Department of Geriatric Neurology of Huashan Hospital, National Clinical Research Center for Aging and Medicine, Fudan University, Shanghai, China.
Department of Medical Examination Center, Huashan Hospital, Fudan University, Shanghai, China.
CNS Neurosci Ther. 2021 Apr;27(4):484-496. doi: 10.1111/cns.13573. Epub 2021 Jan 18.
Type 2 diabetes mellitus (T2DM) can lead to brain dysfunction and a series of neurological complications. Previous research demonstrated that a novel palmitic acid (5-PAHSA) exerts effect on glucose tolerance and chronic inflammation. Autophagy was important in diabetic-related neurodegeneration. The aim of the present study was to investigate whether 5-PAHSA has specific therapeutic effects on neurological dysfunction in diabetics, particularly with regard to autophagy.
5-PAHSA was successfully synthesized according to a previously described protocol. We then carried out a series of in vitro and in vivo experiments using PC12 cells under diabetic conditions, and DB/DB mice, respectively. PC12 cells were treated with 5-PAHSA for 24 h, while mice were administered with 5-PAHSA for 30 days. At the end of each experiment, we analyzed glucolipid metabolism, autophagy, apoptosis, oxidative stress, cognition, and a range of inflammatory factors.
Although there was no significant improvement in glucose metabolism in mice administered with 5-PAHSA, ox-LDL decreased significantly following the administration of 5-PAHSA in serum of DB/DB mice (p < 0.0001). We also found that the phosphorylation of m-TOR and ULK-1 was suppressed in both PC12 cells and DB/DB mice following the administration of 5-PAHSA (p < 0.05 and p < 0.01), although increased levels of autophagy were only observed in vitro (p < 0.05). Following the administration of 5-PAHSA, the concentration of ROS decreased in PC12 cells and the levels of CRP increased in high-dose group of 5-PAHSA (p < 0.01). There were no significant changes in terms of apoptosis, other inflammatory factors, or cognition in DB/DB mice following the administration of 5-PAHSA.
We found that 5-PAHSA can enhance autophagy in PC12 cells under diabetic conditions. Our data demonstrated that 5-PAHSA inhibits phosphorylation of the m-TOR-ULK1 pathway and suppressed oxidative stress in PC12 cells, and exerted influence on lipid metabolism in DB/DB mice.
2 型糖尿病（T2DM）可导致脑功能障碍和一系列神经并发症。先前的研究表明，一种新型棕榈酸（5-PAHSA）对葡萄糖耐量和慢性炎症有作用。自噬在糖尿病相关神经退行性变中很重要。本研究旨在探讨 5-PAHSA 是否对糖尿病患者的神经功能障碍具有特殊的治疗作用，特别是自噬作用。
根据先前的方案成功合成了 5-PAHSA。然后，我们分别在糖尿病条件下的 PC12 细胞和 DB/DB 小鼠中进行了一系列的体外和体内实验。PC12 细胞用 5-PAHSA 处理 24 小时，而小鼠用 5-PAHSA 处理 30 天。在每个实验结束时，我们分析了糖脂代谢、自噬、细胞凋亡、氧化应激、认知和一系列炎症因子。
尽管给予 5-PAHSA 的小鼠的葡萄糖代谢没有显著改善，但给予 5-PAHSA 后 DB/DB 小鼠血清中的 ox-LDL 显著降低（p<0.0001）。我们还发现，给予 5-PAHSA 后，PC12 细胞和 DB/DB 小鼠中 m-TOR 和 ULK-1 的磷酸化均受到抑制（p<0.05 和 p<0.01），尽管仅在体外观察到自噬水平增加（p<0.05）。给予 5-PAHSA 后，PC12 细胞中的 ROS 浓度降低，高剂量 5-PAHSA 组中的 CRP 水平升高（p<0.01）。给予 5-PAHSA 后，DB/DB 小鼠的细胞凋亡、其他炎症因子或认知无明显变化。
我们发现 5-PAHSA 可增强糖尿病条件下 PC12 细胞中的自噬作用。我们的数据表明，5-PAHSA 抑制 m-TOR-ULK1 通路的磷酸化，抑制 PC12 细胞中的氧化应激，并对 DB/DB 小鼠的脂代谢产生影响。
