Traditional Chinese Herb Couples Mitigate Diabetic Macrovascular Disease via the AGE–RAGE Signaling Pathway

Cinnamomi Ramulus-Puerariae Lobatae Radix (CR-PLR) possesses antidiabetic macrovascular pathology pharmacological effects, but its precise pharmacological mechanisms remain to be fully elucidated. A total of 197 CR-PLR targets were identified, with 1015 diabetic macrovascular disease-specific targets through network pharmacological analysis, and 55 intersecting targets were found. We screened five main active ingredients: Puerarin, 3'-methoxydaidzein, cinnamaldehyde, cinnamic acid, and formononetin. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that CR-PLR might ameliorate diabetic macrovascular disease through the AGE-RAGE signaling pathway. In vivo experiments verified that CR-PLR significantly reduced body weight and blood glucose, improved vascular function, and attenuated inflammatory responses (e.g., interleukin-6 [IL-6], IL-4, etc.) and lipid metabolism abnormalities (e.g., triglyceride, total cholesterol, LDL, HDL), which was corroborated by the results of immunofluorescence experiments. WB analysis validated that CR-PLR modulates the AGE-RAGE signaling pathway, thereby attenuating vascular inflammation and metabolic dysregulation. These findings provide novel insights into the therapeutic potential of CR-PLR, suggesting its application as a complementary treatment for diabetic macrovascular disease.