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1.
Medicine (Baltimore) ; 98(40): e17370, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31577739

RESUMO

The aims of this study were to explore the expression of hypoxia inducible factor-1α (HIF-1α) and c-myc protein in triple-negative breast cancer (TNBC) and its clinical prognostic significance, and to establish a prediction model for postoperative survival of TNBC based on nomogram.A total of 87 patients with TNBC at the Department of Breast Surgery, Beijing Chaoyang Hospital, Capital Medical University from January 2012 to December 2015 were enrolled in this study. Immunohistochemistry was performed to detect the expression of HIF-1α and c-myc protein in breast cancer tissues. Cox regression analyses were performed to explore the correlation between HIF-1α/c-myc expression and clinical pathological parameters as well as prognosis. Receiver-operating characteristic curve was generated for cox multivariate analysis. A nomogram was generated based on the cox multivariate analysis, and a calibration curve was prepared for the nomogram to evaluate the consistency between the predicted probability of the nomogram and the actual observed probability. The stability of nomogram model was validated with an external cohort including 39 TNBC patients.The positive expression rates of HIF-1α and c-myc protein in breast cancer tissues were 41.4% (36/87) and 55.2% (48/87), respectively. HIF-1α expression was significantly correlated with age, tumor diameter, histological grade, lymph node status, and tumor TNM stage; c-myc expression was significantly associated with tumor diameter, histological grade, lymph node status, and tumor TNM stage. Cox univariate and multivariate analyses showed that HIF-1α and c-myc protein expression, histological grade, lymph node status, and tumor TNM stage were the independent risk factors for postoperative survival in TNBC patients. The AUC of prediction model was 0.843 (0.809-0.887). The nomogram could predict the probability of 3-year disease-free survival according to each patient's condition. The calibration curve displayed good agreement of the predicted probability with the actual observed probability, indicating that the nomogram model had great value of prediction. The external validation indicated the prediction model had good stability.HIF-1α-positive expression, c-myc positive expression, histological grade III, lymph node positive, and TNM stage III tumors suggested that TNBC patients had a poor prognosis. This prediction model can be used to predict postoperative survival of TNBC.


Assuntos
Genes myc/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Fatores Etários , Biomarcadores Tumorais , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Neoplasias de Mama Triplo Negativas/cirurgia , Carga Tumoral
2.
Int Heart J ; 60(4): 964-973, 2019 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-31257333

RESUMO

Acute myocardial infarction (AMI) is a serious heart disease and the main reason for heart failure and sudden death worldwide. This study investigated the effects of polysaccharides from Enteromorpha prolifera (PEP) on AMI in vitro and in vivo, as well as the underlying mechanisms.Human cardiac microvascular endothelial cells (HCMVEC) were cultured in vitro in an oxygen-glucose deprivation (OGD) environment to induce injury. The viability and apoptosis of HCMVEC were then detected using CCK-8 assay and Annexin V-FITC/PI staining, respectively. ELISA was performed to measure the concentrations of inflammatory cytokines. Cell transfection was conducted to reduce the expression of HIF-1α. Expression of key factors involving in cell proliferation, apoptosis, autophagy, MEK/ERK, and the NF-κB and mTOR pathways were evaluated using Western blotting. In vivo, Wistar rats were pre-treated by PEP and AMI was induced. The infarct size and cardiac functions (LVEDD, LVEF and LVFS) were measured.In vitro, PEP treatment significantly protected HCMVEC from OGD-induced viability loss, proliferation inhibition, apoptosis, inflammatory cytokine expression, and autophagy. Moreover, PEP enhanced the expression of HIF-1α in HCMVEC via the MEK/ERK pathway. HIF-1α participated in the protective effects of PEP on OGD-treated HCMVEC. Furthermore, PEP attenuated OGD-induced NF-κB pathway activation and promoted the mTOR pathway in HCMVEC. In vivo, PEP pre-treatment reduced the infarct size and enhanced the LVEDD, LVEF and LVFS of rats via up-regulation of HIF-1α.PEP ameliorated AMI in vitro and in vivo through up-regulation of HIF-1α. In vitro, PEP could activate the MEK/ERK and mTOR pathways, but inactivate the NF-κB pathway in OGD-treated HCMVEC.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Infarto do Miocárdio/genética , Polissacarídeos Bacterianos/farmacologia , RNA/genética , Regulação para Cima , Animais , Apoptose , Western Blotting , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Ratos , Ratos Wistar , Transdução de Sinais
3.
Neuroreport ; 30(9): 619-627, 2019 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-31045849

RESUMO

Exercise and other forms of physical activity lead to the activation of specific motor and cognitive circuits within the mammalian brain. These activated neuronal circuits are subjected to increased metabolic demand and must respond to transient but significant reduction in available oxygen. The transcription factor hypoxia-inducible factor 1α (HIF-1α) is a regulatory mediator of a wide spectrum of genes involved in metabolism, synaptogenesis, and blood flow. The purpose of this study was to begin to explore the potential relationship between exercise in the form of running on a motorized treadmill and the activation of genes involved in exercise-dependent neuroplasticity to begin to elucidate the underlying molecular mechanisms involved. Mice were subjected to treadmill exercise and striatal tissues analyzed with a commercial microarray designed to identify transcripts whose expression is altered by exposure to hypoxia, a condition occurring in cells under a high metabolic demand. Several candidate genes were identified, and a subset involved in metabolism and angiogenesis were selected to elucidate their temporal and regional patterns of expression with exercise. Transcript analysis included Hif1a (hypoxia-inducible factor 1α), Ldha (lactate dehydrogenase A), Slc2a1 (glucose transporter 1), Slc16a1 (monocarboxylate transporter 1), Slc16a7 (monocarboxylate transporter 2), and Vegf (vascular endothelial growth factor). Overall these results indicate that several genes involved in the elevated metabolic response with exercise are consistent with increased expression of HIF-1α suggesting a regulatory role for HIF-1α in exercise-enhanced neuroplasticity. Furthermore, these increases in gene expression appear regionally specific; occurring with brain regions we have previously shown to be sites for increased cerebral blood flow with activity. Such findings are beginning to lay down a working hypothesis that specific forms of exercise lead to circuit specific neuronal activation and can identify a potentially novel therapeutic approach to target dysfunctional behaviors subserved by such circuitry.


