Department of Laboratory Animal Science, Fudan University, Shanghai, 200032, China.
Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
Cell Biol Toxicol. 2023 Dec;39(6):2587-2613. doi: 10.1007/s10565-022-09789-z. Epub 2023 Jan 25.
The primary symptom of diabetic encephalopathy (DE), a kind of central diabetic neuropathy caused by diabetes mellitus (DM), is cognitive impairment. In addition, the tetracyclic oxindole alkaloid isorhynchophylline (IRN) helps lessen cognitive impairment. However, it is still unclear how IRN affects DM and DE and what mechanisms are involved. The effectiveness of IRN on brain insulin resistance was carefully examined in this work, both in vitro and in vivo. We found that IRN accelerates spliced form of X-box binding protein 1 (sXBP1) translocation into the nucleus under high glucose conditions in vitro. IRN also facilitates the nuclear association of pCREB with sXBP1 and the binding of regulatory subunits of phosphatidylinositol 3-kinase (PI3K) p85α or p85β with XBP1 to restore high glucose impairment. Also, IRN treatment improves high glucose-mediated impairment of insulin signaling, endoplasmic reticulum stress, and pyroptosis/apoptosis by depending on sXBP1 in vitro. In vivo studies suggested that IRN attenuates cognitive impairment, ameliorating peripheral insulin resistance, activating insulin signaling, inactivating activating transcription factor 6 (ATF6) and C/EBP homology protein (CHOP), and mitigating pyroptosis/apoptosis by stimulation of sXBP1 nuclear translocation in the brain. In summary, these data indicate that IRN contributes to maintaining insulin homeostasis by activating sXBP1 in the brain. Thus, IRN is a potent antidiabetic agent as well as an sXBP1 activator that has promising potential for the prevention or treatment of DE.
糖尿病性脑病（DE）是一种由糖尿病（DM）引起的中枢性糖尿病神经病变，其主要症状为认知障碍。此外，四环吲哚里西啶类生物碱异钩藤碱（IRN）有助于减轻认知障碍。然而，IRN 如何影响 DM 和 DE 以及涉及哪些机制仍不清楚。在这项工作中，我们在体外和体内仔细研究了 IRN 对脑胰岛素抵抗的作用。我们发现，IRN 在高葡萄糖条件下可加速 X 盒结合蛋白 1（XBP1）剪接体（sXBP1）向核内转位。IRN 还促进 pCREB 与 sXBP1 的核结合以及磷脂酰肌醇 3-激酶（PI3K）的调节亚基 p85α 或 p85β 与 XBP1 的结合，以恢复高葡萄糖损伤。此外，IRN 治疗通过 sXBP1 在体外改善了高葡萄糖介导的胰岛素信号转导、内质网应激和细胞焦亡/细胞凋亡损伤。体内研究表明，IRN 通过刺激 sXBP1 核易位减轻了认知障碍，改善了外周胰岛素抵抗，激活了胰岛素信号转导，使激活转录因子 6（ATF6）和 C/EBP 同源蛋白（CHOP）失活，并减轻了细胞焦亡/细胞凋亡。综上所述，这些数据表明，IRN 通过激活脑中的 sXBP1 有助于维持胰岛素的动态平衡。因此，IRN 不仅是一种有效的抗糖尿病药物，而且还是一种 sXBP1 激活剂，对预防或治疗 DE 具有很大的应用潜力。
