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

Abstract

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, we aimed to increase its biodisponibility and the effectiveness of the antifibrotic effects of chrysin at oral administration. 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)-, 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. We conclude that both nanocomplexes exert anti-inflammatory effects and antifibrotic effects in a considerably stronger manner than for free chrysin administration.

Chrysin directing an enhanced solubility through the formation of a supramolecular cyclodextrin-calixarene drug delivery system: a potential strategy in antifibrotic diabetes therapeutics

“…Recognized for its various therapeutic properties, CHR exhibits antiinflammatory, anticancer, and antioxidant activities [7,8]. Recent studies have also highlighted its potential antifibrotic effects [9][10][11].…”

Transforming Growth Factor-Beta (TGF-β) Signaling in Cancer-A Betrayal Within

“…Several studies have suggested a critical role of inhibitory Smad, Smad7 in the crosstalk between TGF-β and NF-κB signaling ( Chen et al, 2018b ). The upregulation of Smad7 and its interaction with NF-κB subunit p65 suppresses TGF-β-Smad signaling ( Ciceu et al, 2021 ). On the other hand, an increase in the expression of Smad7 can also induce IκBα, thereby inhibiting NF-κB activation ( Lu et al, 2017 ).…”

Chrysin Attenuates Fructose-Induced Nonalcoholic Fatty Liver in Rats via Antioxidant and Anti-Inflammatory Effects: The Role of Angiotensin-Converting Enzyme 2/Angiotensin (1-7)/Mas Receptor Axis

“…This effect could be attributed to the suppression of NF- κ B. In many other studies, NF- κ B was a common pathway by which chrysin has been shown to exert its beneficial effects [ 52 , 64 , 65 , 71 ].…”