RESUMEN
Aqueous zinc-ion batteries (AZIBs) face challenges in achieving high energy density compared to conventional lithium-ion batteries (LIBs). The lower operating voltage and excessive Zn metal as anode pose constraints on the overall energy storage capacity of these batteries. An effective approach is to reduce the thickness of the Zn metal anode and control its mass appropriately. However, under the condition of using a thin Zn anode, the performance of AZIBs is often unsatisfactory. Through experiments and computational simulations, the electrode structural change and the formation of dead Zn as the primary reasons for the failure of batteries under a high Zn utilization rate are identified. Based on this understanding, a universal synergistic strategy that combines Cu foil current collectors and electrolyte additives to maintain the structural and thermodynamic stability of the Zn anode under a high Zn utilization rate (ZUR) is proposed. Specifically, the Cu current collectors can ensure that the Zn anode structure remains intact based on the spontaneous filling effect, while the additives can suppress parasitic side reactions at the interface. Ultimately, the symmetric cell demonstrates a cycling duration of 900 h at a 70% ZU, confirming the effectiveness of this strategy.
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To explore potential indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors, we designed a series of compounds incorporating urea and 1,2,3-triazole structures. IDO1 enzymatic activity experiments with the synthesized compounds were used to verify their molecular-level activity; for instance, the half maximal inhibitory concentration value of compound 3c was 0.07 µM. Our research has yielded a series of novel IDO1 inhibitors which may be beneficial in the development of drugs targeting IDO1 for cancer treatment.
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Antineoplásicos , Neoplasias , Relación Estructura-Actividad , Triazoles/farmacología , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Indolamina-Pirrol 2,3,-Dioxigenasa/química , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológicoRESUMEN
ABSTRACT: Chronic lower extremity venous insufficiency can cause local dystrophy, and some patients will develop calf dystrophic calcification. In this case report, the authors describe a patient with varicose veins of both lower extremities, venous insufficiency of the lower extremities, recurring ulcers on the left leg for more than 20 years, and diabetes mellitus with dystrophic calcification of the calf. The patient's left leg ulcer showed extensive chronic inflammation, pathological calcification, and necrosis of the subcutaneous tissue with a thickness of approximately 0.5 to 1 cm. The computed tomography, X-ray, and hematoxylin-eosin staining results confirmed calcification; the leg skin thickened because of inflammatory irritation. After 11 months of treatment, the calcified and necrotic calcification and necrotic tissue were removed, and the wound healed.
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Diabetes Mellitus , Úlcera Varicosa , Insuficiencia Venosa , Humanos , Pierna , Extremidad Inferior/irrigación sanguínea , Insuficiencia Venosa/complicaciones , Insuficiencia Venosa/patología , Piel/patología , Úlcera , Úlcera Varicosa/terapiaRESUMEN
Podocytes are unique, highly specialized, terminally differentiated cells, which are restricted in a post-mitotic state with limited ability to repair or regenerate. Re-entering the mitotic phase causes podocyte mitotic catastrophe, thereby leading to podocyte death and glomerular injury. Myeloid-derived growth factor (MYDGF) is a novel secreted protein and plays an important role in the regulation of cardiovascular function. However, whether MYDGF is expressed in kidney parenchymal cells and whether it has biological functions in the kidney remain unknown. Here, we found that MYDGF was expressed in kidney parenchymal cells and was significantly reduced in podocytes from mice with models of focal segmental glomerulosclerosis and diabetic kidney disease. Podocyte-specific deletion of Mydgf in mice exacerbated podocyte injury and proteinuria in both disease models. Functionally, MYDGF protected podocytes against mitotic catastrophe by reducing accumulation of podocytes in the S phase, a portion of the cell cycle in which DNA is replicated. Mechanistically, MYDGF regulates the expression of the transcription factor RUNX2 which mediates some MYDGF effects. Importantly, a significant reduction of MYDGF was found in glomeruli from patients with glomerular disease due to focal segmental glomerulosclerosis and diabetic kidney disease and the level of MYDGF was correlated with glomerular filtration rate, serum creatinine and podocyte loss. Thus, our studies indicate that MYDGF may be an attractive therapeutic target for glomerular disease.
