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Study of rat hepatocytes in primary culture submitted to hypoxia and reoxygenation: action of the cytoprotectors prostaglandin E1, superoxide dismutase, allopurinol and verapamil; Estudo de hepatócitos de rato em cultura primária submetidos a hipóxia e reoxigenação: ação dos citoprotetores prostaglandina E1, superóxido dismutase, alopurinol e verapamil

ANDRADE JR., Dahir Ramos de; ANDRADE, Dahir Ramos de; SANTOS, Sânia Alves dos
Fonte: Instituto Brasileiro de Estudos e Pesquisas de Gastroenterologia - IBEPEGE Colégio Brasileiro de Cirurgia Digestiva - CBCD Sociedade Brasileira de Motilidade Digestiva - SBMD Federação Brasileira de Gastroenterologia - FBGSociedade Brasileira de Hepatologia - SBHSociedade Brasileira de Endoscopia Digestiva - SOBED Publicador: Instituto Brasileiro de Estudos e Pesquisas de Gastroenterologia - IBEPEGE Colégio Brasileiro de Cirurgia Digestiva - CBCD Sociedade Brasileira de Motilidade Digestiva - SBMD Federação Brasileira de Gastroenterologia - FBGSociedade Brasileira de Hepatologia - SBHSociedade Brasileira de Endoscopia Digestiva - SOBED
Tipo: Artigo de Revista Científica
ENG
Relevância na Pesquisa
46.22%
CONTEXT: Exposure of hepatocytes to pathological conditions in a microenvironment of hypoxia and reoxygenation is very frequent in hepatic diseases. Several substances present perspectives for cytoprotective action on hepatocyte submitted to reoxygenation after hypoxia and simple hypoxia. OBJECTIVE: We research therapeutic options for hepatocytes submitted to hypoxia and hypoxia + reoxygenation injury. METHODS: Primary culture of rat hepatocytes was submitted to hypoxia (2 hours) plus reoxygenation (2 hours) and simple hypoxia (4 hours) in the presence or the absence of cytoprotectors. The hepatocyte lesion was evaluated by functional criteria through percentage of lactate dehydrogenase released and cell viability. The effects of the cytoprotectors prostaglandin E1 3 ηg/mL, superoxide dismutase 80 μg/mL, allopurinol 20 μM and verapamil 10-4 M were studied in this model of injury. RESULTS: Reoxygenation after hypoxia induced more significant lesion in cultured hepatocytes compared to simple hypoxia, detected by analysis of functional criteria. There was a significant reduction of percentage of lactate dehydrogenase released and a significant increase of percentage of cell viability in the hypoxia + reoxygenation + cytoprotectors groups compared to hypoxia + reoxygenation groups. Prostaglandin E1...

Modulação da viabilidade de fibroblastos cardíacos em cultura frente a hipóxia: papel de diferentes concentrações de glicose; Modulation of the viability of cardiac fibroblasts in culture against hypoxia: role of different concentrations of glucose

Malfitano, Christiane
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 20/01/2010 PT
Relevância na Pesquisa
46.18%
Estudos mostram que a exposição ao meio hiperglicêmico ou diabetes protege o coração contra insultos patológicos, incluindo isquemia. A ativação de fatores anti-apoptóticos e proliferativos parece estar envolvida com esta cardioproteção. Este estudo foi desenhado para investigar a modulação da viabilidade de fibroblastos cardíacos submetidos à hipóxia tratados previamente com meio hiperglicêmico, e os efeitos de 15 dias de infarto do miocárdio (IM) na função ventricular em ratos diabéticos sobre os fatores de morte e sobrevida celular. Foram utilizados ratos Wistar machos e as análises foram realizadas no ventrículo esquerdo. Para as análises in vitro, os fibroblastos cardíacos foram obtidos por digestão enzimática (tripsina/colagenase), e cultivados em dois meios: baixa Glicose (5mM) e alta Glicose (25mM análogo ao plasma diabético). As células confluentes (80%) foram submetidas à hipóxia por incubadora modular com gás (5,6% de CO2 e 94,4% de N2); após as células foram mantidas em estufa a 37ºC por 6; 12; 24; 48 e 72hs. Experimentos de citometria de fluxo foram realizados para análise da viabilidade celular e fragmentação de DNA, ambas para verificação de apoptose e confirmadas pelas medidas de AnexinaV/FITC/IP. A expressão do fator de crescimento endotelial vascular (VEGF) foi medida no sobrenadante dos meios por ELISA. Para as análises in vivo...

