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Acute lung injury (ALI) is a severe respiratory disease with a high mortality rate. The integrity of the pulmonary endothelial barrier influences the development and prognosis of ALI. Therefore, it has become an important target for ALI treatment. Extracellular vesicles (EVs) are promising nanotherapeutic agents against ALI. Herein, endothelium‐derived engineered extracellular vesicles (eEVs) that deliver microRNA‐125b‐5p (miRNA‐125b) to lung tissues exerting a protective effect on endothelial barrier integrity are reported. eEVs that are modified with lung microvascular endothelial cell‐targeting peptides (LET) exhibit a prolonged retention time in lung tissues and targeted lung microvascular endothelial cells in vivo and in vitro. To improve the efficacy of the EVs, miRNA‐125b is loaded into EVs. Finally, LET‐EVs‐miRNA‐125b is constructed. The results show that compared to the EVs, miRNA‐125b, and EVs‐miRNA‐125b, LET‐EVs‐miRNA‐125b exhibit the most significant treatment efficacy in ALI. Moreover, LET‐EVs‐miRNA‐125b is found to have an important protective effect on endothelial barrier integrity by inhibiting cell apoptosis, promoting angiogenesis, and protecting intercellular junctions. Sequencing analysis reveals that LET‐EVs‐miRNA‐125b downregulates early growth response‐1 (EGR1) levels, which may be a potential mechanism of action. Taken together, these findings suggest that LET‐EVs‐miRNA‐125b can treat ALI by protecting the endothelial barrier integrity. [ABSTRACT FROM AUTHOR]

Mpox virus (MPXV), the most pathogenic zoonotic orthopoxvirus, caused worldwide concern during the SARS-CoV-2 epidemic. Growing evidence suggests that the MPXV surface protein A29 could be a specific diagnostic marker for immunological detection. In this study, a fully synthetic phage display library was screened, revealing two nanobodies (A1 and H8) that specifically recognize A29. Subsequently, an in vitro affinity maturation strategy based on computer-aided design was proposed by building and docking the A29 and A1 three-dimensional structures. Ligand-receptor binding and molecular dynamics simulations were performed to predict binding modes and key residues. Three mutant antibodies were predicted using the platform, increasing the affinity by approximately 10-fold compared with the parental form. These results will facilitate the application of computers in antibody optimization and reduce the cost of antibody development; moreover, the predicted antibodies provide a reference for establishing an immunological response against MPXV. [ABSTRACT FROM AUTHOR]

Sulfur mustard (SM) is a blister‐producing chemical warfare agent which could lead to a cascade of systemic damage, especially severe acute lung injury. Oxidative stress is considered to be vital processes for the SM toxicity mechanism. We previously proved the therapeutic effect of exosomes derived from bone marrow mesenchymal stromal cells in promoting the repair of alveolar epithelial barrier and inhibiting apoptosis. However, the key functional components in exosomes and the underlying mechanisms have not been fully elaborated. This research shed light on the function of the key components of human umbilical cord mesenchymal stem cell‐derived exosomes (HMSCs‐Ex). We noted that HMSCs‐Ex‐derived miR‐199a‐5p played a vital role in reducing pneumonocyte oxidative stress and apoptosis by reducing reactive oxygen species, lipid peroxidation products and increasing the activities of antioxidant enzymes in BEAS‐2B cells and mouse models after exposure to SM for 24 h. Furthermore, we demonstrated that the overexpression of miR‐199a‐5p in HMSCs‐Ex treatment induced a further decrease of Caveolin1 and the activation of the mRNA and protein level of NRF2, HO1 and NQO1, compared with HMSCs‐Ex administration. In summary, miR‐199a‐5p was one of the key molecules in HMSCs‐Ex that attenuated SM‐associated oxidative stress via regulating CAV1/NRF2 signalling pathway. [ABSTRACT FROM AUTHOR]

