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BACKGROUND: The transcription factor BACH1 (BTB and CNC homology 1) suppressed endothelial cells (ECs) proliferation and migration and impaired angiogenesis in the ischemic hindlimbs of adult mice. However, the role and underlying mechanisms of BACH1 in atherosclerosis remain unclear. METHODS: Mouse models of atherosclerosis in endothelial cell (EC)-specific-Bach1 knockout mice were used to study the role of BACH1 in the regulation of atherogenesis and the underlying mechanisms. RESULTS: Genetic analyses revealed that coronary artery disease-associated risk variant rs2832227 was associated with BACH1 gene expression in carotid plaques from patients. BACH1 was upregulated in ECs of human and mouse atherosclerotic plaques. Endothelial Bach1 deficiency decreased turbulent blood flow- or western diet-induced atherosclerotic lesions, macrophage content in plaques, expression of endothelial adhesion molecules (ICAM1 [intercellular cell adhesion molecule-1] and VCAM1 [vascular cell adhesion molecule-1]), and reduced plasma TNF-α (tumor necrosis factor-α) and IL-1ß levels in atherosclerotic mice. BACH1 deletion or knockdown inhibited monocyte-endothelial adhesion and reduced oscillatory shear stress or TNF-α-mediated induction of endothelial adhesion molecules and/or proinflammatory cytokines in mouse ECs, human umbilical vein ECs, and human aortic ECs. Mechanistic studies showed that upon oscillatory shear stress or TNF-α stimulation, BACH1 and YAP (yes-associated protein) were induced and translocated into the nucleus in ECs. BACH1 upregulated YAP expression by binding to the YAP promoter. BACH1 formed a complex with YAP inducing the transcription of adhesion molecules. YAP overexpression in ECs counteracted the antiatherosclerotic effect mediated by Bach1-deletion in mice. Rosuvastatin inhibited BACH1 expression by upregulating microRNA let-7a in ECs, and decreased Bach1 expression in the vascular endothelium of hyperlipidemic mice. BACH1 was colocalized with YAP, and the expression of BACH1 was positively correlated with YAP and proinflammatory genes, as well as adhesion molecules in human atherosclerotic plaques. CONCLUSIONS: These data identify BACH1 as a mechanosensor of hemodynamic stress and reveal that the BACH1-YAP transcriptional network is essential to vascular inflammation and atherogenesis. BACH1 shows potential as a novel therapeutic target in atherosclerosis.
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Aterosclerosis , Placa Aterosclerótica , Animales , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/prevención & control , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/farmacología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Inflamación/genética , Inflamación/metabolismo , Inflamación/prevención & control , Ratones , Ratones Endogámicos C57BL , Placa Aterosclerótica/patología , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: Carotid atherosclerosis is a chronic inflammatory disorder and is responsible for the vast majority of ischemic strokes. Inappropriate innate and adaptive immune responses synergize with malfunctional vascular wall cells to cause atherosclerotic lesions. Yet, functional characteristics of specific immune and endothelial cell subsets associated with atherosclerosis and cerebrovascular events are poorly understood. METHODS: Here, using single-cell RNA sequencing, the unprecedentedly largest data set from 20 patients' carotid artery plaques and paired peripheral blood mononuclear cells was generated, with which an ultra-high-precision cellular landscape of the atherosclerotic microenvironment involving 372 070 cells was depicted. RESULTS: Compared with peripheral blood mononuclear cells, 3 plaque-specific T-cell subsets exhibiting proatherogenic features of both activation and exhaustion were identified. Strikingly, usually antiatherogenic, CD4+FOXP3+ regulatory T cells from plaques of patients with symptomatic disease acquired proinflammatory properties by probably converting to T helper 17 and T helper 9 cells, while CD4+NR4A1+/C0 and CD8+SLC4A10+ T cells related to cerebrovascular events possessed atherogenic attributes including proinflammation, polarization, and exhaustion. In addition, monocyte-macrophage dynamics dominated innate immune response. Two plaque-specific monocyte subsets performed diametrically opposed functions, EREG+ monocytes promoted cerebrovascular events while C3+ monocytes are anti-inflammatory. Similarly, IGF1+ and HS3ST2+ macrophages with classical proinflammatory M1 macrophage features were annotated and contributed to cerebrovascular events. Moreover, SULF1+ (sulfatase-1) endothelial cells were also found to participate in cerebrovascular events through affecting plaque vulnerability. CONCLUSIONS: This compendium of single-cell transcriptome data provides valuable insights into the cellular heterogeneity of the atherosclerotic microenvironment and the development of more precise cardiovascular immunotherapies.
