Wang Ning, Wang Jun, Wu Yifei, Qu Minglan, Hong Junwen, Cui Zhaoyuan, Chen Yinuo, Zhang Rui
School of Food and Biological Engineering, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
Plant Foods Hum Nutr. 2025 Jun 17;80(3):139. doi: 10.1007/s11130-025-01382-z.
Lipotoxicity has raised intense public concerns for its cytotoxicity and associated chronic diseases. Pancreatic β-cells are highly susceptible to lipotoxicity, since the excessive lipids may produce massive reactive oxygen species (ROS), cause severe oxidative stress, induce the dysfunction of endoplasmic reticulum (ER), damage lipid membranes and trigger the eventual cell death. This study explored the mechanism of cynarine (CYN) in preventing rat pancreatic cells (RINm5F) from the cytotoxicity induced by representative fatty acids, palmitate (PA, physiologically abundant) and linoleic acid (LA, prevalent in Western-style diets). In 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, CYN administration significantly enhanced the viability of pancreatic β cells exposed to PA or LA, validating its protective efficacy against lipotoxicity in RINm5F cells. Further experiments demonstrated that CYN treatment prevented PA-treated beta cells from apoptosis by quenching the intracellular ROS, ameliorating the cellular damages of lipid peroxidation, mitigating cellular calcium dysregulation, suppressing crucial ER stress mediator proteins' expression, attenuating aberrant sub-G1 cell population, and inhibiting the expression of key proapoptotic proteins. In the β cells stressed by LA, CYN treatment efficiently abrogated the abnormal elevation of cellular ferric iron content, inhibited lipid peroxidation, improved the declined GSH content, enhanced the expression of glutathione peroxidase 4, and thereby alleviated the LA-provoked ferroptosis. The findings provide experimental evidence for employing CYN as a preferential antagonist to intervene in lipotoxicity and relevant diseases like diabetes mellitus.
脂毒性因其细胞毒性和相关慢性疾病而引起了公众的高度关注。胰腺β细胞对脂毒性高度敏感，因为过量的脂质可能产生大量活性氧（ROS），导致严重的氧化应激，诱导内质网（ER）功能障碍，损伤脂质膜并引发最终的细胞死亡。本研究探讨了绿原酸（CYN）预防大鼠胰腺细胞（RINm5F）免受代表性脂肪酸棕榈酸（PA，生理上丰富）和亚油酸（LA，在西式饮食中普遍存在）诱导的细胞毒性的机制。在3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐测定中，给予CYN显著提高了暴露于PA或LA的胰腺β细胞的活力，证实了其对RINm5F细胞脂毒性的保护作用。进一步的实验表明，CYN处理通过淬灭细胞内ROS、改善脂质过氧化的细胞损伤、减轻细胞钙失调、抑制关键内质网应激介质蛋白的表达、减少异常的亚G1细胞群以及抑制关键促凋亡蛋白的表达，防止了PA处理的β细胞凋亡。在受到LA应激的β细胞中，CYN处理有效地消除了细胞铁离子含量的异常升高，抑制了脂质过氧化，改善了下降的谷胱甘肽含量，增强了谷胱甘肽过氧化物酶4的表达，从而减轻了LA引发的铁死亡。这些发现为使用CYN作为优先拮抗剂干预脂毒性和糖尿病等相关疾病提供了实验证据。
