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. 2024 Oct 2;25(19):10607.
doi: 10.3390/ijms251910607.

Total Iridoid Glycosides from Swertia mussotii Franch. Alleviate Cholestasis Induced by α-Naphthyl Isothiocyanate through Activating the Farnesoid X Receptor and Inhibiting Oxidative Stress

Qi Dong  1 , Zhenhua Wang  2 , Na Hu  1 , Fangfang Tie  1 , Zenggen Liu  1 , Ying Sun  2 , Yue Wang  3 , Nixia Tan  3 , Honglun Wang  1
Affiliations

Total Iridoid Glycosides from Swertia mussotii Franch. Alleviate Cholestasis Induced by α-Naphthyl Isothiocyanate through Activating the Farnesoid X Receptor and Inhibiting Oxidative Stress

Qi Dong et al. Int J Mol Sci. .

Abstract

Cholestasis refers to a physiological and pathological process caused by bile acid (BA) overaccumulation inside the circulatory system and liver, leading to systemic and hepatocellular damage. Activating the farnesol X receptor (FXR) to restore BA homeostasis is a promising strategy for treating cholestasis. The objective of this research is to reveal solid evidence for the fact that the total iridoid glycosides from Swertia mussotii Franch. (IGSM) alleviate cholestasis. In this research, the whole plant of S. mussotii was extracted with 70% ethanol and separated by macroporous adsorption resin. A rat cholestasis model was established by the injection of α-naphthyl isothiocyanate (ANIT) at a dose of 75 mg/kg. Biochemical and oxidative stress indicators were determined using commercial assay kits. The mRNA abundance of FXR and target proteins was assessed using RT-qPCR. In addition, the effects of main compounds with FXR were evaluated by molecular docking after IGSM analysis using UPLC. The results indicated that IGSM alleviated ANIT-induced cholestasis through reducing serum ALT, AST, AKP, and TBA levels; increasing the mRNA levels of Fxr, Besp, Ntcp, and Mep2; and reducing oxidative stress. The proportion of iridoid compounds in IGSM exceeded 50%, which may be the active substance basis of IGSM. This study provides a theoretical reference for IGSM in the treatment of cholestasis, and future studies may delve more deeply into the FXR regulatory pathway.

Keywords: FXR; Swertia mussotii Franch.; cholestasis; iridoid glycosides; oxidative stress.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
IGSM alleviated liver injury and cholestasis by reducing the serum levels of AKP, ALT, AST, and TBA in ANIT-induced cholestasis rats. ** p < 0.01 when compared to the control group; # p < 0.05 when compared to the ANIT model group.
Figure 2
Figure 2
IGSM improved the levels of SOD, MDA, CAT, and GSH-Px in the liver tissues in the ANIT-induced cholestasis rats. * p < 0.05 when compared to the control group; # p < 0.05 when compared to the ANIT model group.
Figure 3
Figure 3
IGSM improved liver pathology in ANIT-induced cholestasis rats (HE stained, 200× magnification). (A) Control, (B) model, (C) high-dose group, (D) medium-dose group, and (E) low-dose group.
Figure 4
Figure 4
IGSM affected the mRNA levels of FXR and related proteins in the liver tissues of ANIT-induced cholestasis rats. ** p < 0.01 when compared to the control group; # p < 0.05 and ## p < 0.01 when compared to the ANIT model group.
Figure 5
Figure 5
Chromatograms of the four reference substances (A) and IGSM (B). 1—sweroside, 2—gentiopicroside, 3—swertiamarin, and 4—mangiferin.
Figure 6
Figure 6
The binding of FXR and compounds: sweroside (1), gentiopicroside (2), swertiamarin (3), mangiferin (4), and obeticholic acid (5).
Figure 7
Figure 7
The interactions between FXR and compounds: sweroside (1), gentiopicroside (2), swertiamarin (3), mangiferin (4), and obeticholic acid (5) by molecular docking analysis.
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