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Aterosclerosis , Estenosis Carotídea , Placa Aterosclerótica , Humanos , Leucocitos Mononucleares , Transcriptoma , Células Endoteliales/patología , Monocitos/patología , Aterosclerosis/patología , Placa Aterosclerótica/patología , Estenosis Carotídea/patologíaRESUMEN
OBJECTIVE: Thromboangiitis obliterans (TAO) remains clinical challenging due to its rarity and underwhelming management outcomes. This study aimed to describe a novel TAO rabbit model that demonstrates a closer resemblance to TAO. METHODS: Thirty-six New Zealand rabbits underwent the surgical implantation of calibrated gelatin sponge particles (CGSPs) into their right femoral artery. The CGSPs were soaked in different solutions to simulate different types of thrombi: normal (NT; normal saline); inflammatory TAO thrombus (TAO; dimethylsulfoxide [DMSO]), and DMSO with methotrexate (MTX). All groups underwent clinical assessment, digital subtraction angiography (DSA) and histopathological analysis at time points day 0 (immediate), week 1 (acute), week 2 (subacute), and week 4 (chronic). RESULTS: The TAO rabbit presented with signs of ischemia of the right digit at week 4. On DSA, the TAO rabbits exhibited formation of corkscrew collaterals starting week 1. On H&E staining, gradual CGSP degradation was observed along with increased red blood cell aggregation and inflammatory cells migration in week 1. On week 2, disorganization of the tunica media layer and vascular smooth muscle cell (VSMC) proliferation was observed. In the TAO rabbit, migrated VSMCs, inflammatory cells, and extracellular matrix with collagen-like substances gradually occluded the lumen. On week 4, the arterial lumen of the TAO rabbit was filled with relatively-organized VSMC and endothelial cell clusters with less inflammatory cells. Neorevascularization was found in the MTX-treated group. CONCLUSION: The novel TAO rabbit model shows a closer resemblance to human TAO clinically, radiographically, and histopathologically. Histological analysis of the IT progression in the TAO model suggests that it is of VSMC origin.
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Objective: This study aimed to identify circular RNA profiles (circRNAs) via high-throughput RNA sequencing and distinguish the differentially expressed (DE) circRNAs between stable and unstable plaques. Methods: RNA sequencing was performed on unstable and stable carotid plaque samples obtained from patients with carotid artery stenosis. DE circRNAs were screened, and six DE circRNAs were verified using quantitative real-time PCR (qRT-PCR). Functional evaluation of the DE circRNAs was conducted via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Results: We screened 344 DE circRNAs in unstable plaques, consisting of 342 upregulated and 2 downregulated circRNAs. GO analysis showed that the host genes of the upregulated circRNAs were related to ER to Golgi transport vesicle membrane, endocytic vesicle membrane, and Ran GTPase binding. KEGG analysis revealed that the host genes of the upregulated circRNAs were primarily associated with protein processing in endoplasmic reticulum, lysine degradation, homologous recombination, epithelial cell signaling in Helicobacter pylori infection, and yersinia infection. The results of qRT-PCR verified three upregulated DE circRNAs and two downregulated DE circRNAs in unstable plaques. Conclusion: Hsa-circ-0001523, hsa-circ-0008950, hsa-circ-0000571, hsa-circ-0001946, and hsa-circ-0000745 may be involved in regulating the stability of atherosclerotic plaques and serves as a therapeutic target for unstable plaques.
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Infecciones por Helicobacter , Helicobacter pylori , Placa Aterosclerótica , Humanos , ARN Circular/genética , ARN Circular/metabolismo , Helicobacter pylori/genética , Helicobacter pylori/metabolismo , Análisis de Secuencia de ARNRESUMEN
The purpose of this study is to determine the effects that debris generated by laser and/or balloon on the brain. Debris generated by laser, balloon, and laser combined with balloon were collected and then injected into rats' left common carotid artery. Rats were divided into five groups: sham, saline, laser (L), balloon (B), and laser combined with balloon (LB). The cognition ability of rats was evaluated by Morris water maze. Cerebral blood flow (CBF) was examined by laser speckle. TTC staining and MRI scan were conducted to detect cerebral ischemic infarction. Intracranial arteries in rats were visualized by MRI angiography via contrast medium injected via tail vein. Immunohistologic staining for NeuN and Iba1 and hematoxylin-eosin staining were performed to assess brain infarction. White matter demyelination was assessed by Luxol fast blue staining. Long-term memory and CBF of rats in different groups exhibited no significant difference. No obstruction sign in intracranial artery tree was noticed in each group. Debris generated by different treatments all caused brain infarction. Infarction lesion caused by debris produced by balloon was much more severe than the one caused by debris generated by laser. While the LB group lay in between. The thickness of white matter decreased in the B group, but not in the L and LB groups. Rat brain has a tolerance for debris as cognition ability and cerebral blood flow are not significantly declined. The severity of cerebral infarction varies by debris generated by different treatments.
