Sulfur mustard (SM) is a highly toxic chemical warfare agent. Exposure to SM results in various pathologies including skin lesions with subsequent impaired wound healing. To date, there are no effective treatments available. Here we discover a SM-triggered pathomechanism involving miR-497-5p and its target survivin which contributes to keratinocyte dysfunction. Transcriptome analysis using RNA-seq in normal human epidermal keratinocytes (NHEK) revealed that SM evoked differential expression of 1896 mRNAs and 25 miRNAs with many of these RNAs known to be involved in keratinocyte function and wound healing. We demonstrated that keratinocyte differentiation and proliferation were efficiently regulated by miRNAs induced in skin cells after exposure to SM. The inhibition of miR-497-5p counteracted SM-induced premature differentiation and stimulated proliferation of NHEK. In addition, we showed that microneedle-mediated transdermal application of lipid-nanoparticles containing miR-497-5p inhibitor restored survivin biosynthesis and cellular functionality upon exposure to SM using human skin biopsies. Our findings expand the current understanding of SM-associated molecular toxicology in keratinocytes and highlight miR-497-5p as feasible clinical target for specific skin therapy in SM-exposed patients and beyond.

Exposure to mustard gas can cause damage or death to human beings, depending on the concentration and duration. Thus, developing high-performance mustard-gas sensors is highly needed for early warning. Herein, ultrathin WO3 nanosheet-supported Pd nanoparticles hybrids (WO3 NSs/Pd) are prepared as chemiresistive sulfur mustard simulant (e.g., 2-chloroethyl ethyl sulfide, 2-CEES) gas sensors. As a result, the optimal WO3 NSs/Pd-2 (2 wt % of Pd)-based sensor exhibits a high response of 8.5 and a rapid response/recovery time of 9/92 s toward 700 ppb 2-CEES at 260 °C. The detection limit could be as low as 15 ppb with a response of 1.4. Moreover, WO3 NSs/Pd-2 shows good repeatability, 30-day operating stability, and good selectivity. In WO3 NSs/Pd-2, ultrathin WO3 NSs are rich in oxygen vacancies, offer more sites to adsorb oxygen species, and make their size close to or even within the thickness of the so-called electron depletion layer, thus inducing a large resistance change (response). Moreover, strong metal-support interactions (SMSIs) between WO3 NSs and Pd nanoparticles enhance the catalytic redox reaction performance, thereby achieving a superior sensing performance toward 2-CEES. These findings in this work provide a new approach to optimize the sensing performance of a chemiresistive sensor by constructing SMSIs in ultrathin metal oxides.

Hydrogen peroxide (H2O2) is a highly effective decontaminant against chemical warfare agents (CWAs) when present both in a liquid and as a solid powder. For the latter, this can be in the form of H2O2 being complexed to a polymer, such as polyvinylpyrrolidone (PVP). While a H2O2-PVP complex is indeed effective at decontaminating CWAs, it is vulnerable to environmental conditions such as high relative humidities (RH), which can dissociate the H2O2 from the complex before it is given the opportunity to react with CWAs. In this paper, we demonstrate that the cross-linked version of PVP forms a highly stable complex with H2O2, which can withstand both high (40 °C) and low (-20 °C) temperatures as well as maintain stability at high RH up to 90% over several days. Collectively, this lays the framework for processing the H2O2-PVP complex in a variety of form factors that can maintain efficacy under a wide range of real-world environmental conditions.