Avaliação de radiofármacos com [[99mTc]glucarato] e (18F)FAZA na determinação de hipóxia em células e tumores de melanoma murino B16F10; Evaluation of radiopharmaceuticals with [[99mTc]glucarate] and (18F)FAZA on determination of hypoxia in B16F10 murine melanoma cells and tumors

Evangelista, Monick Junho do Amaral
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 04/10/2013 PT
Relevância na Pesquisa
46.03%
A baixa oxigenação (hipóxia) altera drasticamente o metabolismo celular e a forma de produção de ATP, que em tumores pode estimular e permitir que as células desenvolvam mecanismos de escape, adaptação e resistência, contribuindo não só para um comportamento maligno e agressivo, mas também lhes conferindo resistência a tratamentos quimioterapêuticos e radioterapêuticos. A detecção de regiões de hipóxia em tumores pode ser realizada com diferentes radiofármacos. Neste trabalho preparamos e avaliamos o comportamento dos radiofármacos (18F)FAZA e [[99mTc]glucarato]- em células de melanoma murino B16F10, correlacionando dados bioquímicos e histopatológicos com a captação celular dos radiofármacos in vitro e com imagens em equipamento PET/SPECT/CT obtidas de camundongos C57Bl6 implantados com tumores. O (18F)FAZA foi obtido em rendimento de 17,9 % e pureza radioquímica de 86,72 %, enquanto que o rendimento e pureza radioquímica do [[99mTc]glucarato]- foi superior a 95 %, sendo que este complexo se liga à proteínas plasmáticas com taxa de aproximadamente 40 % e o complexo é desestabilizados pela mesmas, após 4 horas de incubação a 37 oC. O complexo também não é estável na presença de cisteína e histidina. A captação in vitro do [[99mTc]glucarato]- nas células foi da ordem de 0...

Avaliação dos efeitos de microambiente hipoxico em celulas dendriticas humanas infectadas com Leishmania amazonensis; Effect of hypoxia on human denditic cells infection by Leishmania amazonensis

Maira Cegatti Bosetto
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 04/05/2007 PT
Relevância na Pesquisa
46.1%
As células dendríticas (DCs) são potentes células apresentadoras de antígeno envolvidas principalmente na iniciação da resposta imune primária. As DCs podem ser isoladas a partir do cultivo de monócitos do sangue periférico humano realizado na presença de GM-CSF e IL-4. Protozoários do gênero Leishmania são parasitas intracelulares obrigatórios de células do Sistema Fagocítico Mononuclear como os macrófagos e as DCs. A L. amazonensis, espécie utilizada em nossos estudos, causa principalmente lesões cutâneas que podem se cronificar resultando num processo infeccioso com conseqüente hipóxia tecidual. Neste trabalho avaliamos o papel deletério/terapêutico da hipóxia em modelo in vitro de uma infecção intracelular, a leishmaniose, através da análise dos parâmetros comentados na seqüência. Culturas de DCs humanas infectadas com amastigotas de L. amazonensis foram expostas à hipóxia de 6% de oxigênio. A avaliação fenotípica das culturas indicou que a hipóxia, apesar de não afetar a viabilidade das células, reduziu a expressão dos marcadores de superfície celular CD80, CD86 e CD1a. A hipóxia não afetou a entrada do parasita nas DCs, mas modulou a atividade funcional das DCs, com diminuição da infecção em cerca de 30%. Na presença de ativadores como LPS e INF-g...

Estudos de alterações funcionais de macrofagos submetidos a hipoxia no modelo in vitro da leishmaniose; Studies of funcional alterations of macrophages submetted to hypoxia in ana in vitro model of leishmaniasis

