A zinc-carnosine (ZnCar) metal−organic coordination polymer was fabricated in biologically relevant N-(2hydroxyethyl)piperazine-N′-ethanesulfonic acid (HEPES) buffer for use as a vaccine platform. In vitro, ZnCar exhibited significantly less cytotoxicity than a well-established zeolitic imidazolate framework (ZIF-8). Adsorption of CpG on the ZnCar surface resulted in enhanced innate immune activation compared to soluble CpG. The model antigen ovalbumin (OVA) was encapsulated in ZnCar and exhibited acid-sensitive release in vitro. When injected intramuscularly on days 0 and 21 in C57BL/6 mice, OVA-specific serum total IgG and IgG1 were significantly greater in all groups with ZnCar and antigen compared to soluble controls. Th1-skewed IgG2c antibodies were significantly greater in OVA and CpG groups delivered with ZnCar for all time points, regardless of whether the antigen and adjuvant were co-formulated in one material or co-delivered in separate materials. When broadly acting Computationally Optimized Broadly Reactive Antigen (COBRA) P1 influenza hemagglutinin (HA) was ligated to ZnCar via its His-tag, significantly greater antibody levels were observed at all time points compared to soluble antigen and CpG. ZnCar-formulated antigen elicited increased peptide presentation to B3Z T cells in vitro and production of IL-2 after ex vivo antigen recall of splenocytes isolated from vaccinated mice. Overall, this work displays the formation of a zinc-carnosine metal−organic coordination polymer that can be applied as a platform for recombinant protein-based vaccines.

The nuclear erythroid 2-like 2 transcription factor (NRF2), is a major regulator of cellular redox balance. Although NRF2 activation is generally regarded as beneficial to human health, recent studies have identified that sustained NRF2 activation is over-represented in many cancers. This raises the question regarding the role of NRF2 activation in the development and progression of those cancers. This review focuses on the mechanisms and the effects of NRF2 activation in two hereditary cancer predisposition syndromes: hereditary leiomyomatosis and renal cell cancer (HLRCC) and hereditary tyrosinemia type 1 (HT1). Because the cancer initiating mutations in these hereditary syndromes are well defined, they offer a unique opportunity to explore the roles of NRF2 activation in the early stages of carcinogenesis. Over the years, a variety of approaches have been utilized to study the biology of HLRCC and HT1. In HLRCC, in vitro studies have demonstrated the importance of NRF2 activation in sustaining cancer cell proliferation. In the mouse model of HT1 however, NRF2 activation seems to protect cells from malignant transformation. In both HT1 and HLRCC, NRF2 activation promotes the clearance of electrophilic metabolites, enabling cells to survive cancer-initiating mutations. Biological insights gained from the hereditary syndromes' studies may shed light on to the roles of NRF2 activation in sporadic tumours.

BEAS-2B is a non-malignant, immortalized human cell line that has been used extensively as a model of lung epithelium. Despite ATCC recommendations to culture BEAS-2B in defined, serum-free media, many publications describe culturing BEAS-2B in fetal bovine serum (FBS)-containing media. The objective of this study was to define the effects of FBS on BEAS-2B cells. FBS exposure resulted in increased nuclear levels of transcription factors responsible for regulating epithelial-mesenchymal transition (EMT), increased cell invasiveness and increased anchorage-independent growth. FBS-exposed BEAS-2B cells exhibited a decrease of the epithelial markers, E-cadherin and claudin-1 at the mRNA and protein levels, along with a corresponding increase of the mesenchymal marker, vimentin, at the protein level. Fractionation studies implicated an active moiety in FBS with a molecular weight larger than 30 kD. The mesenchymal phenotype was persistent provided FBS exposure was maintained. Upon FBS removal, both epithelial and mesenchymal markers began to revert toward an epithelial phenotype. Transforming growth factor β1 (TGFβ1) exposure to BEAS-2B recapitulated some key features of FBS-induced EMT. Our data suggest that FBS-exposed BEAS-2B cells do not accurately model the epithelial phenotype. Interpretation of data from BEAS-2B should include careful consideration of the effect of culture conditions.

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Arsenic is a ubiquitous environmental toxicant that has been associated with human respiratory diseases. In humans, arsenic exposure has been associated with increased risk of respiratory infection. Considering the existing epidemiological evidence and the well‐established impact of arsenic on epithelial cell biology, we posited that the effect of arsenic exposure in epithelial cells could enhance viral infection. In this study, we characterized influenza virus A/WSN/33 (H1N1) infection in Madin‐Darby Canine Kidney (MDCK) cells chronically exposed to low levels of sodium arsenite (75 ppb). We observed a 27.3‐fold increase in viral matrix (M2) protein (24 hours postinfection [p.i.]), a 1.35‐fold increase in viral mRNA levels, and a 126% increase in plaque area in arsenite‐exposed MDCK cells (48 hours p.i.). Arsenite exposure resulted in 114% increase in virus attachment‐positive cells (2 hours p.i.) and 224% increase in α‐2,3 sialic acid‐positive cells. Interestingly, chronic exposure to arsenite reduced the effect of the antiviral drug, oseltamivir in MDCK cells. We also found that exposure to sodium arsenite resulted in a 4.4‐fold increase in viral mRNA levels and significantly increased cytotoxicity in influenza A/Udorn/72 (H3N2) infected BEAS‐2B cells. This study suggests that chronic arsenite exposure could result in enhanced influenza infection in epithelial cells, and that this may be mediated through increased sialic acid binding. Finally, the decreased effectiveness of the anti‐influenza drug, oseltamivir, in arsenite‐exposed cells raises substantial public health concerns if this effect translates to arsenic‐exposed, influenza‐infected people.