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T-2 toxin, which is mainly produced by specific strains of Fusarium in nature, can induce immunotoxicity and oxidative stress, resulting in immune organ dysfunction and apoptosis. Betulinic acid (BA), a pentacyclic triterpenoids from nature plants, has been demonstrated to possess immunomodulating and antioxidative bioactivities. The purpose of the study was to explore the effect of BA on T-2 toxin-challenged spleen oxidative damage and further elucidate the underlying mechanism. We found that BA not only ameliorated the contents of serum total cholesterol (TC) and triglyceride (TG) but also restored the number of lymphocytes in T-2 toxin-induced mice. BA dose-dependently reduced the accumulation of reactive oxygen species (ROS), enhanced superoxide dismutase (SOD) activity, and decreased malondialdehyde (MDA) content, as well as increased the total antioxidant capacity (T-AOC) in the spleen of T-2-toxin-exposed mice. Moreover, BA reduced inflammatory cell infiltration in the spleen, improved the morphology of mitochondria and enriched the number of organelles in splenocytes, and dramatically attenuated T-2 toxin-triggered splenocyte apoptosis. Furthermore, administration of BA alleviated the protein phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinases (ERK); decreased the protein expression of kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein1 (Keap1); and increased the protein expression of nuclear factor erythroid 2 [NF-E2]-related factor (Nrf2) and heme oxygenase-1 (HO-1) in the spleen. These findings demonstrate that BA defends against spleen oxidative damage associated with T-2 toxin injection by decreasing ROS accumulation and activating the Nrf2 signaling pathway, as well as inhibiting the mitogen-activated protein kinase (MAPK) signaling pathway.
Li Kong; Lijuan Zhu; Xianglian Yi; You Huang; Haoqiang Zhao; Yazhi Chen; Zhihang Yuan; Lixin Wen; Jing Wu; Jine Yi. Betulinic Acid Alleviates Spleen Oxidative Damage Induced by Acute Intraperitoneal Exposure to T-2 Toxin by Activating Nrf2 and Inhibiting MAPK Signaling Pathways. Antioxidants 2021, 10, 158 .
AMA StyleLi Kong, Lijuan Zhu, Xianglian Yi, You Huang, Haoqiang Zhao, Yazhi Chen, Zhihang Yuan, Lixin Wen, Jing Wu, Jine Yi. Betulinic Acid Alleviates Spleen Oxidative Damage Induced by Acute Intraperitoneal Exposure to T-2 Toxin by Activating Nrf2 and Inhibiting MAPK Signaling Pathways. Antioxidants. 2021; 10 (2):158.
Chicago/Turabian StyleLi Kong; Lijuan Zhu; Xianglian Yi; You Huang; Haoqiang Zhao; Yazhi Chen; Zhihang Yuan; Lixin Wen; Jing Wu; Jine Yi. 2021. "Betulinic Acid Alleviates Spleen Oxidative Damage Induced by Acute Intraperitoneal Exposure to T-2 Toxin by Activating Nrf2 and Inhibiting MAPK Signaling Pathways." Antioxidants 10, no. 2: 158.
