Targeting HMGB1 inhibits T-2 toxin-induced neurotoxicity via regulation of oxidative stress, neuroinflammation and neuronal apoptosis.
Targeting HMGB1 inhibits T-2 toxin-induced neurotoxicity via regulation of oxidative stress, neuroinflammation and neuronal apoptosis.
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DOI：
10.1016/j.fct.2021.112134
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发表时间：
2021-03
期刊：
影响因子：
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通讯作者：
X. Pei;Hai-Lan Jiang;Xinyu Liu;Liu-an Li;Cun Li;Xilong Xiao;Daowen Li;Shusheng Tang
中科院分区：
文献类型：
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作者：
X. Pei;Hai-Lan Jiang;Xinyu Liu;Liu-an Li;Cun Li;Xilong Xiao;Daowen Li;Shusheng Tang
T-2 toxin, a food-derived mycotoxin, has been identified as a neurotoxin. Nonetheless, T-2 toxin-induced neuroinflammation has never been revealed. As an important therapeutic target for inflammatory diseases and cancers, the role of high mobility group B1 (HMGB1) in mycotoxin-mediated neurotoxicity remains a mystery. In current study, we found that PC12 cells were sensitive to trace amounts of T-2 toxin less than 12 ng/mL, distinguished by decreased cell viability and increased release of lactate dehydrogenase (LDH). Oxidative stress and mitochondrial damage were observed in PC12 cells, manifested as accumulation of oxidative stress products, up-regulation of Nrf2/HO-1 pathway and decrease of mitochondrial membrane potential (MMP), leading to mitochondria-dependent apoptosis. Meanwhile, we first discovered that tiny amounts of T-2 toxin triggered neuroinflammation directly, including raising the expression and translocation of NF-κB and promoting secretion of proinflammatory cytokines such as TNF-α, IL-6, IL-8 and IL-1β. Most interestingly, the increased of HMGB1 was detected both inside and outside the cells. Conversely, HMGB1 siRNA reduced T-2 toxin-mediated oxidative stress, apoptosis and neuroinflammatory outbreak, accompanied by lessened caspase-3 and caspase-9, and decreased secretion of pro-inflammatory cytokines. Taken together, T-2 toxin-stimulated PC12 cells simultaneously displayed apoptosis and inflammation, whereas HMGB1 played a critical role in these neurotoxic processes.
