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1.
Life Sci ; 274: 119345, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33713666

RESUMO

AIMS: Clinical studies suggest altered systemic vascular biology in cancer patients. We assessed expression patterns of endothelial activation- and vascular leakage-related genes in tumor as well as in tumor-free peripheral tissues from patients with and without ovarian cancer (OC). MAIN METHODS: Patients being scheduled for laparotomy for either gynecologic benign diagnosis (n = 10) or for advanced-stage OC (n = 22) were prospectively recruited to this observational study. Serum samples were taken preoperatively, and tissue samples were taken from peripheral abdominal wall musculature, tumor-free peritoneum and the tumor itself. KEY FINDINGS: Patients in OC group received significantly more fluid per time intraoperatively (p = 0.01). IL-8 and MCP-1/CCL2, VCAM-1 (CD 106) and ICAM-1 (CD 54) as well as Thrombomodulin were significantly increased in cancer patients' serum at baseline (p = 0.03). Expression of distinct vascular leakage-related genes (Angiopoietin-1 (ANG-1), ANG-2, TIE2, VEGFR1, VEGFR2) was significantly altered in tumor tissue of OC patients (p = 0.003), while in tumor-free peritoneal tissue, ANG-2/1 expression ratio was more than doubled in OC group (p = 0.03). In peripheral musculature, particularly genes from the ANG/TIE axis were significantly changed in OC patients (p = 0.005), suggesting a distinct vascular leakage-related genotype. Gene expression changes in OC patients were significantly associated with the postoperative fluid balance (p = 0.03). SIGNIFICANCE: Altered expression of barrier dysfunction- and angiogenesis-associated genes from the ANG/TIE axis was detected not only in tumor but also in peripheral tissues of cancer patients. This may contribute to a systemic vascular leakage-related genotype.


Assuntos
Angiopoietina-1/metabolismo , Angiopoietina-2/metabolismo , Neoplasias Ovarianas/patologia , Peritônio/metabolismo , Receptor TIE-2/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Angiopoietina-1/genética , Angiopoietina-2/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Prognóstico , Estudos Prospectivos , Receptor TIE-2/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
2.
Zhen Ci Yan Jiu ; 46(2): 95-9, 2021 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-33788428

RESUMO

OBJECTIVE: To observe the effect of moxibustion on the growth of tumor and expression of fibroblast growth factor receptor 1 (FGFR1) and vascular endothelial cell growth factor receptor 2 (VEGFR2) in mice with sarcoma, so as to explore its mechanisms underlying inhibiting sarcoma growth. METHODS: C57BL/6J mice (half male and half female) were inoculated with S180 sarcoma cells to form transplanted tumors, and divided into model control, medication and moxibustion groups, with 10 mice in each group. Moxibustion was applied to the transplanted tumor directly for 10 min, once a day for 14 days. After the treatment, Luminex liquid suspension chip was used to detect the contents of serum vascular endothelial growth factor (VEGF), FGFR1 and VEGFR2. The weight of the transplanted tumor was measured, and the expression of VEGF in the transplanted tumor was detected by immunohistochemistry, and the expression of FGFR1 and VEGFR2 mRNAs in the transplanted tumor was detected by fluorescence in situ hybridization. RESULTS: The tumor weight, VEGF immunoactivity, serum VEGF, VEGFR2 and FGFR1 contents, and expression levels of VEGFR2 and FGFR1 mRNAs in the transplanted tumor were significantly lower in the moxibustion group than in the model group (P<0.001, P<0.01, P<0.05). Compared with the model group, the tumor weight was remarkably lower in the medication group (P<0.001). Compared with the medication group, th VEGF immunoactivity and the contents of serum VEGF, VEGFR2 and FGFR1 were significantly lower in the moxibustion group (P<0.01, P<0.05). H.E. staining showed a large number of red blood cells were observed in the microenvironment of the transplanted tumor in the moxibustion group rather than in the medication group. CONCLUSION: Moxibustion can inhibit the growth of tumor in mice with sarcoma, which may be related to its function in reducing the expression of FGFR1 and VEGFR2 to inhibit angiogenesis.


Assuntos
Moxibustão , Sarcoma , Animais , Feminino , Hibridização in Situ Fluorescente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Sarcoma/genética , Sarcoma/terapia , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
3.
Life Sci ; 276: 119401, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33785341

