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Hypoxia is a common hallmark of cancer and plays a crucial role in promoting epithelial-mesenchymal transition (EMT). Hormonally Upregulated Neu-associated Kinase (HUNK) regulates EMT through its kinase activity. However, whether hypoxia is involved in HUNK-mediated EMT is incompletely understood. This study unveils an association between HUNK kinase activity and hypoxia in colorectal cancer (CRC). Importantly, hypoxia does not alter the expression levels of HUNK, but directly affects the phosphorylation levels of downstream proteins with indication of HUNK activity. Functionally, the upregulation of migration, invasion, and expression of EMT markers in CRC cells under hypoxic conditions can be attributed, in part, to the downregulation of HUNK-mediated phosphorylation of downstream proteins. These findings highlight the intricate relationship between HUNK, hypoxia and the molecular mechanisms of cancer EMT. Understanding these mechanisms may provide valuable insights into therapeutic targets for inhibiting cancer metastasis.
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Neoplasias Colorrectales , Neoplasias , Humanos , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Transición Epitelial-Mesenquimal , Hipoxia , Línea Celular Tumoral , Movimiento Celular , Regulación Neoplásica de la Expresión Génica , Neoplasias Colorrectales/patologíaRESUMEN
Three different subsets of circulating human monocytes, CD14++CD16- (classical), CD14++CD16+ (intermediate), and CD14+CD16+ (non-classical) monocytes, have been recently identified. New evidence suggests that levels of intermediate monocytes or CD16+ (intermediate and non-classical) monocytes are increased in autoimmune diseases. However, studies regarding the role of each monocyte subset in the pathogenesis of Graves' disease (GD) are lacking. We aimed to investigate the clinical implications of these subsets and their potential role in GD pathogenesis. CD14++CD16+ monocytes showed a more activated state in GD patients than other monocyte subpopulations. An increased proportion of circulating CD14++CD16+ monocytes and a decreased proportion of circulating CD14++CD16- monocytes in GD patients were detected, and CD14++CD16+ monocyte frequencies were positively correlated with GD clinical parameters. Additionally, a follow-up analysis indicated that the CD14++CD16- monocyte percentage increased and the CD14++CD16+ monocyte percentage decreased post-treatment. We found that CD14++CD16+ GD monocytes promoted the expansion of IFN-γ+CD4+ cells. The Th1-polarizing cytokine IL-12, secreted after direct contact with patient CD14++CD16+ monocytes and CD4+ T cells, was responsible for IFN-γ+CD4+ cell development. Our results suggest that CD14++CD16+ monocytes are involved in GD pathogenesis and the critical role of CD14++CD16+ monocytes in the generation of potentially pathogenic Th responses in GD.
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Enfermedad de Graves , Monocitos , Humanos , Células TH1 , Receptores de IgG , Receptores de Lipopolisacáridos , Diferenciación CelularRESUMEN
Prostate cancer (PCa) is the most common malignant tumor for men. But the mechanism is unclear. EIF3C was shown to be overexpressed in PCa tissues and cell lines. EIF3C overexpression was correlated to age and tumor stage in PCa patients and indicated poor survival. The proliferation, migration, and invasiveness of PC3 cells were all inhibited after EIF3C knockdown. Additionally, the phosphorylation level of PI3K and Akt was downregulated while total NF-κB and Myc decreased after EIF3C knockdown. But the expression of IκB increased reversely. Therefore, EIF3C at least partially regulates the activity of PI3K/Akt/NF-κB signaling pathway in PC3 cells.
