Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Research Article

Underlying Mechanism of Traditional Herbal Formula Chuang-Ling-Ye in the Treatment of Diabetic Foot Ulcer through Network Pharmacology and Molecular Docking

Author(s): Jinyuan Geng, Guowei Zhou, Song Guo, Chaoqun Ma and Jiangfeng Ma*

Volume 30, Issue 6, 2024

Published on: 09 February, 2024

Page: [448 - 467] Pages: 20

DOI: 10.2174/0113816128287155240122121553

Price: $65

Abstract

Background: Chuang-Ling-Ye (CLY) has been clinically proven to be an effective Chinese medicine for the treatment of diabetic foot ulcers (DFU).

Objectives: This study aimed to investigate the possible mechanism of CLY in relation to DFU using network pharmacology and molecular docking.

Materials and Methods: Firstly, relevant targets of CLY against DFU were obtained from TCMSP, Swiss Target Prediction database and GEO database. Then, topological analysis was employed by Cytoscape to screen the top 6 core active ingredients and the top 8 hub targets. Furthermore, the OmicShare Tools were applied for gene ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis. Finally, the results of network pharmacology were verified by molecular docking method.

Results: CLY has 61 active compounds and 361 targets after de-duplication, and the top 8 hub targets were EGFR, TP53, CCND1, IL-1B, CREBBP, AR, PTGS2 and PGR. GO enrichment analysis is mainly related to signal transducer activity, receptor activity, and molecular transducer activity. KEGG pathway analysis indicated that these shared targets were primarily focused on AGE-RAGE signaling pathway in diabetic complications, HIF-1 signaling pathway, IL-17 signaling pathway, and JAK-STAT signaling pathway. Molecular docking results showed that physciondiglucoside, 2-cinnamoyl-glucose and kinobeon A were well bound with EGFR, IL-1B, AR and PTGS2.

Conclusion: This study demonstrated that CLY has anti-oxidative stress and anti-inflammatory effects in the treatment of DFU through various constituents, multiple targets, and multiple pathways, which provides a valuable point of reference for future investigations on CLY.

Keywords: Traditional herbal formula, Chuang-Ling-Ye, diabetic foot ulcer, network pharmacology, molecular docking, gene ontology.

