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1.
Rev. esp. cardiol. (Ed. impr.) ; 77(3): 256-264, mar. 2024. ilus, tab, graf
Artigo em Espanhol | IBECS | ID: ibc-231062

RESUMO

Introducción y objetivos La reperfusión coronaria produce un daño en la microcirculación y, en concreto, las células endoteliales. Este estudio evalúa el efecto del suero aislado tras la revascularización de pacientes con un infarto agudo de miocardio con elevación del segmento ST (IAMCEST) en la viabilidad celular, el grado de permeabilidad endotelial in vitro y la asociación de estos parámetros con una mayor extensión de los índices de resonancia magnética cardiaca (RMC) relacionados con el daño por reperfusión (edema, hemorragia y obstrucción microvascular). Métodos Se incubaron células endoteliales de arteria coronaria humana con suero aislado 24 h tras la revascularización de 43 pacientes con IAMCEST evaluados mediante RMC y 14 sujetos de control. Se testó el efecto del suero de pacientes con IAMCEST en la pérdida de viabilidad celular por activación de la apoptosis y la necrosis, así como en la permeabilidad y la estructura de la monocapa endotelial. Resultados El suero de pacientes con IAMCEST aumentó la apoptosis (p <0,01) y la necrosis (p <0,05) de células endoteliales de arteria coronaria humana y causó un incremento de la permeabilidad de la monocapa endotelial in vitro (p <0,01) debido a mayores espacios intercelulares (p <0,05 frente a los controles). Una mayor necrosis inducida por suero se asoció con más permeabilidad endotelial in vitro (p <0,05) y con una mayor extensión de los principales índices de daño tras reperfusión y mayor tamaño de infarto. Conclusiones El suero tras la reperfusión de pacientes con IAMCEST induce la apoptosis y la necrosis in vitro de las células endoteliales y la permeabilidad endotelial. Cuanto más potente sea el efecto inductor de necrosis, más deletéreas son las consecuencias en cuanto al daño estructural resultante. (AU)


Introduction and objectives Clinical and experimental studies have shown that, in patients with reperfused ST-segment elevation myocardial infarction (STEMI), abnormalities in the endothelial monolayer are initiated during ischemia but rapidly intensify upon restoration of blood perfusion to the ischemic area. We aimed to evaluate the effect of serum isolated after revascularization from STEMI patients on the degree of endothelial permeability in vitro, by promoting endothelial cell apoptosis and necrosis in vitro. We also investigated the association between the percentage of serum-induced endothelial cell apoptosis or necrosis in vitro and the extent of cardiovascular magnetic resonance (CMR)-derived parameters of reperfusion injury (edema, hemorrhage, and microvascular obstruction). Methods Human coronary artery endothelial cells were incubated with serum isolated 24hours after revascularization from 43 STEMI patients who underwent CMR and 14 control participants. We assessed the effect of STEMI serum on activation of apoptosis and necrosis, as well as on the permeability and structure of the endothelial monolayer. Results Serum from STEMI patients increased apoptosis (P <.01) and necrosis (P <.05) in human coronary artery endothelial cells and caused increased permeability of the endothelial monolayer in vitro (P <.01), due to enlarged intercellular spaces (P <.05 vs control in all cases). Higher serum-induced necrosis was associated with greater endothelial permeability in vitro (P <.05) and with more extensive CMR-derived indices of reperfusion injury and infarct size. Conclusions Postreperfusion serum activates necrosis and apoptosis in endothelial cells and increases the degree of endothelial permeability in vitro. The more potent the necrosis-triggering effect of serum, the more deleterious the consequences in terms of the resulting cardiac structure. (AU)


Assuntos
Humanos , Infarto do Miocárdio , Traumatismo por Reperfusão , Soro , Pacientes , Células Endoteliais , Espectroscopia de Ressonância Magnética , Edema , Hemorragia
3.
J. physiol. biochem ; 79(4): 771-785, nov. 2023.
Artigo em Inglês | IBECS | ID: ibc-227551

RESUMO

With recent advancements in single-cell sequencing and machine learning methods, new insights into hepatocellular carcinoma (HCC) progression have been provided. Protein kinase–related genes (PKRGs) affect cell growth, differentiation, apoptosis, and signaling during HCC progression, making the predictive relevance of PKRGs in HCC highly necessary for personalized medicine. In this study, we analyzed single-cell data of HCC and used the machine learning method of LASSO regression to construct PKRG prediction models in six major cell types. CDK4 and AURKB were found to be the best PKRG prognostic signature for predicting the overall survival of HCC patients (including TCGA, ICGC, and GEO datasets) in hepatocytes. Independent clinical factors were further screened out using the COX regression method, and a nomogram combining PKRGs and cancer status was created. Treatment with Palbociclib (CDK4 Inhibitor) and Barasertib (AURKB Inhibitor) inhibited HCC cell migration. Patients classified as PKRG high- or low-risk groups showed different tumor mutation burdens, immune infiltrations, and gene enrichment. The PKRG high-risk group showed higher tumor mutation burdens and gene set enrichment analysis indicated that cell cycle, base excision repair, and RNA degradation pathways were more enriched in these patients. Additionally, the PKRG high-risk group demonstrated higher infiltration levels of Naïve CD8+ T cells, Endothelial cells, M2 macrophage, and Tregs than the low-risk group. In summary, this study established the hepatocytes-related PKRG signature for prognostic stratification at the single-cell level by using machine learning algorithms in HCC and identified potential HCC treatment targets based on the PKRG signature. (AU)


