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1.
Nat Commun ; 10(1): 4119, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511520

RESUMO

Circular RNAs are non-coding RNAs, and are enriched in the CNS. Dorsal horn neurons of the spinal cord contribute to pain-like hypersensitivity after nerve injury in rodents. Here we show that spinal nerve ligation is associated with an increase in expression of circAnks1a in dorsal horn neurons, in both the cytoplasm and the nucleus. Downregulation of circAnks1a by siRNA attenuates pain-like behaviour induced by nerve injury. In the cytoplasm, we show that circAnks1a promotes the interaction between transcription factor YBX1 and transportin-1, thus facilitating the nucleus translocation of YBX1. In the nucleus, circAnks1a binds directly to the Vegfb promoter, increases YBX1 recruitment to the Vegfb promoter, thereby facilitating transcription. Furthermore, cytoplasmic circAnks1a acts as a miRNA sponge in miR-324-3p-mediated posttranscriptional regulation of VEGFB expression. The upregulation of VEGFB contributes to increased excitability of dorsal horn neurons and pain behaviour induced by nerve injury. We propose that circAnks1a and VEGFB are regulators of neuropathic pain.


Assuntos
Hipersensibilidade/metabolismo , Neuralgia/genética , Neuralgia/metabolismo , Medula Espinal/metabolismo , Animais , Sequência de Bases , Núcleo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Neurônios/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica , Transporte Proteico , Ratos Sprague-Dawley , Roedores , Corno Dorsal da Medula Espinal/metabolismo , Regulação para Cima/genética , Fator B de Crescimento do Endotélio Vascular/metabolismo
2.
Curr Pharm Biotechnol ; 20(11): 955-963, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31322068

RESUMO

BACKGROUND: VEGF-A, VEGF-B, VEGFR-1 and VEGFR-2 are important proteins involved in the induction and development of a new blood vessel network through which the tumor is properly nourished and oxygenated. OBJECTIVES: The aim of the study was to evaluate changes in VEGF-A, VEGF-B, VEGFR-1 and VEGFR-2 expression in endometrial cancer depending on its grade and to determine the VEGFR-1 to VEGFR-2 concentration ratio. METHODS: The study group consisted of 45 patients diagnosed with endometrial cancer (G1, 17; G2, 15; G3, 13). The control group included 15 patients. VEGF-A, VEGF-B, VEGF-R1, VEGFR-2 expression was assessed using the immunohistochemical method. Statistical analysis was carried out using the Statistica 12 PL program (StatSoft, Cracow, Poland). It included the one-way ANOVA and Tukey's post-hoc test (p<0.05). RESULTS: Statistically significant differences in the level of VEGF-A, VEGF-B, VEGF-R1, VEGFR-2 were observed between the majority of analyzed groups (except for VEGF-B; G3 vs. G1, p=0.997700). The expression pattern of VEGF-A, VEGF-R1, VEGFR-2 was as follows: G3>G2>G1>C; VEGF-B: G2> G3> G1>C. A lower concentration of VEGFR-1 than VEGFR-2 was found regardless of the cancer grade. CONCLUSION: VEGF-A, VEGF-B, VEGF-R1, VEGFR-2 are key proteins involved in tumor angiogenesis. The analysis of the entire panel of proteins participating in a given process is an important element of modern diagnostics. The concentration ratio of VEGFR-1 to VEGFR-2 appears to be a determining factor in the patients' survival prognosis.


Assuntos
Neoplasias do Endométrio/metabolismo , Neovascularização Patológica/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator B de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Estudos de Casos e Controles , Neoplasias do Endométrio/irrigação sanguínea , Neoplasias do Endométrio/patologia , Feminino , Humanos , Imuno-Histoquímica , Gradação de Tumores , Prognóstico , RNA Mensageiro/metabolismo
3.
Mol Med Rep ; 20(2): 915-930, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173206

RESUMO

Osteosarcoma is the most common type of malignant bone cancer, which often affects teenagers and young adults. The present study aimed to screen for critical genes and microRNAs (miRNAs/miRs) involved in osteosarcoma. A total of four microarray datasets (accession numbers GSE32981, GSE21257, GSE14827 and GSE14359) were downloaded from the Gene Expression Omnibus database. Following data preprocessing, module analysis was performed to identify the stable modules using the weighted gene co­expression network analysis (WGCNA) package. The differentially expressed genes (DEGs) between metastatic samples and non­metastatic samples were screened, followed by gene co­expression network construction, and Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Subsequently, prognosis­associated genes were screened and a miRNA­target gene regulatory network was constructed. Finally, the data for critical genes were validated. WGCNA analysis identified six modules; blue and yellow modules were significantly positively associated with osteosarcoma metastasis. A total of 1,613 DEGs were screened between primary tissue samples and metastatic samples. Following comparison of the genes in the two (blue and yellow) modules, a total of 166 DEGs were identified (metastatic samples vs. non­metastatic samples). Functional enrichment analysis demonstrated that these DEGs were mainly involved in 'defense response', 'p53 signaling pathway' and 'lysosome'. By utilizing the clinical information in GSE21257, 10 critical genes associated with osteosarcoma prognosis were obtained, including CTP synthase 2 (CTPS2), tumor protein p53 inducible protein 3 (TP53I3) and solute carrier family 1 member 1 (SLC1A1). In addition, hsa­miR­422a and hsa­miR­194 were highlighted in the miRNA­target gene network. Finally, matrix metallopeptidase 3 (MMP3) and vascular endothelial growth factor B (VEGFB) were predicted as critical genes in osteosarcoma metastasis. CTPS2, TP53I3 and SLC1A1 may serve major roles in osteosarcoma development, and hsa­miR­422a, hsa­miR­194, MMP3 and VEGFB may be associated with osteosarcoma metastasis.


