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The drug response phenotype is determined by a combination of genetic and environmental factors. The high clinical conversion failure rate of gene-targeted drugs might be attributed to the lack of emphasis on environmental factors and the inherent individual variability in drug response (IVDR). Current evidence suggests that environmental variables, rather than the disease itself, are the primary determinants of both gut microbiota composition and drug metabolism. Additionally, individual differences in gut microbiota create a unique metabolic environment that influences the in vivo processes underlying drug absorption, distribution, metabolism, and excretion (ADME). Here, we discuss how gut microbiota, shaped by both genetic and environmental factors, affects the host's ADME microenvironment within a new evaluation system for drug-microbiota interactions. Furthermore, we propose a new top-down research approach to investigate the intricate nature of drug-microbiota interactions in vivo. This approach utilizes germ-free animal models, providing foundation for the development of a new evaluation system for drug-microbiota interactions.
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Introduction: Previous study has indicated Dubosiella newyorkensis may act as a potential probiotic in age-related diseases. However, its detailed role in aging has not yet been promulgated. This study aimed to explore the potential anti-aging role of Dubosiella newyorkensis by comparing the anti-aging effect of resveratrol in young and old mice. Method: Measurement of intestinal aging-related factors in colon and serum, and vascular endothelial function-related factors in serum were performed by enzyme-linked immunosorbent assay (ELISA). Gut microbial analysis of intestinal contents were identified by 16S rRNA gene sequencing. Results: The effect of Dubosiella newyorkensis on reducing malondialdehyde (MDA) and increasing superoxide dismutase (SOD) in aged mice were greater than that of resveratrol. While the effect of Dubosiella newyorkensis on nitric oxide (NO) level was less than that of resveratrol, the reduction of vascular endothelial growth factor (VEGF) and pentosidine (PTD) was better than that of resveratrol in young mice. In young mice, Dubosiella newyorkensis promoted an increase in the beneficial genus Lactobacillus, Bifidobacterium and Ileibacterium less effectively as compared with resveratrol treatment. In aged mice, Dubosiella newyorkensis promoted the increase of Bifidobacterium, Ileibacterium less effectively than resveratrol, and promoted the increase of Akkermansia, Staphylococcus, Verrucomicrobiota expression better as compared with resveratrol treatment. Both young and old mice showed the same results for the remaining markers, including changes in gut microbial composition and predictions of function. Conclusion: Dubosiella newyorkensis has similar anti-aging functions with resveratrol. Dubosiella newyorkensis may even be more effective than resveratrol in reducing oxidative stress, improving vascular endothelial function, and redistributing gut microbiota. The research provides an innovative strategy of Dubosiella newyorkensis to improve aging.
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Microbioma Gastrointestinal , Ratones , Animales , Resveratrol/farmacología , ARN Ribosómico 16S , Factor A de Crecimiento Endotelial Vascular , EnvejecimientoRESUMEN
Although excessive salt consumption appears to hasten intestinal aging and increases susceptibility to cardiovascular disease, the molecular mechanism is unknown. In this study, mutual validation of high salt (HS) and aging fecal microbiota transplantation (FMT) in C56BL/6 mice was used to clarify the molecular mechanism by which excessive salt consumption causes intestinal aging. Firstly, we observed HS causes vascular endothelial damage and can accelerate intestinal aging associated with decreased colon and serum expression of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and increased malondialdehyde (MDA); after transplantation with HS fecal microbiota in mice, vascular endothelial damage and intestinal aging can also occur. Secondly, we also found intestinal aging and vascular endothelial damage in older mice aged 14 months; and after transplantation of the older mice fecal microbiota, the same effect was observed in mice aged 6-8 weeks. Meanwhile, HS and aging significantly changed gut microbial diversity and composition, which was transferable by FMT. Eventually, based on the core genera both in HS and the aging gut microbiota network, a machine learning model was constructed which could predict HS susceptibility to intestinal aging. Further investigation revealed that the process of HS-related intestinal aging was highly linked to the signal transduction mediated by various bacteria. In conclusion, the present study provides an experimental basis of potential microbial evidence in the process of HS related intestinal aging. Even, avoiding excessive salt consumption and actively intervening in gut microbiota alteration may assist to delay the aging state that drives HS-related intestinal aging in clinical practice.