RESUMO

As an ambiguous member of vascular endothelial growth factor family, VEGF-B has long been poorly understood in its function. Recent researches showed VEGF-B isoforms exerted their metabolic effect through indirectly activating the VEGF-A/VEGFR2 pathway. Here, we report the lipid-lowing effect of VEGF-B via VEGFR1. We investigated the effect of VEGF-B on lipid metabolism in vivo and in vitro approaches. Treatment of mice with VEGF-B recombinant protein repressed HFD-induced body weight gain. This treatment also alleviated obesity associated hyperlipidemia and fatty liver disease. In the muscle and liver of VEGF-B-treated HFD mice were observed increased protein expression of carnitine palmitoyltransferase-1 (CPT-1) and the phosphorylation of ACC and AMP-activated protein kinase (AMPK). This effect was confirmed in HepG2 cells incubated with VEFG-B in which the increased AMPK activation and CPT-1 expression occurs due to activation of Calcium/calmodulin-dependent Protein Kinase ß (CaMKKß) by VEFG-B. VEGF-B increased expression of key genes responsible for lipid oxidation while reducing those for fatty acid synthesis in vivo and in vitro. In addition, the selective inhibitor of VEGFR1 blocked the lipid clearance effect of VEGF-B in HepG2. Our study unraveled unknown role of VEGF-B/VEGFR1 signaling in regulating lipid metabolism. Furthermore, our findings indicate that VEGF-B may have beneficial effects for the treatment of dyslipidemia.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Intolerância à Glucose/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese , Fator B de Crescimento do Endotélio Vascular/administração & dosagem , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Animais , Dieta Hiperlipídica/efeitos adversos , Intolerância à Glucose/etiologia , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosforilação , Transdução de Sinais , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
4.
Mol Biol (Mosk) ; 55(1): 118-125, 2021.
Artigo em Russo | MEDLINE | ID: mdl-33566031

RESUMO

Crosstalk between the estrogen receptors and the receptor tyrosine kinases, including vascular endothelial growth factor receptor type II (VEGFR2), is a key mechanism in breast cancer resistance to antiestrogen therapy with tamoxifen. A high level of VEGFR2 expression in a tumor serves as a marker of tamoxifen resistance. The tamoxifen efficacy prognostic value of functional polymorphisms in the VEGFR2/KDR gene has not been established. Using qRT-PCR, we detected the rs2071559 and the rs2305948 variants and the levels of KDR gene expression in 122 breast tumor tissue samples from cohorts of patients with progression (distant metastases or relapse) and patients with no progression during tamoxifen therapy. The expression levels of VEGFR2 protein were analyzed by immunohistochemistry. The frequency of heterozygous and mutant genotypes of the rs2305948 SNP was significantly higher in patients without progression than in the cohort with progression. KDR rs2305948 was associated with high survival rates in breast cancer patients. A correlation between the mRNA of the ESR1 and KDR genes in patients without progression was detected. The results indicate the prognostic value of rs2305948 and its potential contribution to the tumor phenotype sensitive to tamoxifen.


Assuntos
Neoplasias da Mama , Fator A de Crescimento do Endotélio Vascular , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Estrogênios , Humanos , Tamoxifeno/uso terapêutico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
5.
Vet J ; 269: 105621, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33593493

RESUMO

Ponatinib is a broad-spectrum tyrosine kinase inhibitor that targets numerous receptor tyrosine kinases (RTKs), including but not limited to fibroblast growth factor receptor (FGFR)-1, platelet derived growth factor receptor (PDGFR)-α, and vascular endothelial growth factor receptor (VEGFR)-2. This study evaluated the expression of FGFR-1, PDGFR-α, and VEGFR-2 in three canine mast cell tumor (MCT) cell lines (CM-MC1, VI-MC1, CoMS) and the effects of ponatinib on these MCT cell lines. Quantitative RT-PCR confirmed the expression of FGFR-1, PDGFR-α, and VEGFR-2 in the three MCT cell lines. Ponatinib exhibited dose- and time-dependent cytotoxicity in MCT cell lines via MTT assay. The IC50 for 24, 48, and 72 h across the three cell lines ranged from 38.47 nM to 103.3 nM, which is clinically comparable to dose ranges established for humans. Significantly increased apoptosis in each cell line was seen between 12 and 18 h after treatment with IC50 of ponatinib via Annexin-V and Caspase-3/7 assays. These data suggest that ponatinib could be a possible therapeutic agent for canine MCTs. Further studies are needed to investigate the prognostic value of FGFR-1, PDGFR-α, and VEGFR-2 in canine MCTs.


Assuntos
Antineoplásicos/farmacologia , Doenças do Cão/tratamento farmacológico , Imidazóis/farmacologia , Mastócitos/patologia , Piridazinas/farmacologia , Receptores Proteína Tirosina Quinases/genética , Neoplasias Cutâneas/veterinária , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Doenças do Cão/enzimologia , Cães , Expressão Gênica , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/patologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
6.
Nat Cell Biol ; 23(1): 61-74, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33420489

RESUMO

Extra-embryonic mesoderm (ExM)-composed of the earliest cells that traverse the primitive streak-gives rise to the endothelium as well as haematopoietic progenitors in the developing yolk sac. How a specific subset of ExM becomes committed to a haematopoietic fate remains unclear. Here we demonstrate using an embryonic stem cell model that transient expression of the T-box transcription factor Eomesodermin (Eomes) governs haemogenic competency of ExM. Eomes regulates the accessibility of enhancers that the transcription factor stem cell leukaemia (SCL) normally utilizes to specify primitive erythrocytes and is essential for the normal development of Runx1+ haemogenic endothelium. Single-cell RNA sequencing suggests that Eomes loss of function profoundly blocks the formation of blood progenitors but not specification of Flk-1+ haematoendothelial progenitors. Our findings place Eomes at the top of the transcriptional hierarchy regulating early blood formation and suggest that haemogenic competence is endowed earlier during embryonic development than was previously appreciated.


