Nitrogen mustard (NM) is a vesicant, and the respiratory tract is one of its primary target organs. The recovery following NM exposure is protracted. Despite the existence of numerous theories regarding the toxic effects of NM, but to date, no studies have investigated the global cellular response profiles across distinct phases after NM exposure. Herein, we examined alterations in pulmonary function in mice before and after NM exposure, characterized the biological changes in human bronchial epithelial cells (HBEs) during acute NM exposure and the subsequent post-exposure recovery phase, and further analyzed the impact of p97 deficiency on cell injury.Following acute NM exposure, the expiratory time and total respiratory cycle time were prolonged in mice, whereas the expiratory flow at 50% of tidal volume (EF50) and alveolar volume were reduced. NM rapidly perturbs nucleic acid-associated biological processes within the nucleus, including the cell cycle, chromatin dynamics, mitosis, and RNA processing and splicing, with concomitant upregulation of the expression of relevant proteins. Acute NM exposure for 1 h exerted no effect on total p97 expression level, but promoted the accumulation of p97 in the cytoplasm. In contrast, nuclear p97 expression was increased at 24 h after NM removal. Although p97 deficiency exerted minimal effects on cellular stress responses during the acute exposure phase, it disrupted intracellular material transport, elicited a tendency toward the suppression of nuclear protein expression, and impeded the recovery process after the termination of NM exposure. P97 deficiency primarily repressed the expression of nucleoporins and histones, and inhibited aerobic respiration during the cellular recovery phase.Collectively, these findings suggest that the perturbation of nucleic acid-associated biological processes constitutes the initial and critical event underlying the respiratory toxicity of NM. Furthermore, p97 deficiency impairs material transport, small-molecule metabolism, and mitochondrial function, and prolongs the recovery time in the aftermath of NM exposure.

T-2 toxin is a widely distributed environmental mycotoxin that poses severe neurotoxic risks to humans and animals. Neuroinflammatory responses constitute a key mechanism underlying the neurotoxicity of T-2 toxin. However, its molecular mechanisms for inducing inflammatory responses in the nervous system remain incompletely understood. This study investigated the role of B-cell translocation gene 2 (BTG2) in T-2 toxin-induced microglial activation and evaluated the neuroprotective potential of resveratrol (Res). In vivo experiments demonstrated that exposure to T-2 toxin resulted in spatial learning, memory impairments and locomotor deficits in mice. These behavioral phenotypes were accompanied by neuroinflammation in the hippocampus and cerebral cortex, characterized by microglial activation and the upregulation of BTG2. Res pre-treatment effectively reversed these neurobehavioral deficits and suppressed the neuroinflammatory response. Mechanistic analyses revealed that Res considerably alleviated T-2 toxin-induced TLR4/MyD88/NF-κB pathway activation. In vitro studies using BV-2 microglial cells confirmed these findings. Notably, siRNA-mediated knockdown of BTG2 also abolished TLR4 pathway activation and subsequent cytokine expression induced by T-2 toxin, establishing BTG2 as a critical upstream regulator. Furthermore, RNA sequencing systematically verified that BTG2 regulates the immune response network, specifically targeting the TLR4 cascades. Collectively, these findings provide novel evidence that Res may target the BTG2-regulated TLR4/MyD88/NF-κB signal pathway to exert neuroprotection, providing a promising intervention option for reducing the environmental and health hazards associated with exposure to T-2 toxin.

