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BACKGROUND: Copeptin stimulation tests can be used in the differential diagnosis of polyuria polydipsia syndrome. Current stimulation methods rely on intravenous or subcutaneous administration. Oral stimulus can further simplify the diagnostic approach. The levodopa stimulation test is widely used in the evaluation of growth hormone deficiency (GHD), and the dopamine pathway was reported to be associated with arginine vasopressin secretion. The study aimed to investigate the effect of oral levodopa on copeptin secretion. METHODS: The study was a prospective observational single-center cohort study. Patients < 18 years old with short stature and no symptoms of polyuria or polydipsia undergoing levodopa stimulation test for suspected GHD were recruited from May 2023 to Nov 2023. Copeptin and growth hormone (GH) were measured at 0, 30, 60, 90, and 120min in the levodopa test. The insulin tolerance test with copeptin and GH measured at the same time points was conducted in part of patients. RESULTS: Forty-four participants were included in the final analysis. In the levodopa stimulation test, the median (interquartile range, IQR) copeptin concentration increased from 5.20 (3.51, 8.25) pmol/L to maximum 19.36 (8.97, 108.08) pmol/L (P < 0.001), 3.94 (1.41, 13.88) times of the baseline (P < 0.001). Compared with insulin tolerance test, peak copeptin in the levodopa test was significantly higher (34.61 (13.67, 98.96) vs 8.88 (7.14, 15.42) pmol/L, P = 0.009). Higher copeptin was associated with larger dose of levodopa. CONCLUSIONS: Oral levodopa could be used to stimulate copeptin.
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Currently, the mechanical performance of carbon fibers (CFs) has yet to fully realize its theoretical potential. This is predominantly attributed to the significant constraints posed by surface defects, greatly impeding the widespread application of carbon fibers. In order to address this issue, we employed a sonochemical-induced approach in this study to achieve in situ growth of nanoscale zeolitic imidazolate framework-8 (ZIF-8) at the surface defects of carbon fibers. After high-temperature treatment, the structure of ZIF-8 decomposed into ZnO and inorganic carbon, reinforcing the carbon fiber structure from both flexible and rigid aspects. Our research indicates that when the temperature reaches 500 °C, a substantial portion of ZIF-8 undergoes thermal decomposition, giving rise to zinc oxide and inorganic carbon. The flexible inorganic carbon and rigid ZnO form a meshlike structure, which welds to the surface defects of carbon fibers, resulting in strong interactions and contributing to the delay of fiber fracture. Compared to unmodified carbon fibers, the mechanical performance increased by approximately 15.86%. Based on the aforementioned analysis, this method can be considered a direct and effective approach for reinforcing carbon fiber structures, presenting a novel approach for the precise elimination of surface defects on carbon fibers.
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BACKGROUND AND AIMS: Liver diseases present a wide range of fibrosis, from fatty liver with no inflammation to steatohepatitis with varying degrees of fibrosis, to established cirrhosis leading to HCC. In a multivariate analysis, serum levels of spermidine were chosen as the top metabolite from 237 metabolites and its levels were drastically reduced along with progression to advanced steatohepatitis. Our previous studies that showed spermidine supplementation helps mice prevent liver fibrosis through MAP1S have prompted us to explore the possibility that spermidine can alleviate or cure already developed liver fibrosis. METHODS: We collected tissue samples from patients with liver fibrosis to measure the levels of MAP1S. We treated wild-type and MAP1S knockout mice with CCl4 -induced liver fibrosis with spermidine and isolated HSCs in culture to test the effects of spermidine on HSC activation and liver fibrosis. RESULTS: Patients with increasing degrees of liver fibrosis had reduced levels of MAP1S. Supplementing spermidine in mice that had already developed liver fibrosis after 1 month of CCl4 induction for an additional 3 months resulted in significant reductions in levels of ECM proteins and a remarkable improvement in liver fibrosis through MAP1S. Spermidine also suppressed HSC activation by reducing ECM proteins at both the mRNA and protein levels, and increasing the number of lipid droplets in stellate cells. CONCLUSIONS: Spermidine supplementation is a potentially clinically meaningful approach to treating and curing liver fibrosis, preventing cirrhosis and HCC in patients.
