Study On The Mechanism Of Keluoxin Capsule For DKD Based On Network Pharmacology

BackgroundDiabetic Kidney Disease(DKD)is a serious chronic disease that often leads to kidney failure.The current treatment is aimed at early control of blood glucose,blood pressure,blood lipids,especially with RAAS inhibitors to reduce or eliminate albuminuria,but there is still a lack of effective treatment to delay or even reverse glomerulosclerosis or renal interstitial fibrosis.In recent years,the therapeutic characteristics of traditional Chinese medicine with small side effects,multi-targets and multi-pathways have made some progress in improving DKD,but its composition is complex and its mechanism is not clear,so its clinical use is limited.As the chief researcher of the Chinese Academy of traditional Chinese Medicine,Professor Lin Lan developed the first proprietary Chinese medicine approved to treat DKD-Keluoxin capsule(KLX).Its therapeutic effects are replenishing qi and nourishing yin,activating blood circulation and removing blood stasis,but its mechanism has not been reported at the molecular level.Research methods and results1 Clinical observation of Keluoxin capsuleA retrospective study was conducted on the clinical therapeutic effect of KLX on patients with DKD diagnosed in a hospital in Chongqing from September 2021 to September 2022.The control group was treated with routine western medicine,and the study group was treated with routine western medicine plus KLX.After treatment,it was found that the contents of FBG,Hb Alc,Scr,urinary protein and UAER in both groups decreased,but the improvement of renal function was more obvious.The results suggest that KLX combined with western medicine is superior to western medicine in the treatment of DKD in terms of glucose metabolism and renal function.2 A meta-analysis of the efficacy of Keluoxin capsules in the treatment of diabetic nephropathyIn order to further confirm the clinical therapeutic effect of KLX and lay a foundation for the study of its mechanism,Meta analysis was carried out.Search the database and screen the literatures of randomized controlled trials(RCT)of KLX in the treatment of DKD.The literature was searched and screened according to the proposed retrieval strategy and criteria,and the literature quality was evaluated by Cochrane risk bias assessment tool,and the literature data were extracted.Rev Man5.3 software was used for quantitative system evaluation.A total of 17 studies were included.The results of Meta analysis showed that compared with the control group,KLX combined with conventional western medicine group had the advantages of improving BUN,Scr,24 h UTP,TC,LDL-C,HDL-C,IL-6 and TNF-α.It fully affirmed the clinical efficacy of KLX in glucose metabolism,lipid metabolism and anti-inflammation in patients with DKD.3 Based on network pharmacology analysis of the mechanism of action of Keluoxin capsulesBased on the clinical effect,the mechanism of KLX was studied.The chemical composition,action target and diabetic nephropathy target of Keluoxin capsule were obtained by searching the drug and disease database.The drug-disease intersection target was used to draw "traditional Chinese medicine-active ingredient-disease target" and PPI network diagram.Then GO function annotation and KEGG pathway enrichment analysis were carried out.Results 672 KLX targets and 1119 DKD targets were obtained,and then165 drug-disease intersection targets were obtained.Through network visualization and topological analysis,it is known that the main active components that may play a therapeutic role are quercetin,kaempferol,luteolin,β-sitosterol,zelanaxanthin,oleanolic acid,ivy and so on.The main targets are VEGFA,IL1 β,CASP3,FN1,MMP9,HIF1 α,ICAM1 and so on.The results of enrichment analysis showed that KLX improved DKD and delayed the progression of disease by acting on PI3K-Akt,MAPK,AGE-RAGE,HIF-1 and other biological processes,such as inflammation,positive and negative regulation of apoptosis,lipid metabolism and cell response to insulin.4 Molecular docking and molecular dynamics of Keluoxin capsule in the treatment of Diabetic Kidney DiseaseIn order to verify the accuracy of network pharmacology,the main active components and targets were used for molecular docking.The docking results showed that the lowest binding energies of 7 active components and 7 key targets were basically between-5.7kcal/mol～-10.6kcal/mol,all less than-5.0kcal/mol,showing good docking activity,forming many kinds of intermolecular forces such as van der Waals force,hydrogen bond and so on.The kinetic simulation of the two complexes with the lowest binding energy of quercetin and luteolin with MMP9 was carried out.The results of RMSD,RMSF and binding free energy calculation showed that the small molecule-protein had a good affinity,the complex was stable and might have biological activity.ConclusionThrough the clinical observation and Meta analysis of Keluoxin capsule in the treatment of diabetic kidney disease,and using network pharmacology,molecular docking and molecular dynamics to explore and verify its mechanism,we can know that traditional Chinese medicine Keluoxin capsule can treat diabetic kidney disease with multi-components,multi-targets and multi-pathways,which provides the modern pharmacological basis of traditional Chinese medicine for clinical treatment of integrated traditional Chinese and western medicine.