基于整合药理学视角的升清降酸方对高尿酸血症及痛风的"病-证-方"关联分子网络机制解析及临床研究OA

This study aims to explore the mechanisms of Shengqing Jiangsuan Formula(SJF)in treating hyperuricemia and gout through"disease-syndrome-formula"association network analysis and evaluate its efficacy via preliminary clinical observation.At first,on the basis of the clinical guidelines,expert consensus,combined with TCM syndrome ontology,each disease stage[hyperuricemia stage(internal accumulation syndrome of dampness-turbidity),acute gouty arthritis stage(dampness-heat-toxin accumulation syndrome),gout intermission stage(internal accumulation syndrome of dampness-turbidity),chronic gouty arthritis stage(phlegm-stasis obstruction syndrome,spleen-deficiency dampness-heat syndrome),and gouty nephropathy stage(spleen-kidney deficiency syndrome)],as well as relevant symptoms and gene sets were collected using the SoFDA and human phenotype ontology(HPO)databases.Meanwhile,candidate target profiles of components in SJF were obtained from the Encyclopedia of Traditional Chinese Medicine 2.0(ETCM 2.0),thereby acquiring target molecule sets for disease/syndrome stages and candidate target sets of the formula.Then,Jaccard similarity of clinical symptoms and target genes,as well as cosine similarity of enriched pathways between the formula and disease stages were calculated to evaluate the intervention potential of SJF in different stages(syndromes).In addition,"disease-syndrome-formula"association networks of SJF in treating hyperuricemia stage(internal accumulation syndrome of dampness-turbidity)and acute gouty arthritis stage(dampness-heat-toxin accumulation syndrome)were constructed and analyzed to extract core network targets and explore their mechanisms.After that,five patients with hyperuricemia and gout were enrolled,treated with oral SJF(one dose per day,decocted for oral administration,one week as one course).Efficacy was evaluated by changes in TCM syndrome scores and serum uric acid(SUA)levels,with clinical safety observed.The results showed that a total of 2 646(1 946),3 069(1 080),2 800(1 946),2 431(897,1 163),and 1 534(872)target sets were collected for each stage(syndrome)of hyperuricemia and gout,and 1 123 predicted target sets of chemical components in SJF were obtained from ETCM 2.0.Intervention potential evaluation of"formula-clinical stage"showed that SJF had high correspondence with hyperuricemia stage and acute gouty arthritis stage in target genes,biological functions,and enriched pathways.Network analysis revealed that core network targets of SJF in the hyperuricemia stage exerted effects in neuroprotection,insulin resistance amelioration,anti-oxidative stress,anti-inflammation,vascular endothelial damage prevention,and interstitial fibrosis delay.Those in acute gouty arthritis stage regulated T cell subset imbalance,inhibited NLRP3 inflammasome activation,and modulated the dynamic balance of neutrophil extracellular traps(NETs).Clinical efficacy evaluation showed that after 1,2,and 10 weeks of treatment,SUA levels decreased by 51.4%,48.0%,and 41.9%,and TCM syndrome scores decreased by 50.0%,36.2%,and 85.7%,with no obvious adverse reactions.The effect size analysis showed that Cohen's d=1.569 and the corrected Hedges' g=1.255,indicating that SJF had a strong effect in reducing uric acid.The study provides a theoretical basis for clarifying the clinically advantageous stages of SJF and guiding its rational clinical application.