RESUMO
The BMP/TGFß-Smad, Notch and VEGF signaling guides formation of endothelial tip and stalk cells. However, the crosstalk of bone morphogenetic proteins (BMPs) and vascular endothelial growth factor receptor 2 (VEGFR2) signaling has remained largely unknown. We demonstrate that BMP family members regulate VEGFR2 and Notch signaling, and act via TAZ-Hippo signaling pathway. BMPs were found to be regulated after VEGF gene transfer in C57/Bl6 mice and in a porcine myocardial ischemia model. BMPs 2/4/6 were identified as endothelium-specific targets of VEGF. BMP2 modulated VEGF-mediated endothelial sprouting via Delta like Canonical Notch Ligand 4 (DLL4). BMP6 modulated VEGF signaling by regulating VEGFR2 expression and acted via Hippo signaling effector TAZ, known to regulate cell survival/proliferation, and to be dysregulated in cancer. In a matrigel plug assay in nude mice BMP6 was further demonstrated to induce angiogenesis. BMP6 is the first member of BMP family found to directly regulate both Hippo signaling and neovessel formation. It may thus serve as a target in pro/anti-angiogenic therapies.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína Morfogenética Óssea 6/metabolismo , Células Endoteliais/metabolismo , Neovascularização Fisiológica , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Sequência de Bases , Proteína Morfogenética Óssea 2/metabolismo , Hipóxia Celular , Núcleo Celular/metabolismo , Via de Sinalização Hippo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Modelos Biológicos , Transporte Proteico , Suínos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: High grade serous ovarian carcinoma (HGSOC) is the most common subtype of epithelial ovarian cancers (EOC) with poor prognosis. In most cases EOC is widely disseminated at the time of diagnosis. Despite the optimal cytoreductive surgery and chemotherapy most patients develop chemoresistance, and the 5-year overall survival being only 25-35%. METHODS: Here we analyzed the gene expression profiles of 10 primary HGSOC tumors and 10 related omental metastases using RNA sequencing and identified 100 differentially expressed genes. RESULTS: The differentially expressed genes were associated with decreased embryogenesis and vasculogenesis and increased cellular proliferation and organismal death. Top upstream regulators responsible for this gene signature were NR5A1, GATA4, FOXL2, TP53 and BMP7. A subset of these genes were highly expressed in the ovarian cancer among the cancer transcriptomes of The Cancer Genome Atlas. Importantly, the metastatic gene signature was suggestive of poor survival in TCGA data based on gene enrichment analysis. CONCLUSION: By comparing the gene expression profiles of primary HGSOC tumors and their matched metastasis, we provide evidence that a signature of 100 genes is able to separate these two sample types and potentially predict patient survival. Our study identifies functional categories of genes and transcription factors that could play important roles in promoting metastases and serve as markers for cancer prognosis.
Assuntos
Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Perfilação da Expressão Gênica , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Transcriptoma , Carcinoma Epitelial do Ovário/mortalidade , Linhagem Celular Tumoral , Biologia Computacional/métodos , Feminino , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Estimativa de Kaplan-Meier , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias Ovarianas/mortalidadeRESUMO
The effect of surfactant on the rheological properties of some cream formulations was studied. Two surfactants from two different series were combined to determine the combination which yielded the most viscoelastic structure for creams. The surfactants were the soybean derivatives soya sterol, polyethylene glycol 10 soya sterol and polyethylene glycol 25 soya sterol and the sorbitol derivatives sorbitan monooleate and sorbitan trioleate. The rheological properties of the creams were studied using oscillation stress sweep, oscillation frequency sweep and viscosity tests. Droplet size distribution and conductivity of the creams were also determined. The combination polyethylene glycol 10 soya sterol and sorbitan trioleate yielded the most viscoelastic structure with linearly viscoelastic behaviour.
Assuntos
Pomadas/química , Reologia/métodos , Tensoativos/química , Condutividade Elétrica , Excipientes , Ligação de Hidrogênio , Tamanho da Partícula , ViscosidadeRESUMO
The effects of graded doses of ethyl alcohol on defence behaviour were studied in nine cats: 0.25 g/kg of body weight had a slight but not significant excitatory effect, 0.5 and 1.0 g/kg had no effect and 1.5 g/kg significantly depressed some behavior components. When taking the scores for all the manifestations combined as an index of gross behaviour, 0.25 significantly intensified, 0.5 and 1.0 did not change and 1.5 g alcohol/kg significantly depressed defence. These results are consistent with the expected effects of alcohol on physiological functions in general.