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Carcinogénesis/genética , Factor 3 de Iniciación Eucariótica/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata/genética , Animales , Carcinogénesis/patología , Línea Celular Tumoral , Proliferación Celular/genética , Regulación hacia Abajo , Factor 3 de Iniciación Eucariótica/genética , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Masculino , Ratones , Persona de Mediana Edad , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/genética , Pronóstico , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proto-Oncogenes , ARN Interferente Pequeño/metabolismo , Transducción de Señal/genética , Tasa de Supervivencia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
WHAT IS KNOWN AND OBJECTIVE: Drug-drug interactions (DDI) are frequent causes of adverse clinical drug reactions. Efforts have been directed at the early stage to achieve accurate identification of DDI for drug safety assessments, including the development of in silico predictive methods. In particular, similarity-based in silico methods have been developed to assess DDI with good accuracies, and machine learning methods have been employed to further extend the predictive range of similarity-based approaches. However, the performance of a developed machine learning method is lower than expectations partly because of the use of less diverse DDI training data sets and a less optimal set of similarity measures. METHOD: In this work, we developed a machine learning model using support vector machines (SVMs) based on the literature-reported established set of similarity measures and comprehensive training data sets. The established similarity measures include the 2D molecular structure similarity, 3D pharmacophoric similarity, interaction profile fingerprint (IPF) similarity, target similarity and adverse drug effect (ADE) similarity, which were extracted from well-known databases, such as DrugBank and Side Effect Resource (SIDER). A pairwise kernel was constructed for the known and possible drug pairs based on the five established similarity measures and then used as the input vector of the SVM. RESULT: The 10-fold cross-validation studies showed a predictive performance of AUROC >0.97, which is significantly improved compared with the AUROC of 0.67 of an analogously developed machine learning model. Our study suggested that a similarity-based SVM prediction is highly useful for identifying DDI. CONCLUSION: in silico methods based on multifarious drug similarities have been suggested to be feasible for DDI prediction in various studies. In this way, our pairwise kernel SVM model had better accuracies than some previous works, which can be used as a pharmacovigilance tool to detect potential DDI.
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Interacciones Farmacológicas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Aprendizaje Automático , Máquina de Vectores de Soporte , Simulación por Computador , Bases de Datos Factuales , Humanos , Farmacovigilancia , Reproducibilidad de los ResultadosRESUMEN
Emerging evidence has indicated that transforming growth factor-beta 1 (TGF-ß1) induces the epithelial-mesenchymal transition (EMT) in cancer cells, thus promoting their motility and invasiveness. Quercetin, a member of the polyphenolic flavonoid family, has been reported to display anticancer activity against a broad range of cancer cell types. Indeed, numerous studies have shown the cancer preventive effects and molecular mechanisms of quercetin in vitro using diverse cell model systems. However, the potential effect of quercetin on EMT remains unclear. In this study, we identified a unique function of quercetin in inhibiting the EMT process induced by TGF-ß1. In particular, quercetin rescued the morphological changes and EMT-like phenotypes in TGF-ß1-activated SW480â¯cells, and this inhibition of TGF-ß1-induced EMT was mediated via the suppression of Twist1 expression. In addition, quercetin strongly suppressed TGF-ß1-induced invasion of SW480â¯cells. Thus, quercetin may be considered a novel therapeutic agent for the treatment of patients with refractory cancer and for the prevention of the metastatic cascade initiated by EMT.
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Cadherinas/genética , Transición Epitelial-Mesenquimal/efectos de los fármacos , Proteínas Nucleares/metabolismo , Quercetina/farmacología , Factor de Crecimiento Transformador beta1/efectos adversos , Proteína 1 Relacionada con Twist/metabolismo , Antígenos CD , Cadherinas/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Metástasis de la Neoplasia , Proteínas Nucleares/genética , Regiones Promotoras Genéticas/genética , Proteína 1 Relacionada con Twist/genéticaRESUMEN
Prostate cancer (PCa) is the most common malignancy and the leading cause of cancer deaths in males. Recent studies demonstrate that long non-coding RNAs (lncRNAs) are involved in many aspects of PCa. However, their biological roles in PCa remain imperfectly understood. Here,wecharacterized anlncRNA, PCaspecific expression and EZH2-associatedtranscript (PCSEAT, annotated as PRCAT38), which is specifically overexpressedin PCa. We further demonstrated that knockdown of PCSEAT results in the reduction of PCa cell growth and motility, and overexpression of PCSEAT reverses these phenotypes. Furthermore, bioactive PCSEAT is incorporated into exosomes and transmitted to adjacent cells, thus promoting cell proliferation and motility. Mechanistically, we found that PCSEAT promotes cell proliferation, at least in part by affecting miR-143-3p- and miR-24-2-5p-mediated regulation of EZH2, suggesting that PCSEAT and EZH2 competitively 'sponge' miR-143-3p and miR-24-2-5p.Overall, ourresultsrevealthat PCSEAT is specifically overexpressed in PCa patients and a potential oncogene in PCa cells via mediating EZH2 activity, indicating that PCSEAT may be a potential therapeutic target in PCa.
