RESUMO
BACKGROUND: Autophagy, as a regulator of cell survival, plays an important role in atherosclerosis (AS). Sperm associated antigen 5 (SPAG5) is closely associated with the classical autophagy pathway, PI3K/Akt/mTOR signaling pathway. This work attempted to investigate whether SPAG5 can affect AS development by regulating autophagy. METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with oxidized-low density lipoprotein (ox-LDL) to induce cell damage. ApoE-/- mice were fed a Western diet to establish an AS mouse model. Haematoxylin and eosin (H&E) staining and Oil Red O staining evaluated the pathological changes and in lipid deposition in aortic tissues. CCK-8 and flow cytometry detected cell proliferation and apoptosis. Immunohistochemistry, Enzyme linked immunosorbent assay, qRT-PCR and western blotting assessed the levels of mRNA and proteins. RESULTS: Ox-LDL treatment elevated SPAG5 expression and the expression of autophagy-related proteins, LC3-I, LC3-II, Beclin-1, and p62, in HUVECs. GFP-LC3 dots were increased in ox-LDL-treated HUVECs and LPS-treated HUVECs. SPAG5 knockdown reversed both ox-LDL and LPS treatment-mediated inhibition of cell proliferation and promotion of apoptosis in HUVECs. SPAG5 silencing further elevated autophagy and repressed the expression of PI3K, p-Akt/Akt, and p-mTOR/mTOR in ox-LDL-treated HUVECs. 3-MA (autophagy inhibitor) treatment reversed SPAG5 silencing-mediated increase of cell proliferation and decrease of apoptosis in ox-LDL-treated HUVECs. In vivo, SPAG5 knockdown reduced atherosclerotic plaques in AS mice through activating autophagy and inhibiting PI3K/Akt/mTOR signaling pathway. CONCLUSION: This work demonstrated that SPAG5 knockdown alleviated AS development through activating autophagy. Thus, SPAG5 may be a potential target for AS therapy.
Assuntos
Apoptose , Aterosclerose , Autofagia , Proliferação de Células , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana , Camundongos Knockout para ApoE , Placa Aterosclerótica , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Serina-Treonina Quinases TOR , Animais , Autofagia/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Aterosclerose/patologia , Aterosclerose/metabolismo , Aterosclerose/genética , Aterosclerose/prevenção & controle , Serina-Treonina Quinases TOR/metabolismo , Apoptose/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proliferação de Células/efeitos dos fármacos , Doenças da Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/prevenção & controle , Doenças da Aorta/metabolismo , Camundongos Endogâmicos C57BL , Lipoproteínas LDL/metabolismo , Masculino , Células Cultivadas , Proteínas Relacionadas à Autofagia/metabolismo , Proteínas Relacionadas à Autofagia/genética , Aorta/patologia , Aorta/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Camundongos , Apolipoproteínas ERESUMO
Soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating antiangiogenic protein, is involved in the pathogenesis of atherosclerosis (AS), and the underlying mechanism is still unclear. Here, we attempted to investigate the mechanism of action of sFlt-1 in AS. Human umbilical vein endothelial cells (HUVECs) were treated with oxidized low density lipoprotein (ox-LDL) to induce cell injury. ox-LDL treatment increased LC3-II/LC3-I ratio, Beclin-1 expression and GFP-LC3 puncta in HUVECs, suggesting that ox-LDL may induce autophagic flux impairment in HUVECs. ox-LDL-treated HUVECs displayed a decrease of sFlt-1 levels. Moreover, ox-LDL treatment reduced cell proliferation and elevated apoptosis in HUVECs, which was abrogated by sFlt-1 overexpression. Up-regulation of sFlt-1 repressed the activity of PI3K/AKT/mTOR signaling pathway and enhanced autophagy in HUVECs following ox-LDL treatment. Additionally, sFlt-1 overexpression-mediated increase of autophagy in ox-LDL-treated HUVECs was abolished by 3-methyladenine (autophagy inhibitor). 3-methyladenine abrogated the impact of sFlt-1 overexpression on proliferation and apoptosis in ox-LDL-treated HUVECs. This work confirmed that overexpression of sFlt-1 activated autophagy by repressing PI3K/Akt/mTOR signaling pathway, and thus alleviated ox-LDL-induced injury of HUVECs. Therefore, this study suggests that sFlt-1 may be a potential target for AS treatment.
