Deciphering the photolysis products and biological concerns of triclosan under UVC and UVA.

Triclosan (TCS) is omnipresent in the environment and has drawn increasing attention due to its potential adverse effects on human health. Direct photolysis of TCS readily occurs, especially in the surface layers of waters that receive abundant ultraviolet radiation during the daytime. However, biological concerns and the identification of toxic products during TCS photolysis have been explored limitedly. Therefore, in the present work, the structural characterization of the photolysis products by UVC and UVA were performed based on the mass spectra and fragmental ions. The results displayed that TCS was more readily eliminated by UVC than UVA, and the product species were completely different when TCS was degraded by UVC and UVA, respectively. Two products, m/z 235 and m/z 252, were produced via reductive dechlorination and nucleophilic substitution with UVC, while three dioxin-like isomer products were generated by dechlorination, cyclization and hydroxylation. Furthermore, the results of biological concerns suggested that the elimination of TCS did not represent the disappearance of biological risks. Specifically, more hazardous and photolysis products were formed during TCS photolysis with ultraviolets. For instance, the dioxin-like isomer products were highly microtoxic and genotoxic, and mildly antiestrogenic. The positive findings highlighted the biological concerns of TCS photolysis by ultraviolet radiation in the aquatic environment.

Direct photolysis of diclofenac under simulated sunlight: Transformation pathway and biological concerns.

Topical diclofenac gels are frequently applied on human skin and, consequently are exposed to sunlight during outdoor activities. The degradation of diclofenac (DCF) with sunlight exposure is known to occur but the detailed transformation characteristics and biological concerns have not been comprehensively investigated. In the present work, the transformation products during diclofenac photolysis were identified with the aid of ultra-performance liquid chromatography coupled with triple time-of-flight mass spectrometry (UPLC-TripleTOF). Biological concerns, including microtoxicity, genotoxicity, cytotoxicity and antiestrogenicity were examined with multiple in-vitro bioassays. Spearman correlation analysis was conducted to obtain further insight into the contributions of photolysis products to overall biological concerns. The results demonstrated that diclofenac was readily degraded under sunlight to form five main photolysis products via substitution, dechlorination, dehydroxylation, homodimerization and heterodimerization. Products P1, P2 and P5 were reported previously, while two dimer products (P3 and P4) are innovative products and have not been found in prior studies. A significant elevation in the microtoxicity was found during the photolysis of diclofenac, resulting mainly from the carbazole-containing photolysis products P2, P3, P4 and P5. Genotoxicity and antiestrogenicity declined along with the reduction of diclofenac, indicating that no photolysis products were genotoxic or anti-estrogenic. Modest cytotoxicity to the human skin epidermis cell line was observed and attributed to the formation of intermediate species. This outcome highlighted the biological concerns of diclofenac to human health when exposed to sunlight.

Keratin 8 reduces colonic permeability and maintains gut microbiota homeostasis, protecting against colitis and colitis-associated tumorigenesis.

Keratin 8 (CK8) is the major component of the intermediate filaments of simple or single-layered epithelia. Gene targeting mice model suggest that CK8 is involved in colonic active ion transport, colorectal hyperplasia and inflammation. In the present study, we found that CK8 is downregulated in the colon during DSS-induced colitis and AOM/DSS-induced colitis-associated colorectal cancer (CAC) development. In human patients with colon cancer, CK8 is downregulated. Using CK8 heterozygous knockout mice (CK8+/-), we found that CK8+/- mice are highly susceptible to DSS-induced colitis and more prone to AOM/DSS-induced CAC than wild type (WT) mice. The colonic permeability is increased with DSS or AOM/DSS treatment, leading to alteration of gut microbiota in CK8+/- mice with CAC. Metagenomic analysis of fecal microbiota suggests Firmicutes and Proteobacteria are increased in CK8+/- mice with CAC, while Bacteroidetes and Verrucomicrobia are decreased. Antibiotic treatment decreases the incidence of colorectal cancer tumorigenesis and TLR4 inhibitor attenuates the susceptibility of CK8+/- mice to DSS-induced colitis. These data suggest CK8 protects mice from colitis and colitis-associated colorectal cancer by modulating colonic permeability and gut microbiota composition homeostasis.

Keratin 8 limits TLR-triggered inflammatory responses through inhibiting TRAF6 polyubiquitination.

Toll-like receptors (TLRs) have critical roles in innate immunity and inflammation and the detailed mechanisms by which TLR signaling is fine tuned remain unclear. Keratin 8 (CK8) belongs to the type II keratin family and is the major compontent of the intermediate filaments of simple or single-layered epithelia. Here we report that down-regulation of CK8 in mice enhanced TLR-mediated responses, rendering mice more susceptible to lipopolysaccharide (LPS)-induced endotoxin shock and Escherichia coli-caused septic peritonitis with reduced survival, elevated levels of inflammation cytokines and more severe tissue damage. We found that CK8 suppressed TLR-induced nuclear factor (NF)-κB activation and interacted with the adaptor tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) to prevent its polyubiquitination. Our findings demonstrate a novel role of CK8 in negative regulation of TLR/NF-κB signaling and highlight a previously unidentified nonclassical function for CK8 in limiting inflammatory responses.