Celastrol-loaded PEG-PCL nanomicelles ameliorate inflammation, lipid accumulation, insulin resistance and gastrointestinal injury in diet-induced obese mice
Celastrol-loaded PEG-PCL nanomicelles ameliorate inflammation, lipid accumulation, insulin resistance and gastrointestinal injury in diet-induced obese mice
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雷公藤红素负载 PEG-PCL 纳米胶束可改善饮食诱导的肥胖小鼠的炎症、脂质积累、胰岛素抵抗和胃肠道损伤
DOI：
10.1016/j.jconrel.2019.08.026
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发表时间：
2019
影响因子：
10.8
通讯作者：
Rong Jianhui
中科院分区：
文献类型：
--
作者：
Zhao Jia;Luo Dan;Zhang Zhong;Fan Ni;Wang Yu;Nie Hong;Rong Jianhui
植物三萜类雷公藤红素是治疗肥胖症的候选药物，但在临床应用中存在安全性问题。本研究旨在研究雷公藤红素纳米胶束(纳米雷公藤红素)对饮食诱导肥胖小鼠的抗肥胖、抗炎和毒性作用。将雷公藤红素负载到聚乙二醇-聚乙二醇酯纳米粒中，得到了尺寸最优、形态圆整、生物利用度好、峰时间较慢、小鼠体内清除性较好的纳米雷公藤红素。将纳米雷公藤红素(5或7.5 mg/kg/d)应用于饮食诱导的肥胖C57BL/6 N雄性小鼠，连续3 周。结果，较高剂量的纳米雷公藤红素以与常规雷公藤红素同样有效的方式减少体重和身体脂肪质量，尽管较低剂量的纳米雷公藤红素显示的活性较小。类似地，纳米雷公藤红素与普通雷公藤红素一样能改善小鼠的糖耐量，而更高剂量的纳米雷公藤红素改善了对胰岛素的反应。在肝脏巨噬细胞M1/M2极化方面，纳米雷公藤红素以剂量依赖的方式降低巨噬细胞M1生物标志物(如IL-6、IL-1β、肿瘤坏死因子-α、诱导型一氧化氮合酶)的表达，并略微增加巨噬细胞M2生物标志物(如精氨酸、IL-10)的表达。此外，雷公藤红素对小鼠有肛门刺激作用，对肠道和结肠的完整性也有影响，而纳米雷公藤红素对小鼠无明显损伤。总的来说，纳米雷公藤红素代表着一种可翻译的治疗机会，用于治疗人类因饮食导致的肥胖。
Botanical triterpene celastrol is a candidate drug for the treatment of obesity, except for concerns over the safety in clinical application. The present study was designed to investigate the anti-obesity, anti-inflammatory and toxic activities of celastrol-loaded nanomicelles (nano-celastrol) in diet-induced obese mice. Celastrol was loaded into PEG-PCL nanoparticles, yielding nano-celastrol with optimal size, spherical morphology, good bioavailability, slower peak time and clearance in mice. Nano-celastrol (5 or 7.5 mg/kg/d of celastrol) was administered into diet-induced obese C57BL/6 N male mice for 3 weeks. As result, higher dose nano-celastrol reduced body weight and body fat mass in an equally effective manner as regular celastrol, although lower dose nano-celastrol showed less activity. Similarly, nano-celastrol improved glucose tolerance in mice equally well as regular celastrol, whereas higher dose nano-celastrol improved the response to insulin. As for macrophage M1/M2 polarization in liver, nano-celastrol reduced the expression of macrophage M1 biomarkers (e.g., IL-6, IL-1β, TNF-α, iNOS) in a dose-dependent manner and marginally increased the expression of macrophage M2 biomarkers (e.g., Arg-1, IL-10). Moreover, celastrol could cause anus irritation and disturb intestinal and colonic integrity, whereas nano-celastrol did not cause any injury to mice. Collectively, nano-celastrol represents a translatable therapeutic opportunity for treating diet-induced obesity in humans.