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Isquemia Encefálica , Ratas , Animales , Isquemia Encefálica/patología , Infarto Cerebral/etiología , Infarto Cerebral/complicaciones , Encéfalo/irrigación sanguínea , Arterias/patología , Rayos LáserRESUMEN
Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease, but effective treatment strategies remain lacking. The objective of this study was to screen underlying therapeutic targets by investigating the molecular mechanisms of AAA using mouse models. The mRNA (GSE109639) and miRNA (GSE51229 and GSE54943) expression profiles of mouse AAA models were downloaded from Gene Expression Omnibus database. A total of 1367 differentially expressed genes (DEGs) were identified between AAA and sham group, 490 of which were used for constructing the Protein-Protein Interaction (PPI) network. NTF3, GNG2 and ITGA7 in the PPI network were suggested to be hub genes according to their ranking of topological features. Furthermore, hub gene GNG2 was enriched in module 1, while ITGA7 was enriched in module 3. Eighteen differentially expressed miRNAs (DEMs) were shared in two datasets, 6 of which were predicted to regulate 130 DEGs (i.e. mmu-miR-677-ITGA7, mmu-miR-350-NTF3 and mmu-miR-292-3p-GNG2) to establish the miRNA-mRNA regulatory network. Function enrichment analysis showed NTF3 was involved in cell motion and MAPK signaling pathway; ITGA7 affected extracellular matrix (ECM)-receptor interaction; GNG2 participated in cell proliferation and chemokine signaling pathway. In conclusion, miRNAs regulating the expressions of NTF3, GNG2 and ITGA7 may represent underlying targets for treatment of AAA.
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Aneurisma de la Aorta Abdominal , MicroARNs , Animales , Antígenos CD , Aneurisma de la Aorta Abdominal/genética , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Cadenas alfa de Integrinas , Integrinas , Ratones , MicroARNs/genéticaAsunto(s)
Aorta Torácica , Implantación de Prótesis Vascular , Procedimientos Endovasculares , Humanos , Procedimientos Endovasculares/métodos , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/instrumentación , Aorta Torácica/cirugía , Aorta Torácica/diagnóstico por imagen , Aorta Torácica/fisiopatología , Implantación de Prótesis Vascular/métodos , Implantación de Prótesis Vascular/instrumentación , Implantación de Prótesis Vascular/efectos adversos , Masculino , Anciano , Resultado del Tratamiento , Arterias Carótidas/cirugía , Arterias Carótidas/fisiopatología , Aneurisma de la Aorta Torácica/cirugía , Aneurisma de la Aorta Torácica/fisiopatología , Aneurisma de la Aorta Torácica/diagnóstico por imagen , Femenino , Persona de Mediana Edad , Prótesis Vascular , Flujo Sanguíneo Regional , StentsRESUMEN
BACKGROUND: To explore Ki67 expression in papillary thyroid carcinoma (PTC) and its clinical-pathological significance. METHODS: A total of 776 consecutive PTC and benign thyroid disease patients underwent thyroidectomy at Shanghai General Hospital from January 2013 to December 2015 and were retrospectively analysed. Ki67 expression was determined in the PTC and benign thyroid disease tissues, and other clinicopathological factors were identified via statistical analyses. RESULTS: The Ki67 expression intensity in the PTC group was significantly higher than that in the benign thyroid disease group. In the PTC group, a tumour size ≥ 1 cm and coexistence with thyroiditis were significantly associated with the Ki67 expression intensity. The TGAb and TPOAb plasma levels were linearly correlated with the Ki67 expression intensity. Moreover, the tumour size and Ki67 expression intensity also showed a linear correlation. Receiver operating characteristic (ROC) curve analysis suggested that the optimal cut-off value of Ki67 was 2.50%. Two groups divided by Ki67 cut-off values showed significant differences in the recurrence survival rate. CONCLUSIONS: Ki67 is a suitable biomarker for distinguishing PTC from benign thyroid disease. Ki67 expression was related to the tumour size, thyroiditis and plasma levels of TGAb and TPOAb in PTC. Ki67 could be used as a prognostic indicator in PTC. Patients with high Ki67 expression are more likely to experience disease recurrence.
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Biomarcadores de Tumor/metabolismo , Carcinoma Papilar/patología , Antígeno Ki-67/metabolismo , Recurrencia Local de Neoplasia/patología , Neoplasias de la Tiroides/patología , Carcinoma Papilar/metabolismo , Carcinoma Papilar/cirugía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/cirugía , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/cirugía , TiroidectomíaRESUMEN
BACKGROUND: This study aimed to evaluate the efficacy of endovascular radiofrequency ablation (RFA) for the treatment of thromboangiitis obliterans (TAO). METHODS: Total 30 males (median age: 46.00 years, interquartile range: 42.00-51.25 years) with unilateral TAO in the lower extremity underwent RFA were retrospectively enrolled from January 2013 and October 2013. The pre-operative and post-operative digital subtraction angiographic (DSA) images were recorded. Pain scores preoperatively and postoperatively were assessed according to the World Health Organization Pain Guideline. The values of ankle brachial index (ABI) at pre-operation, post-operation, 2 weeks and 2 years after surgery were all recorded and analyzed. Additionally, a 2-year follow up was performed by a computed tomographic angiography (CTA) image. RESULTS: The DSA images indicated that occlusion of femoral artery was improved after surgery. Moreover, there was no recurrence of TAO at 2 years of follow-up based on the CTA images. The pain score (P < 0.001) was significantly deceased after surgery. The values of ABI at postoperation, 2 weeks after surgery, and 2 years after surgery were all significantly higher than the preoperative ABI (P < 0.001). Furthermore, the values of ABI at 2 weeks after surgery and 2 years after surgery were all significantly higher than the postoperative ABI (P < 0.001). CONCLUSIONS: These results supported the application of endovascular RFA for treating TAO.