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Proteína Potenciadora del Homólogo Zeste 2/genética , Neoplasias de la Próstata/genética , ARN Largo no Codificante/genética , Unión Competitiva , Carcinogénesis/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Técnicas de Silenciamiento del Gen , Humanos , Masculino , MicroARNs/genética , MicroARNs/metabolismo , Oncogenes , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , ARN Largo no Codificante/antagonistas & inhibidores , ARN Largo no Codificante/metabolismo , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND The aim of this study was to explore the association between glycated hemoglobin (HbA1c) level and albuminuria in young nondiabetic people with obesity. MATERIAL AND METHODS A total of 537 young nondiabetic people with obesity were enrolled in this cross-sectional study, which was approved by the Rui-jin Hospital Ethics Committee. Albuminuria was defined as a urinary albumin-to-creatinine ratio (ACR) ≥30 mg/g. Multivariate logistic regression was used to analyze the association between HbA1c level and albuminuria. RESULTS Urinary ACR progressively increased across the tertiles of HbA1c level (P for trend <0.05). HbA1c levels were positively associated with the risk of albuminuria in the logistic regression analysis after adjustment for confounding factors. The adjusted odds ratio (OR) for albuminuria was 3.72 (95% confidence interval [CI], 1.25-11.00; P=0.017) when comparing between the highest (≥5.7%) and lowest tertiles of HbA1c level (≤5.3%). Moreover, an increment of 1 SD in HbA1c level increased the risk of albuminuria in a fully adjusted model (OR, 1.73; 95% CI, 1.25-2.46). CONCLUSIONS These data suggest that HbA1c level was independently associated with albuminuria in young nondiabetic people with obesity.
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Albuminuria/sangre , Hemoglobina Glucada/análisis , Obesidad/sangre , Adolescente , Adulto , Albúminas/análisis , Creatinina/sangre , Creatinina/orina , Estudios Transversales , Diabetes Mellitus , Progresión de la Enfermedad , Femenino , Glicosilación , Humanos , Masculino , Obesidad/complicaciones , Oportunidad Relativa , Factores de Riesgo , Adulto JovenRESUMEN
Germ cell apoptosis may be associated with the male infertility. The pathogenesis is to be further understood. Viral infection is one of the causative factors of apoptosis of the body cells. This study aims to investigate the role of activation of Toll like receptor (TLR)3 in the induction of germ cell apoptosis. In this study, spermatogonial stem cells (SSC) were isolated from C57BL/6 mouse testes. The expression of TLR3 on SSC was by RT-qPCR and Western blotting. polyinosinic-polycytidylic acid (Poly I:C) was employed to activate TLR3 on SSCs. The results showed that re-activation by PolyI:C induced SSC apoptosis. Exposure to PolyI:C induced interferon regulatory factor 3 (IRF3) phosphorylation in SSCs. TLR3 and IRF3 formed a complex in the SSCs. The complex of TLR3/IRF3 bound to the promoter of Fas ligand and promoted Fas ligand expression in SSC, and thus induced SSC apoptosis. In conclusion, the results of the present study indicate that activation of TLR3 by PolyI:C induces the SSC apoptosis, which implies that viral infection may interfere with the male germ cell development.