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Carcinoma Hepatocelular , Fígado Gorduroso , Cirrose Hepática , Neoplasias Hepáticas , Animais , Camundongos , Autofagia/fisiologia , Carcinoma Hepatocelular/patologia , Fígado Gorduroso/patologia , Fibrose , Células Estreladas do Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Neoplasias Hepáticas/patologia , Proteínas Associadas aos Microtúbulos/metabolismo , Espermidina/farmacologia , Espermidina/uso terapêutico , Espermidina/metabolismo , HumanosRESUMO
BACKGROUND: Endometriosis (EMS) is a "tumour-like" gynaecological disease with distant metastasis, and studies have shown that EMS can induce distant metastasis through vascular vessels, but the driving factors and their mechanism are not clear. METHODS: We used an EMS animal model and gene knockout technique to explore the role of EMS-induced angiogenesis in EMS metastasis in vivo and in vitro and clarify the role and molecular mechanism of oxLDL in promoting EMS-induced angiogenesis. RESULTS: We found that microvascular density (MVD) in metastasized ectopic endometrium and eutopic endometrial tissue was higher than that in normal endometrial tissue, and plasma oxLDL was positively correlated with the distant metastasis of EMS. Furthermore, we clarified that oxLDL enhanced the MVD of endometrial tissue by increasing VEGF-A expression and secretion in endometrial cells. Finally, we illustrated the mechanism by which oxLDL promotes VEGF-A expression through the AKT-HIF-1α signalling pathway. CONCLUSION: OxLDL is a risk factor promoting distant EMS metastasis by increasing VEGF-A expression and secretion through AKT-HIF-1α signalling. This finding may provide theoretical support and therapeutic targets for the clinical prevention and treatment of EMS.
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Endometriose , Fator A de Crescimento do Endotélio Vascular , Humanos , Feminino , Animais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Endométrio/metabolismo , Lipoproteínas LDL/metabolismoRESUMO
BACKGROUND: Circular RNAs (circRNAs) are a new class of noncoding RNAs that have gained increased attention in human tumor research. However, the identification and function of circRNAs are largely unknown in the context of gastric cancer (GC). This study aims to identify novel circRNAs and determine their action networks in GC. METHODS: A comprehensive strategy of data mining, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and computational biology were conducted to discover novel circRNAs and to explore their potential mechanisms in GC. Promising therapeutic drugs for GC were determined by connectivity map (CMap) analysis. RESULTS: Six overlapped differentially expressed circRNAs (DECs) were screened from selected microarray and RNA-Seq datasets of GC, and the six DECs were then validated by sanger sequencing and RNase R treatment. Subsequent RT-qPCR analysis of GC samples confirmed decreased expressions of the six DECs (hsa_circ_0000390, hsa_circ_0000615, hsa_circ_0001438, hsa_circ_0002190, hsa_circ_0002449 and hsa_circ_0003120), all of which accumulated preferentially in the cytoplasm. MiRNA binding sites and AGO2 occupation of the six circRNAs were predicted using online databases, and circRNA-miRNA interactions including the six circRNAs and 33 miRNAs were determined. Then, 5320 target genes of the above 33 miRNAs and 1492 differently expressed genes (DEGs) from The Cancer Genome Atlas (TCGA) database were identified. After intersecting the miRNA target genes and the 889 downregulated DEGs, 320 overlapped target genes were acquired. The Kyoto Encyclopedia of Genes and Genomes enrichment analysis indicated that these target genes were related to two critical tumor-associated signaling pathways. A protein-protein interaction network with the 320 target genes was constructed using STRING, and fifteen hubgenes (ATF3, BTG2, DUSP1, EGR1, FGF2, FOSB, GNAO1, GNAI1, GNAZ, GNG7, ITPR1, ITPKB, JUND, NR4A3, PRKCB) in the network were identified. Finally, bioactive chemicals (including vorinostat, trichostatin A and astemizole) based on the fifteen hubgenes were identifed as therapeutic agents for GC through the CMap analysis. CONCLUSIONS: This study provides a novel insight for further exploration of the pathogenesis and therapy of GC from the circRNA-miRNA-mRNA network perspective.
