Increased intestinal bile acid absorption contributes to age-related cognitive impairment.

Cognitive impairment in the elderly is associated with alterations in bile acid (BA) metabolism. In this study, we observe elevated levels of serum conjugated primary bile acids (CPBAs) and ammonia in elderly individuals, mild cognitive impairment, Alzheimer's disease, and aging rodents, with a more pronounced change in females. These changes are correlated with increased expression of the ileal apical sodium-bile acid transporter (ASBT), hippocampal synapse loss, and elevated brain CPBA and ammonia levels in rodents. In vitro experiments confirm that a CPBA, taurocholic acid, and ammonia induced synaptic loss. Manipulating intestinal BA transport using ASBT activators or inhibitors demonstrates the impact on brain CPBA and ammonia levels as well as cognitive decline in rodents. Additionally, administration of an intestinal BA sequestrant, cholestyramine, alleviates cognitive impairment, normalizing CPBAs and ammonia in aging mice. These findings highlight the potential of targeting intestinal BA absorption as a therapeutic strategy for age-related cognitive impairment.

Salivary metabolite signatures of oral cancer and leukoplakia.

Oral cancer, one of the six most common human cancers with an overall 5-year survival rate of <50%, is often not diagnosed until it has reached an advanced stage. The aim of the current study is to explore salivary metabolomics as a disease diagnostic and stratification tool for oral cancer and leukoplakia and evaluate the potential of salivary metabolome for detection of oral squamous cell carcinoma (OSCC). Saliva metabolite profiling for a group of 37 OSCC patients, 32 oral leukoplakia (OLK) patients and 34 healthy subjects was performed using ultraperformance liquid chromatography coupled with quadrupole/time-of-flight mass spectrometry in conjunction with multivariate statistical analysis. The OSCC, OLK and healthy control groups demonstrate characteristic salivary metabolic signatures. A panel of five salivary metabolites including γ-aminobutyric acid, phenylalanine, valine, n-eicosanoic acid and lactic acid were selected using OPLS-DA model with S-plot. The predictive power of each of the five salivary metabolites was evaluated by receiver operating characteristic curves for OSCC. Valine, lactic acid and phenylalanine in combination yielded satisfactory accuracy (0.89, 0.97), sensitivity (86.5% and 94.6%), specificity (82.4% and 84.4%) and positive predictive value (81.6% and 87.5%) in distinguishing OSCC from the controls or OLK, respectively. The utility of salivary metabolome diagnostics for oral cancer is successfully demonstrated in this study and these results suggest that metabolomics approach complements the clinical detection of OSCC and stratifies the two types of lesions, leading to an improved disease diagnosis and prognosis.

Identification of recombinant coxsackievirus A6 variants in hand, foot and mouth disease in Nanjing, China, 2013.

PURPOSE: Enteroviruses (EV) 71 and coxsackievirus A (CVA) 16 are the most prevalent EV serotypes responsible for hand, foot and mouth disease (HFMD). Nevertheless, CVA6 was found to be the leading cause of HFMD in the Nanjing area, of China in 2013. This study aims to provide insights into the occurrence of the emergent recombinant CVA6 through examination of the evolutionary history and the involved recombination events. METHODOLOGY: The viral protein1 (VP1) and non-structural (NS) 2C and 3D of 28 Nanjing CVA6 strains were aligned, among which the full-length sequences of eight strains were further characterized. RESULTS: We revealed the co-existence of two recombinant forms (RFs), RF-A and RF-J, in the local area. RF-J is a novel RF group, comprising a proportion of local and Shanghai CVA6 strains from 2013. The appearance of RF-J CVA6 strains was most likely the result of two recombination events, with the co-circulating CVA4 and CVA8 providing the regions beyond positions 4001~4045 and 4866~4873, respectively. Evolutionary history analysis showed that the VP1 sequences of RF-J derived from RF-A, which was also probably the ancestor of several other RF groups. The 3D region of RF-J was closely related to CVA8. The point in time of emergence of the most recent common ancestor (tMRCA) of RF-J in China was estimated to be around 2011 in both terms of VP1 and 3D region. CONCLUSION: The emerging recombinant CVA6 variants belong to a novel RF-J group which was most likely formed by at least two recombination events. Continued monitoring on the geographical distribution of various CVA6 RFs is essential.

Sex-dependent effects on gut microbiota regulate hepatic carcinogenic outcomes.

Emerging evidence points to a strong association between sex and gut microbiota, bile acids (BAs), and gastrointestinal cancers. Here, we investigated the mechanistic link between microbiota and hepatocellular carcinogenesis using a streptozotocin-high fat diet (STZ-HFD) induced nonalcoholic steatohepatitis-hepatocellular carcinoma (NASH-HCC) murine model and compared results for both sexes. STZ-HFD feeding induced a much higher incidence of HCC in male mice with substantially increased intrahepatic retention of hydrophobic BAs and decreased hepatic expression of tumor-suppressive microRNAs. Metagenomic analysis showed differences in gut microbiota involved in BA metabolism between normal male and female mice, and such differences were amplified when mice of both sexes were exposed to STZ-HFD. Treating STZ-HFD male mice with 2% cholestyramine led to significant improvement of hepatic BA retention, tumor-suppressive microRNA expressions, microbial gut communities, and prevention of HCC. Additionally the sex-dependent differences in BA profiles in the murine model can be correlated to the differential BA profiles between men and women during the development of HCC. These results uncover distinct male and female profiles for gut microbiota, BAs, and microRNAs that may contribute to sex-based disparity in liver carcinogenesis, and suggest new possibilities for preventing and controlling human obesity-related gastrointestinal cancers that often exhibit sex differences.

A new silymarin preparation based on solid dispersion technique.

Silymarin is a hepatoprotective agent that is poorly soluble in water. The present study describes a new preparation of solid dispersions in the form of "dripping pills" designed to enhance solubility. Dripping pills of silymarin were prepared at a 1:4 ratio by the traditional fusion method with the use of a mixture of silymarin and polyethylene glycol 6000 (PEG 6000). The prepared dripping pills were spherical and 3 to 4 mm in diameter, with an average weight of 30 mg per pill and with each pill containing 5 mg of silymarin. The dissolution rates of silymarin in dripping pill and of 3 other silymarin preparations, including Yiganling Film-Coating Tablet, Yiganling Sugar-Coating Tablet, and Legalon Capsule, were determined in pH 1.2 medium. The dissolution rate (T50) of the silymarin dripping pill was found to be significantly higher (by a factor of 7.5-11) than those of the other 3 preparations.