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Células Madre Adultas/metabolismo , Apoptosis/efectos de los fármacos , Poli I-C/farmacología , Receptor Toll-Like 3/metabolismo , Células Madre Adultas/efectos de los fármacos , Animales , Células Cultivadas , Proteína Ligando Fas/metabolismo , Factor 3 Regulador del Interferón/metabolismo , Masculino , Ratones Endogámicos C57BL , Fosforilación , Testículo/citologíaRESUMEN
Single-cell sequencing is an emerging technology that can effectively identify cell types in tumors. In the tumor microenvironment of bladder cancer, macrophages play a crucial role in invasion and immune escape. This study aimed to assess the expression of macrophage-related genes (MRGs) in the tumor microenvironment of bladder cancer patients and construct a prognostic model based on MRGs using bioinformatics methods. METHODS: Single-cell sequencing data from bladder cancer patients was downloaded from the GEO. After quality control and cell type identification, macrophages in the samples were extracted for re-clustering. Feature genes were then identified, and MRGs were assessed. Genetic data from TCGA database bladder cancer patients was also downloaded and organized. The intersection of MRGs and the TCGA gene set was determined. Clinical information was connected with this intersection, and the data was divided into training and validation sets. The training set was used for model construction and the validation set for model verification. A prognostic model based on MRGs was built using the LASSO algorithm and Cox regression. Patients were divided into high-risk and low-risk groups based on their prognostic features, and survival information in the training and validation sets was observed. The predictive ability of the model was assessed using a ROC curve, followed by a calibration plot to predict 1-, 3-, and 5-year survival rates. RESULTS: Four cell types were identified, and after extracting macrophages, three cell subgroups were clustered, resulting in 1,078 feature genes. The top 100 feature genes from each macrophage subgroup were extracted and intersected with TCGA expressed genes to construct the model. A risk prediction model composed of CD74, METRN, PTPRR, and CDC42EP5 was obtained. The survival and ROC curves showed that this model had good predictive ability. A calibration curve also demonstrated good prognostic ability for patients. CONCLUSION: This study, based on single-cell data, TCGA data, and clinical information, constructed an MRG-based prognostic model for bladder cancer using multi-omics methods. This model has good accuracy and reliability in predicting the survival and prognosis of patients with bladder cancer, providing a reference for understanding the interaction between MRGs and bladder cancer.
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Background: We describe a rare case of giant adrenal calcification as the main cause of sudden onset epigastric pain in a 57-year-old female patient. Case description: Computed tomography (CT) of the whole abdomen in this patient showed calcified foci measuring approximately 7.8 × 5.4 × 7.1 cm in the hepatorenal recess, and no enhancement effect was seen. Secondary causes of adrenal calcification in this patient were ruled out, and a rare diagnosis of a primary giant adrenal calcification was made. Subsequently, the right adrenal gland and calcified mass were completely resected. The calcification did not recur during 6 months of follow up. Conclusions: Although other cases of adrenal calcification of unknown origin have been reported, cases of giant idiopathic adrenal calcification are rare. In this case, huge calcification of the right adrenal gland caused abdominal pain, which disappeared after the mass was excised. The etiology, pathogenesis, clinical symptoms, and prognosis of idiopathic adrenal calcification are still unclear. Additional case reports are needed to gain a better understanding of the diagnosis and treatment of this condition.
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A maternal low-protein diet during pregnancy can increase children's susceptibility to diabetes mellitus in adulthood. However, whether long noncoding RNAs (lncRNAs) in islets participate in the development of diabetes in adult offspring following maternal protein restriction is not fully understood. Female mice were fed a low-protein (LP) diet or control diet throughout gestation and lactation. The male offspring were then randomly divided into two groups according to maternal diet: offspring from control diet group dams (Ctrl group) and offspring from LP group dams (LP group). We observed the glucose metabolism of adult offspring. A lncRNA microarray was constructed for the islets from the LP group and Ctrl group to explore the differently expressed lncRNAs. Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes analyses were subsequently used to predict the functions of the differently expressed lncRNAs. The body weight from birth to 12 weeks of age was significantly lower in the LP offspring. Adult LP offspring exhibited impaired glucose tolerance and decreased insulin secretion, consistent with the reduction in ß-cell proliferation. According to the lncRNA microarray, four lncRNAs, three upregulated lncRNAs, and one downregulated lncRNA were differently expressed in LP offspring islets compared with Ctrl offspring. Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that these differentially expressed lncRNAs were mostly associated with the hypoxia-inducible factor-1α signaling pathway. Additionally, we validated the expression of these four differentially expressed lncRNAs via quantitative real-time polymerase chain reaction. Our findings demonstrated the expression patterns of lncRNAs in islets from adult offspring of mothers who consumed a maternal low-protein diet.