Assuntos
Encéfalo/metabolismo , Regulação da Expressão Gênica/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Plasticidade Neuronal/fisiologia , Condicionamento Físico Animal/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL
4.
J Ovarian Res ; 12(1): 42, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077234

RESUMO

BACKGROUND: Chemokines are involved in the homing of various cancer cells, including those of ovarian cancer (OvCa), to distant organs. They may also promote or inhibit cancer progression and metastasis. Hypoxia, a common phenomenon in malignant tumors, promotes cell proliferation regulated by HIF-1α. Hypoxia-induced genes are involved in metastasis-associated functions and in the epithelial-to-mesenchymal transition (EMT). RESULTS: Tissue microarrays of human OvCa showed elevated expression of CX3CR1 and HIF-1α compared to normal cells, and their levels were higher in adenocarcinoma stages II and III. To substantiate these observations, we performed studies using OvCa cells. Following exposure to hypoxia, OVCAR-3, SW 626, and TOV-112D cells showed high expression of CX3CR1, a transmembrane protein involved in the adhesion and migration of leukocytes, causing an increased chemotactic response to CX3CL1, the ligand for CX3CR1. As determined by flow cytometry, immunofluorescence, RT-PCR, and western blots, there were higher expressions of CX3CR1 and HIF-1α in OvCa cell lines exposed to hypoxia. Further, OvCa cells expressing CX3CR1 were sensitive to the CX3CL1 ligand. Chemotaxis based on chemokine receptors was influential in elevating the expression of EMT markers and matrix metalloproteinases, which are involved in the progression and metastasis of cancer cells. CONCLUSIONS: In OvCa cells, CX3CR1 was upregulated in a process involving hypoxia-mediated regulation of HIF-1α. The elevated levels of CX3CR1, which were sensitive to CX3CL1, increased EMT markers that led to the progression and metastasis of OvCa. Thus, CX3CR1 and HIF-1α are suitable targets for treatment of OvCa.


Assuntos
Receptor 1 de Quimiocina CX3C/biossíntese , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Receptor 1 de Quimiocina CX3C/genética , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Quimiocina CX3CL1/biossíntese , Quimiocina CX3CL1/genética , Transição Epitelial-Mesenquimal , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Invasividade Neoplásica , Neoplasias Ovarianas/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
5.
Mol Cell Biochem ; 458(1-2): 185-195, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31004308

RESUMO

In this study, we aimed to evaluate whether the encapsulation of ellagic acid (EA) into nanoliposomes would improve its potential in preventing cyclophosphamide-induced liver damage. Stability and antioxidative potential of free and encapsulated EA were determined. Experimental study conducted in vivo included ten groups of rats treated with cyclophosphamide and ellagic acid in its free and encapsulated form during 5 days. The protective effect of EA in its free and encapsulated form was determined based on serum liver function, liver tissue antioxidative capacities, and oxidative tissue damage parameters. Also, tissue morphological changes following cyclophosphamide administration were studied using standard histopathological and immunohistochemical analyses. The encapsulation of EA significantly prevented its degradation and improved its antioxidant properties in in vitro conditions. In in vivo experiments in both forms of EA were found to prevent rat liver damage induced by cyclophosphamide estimated through the changes in serum liver-damage parameters and tissue antioxidant capacities, as well as based on oxidatively modified lipids and proteins. Also, changes in morphology of liver cells and the expressions of Bcl-2, HIF-1α, and CD15 molecules in livers of animals of different experimental groups are in accordance with the obtained biochemical parameters. Thus, the encapsulation process might be effective in preventing EA from different environmental influences and could significantly increase its hepatoprotective potential. The encapsulation could prevent ellagic acid degradation and might deliver this potent compound to its target tissue in significantly larger quantities than when it is administered in its free form.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Ciclofosfamida/efeitos adversos , Ácido Elágico/farmacologia , Fígado/metabolismo , Nanopartículas , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Ciclofosfamida/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Antígenos CD15/biossíntese , Lipossomos , Fígado/lesões , Fígado/patologia , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Ratos , Ratos Wistar
6.
Gene ; 701: 169-172, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30930227

RESUMO

Therapeutic inhibition of hypoxia inducible factor-1α (HIF-1α) action has emerged as a potential approach for managing several diseases including breast cancer (BC). Genistein has been found to exert anti-malignant activity. However, its mechanisms of action remain unknown. Studies indicate that it could act by downregulating HIF-1α. Based on these findings, we investigated whether genistein could reduce HIF-1α in BC cell lines. Furthermore, we performed molecular docking studies to characterize the sites of interaction between genistein and HIF-1α. In the present investigation, we prove, for the first time, that genistein downregulates HIF-1α in BC cells. Molecular docking analysis also revealed that genistein binds to the FIH-1 binding site of HIF-1α protein. These findings thus indicate that genistein and/or HIF-1α antagonists could be a potential treatment for BC.


