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Krüppel-like factor 12 (KLF12) has been characterized as a transcriptional repressor, and previous studies have unveiled its roles in angiogenesis, neural tube defect, and natural killer (NK) cell proliferation. However, the contribution of KLF12 to cancer treatment remains undefined. Here, we show that KLF12 is downregulated in various cancer types, and KLF12 downregulation promotes cisplatin resistance and cancer metastasis in esophageal squamous cell carcinoma (ESCC). Mechanistically, KLF12 binds to the promoters of L1 Cell Adhesion Molecule (L1CAM) and represses its expression. Depletion of L1CAM abrogates cisplatin resistance and cancer metastasis caused by KLF12 loss. Moreover, the E3 ubiquitin ligase tripartite motif-containing 27 (TRIM27) binds to the N-terminal region of KLF12 and ubiquitinates KLF12 at K326 via K33-linked polyubiquitination. Notably, TRIM27 depletion enhances the transcriptional activity of KLF12 and consequently inhibits L1CAM expression. Overall, our study elucidated a novel regulatory mechanism involving TRIM27, KLF12 and L1CAM, which plays a substantial role in cisplatin resistance and cancer metastasis in ESCC. Targeting these genes could be a promising approach for ESCC treatment.
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Cisplatino , Resistencia a Medicamentos Antineoplásicos , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição Kruppel-Like , Molécula L1 de Adesão de Célula Nervosa , Humanos , Cisplatino/farmacologia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/genética , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Molécula L1 de Adesão de Célula Nervosa/genética , Linhagem Celular Tumoral , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Metástase Neoplásica , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/efeitos dos fármacos , Camundongos , Proliferação de Células/efeitos dos fármacos , Proteínas com Motivo Tripartido , Proteínas de Ligação a DNA , Proteínas NuclearesRESUMO
Since miRNAs can participate in the posttranscriptional regulation of gene expression, they may provide ideas for the development of new drugs or become new biomarkers for drug targets or disease diagnosis. In this work, we propose an miRNA-disease association prediction method based on meta-paths (MDPBMP). First, an miRNA-disease-gene heterogeneous information network was constructed, and seven symmetrical meta-paths were defined according to different semantics. After constructing the initial feature vector for the node, the vector information carried by all nodes on the meta-path instance is extracted and aggregated to update the feature vector of the starting node. Then, the vector information obtained by the nodes on different meta-paths is aggregated. Finally, miRNA and disease embedding feature vectors are used to calculate their associated scores. Compared with the other methods, MDPBMP obtained the highest AUC value of 0.9214. Among the top 50 predicted miRNAs for lung neoplasms, esophageal neoplasms, colon neoplasms and breast neoplasms, 49, 48, 49 and 50 have been verified. Furthermore, for breast neoplasms, we deleted all the known associations between breast neoplasms and miRNAs from the training set. These results also show that for new diseases without known related miRNA information, our model can predict their potential miRNAs. Code and data are available at https://github.com/LiangYu-Xidian/MDPBMP.
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Neoplasias da Mama , Neoplasias Pulmonares , MicroRNAs , Algoritmos , Neoplasias da Mama/genética , Biologia Computacional/métodos , Feminino , Humanos , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
With an in-depth understanding of noncoding ribonucleic acid (RNA), many studies have shown that microRNA (miRNA) plays an important role in human diseases. Because traditional biological experiments are time-consuming and laborious, new calculation methods have recently been developed to predict associations between miRNA and diseases. In this review, we collected various miRNA-disease association prediction models proposed in recent years and used two common data sets to evaluate the performance of the prediction models. First, we systematically summarized the commonly used databases and similarity data for predicting miRNA-disease associations, and then divided the various calculation models into four categories for summary and detailed introduction. In this study, two independent datasets (D5430 and D6088) were compiled to systematically evaluate 11 publicly available prediction tools for miRNA-disease associations. The experimental results indicate that the methods based on information dissemination and the method based on scoring function require shorter running time. The method based on matrix transformation often requires a longer running time, but the overall prediction result is better than the previous two methods. We hope that the summary of work related to miRNA and disease will provide comprehensive knowledge for predicting the relationship between miRNA and disease and contribute to advanced computation tools in the future.