Assuntos
Células-Tronco Embrionárias/citologia , Hemangioblastos/citologia , Mesoderma/citologia , Proteínas com Domínio T/fisiologia , Saco Vitelino/citologia , Animais , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Células-Tronco Embrionárias/metabolismo , Feminino , Hemangioblastos/metabolismo , Masculino , Mesoderma/metabolismo , Camundongos Knockout , Gravidez , RNA-Seq , Análise de Célula Única , Proteína 1 de Leucemia Linfocítica Aguda de Células T/genética , Proteína 1 de Leucemia Linfocítica Aguda de Células T/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Saco Vitelino/metabolismo
7.
Cancer Lett ; 496: 84-92, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33035615

RESUMO

In cancer genomics, recurrence of mutations in gene families that share homologous domains has recently emerged as a reliable indicator of functional impact and can be exploited to reveal the pro-oncogenic effect of previously uncharacterized variants. Pan-cancer analyses of mutation hotspots in the catalytic domain of a subset of tyrosine kinase receptors revealed that two infrequent mutations of VEGFR2 (R1051Q and D1052N) recur in analogous proteins and correlate with reduced patient survival. Functional validation showed that both R1051Q and D1052N mutations increase the enzymatic activity of VEGFR2. The expression of VEGFR2R1051Q potentiates the PI3K/Akt signaling axis in cancer cells, increasing their tumorigenic potential in vitro and in vivo. In addition, it confers to cancer cells an increased sensitivity to the VEGFR2-targeted tyrosine kinase inhibitor Linifanib. In the context of an efficacious application of anti-cancer targeted therapies, these findings indicate that the screening for uncharacterized mutations, like VEGFR2R1051Q, may help to predict patient prognosis and drug response, with significant clinical implications.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/secundário , Melanoma/patologia , Mutação , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Fosforilação , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Taxa de Sobrevida , Células Tumorais Cultivadas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de Xenoenxerto
8.
PLoS One ; 15(10): e0228695, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33022007

RESUMO

Aedes aegypti is the main vector of dengue, chikungunya, and Zika viruses, which are of great public health importance in Colombia. Aedes control strategies in Colombia rely heavily on the use of organophosphate and pyrethroid insecticides, providing constant selection pressure and the emergence of resistant populations. In recent years, insecticide use has increased due to the increased incidence of dengue and recent introductions of chikungunya and Zika. In the present study, pyrethroid resistance was studied across six populations of Ae. aegypti from the Caribbean coast of Colombia. Susceptibility to λ-cyhalothrin, deltamethrin, and permethrin was assessed, and resistance intensity was determined. Activity levels of enzymes associated with resistance were measured, and the frequencies of three kdr alleles (V1016I, F1534C, V410L) were calculated. Results showed variations in pyrethroid susceptibility across Ae. aegypti populations and altered enzyme activity levels were detected. The kdr alleles were detected in all populations, with high variations in frequencies: V1016I (frequency ranging from 0.15-0.70), F1534C (range 0.94-1.00), and V410L (range 0.05-0.72). In assays of phenotyped individuals, associations were observed between the presence of V1016I, F1534C, and V410L alleles and resistance to the evaluated pyrethroids, as well as between the VI1016/CC1534/VL410 tri-locus genotype and λ-cyhalothrin and permethrin resistance. The results of the present study contribute to the knowledge of the mechanisms underlying the resistance to key pyrethroids used to control Ae. aegypti along the Caribbean coast of Colombia.


Assuntos
Aedes/genética , Resistência a Inseticidas , Mutação , Piretrinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Aedes/efeitos dos fármacos , Animais , Colômbia , Frequência do Gene , Proteínas de Insetos/genética , Masculino , Nitrilos/farmacologia , Permetrina/farmacologia , Fenótipo
9.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(9): 1061-1067, 2020.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-33051419

