Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China.
Department of Biology Science and Technology, Baotou Teacher's College, Baotou 014030, China.
Colloids Surf B Biointerfaces. 2024 Jan;233:113656. doi: 10.1016/j.colsurfb.2023.113656. Epub 2023 Nov 15.
Excessive acetaminophen (APAP) is the main cause of drug-induced acute liver failure, and the pathogenesis has not been elucidated and there is a lack of effective drugs. Hesperidin (Hes), a rich flavanone in citrus peel with excellent biological activities, is a potential agent for treatment liver injury. Due to poor water solubility of Hes, this study prepared mixed micelles using polyvinyl pyrrolidone (PVP K17) and poloxamer 188, and encapsulated Hes (Hes-MMs). The results showed that Hes-MMs exhibited a uniform spherical shape with a particle size of 66.80 ± 0.83 nm, and Hes-MMs significantly improved the dispersibility, antioxidant activity, and cellular uptake of Hes. In vitro results showed that Hes-MMs protected the proliferation inhibition of HepG2 cells induced by APAP, inhibited the production of reactive oxygen species (ROS) and the damage of mitochondrial membrane potential (MMP) induced by APAP. Furthermore, Hes-MMs exerted liver protective effects by inhibiting APAP induced mtDNA release and activating the cGAS-STING pathway. In vivo results demonstrated that Hes-MMs showed protective and therapeutic effects on APAP induced liver injury, and their mechanisms were related to the mtDNA-cGAS-STING signaling pathway. In summary, our study demonstrated that the mtDNA-cGAS-STING pathway was involved in APAP induced acute liver injury, and Hes-MMs might be a potential therapeutic agent for treating APAP induced acute liver injury.
过量的对乙酰氨基酚（APAP）是导致药物性急性肝衰竭的主要原因，其发病机制尚未阐明，且缺乏有效的治疗药物。橙皮苷（Hes）是柑橘皮中丰富的类黄酮，具有极好的生物活性，是治疗肝损伤的潜在药物。由于 Hes 的水溶性差，本研究使用聚乙烯吡咯烷酮（PVP K17）和泊洛沙姆 188 制备混合胶束，并包封 Hes（Hes-MMs）。结果表明，Hes-MMs 呈均匀的球形，粒径为 66.80±0.83nm，且 Hes-MMs 显著提高了 Hes 的分散性、抗氧化活性和细胞摄取能力。体外实验结果表明，Hes-MMs 可保护 HepG2 细胞免受 APAP 诱导的增殖抑制，抑制 APAP 诱导的活性氧（ROS）产生和线粒体膜电位（MMP）损伤。此外，Hes-MMs 通过抑制 APAP 诱导的 mtDNA 释放和激活 cGAS-STING 通路发挥肝保护作用。体内实验结果表明，Hes-MMs 对 APAP 诱导的肝损伤具有保护和治疗作用，其机制与 mtDNA-cGAS-STING 信号通路有关。综上所述，本研究表明 mtDNA-cGAS-STING 通路参与了 APAP 诱导的急性肝损伤，Hes-MMs 可能是治疗 APAP 诱导的急性肝损伤的潜在治疗药物。
