Fenchone and Cinnamyl Acetate Attenuate L-NAME-Induced Hypertension via Modulation of Vascular Dysfunction, Oxidative Stress, and Renal Injury: An Integrated Network Pharmacology, Molecular Docking, and ADMET Study.
Source: PubMed, NCBI / U.S. National Library of Medicine
Hypertension is a major cardiovascular disorder associated with oxidative stress, endothelial dysfunction, and renal damage, necessitating safer therapeutic alternatives. The antihypertensive potential of cinnamyl acetate (Cmyl) and fenchone (Fcon) was assessed using integrated network pharmacology, molecular docking, ADMET, and in vivo validation. Targets and pathways were identified via network pharmacology and KEGG analysis, followed by molecular docking and ADMET profiling. Antihypertensive activity was assessed in an L-NAME-induced hypertensive rat model through blood pressure (BP), oxidative stress markers, renal biomarkers, gene expression, and histopathology. Cmyl (31 targets) and Fcon (17 targets) were linked to PI3K-Akt signaling, lipid metabolism, and inflammatory pathways. Docking showed strong binding of Cmyl with 5-HTR2A (-4.686 kcal/mol) and Fcon with NPC1L1 (-5.541 kcal/mol). ADMET confirmed drug-likeness and safety. L-NAME elevated systolic blood pressure/diastolic blood pressure (SBP/DBP: 145.78/98.88 mmHg; p < 0.0001), which was reduced by Fcon (121.69/81.61 mmHg, 400 mg/kg) and Cmyl (122.63/83.72 mmHg, 50 mg/kg). Antioxidants enzymes (CAT: up to 9.17-10.23 pg/mL; SOD: 3.53-3.84 U/mL; GSH: 700.83-738.82 pg/mL) were improved significantly, and malondialdehyde (MDA) was decreased (2.63-2.40 nmol/L) with the restoration of urea (21.0-22.4 mg/dL) and creatinine (1.30-1.34 mg/dL). Both compounds downregulated iNOS, AGT, renin, 5-HTR2A, and NPC1L1, and restored A
Abstract
Hypertension is a major cardiovascular disorder associated with oxidative stress, endothelial dysfunction, and renal damage, necessitating safer therapeutic alternatives. The antihypertensive potential of cinnamyl acetate (Cmyl) and fenchone (Fcon) was assessed using integrated network pharmacology, molecular docking, ADMET, and in vivo validation. Targets and pathways were identified via network pharmacology and KEGG analysis, followed by molecular docking and ADMET profiling. Antihypertensive activity was assessed in an L-NAME-induced hypertensive rat model through blood pressure (BP), oxidative stress markers, renal biomarkers, gene expression, and histopathology. Cmyl (31 targets) and Fcon (17 targets) were linked to PI3K-Akt signaling, lipid metabolism, and inflammatory pathways. Docking showed strong binding of Cmyl with 5-HTR2A (-4.686 kcal/mol) and Fcon with NPC1L1 (-5.541 kcal/mol). ADMET confirmed drug-likeness and safety. L-NAME elevated systolic blood pressure/diastolic blood pressure (SBP/DBP: 145.78/98.88 mmHg; p < 0.0001), which was reduced by Fcon (121.69/81.61 mmHg, 400 mg/kg) and Cmyl (122.63/83.72 mmHg, 50 mg/kg). Antioxidants enzymes (CAT: up to 9.17-10.23 pg/mL; SOD: 3.53-3.84 U/mL; GSH: 700.83-738.82 pg/mL) were improved significantly, and malondialdehyde (MDA) was decreased (2.63-2.40 nmol/L) with the restoration of urea (21.0-22.4 mg/dL) and creatinine (1.30-1.34 mg/dL). Both compounds downregulated iNOS, AGT, renin, 5-HTR2A, and NPC1L1, and restored Agtr2 expression. Kidney histopathological analysis showed superior renoprotection with Fcon, whereas Cmyl showed mild interstitial fibrosis. Cmyl and Fcon exert potent antihypertensive effects via multi-target mechanisms involving antioxidant, metabolic, and renoprotective pathways. Fcon showed superior efficacy, supporting their potential as natural antihypertensive agents.