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Proteínas Imediatamente Precoces , MicroRNAs , Neoplasias Gástricas , Biologia Computacional , Subunidades alfa de Proteínas de Ligação ao GTP , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP , Humanos , MicroRNAs/genética , RNA Circular , RNA Mensageiro/genética , Neoplasias Gástricas/genética , Proteínas Supressoras de TumorRESUMO
Genome-wide association study (GWAS)-identified single-nucleotide polymorphisms (SNPs) are tag SNPs located in both transcribed and non-coding regulatory DNA regions, rather than representing causal or functional variants for disease. To identify functional variants or genes for melanoma susceptibility, we used functional mapping and annotation (FUMA) to perform functional annotation of the summary statistics of 2541 significant melanoma risk SNPs (P < 5 × 10-8) identified by GWAS. The original GWAS melanoma study included 15 990 cases and 26 409 controls, representing the largest international meta-analysis of melanoma susceptibility. We prioritized 330 unique genes, including those in immune cytokine signaling pathways, from 19 loci through positional, expression quantitative trait locus, and chromatin interaction mapping. In comparison, only 38 melanoma-related genes were identified in the original meta-analysis. In addition to the well-known melanoma susceptibility genes confirmed in the meta-analysis (MC1R, CDKN2A, TERT, OCA2 and ARNT/SETDB1), we also identified additional novel genes using FUMA to map SNPs to genes. Through chromatin interaction mapping, we prioritized IFNA7, IFNA10, IFNA16, IFNA17, IFNA14, IFNA6, IFNA21, IFNA4, IFNE and IFNA5; these 10 most significant genes are all involved in immune system and cytokine signaling pathways. In the gene analysis, we identified 72 genes with a P < 2.5 × 10-6. The genes associated with melanoma risk were DEF8 (P = 1.09 × 10-57), DBNDD1 (P = 2.19 × 10-42), SPATA33 (P = 3.54 × 10-38) and MC1R (P = 1.04 × 10-36). In summary, this study identifies novel putative melanoma susceptibility genes and provides a guide for further experimental validation of functional variants and disease-related genes.
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Biomarcadores Tumorais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Melanoma/genética , Melanoma/patologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Estudos de Casos e Controles , Perfilação da Expressão Gênica , Genótipo , HumanosRESUMO
OBJECTIVE: The aim of this study is to investigate the role of molecular mechanism of microRNA (miR)-21 on tight junction (TJ)-proteins and its protective effects on the intestinal barrier. METHODS: TJ proteins and target genes expression were analyzed in miR-21 inhibition and overexpression NCM460 cell lines. To further verify the role of miR-21, the mmu-miR-21 intestinal epithelial conditional knockout (IKO) mice model was established. MiR-21 expression was detected in clinical specimens of acute stercoral obstruction patients. RESULTS: Rho-associated protein kinase 1 (ROCK1) were identified as target genes of miR-21. There is a negative correlation between miR-21 expression level and TJ proteins levels. TJ protein and ROCK1 were significantly decreased in miR-21 IKO mice, which presented intestinal inflammation response and intestinal barrier dysfunction (both P < 0.05). Determination of clinical samples showed consistent results with NCM460 cell line and miR-21 IKO mice. CONCLUSIONS: MiR-21 could be a protective factor of intestinal barrier dysfunction, which promoting the expression of TJ protein by targeting ROCK1 in vivo and in vitro.
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Mucosa Intestinal/metabolismo , MicroRNAs/metabolismo , Ocludina/biossíntese , Quinases Associadas a rho/metabolismo , Animais , Humanos , Camundongos , Camundongos Knockout , MicroRNAs/genética , Ocludina/genética , Junções Íntimas/genética , Junções Íntimas/metabolismo , Quinases Associadas a rho/genéticaRESUMO
BACKGROUND/AIMS: Let-7b was dramatically reduced after a dicer knockout of mice with intestinal barrier function injuries. This paper aims to investigate the molecular mechanism of let-7b by targeting p38 MAPK in preventing intestinal barrier dysfunction. METHODS: A total of 186 patients were enrolled, with 93 in the control group and 93 in the PRO group. Only 158 patients completed the entire study, whereas the others either did not meet the inclusion criteria or refused to participate. To further verify the role of let-7b, intestinal epithelial conditional knockout (IKO) mice of mmu-let-7b model were established. Serum let-7b, zonulin, IL-6, and TNF-α concentrations were measured by ELISA or quantitative RT-PCR. Permeability assay was done by ussing chamber. The apoptotic cells were identified using an In Situ Cell Death Detection Kit. Protein was detected by western blot. RESULTS: Probiotics can lower infection-related complications, as well as increase the serum and tissue let-7b levels. P38 MAPK was identified as the target of let-7b, as verified by NCM460 cells. P38 MAPK expression was increased, whereas tight-junction (TJ) proteins were significantly decreased in let-7b IKO mice (both P<0.05). Negative regulation of p38 MAPK molecular signaling pathways was involved in the protective effects of let-7b on intestinal barrier function. CONCLUSION: Let-7b was identified as a novel diagnosis biomarker or a potential treatment target for preventing intestinal barrier dysfunction.