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BACKGROUND: CD137 is a target for tumor immunotherapy. However, the role of CD137 in gastric cancer (GC), especially in inducing GC cell apoptosis, has not been studied. METHODS: Foxp3+ and CD8+ T cells in GCs were investigated using immunohistochemistry (IHC). CD137 expression in GCs was detected using flow cytometry, IHC and immunofluorescence (IF). Peripheral blood mononuclear cells (PBMCs) and CD8+ T cells isolated from peripheral blood were stimulated with a CD137 agonist in vitro. CD8+ T cell proliferation and p65 expression was examined using flow cytometry. P65 nuclear translocation was analyzed using IF. IL-10, TGF-ß, IFN-γ, perforin and granzyme B were detected using real-time quantitative PCR (real-time PCR). PBMCs and primary GC cells were cocultured and stimulated with a CD137 agonist in vitro. Apoptosis of primary GC cells was detected using flow cytometry. RESULTS: Our data demonstrated that GC tumors showed characteristics of an immunosuppressive microenvironment. CD137 was predominantly expressed in CD8+ T cells in GCs and had a positive correlation with tumor cell differentiation. The CD137 agonist promoted CD8+ T cell proliferation and increased the secretion of IFN-γ, perforin and granzyme B, which induced primary GC cell apoptosis. Mechanistically, this study found that the CD137 agonist induced NF-κB nuclear translocation in CD8+ T cells. CONCLUSION: Our results demonstrated that a CD137 agonist induced primary GC cell apoptosis by enhancing CD8+ T cells via activation of NF-κB signaling.
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The epithelial-to-mesenchymal transition (EMT) is a critical step in tumor metastasis. NEDD9 has been shown to be an oncogene in colorectal cancer. However, little is known about the relationship between NEDD9 and EMT in colorectal cancer metastasis. A total of 63 pairs of freshly frozen colorectal cancer tissues and adjacent noncancerous tissues were evaluated for NEDD9 gene expression using quantitative real-time PCR. The expression of NEDD9 and three epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin, ß-catenin and vimentin) was examined in 122 colorectal cancers by immunohistochemistry. The expression of NEDD9 was markedly increased in colorectal cancer tissues compared with adjacent noncancerous tissues. The expression level of NEDD9 was positively correlated and TNM stage but not with other clinicopathological features of colorectal tumors. Furthermore, the expression of NEDD9 was strongly associated with the loss of epithelial marker E-cadherin and acquired expression of the mesenchymal markers nuclear ß-catenin and vimentin. These findings suggested that NEDD9 might promote EMT and the progression of colorectal cancer, and thus may be a potential therapeutic target of colorectal cancers.
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Helicobacter pylori infection is a risk factor for gastric cancer. In addition, toll-like receptor 4 (TLR4) plays a fundamental role in pathogen recognition and activation of innate immunity. This study investigated the association of TLR4 polymorphisms with a risk of intestinal metaplasia (IM) and intraepithelial neoplasia (IN) in a Chinese Han population. This study analyzed TLR4 gene polymorphisms in 333 patients (IM, 193 cases; IN, 140 cases) and 312 atypia-free controls in a Chinese Han population using a Taqman allelic discrimination assay. The TLR4 single nucleotide polymorphisms +896A/G and +1196C/T were not associated with the risk of IM or IN. However, the single-locus analysis showed that the C allele of TLR4+2856T/C had significantly reduced risk of IM and IN [adjusted odds ratio (OR)=0.42; 95%CI=0.29-0.62 and OR=0.62; 95%CI=0.41-0.93, respectively] compared with the wild-type homozygote (TT). The frequencies of TLR4+2856T/C TC and T carrier were significantly lower in patients with Sydney's slight IM and low grade IN (P<0.01 and P=0.01, respectively), while the TC genotype showed a lower risk of moderate IM compared to healthy controls (P=0.045). In addition, the data revealed that H. pylori infection, heavy alcohol consumption and high salt uptake were associated with a higher susceptibility for developing this neoplasm. TLR4 rs10759932 TC and C carriers were associated with a lower risk in developing precancerous lesions in the stomach in a Chinese Han population.