RESUMO

OBJECTIVES: To evaluate the expression of myeloid ecotropic viral integration site 1 (Meis1) and vascular endothelial growth factor receptor 2 (VEGFR-2) in early-stage kidney cancers and the clinical significance. METHODS: The cancer tissues and the matched adjacent normal tissues in patients with kidney cancer, who received surgical treatment from April 2005 to September 2018 in the Haikou Hospital Affiliated to Xiangya School of Medicine, Central South University, were collected. The samples included 80 pairs of paraffin specimen, 15 pairs of fresh cancer and the matched adjacent normal tissues from these patients. Real-time PCR and immunohistochemical method were used to detect the expression levels of Meis1 and VEGFR-2 mRNA and protein in kidney tissues and adjacent normal tissues, and the correlation of clinical pathology parameters and the prognosis were analyzed in the patients. RESULTS: The expression levels of Meis1 and VEGFR-2 mRNA and protein in the renal carcinoma tissues were lower than those in the matched adjacent normal tissues (both P<0.01), and the expression levels of Meis1 were positively correlated with that of VEGFR-2 (r=0.681, P<0.01). The analysis of relevant clinical-pathological parameters in the patients showed that: the expression positive rate of Meis1 was significantly related with the pathological type of renal cancer (P<0.01), while the positive rate of Meis1 and VEGFR-2 expression was not related with the gender, age, T stage of patients (all P>0.05), but it was significantly related with the prognosis in the patients (P<0.05). Cox regression analysis showed that: Meis1 was an independent factor for the prognosis of patients (P<0.05). CONCLUSIONS: The mRNA and protein expression levels of Meis1 and VEGFR-2 in the early-stage kidney cancer tissues are significantly decreased compared with those in the adjacent normal tissues. Meis1 may be served as a tumor suppressor to affect the occurrence and development of kidney cancer. Therefore, Meis1 may be used as a biomarker to predict the prognosis of patients with kidney cancer.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Proteína Meis1 , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Neoplasias Renais/genética , Proteína Meis1/metabolismo , Prognóstico , Fator A de Crescimento do Endotélio Vascular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
10.
Nat Commun ; 11(1): 5400, 2020 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-33106502

RESUMO

Slug (SNAI2), a member of the well-conserved Snail family of transcription factors, has multiple developmental roles, including in epithelial-to-mesenchymal transition (EMT). Here, we show that Slug is critical for the pathological angiogenesis needed to sustain tumor growth, and transiently necessary for normal developmental angiogenesis. We find that Slug upregulation in angiogenic endothelial cells (EC) regulates an EMT-like suite of target genes, and suppresses Dll4-Notch signaling thereby promoting VEGFR2 expression. Both EC-specific Slug re-expression and reduced Notch signaling, either by γ-secretase inhibition or loss of Dll4, rescue retinal angiogenesis in SlugKO mice. Conversely, inhibition of VEGF signaling prevents excessive angiogenic sprouting of Slug overexpressing EC. Finally, endothelial Slug (but not Snail) is activated by the pro-angiogenic factor SDF1α via its canonical receptor CXCR4 and the MAP kinase ERK5. Altogether, our data support a critical role for Slug in determining the angiogenic response during development and disease.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Células Endoteliais/metabolismo , Neovascularização Patológica/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas de Ligação ao Cálcio/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neovascularização Patológica/genética , Receptores Notch/genética , Receptores Notch/metabolismo , Transdução de Sinais , Fatores de Transcrição da Família Snail/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
11.
Nat Commun ; 11(1): 3866, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737287

RESUMO

Upon severe head injury (HI), blood vessels of the meninges and brain parenchyma are inevitably damaged. While limited vascular regeneration of the injured brain has been studied extensively, our understanding of meningeal vascular regeneration following head injury is quite limited. Here, we identify key pathways governing meningeal vascular regeneration following HI. Rapid and complete vascular regeneration in the meninges is predominantly driven by VEGFR2 signaling. Substantial increase of VEGFR2 is observed in both human patients and mouse models of HI, and endothelial cell-specific deletion of Vegfr2 in the latter inhibits meningeal vascular regeneration. We further identify the facilitating, stabilizing and arresting roles of Tie2, PDGFRß and Dll4 signaling, respectively, in meningeal vascular regeneration. Prolonged inhibition of this angiogenic process following HI compromises immunological and stromal integrity of the injured meninges. These findings establish a molecular framework for meningeal vascular regeneration after HI, and may guide development of wound healing therapeutics.


Assuntos
Traumatismos Craniocerebrais/genética , Células Endoteliais/metabolismo , Neovascularização Fisiológica/genética , Regeneração/genética , Transdução de Sinais/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Circulação Cerebrovascular , Traumatismos Craniocerebrais/metabolismo , Traumatismos Craniocerebrais/patologia , Modelos Animais de Doenças , Células Endoteliais/patologia , Regulação da Expressão Gênica/genética , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Meninges/lesões , Meninges/metabolismo , Camundongos , Camundongos Knockout , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor TIE-2/genética , Receptor TIE-2/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Cicatrização/genética
12.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 51(4): 556-561, 2020 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-32691567