Adriana Degrossoli
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 07/08/2009 PT
Relevância na Pesquisa
36.21%
Diversas patologias provocam mudanças na pressão parcial de oxigênio, tornando o microambiente tecidual hipóxico. O interesse em analisar as alterações fenotípicas de células em hipóxia deve-se a necessidade de entender os mecanismos patológicos e a resistência aos tratamentos e ao desenvolvimento de terapias celulares. Células como os macrófagos adaptam-se a hipóxia modificando o metabolismo e a produção de citocinas. As lesões causadas pelo parasita intracelular Leishmania amazonensis são hipóxicas e o cultivo de macrófagos (células hospedeiras da Leishmania) em hipóxia induz redução da infecção com o parasita e modula a expressão de proteínas do choque térmico, indicando alterações funcionais e estruturais em ambiente hipóxico. Neste trabalho avaliamos os mecanismos responsáveis pela resistência destas células ao parasita em hipóxia e as modificações dos macrófagos causadas por este microambiente. Macrófagos cultivados em hipóxia não apresentam alterações na produção de óxido nítrico (NO) e na expressão da sua enzima produtora, óxido nítrico sintase (iNOS). Além disso, macrófagos knockout para enzima iNOS, que não produzem NO, são capazes de reduzir a infecção por L. amazonensis semelhante a macrófagos selvagens...

Study of rat hepatocytes in primary culture submitted to hypoxia and reoxygenation: action of the cytoprotectors prostaglandin E1, superoxide dismutase, allopurinol and verapamil

Andrade Jr.,Dahir Ramos de; Andrade,Dahir Ramos de; Santos,Sânia Alves dos
Fonte: Instituto Brasileiro de Estudos e Pesquisas de Gastroenterologia - IBEPEGE ; Colégio Brasileiro de Cirurgia Digestiva - CBCD ; Sociedade Brasileira de Motilidade Digestiva - SBMD ; Federação Brasileira de Gastroenterologia - FBG; Sociedade Brasileira de Hepatologia - SBH; Sociedade Brasileira de Endoscopia Digestiva - SOBED Publicador: Instituto Brasileiro de Estudos e Pesquisas de Gastroenterologia - IBEPEGE ; Colégio Brasileiro de Cirurgia Digestiva - CBCD ; Sociedade Brasileira de Motilidade Digestiva - SBMD ; Federação Brasileira de Gastroenterologia - FBG; Sociedade Brasileira de Hepatologia - SBH; Sociedade Brasileira de Endoscopia Digestiva - SOBED
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/12/2009 EN
Relevância na Pesquisa
46.22%
CONTEXT: Exposure of hepatocytes to pathological conditions in a microenvironment of hypoxia and reoxygenation is very frequent in hepatic diseases. Several substances present perspectives for cytoprotective action on hepatocyte submitted to reoxygenation after hypoxia and simple hypoxia. OBJECTIVE: We research therapeutic options for hepatocytes submitted to hypoxia and hypoxia + reoxygenation injury. METHODS: Primary culture of rat hepatocytes was submitted to hypoxia (2 hours) plus reoxygenation (2 hours) and simple hypoxia (4 hours) in the presence or the absence of cytoprotectors. The hepatocyte lesion was evaluated by functional criteria through percentage of lactate dehydrogenase released and cell viability. The effects of the cytoprotectors prostaglandin E1 3 ηg/mL, superoxide dismutase 80 μg/mL, allopurinol 20 μM and verapamil 10-4 M were studied in this model of injury. RESULTS: Reoxygenation after hypoxia induced more significant lesion in cultured hepatocytes compared to simple hypoxia, detected by analysis of functional criteria. There was a significant reduction of percentage of lactate dehydrogenase released and a significant increase of percentage of cell viability in the hypoxia + reoxygenation + cytoprotectors groups compared to hypoxia + reoxygenation groups. Prostaglandin E1...

The blockade of cyclooxygenases-1 and -2 reduces the effects of hypoxia on endothelial cells

Gloria,M.A.; Cenedeze,M.A.; Pacheco-Silva,A.; Câmara,N.O.S.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/09/2006 EN
Relevância na Pesquisa
46.2%
Hypoxia activates endothelial cells by the action of reactive oxygen species generated in part by cyclooxygenases (COX) production enhancing leukocyte transmigration. We investigated the effect of specific COX inhibition on the function of endothelial cells exposed to hypoxia. Mouse immortalized endothelial cells were subjected to 30 min of oxygen deprivation by gas exchange. Acridine orange/ethidium bromide dyes and lactate dehydrogenase activity were used to monitor cell viability. The mRNA of COX-1 and -2 was amplified and semi-quantified before and after hypoxia in cells treated or not with indomethacin, a non-selective COX inhibitor. Expression of RANTES (regulated upon activation, normal T cell expressed and secreted) protein and the protective role of heme oxygenase-1 (HO-1) were also investigated by PCR. Gas exchange decreased partial oxygen pressure (PaO2) by 45.12 ± 5.85% (from 162 ± 10 to 73 ± 7.4 mmHg). Thirty minutes of hypoxia decreased cell viability and enhanced lactate dehydrogenase levels compared to control (73.1 ± 2.7 vs 91.2 ± 0.9%, P < 0.02; 35.96 ± 11.64 vs 22.19 ± 9.65%, P = 0.002, respectively). COX-2 and HO-1 mRNA were up-regulated after hypoxia. Indomethacin (300 µM) decreased COX-2, HO-1, hypoxia-inducible factor-1alpha and RANTES mRNA and increased cell viability after hypoxia. We conclude that blockade of COX up-regulation can ameliorate endothelial injury...