Assuntos
Aterosclerose/enzimologia , Autofagia/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/enzimologia , Lipoproteínas LDL/toxicidade , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Apoptose/efeitos dos fármacos , Aterosclerose/genética , Aterosclerose/patologia , Proteína Beclina-1/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Transdução de Sinais , Regulação para Cima , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
BACKGROUND: The risk factors contributing to embolism in cardiac myxoma (CM) are yet controversial. This systematic review and meta-analysis aimed to clarify the risk factors of embolism for the CM patients. METHODS: PubMed, Embase, Cochrane library, Web of Science, China National Knowledge Infrastructure, Wan Fang, and Wei Pu databases were searched from inception to June 2019. Statistical analysis was conducted using Stata version 14.0. The pooled odds ratio or mean difference with 95% confidence interval was estimated for each risk factor. RESULTS: Herein, 12 studies, encompassing 1814 patients, were included. The pooled results suggested that New York Heart Association (NYHA) class I/II (P < 0.01), hypertension (P = 0.03), irregular tumor surface (P < 0.01), tumor in atypical location (P = 0.01), narrow base of tumor (P < 0.01), and increased fibrinogen (FIB) (P < 0.01) are significant risk factors of embolism in CM patients. However, sex, age, body mass index, smoking, left ventricular ejection fraction, diabetes, hyperlipidemia, atrial fibrillation, valvular heart disease, coronary heart disease, tumor size, platelet count, white blood cells, and hemoglobin were not associated with embolism (all P > 0.05). CONCLUSIONS: NYHA class (I/II), hypertension, irregular tumor surface, atypical tumor location, the narrow base of tumor, and increased FIB were significant risk factors of embolism in CM patients. For CM patients with these factors, early surgery might be beneficial to prevent embolism.
Assuntos
Embolia/etiologia , Neoplasias Cardíacas/complicações , Mixoma/complicações , Adulto , Idoso , Biomarcadores/sangue , Embolia/diagnóstico , Feminino , Fibrinogênio/análise , Neoplasias Cardíacas/patologia , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Mixoma/patologia , Prognóstico , Medição de Risco , Fatores de Risco , Regulação para CimaRESUMO
PURPOSE: Contrast-enhanced ultrasound (CEUS) has been increasingly used for the diagnostic identification of neoplasms due to its ability to visualize the microvascularization of lesions. In the study of testicular abnormalities, the appropriate use of CEUS can improve the diagnostic accuracy of conventional gray-scale ultrasound and color Doppler ultrasound (CDUS). The purpose of this study is to comprehensively evaluate the diagnostic performance of CEUS in testicular space-occupying lesions. METHODS: A comprehensive search of PubMed, Embase, Cochrane Library, and Web of Science databases was conducted from the inception of each database to November 16, 2022 for relevant studies. The required data were extracted, and the methodological quality of the studies was assessed using the QUADAS-2 tool. The diagnostic value of CEUS was assessed by calculating the combined sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio, and a summary receiver operating characteristic (SROC) curve was used to conduct this meta-analysis. RESULTS: A total of six studies with 354 testicular space-occupying lesions were included in the analysis. The results showed that CEUS could provide additional useful information for the diagnosis of testicular space-occupying lesions, with a sensitivity of 0.92 (95% CI:0.82, 0.97), specificity of 0.91 (95% CI:0.80, 0.96), diagnostic odds ratio of 114 (95% CI:25, 528), respectively, and an overall diagnostic accuracy expressed as area under the SROC curve (AUC) of 0.97 (95% CI:0.95-0.98). Significant heterogeneity was seen in the sensitivity with I2 = 82.53% (95% CI:69.44-95.61). Subgroup analysis revealed that the proportion of infertile patients selected may be the source of heterogeneity. CONCLUSION: CEUS can be used to diagnose testicular space-occupying lesions more accurately and improve diagnostic accuracy when the conventional US cannot accurately differentiate the type of lesion. In particular, CEUS should be recommended for the identification of microscopic lesions so that physicians can provide patients with more appropriate interventions to avoid unnecessary orchiectomy.