Assuntos
Neoplasias da Mama/química , Genisteína/química , Subunidade alfa do Fator 1 Induzível por Hipóxia/química , Simulação de Acoplamento Molecular , Proteínas de Neoplasias/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Domínio Catalítico , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Genisteína/farmacologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Proteínas de Neoplasias/biossíntese
7.
Biomed Res Int ; 2019: 6317015, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31001558

RESUMO

Background: Living at a high plateau in a very hostile environment and low oxygen levels often leads to the development of high-altitude polycythemia (HAPC) and gastric mucosal lesions caused by high-level reactive oxygen species (ROS). Hypoxia-inducible factor-1A (HIF-1A) helps maintain oxygen homeostasis by promoting the transcription of various genes and can be affected by ROS levels. To evaluate the molecular mechanism by which HAPC causes the gastric mucosal lesions, the expression of HIF-1A was measured in Tibetans with HAPC and in healthy subjects. Ultrastructural, histopathological, and immunohistochemical analyses were performed in the gastric tissues of both groups, and the expression of HIF-1A in the gastric mucosa was detected using qPCR and Western Blot. Results: The microvessel density and average diameter of gastric mucosal vessels were significantly greater in the HAPC patients than in the healthy subjects (p < 0.05). The number of red blood cells in the gastric mucosa was also significantly higher in the HAPC group than in the healthy subjects (p < 0.05). In addition, the density of the mitochondrial vacuoles and endoplasmic reticulum and pathological apoptosis were significantly increased in the gastric cells from HAPC patients compared to those from the healthy subjects. The levels of ROS and HIF-1A in the gastric mucosa were increased in HAPC patients compared to those in controls (p < 0.05). Conclusions: An increased level of HIF-1A was associated with HAPC development in the stomach of Tibetans living at a high altitude. ROS upregulated the levels of HIF-1A. Thus, ROS-mediated HIF-1A signaling transduction may be the mechanism associated with HAPC-induced gastric lesions.


Assuntos
Doença da Altitude/metabolismo , Mucosa Gástrica/metabolismo , Regulação da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Policitemia/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Adulto , Doença da Altitude/patologia , Feminino , Mucosa Gástrica/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Policitemia/patologia , Tibet
8.
Nutr. hosp ; 36(2): 315-320, mar.-abr. 2019. tab, graf, ilus
Artigo em Inglês | IBECS | ID: ibc-184324

RESUMO

Introduction: epigallocatechin-3-gallate (EGCG) is the most abundant catechin contained in green tea (Camellia sinensis) and has been associated with anti-obesity and anti-cancer effects, but the exact molecular mechanisms remain elusive. In this context, this study was designed to improve the understanding of the EGCG anti-obesity and anti-cancer action. Objectives: this study was designed to examine the effects of EGCG on the expression of genes involved in obesity and cancer pathways in the peripheral blood mononuclear cells of obese women. Material and methods: this longitudinal interventional study enrolled eleven women with severe obesity that were submitted to eight weeks of green tea (decaffeinated green tea capsules with 450.7 mg of EGCG, two capsules/day) supplementation (intervention group) and ten eutrophic women as a control group. Weight (kg), body mass index (BMI, kg/m2), fat mass (kg) and gene expression (qPCR method) were assessed before and after supplementation. HIF1-alpha (HIF1-α), phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) and rapamycin-insensitive companion of mTOR (RICTOR) were selected as potential targets. Results: after supplementation, body weight (114.9 ± 14.3 versus 115 ± 13.8 kg), body mass index (44.1 ± 3.7 versus 44.1 ± 3.9 kg/m2) and fat mass (47.6 ± 3.3 versus 47.3 ± 3.4 kg) did not change. EGCG upregulated the RICTOR and HIF1-α expression, however, did not modify PI3K expression. Conclusion: this study demonstrated that EGCG has a potential role to obesity and cancer related to obesity control and can be used not only for the purpose of weight loss, but also for the improvement of obesity-related comorbidities


Introducción: la obesidad se asocia con altos niveles de estrés oxidativo (EO) e inflamación. Existe mucha evidencia de que algunos polifenoles, como el té verde, tienen un impacto positivo en el estado del sistema operativo y consecutivamente en la inflamación. Objetivos: los propósitos de este estudio fueron: a) acceso a biomarcadores de EO en mujeres obesas y de peso normal; y b) evaluar si la suplementación con té verde tiene impacto en los biomarcadores de citoquinas inflamatorias y de EO de mujeres obesas. Métodos: evaluamos mujeres obesas (índice de masa corporal - IMC ≥ 40 kg/m²) y peso normal (IMC entre 18,5 y 24,9 kg/m²). Se utilizaron muestras de sangre para acceder al malondialdehído (MDA), la capacidad antioxidante equivalente de Trolox (TEAC) y las citoquinas inflamatorias. Elegimos al azar pacientes obesos (18 individuos) y luego les dimos suplementos de té verde durante 8 semanas. El análisis estadístico incluyó las pruebas de Shapiro-Wilk, Wilcoxon, t pareadas e independientes, p < 0,05 se consideraron significativas. Resultados: se reclutaron 42 mujeres obesas (IMC: 48,2 ± 9,3 kg/m2) y 21 de peso normal (IMC: 22,5 ± 2 kg/m2) con una edad promedio de 36,2 ± 9,1 años. Los niveles séricos de MDA fueron más altos en las personas obesas (2,52 ± 0,31 μmol/L) que en las mujeres eutróficas (2,13 ± 0,26 μmol/L; p = 0.000). Por otro lado, se observaron valores de TEAC más bajos en obesos (0,75 ± 0,06 mM) que en el grupo eutrófico (0,78 ± 0,04 mM; p = 0,009). Después de la intervención del té verde, la MDA disminuyó 4,7% y el TEAC aumentó 10%. Los niveles séricos de interleucina-6 (IL-6) disminuyeron 12,7% después del tratamiento (p = 0,03). Conclusiones: el grupo obeso tenía menor capacidad antioxidante que el eutrófico. La suplementación con té verde mejoró TEAC y MDA y redujo los niveles séricos de IL-6 en mujeres obesas