Regulation of Proliferation-Survival Decisions during Tumor Cell Hypoxia

Schmaltz, Cornelius; Hardenbergh, Patricia Harrigan; Wells, Audrey; Fisher, David E.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /05/1998 EN
Relevância na Pesquisa
46.19%
Hypoxia may influence tumor biology in paradoxically opposing ways: it is lethal as a direct stress trigger, yet hypoxic zones in solid tumors harbor viable cells which are particularly resistant to treatment and contribute importantly to disease relapse. To examine mechanisms underlying growth-survival decisions during hypoxia, we have compared genetically related transformed and untransformed fibroblast cells in vitro for proliferation, survival, clonogenicity, cell cycle, and p53 expression. Hypoxia induces G0/G1 arrest in primary fibroblasts but triggers apoptosis in oncogene-transformed derivatives. Unexpectedly, the mechanism of apoptosis is seen to require accumulated acidosis and is rescued by enhanced buffering. The direct effect of hypoxia under nonacidotic conditions is unique to transformed cells in that they override the hypoxic G0/G1 arrest of primary cells. Moreover, when uncoupled from acidosis, hypoxia enhances tumor cell viability and clonogenicity relative to normoxia. p53 is correspondingly upregulated in response to hypoxia-induced acidosis but downregulated during hypoxia without acidosis. Hypoxia may thus produce both treatment resistance and a growth advantage. Given strong evidence that hypoxic regions in solid tumors are often nonacidotic (G. Helmlinger...

Hypoxia-Inducible Factor 1α Is Essential for Cell Cycle Arrest during Hypoxia

Goda, Nobuhito; Ryan, Heather E.; Khadivi, Bahram; McNulty, Wayne; Rickert, Robert C.; Johnson, Randall S.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /01/2003 EN
Relevância na Pesquisa
36.26%
A classical cellular response to hypoxia is a cessation of growth. Hypoxia-induced growth arrest differs in different cell types but is likely an essential aspect of the response to wounding and injury. An important component of the hypoxic response is the activation of the hypoxia-inducible factor 1 (HIF-1) transcription factor. Although this transcription factor is essential for adaptation to low oxygen levels, the mechanisms through which it influences cell cycle arrest, including the degree to which it cooperates with the tumor suppressor protein p53, remain poorly understood. To determine broadly relevant aspects of HIF-1 function in primary cell growth arrest, we examined two different primary differentiated cell types which contained a deletable allele of the oxygen-sensitive component of HIF-1, the HIF-1α gene product. The two cell types were murine embryonic fibroblasts and splenic B lymphocytes; to determine how the function of HIF-1α influenced p53, we also created double-knockout (HIF-1α null, p53 null) strains and cells. In both cell types, loss of HIF-1α abolished hypoxia-induced growth arrest and did this in a p53-independent fashion. Surprisingly, in all cases, cells lacking both p53 and HIF-1α genes have completely lost the ability to alter the cell cycle in response to hypoxia. In addition...

Hypoxia modulates early events in T cell receptor-mediated activation in human T lymphocytes via Kv1.3 channels