Assuntos
Neoplasias Ósseas/genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Proteínas de Neoplasias/genética , Osteossarcoma/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Carbono-Nitrogênio Ligases/genética , Carbono-Nitrogênio Ligases/metabolismo , Bases de Dados Genéticas , Transportador 3 de Aminoácido Excitatório/genética , Transportador 3 de Aminoácido Excitatório/metabolismo , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Anotação de Sequência Molecular , Metástase Neoplásica , Proteínas de Neoplasias/metabolismo , Osteossarcoma/metabolismo , Osteossarcoma/mortalidade , Osteossarcoma/patologia , Mapeamento de Interação de Proteínas , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Análise de Sobrevida , Fator B de Crescimento do Endotélio Vascular/genética , Fator B de Crescimento do Endotélio Vascular/metabolismo
4.
Free Radic Res ; 53(1): 82-93, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30526144

RESUMO

According to our previous results, resveratrol (RSV, 3, 5, 4-trihydroxystilbene), a naturally polyphenolic phytoalexin, could attenuate myocardial ischemia/reperfusion injury through up-regulation of vascular endothelial growth factor B (VEGF-B) in isolated rat heart or H9c2 cells. However, the molecular mechanism remains unclear. In this study, we investigated the protective effect of RSV on myocardial infarction (MI) in rats and further explored the underlying signal pathway after VEGF-B. Rats received RSV or normal saline by intragastric administration for 7 consecutive days and followed by subcutaneously isoproterenol (ISO) or normal saline injections for another 2 days. We found that RSV pretreatment prevented the unfavourable changes in HW/BW, HW/TL, infarct size, and cell apoptosis in ISO-treated rats. Moreover, superoxide and malondialdehyde (MDA) production were significantly reduced and superoxide dismutase (SOD) was increased by RSV in ISO-treated rats. Furthermore, it showed that RSV pretreatment increased VEGF-B, p-eNOS and p-AMPK expression, and NO production in ISO-treated rats. Using Neonatal Rat Ventricular Myocytes (NRVM), we found that VEGF-B siRNA could abolish the cardio-protective effect of RSV. The enhanced ratios of eNOS phosphorylation to eNOS expression induced by RSV were markedly reversed by VEGF-B siRNA in NRVM also. Meantime, we found that the effect of VEGF-B knock-down on eNOS activation was rescued by AMPK activator AICAR. L-NAME, a NOS inhibitor, could inhibit RSV enhanced eNOS phosphorylation but had no effect on VEGF-B expression in NRVM or in rats. Collectively, our results indicate that RSV exerts cardio-protection from ISO-induced myocardial infarction through VEGF-B/AMPK/eNOS/NO signalling pathway.


Assuntos
Isoproterenol/antagonistas & inibidores , Infarto do Miocárdio/prevenção & controle , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Resveratrol/farmacologia , Fator B de Crescimento do Endotélio Vascular/metabolismo , Animais , Relação Dose-Resposta a Droga , Isoproterenol/farmacologia , Masculino , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Resveratrol/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Fator B de Crescimento do Endotélio Vascular/antagonistas & inibidores
5.
Biomed Res ; 39(6): 287-294, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30531158

