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1.
Medicine (Baltimore) ; 100(3): e23423, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33545926

RESUMO

OBJECTIVE: To uncover the function of lncRNA NEAT1 in ovarian cancer (OC) cells and its mechanism. METHODS: The expression patterns of lncRNA NEAT1 and FGF9 in human OC cells and human ovarian epithelial cells was determined. OC cells were transfected with sh-NEAT1, pcDNA3.1-NEAT1, miR-365 mimic, miR-365 inhibitor or pcDNA3.1-NEAT1 + sh-NEAT1 before cell proliferation rate and cell clone formation rate were measured. After the transfected OC cells were co-cultivated with human umbilical vein endothelial cells (HUVECs), Matrigel angiogenesis assay tested angiogenesis of HUVECs; qRT-PCR and Western blot tested the expressions of vascular endothelial growth factor (VEGF), angiogenin 1 (Ang-1) and matrix metalloproteinase 2 (MMP2). Dual-luciferase reporter assay determined the targeted binding of NEAT1 and FGF9 to miR-365. RESULTS: LncRNA NEAT1 and FGF9 are over-expressed in OC cells. Knockdown of NEAT1 or FGF9, or over-expression of miR-365 results in decreased proliferation rate and cell clones as well as inhibited angiogenesis and down-regulated expressions of VEGF, Ang-1 and MMP2. Over-expression of NEAT1 or knockdown of miR-365 can reverse the effect caused by FGF9 knockdown. NEAT1 can down-regulate the expression of miR-365 while up-regulating that of FGF9. Dual-luciferase reporter assay determined that NEAT1 competes with FGF9 for binding to miR-365. CONCLUSION: LncRNA NEAT1 up-regulates FGF9 by sponging miR-365, thus promoting OC cell proliferation and angiogenesis of HUVECs.


Assuntos
Proliferação de Células/efeitos dos fármacos , Neoplasias Ovarianas/patologia , RNA Longo não Codificante/farmacologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Feminino , Fator 9 de Crescimento de Fibroblastos/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , MicroRNAs/metabolismo , Neovascularização Patológica
2.
Medicine (Baltimore) ; 100(3): e23985, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33545987

RESUMO

PURPOSE: To assess expression levels of Ephrin type-A receptor 2 (EphA2), vascular endothelial growth factor (VEGF), and von Willebrand factor (vWF), and assess their potentials as prognostic biomarkers to predict the risk of poor survival in patients with primary lower grade glioma. METHOD: The study included75 patients with histopathologically confirmed primary glioma (World Health Organization Grade IV). All patients underwent combined surgery and postoperative radiotherapy for the management of primary glioma. Immuno-histochemical analysis was performed to evaluate expression levels ofEphA2 and VEGF. Evaluation of tumor microvessel density was also performed at angiogenesis hot spots due to tumor growth. Main outcomes of the study were the prognostic efficiencies of EphA2, VEGF, and vWF in primary low-grade glioma, as well as whether their expression levels were associated with cancer progression. RESULTS: Of the patients with glioma, 67% had very strong expression of EphA2. Overall survival was inversely correlated with the expression of EphA2. Regarding VEGF expression, 38 patients (51%) had strong expression, 29 patients (39%) had weak expression, and 8 patients (11%) had no expression. Strong VEGF expression was associated with poor prognosis and poor survival. CONCLUSION: EphA2, VEGF, and vWF could be considered prognostic markers for assessment of primary glioma.