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Gastroenteropatias/diagnóstico , MicroRNAs/metabolismo , Ocludina/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Adulto , Idoso , Animais , Biomarcadores/metabolismo , Toxina da Cólera/sangue , Toxina da Cólera/genética , Toxina da Cólera/metabolismo , Colo/patologia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Gastroenteropatias/genética , Gastroenteropatias/metabolismo , Haptoglobinas , Humanos , Interleucina-6/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/sangue , MicroRNAs/genética , Pessoa de Meia-Idade , Ocludina/metabolismo , Precursores de Proteínas , Transdução de Sinais , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic and progressive lung disease characterized by a mixture of small airway disease and lung tissue parenchymal destruction. Abnormal inflammatory responses to cigarette smoking and other noxious particles are generally thought to be responsible for causing of COPD. Since airway inflammation is a key factor in COPD progress, it is crucial to unravel its underlying molecular mechanisms. Unbiased analysis of genome-wide gene expression profiles in lung small airway epithelial cells provides a powerful tool to investigate this. METHODS: Gene expression data of GSE611906, GSE20257, GSE8545 were downloaded from GEO database. All 288 lung small airway samples in these cohorts, including donors with (n = 61) and without (n = 227) COPD, were chosen for differential gene expression analysis. The gene ontology (GO) function, Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses, gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) network analysis were performed. Subsequently, the analyses of IL1B expression level, the Pearson correlation between IL1B and several COPD biomarkers were performed using other cohorts to validate our main findings. RESULTS: With a change ≥ twofold and P value < 0.05 cutoff, we found 38 genes were up-regulated and 114 genes were down-regulated in patients with COPD compared with health controls, while using cutoff fold change 1.5 and P value < 0.05, there were 318 genes up-regulated and 333 genes down-regulated. Among the most up-regulated genes were IL1B, CCL2, CCL23, and CXCL14, all implicated in inflammation triggering. GO, KEGG and WGCNA analysis all disclosed IL1B was highly correlated to COPD disease trait. The expression profile of IL1B was further validated using independent cohorts from COPD airway epithelium, lung tissue, sputum, and blood. We demonstrated higher IL1B gene expression in COPD small airway epithelial cells, but not in COPD lung tissue, sputum, and blood. Strong co-expression of IL1B with COPD biomarkers, such as DUOX2, MMP12, CCL2, and CXCL14, were validated in silico analysis. Finally, PPI network analysis using enriched data showed IL1B, CCL2, CCL7 and BMP7 were in the same hub node with high degrees. CONCLUSIONS: We identified IL1B was significantly up-regulated in COPD small airway epithelial cells and propose IL1B as a novel player in airway inflammation in COPD.
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Células Epiteliais/metabolismo , Interleucina-1beta/genética , Pulmão/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , Quimiocinas/genética , Oxidases Duais/genética , Humanos , Inflamação/genética , Pulmão/citologia , Metaloproteinase 12 da Matriz/genética , Mapas de Interação de Proteínas , Receptores Tipo II de Interleucina-1/genética , TranscriptomaRESUMO
The sensitivity of lateral flow assays (LFA) was increased 30-fold by making use of spherical core-shell gold-silica nanoparticles (AuNP@SiO2 NPs). They can be prepared by silylation of surfactant stabilized AuNPs. The AuNP@SiO2 NPs are highly stable and can be used to label antibodies at virtually any concentration. The detection limit of an LFA for alpha-fetoprotein (AFP) can be decreased from 10 ng·mL-1 to 300 pg·mL-1 which makes it comparable to an enzyme-linked immunosorbent assay. To demonstrate the applicability to an immunoassay, a sandwich assay was developed for vanillin by covalent modification of the AuNP@SiO2 NPs with antibody. By using the method, vanillin can be detected visually in milk powder samples in concentrations as low as 100 ng·g-1. With unique optical property and great stability, this AuNP@SiO2 endows great potential in biosensing applications. Graphical abstract Controlled growth of AuNP@SiO2. The newly prepared AuNP has a negative hydration layer. This layer is further surrounded by a bilayer of CTAB through electrostatic attraction. The hydrophobic inner layer enables the access and assembling of APTES and MTTS. After the hydrolysis of siloxane, a thin layer of silica shell is formed around AuNP.