RESUMO

Peripheral nerve injury has been suggested to up-regulate mRNA for the vascular endothelial growth factor (VEGF) which enhances nerve regeneration. VEGF is known to regulate angiogenesis by binding with a specific receptor, the vascular endothelial growth factor receptor (VEGFR). However, little is known about the involvement of VEGF-VEGFR signaling in the nerve regeneration at early stages though previous studies contained a lengthy observation. The present study examined that relationship between angiogenesis and peripheral nerve regeneration at the early stage after nerve transection by focusing on the chronological changes in the expression patterns of VEGF-VEGFR signaling. This study used our previously reported experimental model for nerve regeneration following the transection of the inferior alveolar nerve (IAN) in mice. In a double staining of PGP9.5 and CD31, respective markers for the nerve fibers and endothelial cells, CD31 immunoreactions first appeared in the injury site on postoperative (PO) day 2 when the transected nerve fibers had not been re-connected. The most intense immunoreaction for CD31 was found around the regenerating nerve fibers extending from the proximal stump on PO day 3, but it gradually lessened to disappear by PO day 7. The expression patterns of VEGFR1 and VEGFR2 showed similar chronological changes through the observation periods, with most intense immunoreaction found on PO day 3. Western blotting of total protein extracted from the injury site demonstrated the clear bands for VEGF-A and VEGF-B on PO day 2, indicating a time lag for the expression of ligands and receptors. A local administration of antibody to VEGF-A inhibited the elongation of the nerve fibers from the proximal stump. Furthermore, this administration of VEGF-A antibody inhibited the expression of CD31 in the gap between proximal and distal stumps. These results indicated that a nerve injury initiates productions in VEGF-A and VEFG-B, followed with the expression of VEGFR1 and VEGFR2 at early stages after the nerve injury. Taken these findings together, it is reasonable to postulate that immediate response of VEGF-VEGFR signaling to nerve injury plays a crucial role in local angiogenesis, resulting in a trigger for the regeneration of the nerve fibers in mouse IAN.


Assuntos
Fatores de Crescimento Endotelial/metabolismo , Regeneração Nervosa , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Células Endoteliais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibras Nervosas , Molécula-1 de Adesão Celular Endotelial a Plaquetas/antagonistas & inibidores , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Ubiquitina Tiolesterase/metabolismo , Fator B de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
6.
Sci Rep ; 8(1): 15188, 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30315228

RESUMO

Graphene and its derivatives have exhibited wide potential applications in electronics, structural engineering and medicine. However, over utilization and untreated discharge may cause its distribution into environmental as well as biological chain, which raised the concerns of potential health risk as a potential hazard. Accumulating evidence has demonstrated that graphene derivatives induce lung fibrosis in vivo, so overall goal of this study was to explore the molecular mechanisms underlying the pulmonary fibrotic responses of reduced graphene oxide (rGO), using in vitro assays. Epithelial-mesenchymal transition (EMT) has profound effect on development of pulmonary fibrosis. Herein, we evaluated the EMT effect of rGO samples on A549 cells. Firstly, rGO penetrated through the A549 cells membrane into the cytosol by endocytosis and located in late endosome and/or lysosomes observed via transmission electron microscopy (TEM), and were well tolerant by cells. Secondly, rGO promoted the cell migration and invasion capacities at lower doses (below 10 µg/ml), but significantly inhibited the capacities at 20 µg/ml. Moreover, rGO-induced EMT were evidenced by decreased expression of epithelial marker like E-cadherin, ß-catenin, Smad4 and increased expression of mesenchymal markers like Vimentin, VEGF-B, TWIST1. Based on our findings, it is supposed that rGO can effectively induce EMT through altering epithelial-mesenchymal transition markers in A549 cells.


Assuntos
Transição Epitelial-Mesenquimal/fisiologia , Grafite/metabolismo , Células A549 , Biomarcadores/metabolismo , Caderinas/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Movimento Celular/fisiologia , Endocitose/fisiologia , Endossomos/metabolismo , Endossomos/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Pulmão/metabolismo , Pulmão/patologia , Lisossomos/metabolismo , Lisossomos/patologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Transdução de Sinais/fisiologia , Proteína Smad4/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Fator B de Crescimento do Endotélio Vascular/metabolismo , Vimentina/metabolismo
7.
Proc Natl Acad Sci U S A ; 115(41): 10351-10356, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30249667

RESUMO

VEGF-B was discovered a long time ago. However, unlike VEGF-A, whose function has been extensively studied, the function of VEGF-B and the mechanisms involved still remain poorly understood. Notwithstanding, drugs that inhibit VEGF-B and other VEGF family members have been used to treat patients with neovascular diseases. It is therefore critical to have a better understanding of VEGF-B function and the underlying mechanisms. Here, using comprehensive methods and models, we have identified VEGF-B as a potent antioxidant. Loss of Vegf-b by gene deletion leads to retinal degeneration in mice, and treatment with VEGF-B rescues retinal cells from death in a retinitis pigmentosa model. Mechanistically, we demonstrate that VEGF-B up-regulates numerous key antioxidative genes, particularly, Gpx1 Loss of Gpx1 activity largely diminished the antioxidative effect of VEGF-B, demonstrating that Gpx1 is at least one of the critical downstream effectors of VEGF-B. In addition, we found that the antioxidant function of VEGF-B is mediated mainly by VEGFR1. Given that oxidative stress is a crucial factor in numerous human diseases, VEGF-B may have therapeutic value for the treatment of such diseases.