Assuntos
Neoplasias do Sistema Nervoso Central/mortalidade , Efrina-A2/metabolismo , Glioma/mortalidade , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator de von Willebrand/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Sistema Nervoso Central/irrigação sanguínea , Neoplasias do Sistema Nervoso Central/genética , Feminino , Glioma/genética , Humanos , Imuno-Histoquímica , Masculino , Microvasos/patologia , Pessoa de Meia-Idade , Neovascularização Patológica , Prognóstico
3.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 52(1): 11-15, 2021 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-33474882

RESUMO

Metastasis is a multistep and low-efficiency biological process driven by acquisition of genetic and/or epigenetic alterations within tumor cells. These evolutionary alterations enable tumor cells to thrive in the inhospitable microenvironment they encounter in the process of metastasis and eventually lead to macroscopic metastases in distant organs. The unfolded protein response (UPR) induced by endoplasmic reticulum (ER) stress is one of the most important mechanisms regulating cellular adaptation to an adverse microenvironment. UPR is involved in all stages of metastasis, playing an important role in tumor cell growth, survival, and differentiation and the process of maintaining protein hemostasis. Sustained activation of ER stress sensors endows tumor cells with better epithelial-mesenchymal transition (EMT), survival, immune escape, angiogenesis, cellular adhesion, dormancy-to reactivation capacity in the process of metastasis. Here, we discussed the role of UPR in regulating the above-mentioned abilities of tumor cells during metastasis, providing a reference for development of new targets for the treatment of tumor metastasis.UPR in regulating the above-mentioned characteristics and mechanisms of tumor cells during metastasis, providing a reference for development of new targets for the treatment of tumor metastasis.


Assuntos
Estresse do Retículo Endoplasmático , Neoplasias , Transição Epitelial-Mesenquimal , Humanos , Neovascularização Patológica , Microambiente Tumoral , Resposta a Proteínas não Dobradas
5.
Viruses ; 13(2)2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33498225

RESUMO

Although ACE2 (angiotensin converting enzyme 2) is considered the primary receptor for CoV-2 cell entry, recent reports suggest that alternative pathways may contribute. This paper considers the hypothesis that viral binding to cell-surface integrins may contribute to the high infectivity and widespread extra-pulmonary impacts of the SARS-CoV-2 virus. This potential is suggested on the basis of the emergence of an RGD (arginine-glycine-aspartate) sequence in the receptor-binding domain of the spike protein. RGD is a motif commonly used by viruses to bind cell-surface integrins. Numerous signaling pathways are mediated by integrins and virion binding could lead to dysregulation of these pathways, with consequent tissue damage. Integrins on the surfaces of pneumocytes, endothelial cells and platelets may be vulnerable to CoV-2 virion binding. For instance, binding of intact virions to integrins on alveolar cells could enhance viral entry. Binding of virions to integrins on endothelial cells could activate angiogenic cell signaling pathways; dysregulate integrin-mediated signaling pathways controlling developmental processes; and precipitate endothelial activation to initiate blood clotting. Such a procoagulant state, perhaps together with enhancement of platelet aggregation through virions binding to integrins on platelets, could amplify the production of microthrombi that pose the threat of pulmonary thrombosis and embolism, strokes and other thrombotic consequences. The susceptibility of different tissues to virion-integrin interactions may be modulated by a host of factors, including the conformation of relevant integrins and the impact of the tissue microenvironment on spike protein conformation. Patient-specific differences in these factors may contribute to the high variability of clinical presentation. There is danger that the emergence of receptor-binding domain mutations that increase infectivity may also enhance access of the RGD motif for integrin binding, resulting in viral strains with ACE2 independent routes of cell entry and novel integrin-mediated biological and clinical impacts. The highly infectious variant, B.1.1.7 (or VUI 202012/01), includes a receptor-binding domain amino acid replacement, N501Y, that could potentially provide the RGD motif with enhanced access to cell-surface integrins, with consequent clinical impacts.


