Navegando por Palavras-chave "angiogênese"
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- ItemAcesso aberto (Open Access)Assinaturas estromais e expressão de microRNAs relacionados à angiogênese em linfomas não-Hodgkin difuso de grandes células B(Universidade Federal de São Paulo (UNIFESP), 2014-11-26) Borges, Natalia Morais [UNIFESP]; Colleoni, Gisele Wally Braga [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Diffuse large B-cell lymphoma (DLBCL) is the most frequent aggressive non-Hodgkin lymphoma (NHL) and, despite advances in treatment, 30% of the cases are refractory or relapse after chemoimmunotherapy. Currently, the relationship between angiogenesis and angiomiRs in DLBCL is unknown. We classified 84 DLBCL according to stromal signatures using tissue microarray and immunohistochemistry (CD34, CD68 and SPARC). We also evaluated the expression of pro- and antiangiomiRs in paraffin embedded tissues of DLBCL by real-time PCR and correlate them with MVD. Approximately 40% of cases were classified as stromal-1, 50% were classified as stromal-2 and 10% were not classified. We observed increased expression of pro-angiomiRs Let-7f, miR-17, miR-18a, miR-19b, miR-126, miR-130a, miR-210, miR-296 and miR-378 in 14%, 57%, 30%, 45%, 12%, 12%, 56%, 58% and 48% of cases, respectively. Among antiangiomiRs we found decreased expression of miR-16, miR-20b, miR-92a, miR-221 and miR-328 in, respectively, 27%, 71%, 2%, 44% and 11%. When comparing the expression of angiomiRs with molecular subtypes according to the algorithm Hans et al. (2004) we found association between increased expression pro-angiomir miR-126, pro-angiomir miR-130a e antiangiomir miR-328 and the subtype ABC (non-GCB). However, only in the case of angiomiRs miR-16, miR-221 and miR-328 we were able to verify expression values compatible with angiogenesis, i.e., higher levels of the three antiangiomiRs in patients with low MVD and stromal-1 signature. The median overall survival has not been reached, with a maximum follow-up of 146.5 months. We observed worse outcome in Ann Arbor stage III/IV, high IPI and CD34 Quartiles III/IV (automated counting). IPI and CD34 confirmed independent impact on survival of the study group. Patients with high-risk IPI showed probability of evolving to death 3.4 times greater than the rest of the group and patients with higher MVD as automated counting (Quartiles III and IV) had chance of evolving to death two times higher than the rest of the group. MicroRNAs showed no prognostic significance in independent serum samples? cohort. Therefore, the stromal-2 signature was found in 50% of cases. We confirmed association between antiangiomirs miR-16, miR-221 and miR-328 and stromal-1 signature. Four angiomiRs emerge as potential therapeutic targets (differentially expressed in ~50% of cases): pro-angiomiRs miR-17, miR-210 and miR-296 and anti-angiomiR miR-20b. Although the four microRNAs seem to be important in DLBCL pathogenesis, they are not predictive of DLBCL onset or relapse.