T-2 toxin, a trichothecene mycotoxin produced by Fusarium, is widely distributed in crops and animal feed and frequently induces intestinal damage. Betulinic acid (BA), a plant-derived pentacyclic lupane-type triterpene, possesses potential immunomodulatory, antioxidant and anti-inflammatory biological properties. The current study aimed to explore the protective effect and molecular mechanisms of BA on intestinal mucosal impairment provoked by acute exposure to T-2 toxin. Mice were intragastrically administered BA (0.25, 0.5, or 1 mg/kg) daily for 2 weeks and then injected intraperitoneally with T-2 toxin (4 mg/kg) once to induce an intestinal impairment. BA pretreatment inhibited the loss of antioxidant capacity in the intestine of T-2 toxin-treated mice by elevating the levels of CAT, GSH-PX and GSH and reducing the accumulation of MDA. In addition, BA pretreatment alleviated the T-2 toxin-triggered intestinal immune barrier dysregulation by increasing the SIgA level in the intestine at dosages of 0.5 and 1 mg/kg, increasing IgG and IgM levels in serum at dosages of 0.5 and 1 mg/kg and restoring the intestinal C3 and C4 levels at a dosage of 1 mg/kg. BA administration at a dosage of 1 mg/kg also improved the intestinal chemical barrier by decreasing the serum level of DAO. Moreover, BA pretreatment improved the intestinal physical barrier via boosting the expression of ZO-1 and Occludin mRNAs and restoring the morphology of intestinal villi that was altered by T-2 toxin. Furthermore, treatment with 1 mg/kg BA downregulated the expression of p-NF-κB and p-IκB-α proteins in the intestine, while all doses of BA suppressed the pro-inflammatory cytokines expression of IL-1β, IL-6 and TNF-α mRNAs and increased the anti-inflammatory cytokine expression of IL-10 mRNA in the intestine of T-2 toxin-exposed mice. BA was proposed to exert a protective effect on intestinal mucosal disruption in T-2 toxin-stimulated mice by enhancing the intestinal antioxidant capacity, inhibiting the secretion of inflammatory cytokines and repairing intestinal mucosal barrier functions, which may be associated with BA-mediated inhibition of the NF-κB signaling pathway activation.
Chenxi Luo; Chenglong Huang; Lijuan Zhu; Li Kong; Zhihang Yuan; Lixin Wen; Rongfang Li; Jing Wu; Jine Yi. Betulinic Acid Ameliorates the T-2 Toxin-Triggered Intestinal Impairment in Mice by Inhibiting Inflammation and Mucosal Barrier Dysfunction through the NF-κB Signaling Pathway. Toxins 2020, 12, 794 .
AMA StyleChenxi Luo, Chenglong Huang, Lijuan Zhu, Li Kong, Zhihang Yuan, Lixin Wen, Rongfang Li, Jing Wu, Jine Yi. Betulinic Acid Ameliorates the T-2 Toxin-Triggered Intestinal Impairment in Mice by Inhibiting Inflammation and Mucosal Barrier Dysfunction through the NF-κB Signaling Pathway. Toxins. 2020; 12 (12):794.
Chicago/Turabian StyleChenxi Luo; Chenglong Huang; Lijuan Zhu; Li Kong; Zhihang Yuan; Lixin Wen; Rongfang Li; Jing Wu; Jine Yi. 2020. "Betulinic Acid Ameliorates the T-2 Toxin-Triggered Intestinal Impairment in Mice by Inhibiting Inflammation and Mucosal Barrier Dysfunction through the NF-κB Signaling Pathway." Toxins 12, no. 12: 794.
T-2 toxin, the most toxic of the trichothecenes, is widely found in grains and feeds, and its intake poses serious risks to the health of humans and animals. An important cytotoxicity mechanism of T-2 toxin is the production of excess free radicals, which in turn leads to oxidative stress. Betulinic acid (BA) has many biological activities, including antioxidant activity, which is a plant-derived pentacyclic triterpenoid. The protective effects and mechanisms of BA in blocking oxidative stress caused by acute exposure to T-2 toxin in the thymus of mice was studied. BA pretreatment reduced ROS production, decreased the MDA content, and increased the content of IgG in serum and the levels of SOD and GSH in the thymus. BA pretreatment also reduced the degree of congestion observed in histopathological tissue sections of the thymus induced by T-2 toxin. Besides, BA downregulated the phosphorylation of the p38, JNK, and ERK proteins, while it upregulated the expression of the Nrf2 and HO-1 proteins in thymus tissues. The results indicated that BA could protect the thymus against the oxidative damage challenged by T-2 toxin by activating Nrf2 and suppressing the MAPK signaling pathway.