Assuntos
Integrinas/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Transtornos da Coagulação Sanguínea/virologia , /patologia , Humanos , Neovascularização Patológica/virologia , Oligopeptídeos , Ligação Proteica , Receptores Virais/metabolismo , Transdução de Sinais , Internalização do Vírus
6.
Bratisl Lek Listy ; 122(2): 132-137, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33502882

RESUMO

OBJECTIVES: We aimed to investigate the effects of juglone on angiogenesis, metastasis and cell proliferation processes in pancreatic cancer  (PC)  and to understand whether its possible effects occur via the Wnt signaling pathway by analyzing the expression levels of target genes of Wnt signaling. BACKGROUND: PC is a silent and lethal cancer type which can only be detectable after metastasis and angiogenesis processes occured. The Wnt signaling pathway is one of the pathways that plays an active role in many biological processes in the cell. Mutations in the genes of this signaling pathway are related to the development of many cancers. Juglone, a natural compound, is shown to have cytotoxic and apoptotic effects on various cancer cells. METHODS: PANC-1 and BxPC-3 pancreatic cancer cells were treated with juglone at

Assuntos
Neoplasias Pancreáticas , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Naftoquinonas , Neovascularização Patológica , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Via de Sinalização Wnt , beta Catenina/genética , beta Catenina/metabolismo
7.
Anticancer Res ; 41(2): 567-582, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517262

RESUMO

The progress of metastatic colorectal cancer (mCRC) depends essentially on two signaling pathways: the first mediated by vascular endothelial growth factor (VEGF) and the second by epidermal growth factor receptor (EGFR). In colorectal cancer (CRC), the balance between pro-angiogenic and anti-angiogenic factors is disturbed in favor of a pro-angiogenic outcome (angiogenic switch) early in the neoplastic progression of adenomas, thus, resulting in neovascularization and eventually in malignant tumor progression. Furthermore, angiogenesis plays an important role in tumor growth and the formation of metastases. Several angiogenic growth factors have been identified to be highly expressed during the progression and metastatic spread of CRC, but VEGFA is the predominant angiogenic cytokine and the most consistently expressed factor during the metastatic process. Agents targeting VEGF/VEGFR signaling have shown efficacy in the treatment of mCRC and are currently approved in this setting. In this review, we summarize the role of antiangiogenic tyrosine kinase inhibitors (TKIs) in the treatment of mCRC, focusing on regorafenib.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neovascularização Patológica , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Piridinas/uso terapêutico , Inibidores da Angiogênese/efeitos adversos , Animais , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/patologia , Humanos , Terapia de Alvo Molecular , Metástase Neoplásica , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Tirosina Quinases/metabolismo , Piridinas/efeitos adversos , Transdução de Sinais , Resultado do Tratamento
8.
Adv Exp Med Biol ; 1270: 123-144, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33123997

RESUMO

Homeostasis is the key to survival. This is as true for the tumour cell as it is for the normal host cell. Tumour cells and normal host cells constantly interact with each other, and the balance of these interactions results in the prevailing homeostatic conditions. The interactions between the milieu of signalling molecules and their effects on the host and tumour cells are known as the tumour microenvironment. The predominant balance of effects within the tumour microenvironment will determine if the tumour cells can evade the host's responses to survive and grow or if the tumour cells will be eradicated. Lysophospholipids (LPLs) are a group of lipid signalling molecules which exert their effects via autocrinic and paracrinic mechanisms. Therefore, LPLs are being explored to determine if they are potentially key signalling molecules within the tumour microenvironment. The effects of LPLs within the tumour microenvironment include modulating cell proliferation, cell survival, cell motility, angiogenesis and the immune system. These are all important activities that affect the balance of host-tumour cell interactions. This chapter expands on these functions and also the role that LPLs could play as a potential treatment target in the future.


Assuntos
Lisofosfolipídeos/metabolismo , Neoplasias/metabolismo , Transdução de Sinais , Microambiente Tumoral , Movimento Celular , Proliferação de Células , Humanos , Sistema Imunitário , Neovascularização Patológica
9.
Life Sci ; 266: 118819, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33333053

