Capolupo Ilaria, Miranda Maria Rosaria, Musella Simona, Di Sarno Veronica, Manfra Michele, Ostacolo Carmine, Bertamino Alessia, Campiglia Pietro, Ciaglia Tania
Department of Pharmacy, University of Salerno, Via G. Paolo II, Fisciano, 84084 Salerno, Italy.
PhD Program in Drug Discovery and Development, University of Salerno, Fisciano, 84084 Salerno, Italy.
Antioxidants (Basel). 2024 Oct 24;13(11):1284. doi: 10.3390/antiox13111284.
The endoplasmic reticulum (ER) is the organelle mainly involved in maintaining cellular homeostasis and driving correct protein folding. ER-dependent defects or dysfunctions are associated with the genesis/progression of several pathological conditions, including cancer, inflammation, and neurodegenerative disorders, that are directly or indirectly correlated to a wide set of events collectively named under the term "ER stress". Despite the recent increase in interest concerning ER activity, further research studies are needed to highlight all the mechanisms responsible for ER failure. In this field, recent discoveries paved the way for the comprehension of the strong interaction between ER stress development and the endocannabinoid system. The activity of the endocannabinoid system is mediated by the activation of cannabinoid receptors (CB), G protein-coupled receptors that induce a decrease in cAMP levels, with downstream anti-inflammatory effects. CB activation drives, in most cases, the recovery of ER homeostasis through the regulation of ER stress hallmarks PERK, ATF6, and IRE1. In this review, we focus on the CB role in modulating ER stress, with particular attention to the cellular processes leading to UPR activation and oxidative stress response extinguishment, and to the mechanisms underlying natural cannabinoids' modulation of this complex cellular machine.
内质网（ER）是主要参与维持细胞稳态和驱动正确蛋白质折叠的细胞器。内质网依赖性缺陷或功能障碍与多种病理状况的发生/发展相关，包括癌症、炎症和神经退行性疾病，这些疾病直接或间接与统称为“内质网应激”的一系列事件相关。尽管最近对内质网活性的关注有所增加，但仍需要进一步的研究来阐明导致内质网功能衰竭的所有机制。在这一领域，最近的发现为理解内质网应激发展与内源性大麻素系统之间的强相互作用铺平了道路。内源性大麻素系统的活性由大麻素受体（CB）的激活介导，CB是一种G蛋白偶联受体，可诱导cAMP水平降低，并具有下游抗炎作用。在大多数情况下，CB激活通过调节内质网应激标志物PERK、ATF6和IRE1来驱动内质网稳态的恢复。在本综述中，我们重点关注CB在调节内质网应激中的作用，特别关注导致未折叠蛋白反应（UPR）激活和氧化应激反应消除的细胞过程，以及天然大麻素调节这一复杂细胞机制的潜在机制。
