Edited by Joel M. GottesfeldChronic benzene exposure is associated with hematotoxicity and the development of aplastic anemia and leukemia. However, the signaling pathways underlying benzene-induced hematotoxicity remain to be defined. Here, we investigated the role of protein phosphatase 2A (PP2A) in the regulation of benzeneinduced hematotoxicity in a murine model. Male mice with a hepatocyte-specific homozygous deletion of the Ppp2r1a gene (encoding PP2A A␣ subunit) (HO) and matched wildtype (WT) mice were exposed to benzene via inhalation at doses of 1, 10, and 100 ppm for 28 days. Peripheral white blood cell counts and activation of bone marrow progenitors were attenuated in the HO mice, indicating that Ppp2r1a deletion protects against benzene-induced hematotoxicity. Moreover, elevation of urinary S-phenyl mercapturic acid, a benzene metabolite, was much greater in WT mice than in HO mice. Real-time exhalation analysis revealed more exhaled benzene but fewer benzene metabolites in HO mice than in WT mice, possibly because of the down-regulation of Cyp2e1, encoding cytochrome P4502E1, in hepatocytes of the HO mice. Loss-of-function screening disclosed that PP2A complexes containing the B56␣ subunit participate in regulating Cyp2e1 expression. Notably, PP2A-B56␣ suppressioninHepG2cellsresultedinpersistent␤-cateninphosphorylation at Ser 33 -Ser 37 -Thr 41 in response to CYP2E1 agonists. In parallel, nuclear translocation of ␤-catenin was inhibited, concomitant with a remarkable decrease of Cyp2e1 expression. These findings support the notion that a regulatory cascade comprising PP2A-B56␣, ␤-catenin, and Cyp2e1 is involved in benzene-induced hematotoxicity, providing critical insight into the role of PP2A in responses to the environmental chemicals.

Background: Caloric restriction (CR) is known to improve health and extend lifespan in human beings. The effects of CR on adverse health outcomes in response to particulate matter (PM) exposure and the underlying mechanisms have yet to be defined. Results: Male C57BL/6 J mice were fed with a CR diet or ad libitum (AL) and exposed to PM for 4 weeks in a realambient PM exposure system located at Shijiazhuang, China, with a daily mean concentration (95.77 μg/m 3) of PM 2.5. Compared to AL-fed mice, CR-fed mice showed attenuated PM-induced pulmonary injury and extrapulmonary toxicity characterized by reduction in oxidative stress, DNA damage and inflammation. RNA sequence analysis revealed that several pulmonary pathways that were involved in production of reactive oxygen species (ROS), cytokine production, and inflammatory cell activation were inactivated, while those mediating antioxidant generation and DNA repair were activated in CR-fed mice upon PM exposure. In addition, transcriptome analysis of murine livers revealed that CR led to induction of xenobiotic metabolism and detoxification pathways, corroborated by increased levels of urinary metabolites of polycyclic aromatic hydrocarbons (PAHs) and decreased cytotoxicity measured in an ex vivo assay. Conclusion: These novel results demonstrate, for the first time, that CR in mice confers resistance against pulmonary injuries and extra-pulmonary toxicity induced by PM exposure. CR led to activation of xenobiotic metabolism and enhanced detoxification of PM-bound chemicals. These findings provide evidence that dietary intervention may afford therapeutic means to reduce the health risk associated with PM exposure.

This research investigated the interaction between chitosan and whey protein molecules in terms of pH and heating. The FTOR, rheological analysis, turbidity, and zeta potential measurements were used to assess this interaction. At pH 4.0, addition of low amount chitosan with chitosan/whey protein isolate (C/WPO) ratio of 1:5 effectively prevented the denaturation of whey proteins after heating, whereas high amount of chitosan (C/WPO,1:2) led to depletion flocculation. The combination of chitosan and whey proteins was electrostatic attracting at pH 5.5 and 6.0. At low chitosan addition, the complexes formed at pH 5.5 showed higher viscosity and the complexes formed at pH 6.0 showed a shear-thinning behaviour. At high chitosan addition, the complexes showed high viscosity at pH 6.0. Heating led to the decrease of viscosity and increase of turbidity. The results manifested that chitosan and whey protein formed different complexes at pH 5.5 and 6.0, and the complexation of C/WPO was influenced by heating and ratio of chitosan and whey proteins.Keywords: chitosan; whey protein; molecule; interaction; pH. Practical Application:The interaction of C/WPO can be applied to improve the mechanical properties of chitosan-based films and the quality of whey protein gel.

Background Long-term exposure to fine particulate matter (PM2.5) increases susceptibility to chronic respiratory diseases, including inflammation and interstitial fibrosis. However, the regulatory mechanisms by which the immune response mediates the initiation of pulmonary fibrosis has yet to be fully characterized. This study aimed to illustrate the interplay between different cell clusters and key pathways in triggering chronic lung injuries in mice following PM exposure. Results Six-week-old C57BL/6J male mice were exposed to PM or filtered air for 16 weeks in a real-ambient PM exposure system in Shijiazhuang, China. The transcriptional profiles of whole lung cells following sub-chronic PM exposure were characterized by analysis of single-cell transcriptomics. The IL-17A knockout (IL-17A−/−) mouse model was utilized to determine whether the IL-17 signaling pathway mediated immune dysregulation in PM-induced chronic lung injuries. After 16-week PM exposure, chronic lung injuries with excessive collagen deposition and increased fibroblasts, neutrophils, and monocytes were noted concurrent with a decreased number of major classes of immune cells. Single-cell analysis showed that activation of the IL-17 signaling pathway was involved in the progression of pulmonary fibrosis upon sub-chronic PM exposure. Depletion of IL-17A led to significant decline in chronic lung injuries, which was mainly triggered by reduced recruitment of myeloid-derived suppressor cells (MDSCs) and downregulation of TGF-β. Conclusion These novel findings demonstrate that immunosuppression via the IL-17A pathway plays a critical role in the initiation of chronic lung injuries upon sub-chronic PM exposure.

No abstract