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AbstractInhibition of sperm motility has recently become a promising target for male contraceptive development. AF-2364, an analogue of Lonidamine (LND), had a contraceptive effect when orally administered to adult Sprague-Dawley rats. LND can also target mitochondria to inhibit oxygen consumption and block energy metabolism in tumour cells. However, there are no reports of the effects of AF-2364 on human sperm function. Herein we describe the action of AF-2364 on human sperm in vitro, as well as the mechanisms involved. AF-2364 specifically blocked human sperm motility in vitro. Further experiments revealed that AF-2364 can target sperm mitochondrial permeability transition (MPT) pores to induce the loss of sperm mitochondrial membrane potential (DeltaPsim) and decrease ATP generation; however, no significant changes in the cytoskeletal network or the human sperm proteome were detected after exposure to AF-2364. Incubation of AF-2364 with other human or mouse cell lines indicated that the spermicidal effect at the lower concentration was specific. In summary, the spermicidal effect of AF-2364 involves direct action on sperm MPT pores, and this compound should be further investigated as a new spermicide candidate.

通过靶向作用于精子线粒体，抑制精子运动进行避孕是一种作用特异的、很有前景的避孕方式。AF-2364，是氯尼达明（Londidamine，LND）的类似物，其毒副作用显著降低，目前被认为是一种很有潜力的男性避孕的候选化合物。LND亦可作用于肿瘤细胞线粒体抑制能量代谢。目前尚无AF-2364对于人类精子功能作用的相关报道。在本研究中，我们探寻了AF-2364的体外杀精子作用及其初步机制。体外实验显示，AF-2364显著抑制人类精子的运动：进一步的研究发现，AF-2364可作用于精子线粒体膜通透性转换（PT）孔，降低线粒体膜电位（mitochondrial membrane potential，△ψm），抑制线粒体能量代谢，使ATP下降，从而使精子制动。我们同时检测了AF-2364作用后细胞骨架一系列蛋白调控通路在人精子中的变化及人精子蛋白组学改变，未见显著差异；AF-2364与人及小鼠其他细胞系孵育实验提示较低浓度下的AF-2364对人精子制动作用的特异性。综上，AF-2364可通过对精子线粒体PT孔的直接作用使精子制动，并可能发展为一种杀精子剂的候选成分。