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Nefropatías Diabéticas , Glomeruloesclerosis Focal y Segmentaria , Interleucinas , Podocitos , Animales , Nefropatías Diabéticas/complicaciones , Nefropatías Diabéticas/genética , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Interleucinas/genética , Glomérulos Renales/patología , Ratones , Mitosis , Podocitos/patologíaRESUMEN
BACKGROUND AND AIM: A considerable number of early-stage colorectal cancer (CRC) patients may develop cancer relapse or metastasis after curative surgery. Isolated tumor cells (ITC) and micrometastasis in lymph nodes (LNMM), which are undetectable by conventional pathological examination, may be one primary reason. Detection of ITC/LNMM is time-consuming and cost-ineffective; we aimed to find biomarkers in primary CRC tissues to help predicting ITC/LNMM status. METHODS: We enrolled 137 node-negative patients with early-stage CRC in this study. Existence of ITC/LNMM was identified by immunohistological staining with cytokeratin 20 in resected lymph nodes. Expression of transducin (ß)-like 1 X-linked receptor 1 (TBL1XR1) in primary CRC tissues was also investigated. Chi-squared test was performed to reveal the correlations between ITC/LNMM and clinicopathological characteristics. Univariate and multivariate analyses were used to determine independent prognostic factors. Knockdown experiment together with proliferation and invasion assays were carried out to explore molecular mechanisms between TBL1XR1 and ITC/LNMM. RESULTS: About 29.2% (40/137) patients were identified as ITC/LNMM positive, and most of them (32/40 cases, 80%) showed high TBL1XR1 expression in primary CRC tissues. Both ITC/LNMM and TBL1XR1 expression were independent prognostic factors for disease relapse or metastasis. In vitro experiments demonstrated that TBL1XR1 can regulate the expression of vascular endothelial growth factor C and epithelial-mesenchymal transition proteins, thus mediate the process of lymph node metastasis. CONCLUSIONS: Identification of ITC/LNMM is significant in evaluating clinical outcome and guiding adjuvant chemotherapy for early-stage CRC patients. TBL1XR1 overexpression in CRC tissues can serve as an efficient biomarker to predict the status of ITC/LNMM.
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Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Expresión Génica , Metástasis Linfática/genética , Micrometástasis de Neoplasia/genética , Proteínas Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Proteínas Represoras/metabolismo , Anciano , Biomarcadores de Tumor/genética , Quimioterapia Adyuvante , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Femenino , Humanos , Inmunohistoquímica , Metástasis Linfática/patología , Masculino , Persona de Mediana Edad , Micrometástasis de Neoplasia/patología , Estadificación de Neoplasias , Proteínas Nucleares/genética , Valor Predictivo de las Pruebas , Receptores Citoplasmáticos y Nucleares/genética , Proteínas Represoras/genética , Células Tumorales CultivadasRESUMEN
Histone deacetylase (HDAC) 9, a member of class II HDACs, regulates a wide variety of normal and abnormal physiological functions, which is usually expressed at high levels in the brain and skeletal muscle. Although studies have highlighted the importance of HDAC-mediated epigenetic processes in the development of ischaemic stroke and very recent genome-wide association studies have identified a variant in HDAC9 associated with large-vessel ischemic stroke, the molecular events by which HDAC9 induces cerebral injury keep unclear. In this study, we found that HDAC9 was up-regulated in the ischaemic cerebral hemisphere after cerebral ischaemia/reperfusion (I/R) injury in rats and in vivo gene silencing of HDAC9 by recombinated lentivirus infection in the brain reduced cerebral injury in experimental stroke. We further demonstrated that HDAC9 contributed to oxygen-glucose deprivation-induced brain microvessel endothelial cell dysfunction as demonstrated by the increased inflammatory responses, cellular apoptosis and endothelial cell permeability dysfunction accompanied by reduced expression of tight-junction proteins. We further found that HDAC9 suppressed autophagy, which was associated with endothelial dysfunction. This study for the first time provides direct evidence that HDAC9 contributes to endothelial cell injury and demonstrates that HDAC9 is one of critical components of a signal transduction pathway that links cerebral injury to epigenetic modification in the brain.