- ItemSomente MetadadadosCaracterização fenotípica e funcional de macrófagos oriundos do carcinoma renal metastático após terapia gênica com endostatina(Universidade Federal de São Paulo (UNIFESP), 2015-10-31) Foguer, Karen [UNIFESP]; Marumo, Maria Helena Bellini Marumo [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)O carcinoma de célula renal (CCR) é o tipo de câncer renal mais comum e representa cerca de 3 a 5% dos tumores malignos humanos. Aproximadamente 90% desses tumores tem origem no túbulo contorcido proximal. O subtipo mais comum em adultos é o CCR de células claras (CCRcc). Grande parte dos pacientes com CCR de células claras possui mutação no gene supressor tumoral de von Hippel-Lindau (VHL), ocasionando em um aumento da transcrição de diversos fatores promotores da angiogênese. A angiogênese é um processo importante para a progressão e metástase tumoral e também na presença do infiltrado inflamatório. Os macrófagos associados ao tumor (TAMs) são os elementos mais abundantes do infiltrado inflamatório. Estes podem desempenhar atividade pró-inflamatória (macrófagos M1), sendo benéficos no combate ao crescimento tumoral, ou anti-inflamatória (macrógafos M2), favorecendo ao desenvolvimento tumoral. Inibidores endógenos da angiogênese são moléculas que estão presentes em nosso organismo em condições normais e patológicas. A endostatina (ES) é o segmento carboxi-terminal do colágeno XVIII, liberado quando há a clivagem do domínio NC1, que apresenta atividade antiangiogênica. Experimentalmente a ES tem mostrado resultados promissores no tratamento do CCR primário e metastático. Camundongos submetidos com terapia gênica com ES apresentaram diminuição no número de nódulos metastáticos com alteração do perfil do infiltrado inflamatório caracterizando uma reposta Th1. Neste trabalho avaliamos as características funcionais dos macrófagos nos nódulos metastáticos de camundongos submetidos à terapia antiangiogênica com ES. O tratamento com a ES promoveu um aumento significativo nos níveis circulantes de ES e a taxa de sobrevida foi significativamente maior nos animais tratados. Os resultados obtidos nesse projeto indicam que o tratamento antiangiogênico com ES apresenta como mecanismo antitumoral secundário a redução da população de macrófagos M2 no microambiente tumoral.
- ItemAcesso aberto (Open Access)Efeitos da prostaglandina E1 (PGE1) na gênese de capilares sanguíneos em músculo esquelético isquêmico de ratos: estudo histológico(Sociedade Brasileira de Angiologia e de Cirurgia Vascular (SBACV), 2007-12-01) Moreschi Jr., Dorival; Fagundes, Djalma José [UNIFESP]; Amado, Luiz Eduardo Bersani; Hernandes, Luzmarina; Moreschi, Hugo Karling; Universidade Estadual de Maringá Departamento de Medicina; Universidade Federal de São Paulo (UNIFESP); Universidade Estadual de Maringá Departamento de Ciências Morfofisiológicas; Pontifícia Universidade Católica de Porto AlegreBACKGROUND: Therapeutic angiogenesis is a treatment modality for patients with chronic arterial insufficiency who do not have indication for direct reconstruction or angioplasty and who were not successfully submitted to clinical treatment. Prostaglandin E1 (PGE1) is one of the drugs used for this purpose. OBJECTIVE: To study morphologic aspects in the genesis of blood capillaries in the lower limb skeletal muscle of rats submitted to ischemia under the action of intramuscular (IM) or endovenous (EV) PGE1. METHODS: Forty-eight Wistar-UEM rats were randomly distributed into three groups of 16, equally redistributed into two subgroups, observed at the 7th and 14th days as follows: one control group, which had only limb ischemia; one group with ischemia and IM injection of PGE1; and one group with ischemia and EV injection of PGE1. To analyze the results, hematoxylin-eosin (HE) and immunohistochemical staining were used. RESULTS: There was a statistically significant increase in the number of capillaries in the subgroups using IM or EV PGE1, through counting in the samples containing HE staining. Immunostaining was not efficient for the quantification of capillaries. CONCLUSIONS: IM or EV PGE1 resulted in an increase in number of capillaries in the skeletal muscle of rats submitted to ischemia after 14 days of observation, which was histologically identifiable through HE staining. Immunostaining was not successful in establishing a correlation with the increase in vessels found in HE staining.