Robbins, Jennifer R; Lee, Susan Molleran; Filipovich, Alexandra H; Szigligeti, Peter; Neumeier, Lisa; Petrovic, Milan; Conforti, Laura
Fonte: Blackwell Science Inc Publicador: Blackwell Science Inc
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
36.24%
T lymphocytes are exposed to hypoxia during their development and when they migrate to hypoxic pathological sites. Although it has been shown that hypoxia inhibits Kv1.3 channels and proliferation in human T cells, the mechanisms by which hypoxia regulates T cell activation are not fully understood. Herein we test the hypothesis that hypoxic inhibition of Kv1.3 channels induces membrane depolarization, thus modulating the increase in cytoplasmic Ca2+ that occurs during activation. Hypoxia causes membrane depolarization in human CD3+ T cells, as measured by fluorescence-activated cell sorting (FACS) with the voltage-sensitive dye DiBAC4(3). Similar depolarization is produced by the selective Kv1.3 channel blockers ShK-Dap22 and margatoxin. Furthermore, pre-exposure to such blockers prevents any further depolarization by hypoxia. Since membrane depolarization is unfavourable to the influx of Ca2+ through the CRAC channels (necessary to drive many events in T cell activation such as cytokine production and proliferation), the effect of hypoxia on T cell receptor-mediated increase in cytoplasmic Ca2+ was determined using fura-2. Hypoxia depresses the increase in Ca2+ induced by anti-CD3/CD28 antibodies in ∼50% of lymphocytes. In the remaining cells...

Hepatocyte Growth Factor and c-Met Inhibition by Hepatic Cell Hypoxia : A Potential Mechanism for Liver Regeneration Failure in Experimental Cirrhosis

Corpechot, Christophe; Barbu, Veronique; Wendum, Dominique; Chignard, Nicolas; Housset, Chantal; Poupon, Raoul; Rosmorduc, Olivier
Fonte: American Society for Investigative Pathology Publicador: American Society for Investigative Pathology
Tipo: Artigo de Revista Científica
Publicado em /02/2002 EN
Relevância na Pesquisa
46.13%
Hepatic resection in cirrhotic patients is associated with impaired liver regeneration and poor clinical outcome. Because experimental cirrhosis is associated with hepatic cell hypoxia, we herein investigated whether hypoxia might alter the mechanisms of liver regeneration in the cirrhotic liver. Cirrhosis was induced by diethylnitrosamine in rats. Immunohistochemistry was performed to assess hepatocellular hypoxia and proliferation 24 hours after a two-thirds partial hepatectomy (PH) in cirrhotic and control rats. Cultured hepatocytes and myofibroblastic hepatic stellate cells were submitted to hypoxia using anaerobic jars. Hepatocyte growth factor (HGF) and c-Met expressions were determined by reverse transcriptase-polymerase chain reaction, Northern blot, and Western blot. In control rats, hypoxia was restricted to perivenular hepatocytes, and PH induced a marked increase in hepatocyte proliferation and in liver HGF expression, whereas c-Met expression remained unchanged. In cirrhotic rats, hypoxia was detected virtually in all of the hepatocytes, and PH induced no significant change in hepatocyte proliferation and in liver HGF expression, whereas c-Met expression was decreased as compared to normal livers. In vitro, the expression of HGF in myofibroblastic hepatic stellate cells and of c-Met in hepatocytes underwent a dramatic decrease under hypoxia. Our results suggest that hepatocellular hypoxia causes inhibition of HGF (and of c-Met)-mediated proliferation and thereby might contribute to liver regeneration failure in cirrhotic liver.

Astrocytic hypoxia inducible factor 1 alpha mediates neuronal cell death in hypoxia

Vangeison, Grace Anna ; Rempe, David A.
Fonte: Universidade de Rochester Publicador: Universidade de Rochester
Tipo: Tese de Doutorado
ENG
Relevância na Pesquisa
36.25%
Thesis (Ph. D.)--University of Rochester. School of Medicine and Dentistry. Dept. of Interdepartmental Graduate Program in Neuroscience, 2008.; Following a stroke, rapid brain tissue loss is inevitable in the core of the infarct. However, surrounding regions, termed the penumbra, while metabolically compromised remain in a tenuous balance between life and death. It is therefore important to understand the molecular mechanisms that mediate cell viability in these regions in order to minimize tissue damage following a stroke. The master regulator of hypoxia, Hypoxia Inducible Factor 1 alpha (HIF-1) is the key transcription factor that is up regulated in response to hypoxia. HIF-1 is capable of inducing a wide array of targets with a diverse profile of activities, both pathological and protective. While much effort has been made to delineate the molecular mechanisms following hypoxia in neurons, little work has been done to understand the role and activities of astrocytes in these conditions. As astrocyte function is critical during normal physiology, their function in pathology is likely. The focus of this thesis is to understand how and if astrocytes can impact neuronal viability in hypoxia utilizing in vitro co-culture models of astrocytes and neurons. Specifically we are interested in the role of HIF-1 in astrocytes compared to neurons in hypoxia. We exposed co-cultures of astrocytes and neurons to hypoxia-reperfusion injury...

