Involvement of endoplasmic reticulum stress-activated PERK-eIF2α-ATF4 signaling pathway in T-2 toxin-induced apoptosis of porcine renal epithelial cells

Liu, Xiangyan; Wang, Ze; Wang, Xianglin; Yan, Xiaona; He, Qing; Liu, Sha; Ye, Mengke; Li, Xiaowen; Yuan, Zhihang; Wu, Jing; Yi, Jine; Wen, Lixin; Li, Rongfang

doi:10.1016/j.taap.2021.115753

Cited by 18 publications

(14 citation statements)

References 69 publications

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“…In our study, compared with the CTN group, co-treatment with 4-PBA significantly reduced Ca 2+ levels to restore calcium homeostasis, downregulated ER stress markers (GRP78, CHOP, and Caspase-12), and decreased Bax/Bcl-2 and cleaved-caspase-3/pro-caspase-3 ratios (p < 0.01) (Figure 9). This is consistent with the fact that 4-PBA can inhibit nephrotoxicity caused by the T-2 toxin via ER stress [44] and hepatotoxicity mediated by 3-Ac-DON [11]. Additionally, CTN induced liver tissue damage (Figure 9), and oxidative stresses (Figure 7) were alleviated after 4-PBA co-treatment, which is consistent with 4-PBA reversed 3-acetyldeoxynivalenol residue levels, decreased hepatic CAT and SOD activities, and increased MDA levels, thereby alleviating liver injury in mice [13].…”

Section: Discussionsupporting

confidence: 89%

“…Interaction between BIP and ER stress sensor could regulate Ca 2+ from exuding from endoplasmic reticulum, and the interaction plays a key role in maintaining ER homeostasis [39]. CHOP is activated when BIP binds to misfolded proteins, can regulate the caspase-12, BCL-2 family proteins (such as Bcl-2) and caspase-3 [44][45][46][47]. Caspase-12, one of the cysteine proteases, can activate Caspase-3 through ER stress, thus inducing apoptosis activated by ER stress and promotes apoptosis [48,49].…”

Section: Discussionmentioning

confidence: 99%

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Citrinin-Induced Hepatotoxicity in Mice Is Regulated by the Ca2+/Endoplasmic Reticulum Stress Signaling Pathway

Yang

et al. 2022

Toxins

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Citrinin (CTN) is a mycotoxin found in crops and agricultural products and poses a serious threat to human and animal health. The aim of this study is to investigate the hepatotoxicity of CTN in mice and analyze its mechanisms from Ca2+-dependent endoplasmic reticulum (ER) stress perspective. We showed that CTN induced histopathological damage, caused ultrastructural changes in liver cells, and induced abnormal values of biochemical laboratory tests of some liver functions in mice. Treatment with CTN could induce nitric oxide (NO), malondialdehyde (MDA), and reactive oxygen species (ROS) accumulation in mice, accompanied with losses of activities of superoxide dismutase (SOD) and catalase (CAT), levels of glutathione (GSH), and capacities of total antioxidant (T-AOC), resulting in oxidative stress in mice. Furthermore, CTN treatment significantly increased Ca2+ accumulation, upregulated protein expressions of ER stress-mediated apoptosis signal protein (glucose regulated protein 78 (GRP78/BIP), C/EBP-homologous protein (CHOP), Caspase-12, and Caspase-3), and induced hepatocyte apoptosis. These adverse effects were counteracted by 4-phenylbutyric acid (4-PBA), an ER stress inhibitor. In summary, our results showed a possible underlying molecular mechanism for CTN that induced hepatocyte apoptosis in mice by the regulation of the Ca2+/ER stress signaling pathway.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Citrinin-Induced Hepatotoxicity in Mice Is Regulated by the Ca2+/Endoplasmic Reticulum Stress Signaling Pathway

Yang

et al. 2022

Toxins

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“…In human primary tubule epithelial cells, T-2 toxin induced apoptosis, whereas its metabolites showed lower cytotoxic effects but still induced apoptosis at higher concentrations [31][32][33]. Maika Königs et al also proved that T-2 toxin increased the apoptosis rate in porcine renal epithelial cells [34]. In this study, the apoptosis rate of all experimental groups was significantly increased.…”

Section: Discussionsupporting

confidence: 60%

Potential Role of Individual and Combined Effects of T-2 Toxin, HT-2 Toxin and Neosolaniol on the Apoptosis of Porcine Leydig Cells