- ItemAcesso aberto (Open Access)Efeitos do anfenaco e de sua combinação com bevacizumabe sobre a secreção de citocinas pró-angiogênicas e inflamatórias pelas células do epitélio pigmentado retiniano(Universidade Federal de São Paulo (UNIFESP), 2015-06-30) Miyamoto, Cristina [UNIFESP]; Burnier Junior, Miguel Noel Nascentes [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)OBJECTIVE: To evaluate the effects of amfenac (the active component of nepafenac) and its combination with bevacizumab on the secretion of pro-angiogenic and inflammatory cytokines by human retinal pigment epithelial cells. Additionally, to evaluate if chemical hypoxia with cobalt chloride, a hypoxia-mimicking agent, produces the same effect of the real hypoxia (hypoxia chamber) on the secretion of these cytokines by human retinal epithelial cells. METHODS: ARPE-19 cells were incubated under normoxia, chemical hypoxia, and real hypoxia. The cells were treated as follows: control, bevacizumab (0,25 mg/mL), amfenac (2 ng/mL), and the combination of bevacizumab (0,25 mg/mL) and amfenac (2,0 ng/mL). Media was harvested after 24h for sandwich ELISA-based angiogenesis and inflammation assays. The secretion of 10 pro-angiogenic cytokines: angiogenin, ANG-2, EGF, bFGF, HB-EGF, PDGF-BB, leptin, PIGF, HGF e VEGF; as well as of 10 inflammatory cytokines: IL-1?, IL-1?, IL-4, IL-6, IL-8, IL-10, IL-13, IFN-?, TNF-?, MCP-1, were measured. The viability/cytotoxicity was also assessed. RESUTS: Under normoxia, amfenac increased the secretion of ANG-2, HB-EGF, leptin, PDGF-BB, and PIGF, almost did not changed the secretion of EGF, and reduced the secretion of angiogenin, bFGF, HGF, and VEGF by ARPE-19 cells; the combination of the drugs elevated the secretion of all pro-angiogenic cytokines, except angiogenin, bFGF, and VEGF, whose secretion was diminished. Under chemical hypoxia, amfenac decreased the secretion of all pro-angiogenic cytokines, except ANG-2, whose secretion was increased, EGF whose secrection was practically unchanged and PIGF whose secretion was not detected by the method after the three treatments; the combination of the drugs reduced the secrection of all pro-angiogenic cytokines, except ANG-2 and HGF whose secretion were raised, and PIGF whose secretion was virtually the same. Under real hypoxia, amfenac increased the secretion of all pro-angiogenic cytokines, except angiogenin, bFGF and VEGF, whose secretion was decreased; the combination of the drugs increased the secretion of all pro-angiogenic cytokines, except VEGF. Under normoxia, amfenac practically did not altered the secretion of IL-1? and IL-13, reduced the secretion of IL-1?, IL-4, IL-8, and IL-10, and increased the secretion of IL-6, MCP-1, and TNF-?; the combination of the drugs virtually did not modified the secretion of IL-1?, IL-8, and IL-10, diminished the secretion of IL-1?, and increased the secretion of the remaining inflammatory cytokines. Under chemical hypoxia, amfenac practically did not changed the secretion of IL-1?, IL-1?, and IFN-?, reduced the secretion of IL-10, IL-13, and TNF-?, and elevated the secretion of all other inflammatory cytokines; the combination of the drugs virtually did not modified the secretion of IL-1?, decreased the secretion of IL-10, IL-13, and TNF-?, and increased the secretion of the remaining inflammatory cytokines. Under real hypoxia, amfenac reduced the secretion of all inflammatory cytokines; the combination of the drugs also decreased the secretion of the inflammatory cytokines apart from IFN-?, whose secretion increased; the combination of the drugs caused a more pronounced reduction in the secretion of the inflammatory cytokines (except MCP-1) compared to bevacizumab. These results were not statistically significant. All the treatments did not reduced the viability of the ARPE-19 cells under normoxia, chemical hypoxia and real hypoxia. Comparing the chemical hypoxia with cobalt chloride and the real hypoxia, the chemical hypoxia produced statistically different results regarding the secretion of 8 out of 10 pro-angiogenic cytokines (except EGF and HB-EGF), and the secretion of two inflammatory cytokines (IL-6 and IL-8). CONCLUSIONS: Amfenac reduced the secretion of pro-angiogenic cytokines (angiogenin, bFGF, and VEGF) and the secretion of all inflammatory cytokines under real hypoxia. Besides, except from MCP-1 and IFN-?, the combination of amfenac with bevacizumab tends to cause higher reduction of the levels of inflammatory cytokines secreted by ARPE-19 cells under real hypoxia than bevacizumab alone. Nepafenac may be a worth therapy for exudative AMD in combination with bevacizumab with additional benefits like the reduction of the frequency of intravitreal injections of anti-VEGF. Further studies are necessary to confirm this hypothesis. Compared with real hypoxia, the chemical hypoxia produced different results, sometimes statistically significant, regarding the levels of the pro-angiogenic and inflammatory cytokines secreted by ARPE-19 cells. This suggests that some cytokines function primarily associated with HIF-1?, while others do not.
