Intestinal farnesoid X receptor (FXR) signaling is involved in the development of obesity, fatty liver disease, and type 2 diabetes. However, the role of intestinal FXR in atherosclerosis and its potential as a target for clinical treatment have not been explored. The serum levels of fibroblast growth factor 19 (FGF19), which is encoded by an FXR target gene, were much higher in patients with hypercholesterolemia than in control subjects and were positively related to circulating ceramide levels, indicating a link between intestinal FXR, ceramide metabolism, and atherosclerosis. Among ApoE^–/– mice fed a high-cholesterol diet (HCD), intestinal FXR deficiency (in Fxr^ΔIE ApoE^–/– mice) or direct FXR inhibition (via treatment with the FXR antagonist glycoursodeoxycholic acid [GUDCA]) decreased atherosclerosis and reduced the levels of circulating ceramides and cholesterol. Sphingomyelin phosphodiesterase 3 (SMPD3), which is involved in ceramide synthesis in the intestine, was identified as an FXR target gene. SMPD3 overexpression or C16:0 ceramide supplementation eliminated the improvements in atherosclerosis in Fxr^ΔIE ApoE^–/– mice. Administration of GUDCA or GW4869, an SMPD3 inhibitor, elicited therapeutic effects on established atherosclerosis in ApoE^–/– mice by decreasing circulating ceramide levels. This study identified an intestinal FXR/SMPD3 axis that is a potential target for atherosclerosis therapy.

Six new phenolic compounds, named smiglabrone A (1), smiglabrone B (2), smilachromanone (3), smiglastilbene (4), smiglactone (5), smiglabrol (6), together with fifty-seven known ones 7–6 3 were isolated from the rhizomes of Smilax glabra. Their structures were elucidated on the basis of extensive spectroscopic analyses, as well as by comparison with literature data. Twenty-seven of these compounds were obtained from and identified in the genus Smilax for the first time. The absolute configuration of (2S)-1,2-O-di-trans-p-coumaroylglycerol (43) was determined for the first time using the exciton-coupled circular dichroism (ECCD) method. Thirty isolated compounds were evaluated for their antimicrobial activity against three Gram-negative bacteria, three Gram-positive bacteria and one fungus, and the corresponding structure-activity relationships were also discussed. Eighteen compounds were found to be antimicrobial against the microorganisms tested and the minimum inhibitory concentrations (MIC) were in the range of 0.0794–3.09 mM. Among them, compound 1 showed antimicrobial activity against Canidia albicans with MIC value of 0.146 mM, which was stronger than cinchonain Ia with an MIC of 0.332 mM. Compounds 3 and 4 exhibited inhibitory activity against Staphylococcus aureus with MIC values of 0.303 and 0.205 mM, respectively. The results indicated that these antimicrobial constituents of this crude drug might be responsible for its clinical antimicrobial effect.

Taxifolin is a ubiquitous bioactive constituent of foods and herbs. To thoroughly explore its metabolism in vivo, an HPLC-ESI-IT-TOF-MSⁿ method combined with specific metabolite detection strategy was used to detect and identify the metabolites of taxifolin in rats. Of the 191 metabolites tentatively identified, 154 were new metabolites, 69 were new compounds and 32 were dimers. This is the first report of the in vivo biotransformation of a single compound into more than 100 metabolites. Furthermore, acetylamination and pyroglutamic acid conjugation were identified as new metabolic reactions. Seventeen metabolites were found to have various taxifolin-related bioactivities. The potential targets of taxifolin and 63 metabolites were predicted using PharmMapper, with results showing that more than 60 metabolites have the same five targets. Metabolites with the same fragment pattern may have the same pharmacophore. Thus these metabolites may exert the same pharmacological effects as taxifolin through an additive effect on the same drug targets. This observation indicates that taxifolin is bioactive not only in the parent form, but also through its metabolites. These findings enhance understanding of the metabolism and effective forms of taxifolin and may provide further insight of the beneficial effects of taxifolin and its derivatives.

To profile absorption of Astragali Radix decoction and identify its orally absorbable constituents and their metabolites, four complementary in silico, in vitro, and in vivo methods, i.e., a computational chemistry prediction method, a Caco-2 cell monolayer model experiment, an improved rat everted gut sac experiment, and a healthy human volunteer experiment, were used. According to the in silico computation result, 26 compounds of Astragali Radix could be regarded as orally available compounds, including 12 flavonoids. In the in vitro and in vivo experiments, 21 compounds were tentatively identified by high-performance liquid chromatography-diode array detection-electrospray ion trap tandem mass spectrometry data, which involved calycosin, formononetin, (6aR,11aR)-3-hydroxy-9,10-dimethoxypterocarpan, 7,2′-dihydroxy-3′,4′-dimethoxyisoflavan, calycosin-7-O-β-d-glucoside, formononetin-7-O-β-d-glucoside, 7,2′-dihydroxy-3′,4′-dimethoxyisoflavan-7-O-β-d-glucoside-6″-O-malonate, (6aR,11aR)-3-hydroxy-9,10-dimethoxypterocarpan-3-O-β-d-glucoside, and phase II metabolites calycosin-7-O-β-d-glucuronide, formononetin-7-O-β-d-glucuronide, (6aR,11aR)-3-hydroxy-9,10-dimethoxypterocarpan-3-O-β-d-glucuronide, 7,2′-dihydroxy-3′,4′-dimethoxyisoflavan-7-O-β-d-glucuronide, and calycosin sulfate. Calycosin and formononetin were proved absorbable by four methods; (6aR,11aR)-3-hydroxy-9,10-dimethoxypterocarpan and 7,2′-dihydroxy-3′,4′-dimethoxyisoflavan were proved absorbable by three methods; formononetin-7-O-β-d-glucoside and (6aR,11aR)-3-hydroxy-9,10-dimethoxypterocarpan-3-O-β-d-glucoside were proved absorbable by two methods. The existence of calycosin-7-O-β-d-glucuronide, formononetin-7-O-β-d-glucuronide, (6aR,11aR)-3-hydroxy-9,10-dimethoxypterocarpan-3-O-β-d-glucuronide, 7,2′-dihydroxy-3′,4′-dimethoxyisoflavan-7-O-β-d-glucuronide, and calycosin sulfate was proved by two or three methods. We found that besides isoflavones, pterocarpans and isoflavans also could be metabolized by the intestine during absorption, and the major metabolites were glucuronides. In conclusion, the present study demonstrated that the flavonoids in Astragali Radix decoction, including isoflavones, pterocarpans, and isoflavans, could be absorbed and metabolized by the intestine. These absorbable compounds, which were reported to have various bioactivities related to the curative effects of Astragali Radix decoction, could be regarded as an important component of the effective constituents of Astragali Radix decoction.