Department of Molecular Medicine, Human Physiology Unit, University of Pavia, I-27100 Pavia, Italy.
Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, I-27100 Pavia, Italy.
Int J Mol Sci. 2021 Sep 10;22(18):9790. doi: 10.3390/ijms22189790.
Sigma1 Receptor (S1R) is involved in oxidative stress, since its activation is triggered by oxidative or endoplasmic reticulum stress. Since specific aquaporins (AQP), called peroxiporins, play a relevant role in controlling HO permeability and ensure reactive oxygen species wasted during oxidative stress, we studied the effect of S1R modulators on AQP-dependent water and hydrogen peroxide permeability in the presence and in the absence of oxidative stress. Applying stopped-flow light scattering and fluorescent probe methods, water and hydrogen peroxide permeability in HeLa cells have been studied. Results evidenced that S1R agonists can restore water permeability in heat-stressed cells and the co-administration with a S1R antagonist totally counteracted the ability to restore the water permeability. Moreover, compounds were able to counteract the oxidative stress of HeLa cells specifically knocked down for S1R. Taken together these results support the hypothesis that the antioxidant mechanism is mediated by both S1R and AQP-mediated HO permeability. The finding that small molecules can act on both S1R and AQP-mediated HO permeability opens a new direction toward the identification of innovative drugs able to regulate cell survival during oxidative stress in pathologic conditions, such as cancer and degenerative diseases.
Sigma1 受体（S1R）参与氧化应激，因为其激活是由氧化或内质网应激触发的。由于特定的水通道蛋白（AQP），称为过氧化物通道蛋白，在控制 HO 通透性方面起着重要作用，并确保在氧化应激过程中浪费的活性氧，因此我们研究了 S1R 调节剂对存在和不存在氧化应激时 AQP 依赖性水和过氧化氢通透性的影响。应用停流光散射和荧光探针方法，研究了 HeLa 细胞中的水和过氧化氢通透性。结果表明，S1R 激动剂可以恢复热应激细胞的水通透性，而 S1R 拮抗剂的共同给药完全抵消了恢复水通透性的能力。此外，这些化合物能够抵抗 S1R 特异性敲低的 HeLa 细胞的氧化应激。这些结果共同支持了这样一种假设，即抗氧化机制是由 S1R 和 AQP 介导的 HO 通透性介导的。小分子可以同时作用于 S1R 和 AQP 介导的 HO 通透性的发现，为鉴定能够在癌症和退行性疾病等病理条件下调节氧化应激期间细胞存活的创新药物开辟了新的方向。
