{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:13:07Z","timestamp":1785420787138,"version":"3.56.0"},"reference-count":38,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,24]],"date-time":"2026-05-24T00:00:00Z","timestamp":1779580800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32273084"],"award-info":[{"award-number":["32273084"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32573446"],"award-info":[{"award-number":["32573446"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["32273084"],"award-info":[{"award-number":["32273084"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["32573446"],"award-info":[{"award-number":["32573446"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Foreign Expert Project","doi-asserted-by":"publisher","award":["H20250517"],"award-info":[{"award-number":["H20250517"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009377","name":"Postgraduate Scientific Research Innovation Project of Hunan Province","doi-asserted-by":"publisher","award":["CX20240647"],"award-info":[{"award-number":["CX20240647"]}],"id":[{"id":"10.13039\/100009377","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Veterinary Sciences"],"abstract":"<jats:p>T-2 toxin is widely present in agricultural products and poses a significant neurotoxicity threat. Betulinic acid (BA), a natural triterpenoid, exhibits strong antioxidant and anti-inflammatory properties. However, its protective role against T-2 toxin-induced neuroinflammation remains poorly understood. This study aimed to elucidate the mechanisms underlying T-2 toxin-induced neurotoxicity and evaluate the therapeutic potential of BA. Our results demonstrated that T-2 toxin (1 mg\/kg\/bw) exposure caused significant pathological damage in the hippocampus and cerebral cortex. T-2 toxin also induced marked oxidative stress, reflected by elevated reactive oxygen species (ROS) accumulation. At the inflammatory level, T-2 toxin upregulated the mRNA expression of pro-inflammatory cytokines (Interleukin-1 beta (IL-1\u03b2), Interleukin-6 (IL-6)) and altered anti-inflammatory IL-10 expression. In addition, T-2 toxin exhibited strong binding affinity for the tight junction proteins Occludin and Claudin-1 (docking energies of \u22124.41 and \u22125.53 kcal\/mol, respectively), and molecular dynamics simulations confirmed stable protein\u2013ligand interactions. At the molecular level, T-2 toxin suppressed Nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression, increased Kelch-like ECH-associated protein 1 (Keap1) expression, and activated the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway. Furthermore, molecular docking analysis revealed that BA displayed strong binding affinity to proteins associated with the blood\u2013brain barrier and the Nrf2\/NLRP3 signaling pathway. Collectively, these findings indicate that BA mitigates T-2 toxin-induced neuroinflammation through regulating the Nrf2\/NLRP3 signaling pathway in mice. Not only do these results clarify a key mechanism of T-2 toxin-induced central nervous system injury, but they also highlight BA as a promising candidate for developing interventions targeting mycotoxin-related neurological disorders.<\/jats:p>","DOI":"10.3390\/vetsci13060509","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T01:45:08Z","timestamp":1779673508000},"page":"509","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Betulinic Acid Ameliorates T-2 Toxin-Induced Neuroinflammation by Suppressing Oxidative Stress via Regulating Nrf2\/NLRP3 Axis"],"prefix":"10.3390","volume":"13","author":[{"given":"Jiao","family":"Wu","sequence":"first","affiliation":[{"name":"Hunan Engineering Research Center of Livestock and Poultry Health Care, College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyi","family":"Ding","sequence":"additional","affiliation":[{"name":"Hunan Engineering Research Center of Livestock and Poultry Health Care, College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayu","family":"He","sequence":"additional","affiliation":[{"name":"Hunan Engineering Research Center of Livestock and Poultry Health Care, College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoping","family":"Ou","sequence":"additional","affiliation":[{"name":"Hunan Engineering Research Center of Livestock and Poultry Health