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Isquemia Encefálica/complicaciones , Isquemia Encefálica/enzimología , Encéfalo/irrigación sanguínea , Células Endoteliales/patología , Histona Desacetilasas/metabolismo , Daño por Reperfusión/enzimología , Daño por Reperfusión/patología , Animales , Apoptosis , Autofagia , Barrera Hematoencefálica/patología , Barrera Hematoencefálica/ultraestructura , Isquemia Encefálica/patología , Permeabilidad de la Membrana Celular , Células Endoteliales/metabolismo , Células Endoteliales/ultraestructura , Silenciador del Gen , Técnicas de Transferencia de Gen , Glucosa/deficiencia , Histona Desacetilasas/genética , Inflamación/patología , Lentivirus/metabolismo , Masculino , Microvasos/patología , Oxígeno , Ratas Sprague-Dawley , Daño por Reperfusión/genética , Regulación hacia ArribaRESUMEN
An increasing number of clinical and animal model studies indicate that activation of the innate immune system and inflammatory mechanisms are important in the pathogenesis of diabetic nephropathy. Nucleotide-binding oligomerization domain containing 2 (NOD2), a member of the NOD-like receptor family, plays an important role in innate immune response. Here we explore the contribution of NOD2 to the pathogenesis of diabetic nephropathy and found that it was upregulated in kidney biopsies from diabetic patients and high-fat diet/streptozotocin-induced diabetic mice. Further, NOD2 deficiency ameliorated renal injury in diabetic mice. In vitro, NOD2 induced proinflammatory response and impaired insulin signaling and insulin-induced glucose uptake in podocytes. Moreover, podocytes treated with high glucose, advanced glycation end-products, tumor necrosis factor-α, or transforming growth factor-ß (common detrimental factors in diabetic nephropathy) significantly increased NOD2 expression. NOD2 knockout diabetic mice were protected from the hyperglycemia-induced reduction in nephrin expression. Further, knockdown of NOD2 expression attenuated high glucose-induced nephrin downregulation in vitro, supporting an essential role of NOD2 in mediating hyperglycemia-induced podocyte dysfunction. Thus, NOD2 is one of the critical components of a signal transduction pathway that links renal injury to inflammation and podocyte insulin resistance in diabetic nephropathy.
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Diabetes Mellitus Experimental/complicaciones , Nefropatías Diabéticas/etiología , Mediadores de Inflamación/metabolismo , Resistencia a la Insulina , Nefritis/etiología , Proteína Adaptadora de Señalización NOD2/metabolismo , Podocitos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Biomarcadores/sangre , Biomarcadores/orina , Glucemia/metabolismo , Células Cultivadas , Creatinina/sangre , Creatinina/orina , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/inmunología , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/inmunología , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/prevención & control , Dieta Alta en Grasa , Femenino , Transportador de Glucosa de Tipo 4/metabolismo , Humanos , Insulina/sangre , Lípidos/sangre , Sistema de Señalización de MAP Quinasas , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Persona de Mediana Edad , Nefritis/genética , Nefritis/inmunología , Nefritis/metabolismo , Nefritis/patología , Nefritis/prevención & control , Proteína Adaptadora de Señalización NOD2/deficiencia , Proteína Adaptadora de Señalización NOD2/genética , Podocitos/patología , Factores de Tiempo , Regulación hacia ArribaRESUMEN
A polypropylene (PP) film is usually used as a dielectric material in capacitors as well as cables. However, PP films may degrade because of the combined effect of temperature and electric field. In an earlier study, plain PP films and PP films loaded with nano-metric natural clay were studied under sinusoidal (AC) electric fields at power frequency and temperatures above the ambient. To better understand the electrical characteristics of PP film under various conditions, the objective of this study is to determine the time-to-breakdown of the plain PP and PP filled with 2% (wt) natural nano-clay when subjected to time-invariant (DC) electric fields at elevated temperatures. In order to achieve this objective, the effects of uniform as well as non-uniform electric fields were compared at the same temperature for the PP film. In this study, experimental results indicated that the time-to-breakdown of all PP films, plain or filled with nano-clay, decreases with the increase in electric field intensity, non-uniformity of the electric field, and temperature. It was also found that the time-to-breakdown of PP film filled with 2% (wt) natural nano-clay under DC electric field is longer and less sensitive to temperature. Furthermore, when compared with the results under the uniform electric field, PP film filled with 2% (wt) nano-metric natural clay indicates shorter time-to-failure under non-uniform DC electric fields. Finally, the morphology of the samples was observed by digital camera, optical micrography, and SEM, to better understand the mechanism of the breakdown.
