinjury intervals. In addition, we examined the potential for converting the adaptive response to one of maladaptive plasticity by attenuating immune reactivity through acute administration of the tricyclic antibiotic minocycline, utilizing a dosing paradigm previously demonstrated to reduce inflammation. To more clearly confirm that OPN has a role in successful synaptic regeneration, we developed a colony of OPN knockout (KO) mice which were used to profile synaptic structure and functional outcome under conditions of UEC-induced synaptogenesis. In Chapter 2, we report that full length OPN responds robustly in the acute (1-2d postinjury) degenerative period following UEC and TBI+BEC. After UEC, time-dependent differences were observed for two alternative, MMP-processed OPN forms, including early increase in a RGD 45 kD, integrin binding fragment (1d), and delayed increase in a C-terminal 32 kD OPN peptide (7d). OPN transcript was also elevated acutely after UEC, a finding which was pronounced in enriched dentate molecular layer (ML) fractions. Parallel immunohistochemistry (IHC) and in situ hybridization localized OPN protein and transcript to reactive glia following UEC. This localization was concentrated within microglia which delineated the border between the intact and deafferented ML, a pattern which was less pronounced in maladaptive TBI+BEC animals. The timing of this glial movement suggests that OPN regulates microglial migration and, potentially, could act as an astrokine to recruit activated astrocytes for influencing subsequent synaptic regeneration. MAP1B staining confirmed dendritic loss during axonal degeneration and dendritic atrophy, with a reemergence during collateral axonal sprouting. However, OPN colocalization with MAP1B was minimal, suggesting a minor role for OPN in reorganization of dendritic/axonal cytoarchitecture in this model of deafferentation. Minocycline reduced acute OPN protein response 2d after UEC, and caused a more random OPN positive glial distribution, similar to that of the maladaptive TBI+BEC. The role of OPN in the inflammation-directed degeneration of terminals is supported by reduced MMP-9 activity, which is temporally correlated with the reduction of MMP-generated OPN lytic fragments (45 kD). Interestingly, this reduction of integrin-binding OPN peptide also matched the impaired removal of presynaptic terminals, evidenced by diminished synapsin 1 clearance in animals which received postinjury minocycline. In Chapter 3, we sought to more precisely evaluate the role of OPN following deafferentation, utilizing wild type (WT) C57BL/6 and OPN KO mice subjected to UEC, comparing the spatio-temporal injury response between WT and KO. To do this we profiled several outcome measures which assessed OPN role in different aspects of recovery: 1) expression of select proteins important in various stages of synaptic recovery, 2) glial response, 3) cognitive recovery, and 4) MMP enzymatic activity. Compared to WT mice, OPN KO mice did not show significant differences in the acute injury-induced alteration of proteins important to cytoarchitectural reorganization (MAP1B) or stabilization of the synaptic junction (N-cadherin). However, both Western blot and IHC analyses showed OPN KO mice had impaired presynaptic terminal clearance, supported by attenuated synapsin 1 breakdown, a result quite similar to that of the minocycline-treated rats with OPN reduction in Chapter 2. This impaired degeneration in OPN KO mice at 2d postinjury correlated with IHC evidence for altered microglial morphology, and hippocampal function assessed by the novel object recognition (NOR) task. Our NOR results confirmed cognitive dysfunction in OPN KO mice during the 4-21d period of synapse reorganization after UEC. In addition, OPN KO decreased MMP-9 activity, an effect associated with reduced MMP-9 bound lipocalin 2 (LCN2), a persistently activated form of that MMP. These latter findings further support the hypothesis that MMP processing of OPN contributes to effective regenerative response after injury. Collectively, the studies presented in the two chapters of this dissertation provide evidence that OPN is a critical element in the acute immune response following injury-induced CNS deafferentation. They suggest that the cytokine can be produced by reactive microglia, may mediate cell migration and acute degenerative clearance, potentially serves as an astrokine to recruit those glia to sites of synaptic repair, and that these processes are disrupted when OPN is either reduced or ablated. Interestingly, this OPN role in synaptogenesis appears to involve ECM interaction with MMP-9, possibly regulated by LCN2. Most importantly, OPN involvement seems to affect the time-dependent progression of synaptic repair, an effect which can be measured by efficacy of functional outcome