Assuntos
Humanos , Feminino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Fármacos Antiobesidade/farmacologia , Anticarcinógenos/farmacologia , Catequina/análogos & derivados , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Alvo Mecanístico do Complexo 2 de Rapamicina/biossíntese , Obesidade/genética , Obesidade/metabolismo , Catequina/farmacologia , Suplementos Nutricionais , Regulação da Expressão Gênica/efeitos dos fármacos , Obesidade/complicações , Fosfatidilinositol 3-Quinases/biossíntese , Fosfatidilinositol 3-Quinases/genética
9.
Nutr Hosp ; 36(2): 315-320, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30868903

RESUMO

Introduction: Introduction: epigallocatechin-3-gallate (EGCG) is the most abundant catechin contained in green tea (Camellia sinensis) and has been associated with anti-obesity and anti-cancer effects, but the exact molecular mechanisms remain elusive. In this context, this study was designed to improve the understanding of the EGCG anti-obesity and anti-cancer action. Objectives: this study was designed to examine the effects of EGCG on the expression of genes involved in obesity and cancer pathways in the peripheral blood mononuclear cells of obese women. Material and methods: this longitudinal interventional study enrolled eleven women with severe obesity that were submitted to eight weeks of green tea (decaffeinated green tea capsules with 450.7 mg of EGCG, two capsules/day) supplementation (intervention group) and ten eutrophic women as a control group. Weight (kg), body mass index (BMI, kg/m2), fat mass (kg) and gene expression (qPCR method) were assessed before and after supplementation. HIF1-alpha (HIF1-α), phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) and rapamycin-insensitive companion of mTOR (RICTOR) were selected as potential targets. Results: after supplementation, body weight (114.9 ± 14.3 versus 115 ± 13.8 kg), body mass index (44.1 ± 3.7 versus 44.1 ± 3.9 kg/m2) and fat mass (47.6 ± 3.3 versus 47.3 ± 3.4 kg) did not change. EGCG upregulated the RICTOR and HIF1-α expression, however, did not modify PI3K expression. Conclusion: this study demonstrated that EGCG has a potential role to obesity and cancer related to obesity control and can be used not only for the purpose of weight loss, but also for the improvement of obesity-related comorbidities.


Assuntos
Fármacos Antiobesidade/farmacologia , Anticarcinógenos/farmacologia , Catequina/análogos & derivados , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Alvo Mecanístico do Complexo 2 de Rapamicina/biossíntese , Obesidade/genética , Obesidade/metabolismo , Adolescente , Adulto , Catequina/farmacologia , Suplementos Nutricionais , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Obesidade/complicações , Fosfatidilinositol 3-Quinases/biossíntese , Fosfatidilinositol 3-Quinases/genética , Adulto Jovem
10.
Biomed Res Int ; 2019: 1937460, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30911540

RESUMO

To explore the antitumor effect of hypoxia-inducible factor-1α short hairpin RNA (HIF-1α shRNA) delivered by ultrasound targeted microbubble destruction (UTMD) and transcatheter arterial embolization (TAE) on rats with hepatic cancer. After the models of transplantation hepatoma were established, Wistar rats were randomly divided into 4 groups: Control group, UTMD group, TAE group, and UTMD+TAE group. Contrast-enhanced ultrasound (CEUS) was used to monitor tumor size on day 14 after four different treatments. Western blotting and immunohistochemistry were applied to measure the protein level of HIF-1α and VEGF in the hepatic cancer tissue. In comparison with UTMD+TAE group (21.25±10.68 days), the mean survival time was noticeably shorter in the Control group and TAE group (13.02±4.30 days and 15.03±7.32 days) (p<0.05, respectively). There was no statistical difference between UTMD+TAE group and UTMD group of the mean survival time (p>0.05). In addition, our results proved that the tumor sizes in UTMD+TAE group were obviously smaller than those in other groups (p<0.05, respectively). By CEUS, we clearly found that the tumor size was the smallest on day 14 in the UTMD+TAE group. The western blotting and immunohistochemistry results proved that the protein levels of HIF-1α and VEGF in UTMD+TAE group were obviously lower than those in TAE group and Control group on days 7 and 14 (p<0.05, respectively). However, there was no statistical difference between UTMD+TAE group and UTMD group (p>0.05). In this study we tried to explore the antitumor effect through a combination of UTMD-mediated HIF-1α shRNA transfection and TAE on rats with hepatic cancer. Our results showed that UTMD-mediated HIF-1α shRNA transfection and TAE can obviously silence HIF-1α and VEGF expression, thereby successfully inhibiting the growth of the tumor.


