Abstract

Endothelial dysfunction and oxidative stress caused by hyperglycemia are the main contributors to vascular complications in patients with diabetes mellitus (DM), which is a significant global health issue. The downregulation of sirtuin 1 (SIRT1), a key regulator of antioxidant defenses, further exacerbates vascular damage in diabetic conditions. This study aimed to investigate the therapeutic effects of brown Yar Ko (YK) rice extract, a traditional variety from southern Thailand, on hyperglycemia-induced oxidative stress in human umbilical vein endothelial cells (HUVECs), with a focus on SIRT1 activation. Methodologically, YK rice was extracted and identified via triple quadrupole GC‒MS/MS. Antioxidant activity was assessed via DPPH and FRAP assays. A 30 mM glucose-stimulated HUVEC model was utilized to mimic diabetes in vitro. Oxidative stress, endothelial function, and DNA damage were evaluated via DCFH-DA, tubulogenesis, and γ-H2AX staining, respectively. SIRT1 expression was analyzed via western blotting, and downstream signaling pathways were predicted via pharmacological network analysis. The results of chemical profiling revealed that YK rice extract is rich in beneficial fatty acids (linoleic, oleic, and palmitic acids) and micronutrients. The extract presented a high total phenolic content and potent antioxidant activity, significantly reducing reactive oxygen species (ROS) levels and DNA damage in hyperglycemia-induced HUVECs. Functional assays demonstrated that YK rice extract improved angiogenic capacity and mitigated endothelial dysfunction under hyperglycemic conditions. Mechanistically, treatment with YK rice extract upregulated SIRT1 expression, as confirmed by immunofluorescence and western blot analyses. Network pharmacology revealed the SIRT1 with PPAR-α and PPAR-γ axis as a key pathway modulated by major YK rice constituents, potentially suggesting enhanced mitochondrial biogenesis and antioxidant gene expression. However, these proposed mechanisms require further experimental validation for definitive elucidation.