RESUMO

Objective: To explore the related risk factors of hemorrhage in human brain cerebral arteriovenous malformations (AVM) and the relationship between endothelial progenitor cells (EPCs) content and stromal cell-derived factor-1 (SDF-1) in different ages. Methods: A retrospective analysis was conducted on 130 patients with cerebral AVM who underwent surgical treatment from May 2012 to October 2018. Univariate and multivariate logistic analysis was used to investigate the related risk factors of cerebral AVM hemorrhage. Forty paraffin specimens of human brain AVM were harvested from 24 cases of cerebral hemorrhage patients and 16 cases of non-cerebral hemorrhage patients Paraffin samples of cerebral cortex from 8 patients with epilepsy during the same period were selected as control. Positive expression of CD34 and vascular endothelial growth factor receptor 2 (KDR2) in brain tissue samples of both groups were used to identify EPCs. Immunofluorescence double staining was used for KDR2 and CD34 positive localization to determine EPCs localization, and SDF-1 expression detection was performed. Results: The size of brain AVM<3 cm, deep brain AVM and single venous drainage are independent risk factors for cerebral AVM hemorrhage. Immunohistochemical results showed that CD34 and KDR2 were expressed in cerebral AVM group, but not in the control group. Double immunofluorescence staining showed that EPCs mainly existed at the edge of vascular wall, while SDF-1 could co-stain with alpha-smooth muscle actin (α-SMA) positive cells and CD31 positive cells. SDF-1 expression in brain AVM tissue was higher than that in control group. There were significant differences in the number of EPCs among the patients of different ages ( P<0.05). There was no significant difference in EPCs between cerebral hemorrhage group and non-hemorrhage group ( P>0.05). Conclusion: Brain AVM (<3 cm), single venous drainage and deep brain AVM are independent risk factors for cerebral AVM hemorrhage. In human brain AVM, EPC appears high level but decrease with age, which may play a role in vascular remodeling in AVM.


Assuntos
Encéfalo , Hemorragia Cerebral , Quimiocina CXCL12 , Células Progenitoras Endoteliais , Malformações Arteriovenosas Intracranianas , Antígenos CD34/genética , Encéfalo/fisiopatologia , Hemorragia Cerebral/etiologia , Hemorragia Cerebral/genética , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Malformações Arteriovenosas Intracranianas/complicações , Malformações Arteriovenosas Intracranianas/genética , Estudos Retrospectivos , Fatores de Risco , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
13.
Gene ; 754: 144856, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32512160

RESUMO

Growing evidence indicates the antitumor and antiangiogenesis activities of testis-specific gene antigen 10 (TSGA10). However, the underlying mechanisms and precise role of TSGA10 in angiogenesis are still elusive. In this study, we isolated human umbilical cord vein endothelial cells (HUVECs) and stably transfected with pcDNA3.1 carrying TSGA10 coding sequence. We demonstrated that TSGA10 over-expression significantly decreases HUVEC tubulogenesis and interconnected capillary network formation. HUVECs over-expressing TSGA10 exhibited a significant decrease in migration and proliferation rates. TSGA10 over-expression markedly decreased expression of angiogenesis-related genes, including VEGF-A, VEGFR-2, Ang-1, Ang-2, and Tie-2. Our ELISA results showed the decrease in VEGF-A mRNA expression level is associated with a significant decrease in its protein secretion. Additionally, over-expressing TSGA10 decreased expression levels of marker genes of cell migration (MMP-2, MMP-9, and SDF-1a) and proliferation (PCNA and Ki-67. Furthermore, ERK-1 and AKT phosphorylation significantly reduced in HUVECs over-expressing TSGA10. Our findings suggest a potent anti-angiogenesis activity of TSGA10 in HUVECs through down-regulation of ERK and AKT signalling pathways, and may provide therapeutic benefits for the management of different pathological angiogenesis.


Assuntos
Inibidores da Angiogênese/metabolismo , Movimento Celular , Proliferação de Células , Proteínas do Citoesqueleto/metabolismo , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Neovascularização Fisiológica , Inibidores da Angiogênese/genética , Proteínas do Citoesqueleto/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Transdução de Sinais , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
14.
Vascul Pharmacol ; 131: 106762, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32585188

RESUMO

4-hydroxynonenal (4HNE) is a reactive aldehyde, which is involved in oxidative stress associated pathogenesis. The cellular toxicity of 4HNE is mitigated by aldehyde dehydrogenase (ALDH) 2. Thus, we hypothesize that ALDH2 inhibition exacerbates 4HNE-induced decrease in coronary endothelial cell (EC) migration in vitro. To test our hypothesis, we pharmacologically inhibited ALDH2 in cultured mouse coronary ECs (MCECs) by disulfiram (DSF) (2.5 µM) before challenging the cells with different doses of 4HNE (25, 50 and 75 µM) for 4, 12, 16 and 24 h. We evaluated MCEC migration by scratch wound migration assay. 4HNE attenuated MCEC migration significantly relative to control (P < .05), which was exacerbated with DSF pretreatment (P < .05). DSF pretreatment exacerbated 4HNE-induced decrease in ALDH2 activity in MCECs. Next, we showed that 75 µM 4HNE significantly decreased the intracellular mRNA levels of vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), focal adhesion kinase (FAK) and other promigratory genes compared to control, which were further decreased by DSF pretreatment. 75 µM 4HNE also decreased the protein levels of VEGFR2, FAK, phospho-FAK, Src and paxillin in MCECs. Thus, we conclude that ALDH2 inhibition potentiates 4HNE-induced decrease in MCECs migration in vitro.