RESUMO

AIMS: To investigate the effects and mechanism of miR-322/424 in liver fibrosis. MAIN METHODS: miR-322/424 expression in liver cirrhosis patients, mouse and rat liver fibrosis was determined by qPCR. Mice liver fibrosis was established by CCl4, and intervened by miR-322/424 agomir or antagomir. Liver hydroxyproline content and Sirius red staining were used to evaluate collagen deposition. CD31 expression was used to evaluate liver microvessel density. In vitro, the effects of miR-322/424 mimic or inhibitor on human hepatic sinusoidal endothelial cells (HHSECs) migration and tube formation were investigated. A dual luciferase reporter assay was performed to confirm the direct interaction between miR-322/424 and Cullin2. mRNA expression of elongin B/C, Cullin2, and RBX1 was determined by qPCR. HIF-1α protein expression was determined by Western blotting. KEY FINDINGS: miR-322/424 level in liver cirrhosis patients, mouse liver fibrosis induced by CCl4 and BDL, and rat liver fibrosis induced by CCl4 and dimethylnitrosamine was increased. miR-322/424 agomir exacerbated CCl4-induced mouse liver fibrosis, whereas the opposite effect was observed for miR-322/424 antagomir. miR-322/424 agomir significantly upregulated liver CD31 expression; opposite effects occurred with miR-322/424 antagomir. In vitro, miR-322/424 mimic significantly promoted tube formation and cell migration, and increased von Willebrand factor expression, whereas miR-322/424 inhibitor had the opposite effect. Dual-Luciferase Reporter Assay identified Cullin2 as miR-322/424 target. miR-322/424 decreased the mRNA expression of elongin B/C, Cullin2, and RBX1 and increased HIF-1α protein expression in HHSECs. SIGNIFICANCE: miR-322/424 plays a central role in the pathogenesis of liver fibrosis by targeting Cullin2, and enhancing HIF-1α-mediated hepatic angiogenesis.


Assuntos
Proteínas Culina/metabolismo , Hemangioma/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Cirrose Hepática/patologia , MicroRNAs/genética , Neovascularização Patológica/patologia , Animais , Células Cultivadas , Proteínas Culina/genética , Modelos Animais de Doenças , Hemangioma/genética , Hemangioma/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Ratos , Ratos Wistar
10.
Microvasc Res ; 133: 104072, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32949573

RESUMO

BACKGROUND: The process of angiogenesis is a key element for tumor growth and proliferation and therefore one of the determining factors for aggressiveness and malignancy. A better understanding of the underlying processes of tumor induced angiogenesis is crucial for superior cancer treatment. Furthermore, the PeriCam perfusion speckle imager (PSI) system high resolution (HR) model by PERIMED presents a noninvasive method for semi-quantitative measurement of blood perfusion, based on laser speckle contrast analysis (LASCA). Aim of the present study was to utilize the chick chorioallantoic membrane (CAM) model as an in-ovo-tumor-model which enables rapid neovascularization of tumors while allowing real-time observation of the microcirculation via LASCA. METHODS: Fertilized chicken eggs were grafted with embryonal/alveolar rhabdomyosarcoma cells or primary sarcoma tumors. The blood perfusion was measured before and after tumor growth using LASCA. The procedure is accelerated and simplified through the integrated PIMSoft software which provides real-time graphs and color-coded images during the measurement. RESULTS: Sarcoma cells and primary sarcoma tumors exhibited satisfactory growth processes on the CAM. LASCA visualized microcirculation accurately and enabled an extensive investigation of the angiogenic potential of sarcoma cells on the CAM. We were able to show that sarcoma cells and primary sarcoma tumors induced larger quantities of neovasculature on the CAM than the controls. CONCLUSIONS: The utilization of LASCA for the investigation of tumor angiogenesis within the CAM model appears to be a highly beneficial, cost-efficient and easily practicable procedure. The proposed model can be used as a drug-screening model for individualized cancer therapy, especially with regards to anti-angiogenic agents.