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BACKGROUND: Bladder cancer (BLCA), which develops from the upper endometrial of the bladder, is the sixth most prevalent cancer across the globe. WDHD1 (WD repeat and HMG-box DNA binding protein 1 gene) directly affects signaling, the cell cycle, and the development of the cell skeleton. Uncertainty surrounds WDHD1's function in BLCA immunity and prognosis, though. MATERIALS AND METHODS: Using weighed gene co-expression network analysis (WGCNA), initially, we first identified 32 risk factors in genes with differential expression for this investigation. Then, using a variety of bioinformatic techniques and experimental validation, we examined the connections between WDHD1 and BLCA expression, clinical pathological traits, WDHD1-related proteins, upper-skin-intermediate conversion (EMT), immune cell immersion, convergence factors, immune markers, and drug sensitivity. RESULT: The findings demonstrated that we constructed a 32-gene risk-predicting model where WDHD1 was elevated as a representative gene expression in BLCA and related to a range of clinical traits. Furthermore, high WDHD1 expression was a standalone predictor associated with a worse survival rate. The most commonly recruited cells and their evolutionary patterns were highlighted to better comprehend WDHD1's function in cancer. High WDHD1 expression was associated with many aspects of immunology. Finally, the study found that individuals with high expression of WDHD1 were drug-sensitive to four different broad-spectrum anti-cancer drugs. CONCLUSION: These results describe dynamic changes in the tumor microenvironment in BLCA and provide evidence for the hypothesis that WDHD1 is a novel biomarker of tumor development. WDHD1 may therefore be a useful target for the detection and management of BLCA.
Assuntos
Biomarcadores Tumorais , Transição Epitelial-Mesenquimal , Neoplasias da Bexiga Urinária , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/mortalidade , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Prognóstico , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de GenesRESUMO
Sentinel lymph node metastasis (SLNM) is a crucial predictor for breast cancer treatment and survival. This study was designed to propose deep learning (DL) models based on grayscale ultrasound, color Doppler flow imaging (CDFI), and elastography images, and to evaluate how DL radiomics can be used to classify SLNM in breast cancer. Clinical and ultrasound data of 317 patients diagnosed with breast cancer at the Second Affiliated Hospital of Nanchang University were collected from January 2018 to December 2021 and randomly divided into training and internal validation cohorts at a ratio of 7:3. An external validation cohort comprising data from Nanchang Third Hospital with 42 patients collected. Three DL models, namely DL-grayscale, DL-CDFI, and DL-elastography, were proposed to predict SLNM by analyzing grayscale ultrasound, CDFI, and elastography images. Three DL models were compared and evaluated to assess diagnostic performance based on the area under the curve (AUC). The AUCs of the DL-grayscale were 0.855 and 0.788 in the internal and external validation cohorts, respectively. For the DL-CDFI model, the AUCs were 0.761 and 0.728, respectively. The diagnostic performance of DL-elastography was superior to that of the DL-grayscale and DL-CDFI. The AUC of the DL-elastography model was 0.879 in the internal validation cohort, with a classification accuracy of 86.13%, sensitivity of 91.60%, and specificity of 82.79%. The generalization capability of DL-elastography remained high in the external cohort, with an AUC of 0.876, and an accuracy of 85.00%. DL radiomics can be used to classify SLNM in breast cancer using ultrasound images. The proposed DL-elastography model based on elastography images achieved the best diagnostic performance and holds good potential for the management of patients with SLNM.
