Cell Biology and Toxicology最新文献

{"title":"The transcriptomic signature of respiratory sensitizers using an alveolar model","authors":"Matthew Gibb, James Y. Liu, Christie M. Sayes","doi":"10.1007/s10565-024-09860-x","DOIUrl":"https://doi.org/10.1007/s10565-024-09860-x","url":null,"abstract":"<p>Environmental contaminants are ubiquitous in the air we breathe and can potentially cause adverse immunological outcomes such as respiratory sensitization, a type of immune-driven allergic response in the lungs. Wood dust, latex, pet dander, oils, fragrances, paints, and glues have all been implicated as possible respiratory sensitizers. With the increased incidence of exposure to chemical mixtures and the rapid production of novel materials, it is paramount that testing regimes accounting for sensitization are incorporated into development cycles. However, no validated assay exists that is universally accepted to measure a substance’s respiratory sensitizing potential. The lungs comprise various cell types and regions where sensitization can occur, with the gas-exchange interface being especially important due to implications for overall lung function. As such, an assay that can mimic the alveolar compartment and assess sensitization would be an important advance for inhalation toxicology. Some such models are under development, but in-depth transcriptomic analyses have yet to be reported. Understanding the transcriptome after sensitizer exposure would greatly advance hazard assessment and sustainability. We tested two known sensitizers (<i>i.e.,</i> isophorone diisocyanate and ethylenediamine) and two known non-sensitizers (<i>i.e.,</i> chlorobenzene and dimethylformamide). RNA sequencing was performed in our in vitro alveolar model, consisting of a 3D co-culture of epithelial, macrophage, and dendritic cells. Sensitizers were readily distinguishable from non-sensitizers by principal component analysis. However, few differentially regulated genes were common across all pair-wise comparisons (<i>i.e.,</i> upregulation of genes <i>SOX9</i>, <i>UACA</i>, <i>CCDC88A</i>, <i>FOSL1</i>, <i>KIF20B</i>). While the model utilized in this study can differentiate the sensitizers from the non-sensitizers tested, further studies will be required to robustly identify critical pathways inducing respiratory sensitization.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3><p>Graphical headlines/headlights</p><ul>\u0000<li>\u0000<p>Pollutants may trigger lung allergies, but no universal method measures respiratory sensitization potential.</p>\u0000</li>\u0000<li>\u0000<p>In vitro systems can detect respiratory sensitizers, aiding in anticipating and reducing the risks of new materials.</p>\u0000</li>\u0000<li>\u0000<p>Sensitizers and non-sensitizers can be distinguished through transcriptome investigation.</p>\u0000</li>\u0000<li>\u0000<p>The sensitizers tested induced cell differentiation and proliferation pathways while inhibiting immune defense and functionality.</p>\u0000</li>\u0000</ul>\u0000","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140559998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Administration of Gas6 attenuates lung fibrosis via inhibition of the epithelial-mesenchymal transition and fibroblast activation","authors":"Ye-Ji Lee, Minsuk Kim, Hee-Sun Kim, Jihee Lee Kang","doi":"10.1007/s10565-024-09858-5","DOIUrl":"https://doi.org/10.1007/s10565-024-09858-5","url":null,"abstract":"<p>The epithelial-mesenchymal transition (EMT) and fibroblast activation are major events in idiopathic pulmonary fibrosis pathogenesis. Here, we investigated whether growth arrest-specific protein 6 (Gas6) plays a protective role in lung fibrosis via suppression of the EMT and fibroblast activation. rGas6 administration inhibited the EMT in isolated mouse ATII cells 14 days post-BLM treatment based on morphologic cellular alterations, changes in mRNA and protein expression profiles of EMT markers, and induction of EMT-activating transcription factors. BLM-induced increases in gene expression of fibroblast activation-related markers and the invasive capacity of primary lung fibroblasts in primary lung fibroblasts were reversed by rGas6 administration. Furthermore, the hydroxyproline content and collagen accumulation in interstitial areas with damaged alveolar structures in lung tissue were reduced by rGas6 administration. Targeting Gas6/Axl signaling events with specific inhibitors of Axl (BGB324), COX-2 (NS-398), EP1/EP2 receptor (AH-6809), or PGD2 DP2 receptor (BAY-u3405) reversed the inhibitory effects of rGas6 on EMT and fibroblast activation. Finally, we confirmed the antifibrotic effects of Gas6 using Gas6^−/− mice. Therefore, Gas6/Axl signaling events play a potential role in inhibition of EMT process and fibroblast activation via COX-2-derived PGE₂ and PGD₂ production, ultimately preventing the development of pulmonary fibrosis.