Genes modulating intestinal permeability and microbial community are dysregulated in sickle cell disease.

Based on previous studies showing abnormalities in the intestinal pathophysiology characterized by disruption in the gut barrier functions, and alteration in the intestinal microbial load and composition, we set out in the study to examine the expression of genes that might be involved in mediating these changes in Townes sickle cell disease (SCD) mice at 6 months old compared to non-SCD control mice. Using qPCR on total RNA isolated from the intestine, we found downregulation of the TJ genes JAM-A, Occludin, and ZO-1 in both the small intestine and colon. E-Cadherin and MUC2 were also downregulated. In contrast, gene encoding claudin-2 that mediates increase permeability to water and ions was upregulated in the small intestine. Claudin-2 upregulation is usually also associated with ongoing inflammation. Intestinal epithelium also includes Paneth cells that produce antimicrobial peptides (AMPs) that regulate intestinal microbial community. We also found that the expression of the genes encoding the AMPs defensin-α4 was reduced in the small intestine and colon and defensin-α1 in the colon in the SCD mice. Our findings are novel and provide direction for further studies into the characteristics and mechanisms of the intestinal pathophysiologic changes observed in SCD.

Intestinal pathophysiological abnormalities in steady state and after vaso-occlusive crisis in murine sickle cell disease.

We showed in the present study that, not unlike in adult patients with sickle cell disease (SCD), Townes mice exhibit increases in serum intestinal fatty acid binding proteins and lipopolysaccharides (LPS), together with a breach in the intestinal barrier. These abnormalities increased rapidly after the induction of vaso-occlusive crisis (VOC). We also confirmed higher intestinal microbial density in SCD. These findings support the concept that SCD and/or its complications, and not hospitalisation or medications, are responsible for the intestinal pathophysiological changes. The present results provide the basis for use of Townes mice to further elucidate the mechanistic relationship between intestinal pathophysiology and VOC.

Influence of the E-Cigarette Emission Profile by the Ratio of Glycerol to Propylene Glycol in E-Liquid Composition.

The use of electronic cigarettes (E-cig) is popular because of the perception that they are less addictive and safer compared to the traditional cigarettes. Nevertheless, there are still harmful effects associated with chemicals emitted from E-cig. Identifying the sources of the emitted compounds can be challenging because of the differences in the design of E-cig devices and the variability in the composition of E-cig liquids used in these devices. In this study, the emission profiles from impurity-free E-liquids containing only propylene glycol and glycerol in various percentage ratios along with two commercially available E-liquids were evaluated using gas chromatography-mass spectrometry (GC-MS). This study approach allows the elucidation of the transformation pathways of the major emitted compounds without the confounding effects of existing impurities or flavor ingredients added to E-liquids. Analysis of the vapor phases of E-cig emissions detected toxicants such as acetaldehyde, acrolein, benzaldehyde, as well as benzene, toluene, ethylbenzene, and xylene (BTEX) compounds. The amount of glycerol in the E-liquids has a major effect on the concentration of these hazardous compounds emitted because the concentration of these chemicals increased with increasing glycerol percentage in the E-liquid. Acetaldehyde and acrolein increased by 175-fold and 28-fold, respectively, when the glycerol composition was increased from 0 to 80%. Benzaldehyde, naphthalene, diphenyl ether, and glycerol along with menthol and nicotine that were present in the commercial E-liquids were also detected in the aerosol condensates. The cascade impactor data on the distribution of the nicotine and menthol in different size fractions from >2.5 to <2.5 µm allow the estimates of the extent of toxicant deposition in different parts of the pulmonary system including the oropharynx region, the trachea as well as inside the alveoli and bronchioles. In summary, users of E-cig are exposed to harmful chemicals even if the E-liquids contain only propylene glycol and glycerol without flavorings, nicotine, or impurities. Furthermore, this study shows that E-liquids containing higher percentages of glycerol will produce higher levels of toxicants compared to E-liquids with similar percentages of propylene glycol. This finding has important implications to E-cigarette vendors and manufacturers, consumers, and regulatory agencies.

Endogenous volatile organic compounds in acute myeloid leukemia: origins and potential clinical applications.

Not unlike many cancer types, acute myeloid leukemia (AML) exhibits many metabolic changes and reprogramming, causing changes in lipid metabolism. Some of the distinct molecular abnormalities associated with AML also modify the metabolic changes. Both processes result in changes in the production of endogenous volatile organic compounds (VOCs). The increasing availability of highly sensitive methods for detecting trace chemicals provides the opportunity to investigate the role of patient-specific VOC finger-prints as biomarkers for detecting early relapse or minimal residual disease in AML. Since VOC production is reliant on metabolic activities, when combined with currently available methods, VOC analysis may identify within a group of patients with flow cytometric or molecular evidence of residual disease those most at risk for disease relapse.