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MicroRNAs , Algoritmos , Biologia Computacional/métodos , Predisposição Genética para Doença , Humanos , MicroRNAs/genéticaRESUMO
It is recognized that the cerebral ischemia/reperfusion (I/R) injury triggers inflammatory activation of microglia and supports microglia-driven neuronal damage. Our previous studies have shown that ginsenoside Rg1 had a significant protective effect on focal cerebral I/R injury in middle cerebral artery occlusion (MCAO) rats. However, the mechanism still needs further clarification. Here, we firstly reported that ginsenoside Rg1 effectively suppressed the inflammatory activation of brain microglia cells under I/R conditions depending on the inhibition of Toll-likereceptor4 (TLR4) proteins. In vivo experiments showed that the ginsenoside Rg1 administration could significantly improve the cognitive function of MCAO rats, and in vitro experimental data showed that ginsenoside Rg1 significantly alleviated neuronal damage via inhibiting the inflammatory response in microglia cells co-cultured under oxygen and glucose deprivation/reoxygenation (OGD/R) condition in gradient dependent. The mechanism study showed that the effect of ginsenoside Rg1 depends on the suppression of TLR4/MyD88/NF-κB and TLR4/TRIF/IRF-3 pathways in microglia cells. In a word, our research shows that ginsenoside Rg1 has great application potential in attenuating the cerebral I/R injury by targeting TLR4 protein in the microglia cells.
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Isquemia Encefálica , Fármacos Neuroprotetores , Traumatismo por Reperfusão , Ratos , Animais , Microglia/metabolismo , Receptor 4 Toll-Like/metabolismo , Fármacos Neuroprotetores/farmacologia , Isquemia Encefálica/tratamento farmacológico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismoRESUMO
The NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome is a key component of the innate immune system that triggers inflammation and pyroptosis and contributes to the development of several diseases. Therefore, blocking the activation of the NLRP3 inflammasome has therapeutic potential for the treatment of these diseases. MCC950, a selective small molecule inhibitor, has emerged as a promising candidate for blocking NLRP3 inflammasome activation. Ongoing research is focused on elucidating the specific targets of MCC950 as well as assessfing its metabolism and safety profile. This review discusses the diseases that have been studied in relation to MCC950, with a focus on stroke, Alzheimer's disease, liver injury, atherosclerosis, diabetes mellitus, and sepsis, using bibliometric analysis. It then summarizes the potential pharmacological targets of MCC950 and discusses its toxicity. Furthermore, it traces the progression from preclinical to clinical research for the treatment of these diseases. Overall, this review provides a solid foundation for the clinical therapeutic potential of MCC950 and offers insights for future research and therapeutic approaches.
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Ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS) was employed to investigate the impacts of Pruni Semen processed with different methods(raw and fried) on the liver and spleen metabolism in mice. A total of 24 male mice were randomly assigned to three groups: raw Pruni Semen group, fried Pruni Semen group, and control(deionized water) group. Mice in the three groups were orally administrated with 0.01 g·mL~(-1) Pruni Semen decoction or deionized water for one week. After that, the liver and spleen tissues were collected, and liquid chromatography-mass spectrometry(LC-MS)-based metabolomic analysis was carried out to investigate the impact of Pruni Semen on the liver and spleen metabolism in mice. Compared with thte control group, the raw Pruni Semen group showed up-regulation of 11 metabolites and down-regulation of 57 metabolites in the spleen(P<0.05), as well as up-regulation of 15 metabolites and down-regulation of 58 metabolites in the liver(P<0.05). The fried Pruni Semen group showed up-regulation of 31 metabolites and down-regulation of 10 metabolites in the spleen(P<0.05), along with up-regulation of 26 metabolites and down-regulation of 61 metabolites in the liver(P<0.05). The differential metabolites identified in the raw Pruni Semen group were primarily associated with alanine, aspartate, and glutamate metabolism, purine metabolism, amino sugar and nucleotide sugar metabolism, and D-glutamine and D-glutamate metabolism. The differential metabolites identified in the fried Pruni Semen group predominantly involved riboflavin metabolism, amino sugar and nucleotide sugar metabolism, purine metabolism, alanine, aspartate, and glutamate metabolism, D-glutamine and D-glutamate metabolism, and glutathione metabolism. The findings suggest that both raw and fried Pruni Semen have the potential to modulate the metabolism of the liver and spleen in mice by influencing the glutamine and glutamate metabolism.
