Sitokiren Malate

As an alternative of antibiotic therapy against drug-resistance or even multi-drug-resistant bacteria, antimicrobial photodynamic therapy (aPDT) is a promising therapeutic approach for cutaneous/oral localized infections as well as an efficient protocol for disinfection of blood products. In this study, a series of BODIPY derivatives modified with multi-quaternary ammonium cations were designed and synthesized. Density functional theory (DFT) showed that the ΔE values of new compounds were significantly reduced compared to the reference compound BDP-1. All new compounds exhibited intense absorption at 650 nm with high molar extinction coefficients for deeper tissue penetration, and obvious singlet oxygen generation ability. They had remarkable photodynamic activity against Staphylococcus aureus, particularly compounds I₁ and II₁ with the lowest minimum inhibitory concentrations (MIC). In vitro aPDT experiments showed that compounds I₁ and II₁ could disrupt the integrity of bacterial cell membranes, causing the leakage of cytoplasmic contents, and eradicate the mature biofilms of S. aureus. Notably, compound I₁ exhibited minimal toxicity toward human hepatocyte cell HL-7702. Since I₁ possessed significant photodynamic inactivation efficacy against S. aureus, obvious disruption capability to the formed biofilm, and minimal toxicity toward normal human cell, it could be suggested as a promising photosensitizer for aPDT and disinfection of blood products.

Emerging evidence suggests that the renin–angiotensin system plays an important role in the pathogenesis of inflammatory bowel disease, but few studies have directly assessed the therapeutic effect of renin inhibitors on colitis development.

Experimental colitis was induced in wild-type C57BL/6 mice and renin transgenic (RenTg) mice by 2,4,6-trinitrobenzene sulfonic acid (TNBS). Following intrarectal TNBS instillation, the mice were treated with SPH3127 (sitokiren), a small-molecule renin inhibitor, twice a day by intraperitoneal injection or oral gavage. The therapeutic effect of SPH3127 was evaluated by assessing clinical symptoms, histological injuries, and colonic mucosal inflammatory parameters in these mice.

SPH3127 treatment by either delivery route markedly attenuated body weight loss, reduced clinical severity, alleviated colon mucosal ulceration in both C57BL/6 and RenTg mice, and prevented animal death in the case of RenTg mice. SPH3127 treatment blocked the local induction of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IFN-γ, IL-17) and promoted the production of anti-inflammatory cytokine IL-10 in the colon. Fluorescence-activated cell sorting analysis revealed that SPH3127 substantially diminished the accumulation of TH1 and TH17 cells in the colonic mucosa and confirmed that SPH3127-induced IL-10 production from mucosal CD25+ T cells in the mice.

These results demonstrate that SPH3127 is able to effectively block colitis development in mouse experimental colitis models. Its anti-colitogenic activity is achieved at least in part by suppressing mucosal TH1 and TH17 activation while promoting IL-10 production from mucosal CD25+ T cells, thus forming an anti-inflammatory environment in the colonic mucosa.