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AIMS: Endoscopic thyroidectomy (ET) using the breast approach and conventional open thyroidectomy (OT) are effective approaches to treating thyroid tumors. This study evaluates the effectiveness of ET and OT regarding safety, cosmetic effects, and feasibility. SUBJECTS AND METHODS: Four hundred and fifty-six patients who underwent thyroidectomy in our department from January 2019 to August 2020 were included in this study. Based on the intraoperative rapid pathology, all patients with papillary thyroid carcinoma underwent unilateral thyroid lobectomy and central neck lymph node dissection. Whereas all benign patients underwent unilateral thyroid lobectomy. Differences in various factors such as clinical characteristics, operation time, postoperative drainage volume, parathyroid hormone (PTH) levels, calcium (Ca) levels, total number of central lymph nodes resected, the number of metastatic central lymph nodes resected, hospital duration, hospitalization costs, and cosmetic effects were compared in each group. RESULTS: Baseline characteristics among the four groups were similar, except for patient age and tumor size. Patients in the malignant ET group were younger than those in the malignant OT group with smaller tumors (P < 0.05). There were no significant differences between the OT and ET groups in postoperative Ca levels, PTH levels, the total number of lymph nodes resected, and the number of metastatic central lymph nodes resected. CONCLUSIONS: Compared with conventional OT, ET is a feasible, practical, and safe procedure with excellent cosmetic benefits.
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Carcinoma Papilar/cirugía , Endoscopía/métodos , Disección del Cuello/métodos , Neoplasias de la Tiroides/cirugía , Tiroidectomía/métodos , Adulto , Carcinoma Papilar/patología , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Neoplasias de la Tiroides/patologíaRESUMEN
The protective effects of histone deacetylase (HDAC) inhibitors were highlighted in the treatment of kidney diseases, especially acute kidney injury (AKI). However, the currently available HDAC inhibitor cannot be delivered to the kidney properly because of its poor solubility in aqueous solutions. Therefore, calcium alginate (Ca-ALG) microspheres were proposed as microcarriers for the delivery of HDAC inhibitors in this study. First, Ca-ALG microspheres with high sphericity were obtained by a single-emulsion microfluidic strategy. Then, we selected suitable Ca-ALG microspheres for HDAC inhibitor loading by analyzing the swelling ratio and the release property using different parameters. Besides, thermal stimulation will change the drug release property of Ca-ALG microspheres in in vitro experiments. Furthermore, the HDAC inhibitor-loaded microspheres were delivered to the kidney by renal subcapsular injection for evaluating the treatment effects in mice with ischemia-reperfusion-induced AKI. The in vivo results showed that the HDAC inhibitor-loaded Ca-ALG microspheres could effectively reduce the renal regional inflammatory response and macrophage infiltration. Taken together, we proposed a promising therapy with an effective kidney-targeted drug delivery for the treatment of AKI.
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BACKGROUND: EGF-containing fibulin-like extracellular matrix protein 2 (EFEMP2) is an extracellular matrix (ECM) glycoprotein, which is regarded as potential prognostic biomarkers in some carcinoma. Little is known about the association of EFEMP2 and breast cancer. METHODS: EFEMP2 expressions in normal breast tissue, benign fibroadenoma, breast cancer, the normal mammary epithelial cell line, and 4 different invasive breast cancer cell lines were evaluated by immunohistochemistry (IHC) or immunocytochemistry (ICC) and real time quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR). Expression and prognostic value of EFEMP2 in breast cancer were verified by the Public databases (Oncomine and Kaplan-Meier plotter database). Lentiviral vector with EFEMP2 cDNA was constructed and used to infect breast cancer cell lines to investigate the effects of EFEMP2 on the biological behavior of breast cancer cells by functional in vitro and in vivo assays. RESULTS: Down-regulated EFEMP2 expression was found in breast cancer tissues and cells, and low expression of EFEMP2 was associated with poor prognosis in patients with breast cancer. Analysis by the Public database leaded to the same conclusion. Up-regulated EFEMP2 expression significantly hampered the invasion and metastasis abilities of breast cancer cells and the process of epithelial interstitial transformation (EMT) via the Wnt/ß-catenin pathway. CONCLUSION: EFEMP2 expression was lower in breast cancer and closely related to the prognosis of patients, its anti-oncogenic roles indicated the underlying therapeutic target for the future treatment of breast cancer.