Assuntos
Carcinoma Hepatocelular , Embolização Terapêutica , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Neoplasias Hepáticas Experimentais , Proteínas de Neoplasias/biossíntese , RNA Interferente Pequeno/farmacologia , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Regulação Neoplásica da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Hepáticas Experimentais/genética , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Neoplasias Hepáticas Experimentais/terapia , Masculino , Proteínas de Neoplasias/genética , Ratos , Ratos Wistar , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/genética
11.
Histopathology ; 75(2): 202-212, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30882922

RESUMO

AIMS: HSP90, as a molecular chaperone, has numerous substrate proteins, including HIF-1α and p-AKT, but the relationships among HSP90, HIF-1α and p-AKT have not been investigated in NPC. We examined and analysed the correlation between expression of HSP90, HIF-1α and p-AKT and clinicopathological features of NPC. METHODS: We collected 445 cases of NPC and 54 cases of non-cancerous nasopharyngeal epithelia tissues, detected expression of HSP90, HIF-1α and p-AKT proteins in these tissues by immunohistochemistry. RESULTS: The results indicated that overexpression of HSP90, HIF-1α and p-AKT in NPC was significantly higher than that in non-cancerous nasopharyngeal epithelia (P < 0.05). The overexpression of HIF-1α in primary NPC was significantly lower than that in matched lymph node metastatic NPC (P = 0.024) or recurrent NPC (P = 0.039). The overexpression of HSP90 (P < 0.001) and HIF-1α (P = 0.031) was evidently higher in late stage NPC. NPC patients with lymph node metastasis (LNM) had a higher overexpression rate of HSP90 (P < 0.001) than those without LNM. Increased HSP90 expression was positively associated with HIF-1α expression (r = 0.367, P < 0.001) and p-AKT (r = 0.142, P = 0.003) expression in NPC. Furthermore, HIF-1α was also related to p-AKT expression (r = 0.114, P = 0.017). The overall survival rate for NPC patients with up-regulated HSP90 was significantly lower than those with down-regulated HSP90 (P < 0.001), as was found with raised HIF-1α (P = 0.036) and increased p-AKT (P = 0.044). Multivariate Cox regression analysis further identified that HSP90 and HIF-1α were independent poor prognostic factors for NPC. CONCLUSIONS: Taken together, elevated HSP90 was associated with expression of HIF-1α and p-AKT in NPC. Furthermore, high expression of HSP90 and HIF-1α could be used as a novel independent poor prognostic biomarker for patients with NPC.


Assuntos
Biomarcadores Tumorais/análise , Proteínas de Choque Térmico HSP90/biossíntese , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Adulto , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/mortalidade , Neoplasias Nasofaríngeas/mortalidade , Prognóstico , Proteínas Proto-Oncogênicas c-akt/biossíntese
12.
Gene ; 701: 41-45, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30902790

RESUMO

BACKGROUND: There is significant controversy in the literature regarding the relationship between hypoxia and salivary gland neoplasms (SGNs). OBJECTIVE: The current study aims to investigate levels of hypoxia markers in both benign and malignant salivary neoplasms. PATIENTS AND METHODS: The current study sample is comprised of a total of 62 samples. HIF-1α expression was evaluated by immunohistochemistry. Additionally, HIF-1α mRNA and miR-210 levels were assessed using qRT-PCR. RESULTS: No differences in HIF-1α expression were observed among the control group, benign and malignant SGNs. Similarly, HIF-1α mRNA levels were similar between benign and malignant SGNs. Also, there was no difference in miR-210 expression between case and control groups. CONCLUSION: The angiogenic markers, miR-210 and HIF-1α, do not appear to distinguish malignancy in salivary glands.


Assuntos
Biomarcadores Tumorais/biossíntese , Regulação Neoplásica da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Proteínas de Neoplasias/biossíntese , Neovascularização Patológica/metabolismo , Neoplasias das Glândulas Salivares , Estudos Transversais , Feminino , Humanos , Masculino , MicroRNAs/biossíntese , Neovascularização Patológica/patologia , RNA Neoplásico/biossíntese , Estudos Retrospectivos , Neoplasias das Glândulas Salivares/irrigação sanguínea , Neoplasias das Glândulas Salivares/metabolismo , Neoplasias das Glândulas Salivares/patologia
13.
J Orthop Surg Res ; 14(1): 56, 2019 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-30782196

RESUMO

BACKGROUND: Recently, many studies have shown the role of hypoxia-inducible factor-1α (HIF-1α) expression in the outcome of bone tumor. However, the results remain inconclusive. It is necessary to carry out a meta-analysis of all the current available data to clarify the relationship between HIF-1α and survival or clinicopathological features of bone tumor. METHODS: PubMed, Cochrane Library, Web of Science, China National Knowledge Internet, and Wanfang databases were used to search the relationship between HIF-1α and bone tumor. Articles investigating clinicopathological and prognostic value of HIF-1α in bone tumor patients were enrolled in this meta-analysis. Overlapping articles, duplicate data, reviews, case reports, and letters without original data were excluded. The pooled risk ratios (RRs) and hazard ratios (HRs) were used to evaluate the clinicopathological and prognostic value of HIF-1α on bone tumor patients, respectively. RESULTS: A total of 28 studies including 1443 patients were included in this meta-analysis, which were involved in three different types of bone tumor including 3 chondrosarcomas, 2 giant cell tumors of bone, and 23 osteosarcomas. Our results showed that high expression levels of HIF-1α were associated with poorer OS (overall survival) (HR = 2.61, 95% CI 2.11-3.23, P <  0.001) and shorter DFS (disease-free survival) (HR = 2.02, 95% CI 1.41-2.89, P <  0.001) in bone tumor. In addition, this study also analyzed the role of HIF-1α expression in clinicopathological features, which were closely related with the severity of bone tumor, including differentiation, clinical stage, metastasis, and microvessel density. Our results indicated that HIF-1α overexpression was significantly associated with differentiation (RR = 1.56, 95% CI 1.00-2.43, P = 0.049), clinical stage (RR = 1.75, 95% CI 1.25-2.45, P = 0.001), metastasis (RR = 1.78, 95% CI 1.58-2.00, P <  0.001), and microvessel density (SMD = 2.34, 95% CI 1.35-3.34, P <  0.001) of bone tumor. CONCLUSIONS: HIF-1α overexpression indicated an unfavorable factor for OS and DFS in bone tumor, suggesting that HIF-1α may serve as a potential prognostic marker for bone tumor.