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Ablación por Catéter/métodos , Procedimientos Endovasculares/métodos , Arteria Femoral/cirugía , Extremidad Inferior/irrigación sanguínea , Tromboangitis Obliterante/cirugía , Adulto , Angiografía de Substracción Digital , Índice Tobillo Braquial , Ablación por Catéter/efectos adversos , Angiografía por Tomografía Computarizada , Procedimientos Endovasculares/efectos adversos , Arteria Femoral/diagnóstico por imagen , Arteria Femoral/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Cese del Hábito de Fumar , Tromboangitis Obliterante/diagnóstico , Tromboangitis Obliterante/fisiopatología , Factores de Tiempo , Resultado del Tratamiento , Grado de Desobstrucción VascularRESUMEN
Importance: The ratio of red blood cell distribution width (RDW) to albumin concentration (RAR) has emerged as a reliable prognostic marker for mortality in patients with various diseases. However, whether RAR is associated with mortality in the general population remains unknown. Objectives: To explore whether RAR is associated with all-cause and cause-specific mortality and to elucidate their dose-response association. Design, Setting, and Participants: This population-based prospective cohort study used data from participants in the 1998-2018 US National Health and Nutrition Examination Survey (NHANES) and from the UK Biobank with baseline information provided from 2006 to 2010. Included participants had complete data on serum albumin concentration, RDW, and cause of death. The NHANES data were linked to the National Death Index records through December 31, 2019. For the UK Biobank, dates and causes of death were obtained from the National Health Service Information Centre (England and Wales) and the National Health Service Central Register Scotland (Scotland) to November 30, 2022. Main Outcomes and Measures: Potential associations between RAR and the risk of all-cause and cause-specific mortality were evaluated using Cox proportional hazards regression models. Restricted cubic spline regressions were applied to estimate possible nonlinear associations. Results: In NHANES, 50â¯622 participants 18 years of age or older years were included (mean [SD] age, 48.6 [18.7] years; 26â¯136 [51.6%] female), and their mean (SD) RAR was 3.15 (0.51). In the UK Biobank, 418â¯950 participants 37 years of age or older (mean [SD], 56.6 [8.1] years; 225â¯038 [53.7%] female) were included, and their mean RAR (SD) was 2.99 (0.31). The NHANES documented 7590 deaths over a median (IQR) follow-up of 9.4 (5.1-14.2) years, and the UK Biobank documented 36â¯793 deaths over a median (IQR) follow-up of 13.8 (13.0-14.5) years. According to the multivariate analysis, elevated RAR was significantly associated with greater risk of all-cause mortality (NHANES: hazard ratio [HR], 1.83 [95% CI, 1.76-1.90]; UK Biobank: HR, 2.08 [95% CI, 2.03-2.13]), as well as mortality due to malignant neoplasm (NHANES: HR, 1.89 [95% CI, 1.73-2.07]; UK Biobank: HR, 1.93 [95% CI, 1.86-2.00]), heart disease (NHANES: HR, 1.88 [95% CI, 1.74-2.03]; UK Biobank: HR, 2.42 [95% CI, 2.29-2.57]), cerebrovascular disease (NHANES: HR, 1.35 [95% CI, 1.07-1.69]; UK Biobank: HR, 2.15 [95% CI, 1.91-2.42]), respiratory disease (NHANES: HR, 1.99 [95% CI, 1.68-2.35]; UK Biobank: HR, 2.96 [95% CI, 2.78-3.15]), diabetes (NHANES: HR, 1.55 [95% CI, 1.27-1.90]; UK Biobank: HR, 2.83 [95% CI, 2.35-3.40]), and other causes of mortality (NHANES: HR, 1.97 [95% CI, 1.86-2.08]; UK Biobank: HR, 2.40 [95% CI, 2.30-2.50]) in both cohorts. Additionally, a nonlinear association was observed between RAR levels and all-cause mortality in both cohorts. Conclusions and Relevance: In this cohort study, a higher baseline RAR was associated with an increased risk of all-cause and cause-specific mortality in the general population. These findings suggest that RAR may be a simple, reliable, and inexpensive indicator for identifying individuals at high risk of mortality in clinical practice.
