Predicting anti-hyperuricemic and anti-gouty activities of fatty acids from Limonia acidissima L. fruit: In silico-in vivo study

Context: As of today, the knowledge of the role of nutraceuticals in treating metabolic diseases such as hyperuricemia is still limited. Aims: To evaluate the mechanisms of anti-hyperuricemic and anti-gouty activity of Limonia acidissima in silico and in vivo.Methods: L. acidissima fruits fine powder was macerated simultaneously using n-hexane, ethyl acetate, ethanol, and methanol sequentially. The structures of the GC-MS-identified phytocompounds were evaluated for their pharmacokinetic properties (SwissADME), traced for receptor targets (SEA Target), and converted to 3D structures and molecular anchoring (MOE software). Networking relationship analyses were performed using Cytoscape version 3.8.2. Anti-hyperuricemia effect was assessed with hyperuricemia rats induced by potassium oxonate. The anti-inflammatory effect was evaluated on acute gouty arthritis induced by monosodium urate (MSU) crystal.Results: The predominant fatty acid contents (oleic acid, palmitoleic acid, and n-hexadecanoic acid) have satisfactory pharmacokinetic properties based on Lipinsky's rules. PPAR-gamma, FABP3, OAT1, and OAT3 were revealed as targets for the fatty acid receptors. The highest interaction was obtained from oleic acid interaction with PPAR-gamma (-12.54 kcal/mol) and FABP3 (-13.09 kcal/mol). The EEL 400 mg/kg effectively upregulated the protein levels of OAT1 (p=0.001) and OAT3 (p=0.048) in the kidneys of hyperuricemic rats. Moreover, EEL 400 mg/kg alleviated the swelling (p<0.001) and reduced inflammatory cell infiltration around the ankle joints in rats with acute gouty arthritis.Conclusions: The networking analysis suggests that PPAR-gamma and FABP3 could form an interaction to modulate XO directly. L. acidissima exhibited anti-hyperuricemic by regulating renal organic ion transporter expression and anti-gout arthritis effects by suppressing inflammation response.