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Ácido Glutâmico , Baço , Camundongos , Masculino , Animais , Sêmen , Glutamina , Ácido Aspártico , Metabolômica/métodos , Fígado/metabolismo , Alanina/metabolismo , Amino Açúcares/metabolismo , Água/metabolismo , Nucleotídeos/metabolismo , Purinas/metabolismo , Açúcares , Cromatografia Líquida de Alta Pressão , Biomarcadores/metabolismoRESUMO
Drug development for Alzheimer's disease, the leading cause of dementia, has been a long-standing challenge. Saponins, which are steroid or triterpenoid glycosides with various pharmacological activities, have displayed therapeutic potential in treating Alzheimer's disease. In a comprehensive review of the literature from May 2007 to May 2023, we identified 63 references involving 40 different types of saponins that have been studied for their effects on Alzheimer's disease. These studies suggest that saponins have the potential to ameliorate Alzheimer's disease by reducing amyloid beta peptide deposition, inhibiting tau phosphorylation, modulating oxidative stress, reducing inflammation, and antiapoptosis. Most intriguingly, ginsenoside Rg1 and pseudoginsenoside-F11 possess these important pharmacological properties and show the best promise for the treatment of Alzheimer's disease. This review provides a summary and classification of common saponins that have been studied for their therapeutic potential in Alzheimer's disease, showcasing their underlying mechanisms. This highlights the promising potential of saponins for the treatment of Alzheimer's disease.
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Doença de Alzheimer , Saponinas , Humanos , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Saponinas/farmacologia , Saponinas/uso terapêutico , Proteínas tauRESUMO
BACKGROUND: PolyC-RNA-binding protein 1 (PCBP1) functions as a tumour suppressor and RNA regulator that is downregulated in human cancers. Here, we aimed to reveal the biological function of PCBP1 in lung adenocarcinoma (LUAD). METHODS: First, PCBP1 was identified as an important biomarker that maintains LUAD through The Cancer Genome Atlas (TCGA) project screening and confirmed by immunohistochemistry and qPCR. Via colony formation, CCK8, IncuCyte cell proliferation, wound healing and Transwell assays, we confirmed that PCBP1 was closely related to the proliferation and migration of LUAD cells. The downstream gene DKK1 was discovered by RNA sequencing of PCBP1 knockdown cells. The underlying mechanisms were further investigated using western blot, qPCR, RIP, RNA pulldown and mRNA stability assays. RESULTS: We demonstrate that PCBP1 is downregulated in LUAD tumour tissues. The reduction in PCBP1 promotes the proliferation, migration and invasion of LUAD in vitro and in vivo. Mechanistically, the RNA-binding protein PCBP1 represses LUAD by stabilizing DKK1 mRNA. Subsequently, decreased expression of the DKK1 protein relieves the inhibitory effect on the Wnt/ß-catenin signalling pathway. Taken together, these results show that PCBP1 acts as a tumour suppressor gene, inhibiting the tumorigenesis of LUAD. CONCLUSIONS: We found that PCBP1 inhibits LUAD development by upregulating DKK1 to inactivate the Wnt/ß-catenin pathway. Our findings highlight the potential of PCBP1 as a promising therapeutic target.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias Pulmonares/patologia , RNA , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , beta Catenina/metabolismoRESUMO
The bifunctional thiourea catalyst system with both electrophilic and nucleophilic centers has been certified to be effective for fixing CO2 under mild reaction conditions; however, many questions remain, especially concerning the relationship between structure and performance. Herein, we systematically studied a series of such bifunctional catalysts with different chain lengths, nucleophilic anions, and substituents, which impact obvious influence on the catalytic performance. The activation energies of catalysts with different chain lengths are calculated via in situ IR. On this basis, we disclosed for the first time that the spacer length of tetramethylene -(CH2)6- is the optimal spatial effect for the coupling of epoxides and CO2. Particularly, the single crystal X-ray diffraction analysis of the molecular structures of the bifunctional catalyst C8 indicated the discovery of the existence of interaction force between the sulfur atom on the thiourea group and one hydrogen atom on the benzene ring, as well as the intermolecular hydrogen bonding interaction of the bromide (Br-) and two NH groups on the thiourea group. The catalyst structure performance, direct observation of the crystal structure, the thermodynamic study, and a wide range of substrates (12 examples) should be informative on the optimization of the existing catalysts or the design of new catalysts in the future.