Assuntos
Aldeído-Desidrogenase Mitocondrial/antagonistas & inibidores , Aldeídos/farmacologia , Movimento Celular/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Dimetil Sulfóxido/farmacologia , Células Endoteliais/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Aldeído-Desidrogenase Mitocondrial/metabolismo , Animais , Linhagem Celular , Vasos Coronários/enzimologia , Células Endoteliais/enzimologia , Quinase 1 de Adesão Focal/genética , Quinase 1 de Adesão Focal/metabolismo , Camundongos , Paxilina/metabolismo , Fosforilação , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Quinases da Família src/metabolismo
15.
Respir Med ; 166: 105944, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32250877

RESUMO

OBJECTIVES: Chronic lung allograft dysfunction including Bronchiolitis obliterans syndrome (BOS) is common after lung transplantation. Histologically, BOS is recognized as fibrotic lesions with accumulated extracellular matrix (ECM) in small airways. Lung fibroblasts are major producers of ECM and vascular endothelial growth factor (VEGF). In this study we hypothesize that VEGF is involved in BOS development after lung transplantation. METHODS: We investigated the effect of profibrotic transforming growth factor (TGF-ß) on VEGF synthesis in lung fibroblasts isolated from distal lung tissue biopsies taken from patients at 3, 6 and 12 months after lung transplantation (n = 14). Co-expression of VEGF receptor (VEGFR) 2 and collagen marker prolyl4-hydroxylase (p4OH) were analyzed in lung tissue from patients with BOS (n = 11). RESULTS: VEGF synthesis from distal derived lung fibroblasts were significantly lower 3 months after lung transplantation (168.6 ± 133.7; n = 7) compared to non-transplanted subjects (451.8 ± 185.9; n = 9; p = 0.0033) and increased over time at 6 months (584.1 ± 264.9; n = 9; p = 0.0033) and 12 months (451.1 ± 207.5; n = 8; p = 0.0065) post transplantation. TGF-ß significantly induced VEGF synthesis at all time points. At 12 months post transplantation there was significantly less VEGF synthesis after TGF-ß stimulation in fibroblasts obtained from BOS patients (1170 ± 450.2; n = 4) compared to patients without any chronic rejection process (1980 ± 417.9; n = 4; p < 0.039). The numbers of cells expressing VEGFR2/p4OH were increased in patients with BOS (33.2 ± 10.9; n = 11) compared to control subjects (10.1 ± 9.9; n = 11; p < 0.001). CONCLUSIONS: Our results support that changes in VEGF/VEGFR2 axis could be involved in BOS development and marker of poor outcome.


Assuntos
Bronquiolite Obliterante/genética , Bronquiolite Obliterante/cirurgia , Expressão Gênica , Transplante de Pulmão , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Adulto , Idoso , Biomarcadores/metabolismo , Bronquiolite Obliterante/diagnóstico , Feminino , Fibroblastos/metabolismo , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/genética , Humanos , Pulmão/citologia , Pulmão/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Prolil Hidroxilases/genética , Prolil Hidroxilases/metabolismo , Adulto Jovem
16.
Diabetes ; 69(6): 1232-1247, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32234721

RESUMO

Hypovascularized diabetic nonhealing wounds are due to reduced number and impaired physiology of endogenous endothelial progenitor cell (EPC) population that limits their recruitment and mobilization at the wound site. For enrichment of the EPC repertoire from nonendothelial precursors, abundantly available mesenchymal stromal cells (MSC) were reprogrammed into induced endothelial cells (iEC). We identified cell signaling molecular targets by meta-analysis of microarray data sets. BMP-2 induction leads to the expression of inhibitory Smad 6/7-dependent negative transcriptional regulation of ID1, rendering the latter's reduced binding to TWIST1 during transdifferentiation of Wharton jelly-derived MSC (WJ-MSC) into iEC. TWIST1, in turn, regulates endothelial gene transcription, positively of proangiogenic KDR and negatively, in part, of antiangiogenic SFRP4 Twist1 reprogramming enhanced the endothelial lineage commitment of WJ-MSC and increased the vasculogenic potential of reprogrammed endothelial cells (rEC). Transplantation of stable TWIST1 rEC into a type 1 and 2 diabetic full-thickness splinted wound healing murine model enhanced the microcirculatory blood flow and accelerated the wound tissue regeneration. An increased or decreased colocalization of GFP with KDR/SFRP4 and CD31 in the regenerated diabetic wound bed with TWIST1 overexpression or silencing (piLenti-TWIST1-shRNA-GFP), respectively, further confirmed improved neovascularization. This study depicted the reprogramming of WJ-MSC into rEC using unique transcription factor TWIST1 for an efficacious cell transplantation therapy to induce neovascularization-mediated diabetic wound tissue regeneration.


