{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:17:15Z","timestamp":1785428235541,"version":"3.56.0"},"reference-count":51,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013801","name":"Minzu University of China","doi-asserted-by":"publisher","award":["SZKY-Y2025194"],"award-info":[{"award-number":["SZKY-Y2025194"]}],"id":[{"id":"10.13039\/501100013801","id-type":"DOI","asserted-by":"publisher"}]},{"award":["SZKY-Y2025194"],"award-info":[{"award-number":["SZKY-Y2025194"]}],"id":[{"id":"https:\/\/ror.org\/0044e2g62","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Type 2 diabetes mellitus (T2DM) is a chronic multifactorial metabolic disorder requiring multi-target therapeutic strategies. This study aimed to predict the potential material basis, key targets and molecular mechanisms by which PuRenDan (PRD) may act against T2DM through an integrated network pharmacology and molecular simulation approach. Methods: Active compounds of PRD were screened from TCMSP, HERB 2.0 and the literature, and compound-related targets were predicted using TCMSP, SwissTargetPrediction and PharmMapper. T2DM-associated targets were collected from OMIM, DrugBank, DisGeNET, HPO, ClinPGx and GeneCards to obtain drug\u2013disease intersection targets. Cytoscape was used to construct herb\u2013compound\u2013target and protein\u2013protein interaction (PPI) networks, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking was performed using AutoDock Vina1.1.2, and representative ligand\u2013receptor complexes were further assessed by 100 ns molecular dynamics (MD) simulations and molecular mechanics\/Poisson\u2013Boltzmann surface area (MM\/PBSA) binding free-energy analysis. Results: A total of 163 active compounds, 597 PRD-related targets, 9138 T2DM-associated targets and 483 intersection targets were identified. \u03b2-sitosterol, emodin, quercetin, kaempferol and formononetin were predicted as major active compounds, whereas AKT1, TP53, SRC, IL6, TNF, EGFR and ESR1 were identified as disease-related network hubs. KEGG enrichment highlighted the PI3K-Akt, MAPK, HIF-1, FoxO, mTOR, AGE-RAGE and TNF signalling pathways. Docking predicted a comparatively favourable multi-target binding tendency for \u03b2-sitosterol. MD and MM\/PBSA analyses further suggested favourable dynamic stability for \u03b2-sitosterol-TNF, \u03b2-sitosterol-AKT1, \u03b2-sitosterol-SRC and emodin-EGFR complexes, with \u03b2-sitosterol-TNF showing the lowest predicted binding free energy among the simulated systems. Conclusions: These in silico findings suggest that PRD may regulate T2DM-related inflammatory, insulin-signalling, oxidative-stress and metabolic networks through coordinated multi-compound, multi-target and multi-pathway actions. \u03b2-sitosterol may represent an important candidate material basis of PRD, with TNF, AKT1, SRC and EGFR as potential key targets. These conclusions remain predictive and require validation in biochemical, cellular and animal experiments.<\/jats:p>","DOI":"10.3390\/ph19071107","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:47:32Z","timestamp":1784508452000},"page":"1107","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Material Basis and Mechanisms of Action of PuRenDan in the Treatment of Type 2 Diabetes Mellitus: An Integrated Network Pharmacology and Molecular Simulation Study"],"prefix":"10.3390","volume":"19","author":[{"given":"Wenshuai","family":"Yang","sequence":"first","affiliation":[{"name":"Key Laboratory of Ethnic Medicine in Ministry of Education, School of Pharmacy, Minzu University of China, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaojie","family":"Ouyang","sequence":"additional","affiliation":[{"name":"College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan 430065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenwen","family":"Zhou","sequence":"additional","affiliation":[{"name":"Key Laboratory of Ethnic Medicine in Ministry of Education, School of Pharmacy, Minzu University of China, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binan","family":"Lu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Ethnic Medicine in Ministry of Education, School of Pharmacy, Minzu University of China, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongran","family":"Pang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Ethnic