Assuntos
Humanos , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/genética , Células Endoteliais , Hepatócitos , Algoritmos
4.
Clin. transl. oncol. (Print) ; 25(8): 2607-2623, aug. 2023. ilus, graf
Artigo em Inglês | IBECS | ID: ibc-222434

RESUMO

Background Renal cancer is one of the common malignant tumors of the urinary tract, prone to distant metastasis and drug resistance, with a poor clinical prognosis. SLC14A1 belongs to the solute transporter family, which plays a role in urinary concentration and urea nitrogen recycling in the renal, and is closely associated with the development of a variety of tumors. Methods Transcription data for renal clear cell carcinoma (KIRC) were obtained from the public databases Gene Expression Omnibus database (GEO) and The Cancer Genome Atlas (TCGA), and we investigated the differences in SLC14A1 expression in cancerous and normal tissues of renal cancer, its correlation with the clinicopathological features of renal cancer patients. Then, we verified the expression levels of SLC14A1 in renal cancer tissues and their Paracancerous tissues using RT-PCR, Western-blotting and immunohistochemistry. Finally, we used renal endothelial cell line HEK-293 and renal cancer cell lines 786-O and ACHN to explore the effects of SLC14A1 on the biological behaviors of renal cancer cell proliferation, invasion and metastasis using EDU, MTT proliferation assay, Transwell invasion assay and scratch healing assay. Results SLC14A1 was lowly expressed in renal cancer tissues and this was further validated by RT-PCR, Western blotting, and immunohistochemistry in our clinical samples. Analysis of KIRC single-cell data suggested that SLC14A1 was mainly expressed in endothelial cells. Survival analysis showed that low levels of SLC14A1 expression were associated with a better clinical prognosis. In biological behavioral studies, we found that upregulation of SLC14A1 expression levels inhibited the proliferation, invasion, and metastatic ability of renal cancer cells. Conclusion SLC14A1 plays an important role in the progression of renal cancer and has the potential to become a new biomarker for renal cancer (AU)


Assuntos
Humanos , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Biomarcadores Tumorais/sangue , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Linhagem Celular Tumoral , Células HEK293 , Prognóstico
5.
Clin. transl. oncol. (Print) ; 25(2): 333-344, feb. 2023.
Artigo em Inglês | IBECS | ID: ibc-215933

RESUMO

Metastasis is the leading cause of mortality related to cancer. In the course of metastasis, cancer cells detach from the primary tumor, enter the circulation, extravasate at secondary sites, and colonize there. All of these steps are rate limiting and decrease the efficiency of metastasis. Prior to their arrival, tumor cells can modify the secondary sites. These favorable microenvironments increase the probability of successful dissemination and are referred to as pre-metastatic niches. Cancer cells use different mechanisms to induce and maintain these niches, among which immune cells play prominent roles. The immune system, including innate and adaptive, enhances recruitment, extravasation, and colonization of tumor cells at distant sites. In addition to immune cells, stromal cells can also contribute to forming pre-metastatic niches. This review summarizes the pro-metastatic responses conducted by immune cells and the assistance of stromal cells and endothelial cells in the induction of pre-metastatic niches (AU)


Assuntos
Humanos , Células Endoteliais/patologia , Metástase Neoplásica/patologia , Células Estromais/patologia , Carcinogênese/patologia , Microambiente Tumoral
6.
Clin. transl. oncol. (Print) ; 25(2): 491-502, feb. 2023.
Artigo em Inglês | IBECS | ID: ibc-215948