Assuntos
Complicações do Diabetes/terapia , Células-Tronco Embrionárias/transplante , Células Endoteliais/fisiologia , Proteínas Nucleares/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Cicatrização/fisiologia , Animais , Diferenciação Celular , Transdiferenciação Celular , Células Cultivadas , Regulação da Expressão Gênica , Marcadores Genéticos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Neovascularização Fisiológica , Proteínas Nucleares/genética , Análise Serial de Proteínas , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Regeneração , Pele , Contenções/efeitos adversos , Transplante de Células-Tronco , Proteína 1 Relacionada a Twist/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
17.
J Pathol ; 251(2): 123-134, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32166747

RESUMO

Spontaneously regressing infantile haemangiomas and aggressive angiosarcomas are vascular tumours with excessive angiogenesis. When analysing haemangiomas and angiosarcomas immunohistochemically with respect to their chaperone profiles we found that angiosarcomas have significantly elevated protein levels of binding immunoglobulin protein (BIP) and PERK with concomitant attenuated IRE1α levels, whereas haemangioma tissue exhibits the same pattern as embryonal skin tissue. We show that BiP is essential for the maintenance of VEGFR2 protein, which is expressed in the endothelium of both tumour types. When studying the effects of BiP, the IRE1α/Xbp1 -, and PERK/ATF4-signalling pathways on the migration and tube-forming potential of endothelial cells, we show that downregulation of BiP, as well as inhibition of the kinase activity of IRE1α, inhibit in vitro angiogenesis. Downregulation of PERK (PKR-like kinase; PKR = protein kinase R) levels promotes Xbp1 splicing in endoplasmic reticulum (ER)-stressed cells, indicating that in angiosarcoma the elevated PERK levels might result in high levels of unspliced Xbp1, which have been reported to promote cell proliferation and increase tumour malignancy. The data presented in this study revealed that in addition to BiP or PERK, the kinase domains of IRE1α and Xbp1 could be potential targets for the development of novel therapeutic approaches for treating angiosarcomas and to control tumour angiogenesis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Endorribonucleases/metabolismo , Células Endoteliais/enzimologia , Proteínas de Choque Térmico/metabolismo , Hemangioma/enzimologia , Hemangiossarcoma/enzimologia , Neovascularização Patológica , Proteínas Serina-Treonina Quinases/metabolismo , eIF-2 Quinase/metabolismo , Movimento Celular , Proliferação de Células , Células Cultivadas , Endorribonucleases/genética , Células Endoteliais/patologia , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas de Choque Térmico/genética , Hemangioma/genética , Hemangioma/patologia , Hemangiossarcoma/genética , Hemangiossarcoma/patologia , Células Endoteliais da Veia Umbilical Humana/enzimologia , Humanos , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteína 1 de Ligação a X-Box/genética , Proteína 1 de Ligação a X-Box/metabolismo , eIF-2 Quinase/genética
18.
Int J Clin Oncol ; 25(6): 1195-1205, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32215805

RESUMO

OBJECTIVE: The aim of this study was to investigate the efficacy and safety of Apatinib mesylate in the treatment of metastatic osteosarcoma patients who progressed after standard therapy and the VEGFR2 gene polymorphism analysis. METHODS: Designed as a retrospective study, a total of 105 metastatic osteosarcoma patients who progressed after standard therapy were included in this study. The metastatic osteosarcoma patients received 500-750 mg Apatinib mesylate according to body surface area until disease progression or unacceptable toxicity with 28 days one cycle. Overall response was evaluated after two cycles Apatinib treatment, then progression-free survival (PFS) and overall survival (OS) were evaluated, and safety data were recorded. Additionally. peripheral blood and peripheral blood mononuclear cell (PBMC) specimens in the osteosarcoma patients were collected for the genotyping of VEGFR2 genetic variation and mRNA expression, respectively. Analysis on the association between genotype and baseline characteristics and VEGFR2 gene mRNA expression was analyzed. The univariate analysis of genotypes and prognosis was carried out by Kaplan-Meier survival analysis, and multivariate analysis was adjusted by Cox regression analysis. RESULTS: The objective response rate (ORR) of the 105 metastatic osteosarcoma patients was 37.14%, disease control rate (DCR) was 77.14%, median PFS was 4.1 months, and median OS was 9.0 months. Regarding the VEGFR2 gene polymorphisms analysis, only - 906 T > C was of clinical significance. The prevalence of - 906 T > C in VEGFR2 among the study population was as follows: TT genotype 62 cases (59.05%), TC genotype 36 cases (34.29%) and CC genotype 7 cases (6.66%), minor allele frequency of - 906 T > C was 0.24. Compared with patients with TC/CC genotype, patients with TT genotype showed longer median PFS (5.0 versus 3.1 months, P = 0.011) and median OS (9.8 versus 7.6 months, P = 0.032). There was no correlation between the polymorphism and adverse reactions. Additionally, the mRNA expression in 69 randomly selected sample indicated that the mRNA expression of VEGFR2 of the patients with CC/TC genotypes were significantly higher than those of the TT genotype patients (P < 0.001). CONCLUSION: Apatinib was safe and effective in the treatment of metastatic osteosarcoma patients who progressed after standard therapy. The clinical outcomes of Apatinib may be influenced by the polymorphism - 906 T > C of VEGFR2 through mediating the mRNA expression of VEGFR2.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Polimorfismo Genético , Piridinas/uso terapêutico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Adolescente , Adulto , Neoplasias Ósseas/genética , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Frequência do Gene , Genótipo , Humanos , Estimativa de Kaplan-Meier , Leucócitos Mononucleares/fisiologia , Masculino , Pessoa de Meia-Idade , Osteossarcoma/genética , Osteossarcoma/mortalidade , Osteossarcoma/patologia , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
19.
Exp Mol Pathol ; 114: 104408, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32088190