Assuntos
Biomarcadores Tumorais/biossíntese , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/patologia , Regulação Neoplásica da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Biomarcadores Tumorais/genética , Neoplasias Ósseas/epidemiologia , China/epidemiologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Prognóstico
14.
Interact Cardiovasc Thorac Surg ; 28(6): 884-892, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668864

RESUMO

OBJECTIVES: Cardioplegic solutions induce cardiac arrest and protect cardiac tissue from ischaemia-reperfusion injury. However, the effects on the brain, which is vulnerable to cardiopulmonary bypass (CPB) surgery and ischaemia-reperfusion injury, mostly remain unknown. We investigated if cardioplegic solutions differ in their effects in altered oxygen conditions and in their ability to induce cerebral inflammation. METHODS: Thirty pigs were subjected to a midline sternotomy and CPB at 34°C with 90 min cardiac arrest followed by 120 min reperfusion. Following randomization on a 1:1:1 basis, they received either a single shot of histidine-tryptophan-α-ketoglutarate (HTK)-Bretschneider solution (n = 10), histidine-tryptophan-α-ketoglutarate-N (HTK-N; n = 10) or HTK plus 1.2 mg/l cyclosporine A (HTK/CsA; n = 10). Brain regions of interest (frontal cortex, cerebellum, brain stem, diencephalon, colliculus superior) were analysed by real time quantitative reverse transcriptase polymerase chain reaction for hypoxia-inducible factor-1α (HIF-1α), tumour necrosis factor-α, interleukin (IL)-10, IL-1ß and IL-1ß receptor as well as by immunohistochemical analysis for HIF-1α. Blood gas and electrolyte analyses were performed. RESULTS: Comparisons between baseline and reperfusion period levels revealed that HTK-N cardioplegia induced a smaller reduction of the haemoglobin content and blood calcium concentrations (hbbaseline: 5.97 ± 0.63 mmol/l; hbreperfusion: 6.16 ± 0.66 mmol/l; P = 0.428; Cabaseline2+: 1.36 ± 0.05 mmol/l; Careperfusion2+: 1.28 ± 0.05 mmol/l; P < 0.001) compared to HTK (hbbaseline: 5.93 ± 0.45 mmol/l; hbreperfusion: 4.72 ± 0.79 mmol/l; P = 0.001; Cabaseline2+: 1.34 ± 0.07 mmol/l; Careperfusion2+: 1.24 ± 0.06 mmol/l; P = 0.004) and HTK/CsA cardioplegia (hbbaseline: 5.88 ± 0.44 mmol/l; hbreperfusion: 5.14 ± 0.87 mmol/l; P = 0.040; Cabaseline2+: 1.38 ± 0.04 mmol/l; Careperfusion2+: 1.20 ± 0.14 mmol/l; P = 0.001). Brain region-specific regulation of the HIF-1α expression, no general HIF-1α activation and a lower tumour necrosis factor-α expression (pto HTK = 0.050, pto HTK/CsA = 0.013) were documented for HTK-N cardioplegia. CONCLUSIONS: HTK-N (Custodiol-N) induced fewer cerebral effects and less inflammation during CPB surgery than HTK and HTK/CsA cardioplegia. These data suggest that HTK-N exerts brain protective effects during and after CPB surgery.


Assuntos
Isquemia Encefálica/prevenção & controle , Regulação da Expressão Gênica , Parada Cardíaca Induzida/métodos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Inflamação/metabolismo , Soluções para Preservação de Órgãos/farmacologia , Animais , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Soluções Cardioplégicas/farmacologia , Ponte Cardiopulmonar/métodos , Modelos Animais de Doenças , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , RNA/genética , Distribuição Aleatória , Suínos
15.
Pathol Res Pract ; 215(3): 506-511, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30638859

RESUMO

BACKGROUND: Different studies have investigated TSGA10 expression in various cancerous tissues but, so far no study has been conducted on newly diagnosed (ND) AML patients. The association of TSGA10 gene expression with hypoxia inducible factor (HIF) and angiogenic factors has remained to be fully elucidated and is still a controversial issue. The present study was designed to investigate this association in patients newly diagnosed with AML. METHODS: We evaluated TSGA10, HIF-1α and VEGF mRNA levels in ND AML patients and healthy subjects using real-time PCR technique. Data were analyzed via comparative Livak method. RESULTS: Based on the results of this study, TSGA10 gene expression was decreased in 28 out of 30 (93.3%) samples while VEGF and HIF-1α expression levels were increased in all ND AML patients compared to healthy controls. Diagnostic evaluation was performed by receiver operating characteristic (ROC) curve and area under the curve (AUC) calculation. Respectively, using cut-off relative quantification of 1.604, 0.0329, and 0.0042, the sensitivity values of TSGA10, VEGF, and HIF-1α gene expression were 86.7%, 90%, and 100%. Also, specificity values were 100%, 100% and 100%, respectively. TSGA10 expression was shown to be reduced in ND AML patients compared with healthy subjects and we found a negative correlation between TSGA10 and VEGF expression. CONCLUSIONS: Since TSGA10 interacts with HIF-1 and affects its transcriptional activity, in ND AML patients with decreased TSGA10 expression, VEGF expression was high suggesting a TSGA10 mediated regulation of HIF-1 target genes. Altogether, the current study showed that TSGA10 could be considered as a tumor suppressor in AML patients.