RESUMO

Background Most studies on subtype identification of colorectal cancer (CRC) were based on expressions of either genes or immune cells. However, few studies have hitherto used the combination of genes with immune and stroma cells for subtype identification. Methods Dataset GSE17536 was obtained from the Gene Expression Omnibus (GEO) database. The xCell algorithm was used to estimate the composition and density of 64 cell types, including immune and stroma cell types. Clustering analysis was then conducted on the top 3000 most variable genes from a total of 20,174 genes for CRC subtype identification. We employed the ensemble method of Similarity network fusion and 112 Consensus Clustering (SNF-CC) for cancer subtype identification. Reactome pathway analysis was conducted to identify the impact of the representative genes on prognosis. The results were validated in independent gene expression data from dataset GSE17537. Results In this study, we identified 3 clinically relevant subtypes and their representative genes, immune and stroma cells. Moreover, we confirmed the correlation of these subtypes with their clinical characteristics. The representative genes of the subtype with poor prognosis correlated with extracellular matrix structural constituent, while the subtype with good prognosis correlated with Toll-like receptor signaling pathway or chemokine signaling pathway. However, different subtypes were associated with distinct cell subtypes; the subtype with poor prognosis had a high abundance of fibroblasts and endothelial cells; the subtype with median prognosis had a higher abundance of immune cells, such as CD4 + T-cell, Th2 cells and aDC; the subtype with good prognosis had a higher abundance of NKT. Conclusion This study highlights the utility of immune and innate cells, especially during gene analysis, to provide the theoretical basis for personalized treatment in colorectal cancer patients (AU)


Assuntos
Humanos , Neoplasias Colorretais/metabolismo , Células-Tronco Mesenquimais/metabolismo , Análise por Conglomerados , Células Endoteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Prognóstico , Transdução de Sinais , Microambiente Tumoral
7.
Allergol. immunopatol ; 50(5): 39-46, sept. 2022. graf
Artigo em Inglês | IBECS | ID: ibc-208624

RESUMO

Sepsis induces multiple organ dysfunction syndromes, such as acute kidney, liver, or lung injury. Septic lung injury is associated with excessive apoptosis and inflammatory responses in hepatocytes. Deoxyelephantopin is a sesquiterpene lactone found in Elephantopus scaberL, and has immunomodulatory, antibacterial, anti-inflammatory, and antifungal properties. The role of deoxyelephantopin in sepsis-associated lung injury was investigated. First, human bronchial epithelial cells (BEAS-2B) and human pulmonary artery endothelial cells (HPAEC) were treated with lipopolysaccharide to induce cytotoxicity. Treatment with lipopolysac-charide reduced cell viability of BEAS-2B and HPAEC, and promoted cell apoptosis through down-regulation of poly (ADP-ribose) polymerase (PARP) and B-cell lymphoma 2 (Bcl-2), and up-regulation of cleaved PARP and B-cell lymphoma-associated X protein (Bax). Second, lipo-polysaccharide-treated BEAS-2B and HPAEC were incubated with increasing concentrations of deoxyelephantopin, that is, 1, 5, or 10 μM. Deoxyelephantopin enhanced cell viability and reduced cell apoptosis of lipopolysaccharide-treated BEAS-2B and HPAEC. Third, deoxyele-phantopin attenuated lipopolysaccharide-induced decrease of superoxide dismutase and glutathione, and increase of malondialdehyde and myeloperoxidase in BEAS-2B and HPAEC. Moreover, deoxyelephantopin also weakened lipopolysaccharide-induced increase of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6. Finally, deoxyelephantopin decreased pro-tein expression of p-p65 and p-signal transducer and activator of transcription 3 (STAT3) in lipopolysaccharide-treated BEAS-2B and HPAEC. In conclusion, deoxyelephantopin exhibited anti-oxidative and anti-inflammatory effects against lipopolysaccharide-treated BEAS-2B and HPAEC through inactivation of nuclear factor kappa B/STAT3 signaling (AU)


Assuntos
Humanos , Anti-Inflamatórios/farmacologia , Lesão Pulmonar/metabolismo , Sepse/metabolismo , Células Endoteliais/metabolismo , Lactonas , Lipopolissacarídeos/farmacologia , NF-kappa B/metabolismo , Poli Adenosina Difosfato Ribose , Inibidores de Poli(ADP-Ribose) Polimerases , Fator de Transcrição STAT3 , Sesquiterpenos
9.
Allergol. immunopatol ; 50(4): 23-30, jul. 2022. graf, ilus
Artigo em Inglês | IBECS | ID: ibc-208891