Assuntos
Antioxidantes/metabolismo , Degeneração Retiniana/genética , Fator B de Crescimento do Endotélio Vascular/metabolismo , Animais , Anticorpos Neutralizantes/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica , Glutationa Peroxidase/genética , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Estresse Oxidativo , Retina/efeitos dos fármacos , Retina/patologia , Degeneração Retiniana/tratamento farmacológico , Retinite Pigmentosa/genética , Fator B de Crescimento do Endotélio Vascular/genética , Fator B de Crescimento do Endotélio Vascular/farmacologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
9.
Cell Physiol Biochem ; 48(2): 433-449, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30016789

RESUMO

BACKGROUND/AIMS: Vagus nerve stimulation (VNS) suppresses arrhythmic activity and minimizes cardiomyocyte injury. However, how VNS affects angiogenesis/arteriogenesis in infarcted hearts, is poorly understood. METHODS: Myocardial infarction (MI) was achieved by ligation of the left anterior descending coronary artery (LAD) in rats. 7 days after LAD, stainless-steel wires were looped around the left and right vagal nerve in the neck for vagus nerve stimulation (VNS). The vagal nerve was stimulated with regular pulses of 0.2ms duration at 20 Hz for 10 seconds every minute for 4 hours, and then ACh levels by ELISA in cardiac tissue and serum were evaluated for its release after VNS. Three and 14 days after VNS, Real-time PCR, immunostaining and western blot were respectively used to determine VEGF-A/B expressions and α-SMA- and CD31-postive vessels in VNS-hearts with pretreatment of α7-nAChR blocker mecamylamine (10 mg/kg, ip) or mACh-R blocker atropine (10 mg/kg, ip) for 1 hour. The coronary function and left ventricular performance were analyzed by Langendorff system and hemodynamic parameters in VNS-hearts with pretreatment of VEGF-A/B-knockdown or VEGFR blocker AMG706. Coronary arterial endothelial cells proliferation, migration and tube formation were evaluated for angiogenesis following the stimulation of VNS in coronary arterial smooth muscle cells (VSMCs). RESULTS: VNS has been shown to stimulate VEGF-A and VEGF-B expressions in coronary arterial smooth muscle cells (VSMCs) and endothelial cells (ECs) with an increase of α-SMA- and CD31-postive vessel number in infarcted hearts. The VNS-induced VEGF-A/B expressions and angiogenesis were abolished by m-AChR inhibitor atropine and α7-nAChR blocker mecamylamine in vivo. Interestingly, knockdown of VEGF-A by shRNA mainly reduced VNS-mediated formation of CD31+ microvessels. In contrast, knockdown of VEGF-B powerfully abrogated VNS-induced formation of α-SMA+ vessels. Consistently, VNS-induced VEGF-A showed a greater effect on EC tube formation as compared to VNS-induced VEGF-B. Moreover, VEGF-A promoted EC proliferation and VSMC migration while VEGF-B induced VSMC proliferation and EC migration in vitro. Mechanistically, vagal neurotransmitter acetylcholine stimulated VEGF-A/B expressions through m/nACh-R/PI3K/Akt/Sp1 pathway in EC. Functionally, VNS improved the coronary function and left ventricular performance. However, blockade of VEGF receptor by antagonist AMG706 or knockdown of VEGF-A or VEGF-B by shRNA significantly diminished the beneficial effects of VNS on ventricular performance. CONCLUSION: VNS promoted angiogenesis/arteriogenesis to repair the infracted heart through the synergistic effects of VEGF-A and VEGF-B.


Assuntos
Infarto do Miocárdio/terapia , Estimulação do Nervo Vago , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator B de Crescimento do Endotélio Vascular/metabolismo , Acetilcolina/análise , Acetilcolina/sangue , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Indóis/farmacologia , Masculino , Microvasos/citologia , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Niacinamida/administração & dosagem , Niacinamida/farmacologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Muscarínicos/química , Receptores Muscarínicos/metabolismo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/genética , Fator B de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator B de Crescimento do Endotélio Vascular/genética , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
10.
Nature ; 557(7707): 724-728, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29769726

RESUMO

Microglia and astrocytes modulate inflammation and neurodegeneration in the central nervous system (CNS)1-3. Microglia modulate pro-inflammatory and neurotoxic activities in astrocytes, but the mechanisms involved are not completely understood4,5. Here we report that TGFα and VEGF-B produced by microglia regulate the pathogenic activities of astrocytes in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Microglia-derived TGFα acts via the ErbB1 receptor in astrocytes to limit their pathogenic activities and EAE development. Conversely, microglial VEGF-B triggers FLT-1 signalling in astrocytes and worsens EAE. VEGF-B and TGFα also participate in the microglial control of human astrocytes. Furthermore, expression of TGFα and VEGF-B in CD14+ cells correlates with the multiple sclerosis lesion stage. Finally, metabolites of dietary tryptophan produced by the commensal flora control microglial activation and TGFα and VEGF-B production, modulating the transcriptional program of astrocytes and CNS inflammation through a mechanism mediated by the aryl hydrocarbon receptor. In summary, we identified positive and negative regulators that mediate the microglial control of astrocytes. Moreover, these findings define a pathway through which microbial metabolites limit pathogenic activities of microglia and astrocytes, and suppress CNS inflammation. This pathway may guide new therapies for multiple sclerosis and other neurological disorders.