Lijuan Zhu; Xianglian Yi; Chaoyang Ma; Chenxi Luo; Li Kong; Xing Lin; Xinyu Gao; Zhihang Yuan; Lixin Wen; Rongfang Li; Jing Wu; Jine Yi. Betulinic Acid Attenuates Oxidative Stress in the Thymus Induced by Acute Exposure to T-2 Toxin via Regulation of the MAPK/Nrf2 Signaling Pathway. Toxins 2020, 12, 540 .
AMA StyleLijuan Zhu, Xianglian Yi, Chaoyang Ma, Chenxi Luo, Li Kong, Xing Lin, Xinyu Gao, Zhihang Yuan, Lixin Wen, Rongfang Li, Jing Wu, Jine Yi. Betulinic Acid Attenuates Oxidative Stress in the Thymus Induced by Acute Exposure to T-2 Toxin via Regulation of the MAPK/Nrf2 Signaling Pathway. Toxins. 2020; 12 (9):540.
Chicago/Turabian StyleLijuan Zhu; Xianglian Yi; Chaoyang Ma; Chenxi Luo; Li Kong; Xing Lin; Xinyu Gao; Zhihang Yuan; Lixin Wen; Rongfang Li; Jing Wu; Jine Yi. 2020. "Betulinic Acid Attenuates Oxidative Stress in the Thymus Induced by Acute Exposure to T-2 Toxin via Regulation of the MAPK/Nrf2 Signaling Pathway." Toxins 12, no. 9: 540.
T-2 toxin is a mycotoxin generated by Fusarium species which has been shown to be highly toxic to human and animals. T-2 toxin induces apoptosis in various tissues/organs. Apoptosis and autophagy are two closely interconnected processes, which are important for maintaining physiological homeostasis as well as pathogenesis. Here, for the first time, we demonstrated that T-2 toxins induce autophagy in human liver cells (L02). We demonstrated that T-2 toxin induce acidic vesicular organelles formation, concomitant with the alterations in p62/SQSTM1 and LC3-phosphatidylethanolamine conjugate (LC3-II) and the enhancement of the autophagic flux. Using mRFP-GFP-LC3 by lentiviral transduction, we showed T-2 toxin-mediated lysosomal fusion and the formation of autophagosomes in L02 cells. The formation of autophagosomes was further confirmed by transmission electron microcopy. While T-2 toxin induced both autophagy and apoptosis, autophagy appears to be a leading event in the response to T-2 toxin treatment, reflecting its protective role in cells against cellular damage. Activating autophagy by rapamycin (RAPA) inhibited apoptosis, while suppressing autophagy by chloroquine greatly enhanced the T-2 toxin-induced apoptosis, suggesting the crosstalk between autophagy and apoptosis. Taken together, these results indicate that autophagy plays a role in protecting cells from T-2 toxin-induced apoptosis suggesting that autophagy may be manipulated for the alleviation of toxic responses induced by T-2 toxin.
Jing Wu; Yu Zhou; Zhihang Yuan; Jine Yi; Jingshu Chen; Naidong Wang; Yanan Tian. Autophagy and Apoptosis Interact to Modulate T-2 Toxin-Induced Toxicity in Liver Cells. Toxins 2019, 11, 45 .
AMA StyleJing Wu, Yu Zhou, Zhihang Yuan, Jine Yi, Jingshu Chen, Naidong Wang, Yanan Tian. Autophagy and Apoptosis Interact to Modulate T-2 Toxin-Induced Toxicity in Liver Cells. Toxins. 2019; 11 (1):45.
Chicago/Turabian StyleJing Wu; Yu Zhou; Zhihang Yuan; Jine Yi; Jingshu Chen; Naidong Wang; Yanan Tian. 2019. "Autophagy and Apoptosis Interact to Modulate T-2 Toxin-Induced Toxicity in Liver Cells." Toxins 11, no. 1: 45.