Objective Mitochondrial dysfunction is the key factor in rotenone-induced neurotoxicity in dopaminergic neurons. This study aimed to investigate the role and potential mechanism of the mitochondrial DNA encoded peptide Humanin (HN) in alleviating rotenone-induced neurotoxicity.Methods Rotenone was added to the cultured PC12 cells to induce neurotoxicity. PC12 cells were preincubated with HN, which has a protective effect. Cell counting kit-8 (CCK-8) was used to evaluate PC12 cell viability. Flow cytometry to detect the content of reactive oxygen species (ROS) in PC12 cells. Western blot analysis was used to detect the expression of superoxide dismutase 2 (SOD2), acetylated SOD (Ac-SOD), sirtuin 3 (SIRT3), nuclear factor erythroid 2-related factor 2 (Nrf2), heme-oxygenase-1 (HO-1), and NAD(P)H:quinone oxidoreductase 1 (NQO1). The corresponding kits were used to measure the NAD+/NADH ratio and SOD content separately.Results HN pretreatment significantly increased PC12 cell survival, reduced ROS formation, and increased the NAD+/NADH ratio. It also increased the expression of SIRT3, Nrf2, HO-1, and NQO1 proteins and decreased the expression of Ac-SOD protein under rotenone exposure. At the same time, it also activated the Nrf2/HO-1 signaling pathway, which depends on HN-mediated SIRT3 activation.Conclusion These results suggest that HN plays a protective role in rotenone-induced neurotoxicity by suppressing oxidative stress and activating the antioxidant response via the Nrf2/HO-1 pathway, which is regulated by SIRT3 in PC12 cells.

Nitrogen mustard (NM) belongs to vesicant agents. Blisters are one of the important characteristics of NM skin damage. It is urgent to further elucidate the mechanism and develop effective countermeasures for the skin damage induced by NM. The endoplasmic reticulum (ER) is an important intracellular organelle, playing an important role in maintaining cellular homeostasis. In this study, we explored the role of endoplasmic reticulum stress (ERS) and the protective effect of asiatic acid (AA) in the HaCaT cells induced by NM. It was found that the key regulatory proteins of ERS, such as glucose regulated protein 78 (GRP78), X-box binding protein 1 (XBP1), inositol requiring enzyme 1 (IRE1), Phospho-IRE1 (pIRE1), and TNF receptor associated factor 2 (TRAF2) were increased respectively in HaCaT cells exposed to NM compared with those of the control group, showing an increasing trend with the increase of NM exposure concentration and exposure time. Additionally, the protein expression of Caspase-3 and the Cleaved-Caspase-3 was also increased by NM in HaCaT cells, resulting in the apoptosis of HaCaT cells. Meanwhile, the content of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) was also increased in HaCaT cells exposed to NM. Further study showed that AA pretreatment could decrease the protein expression of GRP78, XBP1 and IRE1, pIRE1, TRAF2, Caspase-3, and Cleaved-Caspase-3. And moreover, AA also could reduce the content of TNF-α and IL-6. Overall, the present study showed that AA played an important protective effect in HaCaT cells exposed to NM through the inhibition of the ERS-induced apoptosis and inflammatory response.

Rotenone is a natural compound from plants. It is widely used in pesticides because of highly toxic to insects and fish. However, lots of research has reported that rotenone has neurotoxic effects in humans. It is confirmed there is a correlation between rotenone exposure and Parkinson’s disease (PD). Therefore, the role of gut microbiota and related metabolic pathways was investigated in rotenone-induced neurotoxicity. The results showed that the abundance of gut microbiota changed significantly. The differential metabolites were enriched in the nicotinate and nicotinamide metabolism pathways, which had the greatest impact on the entire metabolic system. The contents of acetic acid and butyric acid in intestinal tissues decreased significantly. Additionally, Interleukin-6 (IL-6), Tumor necrosis factor alpha (TNF-α) and vasoactive intestinal peptide (VIP) were significantly up-regulated, while gastrin (GAS) and Ghrelin were significantly down-regulated. Expression of intestinal tight junction protein was significantly reduced. Moreover, nicotinamide adenine dinucleotide (NAD+), a the product of the nicotinate/nicotinamide pathways, decreased significantly. And the expression levels of nicotinamide phosphoribosyl transferase (NAMPT) and Solute Carrier Family 25 Member 51 (SLC25A51) also reduced significantly. Therefore, gut microbiota was influenced obviously in rats exposed to rotenone, leading to a decrease of acetic acid and butyric acid contents, which might in turn affect the change of intestinal barrier permeability and induce inflammatory reactions. Meanwhile, the nicotinate/nicotinamide metabolic pathways might play an important role in rats exposed to rotenone.

