Bile acids facilitate nutrient absorption and are endogenous ligands for nuclear receptors that regulate lipid and energy metabolism. The brain-gut-liver axis plays an essential role in maintaining ...overall glucose, bile acid, and immune homeostasis. Fasting and feeding transitions alter nutrient content in the gut, which influences bile acid composition and pool size. In turn, bile acid signaling controls lipid and glucose use and protection against inflammation. Altered bile acid metabolism resulting from gene mutations, high-fat diets, alcohol, or circadian disruption can contribute to cholestatic and inflammatory diseases, diabetes, and obesity. Bile acids and their derivatives are valuable therapeutic agents for treating these inflammatory metabolic diseases.
Bile acids are physiological detergents that generate bile flow and facilitate intestinal absorption and transport of lipids, nutrients, and vitamins. Bile acids also are signaling molecules and ...inflammatory agents that rapidly activate nuclear receptors and cell signaling pathways that regulate lipid, glucose, and energy metabolism. The enterohepatic circulation of bile acids exerts important physiological functions not only in feedback inhibition of bile acid synthesis but also in control of whole-body lipid homeostasis. In the liver, bile acids activate a nuclear receptor, farnesoid X receptor (FXR), that induces an atypical nuclear receptor small heterodimer partner, which subsequently inhibits nuclear receptors, liver-related homolog-1, and hepatocyte nuclear factor 4α and results in inhibiting transcription of the critical regulatory gene in bile acid synthesis, cholesterol 7α-hydroxylase (CYP7A1). In the intestine, FXR induces an intestinal hormone, fibroblast growth factor 15 (FGF15; or FGF19 in human), which activates hepatic FGF receptor 4 (FGFR4) signaling to inhibit bile acid synthesis. However, the mechanism by which FXR/FGF19/FGFR4 signaling inhibits CYP7A1 remains unknown. Bile acids are able to induce FGF19 in human hepatocytes, and the FGF19 autocrine pathway may exist in the human livers. Bile acids and bile acid receptors are therapeutic targets for development of drugs for treatment of cholestatic liver diseases, fatty liver diseases, diabetes, obesity, and metabolic syndrome.
Activation of farnesoid X receptor (Fxr, Nr1h4) is a major mechanism in suppressing bile‐acid synthesis by reducing the expression levels of genes encoding key bile‐acid synthetic enzymes (e.g., ...cytochrome P450 CYP7A1/Cyp7a1 and CYP8B1/Cyp8b1). FXR‐mediated induction of hepatic small heterodimer partner (SHP/Shp, Nr0b2) and intestinal fibroblast growth factor 15 (Fgf15; FGF19 in humans) has been shown to be responsible for this suppression. However, the exact contribution of Shp/Fgf15 to this suppression, and the associated cell‐signaling pathway, is unclear. By using novel genetically modified mice, the current study showed that the intestinal Fxr/Fgf15 pathway was critical for suppressing both Cyp7a1 and Cyp8b1 gene expression, but the liver Fxr/Shp pathway was important for suppressing Cyp8b1 gene expression and had a minor role in suppressing Cyp7a1 gene expression. Furthermore, in vivo administration of Fgf15 protein to mice led to a strong activation of extracellular signal‐related kinase (ERK) and, to a smaller degree, Jun N‐terminal kinase (JNK) in the liver. In addition, deficiency of either the ERK or JNK pathway in mouse livers reduced the basal, but not the Fgf15‐mediated, suppression of Cyp7a1 and Cyp8b1 gene expression. However, deficiency of both ERK and JNK pathways prevented Fgf15‐mediated suppression of Cyp7a1 and Cyp8b1 gene expression. Conclusion: The current study clearly elucidates the underlying molecular mechanism of hepatic versus intestinal Fxr in regulating the expression of genes critical for bile‐acid synthesis and hydrophobicity in the liver. (HEPATOLOGY 2012;56:1034–1043)
Background
Childhood asthma comprises different phenotypes with complex pathophysiology. Different asthma phenotypes evoke various clinical symptoms and vary in their responses to treatments.
Methods
...We applied k‐means clustering algorithm of twelve objective laboratory tests among 351 asthmatic children enrolled in the Taiwanese Consortium of Childhood Asthma Study (TCCAS). We constructed gene expression profiles of peripheral blood mononuclear cells (PBMC) from children with different asthma phenotypes.
Results
Five distinct phenotypes of childhood asthma were identified and can be characterized by either eosinophil‐predominant or neutrophil‐predominant inflammatory characteristics. In the gene expression profile analysis, significant differences were noted for neutrophil‐predominant asthma, compared with samples from all the other asthma phenotypes. The vast majority of the differentially expressed genes in neutrophil‐predominant asthma was associated with corticosteroid response. From an independent inhaled corticosteroid (ICS) response cohort, we also found neutrophils could be activated in this severe asthma phenotype and neutrophil‐predominant asthma may be associated with corticosteroid nonresponsiveness.