Assuntos
Astrócitos/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/microbiologia , Microglia/metabolismo , Animais , Astrócitos/patologia , Células Cultivadas , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/microbiologia , Sistema Nervoso Central/patologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/prevenção & controle , Receptores ErbB/metabolismo , Feminino , Humanos , Inflamação/metabolismo , Inflamação/microbiologia , Inflamação/patologia , Inflamação/prevenção & controle , Receptores de Lipopolissacarídeos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microglia/patologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Receptores de Hidrocarboneto Arílico/metabolismo , Simbiose , Fator de Crescimento Transformador alfa/biossíntese , Fator de Crescimento Transformador alfa/metabolismo , Triptofano/deficiência , Triptofano/metabolismo , Fator B de Crescimento do Endotélio Vascular/biossíntese , Fator B de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
11.
Exp Neurol ; 304: 67-81, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29522757

RESUMO

Vascular endothelial growth factor (VEGF), also known as VEGF-A, was discovered due to its vasculogenic and angiogenic activity, but a neuroprotective role for VEGF was later proven for lesions and disorders. In different models of motoneuronal degeneration, VEGF administration leads to a significant reduction of motoneuronal death. However, there is no information about the physiological state of spared motoneurons. We examined the trophic role of VEGF on axotomized motoneurons with recordings in alert animals using the oculomotor system as the experimental model, complemented with a synaptic study at the confocal microscopy level. Axotomy leads to drastic alterations in the discharge characteristics of abducens motoneurons, as well as to a substantial loss of their synaptic inputs. Retrograde delivery of VEGF completely restored the discharge activity and synaptically-driven signals in injured motoneurons, as demonstrated by correlating motoneuronal firing rate with motor performance. Moreover, VEGF-treated motoneurons recovered a normal density of synaptic boutons around motoneuronal somata and in the neuropil, in contrast to the low levels of synaptic terminals found after axotomy. VEGF also reduced the astrogliosis induced by axotomy in the abducens nucleus to control values. The administration of VEGF-B produced results similar to those of VEGF. This is the first work demonstrating that VEGF and VEGF-B restore the normal operating mode and synaptic inputs on injured motoneurons. Altogether these data indicate that these molecules are relevant synaptotrophic factors for motoneurons and support their clinical potential for the treatment of motoneuronal disorders.


Assuntos
Neurônios Motores/fisiologia , Sinapses/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator B de Crescimento do Endotélio Vascular/metabolismo , Animais , Axotomia/métodos , Gatos , Feminino
12.
Cell Adh Migr ; 12(3): 215-227, 2018 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-29095085

RESUMO

Angiogenesis plays an important role in controlling tissue development and maintaining normal tissue function. Dysregulated angiogenesis is implicated in the pathogenesis of a variety of diseases, particularly diabetes, cancers, and neurodegenerative disorders. As the major regulator of angiogenesis, the vascular endothelial growth factor (VEGF) family is composed of a group of crucial members including VEGF-B. While the physiological roles of VEGF-B remain debatable, increasing evidence suggests that this protein is able to protect certain type of cells from apoptosis under pathological conditions. More importantly, recent studies reveal that VEGF-B is involved in lipid transport and energy metabolism, implicating this protein in obesity, diabetes and related metabolic complications. This article summarizes the current knowledge and understanding of VEGF-B in physiology and pathology, and shed light on the therapeutic potential of this crucial protein.


Assuntos
Neoplasias/patologia , Neovascularização Patológica/metabolismo , Neovascularização Fisiológica/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator B de Crescimento do Endotélio Vascular/metabolismo , Animais , Humanos , Neoplasias/metabolismo , Transdução de Sinais/fisiologia
13.
Arch Immunol Ther Exp (Warsz) ; 66(2): 145-159, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28951939

RESUMO

Cardiovascular diseases are a growing problem in developing countries; therefore, there is an ongoing intensive search for new approaches to treat these disorders. Currently, cellular therapies are focused on healing the damaged heart by implanting stem cells modified with pro-angiogenic factors. This approach ensures that the introduced cells are capable of fulfilling the complex requirements of the environment, including the replacement of the post-infarction scar with cells that are able to contract and promote the formation of new blood vessels that can supply the ischaemic region with nutrients and oxygen. This study focused on the genetic modification of human skeletal muscle cells (SkMCs). We chose myoblast cells due to their close biological resemblance to cardiomyocytes and the placental growth factor (PlGF) gene due to its pro-angiogenic potential. In our in vitro studies, we transfected SkMCs with the PlGF gene using electroporation, which has previously been proven to be efficient and generate robust overexpression of the PlGF gene and elevate PlGF protein secretion. Moreover, the functionality of the secreted pro-angiogenic proteins was confirmed using an in vitro capillary development assay. We have also examined the influence of PlGF overexpression on VEGF-A and VEGF-B, which are well-known factors described in the literature as the most potent activators of blood vessel formation. We were able to confirm the overexpression of VEGF-A in myoblasts transfected with the PlGF gene. The results obtained in this study were further verified in an animal model. These data were able to confirm the potential therapeutic effects of the applied treatments.


