Acetylcholinesterase (AChE) is a crucial hydrolytic enzyme in the central nervous system, responsible for the rapid degradation of the neurotransmitter acetylcholine (ACh) in the synaptic cleft, thereby maintaining the balance between neuronal excitation and inhibition. AChE is not only the primary target of neurotoxic agents and organophosphorus pesticides but its aberrant activity is also closely associated with various neurodegenerative diseases such as Alzheimer’s disease (AD) and myasthenia gravis. The efficient and rapid discovery and screening of AChE inhibitors hold urgent and significant value for chemical toxin detection, toxicological research, and drug development for neurodegenerative diseases. Addressing the limitations of existing methods, such as low biocompatibility, low detection throughput, relative operational complexity, and high cost, this study innovatively utilizes a genetically encoded biosensor to construct a stable cell line co-expressing the ACh probe and AChE, establishing a novel high-throughput screening method for AChE inhibitors. The results demonstrate that this method achieved to detect AChE inhibitors at micromole level. This method eliminates the need for purified enzymes and toxic chemical reagents (e.g., DTNB in Ellman’s assay), significantly reduces cost (by approximately two orders of magnitude), and offers a simplified, rapid, and high-throughput compatible workflow for applications in neurotoxin detection and neurotherapeutic drug discovery.

Abstract Acute lung injury (ALI) remains a devastating respiratory syndrome, with high mortality and limited therapeutic options. Herein, we report the rational design of a lung epithelial cell membrane-camouflaged full-API nanodrug (FAND) that integrates three bioactive components─bioactive trace element strontium ions (Sr2+), essential coenzyme nicotinamide adenine dinucleotide (NAD+), and FDA-approved anti-inflammatory drug dexamethasone (DEX)─into a supramolecular nanoassembly (DSN FAND@LM) with 100 wt % active pharmaceutical ingredient (API) content. Within this architecture, Sr2+ functions as a pivotal coordination hub, bridging DEX and NAD+ to achieve an ultrahigh NAD+ loading of ∼66.5%, the highest reported to date for NAD+-based nanotherapeutics. The engineered lung epithelial membrane imparts an intrinsic inflammation-homing capability, enabling precise accumulation at injured pulmonary sites. Synergistic therapeutic actions are realized through Sr2+-mediated regulation of apoptosis-associated signaling, NAD+-driven restoration of mitochondrial bioenergetics and suppression of NF-κB activation, and DEX-induced attenuation of oxidative stress. Both in vitro and in vivo studies demonstrate pronounced suppression of inflammatory cascades and enhanced lung epithelial regeneration, culminating in the accelerated repair of injured alveolar tissue. This work establishes a paradigm for FAND that codeliver Sr2+ and NAD+ for targeted, multimodal therapy of ALI and highlights a broadly translatable platform for metal ion-enabled nanotherapeutics.

This study reveals that phospholipase A2 (PLA2), normally stable and nontoxic, can be activated specifically within the alveolar environment to induce rapid, "electric shock-like" lethality, akin to chemical toxins, while also exhibiting extreme toxicity comparable to that of biological toxins, and functioning as a potential "time bomb" in the body. When exacerbated inflammation impairs the pulmonary barrier, PLA2 from the circulation can penetrate into the lungs. Once activated in the alveolar space, it rapidly hydrolyzes pulmonary surfactant phospholipids, causing a drastic decline in surface tension (>30%). This leads to alveolar overdistension, instantaneous respiratory failure, and asphyxiation-an acute mortality effect strikingly similar to that observed in sepsis and severe pulmonary diseases. PLA2 penetration and lethality are more pronounced in aged animals. Based on these findings, a combination therapy comprising phospholipase (dioleoylphosphatidylserine) and an inhibitor (varespladib) was developed, which significantly improved survival rates from 0% to over 90% in mice with sepsis, acute lung injury, and PLA2 poisoning. This study provides critical theoretical foundations and intervention strategies for the clinical treatment of related diseases.

