Inflammatory bowel disease (IBD), a chronic gut immune dysregulation and dysbiosis condition is rapidly increasing in global incidence. Regardless, there is a lack of ideal diagnostic markers, while conventional treatment provides scarce desired results, thus, the exploration for better options. Changes in the gut microbial composition and metabolites either lead to or are caused by the immune dysregulation that characterizes IBD. This study examined the fecal metagenomics and metabolomic changes in IBD patients. A total of 30 fecal samples were collected from 15 IBD patients and 15 healthy controls for 16S rDNA gene sequencing and UHPLC/Q-TOF-MS detection of metabolomics. Results showed that there was a severe perturbation of gut bacteria community composition, diversity, metabolites, and associated functions and metabolic pathways in IBD. This included a significantly decreased abundance of Bacteroidetes and Firmicutes, increased disease-associated phyla such as Proteobacteria and Actinobacteria, and increased Escherichiacoli and Klebsiellapneumoniae in IBD. A total of 3146 metabolites were detected out of which 135 were differentially expressed between IBD and controls. Metabolites with high sensitivity and specificity in differentiating IBD from healthy individuals included 6,7,4′-trihydroxyisoflavone and thyroxine 4′-o-.beta.-d-glucuronide (AUC = 0.92), normorphine and salvinorin a (AUC = 0.90), and trichostachine (AUC = 0.91). Moreover, the IBD group had significantly affected pathways including primary bile acid biosynthesis, vitamin digestion and absorption, and carbohydrate metabolism. This study reveals that the combined evaluation of metabolites and fecal microbiome can be useful to discriminate between healthy subjects and IBD patients and consequently serve as therapeutic and diagnostic targets.
The phenotypic diversity of tumor-associated macrophages (TAMs) increases with tumor development. One of the hallmarks of malignancy is the polarization of TAMs from a pro-immune (M1) phenotype to an immunosuppressive (M2) phenotype. However, the molecular basis of this process is still unclear. Endostatin is a powerful inhibitor of angiogenesis capable of suppressing tumor growth and metastasis. Here, we demonstrate that endostatin induces RAW264.7 cell polarization toward the M1 phenotype in vitro. Endostatin has no effect on TAM numbers in vivo, but results in an increased proportion of F4/80(+)Nos2(+) cells and a decreased proportion of F4/80(+)CD206(+) cells. Overexpression of endostatin in RAW264.7 cells resulted in a decrease in the phosphorylation of STAT3, an increase in expression of vascular endothelial growth factor A and placental growth factor, and an increase in the phosphorylation of STAT1, IκBα and p65 proteins compared with controls. These results indicate that endostatin regulates macrophage polarization, promoting the M1 phenotype by targeting NF-κB and STAT signaling.
Diabetic cardiomyopathy is one of the major complications of diabetes, and due to the increasing number of patients with diabetes it is a growing concern. Diabetes-induced cardiomyopathy has a complex pathogenesis and histone deacetylase-mediated epigenetic processes are of prominent importance. The olfactory bromodomain-containing protein 4 (BRD4) is a protein that recognizes and binds acetylated lysine. It has been reported that the high expression of BRD4 is involved in the process of cardiac hypertrophy. The aim of the present study was to investigate the function of BRD4 in the process of high glucose (HG)-induced cardiac hypertrophy, and to clarify whether epigenetic regulation involving BRD4 is an important mechanism. It was revealed that BRD4 expression levels were increased in H9C2 cells following 48 h of HG stimulation. This result was also observed in a diabetic rat model. Furthermore, HG stimulation resulted in the upregulation of the myocardial hypertrophy marker, atrial natriuretic peptide, the cytoskeletal protein α-actin and fibrosis-associated genes including transforming growth factor-β, SMAD family member 3, connective tissue growth factor and collagen, type 1, α1. However, administration of the specific BRD4 inhibitor JQ1 (250 nM) for 48 h reversed this phenomenon. Furthermore, protein kinase B (AKT) phosphorylation was activated by HG stimulation and suppressed by JQ1. In conclusion, BRD4 serves an important role in the pathogenesis of HG-induced cardiomyocyte hypertrophy through the AKT pathway.
Inflammatory bowel disease (IBD) is associated with chronic gut immune dysregulation and altered microbiome and metabolites composition. Bile acids and their receptors such as the farnesoid X receptor (FXR) form...
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