Jia Qingling, Li Li, Wang Xiangxiang, Wang Yujiao, Jiang Kailin, Yang Keming, Cong Jun, Cai Gan, Ling Jianghong
Department of Gastroenterology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Front Pharmacol. 2022 Aug 12;13:945624. doi: 10.3389/fphar.2022.945624. eCollection 2022.
Hesperidin is one of the main active ingredients of (Rutaceae) and tangerine peel, which have anti-inflammatory and antioxidant effects. In previous study, we found that gastric motility disorder in functional dyspepsia (FD) rats accompanied by excessive autophagy/mitochondrial swelling and even vacuolization in the interstitial cells of cajal (ICC), but the exact mechanism has not yet been investigated. Therefore, we used different doses of hesperidin (50 mg/kg, 100 mg/kg, and 200 mg/kg) to intervene in FD rats, and found that medium doses of hesperidin (100 mg/kg) significantly increased gastric motility in FD rats. Subsequently, FD rats were randomly divided into control group, model group, mdivi-1 group, mdivi-1+hesperidin group and hesperidin group, and mitochondrial division inhibitor (mdivi-1) was injected intraperitoneally to further investigate whether hesperidin could regulate dynamin-related protein 1 (Drp1)-mediated mitophagy in ICC to improve mitochondrial damage. The results showed that compared with the model group, the serum malondialdehyde (MDA) level decreased and the superoxide dismutase (SOD) level increased in the mdivi-1 and hesperidin groups ( < 0.001). Transmission electron microscopy (TEM) observed that the mitochondrial nuclear membrane was intact in gastric tissues with a clear internal cristae pattern, and autophagy lysosomes were rare. The co-localization expression of microtubule associated protein 1 light chain 3 (LC3) and voltage dependent anion channel 1 (VDAC1), Drp1 and translocase of the outer mitochondrial membrane 20 (Tom20) was significantly decreased ( < 0.001), the protein expression of mitochondrial Drp1, Beclin1 and LC3 were significantly decreased ( < 0.001), the protein expression of mitochondrial P62 and ckit in gastric tissue were significantly increased ( < 0.05, < 0.001). The above situation was improved more significantly by the synergistic intervention of mdivi-1 and hesperidin. Therefore, hesperidin can improve mitochondrial damage and promote gastric motility in FD rats by regulating Drp1-mediated ICC mitophagy.
橙皮苷是柑橘（芸香科）和陈皮的主要活性成分之一，具有抗炎和抗氧化作用。在先前的研究中，我们发现功能性消化不良（FD）大鼠存在胃动力障碍，伴有过度自噬/线粒体肿胀，甚至 Cajal 间质细胞（ICC）出现空泡化，但确切机制尚未研究。因此，我们使用不同剂量的橙皮苷（50mg/kg、100mg/kg 和 200mg/kg）干预 FD 大鼠，发现中等剂量的橙皮苷（100mg/kg）可显著增加 FD 大鼠的胃动力。随后，将 FD 大鼠随机分为对照组、模型组、mdivi-1 组、mdivi-1+橙皮苷组和橙皮苷组，并腹腔注射线粒体分裂抑制剂（mdivi-1），以进一步研究橙皮苷是否能调节 ICC 中动力相关蛋白 1（Drp1）介导的线粒体自噬，改善线粒体损伤。结果显示，与模型组相比，mdivi-1 组和橙皮苷组血清丙二醛（MDA）水平降低，超氧化物歧化酶（SOD）水平升高（<0.001）。透射电子显微镜（TEM）观察到胃组织中线粒体核膜完整，内部嵴结构清晰，自噬溶酶体少见。微管相关蛋白 1 轻链 3（LC3）与电压依赖性阴离子通道 1（VDAC1）、Drp1 与线粒体外膜转位酶 20（Tom20）的共定位表达显著降低（<0.001），胃组织中线粒体 Drp1、Beclin1 和 LC3 的蛋白表达显著降低（<0.001），胃组织中线粒体 P62 和 ckit 的蛋白表达显著升高（<0.05，<0.001）。mdivi-1 和橙皮苷的协同干预使上述情况改善更显著。因此，橙皮苷可通过调节 Drp1 介导的 ICC 线粒体自噬改善 FD 大鼠的线粒体损伤并促进胃动力。