The treatment of pulmonary diseases via nucleic acid drugs faces major challenges in targeting specificity and transfection efficiency. While messenger RNA (mRNA) therapeutics hold great potential, their clinical translation requires advanced delivery systems. In this study, inspired by first-principles thinking-deconstructing the mRNA delivery process to its fundamental physicochemical requirements-a simplified lipid system for lungtargeted mRNA delivery was constructed, using the cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) for lung targeting, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000) for enhancing biosafety via steric hindrance and alanine-derived carbon quantum dots (Ala-CQDs) for further enhancing transfection efficiency. Comprehensive safety evaluations confirmed that DSPE-PEG2000 effectively reduced DOTAP-induced cytotoxicity, hemolysis, coagulation dysfunction, and organ damage. Mechanistic studies revealed that Ala-CQDs enhance lung-targeting and transfection efficiency through formation of a lung-tropic protein corona and promotion of endolysosomal escape. Compared with the reported lung-selective organ-targeting lipid nanoparticle (Lung-SORT LNP), the streamlined delivery system-retaining only functionally essential components-not only yielded an approximately 40-fold increase in lung-targeted transfection efficiency but also exhibited markedly improved biocompatibility and reduced toxicity. The system enabled the co-loading of matrix metalloproteinase 13 (MMP13) mRNA and the tyrosine kinase inhibitor nintedanib (Nin) to formulate the nanomedicine mMMP13@Lipo(Nin)/Ala-CQDs. As a combination regimen for pulmonary fibrosis, it proved effective in promoting collagen degradation, restoring lung function, and mitigating alveolar damage. Collectively, this work establishes a streamlined yet potent and biosafe lipid system, providing a novel strategy for mRNA-based therapy for pulmonary diseases.

Vascular calcification is hallmark of cardiovascular disease, which has a high morbidity and mortality. A growing body of evidence suggests that vascular calcification has been linked to particulate matter (PM2.5) exposure. However, the molecular mechanism of how PM2.5 promotes vascular calcification remains unclear. This study demonstrated that PM2.5 exposure promoted calcium phosphate deposition, accompanied by autophagy activation in calcifying vascular cells. Moreover, PM2.5 treatment upregulated autophagy-related proteins and aggravated calcium nodule formation in calcifying vascular cells. Bioinformatic prediction combined with dual-luciferase reporter assays verified that miR-26a-5p directly targeted the 3’UTR of ULK1. PM2.5 exposure markedly reduced endogenous miR-26a-5p abundance, which relieved transcriptional inhibition of ULK1 and elevated autophagy levels. Furthermore, PM2.5 exposure accelerated vascular calcification in Apoe-/- mice, whereas 3-MA (an autophagy inhibitor) significantly alleviated the promoting effect of PM2.5. Our study revealed a key mechanism that underlies PM2.5 exposure promoted vascular calcification, a process in which miR-26a-5p initiates ULK1-independent autophagy and plays a critical regulatory role. Taken together, these findings provide novel insights insights into the association between PM2.5 exposure and vascular calcification both in vitro and in vivo, and provides a theoretical basis for PM2.5-induced harmful health effects.

Paclitaxel (PTX) kills tumor cells by stabilizing microtubules to induce apoptosis, but its efficacy is limited by resistance mediated by the anti-apoptotic protein survivin. Targeted inhibition of survivin with siRNA could synergistically enhance PTX-induced apoptosis; however, nucleic acid-based therapeutics, such as siRNA, exhibit high instability and susceptibility to degradation, making their efficacy highly dependent on specialized delivery systems. Thus, co-delivery systems for PTX and siRNA are critical to achieving synergistic antitumor activity. Natural products present several advantages, including wide availability, high biocompatibility, and multi-target synergistic effects, offering promising approaches for constructing a co-delivery system. In this study, a co-delivery system integrating siRNA and PTX based on natural products was developed. Ginsenoside Rg3 (Rg3) not only serves as the structural backbone but also enhances tumor-targeting capability and inhibits tumor cell migration. The edible cationic polymer chitooligosaccharide (COS) efficiently encapsulates siRNA, ensuring safe and efficient delivery. This co-delivery system based on natural synergy enables multi-level cooperation: Rg3 mediates targeted transport, PTX triggers apoptosis, and COS-assisted siRNA silences survivin, thereby ensuring precise targeting and promoting complete tumor apoptosis, highlighting a promising strategy for the application of natural products in cancer therapy.