Zhao

Guo

et al. 2022

Toxins

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T-2 toxin usually co-occurs with HT-2 toxin and neosolaniol (NEO) in the grains and feed. Our previous studies found that T-2 toxin and its metabolites’ binary or ternary combination exposure to porcine Leydig cells (LCs) displayed synergism in certain range of dosage and cannot be predicted based on individual toxicity. However, the possible mechanism of these mycotoxins’ combined exposure to cell lesions remains unknown. Based on 50% cell viability, the mechanism of apoptosis in porcine Leydig cells was investigated after exposure to T-2, HT-2, NEO individual and binary or ternary combinations. Compared with control, the adenosine triphosphate (ATP) content decreased, reactive oxygen species (ROS) level increased, and mitochondrial membrane potential (MMP) decreased in all treated groups. Additionally, the cell apoptosis rates were significantly increased in test groups (p < 0.05), and the B-cell lymphoma 2 (Bcl-2) Associated X (Bax)/Bcl-2 ratio and the expression of caspase 3, caspase 8, cytochrome c (Cytc) in the treated group are all significantly higher than the control group. Moreover, the expression of Cytc and caspase 8 gene in NEO and T-2+NEO groups was significantly higher than that in other individual and combined groups. It can be concluded that the toxicities of T-2, HT-2, and NEO individually and in combination can induce apoptosis related to the oxidative stress and mitochondrial damage, and the synergistic effect between toxins may be greater than a single toxin effect, which is beneficial for assessing the possible risk of the co-occurrences in foodstuffs to human and animal health.

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“…As a consequence, mitochondrial dysfunction usually triggers the mitochondrial apoptotic pathway, which finally causes cell apoptosis, a classic programmed cell death [ 57 ]. Indeed, apoptotic cell death has been detected in multiple tested cell lines treated with T-2 toxin, including human hepatocytes (L02), murine Leydig cells, mouse N2a neuronal cells, human primary astrocytes, rat PC12 cells, and porcine renal epithelial cells [ 24 , 58 , 59 , 60 ]. Not surprisingly, markedly increased apoptotic rates were detected in BV2 cells ( Figure 3 ).…”

Section: Discussionmentioning

confidence: 99%

T-2 Toxin Induces Apoptotic Cell Death and Protective Autophagy in Mouse Microglia BV2 Cells

Sun

Zhang

et al. 2022

JoF

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T-2 toxin exposure could cause neurotoxicity; however, the precise molecular mechanisms remain unclear. In the present study, we investigated T-2 toxin-induced cytotoxicity and underlying molecular mechanisms using a mouse microglia BV2 cell line. The results show that T-2 toxin treatment-induced cytotoxicity of BV2 cells was dose- and time-dependent. Compared to the control, T-2 toxin treatment at 1.25–5 ng/mL significantly increased reactive oxygen species (ROS) production and triggered oxidative stress. T-2 toxin treatment also caused mitochondrial dysfunction in BV2 cells, which was evidenced by decreased mitochondrial transmembrane potential, upregulated expression of Bax protein, and decreased expression of Bcl-2 protein. Meanwhile, T-2 toxin treatment upregulated the expression of cleaved-caspase-3, cleaved-PARP-1 proteins, and downregulated the expression of HO-1 and nuclear Nrf2 proteins, finally inducing cell apoptosis in BV2 cells. N-acetylcysteine (NAC) supplementation significantly attenuated T-2 toxin-induced cytotoxicity. Moreover, T-2 toxin treatment activated autophagy and upregulated autophagy flux, and the inhibition of autophagy significantly promoted T-2 toxin-induced cell apoptosis. Taken together, our results reveal that T-2 toxin-induced cytotoxicity in BV2 cells involves the production of ROS, the activation of the mitochondrial apoptotic pathway, and the inhibition of the Nrf2/HO-1 pathway. Our study offers new insight into the underlying molecular mechanisms in T-2 toxin-mediated neurotoxicity.

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Involvement of endoplasmic reticulum stress-activated PERK-eIF2α-ATF4 signaling pathway in T-2 toxin-induced apoptosis of porcine renal epithelial cells

Cited by 18 publications

References 69 publications

Citrinin-Induced Hepatotoxicity in Mice Is Regulated by the Ca2+/Endoplasmic Reticulum Stress Signaling Pathway

Citrinin-Induced Hepatotoxicity in Mice Is Regulated by the Ca2+/Endoplasmic Reticulum Stress Signaling Pathway

Potential Role of Individual and Combined Effects of T-2 Toxin, HT-2 Toxin and Neosolaniol on the Apoptosis of Porcine Leydig Cells

T-2 Toxin Induces Apoptotic Cell Death and Protective Autophagy in Mouse Microglia BV2 Cells

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