Assuntos
Membrana Corioalantoide/irrigação sanguínea , Fluxometria por Laser-Doppler , Neovascularização Patológica , Imagem de Perfusão , Rabdomiossarcoma Alveolar/irrigação sanguínea , Rabdomiossarcoma Embrionário/irrigação sanguínea , Sarcoma/irrigação sanguínea , Animais , Velocidade do Fluxo Sanguíneo , Linhagem Celular Tumoral , Embrião de Galinha , Xenoenxertos , Humanos , Fluxo Sanguíneo Regional , Fatores de Tempo , Carga Tumoral , Células Tumorais Cultivadas
11.
Gene ; 766: 145128, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32911026

RESUMO

BACKGROUND: The pathogenesis of osteonecrosis of the femoral head (ONFH) is unclear. Our previous study demonstrated that upregulated miR-335 in bone microvascular endothelial cells (BMECs) might be associated with the disease of steroid-induced ONFH. Here, we study the preventive effect of ICA on steroid-induced ONFH in rats. METHOD: 90 rats were separated into three groups: control group, methylprednisolone (MPS) group, and MPS + Icariin (ICA) group. Four weeks later, histological analyses were performed. Thrombomodulin (TM) and vascular endothelial growth factor (VEGF) were tested. MiRNA-335 expression was screened in the three groups using Agilent Gene Spring GX software. Target genes of miRNA-335 were detected by bioinformatics analysis. The functions of BMECs were analyzed by scratch, angiogenesis and cell survival rate. RESULTS: ICA can prevent the occurrence of steroid-associated ONFH in rats and reduce the amount of TM and VEGF in serum induced by glucocorticoids. ICA could regulate the overexpression of miRNA-335 induced by glucocorticoids. We predicted the Gene ontology (GO) and signaling pathways of target genes. At 24 hours, we found that ICA significantly promoted BMECs migration abilities. We also found that ICA could promote the angioplasty ability of BMECs. ICA could improve the survival rate of BMECs after steroid-induced injury. CONCLUSIONS: ICA is effective to prevent the occurrence of steroidinduced ONFH. ICA has a protective effect against steroid-induced BMECs injury. ICA regulated the imbalance of miRNA-335 expression induced by the glucocorticoid in BMECs, which provides a new viewpoint to explore the mechanism of ICA in preventing steroid-induced ONFH.


Assuntos
Células Endoteliais/efeitos dos fármacos , Necrose da Cabeça do Fêmur/tratamento farmacológico , Cabeça do Fêmur/efeitos dos fármacos , Flavonoides/farmacologia , MicroRNAs/metabolismo , Neovascularização Patológica/tratamento farmacológico , Substâncias Protetoras/farmacologia , Adipogenia/efeitos dos fármacos , Animais , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Endoteliais/metabolismo , Feminino , Cabeça do Fêmur/metabolismo , Necrose da Cabeça do Fêmur/induzido quimicamente , Necrose da Cabeça do Fêmur/metabolismo , Glucocorticoides/metabolismo , Metilprednisolona/farmacologia , Neovascularização Patológica/metabolismo , Osteócitos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Esteroides/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
12.
Adv Exp Med Biol ; 1287: 123-154, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33034030

RESUMO

Since many decades, nonmelanoma skin cancer (NMSCs) is the most common malignancy worldwide. Basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) are the major types of NMSCs, representing approximately 70% and 25% of these neoplasias, respectively. Because of their continuously rising incidence rates, NMSCs represent a constantly increasing global challenge for healthcare, although they are in most cases nonlethal and curable (e.g., by surgery). While at present, carcinogenesis of NMSC is still not fully understood, the relevance of genetic and molecular alterations in several pathways, including evolutionary highly conserved Notch signaling, has now been shown convincingly. The Notch pathway, which was first developed during evolution in metazoans and that was first discovered in fruit flies (Drosophila melanogaster), governs cell fate decisions and many other fundamental processes that are of high relevance not only for embryonic development, but also for initiation, promotion, and progression of cancer. Choosing NMSC as a model, we give in this review a brief overview on the interaction of Notch signaling with important oncogenic and tumor suppressor pathways and on its role for several hallmarks of carcinogenesis and cancer progression, including the regulation of cancer stem cells, tumor angiogenesis, and senescence.


