{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T02:49:39Z","timestamp":1785293379645,"version":"3.55.0"},"reference-count":52,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T00:00:00Z","timestamp":1737676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NIAID","award":["AI118228"],"award-info":[{"award-number":["AI118228"]}]},{"name":"Texas Tech University Health Sciences Center El Paso","award":["AI118228"],"award-info":[{"award-number":["AI118228"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Anthrax represents a disease resulting from infection by toxin-secreting bacteria, Bacillus anthracis. This research aimed to identify new therapeutic targets to combat anthrax. We performed assays to assess cell viability, apoptosis, glycogen consumption, and compound uptake and release in hepatocytes and cardiomyocytes responding to anthrax toxins. Microarray analysis was carried out to identify the genes potentially involved in toxin-induced toxicity. Knockdown experiments were performed to validate the contributions of the identified genes. Our study showed that anthrax edema toxin (EdTx) and lethal toxin (LeTx) induced lethal damage in mouse liver and heart, respectively. Microarray assays showed that 218 genes were potentially involved in EdTx-mediated toxicity, and 18 genes were potentially associated with LeTx-mediated toxicity. Among these genes, the knockdown of Rgs1, Hcar2, Fosl2, Hcar2, Cxcl2, and Cxcl3 protected primary hepatocytes from EdTx-induced cytotoxicity. Plasminogen activator inhibitor 1 (PAI-1)-encoding Serpine1 constituted the most significantly upregulated gene in response to LeTx treatment in mouse liver. PAI-1 knockout mouse models had a higher tolerance to LeTx compared with wild-type counterparts, suggesting that PAI-1 is essential for LeTx-induced toxicity and might represent a therapeutic target in LeTx-induced tissue damage. These results provide potential therapeutic targets for combating anthrax-toxin-induced liver and heart damage.<\/jats:p>","DOI":"10.3390\/toxins17020054","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T08:48:23Z","timestamp":1737708503000},"page":"54","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification of Potential Therapeutic Targets Against Anthrax-Toxin-Induced Liver and Heart Damage"],"prefix":"10.3390","volume":"17","author":[{"given":"Lihong","family":"Wu","sequence":"first","affiliation":[{"name":"Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanping","family":"Chen","sequence":"additional","affiliation":[{"name":"Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8070-6116","authenticated-orcid":false,"given":"Yongyong","family":"Yan","sequence":"additional","affiliation":[{"name":"Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Wang","sequence":"additional","affiliation":[{"name":"Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia D.","family":"Guy","sequence":"additional","affiliation":[{"name":"Liver and GI Pathology Section, Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Carney","sequence":"additional","affiliation":[{"name":"Liver and GI Pathology Section, Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla L.","family":"Moreno","sequence":"additional","affiliation":[{"name":"Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anaisa","family":"Quintanilla-Arteaga","sequence":"additional","affiliation":[{"name":"L. Frederick Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Monsivais","sequence":"additional","affiliation":[{"name":"Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhichao","family":"Zheng","sequence":"additional","affiliation":[{"name":"Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingtao","family":"Zeng","sequence":"additional","affiliation":[{"name":"Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA"},{"name":"L. Frederick Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"20","DOI":"10.12998\/wjcc.v3.i1.20","article-title":"Anthrax: A disease of biowarfare and public health importance","volume":"3","author":"Goel","year":"2015","journal-title":"World J. Clin. Cases"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Makurumidze, R., Gombe, N.T., Magure, T., and Tshimanga, M. (2021). Investigation of an anthrax outbreak in Makoni District, Zimbabwe. BMC Public Health, 21.","DOI":"10.1186\/s12889-021-10275-0"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6590","DOI":"10.1038\/s41467-021-26854-z","article-title":"Multiple stages of evolutionary change in anthrax toxin receptor expression in humans","volume":"12","author":"Choate","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/s41378-021-00242-5","article-title":"The electrochemical detection of bioterrorism agents: A review of the detection, diagnostics, and implementation of sensors in biosafety programs for Class A bioweapons","volume":"7","author":"Varty","year":"2021","journal-title":"Microsyst. Nanoeng."},{"key":"ref_5","first-page":"842843","article-title":"Factors Affecting the Competency of Nursing Students Regarding Bioterrorism","volume":"50","author":"Lee","year":"2021","journal-title":"Iran. J. Public Health"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1556\/1886.2020.00008","article-title":"Review: The risk of contracting anthrax from spore-contaminated soil\u2014A military medical perspective","volume":"10","author":"Finke","year":"2020","journal-title":"Eur. J. Microbiol. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.tim.2014.02.012","article-title":"Anthrax lethal and edema toxins in anthrax pathogenesis","volume":"22","author":"Liu","year":"2014","journal-title":"Trends Microbiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1164\/rccm.201102-0209CI","article-title":"Anthrax infection","volume":"184","author":"Sweeney","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Merritt, C., Chun, E.M., Fattah, R.J., Silva, L.M., Ma, Q.Q., Moayeri, M., Paliga, D., Neumann, S., Heumann, R., and Leppla, S.H. (2021). Imaging of anthrax intoxication in mice reveals shared and individual functions of surface receptors CMG-2 and TEM-8 in cellular toxin entry. J. Biol. Chem., 298.","DOI":"10.1101\/2021.01.22.427304"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Yang, N.J., Neel, D.V., Deng, L., Heyang, M., Kennedy-Curran, A., Tong, V.S., Park, J.M., and Chiu, I.M. (2021). Nociceptive Sensory Neurons Mediate Inflammation Induced by Bacillus anthracis Edema Toxin. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.642373"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1002\/pro.169","article-title":"Insights into the anthrax lethal factor-substrate inter-action and selectivity using docking and molecular dynamics simulations","volume":"18","author":"Dalkas","year":"2009","journal-title":"Protein Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1126\/science.280.5364.734","article-title":"Proteolytic Inactivation of MAP-Kinase-Kinase by Anthrax Lethal Factor","volume":"280","author":"Duesbery","year":"1998","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1006\/bbrc.1998.9040","article-title":"Anthrax lethal factor cleaves the N-terminus of MAPKKs and induces tyrosine\/threonine phosphorylation of MAPKs in cultured macrophages","volume":"248","author":"Vitale","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Tournier, J.-N., and Rougeaux, C. (2020). Anthrax Toxin Detection: From In Vivo Studies to Diagnostic Applications. Microorganisms, 8.","DOI":"10.3390\/microorganisms8081103"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"15730","DOI":"10.1074\/jbc.M113.538587","article-title":"Targeted silencing of anthrax toxin receptors protects against anthrax toxins","volume":"289","author":"Navarro","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"15583","DOI":"10.1073\/pnas.1010145107","article-title":"Heterodimeric integrin complexes containing \u03b21-integrin promote internalization and lethality of anthrax toxin","volume":"107","author":"Martchenko","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1111\/j.1462-5822.2008.01226.x","article-title":"Functional interactions between anthrax toxin receptors and the WNT signalling protein LRP6","volume":"10","author":"Abrami","year":"2008","journal-title":"Cell. Microbiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1016\/j.cell.2005.12.045","article-title":"The LDL receptor-related protein LRP6 mediates internalization and lethality of anthrax toxin","volume":"124","author":"Wei","year":"2006","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/nature12510","article-title":"Key tissue targets responsible for anthrax-toxin-induced lethality","volume":"501","author":"Liu","year":"2013","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.micpath.2004.10.007","article-title":"Mouse model characterisation for anthrax vaccine development: Comparison of one inbred and one outbred mouse strain","volume":"38","author":"Waters","year":"2005","journal-title":"Microb. Pathog."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e00264-17","DOI":"10.1128\/IAI.00264-17","article-title":"Bacillus anthracis Edema Toxin Increases Fractional Free Water and Sodium Reabsorption in an Isolated Perfused Rat Kidney Model","volume":"85","author":"Jaswal","year":"2017","journal-title":"Infect. Immun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"721","DOI":"10.3390\/toxins3060721","article-title":"Hemodynamic effects of anthrax toxins in the rabbit model and the cardiac pathology induced by lethal toxin","volume":"3","author":"Lawrence","year":"2011","journal-title":"Toxins"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"H1592","DOI":"10.1152\/ajpheart.00851.2014","article-title":"Bacillus anthracis edema but not lethal toxin challenge in rats is associated with depressed myocardial function in hearts isolated and tested in a Langendorff system","volume":"308","author":"Li","year":"2015","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"H1108","DOI":"10.1152\/ajpheart.01128.2010","article-title":"Anthrax edema toxin has cAMP-mediated stimulatory effects and high-dose lethal toxin has depressant effects in an isolated perfused rat heart model","volume":"300","author":"Hicks","year":"2011","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Watson, L.E., Kuo, S.-R., Katki, K., Dang, T., Park, S.K., Dostal, D.E., Tang, W.-J., Leppla, S.H., and Frankel, A.E. (2007). Anthrax toxins induce shock in rats by depressed cardiac ventricular function. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0000466"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1128\/IAI.05947-11","article-title":"Anthrax edema toxin impairs clearance in mice","volume":"80","author":"Sastalla","year":"2012","journal-title":"Infect. Immun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1016\/S0002-9440(10)61218-7","article-title":"Bacillus anthracis edema toxin causes extensive tissue lesions and rapid lethality in mice","volume":"167","author":"Firoved","year":"2005","journal-title":"Am. J. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.micpath.2006.05.001","article-title":"Murine macrophage transcriptional and functional responses to Bacillus anthracis edema toxin","volume":"41","author":"Comer","year":"2006","journal-title":"Microb. Pathog."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1128\/IAI.73.3.1879-1885.2005","article-title":"GeneChip analyses of global transcriptional responses of murine macrophages to the lethal toxin of Bacillus anthracis","volume":"73","author":"Comer","year":"2005","journal-title":"Infect. Immun."