Assuntos
Neoplasias da Mama , Aprendizado Profundo , Linfadenopatia , Linfoma , Humanos , Feminino , Metástase Linfática , Neoplasias da Mama/patologia , Estudos Retrospectivos , Ultrassonografia , Linfonodos/patologiaRESUMO
PURPOSE: Hepatocellular carcinoma (HCC) is a prevalent tumor with high morbidity, and an unfavourable prognosis. FARSB is an aminoacyl tRNA synthase, and plays a key role in protein synthesis in cells. Furthermore, previous reports have indicated that FARSB is overexpressed in gastric tumor tissues and is associated with a poor prognosis and tumorigenesis. However, the function of FARSB in HCC has not been studied. RESULTS: The results showed that FARSB mRNA and protein levels were upregulated in HCC and were closely related to many clinicopathological characteristics. Besides, according to multivariate Cox analysis, high FARSB expression was linked with a shorter survival time in HCC and may be an independent prognostic factor. In addition, the FARSB promoter methylation level was negatively associated with the expression of FARSB. Furthermore, enrichment analysis showed that FARSB was related to the cell cycle. And TIMER analysis revealed that the FARSB expression was closely linked to tumor purity and immune cell infiltration. The TCGA and ICGC data analysis suggested that FARSB expression is greatly related to m6A modifier related genes. Potential FARSB-related ceRNA regulatory networks were also constructed. What's more, based on the FARSB-protein interaction network, molecular docking models of FARSB and RPLP1 were constructed. Finally, drug susceptibility testing revealed that FARSB was susceptible to 38 different drugs or small molecules. CONCLUSIONS: FARSB can serve as a prognostic biomarker for HCC and provide clues about immune infiltration, and m6A modification.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Mycobacterium tuberculosis , Humanos , Carcinoma Hepatocelular/genética , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Prognóstico , Neoplasias Hepáticas/genética , BiomarcadoresRESUMO
Background: The galectin 2 (LGALS2) protein has been shown to be associated with the pathogenic progression of a range of cancer types, yet its role in papillary thyroid carcinoma (PTC) remains poorly defined. Accordingly, the present study was conducted to address this gap in the literature. Methods: Eighty pairs of tumor and paracancerous tissues from PTC patients were collected. Western immunoblotting and real-time quantitative polymerase chain reaction (qPCR) were used to compare LGALS2 expression levels in tumor and paracancerous tissues from PTC patients. An LGALS2 overexpression construct was produced by inserting the coding sequence for this gene into a pcDNA4.0 vector, and LGALS2-specific and control siRNA constructs were obtained. CCK-8, EdU uptake, and apoptotic assays were used to gauge the role of LGALS2 as a regulator of in vitro PTC cell growth and apoptosis, while its in vivo role was assessed using a murine xenograft model. Results: LGALS2 mRNA and protein levels were reduced in both PTC tumors and cell lines, and the expression of this gene was related to PTC patient prognosis and clinicopathological features. LGALS2 knockdown enhanced PTC cell proliferative activity while decreasing the sensitivity of these cells to apoptotic death. In contrast, the opposite effect was evident following LGALS2 overexpression in vitro and in vivo. LGALS2 also suppressed the progression of PTC by its ability to induce phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway activation. Conclusions: These data indicate that LGALS2 suppresses PTC progression via PI3K/AKT pathway activation, suggesting that LGALS2 offers value as a treatment target for patients with this cancer type.
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Ataxin-3 (ATXN3) is a ubiquitous deubiquitinating enzyme that plays an essential role in the carcinogenesis of numerous tumors and stabilizes the expression of substrates by deubiquitination. However, the functional role of ATXN3 in anaplastic thyroid carcinoma (ATC) remains unknown. In this research, we report that ATXN3 was overexpressed in ATC compared to that in paracancerous samples. Moreover, various gain/loss functional assays were performed to indicate that ATXN3 overexpression enhanced ATC cell proliferation and metastasis. We also found that ATXN3 and eukaryotic translation initiation factor 5A2 (EIF5A2) protein levels in ATC tissues are positively correlated, and ATXN3 promotes the proliferation and metastasis of ATC cells through EIF5A2. Mechanistically, ATXN3 promotes EIF5A2 expression by directly binding to EIF5A2 to reduce its ubiquitination and degradation. Therefore, for the first time, we clarified the role of ATXN3 in the carcinogenesis of ATC cells, which provides novel insights into potential therapeutic targets for ATC progression.