Assuntos
Carcinogênese , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica , Receptores Notch/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Animais , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Humanos , Neoplasias Cutâneas/irrigação sanguínea
13.
Adv Exp Med Biol ; 1287: 183-200, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33034033

RESUMO

Notch promotes breast cancer progression through tumor initiating cell maintenance, tumor cell fate specification, proliferation, survival, and motility. In addition, Notch is recognized as a decisive mechanism in regulating various juxtacrine and paracrine communications in the tumor microenvironment (TME). In this chapter, we review recent studies on stress-mediated Notch activation within the TME and sequelae such as angiogenesis, extracellular matrix remodeling, changes in the innate and adaptive immunophenotype, and therapeutic perspectives.


Assuntos
Neoplasias da Mama , Receptores Notch/metabolismo , Transdução de Sinais , Microambiente Tumoral , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Humanos , Neovascularização Patológica , Comunicação Parácrina
14.
Int J Nanomedicine ; 15: 10385-10399, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33376327

RESUMO

Gambogic acid (GA), a kind of dry resin secreted by the Garcinia hanburyi tree, is a natural active ingredient with various biological activities, such as anti-cancer, anti-inflammatory, antioxidant, anti-bacterial effects, etc. An increasing amount of evidence indicates that GA has obvious anti-cancer effects via various molecular mechanisms, including the induction of apoptosis, autophagy, cell cycle arrest and the inhibition of invasion, metastasis, angiogenesis. In order to improve the efficacy in cancer treatment, nanometer drug delivery systems have been employed to load GA and form micelles, nanoparticles, nanofibers, and so on. In this review, we aim to offer a summary of chemical structure and properties, anti-cancer activities, drug delivery systems and combination therapy of GA, which might provide a reference to promote the development and clinical application of GA.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Xantonas/administração & dosagem , Xantonas/farmacologia , Antineoplásicos Fitogênicos/administração & dosagem , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Garcinia/química , Humanos , Micelas , Nanoestruturas , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neovascularização Patológica/tratamento farmacológico , Xantonas/química
15.
PLoS Biol ; 18(12): e3000991, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33351793

RESUMO

Hypoxia-induced angiogenesis maintains tissue oxygen supply and protects against ischemia but also enhances tumor progression and malignancy. This is mediated through activation of transcription factors like hypoxia-inducible factor 1 (HIF-1) and c-Myc, yet the impact of hypoxia on negative regulators of angiogenesis is unknown. During vascular development, seryl-tRNA synthetase (SerRS) regulates angiogenesis through a novel mechanism by counteracting c-Myc and transcriptionally repressing vascular endothelial growth factor A (VEGFA) expression. Here, we reveal that the transcriptional repressor role of SerRS is inactivated under hypoxia through phosphorylation by ataxia telangiectasia mutated (ATM) and ataxia telangiectasia mutated and RAD3-related (ATR) at Ser101 and Ser241 to attenuate its DNA binding capacity. In zebrafish, SerRSS101D/S241D, a phosphorylation-mimicry mutant, cannot suppress VEGFA expression to support normal vascular development. Moreover, expression of SerRSS101A/S241A, a phosphorylation-deficient and constitutively active mutant, prevents hypoxia-induced binding of c-Myc and HIF-1 to the VEGFA promoter, and activation of VEGFA expression. Consistently, SerRSS101A/S241A strongly inhibits normal and tumor-derived angiogenesis in mice. Therefore, we reveal a key step regulating hypoxic angiogenesis and highlight the importance of nuclear SerRS in post-developmental angiogenesis regulation in addition to vascular development. The role of nuclear SerRS in inhibiting both c-Myc and HIF-1 may provide therapeutic opportunities to correct dysregulation of angiogenesis in pathological settings.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Neovascularização Patológica/genética , Serina-tRNA Ligase/metabolismo , Indutores da Angiogênese , Animais , Animais Geneticamente Modificados , Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/fisiologia , Linhagem Celular , Feminino , Células HEK293 , Humanos , Hipóxia/metabolismo , Hipóxia/fisiopatologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Camundongos Nus , Fosforilação , Serina-tRNA Ligase/fisiologia , Fatores de Transcrição/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismo
16.
Ann Agric Environ Med ; 27(4): 568-573, 2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33356062

