Journal
JOURNAL OF CONTROLLED RELEASE
Volume 310, Issue -, Pages 188-197Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2019.08.026
Keywords
Obesity; Inflammation; Macrophage polarization; Celastrol; Nanomicelles
Funding
- Hong Kong Scholars Program
- General Research Fund (GRF) from the Research Grants Council of Hong Kong [17120915, 17146216, 17100317]
- National Natural Science Foundation of China [81703726, 21778046]
- Health and Medical Research Fund [15161731, 16171751]
- Science, Technology and Innovation Commission of Shenzhen Municipality (Basic Research Program, Free Exploration Project) [16636]
- University of Hong Kong [201611159156]
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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-1 beta, TNF-alpha, 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.
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