Abstract：
Adipose tissue macrophages (ATMs) are crucial in maintaining a low-grade inflammatory microenvironment in adipose tissues (ATs). Modulating ATM polarization to attenuate inflammation represents a potential strategy for treating obesity with insulin resistance. This study develops a combination therapy of celastrol (CLT) and phenformin (PHE) using chondroitin sulfate-derived micelles. Specifically, CLT-loaded 4-aminophenylboronic acid pinacol ester-modified chondroitin sulfate micelle (CS-PBE/CLT) and chondroitin sulfate-phenformin conjugate micelles (CS-PHE) were synthesized, which were shown to actively target ATs through CD44-mediated pathways. Furthermore, the dual micellar systems significantly reduced inflammation and lipid accumulation via protein quantification and Oil Red O staining. In preliminary in vivo studies, we performed H&E staining, immunohistochemical staining, insulin tolerance test, and glucose tolerance test, and the results showed that the combination therapy using CS-PBE/CLT and CS-PHE micelles significantly reduced the average body weight, white adipose tissue mass, and liver mass of high-fat diet-fed mice while improving their systemic glucose homeostasis. Overall, this combination therapy presents a promising alternative to current treatment options for diet-induced obesity.
摘要：
脂肪组织巨噬细胞（ATM）对于维持脂肪组织（AT）中的低度炎症微环境至关重要。调节ATM极化以减轻炎症代表了治疗具有胰岛素抵抗的肥胖的潜在策略。这项研究使用硫酸软骨素衍生的胶束开发了雷公藤红素（CLT）和苯乙双胍（PHE）的联合疗法。具体来说,合成了负载CLT的4-氨基苯基硼酸频哪醇酯修饰的硫酸软骨素胶束（CS-PBE/CLT）和硫酸软骨素-苯乙双胍共轭胶束（CS-PHE），显示通过CD44介导的途径主动靶向ATs。此外，双胶束系统通过蛋白质定量和油红O染色显着减少炎症和脂质积累。在初步的体内研究中，我们进行了H&E染色,免疫组织化学染色，胰岛素耐量试验,和葡萄糖耐量试验,结果表明，使用CS-PBE/CLT和CS-PHE胶束的联合治疗显着降低了平均体重，白色脂肪组织块，高脂饮食小鼠的肝脏质量，同时改善其全身葡萄糖稳态。总的来说,这种联合疗法为目前饮食诱导的肥胖症的治疗方案提供了有希望的替代方案.