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Benzaldeídos/análise , Ouro/química , Nanopartículas Metálicas/química , Dióxido de Silício/química , alfa-Fetoproteínas/análise , Animais , Técnicas Biossensoriais/métodos , Interações Hidrofóbicas e Hidrofílicas , Imunoensaio/métodos , Limite de Detecção , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Propriedades de SuperfícieRESUMO
BACKGROUND/AIMS: This study aimed to investigate the role of microRNA (miR)-122a in regulating zonulin during the modulation of intestinal barrier. METHODS: Zonulin proteins and their target gene expression were analyzed in miR-122a-overexpressing cell lines and in the target gene of epidermal growth factor receptor (EGFR). An mmu-miR-122a intestinal epithelial conditional transgenic (miR-122a-TG) mouse model was established to investigate EGFR and zonulin expression. MiR-122a was also detected in the clinical specimens of inflammatory bowel disease. RESULTS: EGFR was identified as a target gene of miR-122a. The expression level of miR-122a was positively correlated with that of zonulin. The expression level of zonulin was significantly increased, whereas the expression level of EGFR was significantly decreased in the miR-122a-TG mice and in the corresponding primary epithelial culture (P < 0.05). These results were consistent with the data of the clinical specimens. CONCLUSIONS: miR-122a could be a positive factor of zonulin by targeting EGFR, which increased the intestinal epithelial permeability in vivo and in vitro.
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Toxina da Cólera/biossíntese , Receptores ErbB/biossíntese , Mucosa Intestinal/metabolismo , MicroRNAs/genética , Animais , Toxina da Cólera/genética , Receptores ErbB/genética , Regulação da Expressão Gênica , Haptoglobinas , Humanos , Mucosa Intestinal/patologia , Camundongos , Camundongos Transgênicos , Permeabilidade , Precursores de ProteínasRESUMO
BACKGROUND: As an end-proteolytic enzyme that cleaves the last three residues of proteins with a terminal CAAX, Ras-converting enzyme 1 (RCE1) has an essential role in multiple signaling pathways and take part in the process of differentiation, proliferation and carcinogenesis. The aim of the study is to investigate expression pattern of RCE1 and its prognosis in colorectal carcinoma (CRC). METHODS: The expression of RCE1 and phospho-MAPK family members was confirmed by immunohistochemical staining of CRC tissues. miR-RCE1 lentiviral vectors were transduced into HCT116 and SW489 cells. Reverse transcription PCR (RT-PCR) and western blot were conducted to measure the transfection efficiency. Transwell assays were used to detect the invasiveness of CRC cells. RESULTS: In the present study, we assessed RCE1 expression in 244 CRC specimens and matching adjacent, non-tumorous tissues by immunohistochemistry (IHC). Compared with the matched adjacent non-tumor tissue samples, the RCE1 reduced in the tumor tissue samples (p < 0.001). RCE1 expression was significantly decreased in 106 of 244 (43.4%) CRC cases. In univariate and multivariate analyses, Decreasing expression of RCE1 independently predicts poor prognosis for patients in both overall survival and disease-free survival. Further study indicated that RCE1 influenced tumor invasion through the p38 pathway. Knockdown of RCE1 reduced phosphorylation and significantly increased the invasive capacity of CRC cells. CONCLUSION: Taken together, the outcomes of this study indicate that RCE1 acts as a tumor suppressor in CRC, as its reduced expression may increase CRC cell invasion and independently predict an unsatisfactory prognosis in CRC patients.