Assuntos
Proteínas de Membrana/metabolismo , Músculo Esquelético/citologia , Mioblastos/fisiologia , Infarto do Miocárdio/terapia , Miócitos Cardíacos/fisiologia , Transplante de Células-Tronco , Animais , Diferenciação Celular , Modelos Animais de Doenças , Engenharia Genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos SCID , Mioblastos/transplante , Neovascularização Fisiológica/genética , Transgenes/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator B de Crescimento do Endotélio Vascular/metabolismo
14.
J Cell Biochem ; 119(2): 1511-1520, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28771828

RESUMO

In response to assorted stimuli, the heart will develop into cardiomyocyte hypertrophy, but sustained cardiomyocyte hypertrophy will finally lead to heart failure. This research is aimed to examine the effect of VEGFB on cardiomyocyte hypertrophy by using the cardiomyocyte-derived cell line H9C2 of cultured rates. It turns out that VEGFB can positively prevent the Ang II-induced rising in the size of cardiomyocyte as well as reduce Ang II-induced mRNA and protein levels of ß-MHC (ß-myosin heavy chain), BNP (brain natriuretic peptide), and ANP (atrial natriuretic peptide). Moreover, VEGFB can regulate the decline of the Ang II-induced rising in Ca2+ . After VEGFR1 knockdown, these effects of VEGFB were partially reversed. Moreover, VEGFB attenuated the suppression of PKG I, p-VASP, and RGS2 caused by Ang II; whereas VEGFR1 knockdown partially abolished the indicated effect of VEGFB. In a word, the effect of VEGFB on relevant downstream targets and the pathways of PKG I by VEGFR1 may explain its efficacy on cardiomyocyte hypertrophy. Thus, it can be suggested that it is feasible to apply VEGFB-VEGFR1 for reducing the symptoms of cardiomyocyte hypertrophy.


Assuntos
Angiotensina II/farmacologia , Cálcio/metabolismo , Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo , Miócitos Cardíacos/patologia , Fator B de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Fator Natriurético Atrial/metabolismo , Linhagem Celular , Tamanho Celular/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Hipertrofia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Cadeias Pesadas de Miosina/genética , Peptídeo Natriurético Encefálico/metabolismo , Ratos , Transdução de Sinais , Fator B de Crescimento do Endotélio Vascular/genética
15.
Chin Med J (Engl) ; 130(23): 2829-2835, 2017 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-29176141

RESUMO

BACKGROUND: Safflower extract and aceglutamide (SA) has been used clinically for the treatment of cerebrovascular diseases such as cerebral embolism, hemorrhage, and mental deterioration. This study aimed to investigate the effect and mechanism of SA injection in the recovery of peripheral innervations of diabetic mice. METHODS: The C57BL/6 male mice were divided into four groups: normal control group (n = 44), diabetic group (n = 44), diabetic + SA group (diabetic mice treated with SA injection, n = 44), and diabetic + SA + vascular endothelial growth factor receptor (VEGFR)1-BL group (diabetic mice treated with SA injection and VEGFR 1 blocking antibody n = 24). The streptozotocin-induced diabetic mice model and injured peripheral nerve mice model were built. The mice with injured peripheral nerves were intraperitonealy administered with SA injection for successive 21 days. The corneal sensitivity, number of corneal nerve fibers, and contents of vascular endothelial growth factor (VEGF)-B and various neurotrophic factors such as nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF) in corneal tissue of four groups were observed. RESULTS: The diabetic group showed decreased number of corneal nerve fibers, compared with the control group (P = 0.002). And compared with the diabetic group, the diabetic + SA group showed a significant increase in the number of nerve fibers (P = 0.024) and the contents of VEGF-B, NGF, and GDNF in the cornea (all P < 0.05). However, when the diabetic mice were treated with the blocking antibodies specialized for VEGF-B receptor, the neutralization of VEGFR-1 completely abolished the increased expression of NGF and GDNF stimulated by SA injection. CONCLUSIONS: SA injection could reduce the nerve injury caused by diabetic peripheral neuropathy, and its protective effect might be associated with the promotion of the expressions of VEGF-B, NGF, and GDNF.


Assuntos
Carthamus tinctorius/química , Diabetes Mellitus Experimental/tratamento farmacológico , Glutamina/análogos & derivados , Fator B de Crescimento do Endotélio Vascular/metabolismo , Animais , Diabetes Mellitus Experimental/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Glutamina/farmacologia , Glutamina/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Neural/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
16.
Biosci Rep ; 37(4)2017 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-28798193