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Dieta con Restricción de Proteínas , Islotes Pancreáticos , Fenómenos Fisiologicos Nutricionales Maternos , ARN Largo no Codificante , Animales , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Femenino , Embarazo , Masculino , Islotes Pancreáticos/metabolismo , Efectos Tardíos de la Exposición Prenatal , Ratones , Ratones Endogámicos C57BL , Insulina/metabolismo , Glucosa/metabolismo , Intolerancia a la Glucosa/metabolismoRESUMEN
Type 1 insulin-like growth factor receptor (IGF1R) plays an important role in cancer, however, posttranscriptional regulation such as N6-methyladenosine (m6A) of IGF1R remains unclear. Here, we reveal a role for a lncRNA Downregulated RNA in Cancer (DRAIC) suppress tumor growth and metastasis in clear cell Renal Carcinoma (ccRCC). Mechanistically, DRAIC physically interacts with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) and enhances its protein stability by blocking E3 ligase F-box protein 11 (FBXO11)-mediated ubiquitination and proteasome-dependent degradation. Subsequently, hnRNPA2B1 destabilizes m6A modified-IGF1R, leading to inhibition of ccRCC progression. Moreover, four m6A modification sites are identified to be responsible for the mRNA degradation of IGF1R. Collectively, our findings reveal that DRAIC/hnRNPA2B1 axis regulates IGF1R mRNA stability in an m6A-dependent manner and highlights an important mechanism of IGF1R fate. These findings shed light on DRAIC/hnRNPA2B1/FBXO11/IGF1R axis as potential therapeutic targets in ccRCC and build a link of molecular fate between m6A-modified RNA and ubiquitin-modified protein.
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Ribonucleoproteína Heterogénea-Nuclear Grupo A-B , Neoplasias Renales , Receptor IGF Tipo 1 , Humanos , Receptor IGF Tipo 1/metabolismo , Receptor IGF Tipo 1/genética , Ratones , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/metabolismo , Animales , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/genética , Progresión de la Enfermedad , Estabilidad del ARN/genética , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Estabilidad Proteica , Adenosina/análogos & derivados , Adenosina/metabolismo , Ubiquitinación , Proliferación Celular/genética , Ratones DesnudosRESUMEN
Graves' disease (GD) is a common autoimmune disease that affects the thyroid gland. As a new class of modulators of gene expression, long noncoding RNAs (lncRNAs) have been reported to play a vital role in immune functions and in the development of autoimmunity and autoimmune disease. The aim of this study is to identify lncRNAs in CD4+ T cells as potential biomarkers of GD. lncRNA and mRNA microarrays were performed to identify differentially expressed lncRNAs and mRNAs in GD CD4+ T cells compared with healthy control CD4+ T cells. Quantitative PCR (qPCR) was used to validate the results, and correlation analysis was used to analyze the relationship between these aberrantly expressed lncRNAs and clinical parameters. The microarray identified 164 lncRNAs and 93 mRNAs in GD CD4+ T cells differentially expressed compared to healthy control CD4+ T cells (fold change >2.0 and a P < 0.05). Further analysis consistently showed that the expression of HMlincRNA1474 (P < 0.01) and TCONS_00012608 (P < 0.01) was suppressed, while the expression of AK021954 (P < 0.01) and AB075506 (P < 0.01) was upregulated from initial GD patients. In addition, their expression levels were recovered in euthyroid GD patients and GD patients in remission. Moreover, these four aberrantly expressed lncRNAs were correlated with GD clinical parameters. Moreover, the areas under the ROC curve were 0.8046, 0.7579, 0.8115 for AK021954, AB075506, HMlincRNA1474, respectively. The present work revealed that differentially expressed lncRNAs were associated with GD, which might serve as novel biomarkers of GD and potential targets for GD treatment.