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This study aimed to establish the role of miR-129 and miR-384-5p in cerebral ischemia-induced apoptosis. Using PC12 cells transfected with miR-129 or miR-384-5p mimics or inhibitors, oxygen glucose deprivation (OGD) conditions were applied for 4 h to simulate transient cerebral ischemia. Apoptotic phenotypes were assessed via lactate dehydrogenase (LDH) assay, MTT cell metabolism assay, and fluorescence-activated cell sorting (FACS). The effect of miR overexpression and inhibition was evaluated by protein and mRNA detection of bcl-2 and caspase-3, critical apoptosis factors. Finally, the direct relationship of miR-129 and bcl-2 and miR-384-5p and caspase-3 was measured by luciferase reporter assay. The overexpression of miR-384-5p and miR-129 deficiency significantly enhanced cell viability, reduced LDH release, and inhibited apoptosis. By contrast, overexpression of miR-129 and miR-384-5p deficiency aggravated hypoxia-induced apoptosis and cell injury. miR-129 overexpression significantly reduced mRNA and protein levels of bcl-2 and miR-129 inhibition significantly increased mRNA and protein levels of bcl-2 in hypoxic cells.miR-384-5p overexpression significantly reduced protein levels of caspase-3 while miR-384-5p deficiency significantly increased protein levels of caspase-3. However, no changes were observed in caspase-3 mRNA in either transfection paradigm. Finally, luciferase reporter assay confirmed caspase-3 to be a direct target of miR-384-5p; however, no binding activity was detected between bcl-2 and miR-129.Transient cerebral ischemia induces differential expression of miR-129 and miR-384-5p which influences apoptosis by regulating apoptotic factors caspase-3 and bcl-2, thereby participating in the pathological mechanism of cerebral ischemia, and becoming potential targets for the treatment of ischemic cerebral injury in the future.
Assuntos
Glucose , MicroRNAs , Animais , Apoptose/genética , MicroRNAs/genética , Oxigênio , Células PC12 , RatosRESUMO
The clinical significance and comprehensive features of chemokines and their receptors in lung adenocarcinoma (LUAD) have not been clarified. We aimed to characterize the expression profiles of chemokine and chemokine receptor family members and construct a chemokine- and chemokine receptor-based prognosis signature. A total of 1511 patients with LUAD from seven independent cohorts were included in the study. The training set collected from The Cancer Genome Atlas (TCGA) database containing 468 cases. The validation was performed on the basis of six different cohorts downloaded from Gene Expression Omnibus (GEO) database. A five-chemokine- and chemokine receptor-(CXCL2, CXCL13, CCL26, CCL20, CX3CR1) based prognosis signature was constructed with TCGA dataset using LASSO Cox regression and Cox proportional hazards regression analysis. A multivariate analysis verified that this signature was an independent prognostic factor. The predictive value of this signature was further verified by other six independent cohorts and multiple clinical subtypes. We performed immune cell infiltration analysis and biological pathway analysis which provided more insight into this signature-related immune and inflammatory landscape and clarified the intrinsic molecular mechanism by which this signature could be used to predict clinical prognosis. Furthermore, we explored the close relationship between this signature and tumor mutation burden (TMB), neoantigen burden, PD-1, PD-L1, CTLA4, TIDE score, T cell-inflamed score. This signature provided a robust prognostic biomarker for LUAD and could serve as a predictor for immunotherapy response, which may be used as an important supplement to immunotherapy to achieve individualized tumor treatment by optimizing the prognostic management and immunotherapy for patients with LUAD.