RESUMO

It has been shown that adipose tissue and skeletal muscles in lean individuals respond to meal-induced hyperinsulinemia by increase in perfusion, the effect not observed in patients with metabolic syndrome. In conditions of hyperglycaemia and hypertriglyceridemia, this insufficient vascularization leads to the liberation of reactive oxygen species (ROS), and disruption of nitric oxide (NO) synthesis and endothelial signalling responsible for the uptake of circulating fatty acids (FAs), whose accumulation in skeletal muscles and adipose tissue is widely associated with the impairment of insulin signalling. While the angiogenic role of VEGF-A and its increased circulating concentrations in obesity have been widely confirmed, the data related to the metabolic role of VEGF-B are diverse. However, recent discoveries indicate that this growth factor may be a promising therapeutic agent in patients with metabolic syndrome. Preclinical studies agree over two crucial metabolic effects of VEGF-B: (i) regulation of FAs uptake and (ii) regulation of tissue perfusion via activation of VEGF-A/vascular endothelial growth factor receptor (VEGFR) 2 (VEGFR2) pathway. While in some preclinical high-fat diet studies, VEGF-B overexpression reverted glucose intolerance and stimulated fat burning, in others it further promoted accumulation of lipids and lipotoxicity. Data from clinical studies point out the changes in circulating or tissue expression levels of VEGF-B in obese compared with lean patients. Potentially beneficial effects of VEGF-B, achieved through enhanced blood flow (increased availability of insulin and glucose uptake in target organs) and decreased FAs uptake (prevention of lipotoxicity and improved insulin signalling), and its safety for clinical use, remain to be clarified through future translational research.


Assuntos
Ácidos Graxos/metabolismo , Regulação da Expressão Gênica , Síndrome Metabólica/metabolismo , Obesidade/metabolismo , Transdução de Sinais , Fator B de Crescimento do Endotélio Vascular/metabolismo , Animais , Velocidade do Fluxo Sanguíneo , Humanos , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hipertrigliceridemia/metabolismo , Hipertrigliceridemia/patologia , Síndrome Metabólica/patologia , Óxido Nítrico/metabolismo , Obesidade/patologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
17.
Exp Eye Res ; 164: 74-81, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28803935

RESUMO

The clinical manifestations of pterygium are characterized by rapid growth and postoperative recurrences. We had previously proposed that hypoxia-inducible factor (HIF)-1α recruits progenitor cells during the development and progression of pterygia. Recently, it was reported that various stimuli, including inflammation, could activate HIF-1α even under normoxic conditions. The ocular surface directly faces external environments, and is thus frequently exposed to inflammatory insults. First, we examined the gene expression of HIF-1α, its downstream molecule, vascular endothelial growth factor (VEGF)-A, and VEGF receptor (VEGFR)-2 in corneal and conjunctival cells compared with cultured human umbilical vein endothelial cells. Corneal fibroblasts had high expression of VEGFR-2 in the presence of TNF-α, and HIF-1α was activated by TNF-α in diverse ocular surface cells. The HIF-1α/VEGF/VEGFR signaling pathway in response to TNF-α was evaluated in cultured human pterygium fibroblasts (HPFs) at the gene and protein levels and was compared to treatment with cobalt chloride (CoCl2), a hypoxic mimetic, to exclude the effect of hypoxia. Although VEGF-A expression was not changed by TNF-α, expression of HIF-1α and VEGFR-2 was enhanced in HPFs treated with TNF-α, independent of hypoxia conditioning. In addition, VEGF-C gene expression was activated solely by TNF-α in HPF, but VEGF-B levels were not significantly affected. These results may provide mechanistic explanations for the uniquely vigorous proliferation of pterygium fibrovascular tissue during TNF-α-induced ocular surface inflammation.


Assuntos
Fibroblastos/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pterígio/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Hipóxia Celular/fisiologia , Células Cultivadas , Córnea/citologia , Fibroblastos/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipóxia/metabolismo , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator B de Crescimento do Endotélio Vascular/metabolismo , Fator C de Crescimento do Endotélio Vascular/metabolismo
18.
J Mol Neurosci ; 63(1): 17-27, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28755050

RESUMO

Vascular endothelial growth factor (VEGF) exerts both neuroprotective and proinflammatory effects in the brain, depending on the VEGF (A-E) and VEGF receptor (VEGFR1-3) types involved. Neonatal monosodium glutamate (MSG) treatment triggers an excitotoxic degenerative process associated with several neuropathological conditions, and VEGF messenger RNA (mRNA) expression is increased at postnatal day (PD) 14 in rat hippocampus (Hp) following the treatment. The aim of this work was to establish the changes in immunoreactivity to VEGF-A, VEGF-B, VEGFR-1 and VEGFR-2 proteins induced by neonatal MSG treatment (4 g/kg, subcutaneous, at PD1, 3, 5 and 7) in the cerebral motor cortex (CMC) and Hp. Samples collected from PD2 to PD60 from control and MSG-treated male Wistar rats were assessed by western blotting for each protein. Considering that immunoreactivity measured by western blotting is related to the protein expression level, we found that each protein in each cerebral region has a specific expression profile throughout the studied ages, and all profiles were differentially modified by MSG. Specifically, neonatal MSG treatment significantly increased the immunoreactivity to the following: (1) VEGF-A at PD8-PD10 in the CMC and at PD6-PD8 in the Hp; (2) VEGF-B at PD2, PD6 and PD10 in the CMC and at PD8-PD9 in the Hp; and (3) VEGFR-2 at PD6-PD8 in the CMC and at PD21-PD60 in the Hp. Also, MSG significantly reduced the immunoreactivity to the following: (1) VEGF-B at PD8-PD9 and PD45-PD60 in the CMC; and (2) VEGFR-1 at PD4-PD6 and PD14-PD21 in the CMC and at PD4, PD9-PD10 and PD60 in the Hp. Our results indicate that VEGF-mediated signalling is involved in the excitotoxic process triggered by neonatal MSG treatment and should be further characterized.