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BACKGROUND: This research was aimed to study the expression of Serine/arginine rich splicing factor 2 (SRSF2) in tissues of hepatocellular carcinoma, and explore the relationship between the expression and the clinic pathological and prognosis of human hepatocellular carcinoma (HCC). METHODS: One hundred and fifty-three pairs HCC tissues and adjacent normal tissue were collected from January 2010 to March 2013. The expression of SRSF2 gene was detected by immunohistochemistry, western blotting and real-time quantitative polymerase chain reaction (PCR), and the relationship between the expression and the clinic pathological and prognosis of HCC being analyzed. RESULTS: In 153 cases of hepatocellular carcinoma, SRSF2 was highly expressed in 93 cases, low expression of 60 cases, immunohistochemistry score (6.50 ± 2.82), which was significantly higher than that in adjacent normal tissues (2.94 ± 1.23) (P< 0.05). The expression of SRSF2 in HCC was not associated with gender (χ2= 0.014, P= 0.906), age (χ2= 0.007, P= 0.931), tumor size (χ2= 3.566, P= 0.059) and T stage (χ2= 2.708, P= 0.100), and was significantly correlated with tumor differentiation (χ2= 9.687, P= 0.007), lymph node metastasis (χ2= 4.827, P= 0.028), distal metastasis (χ2= 9.235, P= 0.002), tumor, node, metastasis (TNM) stage (χ2= 3.978, P= 0.046), portal vein invasion and serum alpha-fetoprotein (χ2= 14.919, P= 0.000). The expression of SRSF2 protein in hepatocellular carcinoma was positively correlated (r = 0.704, P< 0.05) with serum alpha-fetoprotein through Pearson analysis. The survival rates of SRSF2 overexpressing hepatocellular carcinoma were 74.19%, 44.09%, 26.88%, 24.73% and 21.51% at 1 year, 2 years, 3 years, 4 years and 5 years respectively, which were lower than those of SRSF2 low expression group (93.33%, 71.67%, 56.67%, 51.67% and 50.00%). CONCLUSION: SRSF2 is highly expressed in hepatocellular carcinoma and its expression increases with the degree of tumor differentiation and TNM staging. It is related to lymph node metastasis and metastasis of tumor cells, and is positively related to serum alpha fetoprotein content, and affects the postoperative survival time of HCC patients.
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Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Factores de Empalme Serina-Arginina/metabolismo , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Carcinoma Hepatocelular/mortalidad , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Factores de Empalme Serina-Arginina/genética , Análisis de Supervivencia , Carga TumoralRESUMEN
BACKGROUND: Liver metastasis is the leading cause of lethal colorectal cancer (CRC). For patients with early stage CRC, metachronous liver metastasis is the primary risk for poor prognosis. Accordingly, identification of prospective biomarkers for metachronous liver metastasis would be invaluable in evaluating patients' clinical outcomes and developing personal treatment therapy. METHODS: Here we investigated the role of transducin (ß)-like 1 X-linked receptor 1 (TBL1XR1) in predicting liver metastasis for early stage CRC. To accomplish this goal, a multi-center retrospective study was performed which included three stages: exploration stage (43 patients), identification stage (162 patients) and validation stage (38 patients). TBL1XR1 expression was evaluated using immunohistochemical staining and RT-qPCR. The prognostic significance of TBL1XR1 in both stage IV CRC patients and early stage CRC patients were evaluated by Kaplan-Meier survival analysis and multivariate analysis, respectively. RESULTS: For stage IV CRC patients, TBL1XR1 expression was correlated with the number of liver metastases (P = 0.036), and high levels of TBL1XR1 in liver metastases indicated poor overall survival (P = 0.028). Moreover, high expressions of TBL1XR1 can serve as a predictor for liver metastasis in early stage CRC patients (P = 0.003). CONCLUSIONS: TBL1XR1 is a promising biomarker for predicting liver metastasis in early stage CRC patients.
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Biomarcadores de Tumor/genética , Neoplasias Colorrectales/patología , Neoplasias Hepáticas/secundario , Proteínas Nucleares/genética , Receptores Citoplasmáticos y Nucleares/genética , Proteínas Represoras/genética , Adulto , Anciano , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/cirugía , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
More than 25% localized CRC patients died from post-operative metastasis, and risk of metastasis varies among individuals due to the high heterogeneity of CRC. Therefore, figuring out potential biomarkers for disease recurrence would be invaluable to improve the follow-up efficiency and clinical treatment. Transducin (ß)-like 1 X-linked receptor 1 (TBL1XR1) is a core component of the nuclear receptor corepressor complex, which functions as a repressive coregulatory factor for multiple transcription factors. The clinical significance of TBL1XR1 in CRC hasn't been fully elucidated. In this study, we investigated the expression of TBL1XR1 in primary CRC tissues and liver metastases from TNM stage IV CRC patients, and found that its expression in primary tumor tissues was an independent prognostic factor for tumor recurrence. Thus, we enrolled another cohort including TNM stage I-III patients to further evaluate the relationship between TBL1XR1 expression and disease recurrence. Accordingly, high TBL1XR1 expression indicates poor disease-free survival of stage I-III CRC patients. Furthermore, we confirmed the importance of ß-catenin signaling pathways in TBL1XR1-mediated CRC cell oncogenicity by clinical and cellular results. Our results emphasize the necessity of individual therapy decisions based on clinical biomarkers, especially for localized CRC patients who are not routinely treated with adjunctive chemotherapy.