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Oxalate and calcium are the major risk factors for calcium oxalate (CaOx) stone formation. However, the exact mechanism remains unclear. This study was designed to confirm the potential function of miR-155-5p in the formation of CaOx induced by oxalate and calcium oxalate monohydrate (COM). The HK-2 cells were treated by the different concentrations of oxalate and COM for 48 h. We found that oxalate and COM treatment significantly increased ROS generation, LDH release, cellular MDA levels, and H2O2 concentration in HK-2 cells. The results of qRT-PCR and western blot showed that expression of NOX2 was upregulated, while that of SOD-2 was downregulated following the treatment with oxalate and COM in HK-2 cells. Moreover, the results of miRNA microarray analysis showed that miR-155-5p was significantly upregulated after oxalate and COM treated in HK-2 cells, but miR-155-5p inhibitor treatment significantly decreased ROS generation, LDH release, cellular MDA levels, and H2O2 concentration in HK-2 cells incubated with oxalate and COM. miR-155-5p negatively regulated the expression level of MGP via directly targeting its 3'-UTR, verified by the Dual-Luciferase Reporter System. In vivo, polarized light optical microphotography showed that CaOx crystal significantly increased in the high-dose oxalate and Ca2+ groups compared to the control group. Furthermore, IHC analyses showed strong positive staining intensity for the NOX-2 protein in the high-dose oxalate and Ca2+-treated mouse kidneys, and miR-155-5p overexpression can further enhance its expression. However, the expression of SOD-2 protein was weakly stained. In conclusion, our study indicates that miR-155-5p promotes oxalate- and COM-induced kidney oxidative stress injury by suppressing MGP expression.
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Oxalato de Calcio/efectos adversos , Proteínas de Unión al Calcio/genética , Proteínas de la Matriz Extracelular/genética , Riñón/lesiones , MicroARNs/metabolismo , Estrés Oxidativo , Regiones no Traducidas 3' , Animales , Oxalato de Calcio/metabolismo , Línea Celular Transformada , Regulación de la Expresión Génica , Humanos , Riñón/metabolismo , Riñón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/antagonistas & inhibidores , Oxalatos/efectos adversos , Proteína Gla de la MatrizRESUMEN
BACKGROUND: The transcription factor YY1 is an important regulator for metabolic homeostasis. Activating mutations in YY1 lead to tumorigenesis of pancreatic ß-cells, however, the physiological functions of YY1 in ß-cells are still unknown. Here, we investigated the effects of YY1 ablation on insulin secretion and glucose metabolism. METHODS: We established two models of ß-cell-specific YY1 knockout mice. The glucose metabolic phenotypes, ß-cell mass and ß-cell functions were analyzed in the mouse models. Transmission electron microscopy was used to detect the ultrastructure of ß-cells. The flow cytometry analysis, measurement of OCR and ROS were performed to investigate the mitochondrial function. Histological analysis, quantitative PCR and ChIP were performed to analyze the target genes of YY1 in ß-cells. RESULTS: Our results showed that loss of YY1 resulted in reduction of insulin production, ß-cell mass and glucose tolerance in mice. Ablation of YY1 led to defective ATP production and mitochondrial ROS accumulation in pancreatic ß-cells. The inactivation of YY1 impaired the activity of mitochondrial oxidative phosphorylation, induced mitochondrial dysfunction and diabetes in mouse models. CONCLUSION: Our findings demonstrate that the transcriptional activity of YY1 is essential for the maintenance of mitochondrial functions and insulin secretion in ß-cells.
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Diabetes Mellitus/metabolismo , Resistencia a la Insulina/genética , Secreción de Insulina/genética , Células Secretoras de Insulina/metabolismo , Mitocondrias/metabolismo , Factor de Transcripción YY1/genética , Animales , Diabetes Mellitus/genética , Modelos Animales de Enfermedad , Glucosa/metabolismo , Ratones , Ratones Noqueados , Mitocondrias/genética , Estrés Oxidativo/fisiología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
SIRT1, a class III histone/protein deacetylase (HDAC), has been associated with autoimmune diseases. There is a paucity of data about the role of SIRT1 in Graves' disease. The aim of this study was to investigate the role of SIRT1 in the pathogenesis of GD. Here, we showed that SIRT1 expression and activity were significantly decreased in GD patients compared with healthy controls. The NF-κB pathway was activated in the peripheral blood of GD patients. The reduced SIRT1 levels correlated strongly with clinical parameters. In euthyroid patients, SIRT1 expression was markedly upregulated and NF-κB downstream target gene expression was significantly reduced. SIRT1 inhibited the NF-κB pathway activity by deacetylating P65. These results demonstrate that reduced SIRT1 expression and activity contribute to the activation of the NF-κB pathway and may be involved in the pathogenesis of GD.
