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Phenotypic switching of vascular smooth muscle cells (VSMCs) is crucial in atherosclerosis. Gypenoside granules, used clinically for hyperlipidemia, show significant atheroprotective effects, but their impact on VSMC phenotypic switching is unclear. This study evaluated the effects and mechanisms of gypenoside granules on VSMC phenotypic switching. Using ApoE−/− mice on a high-fat diet, the study found that gypenoside granules reduced blood lipid levels, decreased necrotic core areas, increased fibrous cap thickness, and inhibited inflammation. In PDGF-BB-induced VSMCs, gypenoside granules suppressed phenotypic switching, proliferation, and migration by downregulating KLF4 expression. The beneficial effects were reversed by KLF4 overexpression. HPLC analysis identified ten key components in the granules. These findings suggest that gypenoside granules may alleviate atherosclerosis by modulating the MAPK/KLF4 pathway and could serve as an alternative treatment for the disease.

As a new and safe food resource, Cyclocarya paliurus (CP), rich in flavonoids, exhibits hypouricemic, anti-inflammatory and antioxidative properties. However, whether CP aqueous extract (CPA) still possesses the ameliorative effects on hyperuricemia (HUA) and urate-induced renal inflammation remains vacant. In HUA mice, CPA could significantly reduce serum uric acid (UA), alleviate kidney damage and liver steatosis, inhibit xanthine oxidase (XOD) activity, ameliorate renal urate transporters and renal inflammation by inhibiting NLRP3 inflammasome and interleukin-1β (IL-1β). Moreover, the flavonoids quercetin-3-O-β-D-galactopyranoside, quercetin-3-O-β-D-glucopyranoside, and quercetin-3-O-α-L-rhamnopyranoside from CPA could significantly reduce IL-1β and interleukin-6 (IL-6) in MSU-challenged THP-1 cells. Noticeably, quercetin-3-O-β-D-galactopyranoside could inhibit the intracellular XOD activity, reduce intracellular ROS and the expression of pro-IL-1β, IL-1β, and NLRP3 inflammasome. Collectively, CPA shows appreciable therapeutic effects on HUA and evoked renal inflammation. Quercetin-3-O-β-D-galactopyranoside, quercetin-3-O-β-D-glucopyranoside, and quercetin-3-O-α-L-rhamnopyranoside might be the major active compounds of CPA, which obtain the favorable effects through blocking the activation of ROS/NLRP3/IL-1β pathway.

Arjunolic acid (AA), as the most abundant triterpenoid component in Cyclocarya paliurus (Batal) Iljinskaja, previously displayed delipidating effects in free fatty acid (FFA)-induced HepG2 steatosis cells. However, whether AA still possesses the ameliorative effects on nonalcoholic fatty liver disease (NAFLD) in normal hepatocytes and in vivo remains vacant and the detailed mechanisms are not defined. In vitro, AA dose-dependently alleviated lipid accumulation in FFA-challenged primary hepatocytes without cytotoxicity. In vivo, AA showed pleiotropic benefits, including attenuating adiposity, mitigating hepatic steatosis and inflammation, improving lipid disorders and insulin resistance, and restoring the impaired gut barrier. Mechanically, we found that AA indirectly activated Sirt1/AMPK-modulated lipid metabolism through elevating NAMPT-mediated NAD+ level, and triggering autophagy, together mediating the lipid-lowering effects. Collectively, our results convey that AA can substantially mitigate NAFLD via indirectly activating Sirt1/AMPK signaling, inducing autophagy and restoring gut barrier, and will be considered as a promising candidate for NAFLD therapy.