BACKGROUND:Pulmonary fibrosis (PF) is a progressive and fatal lung disorder, and emerging evidence suggests that dysregulation of peroxisome proliferator-activated receptor gamma (PPARγ) plays a critical role in its pathogenesis. However, high-throughput screening (HTS) models for identifying fibrogenic chemicals targeting PPARγ remain underdeveloped. This study aimed to establish a reliable HTS cellular model using a PPARγ-responsive luciferase reporter system to rapidly identify chemicals that induce PF via PPARγ dysregulation. METHODS:Hub genes associated with PF were identified through bioinformatics analysis. A stable HTS cellular model was constructed using a lentiviral vector carrying a luciferase reporter gene under the control of PPARγ-responsive elements. The model was validated using RT-qPCR and luciferase assays. To evaluate its accuracy, four known PF-inducing chemicals and ten non-PF chemicals were tested. Furthermore, to evaluate the model's predictive capability for compounds with uncharacterized PF risk, seven anti-cancer compounds were screened. Molecular docking (MOE) and surface plasmon resonance (SPR) were employed to confirm interactions between the identified chemicals and PPARγ. RESULTS:PPARγ was identified as the key hub gene linked to PF. The PPARγ-responsive cellular model exhibited significantly elevated PPARγ mRNA levels and luciferase activity compared to controls. PF-inducing chemicals suppressed luciferase activity, whereas non-PF chemicals had no effect. Notably, screening of anti-cancer compounds revealde a subset that markedly suppressed PPARγ activity. Molecular docking and SPR analyses demonstrated concentration-dependent binding affinities between PF-inducing chemicals and PPARγ. CONCLUSION:This study developed a high-throughput luciferase-based PPARγ-responsive cellular model to screen chemicals that may contribute to PF through the inhibition of PPARγ activity. The model demonstrates potential as a useful tool for preliminary chemical evaluation. These results suggest a possible role of PPARγ-mediated mechanisms in the development of PF. This work may provide a foundational framework for future efforts in hazard screening and drug discovery aimed at mitigating the effects of PF.

Pneumonia is a severe lower respiratory tract infection. This study demonstrates that phospholipase A2 (PLA2), a potential biomarker for pneumonia, contributes to alveoli damage by hydrolyzing pulmonary surfactant phospholipids. This process impairs gas exchange and generates hemolytic phospholipids that disrupt cellular membranes, exacerbating pulmonary injury. Experimental evidence demonstrates that PLA2 inhibitors significantly alleviate cellular damage in lipopolysaccharide (LPS)-induced pulmonary inflammation. These findings reveal a key mechanistic role of PLA2 in pneumonia pathogenesis and suggest novel therapeutic strategies. The results may provide more effective clinical interventions and guide further research in related fields.

BACKGROUND:Astrocytes play a crucial role in Alzheimer's disease (AD) pathogenesis, contributing to inflammation, amyloid plaque formation, and disease progression, making them promising therapeutic targets. Despite extensive research, the mechanisms underlying astrocytic dysfunction in AD and their modulation by phytochemicals remain incompletely understood, representing a critical gap in current knowledge. PURPOSE:This review aims to elucidate the pathological mechanisms involving astrocytes in AD and evaluate the therapeutic potential of phytochemicals in modulating astrocytic activity. METHODS:We systematically analysed recent studies on astrocytic activation, target receptors, and signalling pathways in AD and their regulation by phytochemicals. The studies were identified through searches of databases including PubMed, Web of Science, ScienceDirect, and Google Scholar. RESULTS:Our findings reveal that abnormal activation of astrocytic receptors and downstream signaling pathways, such as RAGE/NF-κB, ERK/c-fos/NFATc1, AKT/Nrf2/NF-κB, and PI3K/Akt/GSK-3β, disrupt immune homeostasis in AD models. Phytochemicals, including tanshinone IIA, honokiol, aucubin, cornuside, luteolin, naringenin, daphnetin, and gelsemine, show promising effects in delaying AD progression. These effects are mediated through multiple mechanisms, such as inhibiting pro-inflammatory pathways, enhancing anti-inflammatory responses, promoting Aβ clearance, stimulating synaptogenesis, regulating neurotrophic factors, and reducing oxidative stress. These findings highlight the pivotal role of astrocytes in AD pathophysiology and the potential of phytochemicals to modulate astrocytic dysfunction. CONCLUSIONS:By providing a comprehensive overview of astrocytic mechanisms and therapeutic interventions, this review offers a theoretical foundation for developing phytochemical-based strategies in AD therapy and underscores the need for further preclinical and clinical investigations to translate these findings into practical treatments.