Conclusion
Phenotype clustering of childhood asthma can be helpful to identify clinically relevant patients and reveal different inflammatory characteristics in asthmatic children. Neutrophil‐predominant asthma is the most severe asthma phenotype with poor corticosteroid response. Gene expression profile of different asthma phenotypes not only improve our knowledge of childhood asthma, but also can guide asthma precision medicine.
Neutrophil‐predominant asthma is the most severe asthma phenotype with poor corticosteroid response. Five distinct phenotypes of childhood asthma identified in this study with differences in lung function, symptom frequency, healthcare utilization, percentages of eosinophils and neutrophils in peripheral blood, and serum IgE. Gene expression signature in PBMC constitutes an easier way to objectively identify corticosteroid‐resistant asthma in clinical settings.
Lung cancer is the leading cause of cancer death worldwide, with metastasis underlying majority of related deaths. Angiomotin (AMOT), a scaffold protein, has been shown to interact with oncogenic ...Yes-associated protein/transcriptional co-activator with a PDZ-binding motif (YAP/TAZ) proteins, suggesting a potential role in tumor progression. However, the functional role of AMOT in lung cancer remains unknown. This study aimed to identify the patho-physiological characteristics of AMOT in lung cancer progression. Results revealed that AMOT expression was significantly decreased in clinical lung cancer specimens. Knockdown of AMOT in a low metastatic CL1-0 lung cancer cell line initiated cancer proliferation, migration, invasion and epithelial-mesenchymal transition. The trigger of cancer progression caused by AMOT loss was transduced by decreased cytoplasmic sequestration and increased nuclear translocation of oncogenic co-activators YAP/TAZ, leading to increased expression of the growth factor, Cyr61. Tumor promotion by AMOT knockdown was reversed when YAP/TAZ or Cyr61 was absent. Further, AMOT knockdown increased the growth and spread of Lewis lung carcinoma in vivo. These findings suggest that AMOT is a crucial suppressor of lung cancer metastasis and highlight its critical role as a tumor suppressor and its potential as a prognostic biomarker and therapeutic target for lung cancer.
Bile acids facilitate intestinal nutrient absorption and biliary cholesterol secretion to maintain bile acid homeostasis, which is essential for protecting liver and other tissues and cells from ...cholesterol and bile acid toxicity. Bile acid metabolism is tightly regulated by bile acid
synthesis in the liver and bile acid biotransformation in the intestine. Bile acids are endogenous ligands that activate a complex network of nuclear receptor farnesoid X receptor and membrane G protein-coupled bile acid receptor-1 to regulate hepatic lipid and glucose metabolic homeostasis
and energy metabolism. The gut-to-liver axis plays a critical role in the regulation of enterohepatic circulation of bile acids, bile acid pool size, and bile acid composition. Bile acids control gut bacteria overgrowth, and gut bacteria metabolize bile acids to regulate host metabolism. Alteration
of bile acid metabolism by high-fat diets, sleep disruption, alcohol, and drugs reshapes gut microbiome and causes dysbiosis, obesity, and metabolic disorders. Gender differences in bile acid metabolism, FXR signaling, and gut microbiota have been linked to higher prevalence of fatty liver
disease and hepatocellular carcinoma in males. Alteration of bile acid homeostasis contributes to cholestatic liver diseases, inflammatory diseases in the digestive system, obesity, and diabetes. Bile acid-activated receptors are potential therapeutic targets for developing drugs to treat
metabolic disorders.
Purpose
In patients with chemotherapy, there is no consensus on the timing of ileostomy closure. Ileostomy reversal could improve the quality of life and minimise the long-term adverse events of ...delayed closure. In this study, we evaluated the impact of chemotherapy on ileostomy closure and searched for the predictive factors for complications.
Methods
We retrospectively analysed 212 patients with rectal cancer who underwent ileostomy closure surgery during and without chemotherapy and were consecutively enrolled between 2010 and 2016. As a result of the heterogeneity of the two groups, propensity score matching (PSM) was performed with a 1:1 PSM cohort.
Results
A total of 162 patients were included in the analysis. The overall stoma closure-related complications (12.4% vs. 11.1%,
p
= 1.00) and major complications (2.5% vs. 6.2%,
p
= 0.44) were not significantly different between the two groups. Multivariate analysis demonstrated that chronic kidney disease and bevacizumab use are risk factors for major complications.