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Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Endopeptidases/genética , Regulação Neoplásica da Expressão Gênica , Adulto , Idoso , Biomarcadores Tumorais , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Feminino , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Fosforilação , Prognóstico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
The high incidence of recurrence and the poor prognosis of hepatocellular carcinoma (HCC) necessitate the discovery of new predictive markers of HCC invasion and prognosis. In this study, we evaluated the expression pattern of two members of a novel oncogene family, Musashi1 (MSI1) and Musashi2 (MSI2) in 40 normal hepatic tissue specimens, 149 HCC specimens and their adjacent non-tumourous tissues. We observed that MSI1 and MSI2 were significantly up-regulated in HCC tissues. High expression levels of MSI1 and MSI2 were detectable in 37.6% (56/149) and 49.0% (73/149) of the HCC specimens, respectively, but were rarely detected in adjacent non-tumourous tissues and were never detected in normal hepatic tissue specimens. Nevertheless, only high expression of MSI2 correlated with poor prognosis. In addition, MSI2 up-regulation correlated with clinicopathological parameters representative of highly invasive HCC. Further study indicated that MSI2 might enhance invasion of HCC by inducing epithelial-mesenchymal transition (EMT). Knockdown of MSI2 significantly decreased the invasion of HCC cells and changed the expression pattern of EMT markers. Moreover, immunohistochemistry assays of 149 HCC tissue specimens further confirmed this correlation. Taken together, the results of our study demonstrated that MSI2 correlates with EMT and has the potential to be a new predictive biomarker of HCC prognosis and invasion to help guide diagnosis and treatment of post-operative HCC patients.
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Carcinoma Hepatocelular/metabolismo , Transição Epitelial-Mesenquimal , Neoplasias Hepáticas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Prognóstico , RNA Interferente Pequeno/genética , Proteínas de Ligação a RNA/genéticaRESUMO
The epigenetic regulation of N6-methyladenosine (m6A) has attracted considerable interest in tumor research, but the potential roles of m6A regulator-related genes, remain largely unknown within the context of gastric cancer (GC) and tumor microenvironment (TME). Here, a comprehensive strategy of data mining and computational biology utilizing multiple datasets based on 28 m6A regulators (including novel anti-readers) was employed to identify m6A regulator-related genes and patterns and elucidate their underlying mechanisms in GC. Subsequently, a scoring system was constructed to evaluate individual prognosis and immunotherapy response. Three distinct m6A regulator-related patterns were identified through the unsupervised clustering of 56 m6A regulator-related genes (all significantly associated with GC prognosis). TME characterization revealed that these patterns highly corresponded to immune-inflamed, immune-excluded, and immune-desert phenotypes, and their TME characteristics were highly consistent with different clinical outcomes and biological processes. Additionally, an m6A-related scoring system was developed to quantify the m6A modification pattern of individual samples. Low scores indicated high survival rates and high levels of immune activation, whereas high scores indicated stromal activation and tumor malignancy. Furthermore, the m6A-related scores were correlated with tumor mutation loads and various clinical traits, including molecular or histological subtypes and clinical stage or grade, and the score had predictive values across all digestive system tumors and even in all tumor types. Notably, a low score was linked to improved responses to anti-PD-1/L1 and anti-CTLA4 immunotherapy in three independent cohorts. This study has expanded the important role of m6A regulator-related genes in shaping TME diversity and clinical/biological traits of GC. The developed scoring system could help develop more effective immunotherapy strategies and personalized treatment guidance.
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Adenosina , Regulação Neoplásica da Expressão Gênica , Neoplasias Gástricas , Microambiente Tumoral , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/imunologia , Humanos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Adenosina/análogos & derivados , Adenosina/metabolismo , Prognóstico , Epigênese Genética , Biologia Computacional/métodos , Biomarcadores Tumorais/genética , Imunoterapia/métodosRESUMO
Room-temperature photocatalytic conversion of CH4 into liquid oxygenates with O2/H2O provides an appealing route for sustainable chemical industry, which, however, suffers from poor efficiency due to the undesired carrier kinetics and low yield of reactive oxygen species of the currently available photocatalysts. Here, we report an effective surface engineering strategy where concurrent constructions of oxygen vacancies and phosphate sites on TiO2 nanosheets address the above challenge. The surface oxygen vacancies and phosphates are respective acceptors of photogenerated electrons and holes for promoted separation and migration of charge carriers. Moreover, in addition to the facilitated activation of O2 to â¢OH by electrons at oxygen vacancies, the surface phosphates also facilely adsorb H2O via hydrogen bonds and thus effectively transfer holes to H2O for enhanced â¢OH production, thereby boosting CH4 conversion. As a result, compared with TiO2 sheets with only oxygen vacancies, a 2.8 times improvement in liquid oxygenate production with near-unity selectivity is achieved by virtue of the synergy of surface oxygen vacancies and phosphate sites, together with an unprecedent quantum efficiency of 19.8% under 365 nm irradiation.