Medicine in Ministry of Education, School of Pharmacy, Minzu University of China, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1016\/S0140-6736(24)02317-1","article-title":"Worldwide trends in diabetes prevalence and treatment from 1990 to 2022: A pooled analysis of 1108 population-representative studies with 141 million participants","volume":"404","author":"Zhou","year":"2024","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Cui, J., Liu, Y., Li, Y., Xu, F., and Liu, Y. (2021). Type 2 Diabetes and Myocardial Infarction: Recent Clinical Evidence and Perspective. Front. Cardiovasc. Med., 8.","DOI":"10.3389\/fcvm.2021.644189"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1007\/s13300-021-01062-6","article-title":"A Target HbA1c Between 7 and 7.7% Reduces Microvascular and Macrovascular Events in T2D Regardless of Duration of Diabetes: A Meta-Analysis of Randomized Controlled Trials","volume":"12","author":"Sinha","year":"2021","journal-title":"Diabetes Ther."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Nedosugova, L.V., Markina, Y.V., Bochkareva, L.A., Kuzina, I.A., Petunina, N.A., Yudina, I.Y., and Kirichenko, T.V. (2022). Inflammatory Mechanisms of Diabetes and Its Vascular Complications. Biomedicines, 10.","DOI":"10.3390\/biomedicines10051168"},{"key":"ref_5","first-page":"175","article-title":"Effect of Purendan on glucolipid metabolism and insulin resistance in ob\/ob mice","volume":"34","author":"Zhang","year":"2017","journal-title":"Tianjin J. Tradit. Chin. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"117627","DOI":"10.1016\/j.jep.2023.117627","article-title":"PuRenDan alleviates type 2 diabetes mellitus symptoms by modulating the gut microbiota and its metabolites","volume":"322","author":"Ma","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"115283","DOI":"10.1016\/j.jep.2022.115283","article-title":"The therapeutic mechanism of PuRenDan for the treatment of diabetic nephropathy: Network pharmacology and experimental verification","volume":"293","author":"Niu","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"ref_8","first-page":"29","article-title":"Study on the PRD on the Glucose-decreasing Effect of Diabetic Rats","volume":"8","author":"Jia","year":"2002","journal-title":"J. Basic Chin. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e142241","DOI":"10.1172\/JCI142241","article-title":"Insulin signaling in health and disease","volume":"131","author":"Saltiel","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"D672","DOI":"10.1093\/nar\/gkae909","article-title":"KEGG: Biological systems database as a model of the real world","volume":"53","author":"Kanehisa","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_11","unstructured":"Kanehisa Laboratories (2026, June 27). KEGG DRUG: Sitagliptin, D08516. Kyoto Encyclopedia of Genes and Genomes. Available online: https:\/\/www.genome.jp\/dbget-bin\/www_bget?drug:D08516."},{"key":"ref_12","unstructured":"Kanehisa Laboratories (2026, June 27). KEGG DRUG: Dapagliflozin, D08897. Kyoto Encyclopedia of Genes and Genomes. Available online: https:\/\/www.genome.jp\/dbget-bin\/www_bget?D08897."},{"key":"ref_13","unstructured":"Kanehisa Laboratories (2026, June 27). KEGG DRUG: Pioglitazone, D08378. Kyoto Encyclopedia of Genes and Genomes. Available online: https:\/\/www.genome.jp\/dbget-bin\/www_bget?drug:D08378."},{"key":"ref_14","unstructured":"Kanehisa Laboratories (2026, June 27). KEGG DRUG\/COMPOUND: Acarbose, D00216\/C06802. Kyoto Encyclopedia of Genes and Genomes. Available online: https:\/\/www.genome.jp\/dbget-bin\/www_bget?cpd:C06802."},{"key":"ref_15","unstructured":"Kanehisa Laboratories (2026, June 27). KEGG DRUG: Insulin Human and Insulin Analogues, D03230. Kyoto Encyclopedia of Genes and Genomes. Available online: https:\/\/www.genome.jp\/dbget-bin\/www_bget?drug:D03230."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Gilbert, M.P., and Pratley, R.E. (2020). GLP-1 analogs and DPP-4 inhibitors in type 2 diabetes therapy: Review of head-to-head clinical trials. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.00178"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/s41392-024-01931-z","article-title":"Glucagon-like peptide-1 receptor: Mechanisms and advances in therapy","volume":"9","author":"Zheng","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Winiarska, A., Knysak, M., Nabrdalik, K., Gumprecht, J., and Stomp\u00f3r, T. (2021). Inflammation and oxidative stress in diabetic kidney disease: The targets for SGLT2 inhibitors and GLP-1 receptor agonists. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910822"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/s13098-024-01325-9","article-title":"Research advances in the anti-inflammatory effects of SGLT inhibitors in type 2 diabetes mellitus","volume":"16","author":"Zhang","year":"2024","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Han, Y.-P., Liu, L.-J., Yan, J.-L., Chen, M.-Y., Meng, X.-F., Zhou, X.-R., and Qian, L.-B. (2023). Autophagy and its therapeutic potential in diabetic nephropathy. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1139444"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Taguchi, K., Fukami, K., and Yamagishi, S. (2023). RAGE signaling regulates the progression of diabetic complications. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1128872"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zhang, S., Wang, Y., Han, L., Fu, X., Wang, S., Li, W., and Han, W. (2021). Targeting N-terminal human maltase-glucoamylase to unravel possible inhibitors using molecular docking, molecular dynamics simulations and adaptive steered molecular dynamics simulations. Front. Chem., 9.","DOI":"10.3389\/fchem.2021.711242"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e66942","DOI":"10.7554\/eLife.66942","article-title":"Akt phosphorylates insulin receptor substrate to limit PI3K-mediated PIP3 synthesis","volume":"10","author":"Kearney","year":"2021","journal-title":"eLife"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4750","DOI":"10.1038\/s41598-020-61531-z","article-title":"Effect of induced hypoglycemia on inflammation and oxidative stress in type 2 diabetes and control subjects","volume":"10","author":"Kahal","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Ding, Q., Gao, Z., Chen, K., Zhang, Q., Hu, S., and Zhao, L. (2022). Inflammation-Related Epigenetic Modification: The Bridge Between Immune and Metabolism in Type 2 Diabetes. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.883410"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Sheng, L., Bayliss, G., and Zhuang, S. (2021). Epidermal Growth Factor Receptor: A Potential Therapeutic Target for Diabetic Kidney Disease. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.598910"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1038\/s12276-022-00810-3","article-title":"Pan-Src kinase inhibitor treatment attenuates diabetic kidney injury via inhibition of Fyn kinase-mediated endoplasmic reticulum stress","volume":"54","author":"Dorotea","year":"2022","journal-title":"Exp. Mol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"R61","DOI":"10.1530\/JOE-16-0324","article-title":"The role of the p53 tumor suppressor in metabolism and diabetes","volume":"231","author":"Kung","year":"2016","journal-title":"J. Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"193","DOI":"10.3892\/mmr.2024.13317","article-title":"Pancreatic \u03b2-cell apoptosis in type 2 diabetes is related to post-translational modifications of p53","volume":"30","author":"Mora","year":"2024","journal-title":"Mol. Med. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"982","DOI":"10.2337\/db13-0425","article-title":"Epidermal growth factor receptor signaling promotes pancreatic \u03b2-cell proliferation in response to nutrient excess in rats through mTOR and FOXM1","volume":"63","author":"Zarrouki","year":"2014","journal-title":"Diabetes"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1002\/mnfr.200900012","article-title":"B-Sitosterol exhibits anti-inflammatory activity in human aortic endothelial cells","volume":"54","author":"Loizou","year":"2010","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/1758-2946-6-13","article-title":"TCMSP: A database of systems pharmacology for drug discovery from herbal medicines","volume":"6","author":"Ru","year":"2014","journal-title":"J. Cheminform."