Assuntos
Ataxina-3/metabolismo , Progressão da Doença , Fatores de Iniciação de Peptídeos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Repressoras/metabolismo , Carcinoma Anaplásico da Tireoide/patologia , Animais , Ataxina-3/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Nus , Metástase Neoplásica , Fatores de Iniciação de Peptídeos/genética , Estabilidade Proteica , Proteínas de Ligação a RNA/genética , Proteínas Repressoras/genética , Carcinoma Anaplásico da Tireoide/genética , Ubiquitinação , Regulação para Cima/genética , Fator de Iniciação de Tradução Eucariótico 5ARESUMO
As a key cell cycle regulator, polo-like kinase 1 (Plk1) has been recognized as a crucial factor involved in the progression of pancreatic cancer (PC). However, its regulatory mechanism is poorly understood. Here, we present evidence that Plk1 is a novel substrate of vaccinia-related kinase 2 (VRK2), a serine-threonine kinase that is highly expressed and predicts poor prognosis in PC. VRK2 phosphorylates Plk1 at threonine 210 and protects it from ubiquitin-dependent proteasomal degradation. We showed that mechanistically complement factor H-related protein (CFHR), as a major E3 ligase, promotes Plk1 degradation by ubiquitinating it at lysine 209. Phosphorylation of Plk1 at threonine 210 by VRK2 interferes with the interaction of Chfr with Plk1 and antagonizes Plk1 ubiquitination, thereby stabilizing the Plk1 protein. Taken together, our data reveal a mechanism of Plk1 overexpression in PC and provide evidence for targeting VRK2 as a potential therapeutic strategy.
Assuntos
Proteínas de Ciclo Celular , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas , Pâncreas , Neoplasias Pancreáticas , Vacínia , Quinase 1 Polo-LikeRESUMO
BACKGROUND: The 4-dimensional automated left atrial quantification (4D Auto LAQ) tool is a new software for analysis of the structure and function of the left atrium (LA). This study aimed to evaluate the relationship between LA strain (LAS) as measured by 4D Auto LAQ echocardiography and thromboembolism risk in patients with non-valvular atrial fibrillation (NVAF). METHODS: Eight-five patients with NVAF were recruited from the cardiovascular center of our hospital, including 39 patients at high risk and 46 patients at low risk of thromboembolism. The study participants were assessed by routine echocardiography; 4D images were obtained, after which 4D Auto LAQ assessment was performed. RESULTS: In the thromboembolism high-risk group, the rates of impaired LA reservoir strain, LA contraction strain, LA reservoir circumferential strain, LA conduit circumferential strain, and LA contraction circumferential strain were found to be significantly higher than in the low-risk group. However, there was no significant difference in volume at onset of LA contraction or LA ejection fraction (LAEF) between the 2 groups. LA contraction circumferential strain was found to be an independent high risk factor for thromboembolism [odds ratio (OR): 2.52; P=0.008]. LA contraction circumferential strain >-4.5% was the cut-off for differentiating between participants with high and low risk of thromboembolism, with an area under the curve (AUC) of 0.95 (P<0.0001), a sensitivity of 0.872, and a specificity of 0.978. Sequential analysis revealed that LA contraction circumferential strain had a high diagnostic efficacy for stroke, as well as a specified accuracy in the diagnosis of hypertension and diabetes in patients aged ≥65 years old. However, it was not found to be effective in the diagnosis of heart failure and vascular diseases. CONCLUSIONS: LAS is a useful index for the dynamic evaluation of LA function in patients with non-valvular AF, with higher sensitivity and accuracy than LA volume. LA contraction circumferential strain is an independent high risk factor for thromboembolism, and LA contraction circumferential strain >-4.5% is a valuable cut-off to guide the use of anticoagulant therapy in patients with non-valvular AF.
RESUMO
Breast cancer is the second leading cause of cancer-related deaths in women. The long noncoding RNA LINC00115 has been reported to be involved in the poor outcome of patients with breast cancer, but the biological function and underlying mechanism remain unclear. Here, we report that LINC00115 expression is increased in triple-negative breast cancer tissue compared with matched normal tissue, and LINC00115 knockdown suppresses breast cancer cell migration and invasion. Furthermore, we show that LINC00115 directly targets miR-7 and inhibits its expression. LINC00115 also reduces the expression of KLF4, which is a direct target of miR-7 and is involved in breast cancer metastasis. Together, our findings suggest that LINC00115 promotes breast cancer metastasis through modulating the expression of miR-7 and KLF4.