| Summary: | Abstract Panax notoginseng, a Chinese traditional food and herb medicine, possesses notable cardiovascular health‐promoting properties, with notoginsenoside (NG)‐R1 being a key active compound. Insulin resistance represents a global health concern associated with various metabolic disorders. This study investigated the effects of NG‐R1 on palmitic acid (PA)‐induced insulin resistance and oxidative stress in human umbilical vein endothelial cells (HUVECs). Our findings demonstrate that NG‐R1 significantly alleviated impaired glucose uptake, enhanced the phosphorylation of protein kinase B (PKB/Akt) at Ser473, and reduced the phosphorylation of insulin receptor substrate 1 (IRS‐1) at Ser307 in PA‐treated HUVECs. Furthermore, NG‐R1 treatment significantly lowered the levels of malondialdehyde (MDA) and 4‐hydroxynonenal (4‐HNE), while increasing the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG). Additionally, NG‐R1 activated the Nrf2/ARE signaling pathway, leading to a substantial increase in the expression of antioxidant enzymes. Notably, knockdown of Nrf2 attenuated the beneficial effects of NG‐R1 on PA‐induced insulin resistance and oxidative stress in HUVECs, suggesting that NG‐R1 exerts its effects through the Nrf2/ARE pathway. In summary, our study reveals that NG‐R1 ameliorated PA‐induced insulin resistance in HUVECs via Nrf2/ARE pathway, providing novel insights into its potential for alleviating metabolic disorders and cardiovascular disease.
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