RESUMEN
Increasing evidence has verified the indispensable effect of microRNAs (miRNAs) in the biological processes of human diseases, including endometriosis. hsa-miR-340-5p was reported to display a low level in patients with endometriosis, but the detailed function of miR-340-5p in endometriosis is unclarified. RT-qPCR was used for the assessment of RNA levels of miR-340-5p and its downstream target genes in endometrial stromal cells (ESCs). Western blotting and Transwell assays revealed that upregulation of miR-340-5p suppressed the migration, invasiveness, and epithelial-mesenchymal transition (EMT) in ESCs. Bioinformatics tools were used to predict miR-340-5p downstream genes. Luciferase reporter assay displayed that miR-340-5p could bind to messenger RNA mitogen-activated protein kinase kinase kinase 2 (MAP3K2). MAP3K2 was targeted by miR-349-5p and could reverse the influence of miR-340-5p. miR-340-5p exerted its impact on the invasive characters of ESCs by inactivating the MAP3K2-mediated MAPK/ERK signaling. In conclusion, miR-340-5p restrains cell migration, invasiveness, and EMT in ESCs by targeting MAP3K2 and inactivating MAPK/ERK signaling.
RESUMEN
Endometriosis (EMs) is one of the most frequent diseases of reproductive-age women and is characterized by the growth of endometrial tissues beyond the uterus. The enhanced proliferative and migratory potential of endometrial stromal cells (ESCs) plays an important role in the progression of EMs. Mounting studies have demonstrated that long noncoding RNAs (lncRNAs) exert an important role in regulating the development and progression of EMs. Given the aberrant expression of lncRNA ADAMTS9-AS1 in ectopic endometrium (ecEM), we investigated the biological effect of ADAMTS9-AS1 on ESC proliferation and migration and explored the underlying mechanism. The current data showed that ADAMTS9-AS1 expression was significantly upregulated in ecEM compared with eutopic endometrium (euEM) in patients with EMs and in a murine model of EMs. Functionally, ADAMTS9-AS1 knockdown in ectopic ESCs (EESCs) decreased cell viability and migration, whereas ADAMTS9-AS1 overexpression in normal ESCs (NESCs) enhanced cell viability and migration. More importantly, the effect of ADAMTS9-AS1 inhibition on decreasing ESC viability was significantly blocked by ferrostatin-1 (Fer-1, a ferroptosis inhibitor), and ADAMTS9-AS1 overexpression repressed erastin (a ferroptosis activator)-induced cell death. Furthermore, the regulatory role of ADAMTS9-AS1 in ferroptosis was defined and evidenced by increased reactive oxygen species (ROS) levels and malonyl dialdehyde (MDA) content and decreased expression of glutathione peroxidase 4 (GPX4) after ADAMTS9-AS1 inhibition. Mechanistically, ADAMTS9-AS1 functioned as a competing endogenous RNA (ceRNA) by sponging miR-6516-5p to derepress the expression of GPX4, the critical repressor of ferroptosis. Taken together, these results demonstrate that upregulated ADAMTS9-AS1 accelerates ESC proliferation and migration by regulating miR-6516-5p/GPX4-dependent ferroptosis and may be a potential target for the treatment of EMs.
