The mitochondria-targeted Kaempferol nanoparticle ameliorates severe acute pancreatitis

作者全名："Wen, E.; Cao, Yi; He, Shiwen; Zhang, Yuezhou; You, Lanlan; Wang, Tingqiu; Wang, Zhigang; He, Jun; Feng, Yi"

作者地址："[Wen, E.; Cao, Yi; He, Shiwen; You, Lanlan; Wang, Tingqiu; Wang, Zhigang] Chongqing Med Univ, Affiliated Hosp 2, Dept Ultrasound, 76, Linjiang Rd, Chongqing, Peoples R China; [Wen, E.] Chongqing Med Univ, Affiliated Hosp 2, Precis Med Ctr, Chongqing, Peoples R China; [Zhang, Yuezhou] Chongqing Med Univ, Affiliated Hosp 2, Dept Hepatobiliary Surg, Chongqing, Peoples R China; [He, Jun] Chengdu Med Coll, First Affiliated Hosp, Dept Pathol, 278,Baoguang Ave, Chengdu 610500, Sichuan, Peoples R China; [Feng, Yi] Third Mil Med Univ, Army Med Univ, Southwest Hosp, Inst Burn Res,State Key Lab Trauma Burn & Combined, 76, Linjiang Rd, Chongqing, Peoples R China"

通信作者："Wang, ZG (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Ultrasound, 76, Linjiang Rd, Chongqing, Peoples R China.; He, J (通讯作者)，Chengdu Med Coll, First Affiliated Hosp, Dept Pathol, 278,Baoguang Ave, Chengdu 610500, Sichuan, Peoples R China.; Feng, Y (通讯作者)，Third Mil Med Univ, Army Med Univ, Southwest Hosp, Inst Burn Res,State Key Lab Trauma Burn & Combined, 76, Linjiang Rd, Chongqing, Peoples R China."

来源：JOURNAL OF NANOBIOTECHNOLOGY

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001197033600001

JCR分区：Q1

影响因子：10.6

年份：2024

卷号：22

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Kaempferol; TK bond; Nanosystem; Mitochondrial homeostasis; Severe acute pancreatitis

摘要："Kaempferol (KA), an natural antioxidant of traditional Chinese medicine (TCM), is extensively used as the primary treatment for inflammatory digestive diseases with impaired redox homeostasis. Severe acute pancreatitis (SAP) was exacerbated by mitochondrial dysfunction and abundant ROS, which highlights the role of antioxidants in targeting mitochondrial function. However, low bioavailability and high dosage of KA leading to unavoidable side effects limits clinical transformation. The mechanisms of KA with poor bioavailability largely unexplored, hindering development of the efficient strategies to maximizing the medicinal effects of KA. Here, we engineered a novel thioketals (TK)-modified based on DSPE-PEG2000 liposomal codelivery system for improving bioavailability and avoiding side effects (denotes as DSPE-TK-PEG2000-KA, DTM@KA NPs). We demonstrated that the liposome exerts profound impacts on damaging intracellular redox homeostasis by reducing GSH depletion and activating Nrf2, which synergizes with KA to reinforce the inhibition of inadequate fission, excessive mitochondrial fusion and impaired mitophagy resulting in inflammation and apoptosis; and then, the restored mitochondrial homeostasis strengthens ATP supply for PAC renovation and homeostasis. Interestingly, TK bond was proved as the main functional structure to improve the above efficacy of KA compared with the absence of TK bond. Most importantly, DTM@KA NPs obviously suppresses PAC death with negligible side effects in vitro and vivo. Mechanismly, DTM@KA NPs facilitated STAT6-regulated mitochondrial precursor proteins transport via interacting with TOM20 to further promote Drp1-dependent fission and Pink1/Parkin-regulated mitophagy with enhanced lysosomal degradation for removing damaged mitochondria in PAC and then reduce inflammation and apoptosis. Generally, DTM@KA NPs synergistically improved mitochondrial homeostasis, redox homeostasis, energy metabolism and inflammation response via regulating TOM20-STAT6-Drp1 signaling and promoting mitophagy in SAP. Consequently, such a TCM's active ingredients-based nanomedicine strategy is be expected to be an innovative approach for SAP therapy."

基金机构："Chongqing Natural Science Foundation for postdoctoral; Second Affiliated Hospital of Chongqing Medical University; State Key Laboratory of Ultrasound in Medicine and Engineering, Institute of Ultrasound Imaging"

基金资助正文："We give our sincere gratitude to the support and assistance of all laboratory personnel. We heartfelt thanks for the platform, including the Second Affiliated Hospital of Chongqing Medical University and State Key Laboratory of Ultrasound in Medicine and Engineering, Institute of Ultrasound Imaging."