Assuntos
Adenocarcinoma de Pulmão/genética , Quimiocinas/genética , Neoplasias Pulmonares/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/terapia , Idoso , Biomarcadores Tumorais/genética , Quimiocinas/imunologia , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Imunoterapia/métodos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/imunologiaRESUMO
Natural killer (NK) cells, a predominant innate lymphocyte subset, mediates eradicating malignant cells. Purinergic signaling by ectonucleotidase CD39 can suppress T-cell response in caner. However, the role of CD39 in NK cells has not been fully elucidated. Here, we characterized CD39 expression on NK cells and its clinical relevance in esophageal squamous cell carcinoma (ESCC). Peripheral blood and tissue samples were collected from 36 ESCC patients. We observed that the proportion of NK cells significantly decreased but CD39 was obviously up-regulated on NK cells from cancerous tissues compared to paired peripheral blood in ESCC patients. Furthermore, tumor-infiltrating NK cells with high CD39 expression exhibited a phenotype of functional impairment. In vitro, conditioned media of ESCC cell lines could induce CD39 expression on peripheral NK cells from healthy donors. IL-6 was identified as the major cytokine produced by ESCC cell lines and also elevated in both tumor tissues and blood serum from ESCC patients. Recombinant IL-6 significantly induced surface CD39 expression in human NK cells, while IL-6-receptor antagonist tocilizumab prevented this effect. Finally, tumor-infiltrating CD39+ NK cells were correlated with poor prognosis in ESCC patients. Thus, tumor-derived IL-6 might impair NK cell functions through induction of CD39 expression. CD39+ NK cells may serve as a potential prognostic biomarker for ESCC patients.
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Apirase/imunologia , Neoplasias Esofágicas/imunologia , Carcinoma de Células Escamosas do Esôfago/imunologia , Interleucina-6/imunologia , Células Matadoras Naturais/imunologia , Apirase/biossíntese , Feminino , Humanos , Interleucina-6/metabolismo , Células Matadoras Naturais/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Prognóstico , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologiaRESUMO
Vascular invasion (VI) in hepatocellular carcinoma (HCC) is an important clinical parameter to predict survival. In this study, we collected microRNA (miRNA) expression data from HCC patients using The Cancer Genome Atlas database and identified a novel miRNA signature associated with VI. First, we categorized HCC patients into groups with or without VI (VI+ and VI-). We identified three miRNAs (miRNA-210, miRNA-10b, and miRNA-9-1) that were associated with VI according to a Kaplan-Meier analysis. This three-miRNA signature exhibited good predictive ability for VI in patients with HCC according to a receiver operating characteristic curve analysis at 1, 3, and 5 years. Patients with HCC with a high risk score exhibited a trend toward worse outcomes as determined by multivariable Cox regression and stratified analyses. This three-miRNA signature provides an accurate prediction of VI and can be used as an independent prognostic indicator for predicting VI in HCC patients.
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Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/genética , Perfilação da Expressão Gênica , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/genética , MicroRNAs/metabolismo , Neovascularização Patológica/genética , Animais , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Estimativa de Kaplan-Meier , Camundongos Nus , MicroRNAs/genética , Prognóstico , Reprodutibilidade dos Testes , Fatores de Risco , Análise de SobrevidaRESUMO
BACKGROUND: Changes in glycogen metabolism is an essential feature among the various metabolic adaptations used by cancer cells to adjust to the conditions imposed by the tumor microenvironment. Our previous study showed that glycogen branching enzyme (GBE1) is downstream of the HIF1 pathway in hypoxia-conditioned lung cancer cells. In the present study, we investigated whether GBE1 is involved in the immune regulation of the tumor microenvironment in lung adenocarcinoma (LUAD). METHODS: We used RNA-sequencing analysis and the multiplex assay to determine changes in GBE1 knockdown cells. The role of GBE1 in LUAD was evaluated both in vitro and in vivo. RESULTS: GBE1 knockdown increased the expression of chemokines CCL5 and CXCL10 in A549 cells. CD8 expression correlated positively with CCL5 and CXCL10 expression in LUAD. The supernatants from the GBE1 knockdown cells increased recruitment of CD8+ T lymphocytes. However, the neutralizing antibodies of CCL5 or CXCL10 significantly inhibited cell migration induced by shGBE1 cell supernatants. STING/IFN-I pathway mediated the effect of GBE1 knockdown for CCL5 and CXCL10 upregulation. Moreover, PD-L1 increased significantly in shGBE1 A549 cells compared to those in control cells. Additionally, in LUAD tumor tissues, a negative link between PD-L1 and GBE1 was observed. Lastly, blockade of GBE1 signaling combined with anti-PD-L1 antibody significantly inhibited tumor growth in vivo. CONCLUSIONS: GBE1 blockade promotes the secretion of CCL5 and CXCL10 to recruit CD8+ T lymphocytes to the tumor microenvironment via the IFN-I/STING signaling pathway, accompanied by upregulation of PD-L1 in LUAD cells, suggesting that GBE1 could be a promising target for achieving tumor regression through cancer immunotherapy in LUAD.