RESUMO

INTRODUCTION: Alcohol consumption causes acute and chronic liver injury. The clinical forms of alcohol liver disease (ALD) include steatosis, hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) associated with liver cirrhosis. OBJECTIVE: The aim of the study was to determine the levels of novel markers of fibrogenesis and angiogenesis in patients with alcoholic liver cirrhosis. Serum levels of angiopoietin-like peptide 4 (ANGPTL-4), asialoglycoprotein receptor 1 (ASGP-R1), and S100 calcium-binding protein A8 (S100A8) were assessed. Levels of hyaluronic acid (Hyal) and collagen IV (Coll IV) werealso determined at various stages of alcoholic liver cirrhosis. MATERIAL AND METHODS: The study group consisted of 72 patients with alcoholic liver cirrhosis, while the control group included 22 healthy subjects without a history of alcohol abuse. The degree of liver cirrhosis was evaluated according to the Pugh-Child criteria (Pugh-Child score). Based on thse scores, patients were assigned to one of three groups: Pugh-Child (P-Ch) A - 21 with stage A, P-Ch B - 23 with stage B and P-Ch C - 28 with stage C liver cirrhosis. Serum levels of markers were determined using ELISA. RESULTS: The study findings demonstrated higher levels of ANGPTL-4, ASGP-R1, S100A, hyaluronic acid and serum collagen IV in the group of patients with alcoholic liver cirrhosis, compared to the control group. Furthermore, their levels increased with the progression of alcoholic liver cirrhosis. CONCLUSIONS: The biomarkers analysed in the study may be useful for diagnosis and prognosis in patients with alcoholic liver cirrhosis.


Assuntos
Biomarcadores/sangue , Fibrose/fisiopatologia , Cirrose Hepática Alcoólica/complicações , Neovascularização Patológica/fisiopatologia , Adulto , Idoso , Feminino , Fibrose/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/sangue , Polônia
17.
Ter Arkh ; 92(10): 23-28, 2020 Nov 24.
Artigo em Russo | MEDLINE | ID: mdl-33346475

RESUMO

AIM: To investigate parameters of angiogenesis system in patients with diabetes mellitus and their relationship with obesity. MATERIALS AND METHODS: 104 patients with diabetes mellitus type 2 were included in the study. Patients were divided in 2 groups: Obesity+ (body mass index30 kg/m2;n=63) and Obesity- (body mass index 30 kg/m2;n=41). In all patients was performed clinico-diagnostical examination. mRNA expression levels of vascular endothelial growth factor (VEGF), its receptors flt-1 (fms-like tyrosine kinase 1), KDR (human kinase insert domain receptor) were determined in blood mononuclear cells. RESULTS: There were no statistically significant differences in investigated parameters between study groups. mRNA expression level of VEGF was slightly lower in men compared to women: 0.19 (0.14; 0.32)vs0.28 (0.12; 0.4) respectively,р=0.2236. MRNA expression level of flt-1 was lower in men compared to women: 0.14 (0.04; 0.3)vs0.25 (0.12; 0.38),р=0.0321 (statistically significant). We found statistically significant correlations of mRNA expression level of VEGF with mRNA expression level of flt-1 and KDR. Also we found strong positive correlations of BMI and mRNA expression levels VEGF, flt-1, KDR (r=0.86107,r=0.86125,r=0.86112, respectively,p0.001). CONCLUSION: Results of the study displayed relationship of obesity and angiogenesis system condition in patients with diabetes mellitus type 2. Further investigations are perspective for the future as a way to new therapeutical approach of obesity and its complications treatment.