Paraquat (PQ), a total contact herbicide, triggers progressive pulmonary fibrosis and multiorgan failure. This toxicity occurs via DNA damage-induced mitochondrial dysfunction and dysregulated extracellular matrix (ECM) remodeling, highlighting the urgent need for novel therapeutic strategies. This study systematically investigated monocytic cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling in PQ-associated fibrotic lung pathology, focusing on its mechanistic involvement in innate immune regulation. Analysis of the single-cell dataset derived from lung tissue of PQ-poisoned patient revealed significant activation of the TGF-β signaling pathway in fibroblasts and marked hyperactivation of the cGAS-STING pathway in monocytes. Cell co-culture assays confirmed that PQ treatment activated the cGAS-STING pathway in monocytes co-cultured with fibroblasts. Consequently, transforming growth factor-β1 (TGF-β1) expression was upregulated, which stimulated fibroblast activation. The pharmacological cGAS antagonist G150 demonstrated significant attenuation of PQ-triggered cGAS-STING pathway in monocytes and downregulated TGF-β1 expression, thereby preventing fibroblast activation in co-culture systems. Similarly, the mouse-specific cGAS inhibitor RU.521 effectively reduced collagen deposition and fibrosis severity while also improving survival rates in PQ-treated mice. Additionally, RU.521 suppressed pulmonary cGAS activity and reduced levels of downstream cGAS-STING pathway proteins. In conclusion, pharmacological targeting of monocyte-driven cGAS-STING pathway emerges as a promising strategy against PQ-associated fibrotic lung disease.

BACKGROUND:Acute hypobaric hypoxia-induced brain injury has been a challenge in the health management of mountaineers; therefore, new neuroprotective agents are urgently required. Meldonium, a well-known cardioprotective drug, has been reported to have neuroprotective effects. However, the relevant mechanisms have not been elucidated. We hypothesized that meldonium may play a potentially novel role in hypobaric hypoxia cerebral injury. METHODS:We initially evaluated the neuroprotection efficacy of meldonium against acute hypoxia in mice and primary hippocampal neurons. The potential molecular targets of meldonium were screened using drug-target binding Huprot™ microarray chip and mass spectrometry analyses after which they were validated with surface plasmon resonance (SPR), molecular docking, and pull-down assay. The functional effects of such binding were explored through gene knockdown and overexpression. RESULTS:The study clearly shows that pretreatment with meldonium rapidly attenuates neuronal pathological damage, cerebral blood flow changes, and mitochondrial damage and its cascade response to oxidative stress injury, thereby improving survival rates in mice brain and primary hippocampal neurons, revealing the remarkable pharmacological efficacy of meldonium in acute high-altitude brain injury. On the one hand, we confirmed that meldonium directly interacts with phosphoglycerate kinase 1 (PGK1) to promote its activity, which improved glycolysis and pyruvate metabolism to promote ATP production. On the other hand, meldonium also ameliorates mitochondrial damage by PGK1 translocating to mitochondria under acute hypoxia to regulate the activity of TNF receptor-associated protein 1 (TRAP1) molecular chaperones. CONCLUSION:These results further explain the mechanism of meldonium as an energy optimizer and provide a strategy for preventing acute hypobaric hypoxia brain injury at high altitudes.