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Chauncey, K.M., Lopez, M.C., Sidhu, G., E Szarowicz, S., Baker, H.V., Quinn, C., and Southwick, F.S. (2012). Bacillus anthracis\u2019 lethal toxin induces broad transcriptional responses in human peripheral monocytes. BMC Immunol., 13.","DOI":"10.1186\/1471-2172-13-33"},{"key":"ref_31","first-page":"217","article-title":"Using blood glucose data as an indicator for epidemic disease outbreaks","volume":"116","author":"Arsand","year":"2005","journal-title":"Stud. Health Technol. Inform."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3121","DOI":"10.2337\/db11-0571","article-title":"Control of blood glucose in the absence of hepatic glucose production during prolonged fasting in mice: Induction of renal and intestinal gluconeogenesis by glucagon","volume":"60","author":"Mutel","year":"2011","journal-title":"Diabetes"},{"key":"ref_33","first-page":"240","article-title":"Investigation and management of the hepatic glycogen storage diseases","volume":"4","author":"Bhattacharya","year":"2015","journal-title":"Transl. Pediatr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"44231","DOI":"10.1074\/jbc.R400011200","article-title":"A novel role for glucose 6-phosphatase in the small intestine in the control of glucose homeostasis","volume":"279","author":"Mithieux","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"567","DOI":"10.5483\/BMBRep.2013.46.12.248","article-title":"CREB and FoxO1: Two transcription factors for the regulation of hepatic gluconeogenesis","volume":"46","author":"Oh","year":"2013","journal-title":"BMB Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4535","DOI":"10.1038\/ncomms5535","article-title":"The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver","volume":"5","author":"Patel","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7557","DOI":"10.4049\/jimmunol.176.12.7557","article-title":"Bacillus anthracis toxins inhibit human neutrophil NADPH oxidase activity","volume":"176","author":"Crawford","year":"2006","journal-title":"J. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4709","DOI":"10.1242\/jcs.02598","article-title":"Receptor-activity-modifying proteins are required for forward trafficking of the calcium-sensing receptor to the plasma membrane","volume":"118","author":"Bouschet","year":"2005","journal-title":"J. Cell Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"18571","DOI":"10.1074\/jbc.REV119.007060","article-title":"Regulator of G-protein signaling (RGS) proteins as drug targets: Progress and future potentials","volume":"294","author":"Wilkinson","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/S0165-6147(99)01369-3","article-title":"Emerging roles for RGS proteins in cell signalling","volume":"20","author":"Hepler","year":"1999","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"19955","DOI":"10.1074\/jbc.M312560200","article-title":"Differential inhibition of adenylyl cyclase isoforms and soluble guanylyl cyclase by purine and pyrimidine nucleotides","volume":"279","author":"Gille","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1165\/rcmb.2008-0091TR","article-title":"Cyclic AMP: Master regulator of innate immune cell function","volume":"39","author":"Serezani","year":"2008","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1007\/s00508-017-1193-z","article-title":"Multiple thrombophilia mutations as a possible cause of premature myocardial infarction","volume":"129","author":"Linhart","year":"2017","journal-title":"Wien. Klin. Wochenschr."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1055\/s-0036-1586228","article-title":"The Role of Plasminogen Activator Inhibitor Type-1 in Fibrosis","volume":"43","author":"Flevaris","year":"2016","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_45","unstructured":"Heiman, M., Gupta, S., Lewandowska, M., Shapiro, A.D., Adam, M.P., Feldman, J., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., and Amemiya, A. (1993). Complete Plasminogen Activator Inhibitor 1 Deficiency, University of Washington. GeneReviews\u00ae."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1165\/rcmb.2016-0184OC","article-title":"Plasminogen Activator Inhibitor-1 Is Critical in Alcohol-Enhanced Acute Lung Injury in Mice","volume":"57","author":"Poole","year":"2017","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Rahman, F.A., and Krause, M.P. (2020). PAI-1, the Plasminogen System, and Skeletal Muscle. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197066"},{"key":"ref_48","unstructured":"Zeng, M., and Ar\u00e9valo, M.T. (2019). RNA Interference-Based Therapeutic Against Anthrax. (10,479,998 B2), U.S. Patent."},{"key":"ref_49","unstructured":"Zeng, M., and Wu, L. (2024). Treatment Strategies Against Anthrax by Interfering Critical Host Factors. (11,946,047 B2), U.S. Patent."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/978-1-62703-321-3_24","article-title":"Isolation of mouse hepatocytes","volume":"987","author":"Edwards","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_51","first-page":"203","article-title":"Bioterrorism and its aftermath: Dealing individually and organizationally with the emotional reactions to an anthrax attack","volume":"7","author":"Sugden","year":"2005","journal-title":"Int. J. Emerg. Ment. Health"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1089\/scd.2013.0485","article-title":"Hepatocyte-like cells derived from human amniotic epithelial cells can be encapsulated without loss of viability or function in vitro","volume":"23","author":"Vaghjiani","year":"2014","journal-title":"Stem Cells Dev."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/17\/2\/54\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:35:31Z","timestamp":1759919731000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/17\/2\/54"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,24]]},"references-count":52,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["toxins17020054"],"URL":"https:\/\/doi.org\/10.3390\/toxins17020054","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,24]]}}}