Parkinson's disease is a neurodegenerative disorder whose pathogenesis remains incompletely understood.Rotenone exposure is reportedly associated with Parkinson's disease.In addition,disulfidptosis is a newly identified form of cell death.Interestingly,an analysis of the Gene Expression Omnibus Parkinson's disease database indicated that approximately 30 genes that are significantly altered in patients with Parkinson's disease are associated with disulfidptosis.In the present study,using proteomics,a number of important proteins related to disulfidptosis were identified as significantly altered in rotenone-exposed dopaminergic neurons.Further analysis revealed that the formation of abnormal disulfide bonds was also increased in rotenone-exposed dopaminergic neurons.The protein expression of solute carrier family 7 member 11 and amino acid transporter heavy chain SLC3A2 was upregulated in rotenone-exposed dopaminergic neurons,and was correlated with extracellular matrix protein 1 protein expression.These findings indicate that in rotenone-exposed PC12 cells,a cystine influx is triggered,and the conversion of cystine to cysteine is inhibited by a reduction in the oxidized nicotinamide adenine dinucleotide phosphate/reduced nicotinamide adenine dinucleotide phosphate ratio,which leads to cystine accumulation.This excessive accumulation of cystine then promotes the formation of abnormal disulfide bonds in cells,ultimately resulting in disulfidptosis of rotenone-exposed dopaminergic neurons.In this process,the Ras-related C3 botulinum toxin substrate 1/WAVE regulatory complex/actin-related protein 2/3 pathway was markedly activated,which led to the collapse of the cytoskeleton in rotenone-exposed PC12 cells.Together,our findings suggest that rotenone may induce solute carrier family 7 member 11 expression through extracellular matrix protein 1 activation to cause cystine accumulation,which results in disulfidptosis characterized by cytoskeleton collapse.The present results provide new perspectives for research into neurodegenerative diseases.

Nitrogen mustard (NM) causes severe skin injury that is lack of effective and targeted therapies. Vitamin D3 (VD3) emerges as a promising treatment option for NM-caused dermal toxicity; however, the underlying mechanisms are currently unclear. Herein, we identified that NM markedly promoted ferroptosis by measurement of decreased cell viability, glutathione, glutathione peroxidase 4 and solute carrier family 7 member 11 levels, and increased ROS, lipid ROS, iron/Fe2+ and malondialdehyde contents in vitro and in vivo. Ferrostin-1 (Fer-1, a ferroptosis inhibitor) attenuated NM-caused cell death in keratinocytes. Meanwhile, NM significantly inhibited phosphorylation of AKT1 and glycogen synthase kinase 3β (GSK3β) and nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, and increased LINC00707 expression. Furthermore, NM-induced ferroptosis in keratinocytes was abolished by treatment with agonists of Nrf2 (tBHQ) and AKT1 (SC79), the inhibitor of GSK3β (AR-A014418), Nrf2 overexpression or LINC00707 knockdown. Mechanistically, LINC00707 directly bound with the protein kinase domain of AKT1 and suppressed its phosphorylation and activated GSK3β thereby inactivating Nrf2, subsequently inducing ferroptosis and cell death in NM-treated keratinocytes. Moreover, VD3 notably suppressed LINC00707 expression, activated AKT1 and inactivated GSK3β, increased Nrf2 nuclear translocation and inhibited ferroptosis and cytotoxicity induced by NM in vitro and in vivo. The protective effects of VD3 against NM-caused dermal toxicity were blocked by erastin (a ferroptosis inducer), Nrf2 siRNA, LINC00707 overexpression and were enhanced by LINC00707 knockdown and Fer-1 in vitro and in vivo. In conclusion, VD3 ameliorated NM-caused dermal toxicity by inhibiting ferroptosis, which was partially mediated through the LINC00707-AKT1-GSK3β-Nrf2 signaling pathway.