- ItemSomente MetadadadosEfeitos do bloqueio das ações da angiotensina ii sobre um modelo murino de carcinoma de células renais(Universidade Federal de São Paulo (UNIFESP), 2014-04-07) Araujo, Wedson Ferreira [UNIFESP]; Teixeira, Vicente de Paulo Castro Teixeira [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)O carcinoma de células renais (CCR) é o câncer mais frequente entre as neoplasias renais em adultos e responde pobremente a rádio e quimioterapia. Há crescentes evidências de que o bloqueio do sistema renina angiotensina (SRA) tem efeitos antineoplásicos. Objetivo: Investigar os efeitos do bloqueio do SRA no carcinoma de células renais (CCR) em um modelo murino. Métodos: Células de carcinoma renal murino (RENCA) foram cultivadas e injetadas (1x105) no espaço subcapsular do rim esquerdo de camundongos BALB/c (8 semanas). Os animais foram divididos em quatro grupos: Grupo controle (sem tratamento), grupo ARA (losartana 100 mg/kg/dia), o grupo IECA (captopril 10 mg/kg/dia) e o grupo ARA/IECA (losartana 100 mg/kg/dia + captopril 10 mg/kg/dia). Os animais receberam fármacos por gavagem 2 dias antes da indução do tumor e continuou até a eutanásia (21 dias após a inoculação). Após o sacrifício, os rins e pulmões foram removidos, pesados e processados para a análise histopatológica. Angiogênese e a microdensidade vascular foram determinadas por avaliação imunohistoquímica para VEGF e CD34. Resultados: Todos os animais inoculados desenvolveram tumor renal. Os animais tratados apresentaram tumores menores, independentemente do regime terapêutico e menos metástases pulmonares em quantidade e dimensão em relação aos controles. As expressões de VEGF e CD34 foram significativamente menores nos tumores renais de animais tratados, quando comparados ao controle. Conclusões: Nossos resultados sugerem que o bloqueio do SRA diminui a capacidade de proliferação tumoral e o potencial metastático do carcinoma de células renais nesse modelo experimental.
- ItemAcesso aberto (Open Access)The effects of the subconjunctival injection of bevacizumab (Avastin®) on angiogenesis in the rat cornea(Academia Brasileira de Ciências, 2007-09-01) Barros, Luiz F.m.; Belfort, Rubens Junior [UNIFESP]; Universidade de São Paulo (USP); Universidade Federal de São Paulo (UNIFESP)The purpose of this study was to evaluate the effects of the use of the subconjunctival injection of bevacizumab (Avastin®) on angiogenesis in the rat cornea. Corneas of 20 Wistar male rats were cauterized with silver nitrate crystal. Animals were divided in four groups: control group (GC) that received subconjunctivally 0.02 ml of 0.9% saline solution on the day of the lesion; group GO that received subconjunctivally 0.02 ml of bevacizumab just after the lesion; group G3 that received bevacizumab on day 3 and group G5 that received bevacizumab on day 5 after lesion. Animals were euthanized on day 7. The newly formed vessels were quantified after China Ink perfusion and photographs were obtained and analyzed in a computerized system (Image Pro-Plus®). In the control group, neovascularization covered 53.56% ± 15.11 (mean ± SD) of the corneal surface, compared with 35.57% ± 18.80 (mean ± SD) in the G0 group, 30.60%±11.82 (mean±SD) in the G3 and 35.86%±0.07 (mean±SD) in the G5. The results showed an inhibition of angiogenesis when the control group was compared with all treated groups. These results suggest that subconjunctival injection of bevacizumab is able to inhibit corneal angiogenesis independently of the day of treatment.
