College of Pharmacy, Pusan National University, Busan, Republic of Korea.
Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea.
Front Endocrinol (Lausanne). 2023 Aug 25;14:1241097. doi: 10.3389/fendo.2023.1241097. eCollection 2023.
Aging is associated with a broad loss of function throughout the body, and gastrointestinal (GI) dysfunction can occur with aging. The endocannabinoid (eCB) system plays a pivotal role in various GI diseases, and alterations in the eCB system have been observed during brain and skin aging. Therefore, we investigated the putative role of the eCB system in aging-related changes in the intestine.
The expression of cannabinoid receptor type 1 (CB) was investigated in rat intestinal tissues using quantitative real-time PCR. Cellular senescence was induced by hydrogen peroxide (HO) and hydroxyurea (HU) in rat and human intestinal epithelial cells. Cellular permeability was evaluated by transepithelial electrical resistance (TEER) measurement.
The expression of CB was decreased in the small intestine of aged rats compared to that of young rats. Senescent cells showed reduced TEER values and decreased expression of ZO-1, indicating increased intestinal permeability, which is tightly regulated by the CB signaling. miRNA analysis suggested that ZO-1 was a direct target gene of miR-191-5p. Increased expression of miR-191-5p by HU was restored by CB agonist ACEA co-treatment. Moreover, NF-κB p65 activation was associated with CB-related miR-191-5p signaling. In conclusion, aging-induced CB reduction leads to increased intestinal permeability and decreased ZO-1 expression via upregulation of miR-191-5p and NF-κB p65 activation. Taken together, these results suggest that CB signaling may be a useful strategy to reduce intestinal permeability in aging-related and other inflammatory conditions in the gut.
衰老与全身功能广泛丧失有关，而胃肠道（GI）功能障碍可能随衰老而发生。内源性大麻素（eCB）系统在各种胃肠道疾病中发挥关键作用，并且在大脑和皮肤衰老过程中观察到 eCB 系统的改变。因此，我们研究了 eCB 系统在与年龄相关的肠道变化中的潜在作用。
使用定量实时 PCR 研究了大鼠肠道组织中大麻素受体 1（CB）的表达。过氧化氢（HO）和羟基脲（HU）在大鼠和人肠上皮细胞中诱导细胞衰老。通过跨上皮电阻（TEER）测量评估细胞通透性。
与年轻大鼠相比，老年大鼠小肠中 CB 的表达降低。衰老细胞表现出降低的 TEER 值和紧密连接蛋白 1（ZO-1）的表达降低，表明肠道通透性增加，而 CB 信号紧密调节着肠道通透性。miRNA 分析表明，ZO-1 是 miR-191-5p 的直接靶基因。HU 增加的 miR-191-5p 表达通过 CB 激动剂 ACEA 共同处理得到恢复。此外，CB 相关的 miR-191-5p 信号与 NF-κB p65 激活相关。总之，衰老诱导的 CB 减少通过上调 miR-191-5p 和 NF-κB p65 激活导致肠道通透性增加和 ZO-1 表达降低。综上所述，CB 信号可能是减少与年龄相关的和其他炎症性肠病肠道通透性的一种有用策略。