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Índices de Eritrocitos , Encuestas Nutricionales , Humanos , Femenino , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto , Anciano , Causas de Muerte , Estados Unidos/epidemiología , Albúmina Sérica/análisis , Modelos de Riesgos Proporcionales , Mortalidad , Factores de Riesgo , Biomarcadores/sangre , Reino Unido/epidemiologíaRESUMEN
Background: As a new ultrasound technology, 2-dimensional shear wave elastography (2D-SWE) can evaluate the elastic characteristics of penile tissue. However, no studies have reported the main factors affecting the shear wave elastic quantitative measurement (SWQ) in penile tissue. Objectives: To analyze the main factors affecting the SWQ reflecting the elastic characteristics of penile tissue by 2D-SWE. Methods: Twenty healthy male Sprague-Dawley rats (5-60 weeks old) were selected for this study. We performed the 2D-SWE examination on the penis using the Aixplorer ultrasound system, with SWQ as the measurement index. We performed penile immunohistochemistry analysis with the positive area proportion (PAP) of alpha-smooth muscle actin (PAPS) and type III collagen fiber (PAPC) as the outcomes. Then, we conducted multiple linear regression analysis to explore the correlation of SWQ with PAPS and PAPC and established the regression equation. Results: The multiple linear regression analysis showed that the linear regression equation (SWQ = 10.376 - 0.05 PAPS - 0.07 PAPC) was statistically significant (F = 21.153, P < 0.001). The content of smooth muscle cells (SMCs) and collagen fibers was negatively correlated with SWQ, affecting 42.6% of the total variation in SWQ (R2 = 0.426). Conclusions: SMCs and collagen fibers are the main factors affecting the SWQ value of penile tissue and the primary tissue components determining the SWQ when using 2D-SWE to quantitatively evaluate the elastic characteristics of penile tissue.
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OBJECTIVE: Two-dimensional shear wave elastography (2-D SWE) has been proven to detect hyperlipidemia-induced elastic abnormality in the corpus cavernosum. This study investigated cytological factors affecting the elasticity of the corpus cavernosum in rabbits with hyperlipidemia using single-cell RNA sequencing (scRNA-seq). METHODS: Male New Zealand white rabbits were randomly divided into a hyperlipidemia group (high-cholesterol diet) and a control group (standard diet). Penile 2-D SWE was performed to detect the elastic abnormality in the corpus cavernosum. ScRNA-seq was performed to observe cellular changes in the corpus cavernosum of rabbits with hyperlipidemia. Immunohistochemistry, immunofluorescence and histological examinations were conducted to verify the results of scRNA-seq. RESULTS: Two-dimensional SWE revealed that the Young's modulus of the corpus cavernosum was significantly greater in the hyperlipidemia group than that in the control group (p < 0.001). Histological findings revealed extracellular matrix accumulation within the corpus cavernosum, with stronger staining of collagen types I and â ¢. ScRNA-seq revealed that fibroblasts, smooth muscle cells, and endothelial cells were the major cell types in the corpus cavernosum. A novel subtype of fibroblasts (myofibroblast) was discovered in the hyperlipidemia group, which was verified by immunofluorescence staining and gene ontology analysis. Fibroblasts, smooth muscle cells and endothelial cells were three cellular sources for myofibroblasts. CONCLUSION: Myofibroblasts are activated and proliferate and secrete large amounts of collagen fibers in the corpus cavernosum during hyperlipidemia, leading to abnormal Young's modulus detected by 2-D SWE and their recognition as a new factor affecting the hyperlipidemia-induced elastic abnormality of the corpus cavernosum.
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Diagnóstico por Imagen de Elasticidad , Hiperlipidemias , Animales , Masculino , Conejos , Colágeno , Diagnóstico por Imagen de Elasticidad/métodos , Células Endoteliales , Hiperlipidemias/complicaciones , Hiperlipidemias/diagnóstico por imagen , Miofibroblastos , Pene/diagnóstico por imagenRESUMEN
Plaque vulnerability is associated with the degree of carotid artery stenosis (CS) and the risk of stroke. MicroRNAs (miRNAs) exert critical functions in disease progression, although only a few miRNAs have been well identified in CS. Therefore, this study aimed to investigate the differential expression profile of miRNAs and their potential functions in plaques of CS patients. Three CS patients with stable plaques and three patients with vulnerable plaques who underwent carotid endarterectomy were enrolled in this study. Differentially expressed miRNAs (DEmiRNAs) between patients with stable and vulnerable plaques were determined using small RNA sequencing. Target genes of DEmiRNAs were predicted and submitted to functional analyses. Validation of dysregulated DEmiRNAs was determined using quantitative real-time polymerase chain reaction (qRT-PCR). After sequencing, 76 DEmiRNAs were identified in vulnerable plaques, including 53 upregulated miRNAs and 23 downregulated miRNAs. Next, 23,495 target genes of the identified DEmiRNAs were predicted and functionally analyzed. This indicated that the target genes of the identified DEmiRNAs were mainly enriched in protein phosphorylation, transcription, nitrogen compound metabolism, endocytosis and autophagy, and related to signaling pathways of Hippo, MAPK, insulin, TGF-ß, FoxO, AMPK and p53. Furthermore, qRT-PCR results for six miRNAs showed that five (83%) of them (hsa-miR-511-5p, hsa-miR-150-5p, hsa-miR-378a-5p, hsa-miR-365b-5p and hsa-miR-6511b-5p) were consistent with the sequencing results. Differential expression profiles and potential function of miRNAs associated with plaque stability in CS patients are identified for the first time, which should help to understand the regulatory mechanism of plaque stability in CS.