Background: Sulfur mustard (SM) is a highly toxic chemical warfare agent that has caused numerous casualties during wars and conflicts in the past century. Specific antidotes or therapeutic strategies are rare due to the complicated mechanism of toxicity, which still awaits elucidation. Clinical data show that acute lung injury (ALI) is responsible for most mortality and morbidity after SM exposure. Extracellular vesicles are natural materials that participate in intercellular communication by delivering various substances and can be modified. In this study, we aim to show that extracellular vesicles derived from human umbilical cord mesenchymal stromal cells (hucMSC-EVs) could exert therapeutic effects on SM-induced ALI, and to explain the underlying mechanism of effects. Methods: MiR-146a-5p contained in hucMSC-EVs may be involved in the process of hucMSC-EVs modulating the inflammatory response to SM-induced ALI. We utilized miR-146a-5p delivered by extracellular vesicles and further modified hucMSCs with a miR-146a-5p mimic or inhibitor to collect miR-146a-5p-overexpressing extracellular vesicles (miR-146a-5p+-EVs) or miR-146a-5p-underexpressing extracellular vesicles (miR-146a-5p−-EVs), respectively. Through in vivo and in vitro experiments, we investigated the mechanism. Results: The effect of miR-146a-5p+-EVs on improving the inflammatory reaction tied to SM injury was better than that of hucMSC-EVs. We demonstrated that miR-146a-5p delivered by hucMSC-EVs targeted TRAF6 to negatively regulate inflammation in SM-induced ALI models in vitro and in vivo. Conclusion: In summary, miR-146a-5p delivered by hucMSC-EVs targeted TRAF6, causing hucMSC-EVs to exert anti-inflammatory effects in SM-induced ALI; thus, hucMSC-EVs treatment may be a promising clinical therapeutic after SM exposure. [ABSTRACT FROM AUTHOR]

Highlights • The probe exhibited good selectivity towards hydrogen polysulfide among other biological species. • The probe can detect hydrogen polysulfide within 10 min. • HQO-PSP has the ability of mitochondrial-targeting. • HQO-PSP can be applied not only at the level of living cells but also to mouse tissues. Abstract Hydrogen polysulfide (H 2 S n) has attracted increasing attention since H 2 S n instead of H 2 S has been shown to be the actual signaling molecule in physiological and pathological processes. Thus, developing accurate and sensitive assays for H 2 S n detection is urgently needed in biological science. In this work, we developed a red emitting mitochondria-targeting fluorescent probe, HQO-PSP, that is capable of tracking H 2 S n. With low cytotoxicity, good selectively and high sensitively, HQO-PSP was able to detect H 2 S n in living cells. Furthermore, we also demonstrated that HQO-PSP could also be successfully applied to recognize H 2 S n in living tissues. [ABSTRACT FROM AUTHOR]

• The probe exhibited good selectivity towards sulfur mustard. • The probe can detect sulfur mustard within 30 min. • A good linear relationship between fluorescence emission intensity and SM concentration. • SM-Flu can be applied not only at the level of living cells but also to whole animals. Sulfur mustard is a potent blister agent and one of the most harmful chemical warfare agents. To explore the toxicokinetics and biodistribution of SM, a reliable detection method for monitoring sulfur mustard would be indispensable. We describe the design, synthesis and application of a selective and sensitive turn-on fluorescent probe for sulfur mustard detection. A good linear relationship between fluorescence emission intensity and SM concentration was observed. The probe, SM-Flu, was applied to the determination and imaging of sulfur mustard in living cells and Aurelia coerulea polyps. With SM-Flu, concentration and time profiles for SM in mouse brain after exposure to SM were first measured. [ABSTRACT FROM AUTHOR]

Context Sulfur mustard (SM), a bifunctional alkylating agent, can react with a variety of biochemical molecules (DNA, RNA, proteins and other cell components) to cause a series of serious health issues or even death. Although a plethora of research has been done, the pathogenesis of SM poisoning has yet to be fully understood due to its high complexity. As a consequence, a specific antidote has not yet been developed and the treatment of SM poisoning remains a medical challenge. In recent years, various biological products and cell transplantation in the treatment of SM poisoning offered a significant clinical treatment progress. By highlighting these and other research studies, we hereby summarize the progress in this field in an effort to provide useful information on the clinical treatment of SM poisoning. Objective This review summarizes the major advances of SM poisoning therapy by means of biological products (peptide and protein drugs, polysaccharides drugs, nucleic acid drugs, etc.), and cell transplantation (e.g., bone marrow, limbal stem cells, mesenchymal stem cells), as well as other relevant biotherapeutic approaches. Method We searched the database PubMed for published domestic and international articles using web based resources for information on histological, immunochemical, ultrastructural, and treatment features of SM-induced manifestations in both animal models and human tissues. To this end, we applied keywords containing mustard gas, chemical warfare, SM, eye, lung and skin. Results and conclusion Our review provides a comprehensive understanding of the advances of available biotherapies in SM poisoning, and its potential for the treatment of SM-induced injuries. Potentially, our review will provide new insights for future research studies in this field. [ABSTRACT FROM AUTHOR]