Conclusion
Patients with oral or intravenous chemotherapy can safely have ileostomy closure with an adequate time delay from chemotherapy. When patients use bevacizumab, major complications related to ileostomy closure should still be cautioned.
Summary
Background
Previous studies have defined transcriptomic subtypes of adult asthma using samples of induced sputum and bronchial epithelium; however, those procedures are not readily applicable ...in the clinic, especially for childhood asthma.
Objective
We aim to dissect the transcriptomic clusters of childhood asthma using highly variably expressed genes of peripheral blood mononuclear cells (PBMC) among patients.
Methods
Gene expression of PBMC from 133 asthmatic children and 11 healthy controls was measured with Illumina microarrays. We applied the k‐means clustering algorithm of 2048 genes to assign asthmatic children into clusters. Genes with differential expression between asthma clusters and healthy controls were used to investigate whether they could identify severe asthma of children and adults.
Results
We identified 3 asthma clusters with distinct inflammatory profiles in peripheral blood. Cluster 1 had the highest eosinophil count. Cluster 2 showed lower counts of both eosinophils and neutrophils. Cluster 3 had the highest neutrophil count and the poorest treatment control. Compared with other patients, Cluster 3 exhibited a unique gene expression pattern which was associated with changes in the glucocorticoid signalling and activation of the T helper 1/T helper 17 (TH1/TH17) immune pathways. In the validation studies, an 84‐gene signature could identify severe asthma in children on leucocytes, as well as severe asthma in adults on CD8+ T cells.
Conclusions and Clinical Relevance
Gene expression profiling of PBMC is useful for the identification of TH1/TH17‐mediated asthma with poor treatment control. PBMC and CD8+ T cells could be important targets for the investigation and identification of severe asthma.
Bile acid synthesis is the most significant pathway for catabolism of cholesterol and for maintenance of whole body cholesterol homeostasis. Bile acids are physiological detergents that absorb, ...distribute, metabolize, and excrete nutrients, drugs, and xenobiotics. Bile acids also are signal molecules and metabolic integrators that activate nuclear farnesoid X receptor (FXR) and membrane Takeda G protein-coupled receptor 5 (TGR5; i.e., G protein-coupled bile acid receptor 1) to regulate glucose, lipid, and energy metabolism. The gut-to-liver axis plays a critical role in the transformation of primary bile acids to secondary bile acids, in the regulation of bile acid synthesis to maintain composition within the bile acid pool, and in the regulation of metabolic homeostasis to prevent hyperglycemia, dyslipidemia, obesity, and diabetes. High-fat and high-calorie diets, dysbiosis, alcohol, drugs, and disruption of sleep and circadian rhythms cause metabolic diseases, including alcoholic and nonalcoholic fatty liver diseases, obesity, diabetes, and cardiovascular disease. Bile acid-based drugs that target bile acid receptors are being developed for the treatment of metabolic diseases of the liver.
Aim
To investigate whether the timing of root canal treatment (primary aim) or other endodontic parameters (secondary aim) is associated with the survival probability of autotransplanted third ...molars, using a nationwide population‐based database.
Methodology
A total of 1811 third molars autotransplanted between 2000 and 2013 met the inclusion criteria and were followed until the end of 2016. The teeth were classified into three groups on the basis of timing between root canal treatment and the autotransplantation: preoperative, extraoral and postoperative treatment groups. Univariate and multivariate Cox proportional hazards models were used to estimate the association between the timing of root canal treatment and the risk of tooth extraction after autotransplantation.
Results
Of the 1811 autotransplanted third molars, 462 were extracted, yielding a 17‐year survival probability of 0.578. The survival probability of autotransplanted teeth that received postoperative root fillings after 17 years was 0.583, which was significantly higher than the 0.434 and 0.566 for teeth that received preoperative and extraoral root fillings, respectively (P = 0.0013). After adjustment for potential confounding factors, teeth that received postoperative root fillings were associated with a significantly lower tooth extraction hazard ratio (HR) compared with those that received extraoral root fillings (adjusted HR, 1.43; 95% confidence interval CI, 1.14–1.78) and those that received preoperative root fillings (adjusted HR, 2.13; 95% CI, 1.19–3.82). Furthermore, the use of a rubber dam during postoperative root filling was associated with a significantly lower extraction rate after autotransplantation (adjusted HR, 0.54; 95% CI, 0.43–0.69).
Conclusions
Postoperative root canal treatment resulted in a significantly lower extraction rate than did preoperative or extraoral root canal treatment amongst autotransplanted third molars during a mean follow‐up period of 8.33 years. Rubber dam use is recommended during postoperative root canal treatment to improve the outcomes of autotransplantation.
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