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"34 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140559989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"YTHDC1 promotes the malignant progression of gastric cancer by promoting ROD1 translocation to the nucleus","authors":"Danhong Dong, Jiangpeng Wei, Weidong Wang, Haikun Zhou, Liu Hong, Gang Ji, Xisheng Yang","doi":"10.1007/s10565-024-09859-4","DOIUrl":"https://doi.org/10.1007/s10565-024-09859-4","url":null,"abstract":"<p>RNA-binding proteins (RBPs) make vital impacts on tumor progression and are important potential targets for tumor treatment. Previous studies have shown that RBP regulator of differentiation 1 (ROD1), enriched in the nucleus, is abnormally expressed and functions as a splicing factor in tumors; however, the mechanism underlying its involvement in gastric cancer (GC) is unknown. In this study, ROD1 is found to stimulate GC cell proliferation and metastasis and is related to poor patient prognosis. In vitro experiments showed that ROD1 influences GC proliferation and metastasis through modulating the imbalance of the level of the oncogenic gene OIP5 and the tumor suppressor gene GPD1L. Further studies showed that the N6-methyladenosine (m6A) “reader” protein YTHDC1 can interact with ROD1 and regulate the balance of the expression of the downstream molecules OIP5/GPD1L by promoting the nuclear enrichment of ROD1. Therefore, YTHDC1 stimulates GC development and progression through modulating nuclear enrichment of the splicing factor ROD1.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"30 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140559995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Establishment and characterization of cytochrome P450 1A1 CRISPR/Cas9 Knockout Bovine Foetal Hepatocyte Cell Line (BFH12).","authors":"Silvia Iori, Caterina D'Onofrio, Nihay Laham-Karam, Isidore Mushimiyimana, Lorena Lucatello, Rosa Maria Lopparelli, Maria Elena Gelain, Francesca Capolongo, Marianna Pauletto, Mauro Dacasto, Mery Giantin","doi":"10.1007/s10565-024-09856-7","DOIUrl":"10.1007/s10565-024-09856-7","url":null,"abstract":"<p><p>The cytochrome P450 1A (CYP1A) subfamily of xenobiotic metabolizing enzymes (XMEs) consists of two different isoforms, namely CYP1A1 and CYP1A2, which are highly conserved among species. These two isoenzymes are involved in the biotransformation of many endogenous compounds as well as in the bioactivation of several xenobiotics into carcinogenic derivatives, thereby increasing the risk of tumour development. Cattle (Bos taurus) are one of the most important food-producing animal species, being a significant source of nutrition worldwide. Despite daily exposure to xenobiotics, data on the contribution of CYP1A to bovine hepatic metabolism are still scarce. The CRISPR/Cas9-mediated knockout (KO) is a useful method for generating in vivo and in vitro models for studying xenobiotic biotransformations. In this study, we applied the ribonucleoprotein (RNP)-complex approach to successfully obtain the KO of CYP1A1 in a bovine foetal hepatocyte cell line (BFH12). After clonal expansion and selection, CYP1A1 excision was confirmed at the DNA, mRNA and protein level. Therefore, RNA-seq analysis revealed significant transcriptomic changes associated with cell cycle regulation, proliferation, and detoxification processes as well as on iron, lipid and mitochondrial homeostasis. Altogether, this study successfully generates a new bovine CYP1A1 KO in vitro model, representing a valuable resource for xenobiotic metabolism studies in this important farm animal species.