Objective To investigate the mechanism and protective effect of Humanin (HN) on rotenone (Rot)-induced toxic damage for dopamine neurons. Methods The Rot-poisened PC12 cell model was constructed, and the control group, the Rot poisening group, the HN pretreated Rot poisening group, and the HN treatment group were set up. ELISA was used to detect the content of HN inside and outside of Rot-infected cells, CCK-8 assay was used to detect cell viability, and ATP detection kit was used to detect the intracellular ATP content. Dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay was used to detect the level of reactive oxygen species (ROS) in cells. Western blotting was performed to detect the expression level of mitochondrial autophagy regulatory proteins Pink1, Parkin, p62, LC3, mitochondrial biogenesis regulatory protein PGC1α, division/fusion regulatory proteins OPA1, MFN2, DRP1, p-DRP1 and antioxidant stress regulatory proteins Keap1 and Nrf2. HBAD-mcherry-EGFP-LC3 adenovirus transfected cells was used to observed the number of autophagosomes and autophagolysosomes. Results The results showed that the intracellular concentration of HN in PC12 in the Rot poisening group was significantly higher than that in the control group (P < 0.05);Compared with the control group, the Rot poisening group had significantly decreased activity of PC12 cells, decreased ATP content and increased production of ROS. After the poisen of Rot in PC12 cells, the expression of Pink1 and p-Parkin, the ratio of LC3Ⅱ/LC3Ⅰ and the expression of p-DRP1 in mitochondrial fusion protein was increased, while the expression of p62, the expression of mitochondrial biogenesis protein PGC1α, mitochondrial fusion proteins MFN2 and OPA1, and antioxidant stress proteins Keap1 and Nrf2 were decreased (all P < 0.05). The number of autophagosomes and autophagolysosomes in PC12 cells in the Rot poisening group was higher than that in the control group (P < 0.05), and HN pretreatment (20 μmol/L) could significantly improve the changes mentioned above caused by Rot poisening (P < 0.05). Conclusion HN ameliorates Rot-induced toxic damage for dopamine neurons by inhibiting mitophagy and mitochondrial division and promoting mitochondrial biogenesis and fusion, and anti-oxidative stress.

Nitrogen mustard (NM) is a chemotherapeutic agent capable of alkylating nucleophilic proteins and DNA, causing severe cell damage. However, no reports have been on the dynamic changes in proteomics induced by NM. In this study, we established a model of acute exposure to NM for 1 h and a continuous cultured model for 24 h after NM removal (repair stage) using 16HBE cells. The nuclear protein spectrum and nuclear proteins crosslinked with DNA were analyzed, and the function of p97 during NM damage was examined. An hour of NM exposure resulted in severe changes in the nuclear protein spectrum and protein into the cell nucleus, which is mainly involved in nuclear acid-related issues. After 24 h, the return to normal process of the types and amounts of differentially expressed proteins was inhibited by si-p97. The main processes involved in si-p97 intervention were nucleocytoplasmic transport, processing in the endoplasmic reticulum, metabolic abnormalities, and DNA-response; however. An hour of exposure to NM increased DNA-protein crosslinking (DPC), total-H2AX, and p-H2AX. In contrast, si-p97 only further increased or maintained their levels at 24 h yet not at 1 h. The effect of the proteasome inhibitor, MG132, was similar to that of si-p97. The siRNA of DVC1, a partner of p97, also increased the DPC content. Both si-p97 and si-DVC1 increased the cytoplasmic levels of the proteasome (PSMD2). These results suggest acute NM exposure induces severe nuclear protein spectral changes, rapid protein influx into the nucleus, DPC formation, and DNA double-strand breaks. Furthermore, our data indicated that p97 is involved in normal protein spectrum maintenance and DPC removal after NM withdrawal, requiring the participation of DVC1 and the proteasome.

To investigate the role of the liver kinase (LK) B1 protein, an activator of AMP-activated protein kinase (AMPK), in AMPK signaling suppression when exposed to vesicant, a kind of chemical warfare agent. Cultured human bronchial epithelial cells were inflicted with sulfur mustard (SM) analog, 2-chloroethyl ethyl sulfide (CEES) of 0.2-1.0 mM concentration, and cell proliferation, apoptosis, autophagy, and cellular ATP level were analyzed up to 24 h after the exposure. Focusing on LKB1, heat shock protein (HSP) 90, and cell division cycle (CDC) 37 proteins, the protein expression, phosphorylation, and interaction were examined with western blot, immunofluorescence staining, and/or immunoprecipitation. AMPK signaling was found to be inhibited 24 h after being exposed to either sub-cytotoxic (0.5 mM) or cytotoxic (1.0 mM) concentration of CEES based on MTS assay. Consistently, the degradation of the LKB1 protein and its less interaction with the HSP90/CDC37 complex was confirmed. It was found that 1.0, not 0.5 mM CEES also decreased the CDC37 protein, proteasome activity, and cellular ATP content that modulates HSP90 protein conformation. Inhibiting proteasome activity could alternatively activate autophagy. Finally, either 0.5 or 1.0 mM CEES activated HSP70 and autophagy, and the application of an HSP70 inhibitor blocked autophagy and autophagic degradation of the LKB1 protein. In conclusion, we reported here that AMPK signaling inactivation by CEES was a result of LKB1 protein loss via less protein complex formation and enhanced degradation.