Complex interactions between hypoxia inducible factors, insulin-like growth Factor-II and oxygen in early murine trophoblasts

Pringle, K.; Kind, K.; Thompson, J.; Roberts, C.
Fonte: W B Saunders Co Ltd Publicador: W B Saunders Co Ltd
Tipo: Artigo de Revista Científica
Publicado em //2007 EN
Relevância na Pesquisa
46.08%
The human first trimester placenta experiences a low oxygen environment. The hypoxia inducible factors (HIFs) mediate the response to low oxygen, inducing genes such as insulin-like growth factor (IGF)-II. Interestingly, IGF-II has been shown to promote placental growth and function. Currently, the interaction between oxygen, IGF-II and HIFs in the regulation of trophoblast behaviour are unclear. Murine implantation sites from days 5.5-10.5 were collected for immunohistochemical analyses. Use of the hypoxia marker pimonidazole indicated that the early mouse implantation site is exposed to low oxygen levels similar to those seen in the early human placenta. HIF-1alpha protein immunostaining was also observed in the implantation site. Culturing murine ectoplacental cones in decreasing oxygen concentrations (20%, 5% and 1% O(2)), either with or without the addition of IGF-II, induced complex responses by trophoblasts in terms of their migration and differentiation. Following 3 days exposure to low oxygen there was reduced EPC outgrowth, reduced Igf2 and increased Tpbp mRNA levels, suggesting commitment to the spongiotrophoblast lineage. In addition, Hif-1alpha mRNA levels were decreased, whilst Hif-2alpha mRNA was unchanged. This decrease in Hif-1alpha may be due to the observed increase in antisense (as) Hif-1alpha mRNA levels in 1% cultures. Furthermore...

Hypoxia-inducible factor-2 is a novel regulator of aberrant CXCL12 expression in multiple myeloma plasma cells

Martin, S.; Diamond, P.; Williams, S.; To, L.; Peet, D.; Fujii, N.; Gronthos, S.; Harris, A.; Zannettino, A.
Fonte: Ferrata Storti Foundation Publicador: Ferrata Storti Foundation
Tipo: Artigo de Revista Científica
Publicado em //2010 EN
Relevância na Pesquisa
36.21%
Background: Multiple myeloma is an incurable malignancy of bone marrow plasma cells. Progression of multiple myeloma is accompanied by an increase in bone marrow angiogenesis. Studies from our laboratory suggest a role for the CXCL12 chemokine in this process, with circulating levels of CXCL12 correlating with bone marrow angiogenesis in patients with multiple myeloma. While the mechanisms responsible for aberrant plasma cell expression of CXCL12 remain to be determined, studies in other systems suggest a role for hypoxia and hypoxia-inducible transcription factors. Design and Methods: The expression of hypoxia-inducible factor protein was examined in patients’ bone marrow biopsy specimens using immunohistochemistry. The hypoxic regulation of CXCL12 was examined in multiple myeloma plasma cell lines using polymerase chain reaction and western blotting. The role of hypoxia-inducible factors-1 and -2 in the regulation of CXCL12 expression was examined using over-expression and short hairpin RNA knockdown constructs, electrophoretic mobility shift assays and chromatin immunoprecipitation. The contribution of CXCL12 to hypoxia-induced angiogenesis was examined in vivo using a subcutaneous murine model of neovascularization. Results: Strong hypoxia-inducible factor-2 protein expression was detected in CD138+ multiple myeloma plasma cells in patients’ biopsy specimens. Prolonged exposure to hypoxia strongly up-regulated CXCL12 expression in multiple myeloma plasma cells and hypoxia-inducible factor-2 was found to play a key role in this response. Promoter analyses revealed increased hypoxia-inducible factor-2 binding to the CXCL12 promoter under hypoxic conditions. Over-expression of hypoxia-inducible factor in multiple myeloma plasma cells strongly induced in vivo angiogenesis...

Monte Carlo modelling of tumour growth, hypoxia and radiotherapy in head and neck squamous cell carcinoma.