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"40 1","pages":"18"},"PeriodicalIF":6.1,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10963470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140287061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis mechanisms and regulations in cardiovascular diseases in the past, present, and future.","authors":"Wenxi Fang, Saiyang Xie, Wei Deng","doi":"10.1007/s10565-024-09853-w","DOIUrl":"10.1007/s10565-024-09853-w","url":null,"abstract":"<p><p>Cardiovascular diseases (CVDs) are the main diseases that endanger human health, and their risk factors contribute to high morbidity and a high rate of hospitalization. Cell death is the most important pathophysiology in CVDs. As one of the cell death mechanisms, ferroptosis is a new form of regulated cell death (RCD) that broadly participates in CVDs (such as myocardial infarction, heart transplantation, atherosclerosis, heart failure, ischaemia/reperfusion (I/R) injury, atrial fibrillation, cardiomyopathy (radiation-induced cardiomyopathy, diabetes cardiomyopathy, sepsis-induced cardiac injury, doxorubicin-induced cardiac injury, iron overload cardiomyopathy, and hypertrophic cardiomyopathy), and pulmonary arterial hypertension), involving in iron regulation, metabolic mechanism and lipid peroxidation. This article reviews recent research on the mechanism and regulation of ferroptosis and its relationship with the occurrence and treatment of CVDs, aiming to provide new ideas and treatment targets for the clinical diagnosis and treatment of CVDs by clarifying the latest progress in CVDs research.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"40 1","pages":"17"},"PeriodicalIF":6.1,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10955039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140173866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The mitochondrial UPR induced by ATF5 attenuates intervertebral disc degeneration via cooperating with mitophagy.","authors":"Wen-Ning Xu, Huo-Liang Zheng, Run-Ze Yang, Yuan-Fang Sun, Bi-Rong Peng, Chun Liu, Jian Song, Sheng-Dan Jiang, Li-Xin Zhu","doi":"10.1007/s10565-024-09854-9","DOIUrl":"10.1007/s10565-024-09854-9","url":null,"abstract":"<p><p>Intervertebral disc degeneration (IVDD) is an aging disease that results in a low quality of life and heavy socioeconomic burden. The mitochondrial unfolded protein response (UPR^mt) take part in various aging-related diseases. Our research intents to explore the role and underlying mechanism of UPR^mt in IVDD. Nucleus pulposus (NP) cells were exposed to IL-1β and nicotinamide riboside (NR) served as UPR^mt inducer to treat NP cells. Detection of ATP, NAD + and NADH were used to determine the function of mitochondria. MRI, Safranin O-fast green and Immunohistochemical examination were used to determine the degree of IVDD in vivo. In this study, we discovered that UPR^mt was increased markedly in the NP cells of human IVDD tissues than in healthy controls. In vitro, UPR^mt and mitophagy levels were promoted in NP cells treated with IL-1β. Upregulation of UPR^mt by NR and Atf5 overexpression inhibited NP cell apoptosis and further improved mitophagy. Silencing of Pink1 reversed the protective effects of NR and inhibited mitophagy induced by the UPR^mt. In vivo, NR might attenuate the degree of IDD by activating the UPR^mt in rats. In summary, the UPR^mt was involved in IVDD by regulating Pink1-induced mitophagy. Mitophagy induced by the UPR^mt might be a latent treated target for IVDD.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"40 1","pages":"16"},"PeriodicalIF":6.1,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10933207/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140109301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fetal growth restriction exhibits various mTOR signaling in different regions of mouse placentas with altered lipid metabolism.","authors":"Jie Dong, Qian Xu, Chenxi Qian, Lu Wang, Alison DiSciullo, Jun Lei, Hui Lei, Song Yan, Jingjing Wang, Ni Jin, Yujing Xiong, Jianhua Zhang, Irina Burd, Xiaohong Wang","doi":"10.1007/s10565-024-09855-8","DOIUrl":"10.1007/s10565-024-09855-8","url":null,"abstract":"<p><p>Fetal growth restriction (FGR) is a common complication of pregnancy and can have significant impact on obstetric and neonatal outcomes. Increasing evidence has shown that the inhibited mechanistic target of rapamycin (mTOR) signaling in placenta is associated with