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"D1197","DOI":"10.1093\/nar\/gkaa1063","article-title":"HERB: A high-throughput experiment- and reference-guided database of traditional Chinese medicine","volume":"49","author":"Fang","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Arif, R., Bukhari, S.A., Mustafa, G., Ahmed, S., and Albeshr, M.F. (2024). Network Pharmacology and Experimental Validation to Explore the Potential Mechanism of Nigella sativa for the Treatment of Breast Cancer. Pharmaceuticals, 17.","DOI":"10.3390\/ph17050617"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Liu, H., Hu, Y., Qi, B., Yan, C., Wang, L., Zhang, Y., and Chen, L. (2022). Network pharmacology and molecular docking to elucidate the mechanism of pulsatilla decoction in the treatment of colon cancer. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.940508"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Xiang, C., Liao, Y., Chen, Z., Xiao, B., Zhao, Z., Li, A., Xia, Y., Wang, P., Li, H., and Xiao, T. (2022). Network Pharmacology and Molecular Docking to Elucidate the Potential Mechanism of Ligusticum Chuanxiong Against Osteoarthritis. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.854215"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"W357","DOI":"10.1093\/nar\/gkz382","article-title":"SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules","volume":"47","author":"Daina","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"W356","DOI":"10.1093\/nar\/gkx374","article-title":"PharmMapper 2017 update: A web server for potential drug target identification with a comprehensive target pharmacophore database","volume":"45","author":"Wang","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","article-title":"The STRING database in 2021: Customizable protein\u2013protein networks, and functional characterization of user-uploaded gene\/measurement sets","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","article-title":"The STRING database in 2023: Protein\u2013protein association networks and functional enrichment analyses for any sequenced genome of interest","volume":"51","author":"Szklarczyk","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/nature05933","article-title":"A transforming mutation in the pleckstrin homology domain of AKT1 in cancer","volume":"448","author":"Carpten","year":"2007","journal-title":"Nature"},{"key":"ref_44","unstructured":"Cheong, H.K., and Kim, H.J. (2026, April 17). Modular Evolution and Design of the Protein Binding Interface: 4j4l. Available online: https:\/\/www.rcsb.org\/structure\/4J4L."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1126\/science.1116304","article-title":"Small-Molecule Inhibition of TNF-\u03b1","volume":"310","author":"He","year":"2005","journal-title":"Science"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"46265","DOI":"10.1074\/jbc.M207135200","article-title":"Structure of the Epidermal Growth Factor Receptor Kinase Domain Alone and in Complex with a 4-Anilinoquinazoline Inhibitor","volume":"277","author":"Stamos","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1021\/jm034243o","article-title":"Estrogen Receptor Ligands. II. Discovery of Benzoxathiins as Potent, Selective Estrogen Receptor \u03b1 Modulators","volume":"47","author":"Kim","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1038\/76797","article-title":"Structure of the negative regulatory domain of p53 bound to S100B(\u03b2\u03b2)","volume":"7","author":"Weber","year":"2000","journal-title":"Nat. Struct. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.str.2005.03.012","article-title":"The Crystal Structure of a c-Src Complex in an Active Conformation Suggests Possible Steps in c-Src Activation","volume":"13","author":"Fendrich","year":"2005","journal-title":"Structure"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1021\/ci500020m","article-title":"g_mmpbsa\u2014A GROMACS Tool for High-Throughput MM-PBSA Calculations","volume":"54","author":"Kumari","year":"2014","journal-title":"J. Chem. Inf. Model."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/7\/1107\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T04:28:53Z","timestamp":1784608133000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/7\/1107"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,17]]},"references-count":51,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ph19071107"],"URL":"https:\/\/doi.org\/10.3390\/ph19071107","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,17]]}}}