Care, College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziming","family":"Wang","sequence":"additional","affiliation":[{"name":"Hunan Engineering Research Center of Livestock and Poultry Health Care, College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyu","family":"Ba","sequence":"additional","affiliation":[{"name":"Hunan Engineering Research Center of Livestock and Poultry Health Care, College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanwei","family":"Li","sequence":"additional","affiliation":[{"name":"Hunan Engineering Research Center of Livestock and Poultry Health Care, College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunqiu","family":"Yan","sequence":"additional","affiliation":[{"name":"Hunan Engineering Research Center of Livestock and Poultry Health Care, College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China"},{"name":"Hunan Xinwufeng Co., Ltd., Changsha 410005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaming","family":"Wang","sequence":"additional","affiliation":[{"name":"Hunan Xinwufeng Co., Ltd., Changsha 410005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jine","family":"Yi","sequence":"additional","affiliation":[{"name":"Hunan Engineering Research Center of Livestock and Poultry Health Care, College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Life Sciences and Medical Technologies, Hainan Medical University, Hainan Academy of Medical Sciences, Haikou 571199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Xu, C., Oliveri Conti, G., Tang, S., Shen, J., and Dai, C. (2026). T-2 Toxin Neurotoxicity: Molecular Mechanisms and Emerging Chemoprotective Strategies. Antioxidants, 15.","DOI":"10.20944\/preprints202602.0182.v1"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"He, W., Zhu, Z., Xu, J., Huang, C., Wang, J., Wang, Q., Zhai, X., and Yang, J. (2025). Integrated Cytotoxicity and Metabolomics Analysis Reveals Cell-Type-Specific Responses to Co-Exposure of T-2 and HT-2 Toxins. Toxins, 17.","DOI":"10.3390\/toxins17080381"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Sun, T., Zhang, Q., Li, M., Tang, S., and Dai, C. (2022). T-2 Toxin Induces Apoptotic Cell Death and Protective Autophagy in Mouse Microglia BV2 Cells. J. Fungi, 8.","DOI":"10.3390\/jof8080761"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"249","DOI":"10.5487\/TR.2018.34.3.249","article-title":"Role of Glutathione Redox System on the T-2 Toxin Tolerance of Pheasant (Phasianus colchicus)","volume":"34","author":"Fernye","year":"2018","journal-title":"Toxicol. Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Gonkowski, S., Gaj\u0119cka, M., and Makowska, K. (2020). Mycotoxins and the Enteric Nervous System. Toxins, 12.","DOI":"10.3390\/toxins12070461"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ku\u0107-Szymanek, A., Kubik-Machura, D., Ko\u015bcielecka, K., M\u0119cik-Kronenberg, T., and Radko, L. (2025). Neurotoxicological Effects of Some Mycotoxins on Humans Health and Methods of Neuroprotection. Toxins, 17.","DOI":"10.3390\/toxins17010024"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Paes, A.S., Koga, R.d.C.R., Sales, P.F., Santos Almeida, H.K., Teixeira, T.A.C.C., and Carvalho, J.C.T. (2023). Phytocompounds from Amazonian Plant Species against Acute Kidney Injury: Potential Nephroprotective Effects. Molecules, 28.","DOI":"10.20944\/preprints202306.1277.v1"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Chen, J., Huang, Z., Cao, X., Chen, X., Zou, T., and You, J. (2022). Plant-Derived Polyphenols as Nrf2 Activators to Counteract Oxidative Stress and Intestinal Toxicity Induced by Deoxynivalenol in Swine: An Emerging Research Direction. Antioxidants, 11.","DOI":"10.3390\/antiox11122379"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.aninu.2023.12.001","article-title":"Effective Protective Agents against the Organ Toxicity of T-2 Toxin and Corresponding Detoxification Mechanisms: A Narrative Review","volume":"16","author":"Wang","year":"2024","journal-title":"Anim. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e23833","DOI":"10.1016\/j.heliyon.2023.e23833","article-title":"Betulinic Acid Arrests Cell Cycle at G2\/M Phase by up-Regulating Metallothionein 1G Inhibiting Proliferation of Colon Cancer Cells","volume":"10","author":"Wang","year":"2024","journal-title":"Heliyon"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"117169","DOI":"10.1016\/j.ecoenv.2024.117169","article-title":"T-2 Toxin Triggers Lipid Metabolism Disorder and Oxidative Stress in Liver of Ducks","volume":"286","author":"An","year":"2024","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3041","DOI":"10.1007\/s00204-019-02577-5","article-title":"T-2 Toxin Neurotoxicity: Role of Oxidative Stress and Mitochondrial Dysfunction","volume":"93","author":"Dai","year":"2019","journal-title":"Arch. Toxicol."},{"key":"ref_13","first-page":"939786","article-title":"The Role of the Innate Immune System in Alzheimer\u2019s Disease and Frontotemporal Lobar Degeneration: An Eye on Microglia","volume":"2013","author":"Ridolfi","year":"2013","journal-title":"J. Immunol. Res."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Taroncher, M., Franco-Campos, F., Rodr\u00edguez-Carrasco, Y., and Ruiz, M.-J. (2025). T-2 Toxin-Induced Hepatotoxicity in HepG2 Cells Involves the Inflammatory and Nrf2\/HO-1 Pathways. Toxins, 17.","DOI":"10.3390\/toxins17080397"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"115982","DOI":"10.1016\/j.bcp.2023.115982","article-title":"Pharmacological Activation of Nuclear Factor Erythroid 2-Related Factor-2 Prevents Hyperglycemia-Induced Renal Oxidative Damage: Possible Involvement of O-GlcNAcylation","volume":"220","author":"Costa","year":"2024","journal-title":"Biochem. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6277","DOI":"10.2147\/JIR.S478683","article-title":"Nrf2 Deficiency Exacerbates Parkinson\u2019s Disease by Aggravating NLRP3 Inflammasome Activation in MPTP-Induced Mouse Models and LPS-Induced BV2 Cells","volume":"17","author":"Lu","year":"2024","journal-title":"J. Inflamm. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1089\/ars.2023.0234","article-title":"The KEAP1-NRF2 System and Neurodegenerative Diseases","volume":"38","author":"Uruno","year":"2023","journal-title":"Antioxid. Redox Signal."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"112746","DOI":"10.1016\/j.ecoenv.2021.112746","article-title":"Betulinic Acid Attenuates Cyclophosphamide-Induced Intestinal Mucosa Injury by Inhibiting the NF-\u03baB\/MAPK Signalling Pathways and Activating the Nrf2 Signalling Pathway","volume":"225","author":"Ou","year":"2021","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8048","DOI":"10.1039\/D5FO00925A","article-title":"Betulinic Acid Protects against LPS-Induced Intestinal Inflammatory Damage via Inhibiting Nrf2\/TXNIP\/NLRP3 Signaling Pathways in Mice","volume":"16","author":"Zhu","year":"2025","journal-title":"Food Funct."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"113811","DOI":"10.1016\/j.fct.2023.113811","article-title":"Betulinic Acid Mitigates Zearalenone-Induced Liver Injury by ERS\/MAPK\/Nrf2 Signaling Pathways in Mice","volume":"177","author":"Wu","year":"2023","journal-title":"Food Chem. Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.7150\/ijbs.57825","article-title":"Betulinic Acid Inhibits Pyroptosis in Spinal Cord Injury by Augmenting Autophagy via the AMPK-mTOR-TFEB Signaling Pathway","volume":"17","author":"Wu","year":"2021","journal-title":"Int. J. Biol. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"52098","DOI":"10.1007\/s11356-022-19498-z","article-title":"Betulinic Acid Attenuates Cognitive Dysfunction, Oxidative Stress, and Inflammation in a Model of T-2 Toxin-Induced Brain Damage","volume":"29","author":"Huang","year":"2022","journal-title":"Environ. Sci. Pollut. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"116692","DOI":"10.1016\/j.ecoenv.2024.116692","article-title":"Viola Yedoensis Makino Alleviates Lipopolysaccharide-Induced Intestinal Oxidative Stress and Inflammatory Response by Regulating the Gut Microbiota and NF-\u03baB-NLRP3\/ Nrf2-MAPK Signaling Pathway in Broiler","volume":"282","author":"Zhao","year":"2024","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1002\/jat.4911","article-title":"Maternal T-2 Mycotoxin Exposure Impairs Liver Function and Growth in Both Dams and Offspring in Mice","volume":"46","author":"Wang","year":"2026","journal-title":"J. Appl. Toxicol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/s12550-024-00518-5","article-title":"Review of Neurotoxicity of T-2 Toxin","volume":"40","author":"Wang","year":"2024","journal-title":"Mycotoxin Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2732","DOI":"10.1021\/acs.jafc.4c10015","article-title":"T-2 Toxin Nephrotoxicity: Toxic Effects, Mechanisms, Mitigations, and Future Perspectives","volume":"73","author":"Wang","year":"2025","journal-title":"J. Agric. Food Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"105577","DOI":"10.1016\/j.psj.2025.105577","article-title":"T-2 Toxin Induces Gut and Liver Injury through Triggering Gut Microbiota Dysbiosis","volume":"104","author":"An","year":"2025","journal-title":"Poult. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.tox.2010.11.006","article-title":"Alteration of Blood Brain Barrier Permeability by T-2 Toxin: Role of MMP-9 and Inflammatory Cytokines","volume":"280","author":"Ravindran","year":"2011","journal-title":"Toxicology"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Weidner, M., H\u00fcwel, S., Ebert, F., Schwerdtle, T., Galla, H.-J., and Humpf, H.-U. (2013). Influence of T-2 and HT-2 Toxin on the Blood-Brain Barrier in Vitro: New Experimental Hints for Neurotoxic Effects. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0060484"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1080\/1028415X.2023.2180865","article-title":"Neuroprotective Properties of Betulin, Betulinic Acid, and Ursolic Acid as Triterpenoids Derivatives: A Comprehensive Review of Mechanistic Studies","volume":"27","author":"Farzan","year":"2024","journal-title":"Nutr. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1007\/s12031-014-0441-1","article-title":"Resveratrol Attenuates the Blood-Brain Barrier Dysfunction by Regulation of the MMP-9\/TIMP-1 Balance after Cerebral Ischemia Reperfusion in Rats","volume":"55","author":"Wei","year":"2015","journal-title":"J. Mol. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"11633","DOI":"10.2147\/IJN.S487628","article-title":"Curcumin-Loaded Gelatin Nanoparticles Cross the Blood-Brain Barrier to Treat Ischemic Stroke by Attenuating Oxidative Stress and Neuroinflammation","volume":"19","author":"Yang","year":"2024","journal-title":"Int. J. Nanomed."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.freeradbiomed.2025.04.013","article-title":"Betulinic Acid Protects against Lipopolysaccharide and Ferrous Sulfate-Induced Oxidative Stress, Ferroptosis, Apoptosis, and Neuroinflammation Signaling Relevant to Parkinson\u2019s Disease","volume":"233","author":"Pandey","year":"2025","journal-title":"Free Radic. Biol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5044","DOI":"10.3390\/ijms26115044","article-title":"Resveratrol Attenuates CSF Markers of Neurodegeneration and Neuroinflammation in Individuals with Alzheimer\u2019s Disease","volume":"26","author":"Liu","year":"2025","journal-title":"Int. J. Mol. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"124359","DOI":"10.1016\/j.envpol.2024.124359","article-title":"Neurotoxic Mechanisms of Mycotoxins: Focus on Aflatoxin B1 and T-2 Toxin","volume":"356","author":"Song","year":"2024","journal-title":"Env. Pollut."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.bbadis.2016.11.005","article-title":"Nrf2 Signaling Pathway: Pivotal Roles in Inflammation","volume":"1863","author":"Ahmed","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Chen, X., Mu, P., Zhu, L., Mao, X., Chen, S., Zhong, H., and Deng, Y. (2021). T-2 Toxin Induces Oxidative Stress at Low Doses via Atf3\u0394Zip2a\/2b-Mediated Ubiquitination and Degradation of Nrf2. Int. J. Mol. Sci., 22.","DOI":"10.21203\/rs.3.rs-506960\/v1"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Tastan, B., Arioz, B.I., and Genc, S. (2022). Targeting NLRP3 Inflammasome With Nrf2 Inducers in Central Nervous System Disorders. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.865772"}],"container-title":["Veterinary Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2306-7381\/13\/6\/509\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T02:14:01Z","timestamp":1779675241000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2306-7381\/13\/6\/509"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,24]]},"references-count":38,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["vetsci13060509"],"URL":"https:\/\/doi.org\/10.3390\/vetsci13060509","relation":{},"ISSN":["2306-7381"],"issn-type":[{"value":"2306-7381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,24]]}}}