FGR. However, interpretation of existing research is limited due to inconsistent methodologies and varying understanding of the mechanism by which mTOR activity contributes to FGR. Hereby, we have demonstrated that different anatomic regions of human and mouse placentas exhibited different levels of mTOR activity in normal compared to FGR pregnancies. When using the rapamycin-induced FGR mouse model, we found that placentas of FGR pregnancies exhibited abnormal morphological changes and reduced mTOR activity in the decidual-junctional layer. Using transcriptomics and lipidomics, we revealed that lipid and energy metabolism was significantly disrupted in the placentas of FGR mice. Finally, we demonstrated that maternal physical exercise during gestation in our FGR mouse model was associated with increased fetal and placental weight as well as increased placental mTOR activity and lipid metabolism. Collectively, our data indicate that the inhibited placental mTOR signaling contributes to FGR with altered lipid metabolism in mouse placentas, and maternal exercise could be an effective method to reduce the occurrence of FGR or alleviate the adverse outcomes associated with FGR.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"40 1","pages":"15"},"PeriodicalIF":6.1,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10920423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140048820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNF115 aggravates tumor progression through regulation of CDK10 degradation in thyroid carcinoma.","authors":"Jinxiang Zhu, Longwei Guo, Hao Dai, Zhiwei Zheng, Jinfeng Yan, Junsong Liu, Shaoqiang Zhang, Xiang Li, Xin Sun, Qian Zhao, Chongwen Xu","doi":"10.1007/s10565-024-09845-w","DOIUrl":"10.1007/s10565-024-09845-w","url":null,"abstract":"<p><strong>Background: </strong>RING Finger Protein 115 (RNF115), a notable E3 ligase, is known to modulate tumorigenesis and metastasis. In our investigation, we endeavor to unravel the putative function and inherent mechanism through which RNF115 influences the evolution of thyroid carcinoma (THCA).</p><p><strong>Methods: </strong>We analyzed RNF115 expression in THCA using the Cancer Genome Atlas (TCGA) database. The influence of RNF115 on the progression of THCA was evaluated using both in vitro and in vivo experimental approaches. The protein regulated by RNF115 was identified through bioinformatics analysis, and its biological significance was further explored.</p><p><strong>Results: </strong>In both THCA tissues and cells, RNF115 showed elevated expression levels. Enhanced expression of RNF115 fostered cell proliferation, tumor growth, and the exacerbation of epithelial-mesenchymal transition (EMT) in THCA, while also promoting tumor lung metastasis. Bioinformatics analysis identified cyclin-dependent kinase 10 (CDK10) as a downstream target of RNF115, which was found to be ubiquitinated and degraded by RNF115 in THCA cells. Functionally, overexpression of CDK10 was found to counteract the promotion of malignant phenotype in THCA induced by RNF115. From a mechanistic perspective, RNF115 activated the Raf-1 pathway and enhanced cancer cell cycle progression by degrading CDK10 in THCA cells.</p><p><strong>Conclusion: </strong>RNF115 triggers cell proliferation, EMT, and tumor metastasis by ubiquitinating and degrading CDK10. The regulation of the Raf-1 pathway and cell cycle progression in THCA may be profoundly influenced by this process.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"40 1","pages":"14"},"PeriodicalIF":6.1,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10879231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139905100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nupr1-mediated vascular smooth muscle cell phenotype transformation involved in methamphetamine induces pulmonary hypertension.","authors":"Jie Zhou, Dan Guo, Zhen-Zhen Xu, Jia-Shun Liao, Xiao-Ting Li, Ke Duan, Shi-You Chen, Wei-Bing Xie","doi":"10.1007/s10565-024-09849-6","DOIUrl":"10.1007/s10565-024-09849-6","url":null,"abstract":"<p><strong>Aims: </strong>Nuclear protein 1 (Nupr1) is a multifunctional stress-induced protein involved in the regulation of tumorigenesis, apoptosis, and autophagy. However, its role in pulmonary hypertension (PH) after METH exposure remains unexplored. In this study, we aimed to investigate whether METH can induce PH and describe the role and mechanism of Nupr1 in the development of PH.