Anacardic acid ameliorates insulin resistance and diabetic nephropathy: network pharmacology, in vivo and molecular docking studies targeting TNF- α / TGFβR1 signaling.

Diabetic nephropathy (DN) is a multifactorial disease, so there is a global attitude to use natural products for DN management due to their polypharmacological effects. Anacardic acid (AA) is a natural product from Anacardium occidentale. We aimed to investigate the protective effect of AA on the kidney and pancreas through targeting hyperlipidemia, hyperglycemia, insulin resistance oxidative stress, TNF-α, TGFβR1, and α-SMA signaling. Network pharmacology, Molecular docking, experimental, and histopathological studies were established to evaluate the efficacy of AA on DN management. Biochemical analyses of glycated hemoglobin, fasting glucose, insulin, lipid profile, renal functions, MDA, GSH, TNF-α, and TGFβR1 parameters were measured. Additionally, immunohistopathological examination of α-SMA and histopathological examinations of pancreas and kidney tissues were performed to explore pancreatic and renal tissues changes. Network pharmacology suggested an association between AA and DN. In vivo results demonstrated that AA treatment had an effective improvement of insulin sensitivity as evidenced by low HOMA-IR, and suppression of DN progression as evidenced by high creatinine clearance, reduction of the bowman capsule space and reduction of collagen fiber deposition in kidney tissues. Molecular docking study showed a promising inhibitory effect of AA against TNF-α and TGFβR1 with binding energies of (-8and-7.1 kcal/mol, respectively), molecular dynamic simulation study for 200 ns assured the molecular docking results and the two complexes were structurally robust with binding free energy of (- 18.56 kcal/mol, - 30.39 kcal/mol, respectively). In conclusion, AA renoprotective effects in type 2 diabetic rats may be related to its inhibitory effect on TNF-α/ TGFβR1/ α-SMA signaling.