Tumor-associated macrophages (TAMs) are closely related to the progression of glioblastoma multiform (GBM) and its development of therapeutic resistance to conventional chemotherapy. TAM-targeted therapy combined with conventional chemotherapy has emerged as a promising strategy to combat GBM. However, the presence of the blood-brain barrier (BBB) severely limits the therapeutic efficacy. Meanwhile, the lack of ability to distinguish different targeted cells also poses a challenge for precise therapy. Herein, we propose a cathepsin B (CTSB)-responsive programmed brain-targeted delivery system (D&R-HM-MCA) for simultaneous TAM-targeted and GBM-targeted delivery. D&R-HM-MCA could cross the BBB via low density lipoprotein receptor-associated protein 1 (LRP1)-mediated transcytosis. Upon reaching the GBM site, the outer angiopep-2 modification could be detached from D&R-HM-MCA via cleavage of the CTSB-responsive peptide, which could circumvent abluminal LRP1-mediated efflux. The exposed p-aminophenyl-alpha-d-mannopyranoside (MAN) modification could further recognize glucose transporter-1 (GLUT1) on GBM and macrophage mannose receptor (MMR) on TAMs. D&R-HM-MCA could achieve chemotherapeutic killing of GBM and simultaneously induce TAM polarization from anti-inflammatory M2 phenotype to pro-inflammatory M1 phenotype, thus resensitizing the chemotherapeutic response and improving anti-GBM immune response. This CTSB-responsive brain-targeted delivery system not only can improve brain delivery efficiency, but also can enable the combination of chemo-immunotherapy against GBM. The effectiveness of this strategy may provide thinking for designing more functional brain-targeted delivery systems and more effective therapeutic regimens.

Background: Idiopathic pulmonary fibrosis (IPF) is a lung disease characterized by a dry cough and progressive dyspnea. Its pathogenesis involves complex interactions between cellular and molecular mechanisms although effective treatment options remain limited. This study explored the role of transient receptor potential ankyrin 1(TRPA1) channels in regulating M2 polarization of macrophages in the progression of IPF, which may provide new ideas for potential therapeutic targets.MethodsI: n this study, we established a pulmonary fibrosis model in C57BL/6J mice using bleomycin aerosol and evaluated the anti-fibrotic effects of TRPA1 inhibitor HC-030031. Fibrosis severity was assessed via behavioral tests, lung histology, and staining (Masson's trichrome, H&E). We investigated TRPA1 and fibrotic markers through Western blot, immunofluorescence, and immunohistochemistry, and analyzed macrophage polarization and TGF-β1/Smad2 pathway activation. Additionally, THP-1 cell responses to bleomycin and HC-030031 were studied in vitro, examining TRPA1 expression and macrophage polarization via RT-qPCR and Western blot.Findings: In our research, bleomycin-induced pulmonary fibrosis in mice significantly upregulated TRPA1 expression, which correlated with lung function impairment and reduced survival. Treatment with a TRPA1 inhibitor mitigated these effects, reducing fibrotic markers α-SMA, Vimentin, and Collagen I, and preserving E-cadherin expression, indicating less collagen deposition and epithelial damage. Furthermore, TRPA1 inhibition corrected the abnormal M2 macrophage polarization seen in bleomycin-induced fibrosis, as shown by flow cytometry and ELISA, and decreased Smad2 phosphorylation in the TGF-β1-Smad2 pathway. These findings suggest TRPA1 inhibition plays a protective role in lung fibrosis by modulating macrophage polarization and fibrotic marker expression.Interpretation: Our study highlights TRPA1 channels as pivotal in IPF, linking their inhibition to decreased pro-fibrotic markers, M2 macrophage polarization, and collagen deposition, offering a novel therapeutic approach for pulmonary fibrosis management.Funding: This study was supported by the National Natural Science Foundation of China [Grant numbers 82273665].Declaration of Interest: The authors have declared that no competing interest exists.Ethical Approval: Experiments involving animals were conducted in accordance with national legislation and approved by the Institutional Animal Care and Use Committee (IACUC number: IACUC- DWZX- 2023 - 579, Laboratory Animal Center of the Academy of Military Medical Science, Beijing, China).