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Estenosis Carotídea , MicroARNs , Humanos , Estenosis Carotídea/genética , Estenosis Carotídea/cirugía , Perfilación de la Expresión Génica/métodos , MicroARNs/genética , MicroARNs/metabolismo , Transducción de Señal/genética , Análisis de Secuencia de ARNRESUMEN
This study explored the usefulness of two-dimensional shear wave elastography (2D-SWE) in the early assessment of corpora cavernosa fibrosis (CCF). New Zealand male rabbits were randomly assigned to an experimental group or a control group. Recombinant human transforming growth factor beta 1 (TGF-ß1) was injected into the dorsal penis tissue of rabbits in the experimental group. Conventional ultrasound and 2D-SWE examinations were performed before and 20 days after injection. Penile histological analysis was performed by hematoxylin-eosin staining, sirius red staining, and immunohistochemistry. Measurement of 2D-SWE examination results was performed using shear wave elastography quantitative measurement (SWQ). Histological analysis outcomes were the proportion of smooth muscle cells (SMCs), collagen fibers (CFs), collagen type I (Col I), and collagen type III (Col III), as well as the SMCs/CFs ratio, measured by sirius red staining. Other histological analysis outcomes were the positive area proportion (PAP) of TGF-ß1 (PAPT), fibronectin (PAPF), and Col III (PAPC), measured by immunohistochemistry. After recombinant human TGF-ß1 injection, SWQ was higher in the experimental group than that in the control group (P < 0.001); however, there were no differences in conventional ultrasound results. There were significant differences in histological outcomes between the two groups (all P < 0.05). These results indicated that 2D-SWE was superior for identifying early histological changes in CCF.
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Diagnóstico por Imagen de Elasticidad , Animales , Diagnóstico por Imagen de Elasticidad/métodos , Fibrosis , Masculino , Pene/patología , Conejos , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
OBJECTIVE: This study aimed to investigate the short-term outcomes of three endovenous procedures in patients with varicose veins (VVs) and severe iliac vein compression syndrome (IVCS). METHODS: A total of 158 consecutive patients were included in this multicenter retrospective study from May 2017 to December 2019; 54 patients underwent endovenous laser ablation (EVLA) alone, 47 patients underwent EVLA and balloon angioplasty (BA), and 57 patients underwent EVLA and stenting angioplasty (SA). Clinical outcomes and complications were assessed at one and twelve months post-surgery. The Quality of life (QoL) was assessed by the venous clinical severity score (VCSS) and Aberdeen Varicose Vein Questionnaire (AVVQ). RESULTS: Patients who underwent the SA procedure were older (P < 0.05). Incidence of laser ablation complications was similar among the three procedures; closure rates of the great saphenous vein were 96.8%, 98.0%, and 98.4%, respectively, at 12 months. Reflux times in the SA procedure were lower than those in the EVLA and BA procedures at 12 months, while ulcer healing time was faster with the SA procedure (P < 0.05) than with the other procedures. The VCSS and AVVQ values were significantly improved post-procedure (P < 0.05), with lower AVVQ scores in the SA procedure than in the EVLA and BA procedures at 12 months post-surgery. The EVLA and BA procedures (stenosis >70%) caused a significantly higher symptom recurrence than the SA procedure, with an odds ratios of 14.04 (95% confidence interval (CI), 1.99-99.18) and 10.50 (95% CI, 1.26-87.15), respectively. CONCLUSIONS: Our results demonstrate that EVLA and SA procedures relieve symptoms, improve the QoL, and decrease symptom recurrence in patients with VVs and severe IVCS (stenosis >70%).
