| 1. |
- Lei, Yang, et al.
(författare)
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Cellular responses to T-2 toxin and/or deoxynivalenol that induce cartilage damage are not specific to chondrocytes
- 2017
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Ingår i: Scientific Reports. - London : Nature Publishing Group. - 2045-2322. ; 7:1, s. 2231-
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Tidskriftsartikel (refereegranskat)abstract
- The relationship between T-2 toxin and deoxynivalenol (DON) and the risk of Kashin-Beck disease is still controversial since it is poorly known about their selectivity in cartilage damage. We aimed to compare the cytotoxicity of T-2 toxin and DON on cell lines representative of cell types encountered in vivo, including human chondrocytes (C28/I2), human hepatic epithelial cells (L-02) and human tubular epithelial cells (HK-2). In addition, we determined the distribution of T-2 toxin and DON in Sprague-Dawley (SD) rats after a single dose exposure. T-2 toxin or DON decreased proliferation in a time- and concentration-dependent manner and their combination showed a similar antagonistic effect in C28/I2, L-02 and HK-2 cells. Moreover, we observed cell cycle arrest and apoptosis, associated with increased oxidative stress and decline in mitochondrial membrane potential induced by T-2 toxin and/or DON. In vivo study showed that T-2 toxin and DON did not accumulate preferentially in the knee joint compared to liver and kidney after an acute exposure in SD rats. These results suggest that T-2 toxin and/or DON inhibit proliferation and induce apoptosis through a possible mechanism involving reactive oxygen species-mediated mitochondrial pathway that is not specific for chondrocytes in vitro or joint tissues in vivo.
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| 2. |
- Lin, Xialu, et al.
(författare)
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Individual and combined toxicity of T-2 toxin and deoxynivalenol on human C-28/I2 and rat primary chondrocytes
- 2019
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Ingår i: Journal of Applied Toxicology. - : John Wiley & Sons. - 0260-437X .- 1099-1263. ; 39:2, s. 343-353
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Tidskriftsartikel (refereegranskat)abstract
- Deoxynivalenol (DON) and T-2 toxin are prevalent mycotoxin contaminants in the food and feed stuffs worldwide, with non-negligible co-contamination and co-exposure conditions. Meanwhile, they are considerable risk factors for Kashin-Beck disease, a chronic endemic osteochondropathy. The aim of this study was to investigate the individual and combined cytotoxicity of DON and T-2 toxin on proliferating human C-28/I2 and newborn rat primary costal chondrocytes by MTT assay. Four molar concentration combination ratios of DON and T-2 toxin were used, 1:1 for R1 mixture, 10:1 for R10, 100:1 for R100 and 1000:1 for R1000. The toxicological interactions were quantified by the MixLow method. DON, T-2 toxin, and their mixtures all showed a clear dose-dependent toxicity for chondrocytes. The cytotoxicity of T-2 toxin was 285-fold higher than DON was in human chondrocytes, and 22-fold higher in the rat chondrocytes. The combination of DON and T-2 toxin was significantly synergistic at middle and high level concentrations of R10 mixtures in rat chondrocytes, but significantly antagonistic at the low concentrations of R100 mixtures in both cells and at the middle concentrations of R1000 mixtures in rat chondrocytes. These results indicated that the combined toxicity was influenced by the cell sensitivity for toxins, the difference between the combination ratio and equitoxic ratio, the concentrations and other factors.
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| 3. |
- Liu, Huan, et al.
(författare)
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The first human induced pluripotent stem cell line of Kashin–Beck disease reveals involvement of heparan sulfate proteoglycan biosynthesis and PPAR pathway
- 2022
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Ingår i: The FEBS Journal. - : John Wiley & Sons. - 1742-464X .- 1742-4658. ; 289:1, s. 279-293
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Kashin-Beck disease (KBD) is an endemic osteochondropathy. Due to a lack of suitable animal or cellular disease models, the research progress on KBD has been limited. Our goal was to establish the first disease-specific human induced pluripotent stem cells (hiPSCs) cellular disease model of KBD, and to explore its etiology and pathogenesis exploiting transcriptome sequencing.METHODS: HiPSCs were reprogrammed from dermal fibroblasts of two KBD and one healthy control donors via integration-free vectors. Subsequently, hiPSCs were differentiated into chondrocytes through three-week culture. Gene expression profiles in KBD, normal primary chondrocytes and hiPSC-derived chondrocytes were defined by RNA sequencing. A Venn diagram was constructed to show the number of shared differentially expressed genes (DEGs) between KBD and normal. Gene oncology and Kyoto Encyclopedia of Genes and Genomes annotations were performed, and six DEGs were further validated in other individuals by real-time quantitative reverse transcription PCR (RT-qPCR).RESULTS: KBD cellular disease models were successfully established by generation of hiPSC lines. Seventeen consistent and significant DEGs present in all compared groups (KBD and normal) were identified. RT-qPCR validation gave consistent results with the sequencing data. Glycosaminoglycan biosynthesis-heparan sulfate/heparin, PPAR signaling pathway and cell adhesion molecules (CAMs) pathways were identified to be significantly altered in KBD.CONCLUSION: Differentiated chondrocytes deriving from KBD-origin hiPSCs provide the first cellular disease model for etiological studies of KBD. This study also provides new sights into the pathogenesis and etiology of KBD and is likely to inform the development of targeted therapeutics for its treatment.
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| 4. |
- Zhang, Yanan, et al.
(författare)
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Dysregulation of Cells Cycle and Apoptosis in Human Induced Pluripotent Stem Cells Chondrocytes Through p53 Pathway by HT-2 Toxin : An in vitro Study
- 2021
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Ingår i: Frontiers in Genetics. - : Frontiers Media S.A.. - 1664-8021. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Kashin–Beck disease (KBD) mainly damages growth plate of adolescents and is susceptible to both gene and gene–environmental risk factors. HT-2 toxin, which is a primary metabolite of T-2 toxin, was regarded as one of the environmental risk factors of KBD. We used successfully generated KBD human induced pluripotent stem cells (hiPSCs) and control hiPSCs, which carry different genetic information. They have potential significance in exploring the effects of HT-2 toxin on hiPSC chondrocytes and interactive genes with HT-2 toxin for the purpose of providing a cellular disease model for KBD. In this study, we gave HT-2 toxin treatment to differentiating hiPSC chondrocytes in order to investigate the different responses of KBD hiPSC chondrocytes and control hiPSC chondrocytes to HT-2 toxin. The morphology of HT-2 toxin-treated hiPSC chondrocytes investigated by transmission electron microscope clearly showed that the ultrastructure of organelles was damaged and type II collagen expression in hiPSC chondrocytes was downregulated by HT-2 treatment. Moreover, dysregulation of cell cycle was observed; and p53, p21, and CKD6 gene expressions were dysregulated in hiPSC chondrocytes after T-2 toxin treatment. Flow cytometry also demonstrated that there were significantly increased amounts of late apoptotic cells in KBD hiPSC chondrocytes and that the mRNA expression level of Fas was upregulated. In addition, KBD hiPSC chondrocytes presented stronger responses to HT-2 toxin than control hiPSC chondrocytes. These findings confirmed that HT-2 is an environmental risk factor of KBD and that p53 pathway interacted with HT-2 toxin, causing damaged ultrastructure of organelles, accelerating cell cycle in G1 phase, and increasing late apoptosis in KBD hiPSC chondrocytes.
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