- ItemSomente MetadadadosObtenção estrutural de um antiagiogênico das vísceras da tilápia (oreochromis niloticus)(Universidade Federal de São Paulo (UNIFESP), 2014-01-29) Souza Junior, Airton Araujo de [UNIFESP]; Nader, Helena Bonciani Nader [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Heparan sulfate (HS) and heparin are GAGs that share similar structure, yet, HS contains reduced levels of O- and N-sulfation together with lower levels of epimerized glucuronic acid; iduronic acid. It is a ubiquitously distributed in cell surface of mammals as well as in other vertebrates and invertebrates, hence, it shows a high biotechnological relevance due to its and structural diversity which leads an extensive ?interactome? and modulatory effects on several biological/pharmacological processes. Thus, the comprehension of HS structures in different cells/tissues is crucial for the total elucidation structure-function relationships. The search for heparan-like compounds in waste material from fish farming is both economical and environmental attractive since it adds value to waste products and solves issues related to waste handling, consolidating tilapia culture as a valuable new source of ecofriendly biotechnological agents. Accordingly, this work aimed on the isolation and structural characterization of a heparan sulfate from Tilapia (Orechromis niloticus) waste material, besides its potential effects on coagulation and angiogenesis. The purified compound showed the same electrophoretic behavior, in different buffer systems, of heparan sulfate from bovine sources and the structural analysis, both chromatographic and spectroscopic, proved that the Tilapia compound has strong structural similarity with HS from bovine pancreas. Also, it was demonstrated that the isolated compound has low anticoagulant activity and inhibited capillary tube formation of endothelial cells on 2D angiogenesis assay in Matrigel. Together, our data suggests the HST is a promising bioproduct that could be used to target angiogenesis in pathophysiological processes.
- ItemSomente MetadadadosPapel dos micrornas 135-a e 210 na fisiopatologia da pre-eclâmpsia(Universidade Federal de São Paulo (UNIFESP), 2016) Korkes, Henri Augusto [UNIFESP]; Oliveira, Leandro Gustavo de Oliveira [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Introduction: Preeclampsia affects 3 to 5% of all pregnancies. The disease is characterized by endothelial dysfunction and systemic inflammatory response. Recent researches on microRNAs suggest important roles for these molecules on several biological processes, including preeclampsia. Objectives: To evaluate the participation of miR-135-a and miR-210 in the pathophysiology of preeclampsia. Methods: This is a case-control study, involving in vitro and in vivo experimental models to evaluate the role of miR-135-a and miR-210 on trophoblastic invasion and hypoxia and angiogenic imbalance in placentas of women with preeclampsia. Results: miR-135-a increased trophoblastic invasion in vitro and its mechanism of action was affected by hypoxia (p<0.05). miR-135-a was able to promote spiral artery remodeling in pregnant mice (p<0.05). Preeclamptic placentas expressed higher amount of mir-210 and it was positively correlated with higher expression of total Flt (p<0.05). These results demonstrated correlation between miR-210 and the angiogenic imbalance found in preeclampsia. Conclusion: Either miR-135-a or miR-210 seem to be involved in the pathophysiology of preeclampsia. Additional functional studies must be developed in order to elucidate the role of these molecules as cause or consequence of preeclampsia and to identify specific target genes.