RESUMEN

Three neolignan glycosides, including a new compound (7S,8R)-dihydro-3'-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1'-benzofuranpropanol-9-O-ß-D-xylopyranoside (1), were isolated from the root of Nothopanax davidii. Their structures were determined by extensive spectroscopic analyses, particularly NMR, HR-ESI-MS, and ECD experiments, and the absolute configuration of 2 was first definitively determined. The anti-tumor activity was assessed on four tumor cells by MTT assay, the anti-inflammatory activity was determined by inhibition of NO production in LPS reduced RAW264.7 cells, and the interaction with iNOS was predicted by molecular docking. At the dose of 100 µM, the three neolignan glycosides showed no cytotoxic activity against HepG2, HCT116, HeLa and A549 human tumor cells, but significantly inhibited LPS induced NO generation in RAW264.7 cells with inhibition rates of 31.53 %, 23.95 %, and 20.79 %, respectively, showing weak anti-inflammatory activity, possibly due to their binding to key residues of iNOs involved in inhibitor binding.

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Oxidized low-density lipoprotein (ox-LDL)-induced endothelial-mesenchymal transition (EndMT), inflammation and apoptosis in endothelial cells play crucial roles in the progression of cardiovascular diseases including atherosclerosis. Vaccarin is a flavonoid glycoside from vaccariae semen associated with powerful cardiovascular protective effects. However, the effects of vaccarin on human umbilical vein endothelial cells (HUVEC) injury in response to ox-LDL remain unknown. Herein, we showed that treatment with vaccarin significantly suppressed ox-LDL-induced HUVEC inflammation, EndMT and apoptosis. Mechanistically, the HUVECs exposed to ox-LDL exhibited enlarged reactive oxygen species (ROS) production and p38 MAPK phosphorylation, which was counteracted by vaccarin. Importantly, ROS activator hydrogen peroxide (H2O2) and p38 MAPK activator anisomycin pretreatment prevent the protective effect of vaccarin on endothelial injury induced by ox-LDL. Our study suggested that vaccarin impeded ox-LDL-triggered HUVEC inflammation, EndMT and apoptosis via inhibition of ROS/p38 MAPK signaling pathway. Vaccarin may have a therapeutic effect on endothelial injury-related disorders.

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Destructive glucose and lipid metabolism in the liver is a crucial characteristic of type 2 diabetes mellitus (T2DM), eventually leading to insulin resistance and subsequent hyperglycemia and hyperlipidemia. Vaccarin is an active flavonoid glycoside associated with various biological functions, but its effects on glucose and lipid metabolic disorder in T2DM are still unclear. In this study, glucosamine (GlcN) and free fatty acids (FFAs, oleate/palmitate, 2:1 ratio) were applied to mimic insulin resistance and lipid deposition in HepG2 cells, respectively. Type 2 diabetic mice were induced using a high-fat diet (HFD) together with streptozotocin (STZ). GlcN stimulation was found to upregulate glucose production and gluconeogenesis but downregulate glycogen synthesis and phosphorylation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) in HepG2 cells, abnormal changes that were reversed by vaccarin. Furthermore, lipid accumulation was enhanced, but AMPK was inactivated in FFAs-exposed HepG2 cells, issues that were rectified by vaccarin treatment. These ameliorative effects of vaccarin on insulin resistance and steatosis were eliminated by AMPK inhibitor Compound C. In type 2 diabetic mice, chronic vaccarin administration decreased fasting blood glucose and lipid levels in both serum and the liver, and improved insulin sensitivity and steatosis in the liver. Taken together, these results suggest that vaccarin attenuates insulin resistance and steatosis by activating the AMPK signaling pathway.

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Vaccarin (VAC), an active flavonoid glycoside from vaccariae semen, exhibits extensive biological activities including vascular endothelial cell protective effects. Histone deacetylase1 (HDAC1) is an epigenetic regulator in cellular apoptosis. In this study, we evaluated the protective effects of VAC on high glucose (HG)-induced cell apoptosis in human microvascular endothelial cells (HMEC-1). The levels of reactive oxygen species, activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were measured. Expressions of HDAC1, Bax, Bcl-2, caspase-3 and cleaved caspase-3 were detected with western blot. Flow cytometry was used to determine cell apoptosis and cell cycle. We found that HG treatment decreased cell vitality, upregulated HDAC1 protein level, promoted reactive oxygen species production, induced cell cycle arrest and cell apoptosis in HMEC-1 cells, which were all rectified by VAC. Both scavenging reactive oxygen species and inhibition of HDAC1 alleviated the apoptosis of HMEC-1 cells in response to HG. Pretreatment with VAC prevented HG-stimulated reactive oxygen species generation and HDAC1 expression in HMEC-1 cells. Taken together, these data suggested that VAC protected against HG-induced endothelial cell apoptosis via inhibition of reactive oxygen species accumulation and HDAC1 expression. VAC may be a potential therapeutic agent for treatment of diabetes mellitus (DM)-related endothelial dysfunction.

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