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Solar energy-driven direct CH4 conversion to liquid oxygenates provides a promising avenue toward green and sustainable CH4 industry, yet still confronts issues of low selectivity toward single oxygenate and use of noble-metal cocatalysts. Herein, for the first time, we report a defect-engineering strategy that rationally regulates the defective layer over TiO2 for selective aerobic photocatalytic CH4 conversion to HCHO without using noble-metal cocatalysts. (Photo)electrochemical and in situ EPR/Raman spectroscopic measurements reveal that an optimized oxygen-vacancy-rich surface disorder layer with a thickness of 1.37 nm can simultaneously promote the separation and migration of photogenerated charge carriers and enhance the activation of O2 and CH4, respectively, to â¢OH and â¢CH3 radicals, thereby synergistically boosting HCHO production in aerobic photocatalytic CH4 conversion. As a result, a HCHO production rate up to 3.16 mmol g-1 h-1 with 81.2% selectivity is achieved, outperforming those of the reported state-of-the-art photocatalytic systems. This work sheds light on the mechanism of O2-participated photocatalytic CH4 conversion on defective metal oxides and expands the application of defect engineering in designing low-cost and efficient photocatalysts.
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OBJECTIVES: Cardiac protection of resveratrol is related to the improvement of mitochondrial function through sirtuin1 (SIRT1) activation and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) deacetylation. Asymmetric dimethylarginine (ADMA) as an endogenous inhibitor of nitric oxide synthases is associated with diabetic cardiovascular complications and has a cross-talk with lysine acetylation. This study was to determine whether resveratrol reverses ADMA's pathogenic role in diabetic cardiomyopathy and elucidate the underlying mechanisms in type 2 diabetic (T2DM) rats and cardiomyocytes. METHODS: T2DM Rats were induced by high-fat diet plus small-dose streptozotocin injection (35 mg/kg). Resveratrol was given by gavage (50 mg/kg/d) to some rats for 16w. Cardiac function was measured by echocardiography, and PGC-1α acetylation was detected by immunoprecipitation. Mitochondrial DNA and ATP contents were analyzed to evaluate mitochondrial biogenesis and function. RESULTS: Endogenous ADMA accumulation and its signal disorders were associated with cardiac and mitochondrial dysfunctions in accompany with increased PGC-1α acetylation and decreased PGC-1α expression in the myocardium of T2DM rats compared with control rats. Resveratrol treatment attenuated ADMA accumulation, cardiac and mitochondrial dysfunctions in parallel with reversing altered PGC-1α expression and acetylation in the myocardium of T2DM rats. Exogenous ADMA not only reproduced mitochondrial dysfunction and cardiac hypertrophy but also reduced PGC-1α expression and enhanced PGC-1α acetylation in accompany of down-regulating SIRT1 and up-regulating acetyltransferase expression, all of which could be prevented by resveratrol pretreatment in cardiomyocytes. CONCLUSIONS: These results indicate that ADMA promotes PGC-1α acetylation as a potential therapeutic target for resveratrol of management diabetic cardiomyopathy in T2DM rats.