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Infecciones por Helicobacter/inmunología , Helicobacter pylori/fisiología , Mucosa Intestinal/fisiología , Intestinos/patología , Neoplasias Gástricas/inmunología , Receptor Toll-Like 4/genética , Adulto , Anciano , Estudios de Casos y Controles , China , Progresión de la Enfermedad , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/genética , Humanos , Inmunidad Innata/genética , Masculino , Persona de Mediana Edad , Neoplasias , Polimorfismo de Nucleótido Simple , Riesgo , Neoplasias Gástricas/etiología , Neoplasias Gástricas/genética , Adulto JovenRESUMEN
Pancreatic ductal adenocarcinoma (PDA) is one of the most aggressive malignancies in humans, and its prognosis is generally poor even after surgery. Many advances have been made to understand the pathogenesis of PDA; however, the molecular mechanisms that lead to pancreatic carcinogenesis are still not clearly understood. The aims of this study were to investigate the relationship between DLC-1 methylation status and clinicopathological characteristics of PDA patients and evaluate the role of DLC-1 methylation status in PDA. The expression of DLC-1 mRNA in PDA tissues was analyzed by real-time PCR. The methylation status of DLC-1 was analyzed by methylation-specific polymerase chain reaction (MSP). Furthermore, we determined the prognostic importance of DLC-1 methylation status in PDA patients. Our results showed that the expression level of DLC-1 mRNA in PDA tissues was lower than that in non-cancerous tissues. The rate of DLC-1 promoter methylation was significantly higher in PDA tissues than in adjacent non-cancerous tissues (p < 0.001). Downregulation of DLC-1 was strongly correlated with promoter methylation (P = 0.003). The presence of DLC-1 methylation in PDA tissue samples was significantly correlated with clinical stage (P = 0.005), histological differentiation (P = 0.05), and lymph node metastasis (P = 0.006). Kaplan-Meier survival analysis showed that DLC-1 methylation status was inversely correlated with overall survival of the PDA patients. Further, Cox multivariate analysis indicated that DLC-1 methylation status was an independent prognostic factor for the overall survival rate of PDA patients. In conclusion, our data suggest that downregulation of DLC-1 may be explained by DNA methylation; DLC-1 may be a biomarker for PDA.
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Biomarcadores de Tumor/genética , Carcinoma Ductal Pancreático/genética , Proteínas Activadoras de GTPasa/genética , Neoplasias Pancreáticas/genética , Proteínas Supresoras de Tumor/genética , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/mortalidad , Metilación de ADN , Regulación hacia Abajo , Femenino , Proteínas Activadoras de GTPasa/metabolismo , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Páncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidad , Pronóstico , Regiones Promotoras Genéticas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Supresoras de Tumor/metabolismoRESUMEN
The aim of this study was to investigate the expression and prognostic significance of NEDD9 in pancreatic ductal adenocarcinoma (PDA). Expressional levels of NEDD9 mRNA and protein in paired pancreatic cancer lesions and adjacent noncancerous tissues were examined by quantitative real-time PCR and western blotting. NEDD9 expression was analyzed by immunohistochemistry in 106 patients with PDA. The correlations between NEDD9 immunostaining levels and clinicopathologic factors, as well as the follow-up data of patients, were analyzed statistically. NEDD9 protein and mRNA levels were elevated in pancreatic carcinoma lesions compared with the paired adjacent noncancerous tissues. A high level of expression of NEDD9 was significantly correlated with clinical staging (P < 0.001), lymph node metastasis (P < 0.001), and histological differentiation (P < 0.001). Patients with a higher NEDD9 expression had a significantly shorter survival time than those patients with lower NEDD9 expression. The multivariate analysis revealed that NEDD9 could serve as an independent factor of poor prognosis. Our finding indicates that NEDD9 could be used as prognostic molecular marker and therapeutic target for PDA.