Assuntos
Ácido Glutâmico/toxicidade , Hipocampo/efeitos dos fármacos , Córtex Motor/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator B de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Masculino , Córtex Motor/crescimento & desenvolvimento , Córtex Motor/metabolismo , Ratos , Ratos Wistar , Fator A de Crescimento do Endotélio Vascular/genética , Fator B de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
19.
J Transl Med ; 15(1): 138, 2017 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-28623914

RESUMO

BACKGROUND: The interaction of vascular endothelial growth factor-C (VEGF-C)/VEGF-D/VEGF receptor-3 is considered to be a major driver of lymphangiogenesis, however the mechanism of this process remains unclear. We aimed to investigate the possible lymphangiogenic significance of synaptonemal complex protein 3 (SCP3) in non-small cell lung cancer (NSCLC). METHODS: The expression of SCP3, VEGF-C, and VEGF-D were measured and examined a correlation between SCP3 and VEGF-C or VEGF-D in various human lung cancer cell lines. Subsequently, we assessed SCP3, VEGF-A, VEGF-B, VEGF-C, and VEGF-D expression in archival tumor tissues from 89 NSCLC patients with lymph node (LN) metastasis by combined immunohistochemistry with quantitative digital image analysis. RESULTS: Positive correlations between SCP3 and VEGF-C expression (R 2  = 0.743) and VEGF-D expression (R 2  = 0.932) were detected in various human lung cancer cell lines. The high expression of SCP3, VEGF-A, VEGF-B, VEGF-C, and VEGF-D were detected in 24 (27.0%), 22 (24.7%), 27 (30.3%), 27 (30.3%), and 24 cases (27.0%), respectively. Notably, SCP3 positively correlated with VEGF-C and VEGF-D expression (for both, P < 0.001) and negatively correlated with VEGF-A and VEGF-B expression (P = 0.029 and P = 0.026, respectively). In multivariate analysis of patients with LN metastasis, SCP3 expression predicted worse overall survival (hazard ratio = 1.86, P = 0.008). CONCLUSIONS: SCP3 is associated with lymphangiogenesis and provides insight into the SCP3-VEGF-C/VEGF-D axis based cancer therapy strategy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Linfangiogênese , Metástase Linfática/patologia , Proteínas Nucleares/metabolismo , Idoso , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Análise de Sobrevida , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator B de Crescimento do Endotélio Vascular/metabolismo , Fator C de Crescimento do Endotélio Vascular/metabolismo , Fator D de Crescimento do Endotélio Vascular/metabolismo
20.
Physiol Rep ; 5(6)2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28351964

RESUMO

Cardiac-specific overexpression of vascular endothelial growth factor (VEGF)-B167 is known to induce left ventricular hypertrophy due to altered lipid metabolism, in which ceramides accumulate to the heart and cause mitochondrial damage. The aim of this study was to evaluate and compare different imaging methods to find the most sensitive way to diagnose at early stage the progressive left ventricular remodeling leading to heart failure. Echocardiography and cardiovascular magnetic resonance imaging were compared for imaging the hearts of transgenic mice with cardiac-specific overexpression of VEGF-B167 and wild-type mice from 5 to 14 months of age at several time points. Disease progression was verified by molecular biology methods and histology. We showed that left ventricular remodeling is already ongoing at the age of 5 months in transgenic mice leading to heart failure by the age of 14 months. Measurements from echocardiography and cardiovascular magnetic resonance imaging revealed similar changes in cardiac structure and function in the transgenic mice. Changes in histology, gene expressions, and electrocardiography supported the progression of left ventricular hypertrophy. Longitudinal relaxation time in rotating frame (T1ρ ) in cardiovascular magnetic resonance imaging could be suitable for detecting severe fibrosis in the heart. We conclude that cardiac-specific overexpression of VEGF-B167 leads to left ventricular remodeling at early age and is a suitable model to study heart failure development with different imaging methods.


Assuntos
Insuficiência Cardíaca/metabolismo , Ventrículos do Coração/metabolismo , Miocárdio/metabolismo , Fator B de Crescimento do Endotélio Vascular/metabolismo , Remodelação Ventricular/fisiologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Ecocardiografia , Eletrocardiografia , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Camundongos , Fator B de Crescimento do Endotélio Vascular/genética
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