CD-complexation enhances in vivo anti-fibrotic and anti-inflammatory effects of chrysin

Chrysin (CHR) is a natural flavonoid with a wide range of pharmacological activities, including hepatoprotection, but poor water solubility. By including water-soluble hydroxypropyl (HPBCD) and randomly methylated (RAMEB) β-cyclodextrin the solubility was enhanced (1) and hepatoprotective egffect was proved by in vitro (2) and in vivo studies(3)

Liver fibrosis in mice was induced in 7 weeks by CCl₄ i.p. administration, and afterwards treated with 50 mg/kg of CHR-HPBCD, CHR-RAMEB, and free chrysin. CCl₄ administration increased hepatic inflammation (which was augmented by the upregulation of nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB), tumor necrosis factor (TNF)-α, and interleukin 6 (IL-6) and induced fibrosis, as determined using histopathology and electron microscopy. These results were also confirmed by the upregulation of Collagen I (Col I) and matrix metalloproteinase (MMP) expression, which led to extracellular fibrotic matrix proliferation. Moreover, the immunopositivity of alpha-smooth muscle actin (a-SMA) in the CCl₄ group was evidence of hepatic stellate cell (HSC) activation. The main profibrotic pathway was activated, as confirmed by an increase in the transforming growth factor- β1 (TGF-β1) and Smad 2/3 expression, while Smad 7 expression was decreased. Treatment with CHR–HPBCD and CHR–RAMEB considerably reduced liver injury, attenuated inflammation, and decreased extracellular liver collagen deposits. CHR–RAMEB was determined to be the most active antifibrotic complex. It was concluded that both nanocomplexes exert anti-inflammatory effects and antifibrotic effects in a considerably stronger manner than for free chrysin administration.

(1) Fenyvesi, F.; Nguyen, T.L.P.; Haimhoffer, Á.; Rusznyák, Á.; Vasvári, G.; Bácskay, I.; Vecsernyés, M.; Ignat, S.-R.; Dinescu, S.; Costache, M.; Ciceu, A.; Hermenean, A.; Váradi, J. (2020)
Cyclodextrin complexation improves the solubility and Caco-2 permeability of chrysin. Materials13(16),3618. https://doi.org/10.3390/ma13163618

(2) Ignat, S.-R.; Dinescu, S.; Váradi, J.; Fenyvesi, F.; Nguyen, T.L.P.; Ciceu, A.; Hermenean, A.; Costache, M. (2020) Complexation with random methyl-β-Cyclodextrin and (2-Hydroxypropyl)-β-Cyclodextrin promotes chrysin effect and potential for liver fibrosis therapy. Materials 13(21),5003, pp. 1-14. https://doi.org/10.3390/ma13215003

(3) Ciceu, A.; Balta, C.; Herman, H.; Gharbia, S.; Ignat, S.-R.; Dinescu, S.; Váradi, J.; Fenyvesi, F.; Gyöngyösi, S.; Hermenean, A.; Costache, M. Complexation with Random Methyl-β-Cyclodextrin and (2-Hidroxypropyl)-β-Cyclodextrin Enhances In Vivo Anti-Fibrotic and Anti-Inflammatory Effects of Chrysin via the Inhibition of NF-κB and TGF-β1/Smad Signaling Pathways and Modulation of Hepatic Pro/Anti-Fibrotic miRNA. Int. J. Mol. Sci. 2021, 22, 1869. https://doi.org/10.3390/ijms22041869