</p><p><strong>Methods and results: </strong>Mice were made to induce pulmonary hypertension (PH) upon chronic intermittent treatment with METH. Their right ventricular systolic pressure (RVSP) was measured to assess pulmonary artery pressure. Pulmonary artery morphometry was determined by H&E staining and Masson staining. Nupr1 expression and function were detected in human lungs, mice lungs exposed to METH, and cultured pulmonary arterial smooth muscle cells (PASMCs) with METH treatment. Our results showed that chronic intermittent METH treatment successfully induced PH in mice. Nupr1 expression was increased in the cultured PASMCs, pulmonary arterial media from METH-exposed mice, and METH-ingested human specimens compared with control. Elevated Nupr1 expression promoted PASMC phenotype change from contractile to synthetic, which triggered pulmonary artery remodeling and resulted in PH formation. Mechanistically, Nupr1 mediated the opening of store-operated calcium entry (SOCE) by activating the expression of STIM1, thereby promoting Ca²⁺ influx and inducing phenotypic conversion of PASMCs.</p><p><strong>Conclusions: </strong>Nupr1 activation could promote Ca²⁺ influx through STIM1-mediated SOCE opening, which promoted METH-induced pulmonary artery remodeling and led to PH formation. These results suggested that Nupr1 played an important role in METH-induced PH and might be a potential target for METH-related PH therapy.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"40 1","pages":"13"},"PeriodicalIF":6.1,"publicationDate":"2024-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10861617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139721782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repositioning baloxavir marboxil as VISTA agonist that ameliorates experimental asthma.","authors":"Jian-Wen Di, Yi-Xin Wang, Rui-Xue Ma, Zhi-Jie Luo, Wen-Ting Chen, Wan-Mei Liu, Ding-Yi Yuan, Yu-Ying Zhang, Yin-Hao Wu, Cai-Ping Chen, Jun Liu","doi":"10.1007/s10565-024-09852-x","DOIUrl":"10.1007/s10565-024-09852-x","url":null,"abstract":"<p><p>V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA), a novel negative checkpoint regulator, plays an essential role in allergic pulmonary inflammation in mice. Treatment with a VISTA agonistic antibody could significantly improve asthma symptoms. Thus, for allergic asthma treatment, VISTA targeting may be a compelling approach. In this study, we examined the functional mechanism of VISTA in allergic pulmonary inflammation and screened the FDA-approved drugs for VISTA agonists. By using mass cytometry (CyTOF), we found that VISTA deficiency primarily increased lung macrophage infiltration in the OVA-induced asthma model, accompanied by an increased proportion of M1 macrophages (CD11b⁺F4/80⁺CD86⁺) and a decreased proportion of M2 macrophages (CD11b⁺F4/80⁺CD206⁺). Further in vitro studies showed that VISTA deficiency promoted M1 polarization and inhibited M2 polarization of bone marrow-derived macrophages (BMDMs). Importantly, we discovered baloxavir marboxil (BXM) as a VISTA agonist by virtual screening of FDA-approved drugs. The surface plasmon resonance (SPR) assays revealed that BXM (KD = 1.07 µM) as well as its active form, baloxavir acid (BXA) (KD = 0.21 µM), could directly bind to VISTA with high affinity. Notably, treatment with BXM significantly ameliorated asthma symptoms, including less lung inflammation, mucus secretion, and the generation of Th2 cytokines (IL-5, IL-13, and IL-4), which were dramatically attenuated by anti-VISTA monoclonal antibody treatment. BXM administration also reduced the pulmonary infiltration of M1 macrophages and raised M2 macrophages. Collectively, our study indicates that VISTA regulates pulmonary inflammation in allergic asthma by regulating macrophage polarization and baloxavir marboxil, and an old drug might be a new treatment for allergic asthma through targeting VISTA.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"40 1","pages":"12"},"PeriodicalIF":6.1,"publicationDate":"2024-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10858940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139715878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}