RESUMO

Polyphyllin I is an active steroidal saponin isolated from Paris polyphylla with anti-cancer and anti-inflammatory properties. The present study investigates the role of polyphyllin I in acute lung injury. Firstly, the human bronchial epithelial cells (BEAS-2B) and human pulmonary artery endo-thelial cells (HPAEC) were stimulated with increasing concentrations of lipopolysaccharide at 2, 5, and 10 μg/mL. The treatment with lipopolysaccharide reduced the cell viabilities of BEAS-2B and HPAEC, downregulated superoxide dismutase (SOD) and glutathione (GSH), and up-regulated myeloperoxidase (MPO) and malondialdehyde (MDA). Moreover, the levels of TNF-α, I L-1β, and IL-6 were also up-regulated in lipopolysaccharide-treated BEAS-2B/HPAEC cells. Secondly, the lipopolysaccharide-treated cells were then incubated with different concentrations of polyphyl-lin I. Incubation with polyphyllin I enhanced the cell viabilities of lipopolysaccharide-treated BEAS-2B/HPAEC, up-regulated levels of SOD and GSH, and reduced MPO and MDA. Moreover, polyphyllin I reduced TNF-α, I L-1β, and IL-6 in lipopolysaccharide-treated BEAS-2B/HPAEC cells. Thirdly, the up-regulation of GSDMD-N, pro-caspase-1, and cleaved caspase-1 proteins in lipo-polysaccharide-treated BEAS-2B/HPAEC cells were decreased by polyphyllin I. Polyphyllin I increased the protein expression of GSDMD-D in the lipopolysaccharide-treated BEAS-2B/HPAEC cells, and inhibited the translocation of GSDMD from cytoplasm to plasma membrane. Lastly, polyphyllin I reduced the expression of p-p65 in lipopolysaccharide-treated BEAS-2B/HPAEC cells. The over-expression of p65 counteracted with the inhibitory effects of polyphyllin I on oxi-dative stress and inflammation in lipopolysaccharide-treated BEAS-2B. In conclusion, polyphyllin (AU)


Assuntos
Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , NF-kappa B/metabolismo , Estresse Oxidativo , Diosgenina/análogos & derivados , Células Endoteliais/metabolismo , Interleucina-6 , Piroptose , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
10.
Arch. Soc. Esp. Oftalmol ; 97(7): 409-412, jul. 2022. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-209074

RESUMO

La hiperplasia endotelial papilar intravascular (IPEH) se caracteriza por la proliferación de células endoteliales generalmente producida dentro de una malformación vascular previa o un tumor. La IPEH suele afectar cuello, cabeza y extremidades inferiores, se han publicado pocos casos en la órbita ocular y párpados. Presentamos un caso único, un hombre de 48 años con una lesión conjuntival púrpura, elevada y multilobular de tres semanas de duración que se sometió a una biopsia excisional. Las características patológicas revelaron una hiperplasia endotelial papilar intravascular (tumor de Masson) (AU)


Intravascular papillary endothelial hyperplasia (IPEH) is characterized by proliferation of endothelial cells usually occurring within a long-standing vascular malformation or tumor. IPEH usually affects neck, head and lower extremities, and few orbital and eyelid cases have been reported. We present a unique case, a 48-year-old man with a purple, elevated, multilobular conjunctival lesion of three-weeks duration that underwent an excisional biopsy. Pathological features revealed intravascular papillary endothelial hyperplasia (Masson's tumor) (AU)


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Vasculares/patologia , Células Endoteliais/patologia , Túnica Conjuntiva/patologia , Hiperplasia/patologia
11.
Clin. transl. oncol. (Print) ; 24(6): 959-967, junio 2022.
Artigo em Inglês | IBECS | ID: ibc-203799

RESUMO

Colorectal cancer (CRC) is the third most common cancer in both men and women, accounting for 8% of all new cancer cases in both. CRC is typically diagnosed at advanced stages, which leads to a higher mortality rate. The 5-year survival rate for CRC is 64% in all cases and just 12% in metastatic cases. Mesenchymal stem cells (MSCs) are one of the most recent approaches for therapeutic interventions in cancer. MSCs have multiple properties, including paracrine signaling, immunologic functions, and the ability to migrate to the targeted tissue. MSCs can produce and secrete exosomes in tumor microenvironments. These exosomes can transfer compounds across tumor cells, stromal cells, fibroblasts, endothelial cells, and immune cells. Studies showed that modified MCS-derived exosomes have enhanced specificity, reduced immunogenicity, and better targeting capabilities in comparison to other frequently used delivery systems such as liposomes. Therefore, this study aimed to provide a comprehensive view of the role of natural MSC-derived exosomes in CRC, as well as the most current and prospective advancements in MSC-derived exosome therapeutic modifications.


Assuntos
Humanos , Neoplasias Colorretais/terapia , Células Endoteliais , Exossomos , Microambiente Tumoral , Células-Tronco Mesenquimais , Estudos Prospectivos
12.
Neurología (Barc., Ed. impr.) ; 37(5): 371-382, Jun. 2022. ilus, tab, graf
Artigo em Inglês, Espanhol | IBECS | ID: ibc-205987

