RESUMO
Strengthening the gut epithelial barrier is a potential strategy for management of gut microbiota-associated illnesses. Here, we demonstrate that dual-specificity phosphatase 6 (Dusp6) knockout enhances baseline colon barrier integrity and ameliorates dextran sulfate sodium (DSS)-induced colonic injury. DUSP6 mutation in Caco-2 cells enhances the epithelial feature and increases mitochondrial oxygen consumption, accompanied by altered glucose metabolism and decreased glycolysis. We find that Dusp6-knockout mice are more resistant to DSS-induced dysbiosis, and the cohousing and fecal microbiota transplantation experiments show that the gut/fecal microbiota derived from Dusp6-knockout mice also confers protection against colitis. Further culturomics and mono-colonialization experiments show that one gut microbiota member in the genus Duncaniella confers host protection from DSS-induced injury. We identify Dusp6 deficiency as beneficial for shaping the gut microbiota eubiosis necessary to protect against gut barrier-related diseases.
Assuntos
Colite/microbiologia , Fosfatase 6 de Especificidade Dupla/metabolismo , Microbioma Gastrointestinal/fisiologia , Animais , Células CACO-2 , Colite/prevenção & controle , Colo/metabolismo , Sulfato de Dextrana/farmacologia , Modelos Animais de Doenças , Fosfatase 6 de Especificidade Dupla/deficiência , Fosfatase 6 de Especificidade Dupla/genética , Disbiose/metabolismo , Células Epiteliais/metabolismo , Fezes , Feminino , Humanos , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Ribossômico 16S/metabolismoRESUMO
Antrodia cinnamomea (AC) is a nutraceutical fungus and studies have suggested that AC has the potential to prevent or alleviate diseases. However, little is known about the AC-induced phenotypes on the intestine-liver axis and gut microbial alterations. Here, we performed two-dimensional difference gel electrophoresis (2D-DIGE) and MALDI-Biotyper to elaborate the AC-induced phenotypes on the intestine-liver axis and gut microbial distribution of C57BL/6 mice. The experimental outcomes showed that the hepatic density may increase by elevating hepatic redox regulation, lipid degradation and glycolysis-related proteins and alleviating cholesterol biosynthesis and transport-related proteins in C57BL/6 mice with AC treatment. Moreover, AC facilitates intestinal glycolysis, TCA cycle, redox and cytoskeleton regulation-related proteins, but also reduces intestinal vesicle transport-related proteins in C57BL/6 mice. However, the body weight, GTT, daily food/water intake, and fecal/urine weight were unaffected by AC supplementation in C57BL/6 mice. Notably, the C57BL/6-AC mice had a higher gut microbial abundance of Alistipes shahii (AS) than C57BL/6-Ctrl mice. In summary, the AC treatment affects intestinal permeability by regulating redox and cytoskeleton-related proteins and elevates the gut microbial abundance of AS in C57BL/6 mice that might be associated with increasing hepatic density and metabolism-related proteins of the liver in C57BL/6 mice. Our study provides an insight into the mechanisms of AC-induced phenotypes and a comprehensive assessment of AC's nutraceutical effect in C57BL/6 mice.
Assuntos
Suplementos Nutricionais , Microbioma Gastrointestinal/efeitos dos fármacos , Polyporales , Proteoma/metabolismo , Animais , Hepatócitos/metabolismo , Intestinos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BLRESUMO
The early onset breast cancer patients (age ≤ 40) often display higher incidence of axillary lymph node metastasis, and poorer five-year survival than the late-onset patients. To identify the genes and molecules associated with poor prognosis of early onset breast cancer, we examined gene expression profiles from paired breast normal/tumor tissues, and coupled with Gene Ontology and public data base analysis. Our data showed that the expression of GAS7b gene was lower in the early onset breast cancer patients as compared to the elder patients. We found that GAS7 was associated with CYFIP1 and WAVE2 complex to suppress breast cancer metastasis via blocking CYFIP1 and Rac1 protein interaction, actin polymerization, and ß1-integrin/FAK/Src signaling. We further demonstrated that p53 directly regulated GAS7 gene expression, which was inversely correlated with p53 mutations in breast cancer specimens. Our study uncover a novel regulatory mechanism of p53 in early onset breast cancer progression through GAS7-CYFIP1-mediated signaling pathways.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias da Mama/genética , Metástase Linfática/genética , Proteínas do Tecido Nervoso/genética , Transdução de Sinais/genética , Proteína Supressora de Tumor p53/genética , Regulação para Cima/genética , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Quinase 1 de Adesão Focal/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Integrina beta1/genética , Metástase Linfática/patologia , Células MCF-7 , Camundongos , Proteínas Proto-Oncogênicas pp60(c-src)/genética , Família de Proteínas da Síndrome de Wiskott-Aldrich/genéticaRESUMO
The aim of this study is to test whether inflammatory responsiveness of rat microglial cells is strain-specific in primary microglia derived from neonatal LEW/N and F344/N rats. In contrast to F344/N microglia, LEW/N microglia constitutively and upon lipopolysaccharide challenge expressed higher levels of mRNA for the majority of inflammatory mediators studied. In addition, LEW/N microglia exhibited enhanced secretion of tumor necrosis factor-alpha and CCL2, as well as elevated nitric oxide production. On the contrary, activated LEW/N microglia transcribed and secreted less interleukin-10. Hence, compared to F344/N microglia, LEW/N microglia might be more reactive to lipopolysaccharide and incompetent to suppress inflammation.