Assuntos
Biomarcadores Tumorais/análise , Leucemia Mieloide Aguda/patologia , Proteínas/metabolismo , Adolescente , Adulto , Idoso , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Sensibilidade e Especificidade , Transcriptoma , Proteínas Supressoras de Tumor , Fator A de Crescimento do Endotélio Vascular/biossíntese , Adulto Jovem
16.
Neurochem Res ; 44(1): 258-268, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29589179

RESUMO

The hypoxia inducible factor 1 (HIF-1) and the cyclic AMP-responsive element binding protein (CREB) are two transcription factors that have been studied in the context of neuronal survival and neurodegeneration. HIF-1 upregulation and CREB activation have been observed not only in neurons but also in astrocytes under conditions of hypoxia. We hypothesized that activation of CREB regulate HIF-1α expression in the nucleus of cortical astrocytes under in vitro ischemic condition. To test the hypothesis, we determined the effects of inhibiting the CREB activation pathway on the expression of HIF-1α protein in astrocytes exposed to CoCl2 and severe hypoxia (near anoxia, 0.1% O2). The results demonstrated that inhibition of CaMKII and CaMKIV had no effect on both HIF-1α and pCREB expression in cortical astrocytes exposed to CoCl2 and anoxia. In contrast, PKA inhibition lowered the expression of HIF-1α and pCREB expression. Furthermore, the inhibition of PKA but not CaMKII or CaMKIV increased cell death of astrocytes exposed to near anoxia. The results suggest that PKA plays an important role in the cell survival signaling pathways in astrocytes.


Assuntos
Astrócitos/metabolismo , Córtex Cerebral/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/biossíntese , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Animais , Proteína de Ligação a CREB/biossíntese , Proteína de Ligação a CREB/genética , Hipóxia Celular/fisiologia , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/genética , Inibidores Enzimáticos/farmacologia , Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Ratos , Ratos Sprague-Dawley
17.
Exp Hematol ; 70: 55-69.e4, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30414989

RESUMO

Despite a high remission rate after therapy, only 40-50% of acute myeloid leukemia (AML) patients survive 5 years after diagnosis. The main cause of treatment failure is thought to be insufficient eradication of CD34+CD38- AML cells. In order to induce preferential cell death in CD34+CD38- AML cells, two separate events may be necessary: (1) inhibition of survival signals such as nuclear factor kappa-beta (NF-κB) and (2) induction of stress responses such as the oxidative stress response. Therefore, regimens that mediate both effects may be favorable. Deferasirox is a rationally designed oral iron chelator mainly used to reduce chronic iron overload in patients who receive long-term blood transfusions. Our study revealed that clinically relevant concentrations of deferasirox are cytotoxic in vitro to AML progenitor cells, but even more potent against the more primitive CD34+CD38- cell population. In addition, we found that deferasirox exerts its effect, at least in part, by inhibiting the NF-κB/hypoxia-induced factor 1-alpha (HIF1α) pathway and by elevating reactive oxygen species levels. We believe that, pending further characterization, deferasirox can be considered as a potential therapeutic agent for eradicating CD34+CD38- AML cells.


Assuntos
ADP-Ribosil Ciclase 1 , Antígenos CD34 , Deferasirox/farmacologia , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Quelantes de Ferro/farmacologia , Leucemia Mieloide Aguda/metabolismo , Glicoproteínas de Membrana , Proteínas de Neoplasias/biossíntese , Espécies Reativas de Oxigênio/metabolismo , Morte Celular/efeitos dos fármacos , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Masculino
18.
Biomed Pharmacother ; 109: 1688-1697, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551423

RESUMO

Hypoxia-induced oxidative stress and apoptosis are the major hallmark explanations underlying brain dysfunction. Hypoxia in the current study was induced by Cobalt chloride (CoCl2) treatment in rats. The aim of this experiment was to explore the potential ameliorative potency of Moringa oleifera ethanolic extract (MO) against experimentally induced hypoxia on the structure and function of the rat's brain. Fifty male rats were allocated to five groups (10 rats each): a control group, a MO-treated group (400 mg/kg bw, orally), a CoCl2-treated group (40 mg/kg bw/day, orally), a prophylaxis group, and a therapeutic co-treated group. Oxidative stress biomarkers and monoamine neurotransmitter were evaluated in brain tissue. In addition, qRT-PCR for expression pattern of HIF-1α, EPO, CYTO, NF-kB, and MAO-A. Glial fibrillary acidic protein (GFAP), apoptotic markers (BCL-2 and caspase 3) were detected immunohistochemically in brain cells. The results revealed a significantly lower concentration of GABA, monoamine neurotransmitter in hypoxic rat's brain. Moreover, an evident up-regulation of the mRNA expression of HIF-1α, EPO, CYTO, NF-kB, and MAO-A. There was marked encephalopathy manifested by pyknotic neurons with eosinophilic cytoplasm, vacuolations and cerebral congestions in the hypoxic rat brains. Additionally, the score of neuronal expression occupied by GFAP- positive astroglia, Caspase-3 and microglial CD68 were elevated but Bcl-2 expression was found decreased in the hypoxic group than control. The endpoints of this study clearly stated that MO ethanolic extract suggestively counteracted neurotoxic impacts caused by hypoxia, particularly when it administered prior to and concurrently with CoCl2 administration.