Idiopathic pulmonary fibrosis (IPF) poses significant challenges due to limited treatment options despite its complex pathogenesis involving cellular and molecular mechanisms. This study investigated the role of transient receptor potential ankyrin 1 (TRPA1) channels in regulating M2 macrophage polarization in IPF progression, potentially offering novel therapeutic targets. Using a bleomycin-induced pulmonary fibrosis model in C57BL/6J mice, we assessed the therapeutic potential of the TRPA1 inhibitor HC-030031. TRPA1 upregulation was observed in fibrotic lungs, correlating with worsened lung function and reduced survival. TRPA1 inhibition mitigated fibrosis severity, evidenced by decreased collagen deposition and restored lung tissue stiffness. Furthermore, TRPA1 blockade reversed aberrant M2 macrophage polarization induced by bleomycin, associated with reduced Smad2 phosphorylation in the TGF-β1-Smad2 pathway. In vitro studies with THP-1 cells treated with bleomycin and HC-030031 corroborated these findings, highlighting TRPA1's involvement in fibrotic modulation and macrophage polarization control. Overall, targeting TRPA1 channels presents promising therapeutic potential in managing pulmonary fibrosis by reducing pro-fibrotic marker expression, inhibiting M2 macrophage polarization, and diminishing collagen deposition. This study sheds light on a novel avenue for therapeutic intervention in IPF, addressing a critical need in the management of this challenging disease.

Abstract Background Stroke is a globally dangerous disease capable of causing irreversible neuronal damage with limited therapeutic options. Meldonium, an inhibitor of carnitine-dependent metabolism, is considered an anti-ischemic drug. However, the mechanisms through which meldonium improves ischemic injury and its potential to protect neurons remain largely unknown. Methods A rat model with middle cerebral artery occlusion (MCAO) was used to investigate meldonium’s neuroprotective efficacy in vivo. Infarct volume, neurological deficit score, histopathology, neuronal apoptosis, motor function, morphological alteration and antioxidant capacity were explored via 2,3,5-Triphenyltetrazolium chloride staining, Longa scoring method, hematoxylin and eosin staining, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay, rotarod test, transmission electron microscopy and Oxidative stress index related kit. A primary rat hippocampal neuron model subjected to oxygen–glucose deprivation reperfusion was used to study meldonium’s protective ability in vitro. Neuronal viability, mitochondrial membrane potential, mitochondrial morphology, respiratory function, ATP production, and its potential mechanism were assayed by MTT cell proliferation and cytotoxicity assay kit, cell-permeant MitoTracker® probes, mitochondrial stress, real-time ATP rate and western blotting. Results Meldonium markedly reduced the infarct size, improved neurological function and motor ability, and inhibited neuronal apoptosis in vivo. Meldonium enhanced the morphology, antioxidant capacity, and ATP production of mitochondria and inhibited the opening of the mitochondrial permeability transition pore in the cerebral cortex and hippocampus during cerebral ischemia–reperfusion injury (CIRI) in rats. Additionally, meldonium improved the damaged fusion process and respiratory function of neuronal mitochondria in vitro. Further investigation revealed that meldonium activated the Akt/GSK-3β signaling pathway to inhibit mitochondria-dependent neuronal apoptosis. Conclusion Our study demonstrated that meldonium shows a neuroprotective function during CIRI by preserving the mitochondrial function, thus prevented neurons from apoptosis.

Skin damage caused by chemical corrosion is currently one of the common skin diseases and poisoning symptoms, with nitrogen mustard compounds causing the most persistent and severe damage. These chemicals penetrate the top layer of the skin, enter the dermis, and cause DNA damage, oxidative stress, and inflammation. However, to date, no effective drug treatment has been found. Even the potential antidotes could not effectively penetrate the top layer of the skin to exert their effects due to the skin barrier. To address this problem, an innovative transdermal drug delivery strategy based on aspirin microneedles was proposed. The classic medicine aspirin was first discovered not only to reduce inflammation and oxidative stress but also to promote DNA repair and reduce DNA damage. The aspirin microneedles directly delivered the drug to the damaged area, released aspirin through the skin barrier, and exhibited good biocompatibility. These findings indicate that aspirin microneedles have great potential for promoting wound healing and broad application prospects.