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Procedimientos Endovasculares , Terapia por Láser , Síndrome de May-Thurner , Várices , Constricción Patológica/etiología , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/métodos , Humanos , Vena Ilíaca/cirugía , Terapia por Láser/efectos adversos , Terapia por Láser/métodos , Síndrome de May-Thurner/cirugía , Calidad de Vida , Estudios Retrospectivos , Vena Safena/cirugía , Resultado del Tratamiento , Várices/cirugíaRESUMEN
A previous bioinformatic analysis from our group predicted that the interaction of microRNA (miRNA/miR)-15b with the acyl-CoA synthetase short chain family member 2 (ACSS2) gene was important for the development of abdominal aortic aneurysm (AAA). Apoptosis of aortic vascular smooth muscle cells (VSMCs) is a pathological feature of AAA. The present study aimed to explain the roles of miR-15b/ACSS2 in AAA by exploring their effects on the proliferation and apoptosis of aortic VSMCs. Human aortic VSMCs (T/G HA-VSMC cell line) were divided into six groups and were transfected with miR-15b-5p mimics, mimic negative control (NC), miR-15b-5p inhibitors, inhibitor NC, miR-15b-5p mimics+pcDNA3.1 and miR-15b-5p mimics+ACSS2-overexpessing vector. CCK-8 assay was used to determine cell proliferation. Annexin V-FITC/PI staining and flow cytometry assays were used to measure cell apoptosis. Dual-luciferase reporter assays were used to confirm the targeted relationship between miR-15b-5p and ACSS2. Reverse transcription-quantitative PCR and/or western blotting were used to examine the expression levels of miR-15b-5p, ACSS2 and prostaglandin-endoperoxide synthase 2 (PTGS2). Following transfection of T/G HA-VSMCs with mimics and inhibitors to respectively upregulate and downregulate miR-15b-5p, the results demonstrated that overexpression of miR-15b-5p inhibited cell proliferation and promoted cell apoptosis; silencing of miR-15b-5p obtained the opposite results. ACSS2 may be a direct target of miR-15b-5p, since the luciferase activity of a ACSS2 wild-type vector, but not that of a ACSS2 mutant reporter, was significantly inhibited by miR-15b-5p mimics compared with controls. Additionally, the expression levels of ACSS2 and its downstream gene PTGS2 were significantly reduced or increased following transfection with miR-15b-5p mimics or inhibitors, respectively. Furthermore, overexpression of ACSS2 reversed the antiproliferative and proapoptotic effects of miR-15b-5p mimics by blocking the production of PTGS2 protein. In conclusion, miR-15b-5p may promote the apoptosis and inhibit the proliferation of aortic VSMCs via targeting the ACSS2/PTGS2 axis. The present study provided preliminary evidence indicating that the miR-15b-5p/ACSS2/PTGS2 axis may be a potential target for the treatment of AAA.
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Background: Exosomes-encapsulated microRNAs (miRNAs) have been established to be implicated in the pathogenesis of different diseases. Nevertheless, circulating exosomal miRNAs of thromboangiitis obliterans (TAO) remains poorly understood. This study aimed to explore the effects of exosomal miRNAs associated with TAO on human vascular smooth muscle cells (HVSMCs).Methods: The exosomes were isolated from the plasma of TAO patients and normal controls and then were sent for small RNA sequencing. Differentially expressed miRNAs (DE-miRNAs) were identified by bioinformatics analysis and were confirmed by RT-qPCR. After that, PKH67 staining was used to label exosomes and co-cultured with HVSMCs. Cell viability and apoptosis were, respectively, tested by CCK-8 assay and flow cytometry. Finally, dual-luciferase reporter assay was used to confirm the downstream targets of miR-223-5p.Results: A total of 39 DE-miRNAs were identified between TAO patients and normal controls, of which, miR-223-5p was one of the most significantly up-regulated miRNAs. TAO plasma-derived exosomes or miR-223-5p mimics inhibited cell viability of HVSMCs and promoted cell apoptosis. The pro-apoptotic effect of TAO plasma-derived exosomes was alleviated by miR-223-5p inhibitor. Additionally, the expressions of VCAM1 and IGF1R were down-regulated by exosomes and miR-223-5p mimics, and were abrogated by miR-223-5p inhibitor. Dual-luciferase report showed that VCAM1 was the target of miR-223-5p.Conclusions: Our findings imply that circulating exosomal miR-223-5p may play an essential role in the pathogenesis of TAO, and provide a basis for miR-6515-5p/VCAM1 as novel therapeutic targets and pathways for TAO treatment.
