Akaganeite is an Fe(III) (hydr)oxide with a tunnel structure typically occupied by chloride. The mineral can undergo anion-exchange reactions in aqueous solution, resulting in incorporation of other anions together with Cl– into the tunnels. Identification of anions present in akaganeite tunnels may permit characterization of solution compositions in which akaganeite precipitated and/or existed. Akaganeite has been reported in several locations on Mars, including Yellowknife Bay in Gale crater. However, the nature of the tunnel anions has not been investigated. In order to constrain the nature of the tunnel anions in martian akaganeite, synthetic akaganeite (72 mg/g total Cl– content) was reacted with Mars-relevant anions (F–, OH–, and SO4 2–). Release of Cl– into solution was monitored with ion chromatography. Anion-reacted akaganeite was characterized with instruments analogous to instruments onboard robotic space crafts including X-ray diffraction (XRD), Mössbauer spectroscopy, thermal and evolved gas analysis (TA/EGA), and visible and near-infrared reflectance spectroscopy (vis–NIR). The results demonstrated that 17–71% of Cl– was released from akaganeite during 96 h incubation in water and anion-bearing solutions. A combination of XRD and TA/EGA, similar to the instruments onboard the Mars Science Laboratory rover Curiosity, can distinguish between unreacted akaganeite and akaganeite reacted with SO4 2–, F–, and OH– based on diffraction peak positions and evolved HCl, HF, and SO2. The vis–NIR analogous to the instrument on the Mars Reconnaissance Orbiter is only sensitive to Cl– replacement by OH– but not by SO4 2– and F– as evident from the changes in the shape and position of OH combination band. Mössbauer measurements at room temperature with instruments similar to those onboard the Mars Exploration Rovers did not distinguish among different tunnel anion compositions. The laboratory data are collectively consistent that akaganeite detected in Yellowknife Bay contains only Cl– in tunnels and likely formed and/or was in contact with Cl-bearing solutions during late stage diagenesis or aqueous alteration.
Chemoradiation-induced mucositis is a debilitating condition of the gastrointestinal tract eventuating from antineoplastic treatment. It is believed to occur primarily due to oxidative stress mechanisms, which generate Reactive Oxygen Species (ROS). The aim of this scoping review was to assess the role of oxidative stress in the development of Oral Mucositis (OM). Studies from the literature, published in MEDLINE and SCOPUS, that evaluated the oxidative stress pathways or antioxidant interventions for OM, were retrieved to elucidate the current understanding of their relationship. Studies failing inclusion criteria were excluded, and those suitable underwent data extraction, using a predefined data extraction table. Eighty-nine articles fulfilled criteria, and these were sub-stratified into models of study (in vitro, in vivo, or clinical) for evaluation. Thirty-five clinical studies evaluated antioxidant interventions on OM’s severity, duration, and pain, amongst other attributes. A number of clinical studies sought to elucidate the protective or therapeutic effects of compounds that had been pre-determined to have antioxidant properties, without directly assessing oxidative stress parameters (these were deemed “indirect evidence”). Forty-seven in vivo studies assessed the capacity of various compounds to prevent OM. Findings were mostly consistent, reporting reduced OM severity associated with a reduction in ROS, malondialdehyde (MDA), myeloperoxidase (MPO), but higher glutathione (GSH) and superoxide dismutase (SOD) activity or expression. Twenty-one in vitro studies assessed potential OM therapeutic interventions. The majority demonstrated successful a reduction in ROS, and in select studies, secondary molecules were assessed to identify the mechanism. In summary, this review highlighted numerous oxidative stress pathways involved in OM pathogenesis, which may inform the development of novel therapeutic targets.
Cancer development requires a favorable tissue microenvironment. By deleting Myd88 in keratinocytes or specific bone marrow subpopulations in oncogenic RAS-mediated skin carcinogenesis, we show that IL17 from infiltrating T cells and IkBz signaling in keratinocytes are essential to produce a permissive microenvironment and tumor formation. Both normal and RAS-transformed keratinocytes respond to tumor promoters by activating canonical NF-kB and IkBz signaling, releasing specific cytokines and chemokines that attract Th17 cells through MyD88-dependent signaling in T cells. The release of IL17 into the microenvironment elevates IkBz in normal and RAS-transformed keratinocytes. Activation of IkBz signaling is required for the expression of specific promoting factors induced by IL17 in normal keratinocytes and constitutively expressed in RAS-initiated keratinocytes. Deletion of Nfkbiz in keratinocytes impairs RAS-mediated benign tumor formation. Transcriptional profiling and gene set enrichment analysis of IkBzÀdeficient RAS-initiated keratinocytes indicate that IkBz signaling is common for RAS transformation of multiple epithelial cancers. Probing The Cancer Genome Atlas datasets using this transcriptional profile indicates that reduction of IkBz signaling during cancer progression associates with poor prognosis in RAS-driven human cancers. Implications:The paradox that elevation of IkBz and stimulation of IkBz signaling through tumor extrinsic factors is required for RAS-mediated benign tumor formation while relative IkBz expression is reduced in advanced cancers with poor prognosis implies that tumor cells switch from microenvironmental dependency early in carcinogenesis to cell-autonomous pathways during cancer progression.
Reactive oxygen species (ROS) are highly reactive molecules generated in living organisms and an excessive production of ROS culminates in oxidative stress and cellular damage. Notably, oxidative stress plays a critical role in the pathogenesis of a number of oral mucosal diseases, including oral mucositis, which remains one of cancer treatments’ most common side effects. We have shown previously that oral keratinocytes are remarkably sensitive to oxidative stress, and this may hinder the development and reproducibility of epithelial cell-based models of oral disease. Here, we examined the oxidative stress signatures that parallel oral toxicity by reproducing the initial events taking place during cancer treatment-induced oral mucositis. We used three oral epithelial cell lines (an immortalized normal human oral keratinocyte cell line, OKF6, and malignant oral keratinocytes, H357 and H400), as well as a mouse model of mucositis. The cells were subjected to increasing oxidative stress by incubation with hydrogen peroxide (H2O2) at concentrations of 100 μM up to 1200 μM, for up to 24 h, and ROS production and real-time kinetics of oxidative stress were investigated using fluorescent dye-based probes. Cell viability was assessed using a trypan blue exclusion assay, a fluorescence-based live–dead assay, and a fluorometric cytotoxicity assay (FCA), while morphological changes were analyzed by means of a phase-contrast inverted microscope. Static and dynamic real-time detection of the redox changes in keratinocytes showed a time-dependent increase of ROS production during oxidative stress-induced epithelial injury. The survival rates of oral epithelial cells were significantly affected after exposure to oxidative stress in a dose- and cell line-dependent manner. Values of TC50 of 800 μM, 800 μM, and 400 μM were reported for H400 cells (54.21 ± 9.04, p < 0.01), H357 cells (53.48 ± 4.01, p < 0.01), and OKF6 cells (48.64 ± 3.09, p < 0.01), respectively. Oxidative stress markers (MPO and MDA) were also significantly increased in oral tissues in our dual mouse model of chemotherapy-induced mucositis. In summary, we characterized and validated an oxidative stress model in human oral keratinocytes and identified optimal experimental conditions for the study of oxidative stress-induced oral epithelial toxicity.
<p>Supplemental table 3: List of genes from RNA profiling, the expression of which is significantly affected (by at least 1.5-fold change and FDR <5%) by IkBz deficiency in RAS-keratinocytes.</p>
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