Sulfur mustard (2,2′-dichloroethylsulfide; SM) is a bifunctional alkylating agent that can easily penetrate skin and cause persistent pain and damage. Effective biological dressings are required to treat wounds caused or poisoned by SM. Though the use of SM is regulated under the Chemical Weapons Convention, it is still a threat during wars and terrorist attacks. Herein, we present a photothermal-enhanced detoxification microneedles array (MNA) encapsulated with ZnIn2S4@UiO-66-NH2 (ZnInS/UIO) catalysts for the treatment of 2-chloroethyl ethyl sulfide (CEES, SM analog)-poisoned wounds under simulated sunlight (SSL) irradiation. Due to the excellent photothermal detoxification capability possessed by ZnInS/UIO, the conversion rate of CEES can be significantly increased under SSL exposure. When encased in a polyvinyl alcohol (PVA) MNA and piercing into the skin, ZnInS/UIO catalysts can be released quickly from MNA for detoxification. After applying the resultant ZnInS/UIO-MNA to the CEES-poisoned wound bed, acceleration of the wound healing process and a reduced inflammatory response can be confirmed. In conclusion, ZnInS/UIO-MNA has encouraging potential as a first-aid dressing for CEES-poisoned wound healing in battlefields and injuries related to acts of terrorism.

Emerging and recurrent infectious diseases caused by human coronaviruses (HCoVs) continue to pose a significant threat to global public health security. In light of this ongoing threat, the development of a broad-spectrum drug to combat HCoVs is an urgently priority. Herein, we report a series of anti-pan-coronavirus ssDNA aptamers screened using Systematic Evolution of Ligands by Exponential Enrichment (SELEX). These aptamers have nanomolar affinity with the nucleocapsid protein (NP) of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and also show excellent binding efficiency to the N proteins of both SARS, MERS, HCoV-OC43 and -NL63 with affinity KD values of 1.31 to 135.36 nM. Such aptamer-based therapeutics exhibited potent antiviral activity against both the authentic SARS-CoV-2 prototype strain and the Omicron variant (BA.5) with EC50 values at 2.00 nM and 41.08 nM, respectively. The protein docking analysis also evidenced that these aptamers exhibit strong affinities for N proteins of pan-coronavirus and other HCoVs (−229E and -HKU1). In conclusion, we have identified six aptamers with a high pan-coronavirus antiviral activity, which could potentially serve as an effective strategy for preventing infections by unknown coronaviruses and addressing the ongoing global health threat.

The Multi-Threat Medical Countermeasure (MTMC) technique is crucial for developing common biochemical signaling pathways, molecular mediators, and cellular processes. This study revealed that the Nod-like receptor 3 (NLRP3) inflammasome pathway may be a significant contributor to the cytotoxicity induced by various organophosphorus pesticides (OPPs). The study demonstrated that exposure to six different types of OPPs (paraoxon, dichlorvos, fenthion, dipterex, dibrom, and dimethoate) led to significant cytotoxicity in BV2 cells, which was accompanied by increased expression of NLRP3 inflammasome complexes (NLRP3, ASC, Caspase-1) and downstream inflammatory cytokines (IL-1β, IL-18), in which the order of cytotoxicity was dichlorvos > dipterex > dibrom > paraoxon > fenthion > dimethoate, based on the IC50 values of 274, 410, 551, 585, 2,158, and 1,527,566 μM, respectively. The findings suggest that targeting the NLRP3 inflammasome pathway could be a potential approach for developing broad-spectrum antitoxic drugs to combat multi-OPPs-induced toxicity. Moreover, inhibition of NLRP3 efficiently protected the cells against cytotoxicity induced by these six OPPs, and the expression of NLRP3, ASC, Caspase-1, IL-1β, and IL-18 decreased accordingly. The order of NLRP3 affinity for OPPs was dimethoate > paraoxon > dichlorvos > dibrom > (fenthion and dipterex) based on K D values of 89.8, 325, 1,460, and 2,690 μM, respectively. Furthermore, the common molecular mechanism of NLRP3-OPPs was clarified by the presence of toxicity effector groups (benzene ring, nitrogen/oxygen-containing functional group); =O, -O-, or =S (active) groups; and combination residues (Gly271, Asp272). This finding provided valuable insights into exploring the common mechanisms of multiple threats and developing effective therapeutic strategies to prevent OPPs poisoning.