Assuntos
Eritropoetina/biossíntese , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Hipóxia/metabolismo , Monoaminoxidase/biossíntese , Moringa oleifera , NF-kappa B/biossíntese , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cobalto/toxicidade , Eritropoetina/genética , Expressão Gênica , Hipóxia/induzido quimicamente , Hipóxia/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Monoaminoxidase/genética , NF-kappa B/genética , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar
19.
Biomed Pharmacother ; 111: 151-161, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30579254

RESUMO

Promoting epidermal cell survival in an oxidative stress microenvironment is vital for skin regeneration after burns and/or wounds. However, few studies have explored the mediators related to epidermal cell apoptosis in an oxidative stress microenvironment. Cellular viability was determined using the MTT assay, TUNEL staining, western blot analysis and LDH release assay. Two independent siRNAs were transfected into HaCaT cell to repress INF2 and/or HIF1 in the presence of H2O2. Mitochondrial function was determined using JC-1 staining, mitochondrial ROS staining, immunofluorescence staining and western blotting. In the present study, our data demonstrated that the expression of inverted formin-2 (INF2) increased rapidly when the cells were exposed to H2O2. Interestingly, INF2 knockdown promoted HaCaT cell survival via reducing H2O2-mediated cell apoptosis. Molecular investigations demonstrated that INF2 deletion attenuated mitochondrial ROS overloading, restored the cellular redox balance, sustained the mitochondrial membrane potential, improved mitochondrial respiratory function and corrected the mitochondrial dynamics disorder in an H2O2-mimicking oxidative stress microenvironment. In addition, INF2 deletion upregulated the expression of HIF1. Interestingly, the inhibition of HIF1 increased cell death and caused mitochondrial stress despite the deletion of INF2, suggesting that the HIF1 signaling pathway is required for INF2 deletion-mediated HaCaT cell survival and mitochondrial protection. Altogether, our results identified INF2 as a novel apoptotic mediator for oxidative stress-mediated HaCaT cell death via modulating mitochondrial stress and repressing the HIF1 signaling pathway. This finding provides evidence to support the critical role played by the INF2-HIF1 axis in regulating mitochondrial stress and epidermal cell viability in an oxidative stress microenvironment.


Assuntos
Apoptose/fisiologia , Células Epidérmicas/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Proteínas dos Microfilamentos/fisiologia , Estresse Oxidativo/fisiologia , Transdução de Sinais/fisiologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Células Epidérmicas/efeitos dos fármacos , Células Epidérmicas/patologia , Humanos , Peróxido de Hidrogênio/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
20.
Am J Med Sci ; 356(2): 168-176, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30219159

RESUMO

BACKGROUND: This study aimed to investigate the interactions between silent information regulator 1 (SIRT1) and mammalian target of rapamycin (mTOR) in intraplaque angiogenesis and their potential mechanisms through in vivo and in vitro studies. METHODS: An atherosclerosis model was established in 12 rabbits on a high-cholesterol diet. The rabbits were equally divided into 3 groups: a control group (high-lipid diet), RAP group (high-lipid diet supplemented with rapamycin) and RAP + NAM group (high-lipid diet supplemented with rapamycin and nicotinamide). At the end of 4 weeks, the area of plaques in the aorta was determined and the protein expression of CD31 and vascular endothelial growth factor (VEGF) was detected through hematoxylin and eosin staining and immunohistochemical staining, respectively. For in vitro study, a hypoxia model was established in human umbilical vein endothelial cells (HUVECs) by using the chemical method (CoCl2). The MTT assay, scratch assay and tube formation assay were performed to evaluate the proliferation and angiogenesis abilities of HUVECs. Reverse transcription polymerase chain reaction was used to examine the mRNA levels of SIRT1, hypoxia-inducible factor-1α (HIF-1α), mTOR and p70 ribosomal S6 kinase (p70S6K). Western blotting was used to examine the protein levels of SIRT1, HIF-1α, mTOR, p-mTOR, p-raptor and p-p70S6K. RESULTS: The results of the in vivo study indicated a significant inhibitory effect of rapamycin on plaque size and intraplaque angiogenesis (0.05 ± 0.02mm2 versus 5.44 ± 0.50mm2, P < 0.05). This effect was attenuated by nicotinamide (0.76 ± 0.15mm2 versus 0.05 ± 0.02mm2, P < 0.05). Compared with the RAP group, CD31- and VEGF-positive vessels were abundant in the RAP + NAM group. The RAP group showed lower expression of p-mTOR, p-p70S6K and HIF-1α than did the control group (P < 0.05), whereas the RAP + NAM group showed slightly higher expression of these factors than did the RAP group (P < 0.05). Furthermore, in vitro studies revealed that the inhibitory effect of rapamycin on the angiogenic ability of HUVECs and its significant inhibitory effects on the protein level of HIF-1α and the phosphorylation of proteins involved in the mTORC1 pathway, including mTOR, raptor and p70S6K (P < 0.05), were enhanced by cotreatment with SRT1720 and rapamycin (P < 0.05). In contrast to mTOR and SIRT1, the mRNA levels of p70S6K and HIF-1α were reduced by rapamycin (P < 0.05) and further reduced by cotreatment with SRT1720 and rapamycin. CONCLUSIONS: The study results indicate that SIRT1 might negatively regulate atherosclerotic angiogenesis via mTORC1 and HIF-1α signaling pathway and cointervention of SIRT1 and mTOR may serve as a crucial therapeutic strategy in cardiovascular medicine.


Assuntos
Aterosclerose/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Neovascularização Patológica/metabolismo , Transdução de Sinais , Sirtuína 1/biossíntese , Animais , Aterosclerose/patologia , Proliferação de Células , Modelos Animais de Doenças , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Neovascularização Patológica/patologia , Coelhos , Proteínas Quinases S6 Ribossômicas 70-kDa/biossíntese , Serina-Treonina Quinases TOR/biossíntese
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