RESUMO

Introducción: Los plexos coroideos, los vasos sanguíneos y las barreras cerebrales están íntimamente relacionados tanto morfológica como funcionalmente. Por otro lado, la hipertensión produce cambios en el flujo sanguíneo y en los pequeños vasos y capilares cerebrales. El propósito de la presente revisión es estudiar los efectos de la hipertensión arterial sobre los plexos coroideos y las barreras cerebrales. Desarrollo: Los plexos coroideos (PC) son una estructura del cerebro situada en los ventrículos cerebrales, altamente conservada filogenética y ontogénicamente. Los PC se desarrollan temprano durante la embriogénesis y constituyen una barrera funcional en las primeras semanas de gestación. Están compuestos por tejido epitelial altamente vascularizado, cubiertos por microvellosidades y su función principal es la producción del líquido cefalorraquídeo (LCR). El sistema nervioso central se encuentra aislado y protegido por la barrera hematoencefálica (BHE) y por la barrera sangre-LCR (BSLCR). Mientras que la BHE se localiza al nivel de las células endoteliales en la microvasculatura del encéfalo, la BSLCR está formada por las células epiteliales de los plexos coroideos. La hipertensión arterial crónica induce una remodelación vascular para adaptarse a los valores elevados de presión arterial, con lo que se evita el riesgo de hiperperfusión ante presiones elevadas, pero se incrementa el riesgo de isquemia a presiones bajas; en cambio, en las personas normotensas la circulación cerebral se autorregula y el flujo sanguíneo permanece constante y se mantiene la integridad de la BHE. [...] (AU)


Introduction: The choroid plexuses, blood vessels, and brain barriers are closely related both in terms of morphology and function. Hypertension causes changes in cerebral blood flow and in small vessels and capillaries of the brain. This review studies the effects of high blood pressure (HBP) on the choroid plexuses and brain barriers. Development: The choroid plexuses (ChP) are structures located in the cerebral ventricles, and are highly conserved both phylogenetically and ontogenetically. The ChPs develop during embryogenesis, forming a functional barrier during the first weeks of gestation. They are composed of highly vascularised epithelial tissue covered by microvilli, and their main function is cerebrospinal fluid (CSF) production. The central nervous system (CNS) is protected by the blood-brain barrier (BBB) and the blood–CSF barrier (BCSFB). While the BBB is formed by endothelial cells of the microvasculature of the CNS, the BCSFB is formed by epithelial cells of the choroid plexuses. Chronic hypertension induces vascular remodelling. This prevents hyperperfusion at HBPs, but increases the risk of ischaemia at low blood pressures. In normotensive individuals, in contrast, cerebral circulation is self-regulated, blood flow remains constant, and the integrity of the BBB is preserved. Conclusions: HBP induces changes in the choroid plexuses that affect the stroma, blood vessels, and CSF production. HBP also exacerbates age-related ChP dysfunction and causes alterations in the brain barriers, which are more marked in the BCSFB than in the BBB. Brain barrier damage may be determined by quantifying blood S-100β and TTRm levels. (AU)


Assuntos
Humanos , Envelhecimento , Células Endoteliais , Hipertensão , Cérebro , Corioide
13.
Rev. esp. enferm. dig ; 114(6): 350-351, junio 2022.
Artigo em Inglês | IBECS | ID: ibc-205656

RESUMO

A 31-year-old human immunodeficiency virus (HIV) positive male presented with weight loss, asthenia and anorexia of three weeks evolution. On physical exam, the patient had painless purple-colored papules on the trunk and upper limbs. Laboratory studies showed severe immunosuppression, with an absolute CD4 cell count of 114 cell/ul and HIV1-RNA level of 180,000 copies/ml. Esophagogastroduodenoscopy showed an exophytic lesion in the distal esophagus composed of three polyps and multiple flat and nodular maculopapular erythematous lesions in the gastric body, antrum and duodenum. Colonoscopy was also performed and identified several flat erythematous lesions in the colorectal mucosa. A neoplasm composed of small irregular vascular channel proliferation and spindled endothelial cells with minimal atypia was observed in all the esophageal, gastric, duodenal, colic and skin biopsies. (AU)


Assuntos
Humanos , Colonoscopia , Células Endoteliais/patologia , Sarcoma de Kaposi/patologia , Pacientes
14.
Clin. transl. oncol. (Print) ; 24(5): 892-901, mayo 2022.
Artigo em Inglês | IBECS | ID: ibc-203791

RESUMO

PurposeThe aim of this study was to investigate the involvement of the SDF-1/CXCR4 axis in the process of BMMSC homing in prostate cancer (PCa) in vivo and in vitro.MethodsAfter verification of BMMSCs, we fixed the concentration gradient of SDF-1 for BMMSC cultivation to analyze CXCR4 expression by qRT-PCR and flow cytometric analysis. Furthermore, we developed a non-contact co-culture system and explored the participation of the SDF-1/CXCR4 axis in PCa using qRT-PCR, flow cytometry, and ELISA. In addition, A green fluorescent protein (GFP)-transplanted methylnitrosourea (MNU)-induced PCa mouse model was established to investigate the CXCR4 expression in vivo.ResultsThe CXCR4 expression was up-regulated with the increase in SDF-1 concentrations, and elevated SDF-1 had a significant promoting effect on cell proliferation and migration in BMMSCs. Moreover, the CXCR4 expression of BMMSCs was significantly increased in the non-contact co-culture model with vascular endothelial cells (VECs), and analysis of this model also showed that the proliferation and migration of BMMSCs were promoted in the presence of VECs. The ELISA assay showed that the SDF-1 levels in the co-culture model at 48 h were significantly increased. Twenty of the GFP-transplanted mice were divided into a PCa group and a control group, and four GFP-transplanted mice were observed to have prostate tumorigenesis. It also showed that CXCR4 was obviously increased in the prostate tissue of PCa mice.ConclusionOur findings suggest that BMMSCs could home and promote the proliferation and migration of PCa through the SDF-1/CXCR4 axis in vivo and in vitro.