Abstract Nitrogen mustard (NM) can alkylate nucleophilic proteins and DNA, causing severe cell damage. However, there are no reports on NM-induced proteomics dynamic changes. In this study, nuclear and cytoplasmic proteins of 16HBE cell were separated and the components and amounts were detected and analyzed. The amount of DNA protein cross-linking (DPC) and the function of p97 were also explored. One-hour-NM-exposure caused a tremendous number of proteins entered into the nucleus and DPC formation. As repair progressed, proteins exited. Although the protein influx at 1 h was delayed by si-p97 intervention, it continued to 24 h after NM withdrawal. In the early damage, the affected pathways mainly included spliceosome, ribosome biogenesis in eukaryotes, and mRNA surveillance, which switched to protein processing in endoplasmic reticulum and energy production in presumed repair stage. Si-p97 aggravated ferroptosis, cysteine and methionine metabolism at beginning of the damage, followed by downward ranking the transcription related pathways at 24 h. NM caused DPC and H2AX increases at 1 h. Si-p97 suppressed them at 1 h and extended the increase time to 24 h. MG132 effected similar to si-p97. Si-p97 and si-DVC1 increased the cytoplasmic level of proteasome (PSMD2). Si-DVC1 also increased the DPC content. These results suggest that NM caused a severe and rapid protein influx and crosslink in the nucleus in the early stage of injury, followed by the formation of secondary double-strand breaks. P97 was involved in the clearance of proteins in nucleus and DPC for repair, which required the participation of DVC1 and proteasome.

Using sulfur mustard analog 2-chloroethyl ethyl sulfide (CEES), we established an in vitro model by poisoning cultured immortalized human bronchial epithelial cells. Nile Red staining revealed lipids accumulated 24 h after a toxic dose of CEES (0.9 mM). Lipidomics analysis showed most of the increased lipids were triglycerides (TGs), and the increase in TGs was further confirmed using a Triglyceride-Glo (TM) Assay kit. Protein and mRNA levels of DGAT1, an important TG biogenesis enzyme, were increased following 0.4 mM CEES exposure. Under higher dose CEES (0.9 mM) exposure, protein and mRNA levels of PPAR gamma coactivator-1alpha (PGC-1alpha), a well-known transcription factor that regulates fatty acid oxidation, were decreased. Finally, application with DGAT1 inhibitor A 922500 or PGC1alpha agonist ZLN005 was able to block the CEES-induced TGs increase. Overall, our dissection of CEES-induced TGs accumulation provides new insight into energy metabolism dysfunction upon vesicant exposure.

MOTS-c is a 16-amino acid mitochondrial-derived peptide reported to be involved in regulating energy metabolism. However, few studies have reported the role of MOTS-c on neuron degeneration. In this study, it was aimed to explore the action of MOTS-c in rotenone-induced dopaminergic neurotoxicity. In an in vitro study, it was observed that rotenone could influence the expression and localization of MOTS-c significantly in PC12 cells, with more MOTS-c translocating into the nucleus from mitochondria. Further study showed that the translocation of MOTS-c from the mitochondria into the nucleus could directly interact with Nrf2 to regulate HO-1 and NQO1 expression in PC12 cells exposed to rotenone, which had been suggested to be involved in the antioxidant defense system. In vivo and in vitro experiments demonstrated that exogenous MOTS-c pretreatment could protect PC12 cells and rats from mitochondrial dysfunction and oxidative stress induced by rotenone. Moreover, MOTS-c pretreatment significantly decreased the loss of TH, PSD95, and SYP protein expression in the striatum of rats exposed to rotenone. In addition, MOTS-c pretreatment could clearly alleviate the downregulated expression of Nrf2, HO-1, and NQO1, as well as the upregulated Keap1 protein expression in the striatum of rotenone-treated rats. Taken together, these findings suggested that MOTS-c could directly interact with Nrf2 to activate the Nrf2/HO-1/NQO1 signal pathway to defend the antioxidant system to prevent dopaminergic neurons from rotenone-induced oxidative stress and neurotoxicity in vitro and in vivo.