Abstract Sulfur mustard (SM) is a chemical warfare agent that was applied in a series of military conflicts and still poses a severe threat to civilians and military personnel. Although the cellular and molecular mechanisms of SM toxicity are still not fully understood, oxidative stress has been considered as the initial vital process for damage. Polydatin, the product of resveratrol and glucose, is a promising candidate for the treatment of oxidative stress-related diseases. However, its effects on SM-induced hepatic injury remain unknown. Thus, we investigated the protective effects of polydatin against SM-induced hepatic injury and its possible mechanism. We found that treatment with polydatin remarkably improved the survival rate of mice bear subcutaneously injected with SM. Polydatin decreased the SM-induced increase of serum aminotransferase levels and ameliorated hepatic pathological damage. We also found that indexes of oxidative stress were improved in mouse liver samples and L02 cells. Meanwhile, changes in the Sirtuin family after treatment with SM were explored in mice and cells since polydatin is a potent activator of Sirt1 and Sirt3. Polydatin significantly increased the expression of Sirt1, HO-1, and NQO1; and the nuclear translocation of Nrf2 in mouse liver and L02 cells. Furthermore, we also observed that either Sirt1 or Nrf2 knockdown abolished the protective effect of polydatin. Our data indicated that polydatin could provide protection against SM-induced hepatic injury through the Sirt1/Nrf2 pathway, suggesting that polydatin is a novel potential antidote for sulfur mustard. Highlights • Polydatin could improve the survival rate of SM-treated mice. • Sirt1 was significantly reduced after SM-treatment. • Polydatin protects against SM-induced liver injury via Sirt1/Nrf2. • First correlation between polydatin and a chemical warfare agent [ABSTRACT FROM AUTHOR]

Sulfur mustard is one of the most harmful chemical warfare agents and can induce skin, eye, and lung injuries. However, it is hard for medical stuff to diagnose sulfur mustard poisoning early because of the incubation period after sulfur mustard exposure. Detecting intact sulfur mustard in vivo might be an effective approach for the early diagnosis of sulfur mustard poisoning. A series of fluorescent probes for intact sulfur mustard detection were developed in this study. All of the developed probes could react with sulfur mustard selectivity. Among these probes, SiNIR-SM exhibited an extremely good response rate and a high off/on contrast. To the best of our knowledge, SiNIR-SM is the first near-infrared fluorescent probe for the sulfur mustard detection. Both SiNIR-SM and OxSM-1 were successfully applied to image sulfur mustard in living cells. Using SiNIR-SM, we found that sulfur mustard accumulates in the mitochondria of living cells. This result could provide a new insight for the treatment of sulfur mustard injuries. We also found that SiNIR-SM is suitable for the early diagnostic imaging of sulfur mustard poisoning in SKH-1 mice via the detection of intact sulfur mustard.

Sulfur mustard (SM) is a chemical warfare agent and a terrorism choice that targets various organs and tissues, especially lung tissues. Its toxic effects are tightly associated with oxidative stress. The signaling molecule hydrogen sulfide (H 2 S) protects the lungs against oxidative stress and activates the NF-E2 p45-related factor 2 (Nrf2) pathway. Here, we sought to establish whether endogenous H 2 S plays a role in SM induced lesion in mouse lungs and lung cells and whether endogenous H 2 S plays the role through Nrf2 pathway to protect against SM-induced oxidative damage. Furthermore, we also explored whether activation of Nrf2 by H 2 S involves sulfhydration of Kelch-like ECH-associated protein-1 (Keap1). Using a mouse model of SM-induced lung injury, we demonstrated that SM-induced attenuation of the sulfide concentration was prevented by NaHS. Concomitantly, NaHS attenuates SM-induced oxidative stress. We also found that H 2 S enhanced Nrf2 nuclear translocation, and stimulated expression of Nrf2-targeted downstream protein and mRNA levels. Incubation of the lung cells with NaHS decreased SM-induced ROS production. Furthermore, we also found that H 2 S S-sulfhydrated Keap1, which induced Nrf2 dissociation from Keap1, and enhanced Nrf2 nuclear translocation. Our data indicate that H 2 S is a critical, however, being long neglected signal molecule in SM-induced lung injury.