Harriss, Wendy Michelle
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2012
Relevância na Pesquisa
36.23%
Tumour hypoxia is the inadequate supply of oxygen in living tissue. Hypoxia is a major problem in the treatment cancer with ionising radiation because of the associated increase in radioresistance of hypoxic tumour cells. This effect can cause up to a three fold increase in the radiation dose required to kill the hypoxic cells compared to well oxygenated cells. Many locally advanced head and neck tumours exhibit hypoxia to some degree, and there is direct evidence that hypoxic tumour sub-volumes and their associated mean oxygenation levels have a direct influence on local tumour control after radiotherapy (Nordsmark 2005). Currently, head and neck cancer radiotherapy local control rates lie at approximately 80% for early stage disease, but reduce significantly (often below 50%) for locally advanced tumours. Efforts to improve these statistics through dose and fractionation modifications in randomised clinical trials have been made in recent decades using alternate fractionation schedules, but the average prognosis has not improved significantly. The effects of tumour reoxygenation during fractionated radiotherapy can assist in re-sensitising previously hypoxic tissue; however the complex dynamics and patient dependent characteristics of this phenomenon make the benefits difficult to quantify. Head and neck cancers...

Wirkungen von YC-1 (3-(5´-hydroxymethyl-2´furyl)-1-benzylindazole) auf Zellwachstum, Vitalität und Radiosensibilität von Tumorzellen unter hypoxischem Stress; Effects of YC-1 (3-(5´-hydroxymethyl-2´furyl)-1-benzylindazole) on cell growth, vitality and radiosensitivity of tumour cells in hypoxic distress

Strickmann, Sarah
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
DE_DE
Relevância na Pesquisa
36.24%
Tumorzellen in akuter aber auch in wechselnden Phasen chronischer Hypoxie sind deutlich resistenter gegenüber Bestrahlung mit ionisierenden Strahlen als Zellen, die ausreichend mit Sauerstoff versorgt sind. Gleichzeitig weist die Mehrzahl aller soliden Tumore zumindest Regionen mit erniedrigten Sauerstoffpartialdrücken auf. Dies ist eines der großen aktuellen Probleme der Strahlentherapie. Eine zentrale Rolle in diesem Anpassungsprozess spielt der Hypoxie-induzierte Transkriptionsfaktor HIF-1 (hypoxia inducible factor 1), der nicht nur die Anpassung zellulärer Stoffwechselvorgänge an Sauerstoff-reduzierte Umgebungsbedingungen reguliert, sondern auch an zahlreichen anderen regulatorischen Vorgängen beteiligt ist. In der vorliegenden Arbeit konnte gezeigt werden, dass der postulierte HIF-1 Inhibitor YC-1 die hypoxie-induzierte Expression von HIF-1 und HIF-1 regulierter Gene vermindert. Hypoxie alleine führte zu einer Reduktion der Zellproliferation, starke Hypoxie dagegen zur Induktion der Apoptose in Jurkat- und NCI-H460-Zellen, was mit mitochondrialen Veränderungen und der Aktivierung von Caspasen einherging. YC-1 verminderte das Wachstum von Tumorzellen in Normoxie und verstärkte den Hypoxie-induzierten Wachstumsarrest. Darüber hinaus wirkte YC-1 selbst zytotoxisch und verstärkte die hypoxie-induzierte Apoptose. Mögliche Mediatoren der YC-1 vermittelten zytostatischen und zytotoxischen Wirkung sind zum einen die von uns angestrebte HIF-1 Hemmung in hypoxischen Zellen...

The HIF1α-inducible pro-cell death gene BNIP3 is a novel target of SIM2s repression through cross-talk on the hypoxia response element; The HIF1 alpha-inducible pro-cell death gene BNIP3 is a novel target of SIM2s repression through cross-talk on the hypoxia response element

