The myth of cobra venom cytotoxin: More than just direct cytolytic actions

IF 3.6 Q2 TOXICOLOGY Toxicon: X Pub Date : 2022-06-01 DOI:10.1016/j.toxcx.2022.100123
Jia Jin Hiu , Michelle Khai Khun Yap
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引用次数: 6

Abstract

Cobra venom cytotoxin (CTX) is a non-enzymatic three-finger toxin that constitutes 40–60% of cobra venom. Thus, it plays an important role in the pathophysiology of cobra envenomation, especially in local dermonecrosis. The three-finger hydrophobic loops of CTX determine the cytotoxicity. Nevertheless, the actual mechanisms of cytotoxicity are not fully elucidated as they involve not only cytolytic actions but also intracellular signalling-mediated cell death pathways. Furthermore, the possible transition cell death pattern remains to be explored. The actual molecular mechanisms require further studies to unveil the relationship between different CTXs from different cobra species and cell types which may result in differential cell death patterns. Here, we discuss the biophysical interaction of CTX with the cell membrane involving four binding modes: electrostatic interaction, hydrophobic partitioning, isotropic phase, and oligomerisation. Oligomerisation of CTX causes pore formation in the membrane lipid bilayer. Additionally, the CTX-induced apoptotic pathway can be executed via death receptor-mediated extrinsic pathways and mitochondrial-mediated intrinsic pathways. We also discuss lysosomal-mediated necrosis and the occurrence of necroptosis following CTX action. Collectively, we provided an insight into concentration-dependent transition of cell death pattern which involves different mechanistic actions. This contributes a new direction for further investigation of cytotoxic pathways activated by the CTXs for future development of biotherapeutics targeting pathological effects caused by CTX.

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眼镜蛇毒液细胞毒素的神话:不仅仅是直接的细胞溶解作用
眼镜蛇毒液细胞毒素(CTX)是一种非酶的三指毒素,占眼镜蛇毒液的40-60%。因此,它在眼镜蛇中毒的病理生理中起重要作用,特别是在局部皮肤坏死中。CTX的三指疏水环决定细胞毒性。然而,细胞毒性的实际机制尚未完全阐明,因为它们不仅涉及细胞溶解作用,还涉及细胞内信号介导的细胞死亡途径。此外,可能的过渡细胞死亡模式仍有待探索。实际的分子机制需要进一步研究,以揭示不同眼镜蛇物种的不同ctx与细胞类型之间的关系,这可能导致不同的细胞死亡模式。在这里,我们讨论了CTX与细胞膜的生物物理相互作用,涉及四种结合模式:静电相互作用、疏水分配、各向同性相和寡聚化。CTX的寡聚化导致膜脂双分子层形成孔。此外,ctx诱导的凋亡途径可以通过死亡受体介导的外在途径和线粒体介导的内在途径来实现。我们还讨论了溶酶体介导的坏死和CTX作用后坏死下垂的发生。总的来说,我们提供了对涉及不同机制作用的细胞死亡模式的浓度依赖性转变的见解。这为进一步研究CTX激活的细胞毒性途径提供了新的方向,为未来开发针对CTX病理作用的生物治疗药物提供了新的思路。
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来源期刊
Toxicon: X
Toxicon: X Pharmacology, Toxicology and Pharmaceutics-Toxicology
CiteScore
6.50
自引率
0.00%
发文量
33
审稿时长
14 weeks
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