: Sulfur mustard (SM), a classic chemical weapon in the vesicant category, can induce severe damage, for which the therapy is still limited even today. Laboratory work is essential in unveiling toxicological effects and developing medical countermeasures. Sulfur mustard analog 2-chloroethyl ethyl sulfide (CEES), is employed in the lab for less toxicity. However, due to its similar characteristics to SM (being oily, hydrophobic, and volatile), the manipulation of CEES still needs special attention to avoid personnel injury and laboratory pollution. Here, to clear the chemical safety concerns in the laboratory study of CEES, the working procedure and experimental data are summarized, which might help educate new researchers to be skilled and professional.

TDCPP is a flame retardant which has nervous and reproductive toxicity. Although there is a close association between nervous and reproductive system, the exact toxic mechanism of TDCPP in these systems is still seldom, especially in a genome scale. In this study, we explored the transcriptomic landscape of TDCPP in PC12 and GC2 cells using RNAseq method. A total of 465 co-differential expressed genes were found. These genes were mainly enriched in extra-cellular matrix, cell adhesion, cell cycle arrest, oxidoreductase activity GO terms, and PI3K/AKT, focal adhesion, ECM-receptor interaction KEGG pathways. Hub genes (ANXA1, COL27A1, GAS6, GNB4 and THBS1) were extracted using STRING and confirmed by qPCR experiment. Vimentin, HSPA5 and Caspase3 were proved to be responsible to TDCPP in GC2 and PC12 cells. Knockdown assay in PC12 cells showed that these hub genes could also affect the protein expression of vimentin, HSPA5 and Caspase3. In summary, TDCPP might exert its toxic effect through disturbing focal adhesion, ECM-receptor interaction and PI3K/Akt pathways. One of the mechanisms could be influence on the cytoskeleton (vimentin), ER stress (HSPA5) and apoptosis (Caspase3). The sequence data in this study might be a useful resource for future TDCPP related researches.

军事医学综合演练是军医大学组织学员进行的军事医学卫勤教学演练，是军事医学实践教学的一种重要形式，通常在学员完成医学基础理论、临床医学和军事医学课程及卫生勤务基本理论之后，按教学计划由学校教务处统一组织实施的实践教学活动。在卫勤想定的引导下，军事医学综合演练通过战备等级转换、救治机构开进、展开、撤收，模拟伤病员分类、救治和后送，在近似实战条件下，组织不同作战样式或特殊条件下的卫勤保障活动。军事医学综合演练能够综合训练参训学员的临床医学和军事医学的基本知识、基本理论和基本技能，促使学员掌握战术卫勤组织指挥工作的内容和程序、战伤伤员的分类、救治技术方法，全面提升学员的军事医学综合素质。军事医学综合演练是军事医学训练的高级阶段，不仅是军医大学培养高素质军事医学人才的需要，也是做好新时期军事斗争卫勤准备的有效途径之一[1-3]。

防化医学是军事预防医学的主干课程之一,主要教授军医大学学员化学武器相关损伤的防护救治及平时化学事件的医学处置能力.该课程不仅涉及化学武器损伤的基础与临床问题,还学习相关医学防护技能.防化医学实验课教学是防化医学教学的重要组成部分,在教学实践探索中,综合运用案例教学、实践技能培训、虚拟仿真、军事医学综合演练及自主实验设计等手段构建复合式教学模式,旨在提高学员对防化医学相关理论和实践技能的掌握,培养其科研思维和动手能力.通过运用复合教学模式,增强了学员综合实践能力,为今后岗位任职和完成多样化保障任务打下良好基础.

