Cyclodextrin host-guest complexes-derived exosomal miRNAs for enhancing the antifatigue effects of resveratrol

Objectives: To study the encapsulation of resveratrol by three cyclodextrin derivatives, investigate the impact of encapsulation technology on its anti-fatigue effect, and explore the anti-fatigue mechanism of the encapsulated resveratrol via transcriptomics analysis of exosomal miRNAs. Methods (1) UV spectroscopy and nuclear magnetic resonance (NMR) were used to investigate the encapsulation and encapsulation modes of resveratrol by β-CD, HP-β-CD and CM-β-CD; and the phase solubility method was used to calculate the solubilisation multiplicity of resveratrol by the three cyclodextrin derivatives. (2) Male C57BL/6 J mice were randomly divided into: fatigue model group (FM), FM+resveratrol group (SF+Res), FM+β-CD, FM+HP-β-CD, FM+CM-β-CD, FM+β-CD+Res, FM+HP-β-CD+Res, FM+CM-β-CD +Res, and after 30 days of rearing, the mice were subjected to exhaustion swimming experiment to detect fatigue-related indexes and observe the effects of the three cyclodextrin derivatives on the anti-fatigue effects of resveratrol. (3) Male C57BL/6 J mice were randomly divided into Control, FM, and FM+HP-β-CD+Res. After 30 days of rearing, except for the Control group, the remaining mice were subjected to exhaustion swimming experiments, and exosomes were extracted from cardiac tissue, skeletal muscle tissue, and liver tissue of the three groups of mice, and the transcriptomics technology was applied to sequence the exosomal miRNAs and to explore the mechanism of the effect of the HP-β-CD+Res envelope on fatigue. Results (1) The inclusion ratios of β-CD, HP-β-CD, and CM-β-CD encapsulated resveratrol were 1:1, 1:2, and 1:1, and the solubilisation multiplicities of resveratrol were 23, 39, and 21 fold, respectively; β-CD and CM-β-CD encapsulated Res, which was the benzene ring with two hydroxyl‑terminal ends of Res entered the cavity from the small-ported end of the cyclodextrins; HP-β-CD encapsulated Res, which was the Res containing one hydroxyl‑terminated benzene ring enters the cavity from the wide-mouth end of HP-β-CD. (2) Compared with the FM+Res group, all three inclusions were able to prolong the exhaustion swimming time of mice, with HP-β-CD+Res being the most effective. (3) After HP-β-CD+Res acted on the fatigued mouse model, cardiac tissue showed 1726 differentially expressed exosomal miRNAs, of which 840 were up-regulated and 886 were down-regulated, reversing the fatigue-induced changes in 64.96 % of the exosomal miRNAs (1170 shared differential exosomal miRNAs); Skeletal muscle tissue showed 1948 differentially expressed exosomal miRNAs, of which 718 were up-regulated and 1230 were down-regulated, reversing 80.57 % of the fatigue-induced changes in exosomal miRNAs (1576 shared differential exosomal miRNAs); Liver tissue showed 1442 differentially expressed exosomal miRNAs, of which 451 were up-regulated and 991 were down-regulated, reversing 84.31 % of fatigue-induced changes in exosomal miRNAs (1214 shared differential exosomal miRNAs). Target gene enrichment analysis of differentially expressed exosomal miRNAs in cardiac tissue, skeletal muscle tissue, and liver tissue had similar results, and the biological processes involved in HP-β-CD+Res were related to biological_process, signal transduction, G protein-coupled receptor signaling pathway, etc., and cellular components such as membrane, cytoplasm, integral component of membrane, etc., and molecular functions are closely related to protein binding, metal ion binding, molecular_function, etc.; mainly enriched in Axon guidance, MicroRNAs in cancer, Apoptosis and other signalling pathways. Conclusions (1) All three cyclodextrin derivatives encapsulated increased the solubility of resveratrol, with HP-β-CD having the best effect. (2) All three cyclodextrin derivative encapsulation techniques improved the anti-fatigue effect of resveratrol, with HP-β-CD being the most effective. (3) HP-β-CD+Res was able to induce differential expression of exosomal miRNAs in cardiac tissue, skeletal muscle tissue and liver tissue of fatigued mice.