Assuntos
Humanos , Animais , Movimento Celular , Quimiocina CXCL12/metabolismo , Células Endoteliais/metabolismo , Células-Tronco Mesenquimais , Transdução de Sinais , Neoplasias da Próstata/metabolismo , Receptores CXCR4/metabolismo
16.
Clin. transl. oncol. (Print) ; 24(1): 145-153, enero 2022.
Artigo em Inglês | IBECS | ID: ibc-203422

RESUMO

PurposeVascular mimicry (VM) tubules are lumen structures comprised of malignant tumor cells without the participation of endothelial cells. VM simulates blood vessel function in tumors to deliver a sufficient blood supply for proliferation, invasion, and metastasis of malignant tumors, thereby reducing the clinical effects of anti-angiogenic treatments. The elimination or prevention of malignant tumor VM development therefore represents an urgent research goal as a therapeutic strategy to and cut off nutrients required for tumor growth. The GATA transcription factor TRPS1 is abnormally up-regulated in breast cancer, osteosarcoma, prostate cancer, and other tumor tissues, and is instrumental in regulating cell proliferation, differentiation, and tissue growth and development.MethodsHere, we explored the effects of TRPS1 knockdown on VM and the proteins underlying its development in triple-negative breast cancer cell line MDA-MB-231.ResultsWe found that TRPS1 knockdown resulted in obvious inhibition of VM development. Fluorescence microscopy of F-actin and tubulin revealed that loss of TRPS1 function resulted in disruption of cytoskeleton and microtubule formation, respectively. In addition, TRPS1-suppressed cells exhibited reduced accumulation of VM-associated proteins EphA2, MMP-2, MMP-9, VEGF, and VE-cadherin. Moreover, it is interesting to know that the capacity for migration and invasion were limited in MDA-MB-231cells after TRPS1 knockdown and that the average number of VM tubules, their length, and number of intersections were also significantly decreased.ConclusionsBased on our results, and in light of previous studies, we thus proposed that TRPS1 suppression negatively affects vascular mimicry possibly through reduced TRPS1-mediated transcriptional regulation of VM-related protein VEGF-A.


Assuntos
Humanos , Ciências da Saúde , Células Endoteliais , Neoplasias da Mama , Vasos Sanguíneos , Neoplasias , Estudos Clínicos como Assunto , Neoplasias da Próstata , Proliferação de Células
17.
Clín. investig. arterioscler. (Ed. impr.) ; 32(5): 193-199, sept.-oct. 2020. graf
Artigo em Espanhol | IBECS | ID: ibc-196742

RESUMO

INTRODUCCIÓN Y OBJETIVOS: Se ha demostrado que el inflamasoma NLRP1 es clave en la disfunción endotelial, estando las plaquetas implicadas en las reacciones inflamatorias que la desencadenan. Investigamos la inhibición in vivo de la inflamación plaquetario-dependiente mediante inhibición del receptor P2Y vía ADP comparada con la de la enzima COX sobre la transcripción del NLRP1 en las células endoteliales. MÉTODOS: Estudio prospectivo, aleatorizado, abierto y cruzado con 2 periodos de inhibición plaquetaria en 20 voluntarios sanos, administrando clopidogrel 75mg/día/7días y aspirina 100mg/día/7días de forma cruzada tras un periodo de lavado de una semana. Las células endoteliales aórticas humanas (HAEC) fueron estimuladas 2h con plasma obtenido de los pacientes antes y después de la inhibición plaquetaria. La cuantificación de la expresión de NLRP1 se determinó mediante análisis qRT PCR. RESULTADOS: Las HAEC expuestas a plasma basal de individuos sanos presentaron niveles más elevados del NLRP1 que las expuestas a plasma de los participantes tras la administración de aspirina o clopidogrel [cuantificación relativa (CR), 1,077±0,05 vs. 1,002±0,06; OR, 1,8; IC95, 1,1-2,9; p < 0,01 y 1,077±0,05 vs. 1,04±0,03; OR, 1,7; IC95, 1,2-2,6; p < 0,001, respectivamente]. La expresión del NLRP1 en HAEC expuestas a plasma de los participantes tras la administración de aspirina o clopidogrel fue similar a las HAEC sin exposición a plasma humano (PBS) [CR 1,002±0,06 vs. 1,009±0,03; OR, 0,9; IC95, 0,5-1,4; p = 0,7 y 1,04±0,03 vs. 1,009±0,03; OR, 0,8; IC95, 0,3-1,2; p = 0,5, respectivamente]. No hubo diferencias en el porcentaje de reducción del NLRP1 en las HAEC expuestas al plasma tras la toma de aspirina comparado con la provocada por el plasma de estos mismos sujetos tras clopidogrel (3,8% vs. 2,8%, p = 0,3, respectivamente). CONCLUSIONES: La inhibición plaquetaria por vías P2Y y COX provoca similar efecto en la inhibición del inflamasoma proaterogénico NLRP1 en las HAEC


