Characterization of brusatol self-microemulsifying drug delivery system and its therapeutic effect against dextran sodium sulfate-induced ulcerative colitis in mice

Abstract

Brusatol (BR) is one of the main bioactive components derived from Brucea javanica, a medicinal herb historically used in the treatment of dysenteric disorders (also known as ulcerative colitis(UC)). Due to its poor aqueous solubility, a novel brusatol self-microemulsifying drug delivery system (BR-SMEDDS) nanoformulation with smaller size, higher negative zeta potential and drug content, and excellent stability was developed. The appearance of BR-SMEDDS remained clear and transparent, and transmission electron microscopy showed microemulsion droplets to be spherical with homogeneous distribution. Pharmacokinetic parameters indicated that oral bioavailability was greatly improved by BR-SMEDDS as compared with aqueous suspension. Meanwhile, the anti-colitis activity of BR-SMEDDS was evaluated on dextran sodium sulfate (DSS)-induced colitis mice model. The result illustrated that the nano-formation significantly reduced the body weight loss, recovered colon length, decreased disease activity index and microscopic score, regulated immune-inflammatory cytokines, diminished oxidative stress and repressed the colonic expression of myeloid differentiation factor 88 (MyD88), toll-like receptor 4 (TLR4) and nuclear factor kappa B p65 (NF-κB p65) proteins. Our findings demonstrated for the first time that BR could effectively attenuate colonic inflammation in mice, at least partially, via favorable regulation of anti-oxidative and anti-inflammatory status and inhibition of the TLR4-linked NF-κB signaling pathway. The BR nano-formulation was superior to BR suspension and sulphasalazine, in treating experimental UC, and exhibited similar effect with azathioprine, with much smaller dosage. The enhanced anti-UC effect of BR might be intimately associated with the improved pharmacokinetic property by SMEDDS. The developed nano-delivery system might thus be a promising candidate for colitis treatment.

The natural flavonoid galangin ameliorates dextran sulphate sodium–induced ulcerative colitis in mice: Effect on Toll‐like receptor 4, inflammation and oxidative stress

“…Galangin, sulphasalazine and the combination significantly lowered TLR4 mRNA levels compared with the disease group. Sulphasalazine was previously demonstrated to counteract DSS‐induced elevation in TLR4 expression . In addition, galangin was reported to counteract LPS‐induced inflammation .…”

Targeting NF-κB pathway for treating ulcerative colitis: comprehensive regulatory characteristics of Chinese medicines

“…Moreover, treatment with aqueous solution of BR significantly attenuates the expressions of TLR4, MyD88 and NF-κBp65 in colon tissue. It suggests that BR treatment is able to alleviate a certain degree of symptoms in mice with colonic inflammation by regulation of anti-inflammatory status [81]. Additionally, the ethyl acetate extract of the ripe fruit of B. javanica, brucea javanica oil (BJO) (0.5 1 and 2 g/kg) treatment reduces the body weight loss, restores the colon length and decreases the levels of TNF-α, IL-1β, IL-6, IL-8, IL-17 and IFN-γ via the suppression of NF-κB pathway in DSS-induced mice [82].…”

Bilobalide Alleviated Dextran Sulfate Sodium-Induced Experimental Colitis by Inhibiting M1 Macrophage Polarization Through the NF-κB Signaling Pathway

“…The activation of the NF-κB signaling pathway triggers an important inflammatory response, which is closely related to colorectal tumorigenesis ( Ye et al., 2019 ). Existing literature has reviewed that the anti-inflammatory effects of some drugs against DSS-induced colitis models are via the inhibition of NF-κB signaling pathway ( Cheon et al., 2006 ; Zhou et al., 2017 ; Zhu et al., 2019 ). The activation of NF-κB signal pathway was suppressed by bilobalide based on the studied mechanisms.…”