OBJECTIVE: People with mustard gas lung disease experience cough, sputum, breathlessness and exercise limitation. We hypothesised that pulmonary rehabilitation (PR) would be beneficial in this condition.
METHODS: An assessor-blind, two-armed, parallel-design randomised controlled clinical trial.
METHODS: Secondary care clinics in Iran.
METHODS: 60 men with breathlessness due to respiratory disease caused by documented mustard gas exposure, mean (SD) age 52.7 (4.36) years, MRC dyspnoea score 3.5 (0.7), St. George\'s Respiratory Questionnaire (SGRQ) 72.3 (15.2).
METHODS: Participants were allocated either to a 6-week course of thrice-weekly PR (n=31) or to usual care (n=29), with 6-week data for 28 and 26, respectively.
METHODS: Primary endpoint was change in cycle endurance time at 70% baseline exercise capacity at 6 weeks. Secondary endpoints included 6 min walk distance, quadriceps strength and bulk, body composition and health status. For logistical reasons, blood tests that had been originally planned were not performed and 12-month follow-up was available for only a small proportion.
RESULTS: At 6 weeks, cycle endurance time increased from 377 (140) s to 787 (343) s with PR vs 495 (171) s to 479 (159) s for usual care, effect size +383 (231) s (p<0.001). PR also improved 6 min walk distance+103.2 m (63.6-142.9) (p<0.001), MRC dyspnoea score -0.36 (-0.65 to -0.07) (p=0.016) and quality of life; SGRQ -8.43 (-13.38 to -3.48) p<0.001, as well as quadriceps strength+9.28 Nm (1.89 to 16.66) p=0.015.
CONCLUSIONS: These data suggest that PR can improve exercise capacity and quality of life in people with breathlessness due to mustard gas lung disease and support the wider provision of this form of care.
BACKGROUND: IRCT2016051127848N1.

Sesquimustard (Q) is a powerful blistering agent that contains additional sulfur atoms. Sulfur mustard causes covalent bonding by alkylating nucleophilic groups of biologically important macromolecules such as lipids, proteins, DNA, or RNA. Most cells maintain relatively high amounts of a unique tripeptide called glutathione (GSH) (γ-glutamyl-cysteinyl glycine), which possesses a free thiol group, to prevent unwanted reactions caused by reactive chemical entities. Moreover, these thiol groups on cysteines (Cys) are the main target for alkylation. Although Q is the most potent vesicant among sulfur mustards, research studies identifying biomarkers of Q are very limited. Therefore, here in this study, we aimed to identify the GSH and Cys conjugates of Q using mass spectrometric methods and to observe the formation of these conjugates in HaCat cell culture following exposure to different doses. We identified four different conjugates of Q, which are bis-glutathionyl ethylthioethylthioethyl conjugate (GSH-ETETE-GSH), hydroxyethylthioethylthioethyl glutathione conjugate (HETETE-GSH), bis-cysteinyl ethylthioethylthioethyl conjugate (Cys-ETETE-Cys), and hydroxyethylthioethylthioethyl cysteine conjugate (HETETE-Cys). The identity of the conjugates was elucidated using liquid chromatography-high-resolution mass spectrometry (LC-HRMS). We also investigated changes in conjugate formation with exposure concentration and time elapsed after exposure in the cell culture. After exposure, GSH conjugates decreased until 1st hour, while Cys conjugates increased until 6th hour. We also observed that conjugate formation depended on the concentration of Q. This is the first study to elucidate the conjugates of Q dependent on GSH conjugation. As biomarkers are essential tools for evaluating exposure to Q, this study contributes to the limited number of studies identifying biomarkers for Q.

Sulfur mustard (SM, dichlorodiethyl sulfide) is a potent erosive chemical poison that can cause pulmonary lung, skin and eye disease complications in humans. Currently, there is no designated remedy for SM, and its operation\'s toxicological process remains unidentified. This work employed zebrafish as a model organism to investigate the toxic manifestations and mechanisms of exposure to SM, aiming to offer novel insights for preventing and treating this condition. The results showed that SM caused a decrease in the survival rate of the zebrafish larvae (LC50 = 2.47 mg/L), a reduction in the hatching rate, an increase in the pericardial area, and small head syndrome. However, T-5224 (a selective inhibitor of c-Fos/activator protein) attenuated the reduction in mortality (LC50 = 2.79 mg/L), the reduction in hatching rate, and the worsening of morphological changes. We discovered that SM causes cartilage developmental disorders in zebrafish larvae. The reverse transcription-quantitative polymerase chain reaction found that SM increased the expression of inflammation-related genes (IL-1β, IL-6, and TNF-α) and significantly increased cartilage development-related gene expression (fosab, mmp9, and atf3). However, the expression of sox9a, sox9b, and Col2a1a was reduced. The protein level detection also found an increase in c-fos protein expression and a significant decrease in COL2A1 expression. However, T-5224,also and mitigated the changes in gene expression, and protein levels caused by SM exposure. The results of this study indicate that SM-induced cartilage development disorders are closely related to the c-Fos/AP-1 pathway in zebrafish.