Asunto(s)
Proteína ADAMTS9/fisiología , Endometriosis/genética , Endometriosis/fisiopatología , Endometrio/citología , Endometrio/fisiología , Ferroptosis/genética , Ferroptosis/fisiología , Expresión Génica/genética , MicroARNs/genética , MicroARNs/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , ARN Largo no Codificante/fisiología , Células del Estroma/fisiología , Animales , Movimiento Celular/genética , Proliferación Celular/genética , Células Cultivadas , Modelos Animales de Enfermedad , Endometriosis/patología , Endometriosis/terapia , Femenino , Humanos , Ratones Endogámicos BALB C , Terapia Molecular DirigidaRESUMEN
Endometriosis (EMS) is a prevalent disease in women characterized by the presence of endometrial stroma and glands outside the uterus. Recent studies have showed that EMS is correlated with the resistance of endometrial stromal cells (ESCs) to ferroptosis, an iron-dependent nonapoptotic cell death. Fibulin-1 (FBLN1) is a newly identified target regulated by progesterone in the process of ESC decidualization. However, the role of FBLN1 in regulating ESC ferroptosis and EMS remains unclear. In the present study, the gene expression profiles of GSE58178, GSE23339, and GSE25628 were downloaded from the Gene Expression Omnibus (GEO) database, and the commonly differential genes were identified using Venn diagram analysis. The role of FBLN1 in ESC viability and migration was evaluated using Cell Counting Kit-8, transwell, and western blot analysis. We found that the FBLN1 expression was increased significantly in eutopic and ectopic endometrial tissues of patients with EMS compared with normal endometrium. FBLN1 overexpression in normal ESCs (NESCs) promoted cell viability and migration, whereas FBLN1 inhibition in ectopic ESCs (EESCs) decreased cell viability and migration. Furthermore, FBLN1 inhibition facilitated EESC death by triggering ferroptosis, as evidenced by increased Fe2+, lipid ROS, and malondialdehyde (MDA) level and decreased glutathione peroxidase 4 (GPX4) expression and glutathione (GSH) level. Mechanistically, FBLN1 interacted with EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) and increased the protein stability of EFEMP1. More importantly, EFEMP1 silencing repressed the effect of FBLN1 on regulating EESC ferroptosis, death, and migration. Taken together, these results verify the role of the FBLN1/EFEMP1/ferroptosis pathway in the pathogenesis of EMS, and silencing of FBLN1/EFEMP1 might be an effective approach to treat EMS.
Asunto(s)
Proteínas de Unión al Calcio , Endometriosis , Proteínas de la Matriz Extracelular , Ferroptosis , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Movimiento Celular/genética , Supervivencia Celular/genética , Endometriosis/patología , Endometrio/patología , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Femenino , Ferroptosis/genética , Humanos , Células del Estroma/metabolismoRESUMEN
Deficient visual organization ability not only indicates possible brain dysfunctions but further affects an individual's daily activities. This study aimed to use functional magnetic resonance imaging (fMRI) to investigate the neural network contributing to visual organization abilities in children and adolescents. A two-choice version of the Hooper Visual Organization Test (T-HVOT) was adapted as the fMRI task for the present study. The effects of age and gender on overall visual perceptual functions and related neural foundations were also analyzed. Seventy children and adolescents were administered with the Test of Visual Perceptual Skill-Third Edition and 41 completed the fMRI scans. The whole-brain fMRI mapping results showed the cortical activation of multiple brain areas relating to visual organization. The greatest cortical activities were seen in the middle occipital gyrus, middle temporal gyrus, middle frontal gyrus and inferior frontal gyrus, and two age groups showed significant differences in cortical activation patterns as well. Gender had no significant effects on visual perceptual functions nor related cortical activation patterns. The overall visual perception functions improve with age, and the different cortical activation patterns indicated that the two groups adopt different strategies while performing visual organization tasks. The sensitivity and spatial resolution of fMRI allowed us to make specific conclusions about cortical regions involved in visual organization function and to provide a reference for objectively judging rehabilitative outcomes.
Asunto(s)
Mapeo Encefálico , Imagen por Resonancia Magnética , Adolescente , Encéfalo/fisiología , Niño , Humanos , Imagen por Resonancia Magnética/métodos , Lóbulo Temporal , Percepción Visual/fisiologíaRESUMEN
The role of ethanol (C2H5OH) in pitting corrosion behavior of AISI 316L austenitic stainless steel was investigated in aqueous ethanolic solution with chloride. The pitting susceptibility and surface morphology of 316L in a series of ethanol-containing solutions were examined using X-ray photoelectron spectroscopy (XPS), optical microscopy with 3D stitching, immersion tests, and potentiodynamic polarization measurements. Results demonstrated that the ethanol concentration impacted little on the passive film stability while it dramatically influenced the pitting corrosion susceptibility. Corrosion rate of 316L after immersion tests first increased and then decreased as the concentration of ethanol increased from 0 to 10 M in ferric chloride solution. This, however, did not correspond to the breakdown potential which directly decreased from 489 to 249 mV as the water concentration decreased in ethanolic NaCl solutions. The pits density after both immersion and electrochemical tests showed that the initiation of pitting in ethanolic solution tended to occur at multiple points at the same time. The synergy effect on pitting behavior of hydrolysis enhancement and solubility reduction of metal cations due to the introduction of ethanol has also been discussed.