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Adenocarcinoma de Pulmão/patologia , Perfilação da Expressão Gênica/métodos , Sistema da Enzima Desramificadora do Glicogênio/genética , Neoplasias Pulmonares/patologia , Análise de Sequência de RNA/métodos , Células A549 , Adenocarcinoma de Pulmão/genética , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Quimiocina CCL5/genética , Quimiocina CXCL10/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/genética , Proteínas de Membrana/metabolismo , Transplante de Neoplasias , Transdução de SinaisRESUMO
Mutations in the isocitrate dehydrogenase (IDH) 1 gene, especially the R132H mutation, have been reported to be associated with a better prognosis in glioma patients. However, the underlying molecular mechanisms are not yet well understood. Many factors may contribute to differences in the survival of IDH1 wild-type and IDH1 mutant glioma patients, in which immune components play a potentially important role. In this study, we analyzed The Cancer Genome Atlas (TCGA), and the Chinese Glioma Genome Atlas (CGGA) databases, as well as glioma patient-derived tumor samples. We found that there was a higher infiltration of natural killer (NK) cells in IDH1 mutant glioma patients, and this was correlated with a better prognosis. We also showed that IDH1-R132 tumor cells had higher expression levels of the chemokine CX3CL1. This arises as a result of the conversion of α-ketoglutarate to R(-)-2-hydroxyglutarate by the IDH1 mutant and the resultant phosphorylation of nuclear factor kappa B. Knockdown of CX3CL1 decreased the migration of NK cells. In addition, the high levels of expression of CX3CL1 were positively correlated with glioma patient survival in the TCGA and CGGA databases, and in the clinical samples. Overall, our data have identified a novel mechanism in which R132H mutation of the IDH1 gene serves as a tumor suppressor by promoting the recruitment of NK cells through CX3CL1/CX3CR1 chemotaxis.
Assuntos
Receptor 1 de Quimiocina CX3C/imunologia , Quimiocina CX3CL1/imunologia , Quimiotaxia , Regulação Neoplásica da Expressão Gênica/imunologia , Glioma , Isocitrato Desidrogenase , Células Matadoras Naturais/imunologia , Mutação de Sentido Incorreto , Proteínas Supressoras de Tumor , Substituição de Aminoácidos , Receptor 1 de Quimiocina CX3C/genética , Linhagem Celular Tumoral , Quimiocina CX3CL1/genética , Quimiotaxia/genética , Quimiotaxia/imunologia , Feminino , Glioma/genética , Glioma/imunologia , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/imunologia , Células Matadoras Naturais/patologia , Masculino , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/imunologiaRESUMO
BACKGROUND: Impairment of natural killer (NK) cell activity is an important mechanism of tumor immunoevasion. T cell immunoglobulin domain and mucin domain-3 (Tim-3) is an activation-induced inhibitory molecule, inducing effector lymphocyte exhaustion in chronic viral infection and cancers. However, its function in NK cells in human esophageal cancer remains unclear. METHODS: We prospectively collected peripheral blood and tumor samples from 53 patients with esophageal cancer. Peripheral and tumor-infiltrating NK cells were analyzed for Tim-3, Annexin V, CD69, CD107a and IFN-γ expression by flow cytometry. Quantitative real-time PCR was used to test relative mRNA expression of IFN-γ, granzyme B, perforin and NKG2D in sorted Tim-3+ NK cells and Tim-3- NK cells, respectively. NK cells isolated from healthy donors were treated with recombinant TNF-α to induce Tim-3 expression. Tim-3 and TNF-α mRNA levels in tumor tissues were measured in both humans and mice. Finally, associations between NK cell frequencies with pathological parameters were investigated. RESULTS: We observed up-regulation of Tim-3 expression on NK cells from esophageal cancer patients, especially at the tumor site. Furthermore, tumor-infiltrating NK cells with high Tim-3 expression exhibited a phenotype with enhanced dysfunction. In vitro, Tim-3 expression on NK cells isolated from blood of healthy donors can be induced by recombinant TNF-α via NF-κB pathway. In both animal models and patients, the Tim-3 level was positively correlated with TNF-α expression in esophageal cancer tissues. Finally, higher Tim-3 level on tumor-infiltrating NK cells is correlated with tumor invasion, nodal status and poor stage in patients with esophageal cancer. CONCLUSIONS: Taken together, Tim-3 may play a crucial role to induce NK cell dysfunction in tumor microenvironment and could serve as a potential biomarker for prognosis of esophageal cancer.