Nuclear and chemical weapons of mass destruction share both a tragic and beneficial legacy in mankind\'s history and health. The horrific health effects of ionizing radiation and mustard gas exposures unleashed during disasters, wars, and conflicts have been harnessed to treat human health maladies. Both agents of destruction have been transformed into therapies to treat a wide range of cancers. The discovery of therapeutic uses of radiation and sulfur mustard was largely due to observations by clinicians treating victims of radiation and sulfur mustard gas exposures. Clinicians identified vulnerability of leukocytes to these agents and repurposed their use in the treatment of leukemias and lymphomas. Given the overlap in therapeutic modalities, it goes to reason that there may be common mechanisms to target as protective strategies against their damaging effects. This commentary will highlight oxidative stress as a common mechanism shared by both radiation and sulfur mustard gas exposures and discuss potential therapies targeting oxidative stress as medical countermeasures against the devastating lung diseases wrought by these agents.

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Nerve agents are the most notorious substances, which can be fatal to an individual because they block the activity of acetylcholinesterase. Fighting against unpredictable terrorist assaults and wars requires the simple and quick detection of chemical warfare agent vapor. In the present contribution, we have introduced a rhodamine-based chemosensor, BDHA, for the detection of nerve gas-mimicking agents diethylchlorophosphate (DCP) and diethylcyanophosphonate (DCNP) and mustard gas-mimicking agent 2-chloroethyl ethyl sulfide (CEES), both in the liquid and vapor phase. Probe BDHA provides the ability for detection by the naked eye in terms of colorimetric and fluorometric changes. It has been revealed that the interaction between nerve agents mimics and probe BDHA facilitates spirolactam ring opening due to the phosphorylation process. Thus, the highly fluorescent and colored species developed while probe BDHA is colorless and non-fluorescent due to the intramolecular spirolactam ring. Moreover, probe BDHA can effectively recognize DCP, DCNP, and CEES in the µM range despite many toxic analytes and could be identified based on the response times and quantum yield values. Inexpensive, easily carried paper strips-based test kits were developed for the quick, on-location solid and vapor phase detection of these mustard gas imitating agents (CEES) and nerve gas mimicking agents (DCP and DCNP) without needing expensive equipment or skilled personnel. More remarkably, the test strips\' color and fluorescence can be rapidly restored, exposing them to triethyl amine (TEA) for cyclic use, suggesting a potential application in the real-time identification of chemical warfare agents. To accomplish the on-location application of BDHA, we have experimented with soil samples to find traces of DCP. Therefore, the chromo-fluorogenic probe BDHA is a promising, instantaneous, and on-the-spot monitoring tool for the selective detection of DCP, DCNP, and CEES in the presence of others.

Functional materials that can quickly absorb and degrade mustard gas are essential for chemical warfare emergency response kits. In this study, a fiber membrane with excellent adsorption and catalytic degradation activity was developed by solution blow spinning polystyrene (PS)/polyurethane (PU) and hydrothermal in situ growth of a zirconium-based MOF (MOF-808). The mechanical properties of the PS/PU fibers were improved by adding a trimethylolpropane tris (2-methyl-1-aziridine propionate) (TTMA) cross-linking agent. Moreover, the C═O bonds in TTMA provided abundant growth sites for MOF-808 in the hydrothermal process, thereby greatly increasing the loading capacity. The fiber surface was completely covered with the MOF-808 particles within 24 h. The PS/PU/TTMA/MOF-808 fiber membrane was used for the catalytic degradation of 2-chloroethyl ethyl sulfide (CEES). The degradation efficiency reached 97.7% after 72 h, indicating its great application potential in emergency wiping cloths for mustard gas adsorption and degradation.