RESUMO

Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)1 and 2 signaling is a potent activator of tumor angiogenesis. Although the expressions of VEGFR1 and VEGFR2 were initially thought to be limited to the endothelial cells, it is now known that both the receptors are expressed in tumor cells. This is the first study wherein VEGFRs-positive tumor cells are quantitatively evaluated for brain tumors with upregulated VEGF/VEGFR signaling. The percentage of VEGFRs-positive tumor cells was quantitatively evaluated in various brain tumors (10 glioblastomas, 22 neurofibromatosis type 2 [NF2]-related schwannomas, 21 sporadic schwannomas, 27 chordomas, 36 meningiomas, 29 hemangioblastomas, 11 hemangiopericytoma, and 13 ependymomas) using immunohistochemistry. VEGF-A expression was also analyzed using quantitative real-time polymerase chain reaction. Double immunofluorescence staining using anti-PDGFR-ß and anti-CD34 antibody, microvessel density, and vessel diameter were analyzed to evaluate the vascular characteristics. Chordomas demonstrated an extremely higher percentage of VEGFR1 and VEGFR2-positive tumor cells than other tumors. In contrast, meningiomas and hemangiopericytomas showed few VEGFRs-positive tumor cells. The percentage of positive tumor cells in chordomas, hemangioblastomas, and NF2 schwannomas was associated with clinical courses, such as shorter progression free survival, and growth speed. Glioblastomas and NF2 schwannomas showed larger tumor vessels without pericyte coverage. The present study is the first to quantitatively analyze VEGFR1- and VEGFR2- positive tumor cells in various types of refractory brain tumors. This novel parameter significantly correlated with the progressive clinical courses.


Assuntos
Neoplasias Encefálicas/genética , Neovascularização Patológica/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Adulto , Idoso , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/patologia , Cordoma/genética , Cordoma/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Ependimoma/genética , Ependimoma/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Glioblastoma/genética , Glioblastoma/patologia , Hemangioblastoma/genética , Hemangioblastoma/patologia , Humanos , Imuno-Histoquímica , Masculino , Meningioma/genética , Meningioma/patologia , Pessoa de Meia-Idade , Neovascularização Patológica/patologia , Neurilemoma/genética , Neurilemoma/patologia , Transdução de Sinais/genética , Fator A de Crescimento do Endotélio Vascular/genética
20.
Biomed Res Int ; 2020: 8954513, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32047817

RESUMO

PBX3 (Pre-B-cell leukemia homeobox 3) had been considered to be a multifunctional oncogene which involved in tumor growth, invasion, and metastasis in leukemia and some solid tumors. However, the contribution of PBX3 to papillary thyroid carcinoma (PTC) remains unclear. In this study, we found that PBX3 expression was significantly upregulated in PTC tissues compared to adjacent normal tissues, and high levels of PBX3 were correlated with tumor size, lymphatic metastasis, TMN stage, and poor prognosis of PTC patients. Overexpression of PBX3 in PTC cell lines promoted cell proliferation. Consistently, knockdown of PBX3 by shRNA induced cell cycle arrest at G0/G1 phase, and inhibited angiogenesis and tumor growth in vitro and in vivo. Furthermore, PBX3 promoted PTC cell proliferation and angiogenesis through activation of AT1R/VEGFR2 pathway while overexpression of AT1R and treatment with VEGFA reversed PBX3-shRNA-induced decreased phosphorylation of VEGFR2 and its downstream (ERK1/2, AKT and Src). It demonstrated that PBX3 could be used as a potential prognostic biomarker and therapeutic target for PTC.


Assuntos
Proteínas de Homeodomínio/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Câncer Papilífero da Tireoide/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Humanos , Metástase Linfática , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas/genética , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Regulação para Cima , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
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