Statins as Potential Preventative Treatment of ETX and Multiple Pore-Forming Toxin-Induced Diseases.
Statins as Potential Preventative Treatment of ETX and Multiple Pore-Forming Toxin-Induced Diseases.
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DOI：
10.3390/ijms24065414
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发表时间：
2023-03-12
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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由产气荚膜梭菌B和D型菌株产生的埃帕霉素毒素（ETX）可引起反刍动物（特别是绵羊、牛和山羊）的致命性肠毒血症。以往的研究表明，ETX的细胞毒性依赖于脂筏的完整性，而脂筏的维持是由胆固醇保证的。Zaragozic acid（ZA）是一种他汀类药物，可减少角鲨烯的合成，而角鲨烯是胆固醇合成的主要原因。在本研究中，ZA显著降低了ETX在Madin-Darby犬肾（MDCK）细胞中的毒性。我们表明ZA不影响ETX与MDCK细胞的结合，但碘化丙啶染色（PI）和蛋白质印迹证实ZA显著破坏了ETX在MDCK细胞中形成孔或寡聚体的能力。此外，ZA降低了质膜上的磷脂酰丝氨酸暴露，并增加了细胞的Ca 2+内流。密度梯度离心结果表明，ZA可减少MDCK膜中脂筏的数量，这可能是其抑制膜孔形成的原因之一。此外，ZA还在体内保护小鼠免受ETX的影响。在暴露于绝对致死剂量的ETX（6400 ng/kg）之前用ZA预处理48小时的所有小鼠存活。总之，这些发现为预防ETX中毒提供了一种创新方法。考虑到许多致孔毒素需要脂筏的作用，我们测试发现ZA还能抑制产气荚膜梭菌Net B和β-毒素（CP B）以及金黄色葡萄球菌α-溶血素（Hla）的毒性。因此，我们期望ZA可以被开发为治疗多种毒素的广谱药物。此外，其他他汀类药物，如洛伐他汀（LO），也降低了ETX的毒性。这些发现表明，他汀类药物是预防和治疗多种毒素诱导疾病的潜在候选药物。
Epsilon toxin (ETX), produced by type B and D strains of Clostridium perfringens, can cause fatal enterotoxaemia in ruminant animals, particularly sheep, cattle, and goats. Previous studies show that the cytotoxicity of ETX is dependent on the integrity of lipid rafts, the maintenance of which is ensured by cholesterol. Zaragozic acid (ZA) is a statin drug that reduces the synthesis of squalene, which is responsible for cholesterol synthesis. In this study, ZA significantly reduced the toxicity of ETX in Madin–Darby canine kidney (MDCK) cells. We show that ZA does not affect the binding of ETX to MDCK cells, but propidium iodide staining (PI) and Western blotting confirmed that ZA significantly disrupts the ability of ETX to form pores or oligomers in MDCK cells. Additionally, ZA decreased the phosphatidylserine exposure on the plasma membrane and increased the Ca2+ influx of the cells. Results of density gradient centrifugation suggest that ZA decreased the number of lipid rafts in MDCK membranes, which probably contributed to the attenuation of pore-formation. Moreover, ZA protected mice against ETX in vivo. All mice pre-treated with ZA for 48 h before exposure to an absolute lethal dose of ETX (6400 ng/kg) survived. In summary, these findings provide an innovative method to prevent ETX intoxication. Considering many pore-forming toxins require lipid rafts, we tested and found ZA also inhibited the toxicity of other toxins such as Clostridium perfringens Net B and β-toxin (CPB) and Staphylococcus aureus α-hemolysin (Hla). We expect ZA can thus be developed as a broad-spectrum medicine for the treatment of multiple toxins. In addition, other statins, such as lovastatin (LO), also reduced the toxicity of ETX. These findings indicate that statin medicines are potential candidates for preventing and treating multiple toxin-induced diseases.
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影响因子：
2.6
作者：
Minami, J;Katayama, S;Okabe, A
通讯作者：
Okabe, A
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影响因子：
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作者：
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DOI：
10.1152/ajprenal.00199.2007
发表时间：
2007-09-01
影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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