Asunto(s)
Exosomas/metabolismo , MicroARNs/metabolismo , Músculo Liso Vascular/metabolismo , Tromboangitis Obliterante/genética , Apoptosis , Supervivencia Celular , Biología Computacional , Exosomas/genética , Humanos , MicroARNs/genética , Tromboangitis Obliterante/sangre , Regulación hacia ArribaRESUMEN
INTRODUCTION: Endovascular therapies have not yet had an ideal effect on thromboangiitis obliterans (TAO) and no data have been published about laser-assisted angioplasty (LA) combined with radiofrequency ablation (RFA) for TAO. This study aimed to investigate the outcome of LA combined with RFA for TAO. METHODS: Sixteen consecutive patients underwent LA and RFA procedures between June 2018 and March 2019 in this prospective pilot study. The clinical outcomes and complications were assessed at 6, 12, and 18 months after the procedure. The primary endpoint was defined as the limb salvage rate and freedom of target-lesion revascularization (f-TLR) of the limb, and the effect on the outcome was assessed by the ankle brachial index (ABI), numerical rating scores (NRSs), and the EuroQol Group 5-Dimension Self-Report Questionnaire (EQ-5D). RESULTS: Men accounted for 87.5% of the patients. All patients underwent LA, and following the RFA procedure, two patients received bailout stenting (12.50%). The technique success rate was 100%, and no severe complications occurred. The ABI was significantly higher at the 18-month follow-up than at baseline (P < 0.001). The primary and secondary patency rates were 71.82% and 79.80%, respectively, and the f-TLR and limb salvage rates were 90% and 92.86% based on Kaplan-Meier analysis. The EQ-5D value was higher after the procedure than at baseline (P < 0.001), and the NRS value was lower after the procedure than at baseline (P < 0.001). CONCLUSIONS: Our results confirmed that LA combined with RFA was a feasible procedure that resulted in acceptable limb salvage and f-TLR rates.
Asunto(s)
Angioplastia de Balón Asistida por Láser , Ablación por Radiofrecuencia , Tromboangitis Obliterante , Humanos , Masculino , Proyectos Piloto , Estudios Prospectivos , Estudios Retrospectivos , Factores de Riesgo , Stents , Tromboangitis Obliterante/cirugía , Resultado del TratamientoRESUMEN
Thromboangiitis obliterans (TAO) is a non-atherosclerotic, segmental, chronic vascular inflammatory disease. Our aim was to explore the underlying mechanisms of long non-coding RNA (lncRNA)-related competing endogenous RNAs (ceRNAs) in TAO. Six blood samples were collected from patients with TAO and healthy individuals (three for each category). Total RNA was extracted from the blood of each participant and sequenced. Differentially expressed lncRNAs (DE-lncRNAs) and miRNAs (DE-miRNAs) were screened, and ceRNA networks associated with TAO were constructed. Thereafter, the genes in the ceRNA network were subjected to functional analyses. Finally, a ceRNA relationship (lncRNA NEAT1-hsa-miR-1-3p-mRNA GNA12) was selected for further validation. Analysis revealed that 347 DE-lncRNAs (150 downregulated and 197 upregulated) and 16 DE-miRNAs (3 downregulated and 13 upregulated) were identified in TAO. Further, TAO-associated ceRNA networks, which included 219 lncRNAs, 6 miRNAs, and 53 mRNAs, were proposed and subjected to gene annotation and pathway analysis. Additionally, NEAT1 and GNA12 levels were significantly upregulated, while miR-1-3p levels were evidently downregulated in TAO patients, as compared with those in healthy controls. Dual luciferase reporter assays showed that NEAT1, miR-1-3p, and GNA12 interacted with each other. We report potential TAO-associated ceRNA regulatory networks and suggest activation of NEAT1/miR-1-3p/GNA12 signaling as a novel mechanism for TAO progression.
Asunto(s)
Redes Reguladoras de Genes , MicroARNs/genética , ARN Largo no Codificante/genética , ARN Mensajero/genética , Tromboangitis Obliterante/genética , Adulto , Estudios de Casos y Controles , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Masculino , MicroARNs/metabolismo , ARN Largo no Codificante/metabolismo , ARN Mensajero/metabolismoRESUMEN
Clinical evidence indicates that high periostin expression correlates with aggressive phenotype in thyroid carcinoma. However, the biological roles of periostin in thyroid carcinoma development and progression are still unclear. In this study, we explored the effects of periostin silencing on thyroid carcinoma cell growth, invasion, and tumorigenesis. We also studied the impact of periostin on the activation of phosphoinositide 3-kinase (PI3-K)/Akt signaling, which is involved in the pathogenesis of thyroid carcinoma. It was found that downregulation of periostin significantly inhibited the proliferation, colony formation, and invasion in both FTC-133 and BCPAP thyroid carcinoma cells. In vivo tumorigenic studies confirmed that periostin depletion retarded the growth of subcutaneous FTC-133 xenograft tumors, which was coupled with a significant decline in the percentage of Ki-67-positive proliferating cells. Western blot analysis demonstrated that periostin downregulation caused a marked inhibition of thyroid stimulating hormone receptor (TSHR) expression and Akt phosphorylation in FTC-133 and BCPAP cells. Co-expression of constitutively active Akt (CA-Akt) significantly reversed periostin-mediated downregulation of TSHR. Most importantly, overexpression of TSHR or CA-Akt rescued FTC-133 cells from periostin-induced growth and invasion suppression. Collectively, periostin regulates thyroid carcinoma growth and progression via the Akt/TSHR axis and represents a promising therapeutic target for this malignancy.