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Enfermedad de Graves/metabolismo , Sirtuina 1/metabolismo , Glándula Tiroides/metabolismo , Enfermedad de Graves/genética , Humanos , FN-kappa B/genética , FN-kappa B/metabolismo , Transducción de Señal/genética , Transducción de Señal/fisiología , Sirtuina 1/genéticaRESUMEN
According to the X-ray crystal structures of CYP17A1 (including its complexes with inhibitors), it is shown that a hydrogen bond exists between CYP17A1 and its inhibitors (such as abiraterone and TOK-001). Previous short MD simulations (50 ns) suggested that the binding of abiraterone to CYP17A1 is stronger than that of TOK-001. In this work, by carrying out long atomistic MD simulations (200 ns) of CYP17A1 and its complexes with abiraterone and TOK-001, we observed a binding mode between CYP17A1 and abiraterone, which is different from the binding mode between CYP17A1 and TOK-001. In the case of abiraterone binding, the unfilled volume in the active site cavity increases the freedom of movement of abiraterone within CYP17A1, leading to the collective motions of the helices G and B' as well as the breaking of hydrogen bond existing between the 3ß-OH group of abiraterone and N202 of CYP17A1. However, the unfilled volume in the active site cavity can be occupied by the benzimidazole ring of TOK-001, restraining the motion of TOK-001. By pulling the two inhibitors (abiraterone and TOK-001) out of the binding pocket in CYP17A1, we discovered that abiraterone and TOK-001 were moved from their binding sites to the surface of protein similarly through the channels formed by the helices G and B'. In addition, based on the free energy calculations, one can see that it is energetically favorable for the two inhibitors (abiraterone and TOK-001) to enter into the binding pocket in CYP17A1.
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Androstadienos/química , Androstenos/química , Antineoplásicos/química , Bencimidazoles/química , Citocromo P-450 CYP1A1/antagonistas & inhibidores , Citocromo P-450 CYP1A1/química , Neoplasias de la Próstata/tratamiento farmacológico , Androstadienos/farmacología , Androstenos/farmacología , Antineoplásicos/farmacología , Bencimidazoles/farmacología , Sitios de Unión , Dominio Catalítico , Hemo/química , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Hierro/química , Masculino , Simulación del Acoplamiento Molecular , Conformación Proteica en Hélice alfaRESUMEN
Cholesterol increases the risk of aggressive prostate cancer and has emerged as a potential therapeutic target for prostate cancer. The functional roles of cholesterol in prostate cancer metastasis are not fully understood. Here, we found that cholesterol induces the epithelial-to-mesenchymal transition (EMT) through extracellular-regulated protein kinases 1/2 pathway activation, which is mediated by EGFR and adipocyte plasma membrane-associated protein (APMAP) accumulation in cholesterol-induced lipid rafts. Mechanistically, APMAP increases the interaction with EGFR substrate 15-related protein (EPS15R) to inhibit the endocytosis of EGFR by cholesterol, thus promoting cholesterol-induced EMT. Both the mRNA and protein levels of APMAP are upregulated in clinical prostate cancer samples. Together, these findings shed light onto an APMAP/EPS15R/EGFR axis that mediates cholesterol-induced EMT of prostate cancer cells. SIGNIFICANCE: This study delineates the molecular mechanisms by which cholesterol increases prostate cancer progression and demonstrates that the binding of cholesterol-induced APMAP with EPS15R inhibits EGFR internalization and activates ERK1/2 to promote EMT. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/12/3063/F1.large.jpg.
