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Acute respiratory distress syndrome (ARDS) features pulmonary dysfunction capable of causing life-threatening hypoxaemia. Ventilation and hyperoxic therapies force oxygen through dysfunctional alveoli but risk exacerbating damage. Ox66™ is an ingestible, solid-state oxygen product designed for oxygen supplementation. Eighteen anaesthetized, ventilated rats were subjected to a 40% reduction in tidal volume to produce a hypoventilatory simulation of the hypoxia in ARDS (HV-ARDS). After 60 min, animals were randomized to receive either normal saline (Saline; volume control) or Ox66

Human exposures to perfluoroalkyl and polyfluoroalkyl substances (PFAS) have been linked to several diseases associated with adverse health outcomes. Animal studies have been conducted, though these may not be sufficient due to the inherent differences in metabolic processes between humans and rodents. Acquiring relevant data on the health effects of short-chain PFAS can be achieved through methods supported by in vitro human cell-based models. Specifically, cytotoxicity assays are the crucial first step to providing meaningful information used for determining safety and providing baseline information for further testing. To this end, we exposed human cell lines representative of six different tissue types, including colon (CaCo-2), liver (HepaRG), kidney (HEK293), brain (HMC-3), lung (MRC-5), and muscle (RMS-13) to five short-chain PFAS and two legacy PFAS. The exposure of the individual PFAS was assessed using a range of concentrations starting from a low concentration (10

Ox66™ is a novel solid state oxygenating compound. In order to support the use of Ox66™ as a potential oxygenating supplement to injured cells, this study evaluated the safety of Ox66™, its ability to withstand the conditions in the digestive tract, and its potential to increase oxygenation in the mesentery in rats. The toxicity of Ox66™ was evaluated by performing acute (10-day) and chronic (90-day) feeding studies on rats, the stability of the compound in the digestive tract was evaluated via ex vivo simulated digestion and subsequent CFDA viability assay on gut epithelial cells, and its capacity for oxygenation in the mesenteric microcirculation was determined by interstitial fluid pressure (PISF) O2 measurements upon injection into the small intestine of rats. No toxicity was found associated with acute or chronic oral administration of the compound in rats, and the compound was able to withstand the environment of the digestive tract in vitro. Based on the acute animal feeding study, the NOAEL was considered to be 1000 mg/kg/day. This proof-of-concept study further demonstrates the potential of Ox66™ to function as an oxygenating supplement that might be useful for treating either pathological hypoxic-related conditions or to improve oxygenation levels during or after exercise under healthy conditions.

Traumatic brain injury (TBI) is a leading cause of death and disability in every developed country in the world and is believed to be a risk factor in the later development of depression, anxiety disorders and neurodegenerative diseases including chronic traumatic encephalopathy (CTE), Alzheimer's Disease (AD), Parkinson's Disease (PD), and amyotrophic lateral sclerosis (ALS). One challenge faced by those who conduct research into TBI is the lack of a verified and validated biomarker that can be used to diagnose TBI or for use as a prognostic variable which can identify those at risk for poor recovery following injury or at risk for neurodegeneration later in life. Neuroimaging continues to hold promise as a TBI biomarker but is limited by a lack of clear relationship between the neuropathology of injury/recovery and the quantitative and image based data that is obtained. Specifically lacking is the data on biochemical and biologic changes that lead to alterations in neuroimaging markers. There are multiple routes towards developing the knowledge required to more definitively link pathology to imaging but the most efficient approach is expanded leveraging of in vivo human blood, serum, and imaging biomarkers with both in vivo and ex vivo animal findings. This review describes the current use and limitations of imaging in TBI including a discussion of currently used animal injury models and the available animal imaging data and extracted markers that hold the greatest promise for helping translate alterations in imaging back to injury pathology. Further, it reviews both the human and animal TBI literature supporting current standards, identifies the remaining voids in the literature, and briefly highlights recent advances in molecular imaging. This article is part of a Special Issue entitled 'Traumatic Brain Injury'.

Non-gaseous oxygen therapeutics are emerging technologies in regenerative medicine that aim to sidestep the undesirable effects seen in traditional oxygen therapies, while enhancing tissue and wound regeneration. Using a novel oxygenating therapeutic (Ox66™) several in vitro models including fibroblast and keratinocyte monocultures were evaluated for potential drug toxicity, the ability of cells to recover after chemical injury, and cell migration after scratch assay. It was determined that in both cell lines, there was no significant cytotoxicity found after independent treatment with Ox66™. Similarly, after DMSO-induced chemical injury, the health parameters of cells treated with Ox66™ were improved when compared to their untreated counterparts. Particles were also characterized using scanning electron microscopy and electron dispersive spectroscopy both individually and in conjunction with fibroblast growth. The data in this study showed that the novel wound healing therapeutic has potential in advancing the treatment of various types of acute and chronic wounds.