INTRODUCTION AND OBJECTIVES: NRP1 inflammasome is crucial in endothelial dysfunction. Platelets are mandatory for the inflammation that precedes it. Aspirin could inhibit NLRP1 inflammasome in endothelial cells, and clopidogrel could also provoke a reduction in vascular inflammation. A study was carried out on the influence of platelet inflammatory inhibition by P2Y receptor inhibition versus COX enzyme inhibition on the transcription of NLRP1 inflammasome in endothelial cells. METHODS: An open-label, prospective, randomised crossover study with two periods of platelet inhibition enrolled 20 healthy volunteers. They received clopidogrel 75mg/day/7days and aspirin 100mg/day/7days. A venous blood sample was collected from all participants before and after this period. Human aortic endothelial cells (HAECs) were exposed for 2h in cultures. NLRP1 gene expression was then analysed in these cultures. RESULTS: HAEC cultures that were exposed to baseline plasma showed higher expression of NLRP1 than HAECs exposed to plasma after one week of aspirin or clopidogrel intake [relative quantification (RQ), 1.077±0.05 vs. 1.002±0.06; OR, 1.8; 95% CI, 1.1-2.9; P<.01 and 1.077±0.05 vs. 1.04±0.03; OR, 1.7; 95% CI, 1.2-2.6; P<.001, respectively]. NLRP1 expression in HAEC cultures exposed to plasma after one week of aspirin or clopidogrel was similar to that observed in control HAECs that was no exposed to human plasma (PBS) [RQ; 1.002±0.06 vs. 1.009±0.03; OR, 0.9; 95% CI, 0.5-1.4; P=.7, and 1.04±0.03 vs. 1.009±0.03; OR, 0.8; 95% CI, 0.3-1.2; P=.5, respectively]. No difference was observed in NLRP1 percentage reduction in HAEC after aspirin or clopidogrel exposure (3.8% vs. 2.8%, P=.3, respectively). CONCLUSIONS: Platelet inhibition by P2Y pathway is similar to COX pathway in NLRP1 expression inhibition in HAECs


Assuntos
Humanos , Feminino , Adulto Jovem , Adulto , Inflamassomos/antagonistas & inibidores , Aspirina/administração & dosagem , Clopidogrel/administração & dosagem , Células Endoteliais/efeitos dos fármacos , Inflamassomos/metabolismo , Estudos Prospectivos , Índice de Massa Corporal , Voluntários Saudáveis/estatística & dados numéricos , Fator de Crescimento Epidérmico/efeitos dos fármacos
19.
Arch. bronconeumol. (Ed. impr.) ; 55(6): 306-311, jun. 2019. graf
Artigo em Inglês | IBECS | ID: ibc-181765

RESUMO

Introduction: The endotoxin lipopolysaccharide (LPS)-induced pulmonary endothelial barrier disruption is a key pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). However, the molecular mechanisms underlying LPS-impaired permeability of pulmonary microvascular endothelial cells (PMVECs) are not fully understood. Methods: Rat PMVECs were isolated and monolayered cultured, then challenged with different doses of LPS (0.1 mg/L, 1 mg/L, and 10 mg/L). Trans-endothelial electrical resistance (TER) was utilized to measure the integrity of the endothelial barrier. Ras-related C3 botulinum toxin substrate 1 (Rac1) activity and the phosphorylation of Ezrin/Radixin/Moesin proteins (ERM) were assessed by pulldown assay and Western Blotting. Small interfering RNA (siRNA) inhibition of Rac1 and Moesin were applied to evaluate the effect of PMVEs permeability and related pathway. Results: LPS induced dose and time-dependent decreases in TER and increase in ERM threonine phosphorylation, while inactivated Rac1 activity in PMVEC. siRNA study demonstrated that both Rac1 and Moesin were involved in the mediation of the LPS-induced hyperpermeability in PMVECs monolayers, and Rac1 and Moesin could regulate each other. Conclusion: Phosphorylated ERM mediates LPS induced PMVECs permeability through negatively regulating Rac1 activity