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Diabetes Mellitus Tipo 2 , Cardiomiopatias Diabéticas , Animais , Ratos , Acetilação , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/prevenção & controle , Miócitos Cardíacos , PPAR gama , Resveratrol/farmacologia , Sirtuína 1 , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismoRESUMO
PURPOSE: Increasing evidences have revealed the anti-cancer effect of disulfiram. Current disulfiram-based cancer therapies still have limitations, such as poor tumor-targeting ability and insufficient studies on anti-tumor mechanisms. METHODS: In the present study, tumor-targeting liposomes were prepared as drug carriers to increase retention of disulfiram in tumor cells. Then, anti-tumor efficacy of liposomes and the underlying mechanisms were investigated in in vitro, in vivo, and transcriptomic level. RESULTS: The results showed that disulfiram enhanced sensitivity of human hepatocellular carcinoma cells to doxorubicin by 15-27-fold, and increased reactive oxygen species (ROS) production as well as caspase-dependent apoptosis. Inhibition of tumor migration and invasion by doxorubicin were further enhanced by disulfiram. In vivo study showed that disulfiram additive doxorubicin liposomes had better performance in suppressing tumor growth than single doxorubicin liposomes. Gene expression profiling found that cellular components destruction, cell stress, check point regulation, and immunoregulation were the main anti-tumor mechanisms of disulfiram. More importantly, disulfiram possessed a great potential to be a protein ubiquitination and murine double minute 4 (MDM4) targeting compound. CONCLUSIONS: Due to its low price and good safety, it is worth to repurposing disulfiram as a chemotherapeutic drug. Furthermore, MDM4 may act as a biomarker for observation the clinical effect of disulfiram-based treatment.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Camundongos , Animais , Carcinoma Hepatocelular/patologia , Dissulfiram/farmacologia , Lipossomos , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Hepáticas/metabolismo , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Proteínas Proto-Oncogênicas , Proteínas de Ciclo CelularRESUMO
This study aimed to explore the anti-tumor effect of icaritin loading poly (lactic-co-glycolic acid) nanoparticles (refer to PLGA@Icaritin NPs) on gastric cancer (GC) cells. Transmission Electron Microscope (TEM), size distribution, zeta potential, drug-loading capability, and other physicochemical characteristics of PLGA@Icaritin NPs were carried out. Furthermore, flow cytometry, confocal laser scanning microscope (CLSM), Cell Counting Kit-8 (CCK-8), Transwell, Elisa assay and Balb/c mice were applied to explore the cellular uptake, anti-proliferation, anti-metastasis, immune response activation effects, and related anti-tumor mechanism of PLGA@Icaritin NPs in vitro and in vivo. PLGA@Icaritin NPs showed spherical shape, with appropriate particle sizes and well drug loading and releasing capacities. Flow cytometry and CLSM results indicated that PLGA@Icaritin could efficiently enter into GC cells. CCK-8 proved that PLGA@Icaritin NPs dramatically suppressed cell growth, induced Lactic dehydrogenase (LDH) leakage, arrested more GC cells at G2 phase, and inhibited the invasion and metastasis of GC cells, compared to free icaritin. In addition, PLGA@Icaritin could help generate dozens of reactive oxygen species (ROS) within GC cells, following by significant mitochondrial membrane potentials (MMPs) loss and excessive production of oxidative-mitochondrial DNA (Ox-mitoDNA). Since that, Ox-mitoDNA further activated the releasing of damage associated molecular pattern molecules (DAMPs), and finally led to immunogenic cell death (ICD). Our in vivo data also elaborated that PLGA@Icaritin exerted a powerful inhibitory effect (â¼80%), compared to free icaritin (â¼60%). Most importantly, our results demonstrated that PLGA@Icaritin could activate the anti-tumor immunity via recruitment of infiltrating CD4+ cells, CD8+ T cells and increased secretion of cytokine immune factors, including interferon-γ (IFN-γ) tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1).++ Our findings validate that the successful design of PLGA@Icaritin, which can effectively active ICD and facilitate tumor recruitment in GC through inducing mitoDNA oxidative damage.
Assuntos
Nanopartículas , Neoplasias Gástricas , Animais , Flavonoides , Morte Celular Imunogênica , Ácido Láctico/química , Camundongos , Nanopartículas/química , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Neoplasias Gástricas/tratamento farmacológicoRESUMO
Cancer becomes one of the main causes of human deaths in the world due to the high incidence and mortality rate and produces serious economic burdens. With more and more attention is paid on cancer, its therapies are getting more of a concern. Previous research has shown that the occurrence, progression, and treatment prognosis of malignant tumors are closely related to genetic and gene mutation. CRISPR/Cas9 has emerged as a powerful method for making changes to the genome, which has extensively been applied in various cell lines. Establishing the cell and animal models by CRISPR/Cas9 laid the foundation for the clinical trials which possibly treated the tumor. CRISPR-Cas9-mediated genome editing technology brings a great promise for inhibiting migration, invasion, and even treatment of tumor. However, the potential off-target effect limits its clinical application, and the effective ethical review is necessary. The article reviews the molecular mechanisms of CRISPR/Cas9 and discusses the research and the limitation related to cancer clinical trials.