Geng Yining, Song Manping, Huang Bing, Lin Ru, Wu Shiwen, Lin An
Department of Acupuncture, Hainan General Hospital, Hainan Medical University Hainan Hospital, No. 19, Xiuhua Road, Xiuying District, Haikou, 570300, China.
Department of Traditional Chinese Medicine and Western Medicine, Hainan General Hospital Branch-Tunchang Hospital, Tunchang, China.
J Nat Med. 2025 May 14. doi: 10.1007/s11418-025-01913-7.
Atherosclerosis (AS) remains the main cause of vascular diseases. This study reveals the effects of safranal and underlying mechanisms in RAW264.7 macrophages under AS context, which is hoped to facilitate its clinical application. Safranal reduced AS progression in ApoE (-/-) mice, and it also increased the serum level of HDL-C and decreased the levels of TG, TC, and LDL-C as well as ALT and AST. Besides, safranal repressed the pathophysiological processes of OS (downregulated levels of ROS and MDA and upregulated biosynthesis of GSH), ERS (decreased protein levels of activating transcription factor 6, X-Box Binding Protein 1, and glucose-regulated protein, 78 kDa), and inflammation (downregulated serum levels of TNF-α, IL-1β, and IL-6) in vivo. Mechanistically, safranal repressed PI3K/Akt and NF-κB signaling pathways in vivo. On the cellular level, safranal treatment relieved the uptake of ox-LDL, and decreased contents of TG, TC, and LDL-C while increasing HDL-C level in ox-LDL-treated RAW264.7 macrophages. It also reduced the molecular indexes of pathophysiological processes (OS, ESR, and release of inflammatory mediators) in ox-LDL-exposed RAW264.7 macrophages. Notably, safranal treatment also impaired PI3K/Akt and NF-κB signaling pathways in ox-LDL-exposed RAW264.7 macrophages. Additionally, the PI3K agonist 740Y-P notably reversed the in vitro inhibitory effects of safranal on lipid deposition, productions of TC and TNF-α, and protein levels of molecules of PI3K/Akt and NF-κB signaling pathways. Safranal exerts anti-AS effects via repressing OS, ERS, and inflammation in ApoE (-/-) mice, and it also negatively modulates PI3K/Akt and NF-κB signaling pathways in RAW264.7 macrophages.
动脉粥样硬化（AS）仍然是血管疾病的主要病因。本研究揭示了在AS背景下藏红花醛对RAW264.7巨噬细胞的影响及其潜在机制，希望能促进其临床应用。藏红花醛可减缓ApoE（-/-）小鼠的AS进展，还能提高血清高密度脂蛋白胆固醇（HDL-C）水平，降低甘油三酯（TG）、总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-C）以及谷丙转氨酶（ALT）和谷草转氨酶（AST）的水平。此外，藏红花醛在体内可抑制氧化应激（ROS和丙二醛水平下调，谷胱甘肽生物合成上调）、内质网应激（激活转录因子6、X盒结合蛋白1和78 kDa葡萄糖调节蛋白的蛋白水平降低）和炎症（血清肿瘤坏死因子-α、白细胞介素-1β和白细胞介素-6水平下调）的病理生理过程。机制上，藏红花醛在体内可抑制PI3K/Akt和NF-κB信号通路。在细胞水平上，藏红花醛处理可减轻氧化型低密度脂蛋白（ox-LDL）处理的RAW264.7巨噬细胞对ox-LDL的摄取，降低TG、TC和LDL-C含量，同时提高HDL-C水平。它还降低了ox-LDL处理的RAW264.7巨噬细胞中病理生理过程（氧化应激、内质网应激和炎症介质释放）的分子指标。值得注意的是，藏红花醛处理还损害了ox-LDL处理的RAW264.7巨噬细胞中的PI3K/Akt和NF-κB信号通路。此外，PI3K激动剂740Y-P显著逆转了藏红花醛对脂质沉积、TC和肿瘤坏死因子-α产生以及PI3K/Akt和NF-κB信号通路分子蛋白水平的体外抑制作用。藏红花醛通过抑制ApoE（-/-）小鼠的氧化应激、内质网应激和炎症发挥抗AS作用，并且在RAW264.7巨噬细胞中对PI3K/Akt和NF-κB信号通路产生负向调节作用。