[1]
Lipsky BA, Berendt AR, Deery HG, et al. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2004; 39(7): 885-910.
[http://dx.doi.org/10.1086/424846] [PMID: 15472838]
[2]
Jiang Y, Wang X, Xia L, et al. A cohort study of diabetic patients and diabetic foot ulceration patients in China. Wound Repair Regen 2015; 23(2): 222-30.
[http://dx.doi.org/10.1111/wrr.12263] [PMID: 25682850]
[3]
Sun H, Saeedi P, Karuranga S, et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract 2022; 183: 109119.
[http://dx.doi.org/10.1016/j.diabres.2021.109119] [PMID: 34879977]
[4]
Vijayakumar V, Samal SK, Mohanty S, Nayak SK. Recent advancements in biopolymer and metal nanoparticle-based materials in diabetic wound healing management. Int J Biol Macromol 2019; 122: 137-48.
[http://dx.doi.org/10.1016/j.ijbiomac.2018.10.120] [PMID: 30342131]
[5]
Lim JZM, Ng NSL, Thomas C. Prevention and treatment of diabetic foot ulcers. J R Soc Med 2017; 110(3): 104-9.
[http://dx.doi.org/10.1177/0141076816688346] [PMID: 28116957]
[6]
Tseng CH. Prevalence and risk factors of diabetic foot problems in Taiwan: A cross-sectional survey of non-type 1 diabetic patients from a nationally representative sample. Diabetes Care 2003; 26(12): 3351-1.
[http://dx.doi.org/10.2337/diacare.26.12.3351] [PMID: 14633829]
[7]
Zhou X, Guo Y, Yang K, Liu P, Wang J. The signaling pathways of traditional Chinese medicine in promoting diabetic wound healing. J Ethnopharmacol 2022; 282: 114662.
[http://dx.doi.org/10.1016/j.jep.2021.114662] [PMID: 34555452]
[8]
Wang Y, Yuan Y, Wang W, et al. Mechanisms underlying the therapeutic effects of Qingfeiyin in treating acute lung injury based on GEO datasets, network pharmacology and molecular docking. Comput Biol Med 2022; 145: 105454.
[http://dx.doi.org/10.1016/j.compbiomed.2022.105454] [PMID: 35367781]
[9]
Xue J-X, Ye B, Liu S, Cao S-H, Bian W-H, Yao C. Treatment efficacy of Chuang Ling Ye, a traditional chinese herbal medicine compound, on idiopathic granulomatous mastitis: A randomized controlled trial. Evid-Based Complem Altern Med 2020; 2020: 6964801.
[http://dx.doi.org/10.1155/2020/6964801]
[10]
Lv D, Chen X, Zhang N, Wu X, Jiang M. Total flavone of Abelmoschl manihot L. medic exhibits protective effect against hind-limb ischemia in rat model. Pak J Pharm Sci 2019; 32(1): 1-5.
[PMID: 30772783]
[11]
Tang L, Pan W, Zhu G, Liu Z, Lv D, Jiang M. Total flavones of Abelmoschus manihot enhances angiogenic ability both in vitro and in vivo. Oncotarget 2017; 8(41): 69768-78.
[http://dx.doi.org/10.18632/oncotarget.19264] [PMID: 29050240]
[12]
Huo X, Gu Y, Zhang Y. The discovery of multi-target compounds with anti-inflammation activity from traditional Chinese medicine by TCM-target effects relationship spectrum. J Ethnopharmacol 2022; 293: 115289.
[http://dx.doi.org/10.1016/j.jep.2022.115289] [PMID: 35427724]
[13]
Liu Y, Shao S, Guo H. Schwann cells apoptosis is induced by high glucose in diabetic peripheral neuropathy. Life Sci 2020; 248: 117459.
[http://dx.doi.org/10.1016/j.lfs.2020.117459] [PMID: 32092332]
[14]
Wang H, Shi S, Wang S. Can highly cited herbs in ancient Traditional Chinese medicine formulas and modern publications predict therapeutic targets for diabetes mellitus? J Ethnopharmacol 2018; 213: 101-10.
[http://dx.doi.org/10.1016/j.jep.2017.10.032] [PMID: 29102765]
[15]
Hu Y, Huang W, Luo Y, et al. Assessment of the anti-inflammatory effects of three rhubarb anthraquinones in LPS-Stimulated RAW264.7 macrophages using a pharmacodynamic model and evaluation of the structure-activity relationships. J Ethnopharmacol 2021; 273: 114027.
[http://dx.doi.org/10.1016/j.jep.2021.114027] [PMID: 33741438]
[16]
Wang Y, Zhang J, Xu Z, et al. Identification and action mechanism of lipid regulating components from Rhei Radix et rhizoma. J Ethnopharmacol 2022; 292: 115179.
[http://dx.doi.org/10.1016/j.jep.2022.115179] [PMID: 35278606]
[17]
Fu S, Zhou Y, Hu C, Xu Z, Hou J. Network pharmacology and molecular docking technology-based predictive study of the active ingredients and potential targets of rhubarb for the treatment of diabetic nephropathy. BMC Complem Med Therap 2022; 22(1): 210.
[http://dx.doi.org/10.1186/s12906-022-03662-6] [PMID: 35932042]
[18]
Stompor-Gorący M. The health benefits of emodin, a natural anthraquinone derived from rhubarb-A summary update. Int J Mol Sci 2021; 22(17): 9522.
[http://dx.doi.org/10.3390/ijms22179522] [PMID: 34502424]
[19]
Zhang XR, Qiao YJ, Zhu HT, et al. Multiple in vitro biological effects of phenolic compounds from Terminalia chebula var. tomentella. J Ethnopharmacol 2021; 275: 114135.
[http://dx.doi.org/10.1016/j.jep.2021.114135] [PMID: 33892063]
[20]
Kim HJ, Song HK, Park SH, et al. Terminalia chebula Retz. extract ameliorates the symptoms of atopic dermatitis by regulating anti-inflammatory factors in vivo and suppressing STAT1/3 and NF-ĸB signaling in vitro. Phytomedicine 2022; 104: 154318.
[http://dx.doi.org/10.1016/j.phymed.2022.154318] [PMID: 35830757]
[21]
Wang Z, Fang C, Yao M, et al. Research progress of NF-κB signaling pathway and thrombosis. Front Immunol 2023; 14: 1257988.
[http://dx.doi.org/10.3389/fimmu.2023.1257988] [PMID: 37841272]
[22]
Qiu F, Fan S, Diao Y, et al. The mechanism of Chebulae fructus immaturus promote diabetic wound healing based on network pharmacology and experimental verification. J Ethnopharmacol 2024; 322: 117579.