Farrall, A.; Whitelaw, M.
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Publicado em //2009 EN
Relevância na Pesquisa
36.22%
The short isoform of single-minded 2 (SIM2s), a basic helix–loop–helix/PAS (bHLH/PAS) transcription factor, is upregulated in pancreatic and prostate tumours; however, a mechanistic role for SIM2s in these cancers is unknown. Microarray studies in prostate DU145 cells identified the pro-cell death gene, BNIP3 (Bcl-2/adenovirus E1B 19 kDa interacting protein 3), as a novel putative target of SIM2s repression. Further validation showed BNIP3 repression in several prostate and pancreatic carcinoma-derived cell lines with ectopic expression of human SIM2s. BNIP3 levels are enhanced in prostate carcinoma cells upon short interfering (si)RNA-mediated knockdown of endogenous SIM2s. Chromatin immunoprecipitation and promoter studies show that SIM2s represses BNIP3 through its activities at the proximal promoter hypoxia response element (HRE), the site through which the bHLH/PAS family member, hypoxia-inducible factor 1α (HIF1α), induces BNIP3. SIM2s attenuates BNIP3 hypoxic induction via the HRE, and increased hypoxic induction of BNIP3 occurs with siRNA knockdown of endogenous SIM2s in prostate PC3AR+ cells. BNIP3 is implicated in hypoxia-induced cell death processes. Prolonged treatment of PC3AR+ cells with hypoxia mimetics, DP and DMOG...

A Paradoxical Role for PTEN in the Cellular Response to Hypoxia

Melonakos, Janet Hart
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação Formato: 6543234 bytes; application/pdf
Publicado em //2010 EN_US
Relevância na Pesquisa
36.21%

Regulation of cell growth is controlled by a variety of factors, including a number of oncogenes and tumor suppressors. PTEN is an inositol phosphatase that regulates cell growth by hydrolyzing the phospholipid products of PI3K. PTEN is mutated in a number of cancers, leading to its characterization as an important tumor suppressor. Recent data indicate that PTEN may also perform important functions that are independent of its phosphatase activity, most notably within the nucleus. Studies in this thesis addressed a novel role for PTEN in the regulation of the cellular response to hypoxia.

PTEN overexpression significantly increased hypoxic gene expression independent of its catalytic activity, while shRNA-mediated silencing of PTEN significantly inhibited hypoxia-mediated HRE-luciferase activity. Nuclear-localized PTEN was more effective in promoting HRE activity than nuclear-excluded PTEN. These results suggested a scaffolding function of PTEN in the hypoxic nucleus. To identify specific gene targets regulated by PTEN in hypoxia, a custom oligo-array consisting of 46 hypoxia-responsive genes was utilized following both gain- and loss-of- PTEN function. Based on real-time quantitative results, PTEN positively regulated genes involved in metabolism (PFKFB3...

Differential Angiogenic Capability and Hypoxia Responses in Glioma Stem Cells

Li, Zhizhong
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação Formato: 18566518 bytes; application/pdf
Publicado em //2009 EN_US
Relevância na Pesquisa
36.22%

Malignant gliomas are highly lethal cancers characterized by florid angiogenesis. Glioma stem cells (GSCs), enriched through CD133 (Prominin1) selection, are highly tumorigenic and therapy resistance. However, the mechanism through which GSCs promote tumor growth was largely unknown. As we noticed that tumors derived from GSCs contain widespread tumor angiogenesis, necrosis, and hemorrhage, we examined thepotential of GSCs to support tumor angiogenesis. We measured the expression of a panel of angiogenic factors secreted by GSCs. In comparison with matched non-GSC populations, GSCs consistently secreted markedly elevated levels of vascular endothelial growth factor (VEGF), which were further induced by hypoxia. In an in vitro model of angiogenesis, GSC-conditioned medium significantly increased endothelial cell migration and tube formation compared with non-GSC glioma cell-conditioned medium. The proangiogenic effects of GSCs on endothelial cells were specifically abolished by the anti-VEGF neutralizing antibody bevacizumab, which is in clinical use for cancer therapy. Furthermore, bevacizumab displayed potent antiangiogenic efficacy in vivo and suppressed growth of xenografts derived from GSCs but limited efficacy against xenografts derived from a matched non-GSC population. As hypoxia is a key regulator of angiogenesis...

Acute Oxygen Supplementation Restores Markers of Hepatocyte Energy Status and Hypoxia in Cirrhotic Rats

Harvey, Peta; Gready, Jill; Yin, Zhan-Li; Le Couteur, D; McLean, Allan
Fonte: American Society for Pharmacology and Experimental Therapeutics Publicador: American Society for Pharmacology and Experimental Therapeutics
Tipo: Artigo de Revista Científica
Relevância na Pesquisa
46.05%
The oxygen limitation hypothesis states that hepatocyte hypoxia is the mechanism determining metabolic restriction in the cirrhotic liver. Therefore we studied markers of hepatocyte energy state and cellular hypoxia in livers of normal and cirrhotic rats