Synthesis and functional evaluation of low-molecular-weight dextran sulfate as an inhibitor of TGF-β1-induced epithelial-to-mesenchymal transition in A549 cells  

低分子量硫酸葡聚糖的合成及其在抑制TGF-β1诱导的A549上皮-间充质转化中的作用

作　　者：Guohao Song Linbo Fu Yidian Mo Tongtong Geng Ximin Lv Xiangbao Meng Heng Wang Zhongtang Li Zhongjun Li 宋国豪;符林波;莫伊点;耿彤彤;吕禧敏;孟祥豹;王恒;李忠堂;李中军(石河子大学药学院/新疆植物药资源利用教育部重点实验室/红花产业研究院,新疆石河子832003;北京大学药学院,天然药物及仿生药物全国重点实验室,北京100191)

机构地区：[1]School of Pharmacy/Key Laboratory of Xinjiang Phytomedicine Resource and Utilization Ministry of Education/Institute for Safflower Industry Research,Shihezi University,Shihezi 832003,Xinjiang,China [2]State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University,Beijing 100191,China

出　　处：《Journal of Chinese Pharmaceutical Sciences》2025年第3期210-222,共13页中国药学(英文版)

基　　金：the National Natural Science Foundation of China(Grant Nos.92478133,81930097,and 82151223);by the State Key Laboratory of Natural and Biomimetic Drugs(Grant No.K202430).

摘　　要：Idiopathic pulmonary fibrosis(IPF)is a progressive and fatal interstitial lung disease characterized by excessive fibrotic remodeling,for which effective therapeutic options remain severely limited.Among the pathogenic mechanisms implicated in IPF,epithelial-to-mesenchymal transition(EMT)is recognized as a pivotal driver of fibroblast activation and extracellular matrix deposition.In this study,we aimed to develop low-molecular-weight dextran sulfate sodium(LMW-DSS)derivatives and assess their capacity to interfere with EMT,thereby offering novel therapeutic avenues for IPF management.Starting with dextran(2 kDa)as a precursor,we successfully synthesized two sulfated derivatives,DSS-LS and DSS-HS,via distinct sulfonation processes.Using a TGF-β1-stimulated A549 alveolar epithelial cell model,we demonstrated that LMW-DSS compounds exhibited no cytotoxicity,as validated by CCK-8 viability assays.Importantly,Transwell migration assays revealed that LMW-DSS markedly attenuated TGF-β1-induced A549 cell migration,indicating a potent anti-fibrotic effect.Moreover,qPCR and Western blotting analyses confirmed that LMW-DSS significantly suppressed the expression and secretion of key pro-fibrotic mediators,including TGF-β1 and VEGF-A,and downregulated critical EMT-associated markers such as Snail and vimentin.Notably,reducedα-SMA expression following LMW-DSS treatment further substantiated its role in hindering EMT progression.Collectively,these findings highlighted the capacity of LMW-DSS to effectively impede EMT and fibrotic processes,thereby delaying the progression of pulmonary fibrosis.This work not only underscored the therapeutic potential of LMW-DSS in IPF but also provided compelling experimental evidence to support its development as a promising anti-fibrotic agent for clinical application.特发性肺纤维化(IPF)是一种慢性肺部疾病,目前治疗方案有限。上皮间质转化(EMT)被认为是其核心病理机制。本研究旨在合成低分子量硫酸葡聚糖(LMW-DSS),并评价其潜在的EMT抑制效应,探索新型IPF治疗策略。以分子量2 kDa的葡聚糖为起始原料,采用不同的硫酸化试剂制备了两种硫酸化产物:DSS-LS和DSS-HS。体外实验中,我们以TGF-β1诱导的A549细胞作为肺纤维化模型,通过CCK-8实验验证LMW-DSS无细胞毒性,Transwell实验显示LMW-DSS能显著抑制TGF-β1诱导的A549细胞迁移。通过qPCR和Western Blot实验验证LMW-DSS可以减少促纤维化细胞因子TGF-β1和VEGF-A的表达释放,抑制EMT关键转录因子Snail及间充质标志物Vimentin的表达。因此,在LMW-DSS治疗中观察到α-SMA的下调,表现出对EMT发展进程的显着抑制。低分子量硫酸葡聚糖可以有效减缓肺纤维化进程,展现出潜在的临床应用价值,为开发新型抗肺纤维化药物提供了实验依据。

关 键 词：Idiopathic pulmonary fibrosis Epithelial to mesenchymal transition Dextran sulfate sodium Transforming growth factor-β1 A549 

分 类 号：R916[医药卫生—药学]