Psammaplins are sulfur containing bromotyrosine alkaloids that have shown antitumor activity through the inhibition of class I histone deacetylases (HDACs). The cytotoxic properties of psammaplin A (1), the parent compound, are related to peroxisome proliferator-activated receptor γ (PPARγ) activation, but the mechanism of action of its analogs psammaplin K (2) and bisaprasin (3) has not been elucidated. In this study, the protective effects against oxidative stress of compounds 1–3, isolated from the sponge Aplysinella rhax, were evaluated in SH-SY5Y cells. The compounds improved cell survival, recovered glutathione (GSH) content, and reduced reactive oxygen species (ROS) release at nanomolar concentrations. Psammaplins restored mitochondrial membrane potential by blocking mitochondrial permeability transition pore opening and reducing cyclophilin D expression. This effect was mediated by the capacity of 1–3 to activate PPARγ, enhancing gene expression of the antioxidant enzymes catalase, nuclear factor E2-related factor 2 (Nrf2), and glutathione peroxidase. Finally, HDAC3 activity was reduced by 1–3 under oxidative stress conditions. This work is the first description of the neuroprotective activity of 1 at low concentrations and the mechanism of action of 2 and 3. Moreover, it links for the first time the previously described effects of 1 in HDAC3 and PPARγ signaling, opening a new research field for the therapeutic potential of this compound family.

中文翻译：

---

Psammaplin A 及其类似物通过过氧化物酶体增殖物激活受体 γ 激活减轻神经细胞的氧化应激

Psammaplins 是含硫的溴酪氨酸生物碱，通过抑制 I 类组蛋白脱乙酰酶 (HDAC) 表现出抗肿瘤活性。母体化合物 psammaplin A ( 1 )的细胞毒性特性与过氧化物酶体增殖物激活受体 γ (PPARγ) 激活有关，但其类似物 psammaplin K ( 2 ) 和 bisaprasin ( 3 ) 的作用机制尚未阐明。在本研究中，在 SH-SY5Y 细胞中评估了从海绵海兔中分离出的化合物1 – 3对氧化应激的保护作用。这些化合物提高了细胞存活率，恢复了谷胱甘肽 (GSH) 含量，并减少了纳摩尔浓度的活性氧 (ROS) 释放。 Psammaplins 通过阻断线粒体通透性转换孔开放和减少亲环蛋白 D 表达来恢复线粒体膜电位。这种效应是由1 – 3激活 PPARγ的能力介导的，从而增强抗氧化酶过氧化氢酶、核因子 E2 相关因子 2 (Nrf2) 和谷胱甘肽过氧化物酶的基因表达。最后，在氧化应激条件下，HDAC3活性降低了1-3倍。这项工作首次描述了1在低浓度下的神经保护活性以及2和3的作用机制。此外，它首次将之前描述的1在 HDAC3 和 PPARγ 信号传导中的作用联系起来，为该化合物家族的治疗潜力开辟了一个新的研究领域。