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Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Células Matadoras Naturais/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Animais , Apoptose , Carcinógenos , Modelos Animais de Doenças , Progressão da Doença , Humanos , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Transdução de Sinais , Regulação para CimaRESUMO
There is increasing evidence that cytoskeleton remodeling is involved in cancer progression. Wiskott-Aldrich syndrome protein (WASP) family represents a key regulator of actin cytoskeleton remodeling. However, the underlying mechanism of the WASP family in cancer progression remains elusive. Here, we studied the role of WASP and SCAR Homolog (WASH), a recently identified WASP family member, in human esophageal squamous cell carcinoma (ESCC). Using three human ESCC cell lines, we found that WASH expression was significantly elevated in cancer stem-like cells enriched by sphere formation assay. WASH knockdown decreased the sphere-forming capacity of esophageal cancer cells whereas WASH over-expression exhibited the opposite effect. Mechanistically, we identified interleukin-8 (IL-8) as a key downstream target of WASH. IL-8 knockdown completely attenuated tumor sphere formation induced by WASH overexpression. WASH knockdown also delayed the growth of human ESCC xenografts in BALB/c nude mice. Importantly, high WASH levels were associated with poor clinical prognosis in a total of 145 human ESCC tissues. Collectively, our results suggest an essential role of the WASH/IL-8 pathway in human ESCC by maintaining the stemness of cancer cells. Hence, targeting this pathway might represent a promising strategy to control human esophageal carcinoma.
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Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Proteínas dos Microfilamentos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Animais , Carcinoma de Células Escamosas/mortalidade , Neoplasias Esofágicas/mortalidade , Carcinoma de Células Escamosas do Esôfago , Xenoenxertos , Humanos , Estimativa de Kaplan-Meier , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , PrognósticoRESUMO
Emotion recognition utilizing EEG signals has emerged as a pivotal component of human-computer interaction. In recent years, with the relentless advancement of deep learning techniques, using deep learning for analyzing EEG signals has assumed a prominent role in emotion recognition. Applying deep learning in the context of EEG-based emotion recognition carries profound practical implications. Although many model approaches and some review articles have scrutinized this domain, they have yet to undergo a comprehensive and precise classification and summarization process. The existing classifications are somewhat coarse, with insufficient attention given to the potential applications within this domain. Therefore, this article systematically classifies recent developments in EEG-based emotion recognition, providing researchers with a lucid understanding of this field's various trajectories and methodologies. Additionally, it elucidates why distinct directions necessitate distinct modeling approaches. In conclusion, this article synthesizes and dissects the practical significance of EEG signals in emotion recognition, emphasizing its promising avenues for future application.
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Calpain, a key member of the Calpain cysteine protease superfamily, performs limited protein hydrolysis in a calcium-dependent manner. Its activity is tightly regulated due to the potential for non-specific cleavage of various intracellular proteins upon aberrant activation. A thorough review of the literature from 2010 to 2023 reveals 121 references discussing cardiovascular and cerebrovascular diseases. Dysregulation of the Calpain system is associated with various pathological phenomena, including lipid metabolism disorders, inflammation, apoptosis, and excitotoxicity. Although recent studies have revealed the significant role of Calpain in cardiovascular and cerebrovascular diseases, the precise mechanisms remain incompletely understood. Exploring the potential of Calpain inhibition as a therapeutic approach for the treatment of cardiovascular and cerebrovascular diseases may emerge as a compelling area of interest for future calpain research.