AbstractNitrogen mustard (NM) causes severe skin injury with an obvious inflammatory response, which is lack of effective and targeted therapies. Vitamin D3 (VD3) has excellent anti‐inflammatory properties and is considered as a potential candidate for the treatment of NM‐induced dermal toxicity; however, the underlying mechanisms are currently unclear. Cyclooxygenase‐2 (COX2; a widely used marker of skin inflammation) plays a key role in NM‐induced cutaneous inflammation. Herein, we initially confirmed that NM markedly promoted COX2 expression in vitro and in vivo. NM also increased NOD‐like receptor family pyrin domain containing 3 (NLRP3) expression, caspase‐1 activity, and interleukin‐1β (IL‐1β) release. Notably, treatment with a caspase‐1 inhibitor (zYVAD‐fmk), NLRP3 inhibitor (MCC950), and NLRP3 or caspase‐1 siRNA attenuated NM‐induced NLRP3 inflammasome activation, with subsequent suppression of COX2 expression and IL‐1β release in keratinocytes. Meanwhile, NM increased mitochondrial reactive oxygen species (mtROS) and decreased manganese superoxide dismutase 2 (SOD2) and sirtuin 3 (SIRT3) activities. Mito‐TEMPO (a mtROS scavenger) ameliorated NM‐caused NLRP3 inflammasome activation in keratinocytes. Moreover, VD3 improved SIRT3 and SOD2 activities, decreased mtROS contents, inactivated the NLRP3 inflammasome, and attenuated cutaneous inflammation induced by NM in vitro and in vivo. The beneficial activity of VD3 against NM‐triggered cutaneous inflammation was enhanced by the inhibitors of IL‐1, mtROS, NLRP3, caspase‐1, and NLRP3 or caspase‐1 siRNAs, which was abolished in SIRT3 inhibitor or SIRT3 siRNA‐treated keratinocytes and skins from SIRT3−/− mice. In conclusion, VD3 ameliorated NM‐induced cutaneous inflammation by inactivating the NLRP3 inflammasome, which was partially mediated through the SIRT3–SOD2–mtROS signaling pathway.

Respiratory system injury is the main cause of mortality for nitrogen mustard (NM)-induced damage. Previous studies indicate that reactive oxygen species (ROS) participates in NM-mediated respiratory injuries, but the detailed mechanism is not quite clear. Human bronchial epithelial cell lines 16HBE and BEAS-2B were treated with HN2, a type of NM. In detail, it was shown that HN2 treatment induced impaired cell viability, excessive mitochondrial ROS production and enhanced cellular apoptosis in bronchial epithelial cells. Moreover, impaired Sirt3/SOD2 axis was observed upon HN2 treatment, with decreased Sirt3 and increased acetylated SOD2 expression levels. Sirt3 overexpression partially ameliorated HN2-induced cell injury. Meanwhile, vitamin D3 treatment partially attenuated HN2-induced apoptosis and improved the mitochondrial functions upon HN2 intervention. In addition, HN2 exposure decreased VDR expression, thus inhibiting the Nrf2 phosphorylation and Sirt3 activation. Inhibition of Nrf2 or Sirt3 could decrease the protective effects of vitamin D3 and enhance mitochondrial ROS production via modulating mitochondrial redox balance. In conclusion, impaired VDR/Nrf2/Sirt3 axis contributed to NM-induced apoptosis, while vitamin D3 supplementation provides protective effects via the activation of VDR and the improvement of mitochondrial functions. This study provides novel mechanism and strategy for NM exposure-induced pulmonary injuries.

化学、生物、放射和核(CBRN)威胁可能造成大规模伤亡,是战场防御的重点内容.CBRN武器医学防护学是军队医学院校学员的必修课程.该文介绍了野战演练中防化医学课程设立的以防护姿态通过污染区、操作防化装备、化学攻击后的现场救援和化学污染伤员早期救治4个模块的训练内容,以及将各模块整合到全功能性演习中的实施过程;讨论了在野外军事医学综合演习过程中模块化设计的思路和学员借此训练应建立的防化医学核心意识.模块化训练可为CBRN防御医学野战演练的有效实施提供新的借鉴.