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Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/genética , Recurrencia Local de Neoplasia/genética , Proteínas Nucleares/genética , Receptores Citoplasmáticos y Nucleares/genética , Proteínas Represoras/genética , Anciano , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Estudios de Cohortes , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Femenino , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/secundario , Metástasis Linfática , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Proteínas Nucleares/metabolismo , Pronóstico , Receptores Citoplasmáticos y Nucleares/metabolismo , Proteínas Represoras/metabolismo , Transducción de Señal , Análisis de Supervivencia , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
Although the innate immune response to induce postischemic inflammation is considered as an essential step in the progression of cerebral ischemia injury, the role of innate immunity mediator NLRP3 in the pathogenesis of ischemic stroke is unknown. In this study, focal ischemia was induced by middle cerebral artery occlusion in NLRP3(-/-), NOX2(-/-), or wild-type (WT) mice. By magnetic resonance imaging (MRI), Evans blue permeability, and electron microscopic analyses, we found that NLRP3 deficiency ameliorated cerebral injury in mice after ischemic stroke by reducing infarcts and blood-brain barrier (BBB) damage. We further showed that the contribution of NLRP3 to neurovascular damage was associated with an autocrine/paracrine pattern of NLRP3-mediated interleukin-1ß (IL-1ß) release as evidenced by increased brain microvessel endothelial cell permeability and microglia-mediated neurotoxicity. Finally, we found that NOX2 deficiency improved outcomes after ischemic stroke by mediating NLRP3 signaling. This study for the first time shows the contribution of NLRP3 to neurovascular damage and provides direct evidence that NLRP3 as an important target molecule links NOX2-mediated oxidative stress to neurovascular damage in ischemic stroke. Pharmacological targeting of NLRP3-mediated inflammatory response at multiple levels may help design a new approach to develop therapeutic strategies for prevention of deterioration of cerebral function and for the treatment of stroke.
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Barrera Hematoencefálica/patología , Proteínas Portadoras/metabolismo , Ataque Isquémico Transitorio/patología , Glicoproteínas de Membrana/metabolismo , NADPH Oxidasas/metabolismo , Accidente Cerebrovascular/patología , Animales , Astrocitos/metabolismo , Astrocitos/patología , Barrera Hematoencefálica/metabolismo , Proteínas Portadoras/genética , Células Cultivadas , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Células Endoteliales/patología , Glucosa/metabolismo , Ataque Isquémico Transitorio/metabolismo , Imagen por Resonancia Magnética , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/metabolismo , Microglía/patología , NADPH Oxidasa 2 , NADPH Oxidasas/genética , Proteína con Dominio Pirina 3 de la Familia NLR , Neuronas/metabolismo , Neuronas/patología , Estrés Oxidativo/fisiología , Oxígeno/metabolismo , Transducción de Señal , Accidente Cerebrovascular/metabolismoRESUMEN
Although NADPH oxidase (NOX)-mediated oxidative stress is considered one of the major mechanisms triggering the pathogenic actions of ischemic stroke and very recent studies have indicated that NADPH oxidase is a major source of reactive oxygen species (ROS) production controlling glutamate release, how neuronal NADPH oxidase activation is coupled to glutamate release is not well understood. Therefore, in this study, we used an in vivo transient middle cerebral artery occlusion model and in vitro primary cell cultures to test whether complexins, the regulators of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes necessary for vesicle fusion, are associated with NOX2-derived ROS and contribute to glutamate-mediated excitotoxicity in ischemic stroke. In this study, we first identified the upregulation of complexin II in the ischemic brain and evaluated its potential role in ischemic stroke showing that gene silencing of complexin II ameliorated cerebral injury as evidenced by reduced infarction volume, neurological deficit, and neuron necrosis accompanied by decreased glutamate levels, consistent with the results from NOX2(-/-) mice with ischemic stroke. We further demonstrated that complexin II expression was mediated by NOX2 in primary cultured neurons subjected to oxygen-glucose deprivation (OGD) and contributed to OGD-induced glutamate release and neuron necrosis via SNARE signaling. Taken together, these findings for the first time provide evidence that complexin II is a central target molecule that links NADPH oxidase-derived ROS to glutamate-mediated neuronal excitotoxicity in ischemic stroke.