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Colesterol/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glicoproteínas de Membrana/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Proteolisis/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Apoptosis , Estudios de Casos y Controles , Proliferación Celular , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Masculino , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos NOD , Ratones SCID , Pronóstico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Effective targeting therapies for common chronic liver disease nonalcoholic steatohepatitis (NASH) are in urgent need. MicroRNA-targeted therapeutics would be potentially an effective treatment strategy of hepatic diseases. Here we investigated the functional role of miR-221/222 and the therapeutic effects of antimiRs-221/222 in NASH mouse models. METHODS: We generated the miR-221/222flox/flox mice on a C57BL/6â¯J background and the hepatic miR-221/222 knockout (miR-221/222-LKO) mice. The mice were challenged with the methionine and choline deficient diet (MCDD) or chronic carbon tetrachloride (CCl4) treatment to generate experimental steatohepatitis models. Adenovirus-mediated re-expression of miR-221/222 was performed on the MCDD-fed miR-221/222-LKO mice. The MCDD and control diet-fed mice were treated with locked nucleic acid (LNA)-based antimiRs of miR-221/222 to evaluate the therapeutic effects. Histological analysis, RNA-seq, quantitative PCR and Western blot of liver tissues were carried out to study the hepatic lipid accumulation, inflammation and collagen deposition in mouse models. FINDINGS: Hepatic deletion of miR-221/222 resulted in significant reduction of liver fibrosis, lipid deposition and inflammatory infiltration in the MCDD-fed and CCl4-treated mouse models. The hepatic steatosis and fibrosis were dramatically aggravated by miR-221/222 re-expression in MCDD-fed miR-221/222-LKO mice. AntimiRs of miR-221/222 could effectively reduce the MCDD-mediated hepatic steatosis and fibrosis. Systematically mechanistic study revealed that hepatic miR-221/222 controlled the expression of target gene Timp3 and promoted the progression of NASH. INTERPRETATION: Our findings demonstrate that miR-221/222 are crucial for the regulation of lipid metabolism, inflammation and fibrosis in the liver. LNA-antimiRs targeted miR-221/222 could reduce steatohepatitis with prominent antifibrotic effect in NASH mice. FUND: This work is supported by the Natural Science Foundation of China (81530020, 81390352 to Dr. Ning and 81522032 to Dr. Cao and 81670793 to Dr. Jiang); National Key Research and Development Program (No. 2016YFC0905001 and 2017YFC0909703 to Dr. Cao); the Shanghai Rising-Star Program (15QA1402900 to Dr. Cao); Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (20171905 to Dr. Jiang).
Asunto(s)
Adenoviridae , Marcación de Gen , Vectores Genéticos , MicroARNs , Enfermedad del Hígado Graso no Alcohólico , Animales , Línea Celular , Metabolismo de los Lípidos/genética , Hígado/metabolismo , Hígado/patología , Ratones , Ratones Noqueados , MicroARNs/genética , MicroARNs/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/terapiaRESUMEN
BACKGROUND: MicroRNAs are often abnormally expressed in human non-small cell lung cancer (NSCLC) and are thought to play a critical role in the emergence or maintenance of NSCLC by binding to its target messenger RNA. We assessed the effects of miR-155 on cell proliferation and invasion to elucidate the role played by miR-155/PDCD4 in NSCLC. METHODS: Quantitative reverse transcription-PCR, Western blotting, and cell counting kit-8, luciferase, and transwell invasion assays were conducted on a normal human bronchial epithelial cell line (BEAS-2B) and three NSCLC cell lines (SPC-A-1, A549, and H2170). RESULTS: We confirmed that miR-155 was upregulated, while PDCD4 messenger RNA and protein levels were downregulated in NSCLC cell lines. miR-155 negatively regulated PDCD4 at both transcriptional and post-transcriptional levels. Moreover, PDCD4 was forecast as an assumed target of miR-155 using bioinformatic methods and we demonstrated that PDCD4 was a direct target of miR-155 using luciferase reporter assays. Furthermore, PDCD4 overexpression could restrain NSCLC proliferation and invasion induced by miR-155. CONCLUSION: Our results collectively demonstrate that miR-155 exerts an oncogenic role in NSCLC by directly targeting PDCD4.