Assuntos
Diabetes Mellitus Tipo 2 , Fator A de Crescimento do Endotélio Vascular , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Masculino , Neovascularização Patológica , Obesidade/genética , Receptores de Fatores de Crescimento do Endotélio Vascular , Fator A de Crescimento do Endotélio Vascular/genética , Fatores de Crescimento do Endotélio Vascular
18.
Ter Arkh ; 92(6): 93-98, 2020 Jul 09.
Artigo em Russo | MEDLINE | ID: mdl-33346501

RESUMO

Neoangiogenesis is a basic factor for most physiological as well as pathological processes i.e. tumor metastases. The most important is vascular endothelium growth factor (VEGF) and its receptors (VEGFR1/2) in angiogenesis processes. Nowadays antiangiogenic agents (which inhibit VEGF like bevacizumab neither VEGFR2 like ramucirumab) are widely used in very different chemotherapeutic regimens in clinical oncology. The signalling pathway VEGF-VEGFR plays a crucial role in supporting of adequate kidney function. Appearance of antiangiogenic drugs led to adverse nephrotoxic effects: arterial hypertension, proteinuria, rarely nephrotic syndrome, and kidney dysfunction. Various hystological variants of nephropathy are described, however, in most cases, signs of thrombotic microangiopathy of the renal vessels are noted. This literature review discusses mechanisms, clinical and morphological aspects of nephropathy associated with antiangiogenic drugs.


Assuntos
Inibidores da Angiogênese , Preparações Farmacêuticas , Inibidores da Angiogênese/efeitos adversos , Bevacizumab , Humanos , Neovascularização Patológica/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular
19.
J Vis Exp ; (166)2020 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-33346189

RESUMO

Cancer stem cells (CSCs) reside in a supportive niche, constituting a microenvironment comprised of adjacent stromal cells, vessels, and extracellular matrix. The ability of CSCs to participate in the development of endothelium constitutes an important characteristic that directly contributes to the general understanding of the mechanisms of tumorigenesis and tumor metastasis. The purpose of this work is to establish a reproducible methodology to investigate the tumor-initiation capability of ovarian cancer stem cells (OCSCs). Herein, we examined the neovascularization mechanism between endothelial cells and OCSCs along with the morphological changes of endothelial cells using the in vitro co-culture model NICO-1. This protocol allows visualization of the neovascularization step surrounding the OCSCs in a time course manner. The technique can provide insight regarding the angiogenetic properties of OCSCs in tumor metastasis.


Assuntos
Técnicas de Cocultura/métodos , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/patologia , Neoplasias Ovarianas/irrigação sanguínea , Linhagem Celular Tumoral , Transformação Celular Neoplásica/patologia , Células Endoteliais/patologia , Feminino , Humanos , Neoplasias Ovarianas/patologia , Microambiente Tumoral
20.
J Biomed Nanotechnol ; 16(6): 975-984, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33187592

RESUMO

Implementation of carbon nanofibers (CNFs) in biomedical applications have successful outcomes, however, they are still considered as a potential hazard. We herein used avian embryos at 3 days and its chorioallantoic membrane (CAM) at 6 days of incubation to evaluate the impact of synthesized CNFs on the early stage of embryogenesis and angiogenesis. Our data point out that 50 µg/embryo concentration of CNFs provoke adverse effects as 75% of CNFs-exposed embryos die within 1-5 days after exposure compared with their matched controls. Furthermore, CNFs significantly inhibit angiogenesis of the CAM after 48-hours post-treatment. Additionally, RT-PCR analysis on seven key controller genes responsible for proliferation, survival, angiogenesis, and apoptosis showed that these genes are deregulated in brain, heart, and liver tissues of CNFs-exposed embryos compared to their matched control. Our investigation suggests that CNFs could have a toxic effect on the early stages of embryogenesis as well as angiogenesis. Nevertheless, further investigations are required to evaluate the effects of CNFs and elucidate their mechanism on the early stage of the normal development and human health.


Assuntos
Nanofibras , Animais , Apoptose , Carbono , Membrana Corioalantoide , Humanos , Nanofibras/toxicidade , Neovascularização Patológica
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