Jiang Honghui, Min Chen, Wang Biyao, Wang Ziling, Sun Nianci, Du Kunhang, Wang Cheng, Huang Caihong, Wang Yaping, Wang Lu
Laboratory of Stem Cells and Tissue Engineering, Department of Histology and Embryology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China.
Laboratory of Stem Cells and Tissue Engineering, Department of Histology and Embryology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China.
J Ethnopharmacol. 2026 Mar 1;358:120968. doi: 10.1016/j.jep.2025.120968. Epub 2025 Nov 26.
Traditional Chinese medicine has garnered increasing attention for its efficacy in alleviating stress-induced myelosuppression. Angelica sinensis (Oliv.) Diels root, a crucial traditional medicinal material, was widely utilized for its blood-invigorating effects in conditions such as menstrual disorder, stress-induced anemia, and myelosuppression. Angelica sinensis polysaccharides (ASP), a key natural active ingredient of Angelica sinensis, exhibited a significant potential in antagonizing 5-fluorouracil (5-FU)-induced stress-related oxidative damage to bone marrow cells; however, the underlying mechanism remains to be fully elucidated.
To explore the protective effect and underlying mechanism of ASP on the regulatory axis involving endoplasmic reticulum (ER) stress, mitochondrial dysfunction, apoptosis, and adaptive metabolism, under hematopoietic stress conditions.
Comprehensive approaches combining network pharmacology, RNA-sequencing, in vivo experimental validation including electron microscopy, Western Blot, qRT-PCR techniques, and mitochondrial function assays were performed on marrow cells in C57BL/6J mice.
ASP significantly preserved the morphology and function of ER and mitochondria under 5-FU stress, alleviating 5-FU-induced apoptosis. Mechanistically, ASP ameliorated ER stress via downregulating signals of unfolded protein response including GRP78, IRE1, ATF6, CHOP and inflammatory factor NF-ĸB, reducing ER-released Ca and Ca/ ROS positive feedback cascade reaction. ASP maintained IP3R-GRP75-VDAC1 calcium channel of mitochondria-associated-membranes (MAMs), invigorating mitochondrial functional proteins, and inhibiting Cytochrome C release. Strikingly, ASP enhanced glycolytic-related genetic and protein expression via PI3K/AKT/HIF pathway.
These findings elucidate a novel protective mechanism of ASP against hematopoietic stress caused by chemotherapeutic drug, and identify its multi-target regulation of ER-MAMs-mitochondria and an coincident adaptive metabolism of glycolysis for marrow cell to survive, outlining the prospects for its clinical application in hematopoietic stress.
中药因其在缓解应激诱导的骨髓抑制方面的功效而受到越来越多的关注。当归根是一种重要的传统药材，因其在月经紊乱、应激性贫血和骨髓抑制等病症中的补血作用而被广泛应用。当归多糖（ASP）是当归的一种关键天然活性成分，在拮抗5-氟尿嘧啶（5-FU）诱导的骨髓细胞应激相关氧化损伤方面具有显著潜力；然而，其潜在机制仍有待充分阐明。
探讨ASP在造血应激条件下对涉及内质网（ER）应激、线粒体功能障碍、细胞凋亡和适应性代谢的调节轴的保护作用及其潜在机制。
对C57BL/6J小鼠的骨髓细胞采用网络药理学、RNA测序、体内实验验证（包括电子显微镜、蛋白质免疫印迹、qRT-PCR技术和线粒体功能测定）相结合的综合方法。
ASP在5-FU应激下显著保留了内质网和线粒体的形态和功能，减轻了5-FU诱导的细胞凋亡。机制上，ASP通过下调未折叠蛋白反应信号（包括GRP78、IRE1、ATF6、CHOP和炎性因子NF-κB）改善内质网应激，减少内质网释放的Ca和Ca/ROS正反馈级联反应。ASP维持线粒体相关膜（MAMs）的IP3R-GRP75-VDAC1钙通道，增强线粒体功能蛋白，抑制细胞色素C释放。引人注目的是，ASP通过PI3K/AKT/HIF途径增强糖酵解相关基因和蛋白表达。
这些发现阐明了ASP对化疗药物引起的造血应激的一种新的保护机制，并确定了其对内质网-线粒体相关膜-线粒体的多靶点调节以及骨髓细胞生存所需的糖酵解适应性代谢，为其在造血应激中的临床应用前景提供了依据。