Polycyclic aromatic hydrocarbons (PAHs) have been labeled contaminants of concern due to their carcinogenic potential, insufficient toxicological data, environmental ubiquity, and inconsistencies in the composition of environmental mixtures. The Environmental Protection Agency is reevaluating current methods for assessing the toxicity of PAHs, including the assumption of toxic additivity in mixtures. This study was aimed at testing mixture interactions through in vitro cell culture experimentation, and modeling the toxicity using quantitative structure-activity relationships (QSAR). Clone-9 rat liver cells were used to analyze cellular proliferation, viability, and genotoxicity of 15 PAHs in single doses and binary mixtures. Tests revealed that many mixtures have nonadditive toxicity, but display varying mixture effects depending on the mixture composition. Many mixtures displayed antagonism, similar to other published studies. QSARs were then developed using the genetic function approximation algorithm to predict toxic activity both in single PAH congeners and in binary mixtures. Effective concentrations inhibiting 50% of the cell populations were modeled, with R(2) = 0.90, 0.99, and 0.84, respectively. The QSAR mixture algorithms were then adjusted to account for the observed mixture interactions as well as the mixture composition (ratios) to assess the feasibility of QSARs for mixtures. Based on these results, toxic addition is improbable and therefore environmental PAH mixtures are likely to see nonadditive responses when complex interactions occur between components. Furthermore, QSAR may be a useful tool to help bridge these data gaps surrounding the assessment of human health risks that are associated with PAH exposures.

Surface-functionalized silver nanoparticles (AgNPs) are the most deployed engineered nanomaterials in consumer products because of their optical, antibacterial and electrical properties. Almost all engineered nanoparticles are coated with application-specific capping agents (i.e. organic/inorganic ligands on particle surface) to enhance their stability in suspension or increase their biocompatibility for biomedicine. The aim of this study was to investigate the contribution of the selected capping agents to their observed health impacts using realistic dose ranges. AgNPs capped with citrate, polyvinylpyrrolidone (PVP) and tannic acid were studied with human bronchoalveolar carcinoma (A549) and human colon adenocarcinoma (Caco-2) cell lines and compared against exposures to Ag ions. Cellular uptake and cytotoxicity were evaluated up to 24 h. Tannic acid capped AgNPs induced higher cellular uptake and rate in both cell lines. Citrate-capped and PVP-capped AgNPs behaved similarly over 24 h. All three of the capped AgNPs penetrated more into the A549 cells than Caco-2 cells. In contrast, the uptake rate of Ag ions in Caco-2 cells (0.11 ± 0.0001 µg h(-1) ) was higher than A549 cells (0.025 ± 0.00004 µg h(-1) ). The exposure concentration of 3 mg l(-1) is below the EC50 value for all of the AgNPs; therefore, little cytotoxicity was observed in any experiment conducted herein. Exposure of Ag ions, however, interrupted cell membrane integrity and cell proliferation (up to 70% lysed after 24 h). These findings indicate cellular uptake is dependent on capping agent, and when controlled to realistic exposure concentrations, cellular function is not significantly affected by AgNP exposure.

Polybrominated diphenyl ethers (PBDEs) are known as effective flame retardants and have vast industrial application in products like plastics, building materials and textiles. They are found to be structurally similar to thyroid hormones that are responsible for regulating metabolism in the body. Structural similarity with the hormones poses a threat to human health because, once in the system, PBDEs have the potential to affect thyroid hormone transport and metabolism. This study was aimed at designing quantitative structure-activity relationship (QSAR) models for predicting toxic endpoints, namely cell viability and apoptosis, elicited by PBDEs in mammalian cells. Cell viability was evaluated quantitatively using a general cytotoxicity bioassay using Janus Green dye and apoptosis was evaluated using a caspase assay. This study has thus modelled the overall cytotoxic influence of PBDEs at an early and a late endpoint by the Genetic Function Approximation method. This research was a twofold process including running in vitro bioassays to collect data on the toxic endpoints and modeling the evaluated endpoints using QSARs. Cell viability and apoptosis responses for Hep G2 cells exposed to PBDEs were successfully modelled with an r(2) of 0.97 and 0.94, respectively.

Quantitative structure-activity relationships (QSAR) offer a reliable, cost-effective alternative to the time, money, and animal lives necessary to determine chemical toxicity by traditional methods. Additionally, humans are exposed to tens of thousands of chemicals in their lifetimes, necessitating the determination of chemical toxicity and screening for those posing the greatest risk to human health. This study developed models to predict toxic endpoints for three bioassays specific to several stages of carcinogenesis. The ethoxyresorufin O-deethylase assay (EROD), the Salmonella/microsome assay, and a gap junction intercellular communication (GJIC) assay were chosen for their ability to measure toxic endpoints specific to activation-, induction-, and promotion-related effects of polycyclic aromatic hydrocarbons (PAH). Shape-electronic, spatial, information content, and topological descriptors proved to be important descriptors in predicting the toxicity of PAH in these bioassays. Bioassay-based toxic equivalency factors (TEF(B)) were developed for several PAH using the quantitative structure-toxicity relationships (QSTR) developed. Predicting toxicity for a specific PAH compound, such as a bioassay-based potential potency (PP(B)) or a TEF(B), is possible by combining the predicted behavior from the QSTR models. These toxicity estimates may then be incorporated into a risk assessment for compounds that lack toxicity data. Accurate toxicity predictions are made by examining each type of endpoint important to the process of carcinogenicity, and a clearer understanding between composition and toxicity can be obtained.