Deciphering the molecular mechanisms of Simiaowan in the treatment of hyperuricemia: in vivo and in silico approaches

Background:Simiaowan(SMW),a well-known traditional Chinese medicine,has been employed to treat hyperuricemia(HUA)and gout for centuries.However,the bioactive components and underlying mechanisms have not been elucidated.The objective of this study was to identify the active components and potential mechanisms of SMW by integrating pharmacological experimentation,serum pharmacochemistry,network pharmacology and molecular docking.Methods:HUA rats modelling by high-fat/high-sugar diet and potassium oxonate/adenine oral administration were used to evaluate the pharmacodynamic effects of SMW.UPLC-Q-Exactive-MS/MS was employed to detect the bioactive components present in SMW-containing serum.Network pharmacology and molecular docking were utilized to elucidate the potential targets and underlying mechanisms.Results:SMW effectively ameliorated HUA rats via the inhibition of uric acid(UA)production,promotion of UA excretion,improvement of lipid and glucose metabolic abnormalities,antioxidant,anti-inflammatory and anti-insulin resistance effects.A total of 73 compounds detected in SMW-containing serum were identified as potential active components,with alkaloids,flavonoids,organic acids,and terpenoids emerging as the primary active ingredients.Totally 203 corresponding targets were obtained as SMW anti-HUA/gout targets,which mainly participated in apoptosis,insulin resistance,TNF,PI3K-Akt,HIF-1,NF-κB,MAPK,IL-17 and TLR signaling pathways.Molecular docking indicated that active compounds(e.g.berberine,phellodendrine,quercetin,formononetin,ferulic acid)had superior binding abilities to the key targets(e.g.solute carrier family 22 member 12(URAT1),solute carrier family 22 member 6(OAT1),ATP-binding cassette sub-family G member 2(ABCG2),solute carrier family 2,facilitated glucose transporter member 9(GLUT9),xanthine dehydrogenase/oxidase(XDH),transcription factor p65(RELA),toll-like receptor 4(TLR4),prostaglandin G/H synthase 2(PTGS2),caspase-3(CASP3),insulin(INS)).Conclusion:SMW exerted regulatory influence over the disease network of HUA and gout through a multiplicity of components,targets,and pathways.Alkaloids,flavonoids,organic acids,and terpenoids were the primary active components,exerting anti-HUA/gout effects via antioxidant,anti-inflammatory,anti-insulin resistance,anti-apoptosis,inhibition of UA production,and promotion of UA excretion.This study revealed the active components and molecular mechanisms of SMW,providing insights into the development of natural products derived from SMW.

Pharmacokinetic studies of multi-bioactive components in rat plasma after oral administration of Xintiantai Ⅰ extract and effects of guide drug borneol on pharmacokinetics

Objective:To investigate the in vivo pharmacokinetic characteristics of 17 bioactive components including ginsenoside Rg1,Rb1,Rd,berberine,epiberberine,jatrorrhizine,palmatine,columbamine,coptisine,evodiamine,dehydroevodiamine,rutaecarpine,limonin,hyperin,curcumin,demethoxycurcumin and bisdemethoxycurcumin in rat plasma after oral administration of Xintiantai I extract powder(XI)and Xintiantai I without guide drug borneol extract powder(XI without borneol),and study the compatibility effects of guide drug borneol on the pharmacokinetics.Methods:A UHPLC-MS/MS method was established and fully validated for the comparative pharmacokinetics of 17 bioactive components.The pharmacokinetics parameters of 17 bioactive components after oral administration of XI and XI without borneol were calculated by the software of DAS 3.0 and intercompared.Results:The specificity,linearity,lower limit of quantification(LLOQ),precision,accuracy,extraction recovery rates,matrix effects,and stability of the UHPLC-MS/MS assay were good within the acceptance criteria from FDA guidelines.Guide drug borneol can significantly increase AUC of G-Rd,palmatine,hyperin,curcumin,demethoxycurcumin,bisdemethoxycurcumin and Cmaxof 16 bioactive components except for dehydroevodiamine(P<0.05),decrease Tmaxof G-Rd,berberine,columbamin,coptisine,limonin and MRT of 17 bioactive components in XI group(P<0.05).Conclusion:Guide drug borneol enhanced the absorption of G-Rd,palmatine,hyperin,curcumin,demethoxycurcumin and bisdemethoxycurcumin.