RESUMEN
This study investigated the effectiveness of the Computerized Visual Perception Training (CVPT) program on individuals with Down syndrome (DS, mean age=13.17±4.35years, age range: 6.54-20.75 years). All participants have mild intellectual disability classified by the standard IQ measures (mean=61.2, ranges from 55 to 68). Both the Test of Visual Perceptual Skill- Third Edition (TVPS-3) and functional magnetic resonance imaging (fMRI) were used to evaluate the training outcomes. Results of TVPS-3 and fMRI showed that DS group had visual perceptual deficits and abnormal neural networks related to visual organization. The results showed that DS intervention group had significant improvements on TVPS-3 after intervention. The fMRI results indicated more activation in superior and inferior parietal lobes (spatial manipulation), as well as precentral gyrus and dorsal premotor cortex (motor imagery) in DS intervention group. The CVPT program was effective in improving visual perceptual functions and enhancing associated cortical activations in DS.
Asunto(s)
Instrucción por Computador/métodos , Síndrome de Down , Educación de las Personas con Discapacidad Intelectual/métodos , Educación de Personas con Discapacidad Visual/métodos , Percepción Visual/fisiología , Adolescente , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Niño , Síndrome de Down/diagnóstico , Síndrome de Down/fisiopatología , Síndrome de Down/psicología , Educación , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Evaluación de Programas y Proyectos de Salud , Percepción Espacial/fisiología , TaiwánRESUMEN
Hypoxia in tumors is closely related to drug resistance. It has not been verified whether hypoxia-inducible factor-1α (HIF-1α) or ABCG2 is related to hypoxia-induced resistance. Ursolic acid (UA), when used in combination with cisplatin can significantly increase the sensitivity of ovarian cancer stem cells (CSCs) to cisplatin, but the exact mechanism is unknown. The cell growth inhibitory rate of cisplatin under different conditions was evaluated using Cell Counting Kit-8 (CCK-8) in adherence and sphere cells (SKOV3, A2780, and HEY). The expression of HIF-1α and ABCG2 was tested using quantitative PCR, western blotting, and immuno-fluorescence under different culture conditions and treated with UA. Knockdown of HIF-1α by shRNA and LY294002 was used to inhibit the activity of PI3K/Akt pathway. Ovarian CSCs express stemness-related genes and drug resistance significantly higher than normal adherent cells. Under hypoxic conditions, the ovarian CSCs grew faster and were more drug resistant than under normoxia. UA could inhibit proliferation and reverse the drug resistance of ovarian CSC by suppressing ABCG2 and HIF-1α under different culture conditions. HIF-1α inhibitor YC-1 combined with UA suppressed the stemness genes and ABCG2 under hypoxic condition. The PI3K/Akt signaling pathway activation plays an important functional role in UA-induced downregulation of HIF-1α and reduction of ABCG2. UA inhibits the proliferation and reversal of drug resistance in ovarian CSCs by suppressing the expression of downregulation of HIF-1α and ABCG2.
Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas de Neoplasias/genética , Células Madre Neoplásicas/efectos de los fármacos , Neoplasias Ováricas/tratamiento farmacológico , Triterpenos/farmacología , Hipoxia de la Célula/efectos de los fármacos , Hipoxia de la Célula/genética , Línea Celular Tumoral , Cisplatino/farmacología , Regulación hacia Abajo/genética , Resistencia a Antineoplásicos/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias Ováricas/genética , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , ARN Interferente Pequeño/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Ácido UrsólicoRESUMEN
The primary purpose of this study was to investigate the visual perceptual functions measured by the Test of Visual Perceptual Skill-Third Edition (TVPS-3) in Down syndrome (DS). Seventy individuals with DS, seventy with typical development (TD), and forty mental-age-matched participants with intellectual disabilities (ID) were recruited for the assessment session. Significant between-group differences in TVPS-3 were observed between either DS or ID and TD groups. There was no significant difference on TVPS-3 between DS and ID groups. Implications for clinical professionals and recommendations for further research are discussed.