Introducción: La disrupción de la barrera endotelial pulmonar inducida por endotoxina o lipopolisacárido (LPS) es un factor patogénico clave en la lesión pulmonar aguda (LPA) y el síndrome de distrés respiratorio agudo (SDRA). Sin embargo, los mecanismos que subyacen al empeoramiento de la permeabilidad de las células endoteliales de la microvasculatura pulmonar (PMVECs, por sus siglas en inglés) no se conocen. Métodos: Se aislaron y cultivaron en monocapa PMVEC de rata, y se expusieron a diferentes dosis de LPS (0,1, 1 y 10 mg/l). Se utilizó la resistencia eléctrica transendotelial (TER, por sus siglas en inglés) para medir la integridad de la barrera endotelial. Se analizó la actividad del sustrato 1 de la toxina botulínica C3 relacionado con Ras (Rac1) y la fosforilación de las proteínas erzina/raxidina/moesina (ERM) mediante ensayos pulldown y Western blot. Para evaluar la permeabilidad de las PMVEC y las vías relacionadas se inhibieron Rac1 y moesina mediante ARN pequeño de interferencia (siRNA, por sus siglas en inglés). Resultados: El LPS indujo una disminución dependiente de dosis y tiempo de la TER e incrementó la fosforilación en treonina de ERM, al mismo tiempo que inactivó a Rac1 en las PMVEC. El estudio con siRNA demostró que, tanto Rac1 como la moesina estaban implicadas en la mediación de la permeabilidad de las PMVEC en monocapa inducida por LPS, y que Rac1 y la moesina podrían regularse mutuamente. Conclusión: La fosforilación de ERM media la permeabilidad de las PMVECs inducida por LPS mediante la regulación negativa de la actividad de Rac1


Assuntos
Animais , Masculino , Ratos , Polissacarídeos/farmacologia , Fosforilação/fisiologia , Células Endoteliais/metabolismo , Permeabilidade Capilar/efeitos da radiação , Pulmão/irrigação sanguínea , Proteínas rac1 de Ligação ao GTP/metabolismo , Ratos Sprague-Dawley
20.
Rev. senol. patol. mamar. (Ed. impr.) ; 32(1): 17-25, ene.-mar. 2019. ilus, graf
Artigo em Espanhol | IBECS | ID: ibc-187029

RESUMO

A pesar de los avances conseguidos en el tratamiento del cáncer de mama, todavía sigue siendo una causa importante de mortalidad en las mujeres. Por tanto, resulta necesario plantear nuevos enfoques de la fisiopatología de la enfermedad que contribuyan a realizar una mejor evaluación pronóstica, y a la mejora de las estrategias terapéuticas. Para ello, deberíamos considerar que el cáncer no es solo una transformación maligna de las células epiteliales y su progresión meramente autónoma; sino que, hoy en día, existen datos que apoyan el concepto del cáncer como un ecosistema basado en una sociología de diferentes tipos celulares, con sus interacciones complejas. Entre los diversos tipos de células que conforman el estroma tumoral, y que tienen un papel relevante en la progresión del cáncer de mama, se encuentran los fibroblastos asociados al cáncer, las células inflamatorias y las células endoteliales. Existen diferentes factores moleculares expresados por esas células que se asocian con el desarrollo de metástasis, tales como las metaloproteasas de matriz y sus inhibidores tisulares, citoquinas o receptores tipo toll. En base a la expresión de todos ellos, aquí proponemos 2 fenotipos de estroma del cáncer de mama con influencias marcadamente diferentes sobre el pronóstico de las pacientes. También analizamos los mecanismos involucrados en la interrelación tumor-estroma que pueden llevarnos a mejorar las estrategias terapéuticas en el cáncer de mama


Despite advances in the treatment of breast cancer, it remains an important cause of mortality in women. Therefore, it is necessary to propose new approaches to the pathophysiology of the disease that could help to improve prognostic evaluation and therapeutic strategies. To do this, we should consider that cancer is not only a malignant transformation of the epithelial cells or their purely autonomous growth; nowadays, there are data that support the concept of cancer as a system based on a sociology of different cell types, with complex interactions. Among the various types of cells that make up the tumour stroma and which play an important role in the progression of breast cancer are cancer-associated fibroblasts, inflammatory cells and endothelial cells. Several molecular factors expressed by these cells are associated with the development of metastases, such as matrix metalloproteases and their tissue inhibitors, cytokines or toll-like receptors. Based on the expression of all of these factors, here we propose two types of stroma from breast cancer that display markedly different influences on patient prognosis. We also analyse mechanisms involved in the tumour-stroma interrrelationship that could help to improve therapeutic strategies in breast cancer


Assuntos
Humanos , Células Estromais/patologia , Neoplasias da Mama/patologia , Fibroblastos/patologia , Células Endoteliais/patologia , Mediadores da Inflamação/análise , Prognóstico , Receptores Toll-Like/análise , Junções Intercelulares/patologia
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