[http://dx.doi.org/10.1016/j.jep.2023.117579] [PMID: 38104882]
[23]
Ruyvaran M, Zamani A, Mohamadian A, et al. Safflower (Carthamus tinctorius L.) oil could improve abdominal obesity, blood pressure, and insulin resistance in patients with metabolic syndrome: A randomized, double-blind, placebo-controlled clinical trial. J Ethnopharmacol 2022; 282: 114590.
[http://dx.doi.org/10.1016/j.jep.2021.114590] [PMID: 34487844]
[24]
Gao SQ, Chang C, Niu XQ, Li LJ, Zhang Y, Gao JQ. Topical application of Hydroxysafflor Yellow A accelerates the wound healing in streptozotocin induced T1DM rats. Eur J Pharmacol 2018; 823: 72-8.
[http://dx.doi.org/10.1016/j.ejphar.2018.01.018] [PMID: 29408092]
[25]
Luan F, Wu Q, Yang Y, et al. Traditional uses, chemical constituents, biological properties, clinical settings, and toxicities of Abelmoschus manihot L.: A comprehensive review. Front Pharmacol 2020; 11: 1068.
[http://dx.doi.org/10.3389/fphar.2020.01068] [PMID: 32973492]
[26]
Zhu GS, Tang LY, Lv DL, Jiang M. Total flavones of Abelmoschus manihot exhibits pro-angiogenic activity by activating the VEGF-A/VEGFR2-PI3K/Akt signaling axis. Am J Chin Med 2018; 46(3): 567-83.
[http://dx.doi.org/10.1142/S0192415X18500295] [PMID: 29595071]
[27]
Liu BH, Tu Y, Ni GX, et al. Total flavones of Abelmoschus manihot ameliorates podocyte pyroptosis and injury in high glucose conditions by targeting METTL3-dependent m6a modification-mediated NLRP3-inflammasome activation and PTEN/PI3K/Akt signaling. Front Pharmacol 2021; 12: 667644.
[http://dx.doi.org/10.3389/fphar.2021.667644] [PMID: 34335245]
[28]
Nogales C, Mamdouh ZM, List M, Kiel C, Casas AI, Schmidt HHHW. Network pharmacology: Curing causal mechanisms instead of treating symptoms. Trends Pharmacol Sci 2022; 43(2): 136-50.
[http://dx.doi.org/10.1016/j.tips.2021.11.004] [PMID: 34895945]
[29]
Ru J, Li P, Wang J, et al. TCMSP: A database of systems pharmacology for drug discovery from herbal medicines. J Cheminform 2014; 6(1): 13.
[http://dx.doi.org/10.1186/1758-2946-6-13] [PMID: 24735618]
[30]
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 2001; 46(1-3): 3-26.
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]
[31]
Tao W, Xu X, Wang X, et al. Network pharmacology-based prediction of the active ingredients and potential targets of Chinese herbal Radix Curcumae formula for application to cardiovascular disease. J Ethnopharmacol 2013; 145(1): 1-10.
[http://dx.doi.org/10.1016/j.jep.2012.09.051] [PMID: 23142198]
[32]
Viswanadhan VN, Ghose AK, Revankar GR, Robins RK. Atomic physicochemical parameters for three dimensional structure directed quantitative structure-activity relationships. 4. Additional parameters for hydrophobic and dispersive interactions and their application for an automated superposition of certain naturally occurring nucleoside antibiotics. J Chem Inf Comput Sci 1989; 29(3): 163-72.
[http://dx.doi.org/10.1021/ci00063a006]
[33]
Fang S, Dong L, Liu L, et al. HERB: A high-throughput experiment- and reference-guided database of traditional Chinese medicine. Nucleic Acids Res 2021; 49(D1): D1197-206.
[http://dx.doi.org/10.1093/nar/gkaa1063] [PMID: 33264402]
[34]
Daina A, Michielin O, Zoete V. SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res 2019; 47(W1): W357-64.
[http://dx.doi.org/10.1093/nar/gkz382] [PMID: 31106366]
[35]
Coudert E, Gehant S, de Castro E, et al. Annotation of biologically relevant ligands in UniProtKB using ChEBI. Bioinformatics 2023; 39(1): btac793.
[http://dx.doi.org/10.1093/bioinformatics/btac793] [PMID: 36484697]
[36]
Otasek D, Morris JH, Bouças J, Pico AR, Demchak B. Cytoscape automation: Empowering workflow-based network analysis. Genome Biol 2019; 20(1): 185.
[http://dx.doi.org/10.1186/s13059-019-1758-4] [PMID: 31477170]
[37]
Barrett T, Wilhite SE, Ledoux P, et al. NCBI GEO: Archive for functional genomics data sets-update. Nucleic Acids Res 2013; 41(Database issue): D991-5.
[PMID: 23193258]
[38]
Shen W, Song Z, Zhong X, et al. Sangerbox: A comprehensive, interaction-friendly clinical bioinformatics analysis platform. iMeta 2022; 1(3): e36.
[http://dx.doi.org/10.1002/imt2.36]
[39]
Zhou J, Xiong W, Wang Y, Guan J. Protein function prediction based on PPI networks: Network reconstruction vs edge enrichment. Front Genet 2021; 12: 758131.
[http://dx.doi.org/10.3389/fgene.2021.758131] [PMID: 34970299]
[40]
Szklarczyk D, Kirsch R, Koutrouli M, et al. The STRING database in 2023: Protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res 2023; 51(D1): D638-46.
[http://dx.doi.org/10.1093/nar/gkac1000] [PMID: 36370105]
[41]
Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K. KEGG: New perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res 2017; 45(D1): D353-61.
[http://dx.doi.org/10.1093/nar/gkw1092] [PMID: 27899662]
[42]
Hou F, Yu Z, Cheng Y, Liu Y, Liang S, Zhang F. Deciphering the pharmacological mechanisms of Scutellaria baicalensis Georgi on oral leukoplakia by combining network pharmacology, molecular docking and experimental evaluations. Phytomedicine 2022; 103: 154195.
[http://dx.doi.org/10.1016/j.phymed.2022.154195] [PMID: 35667260]
[43]
Ramirez HA, Pastar I, Jozic I, et al. Staphylococcus aureus triggers induction of miR-15B-5P to diminish DNA repair and deregulate inflammatory response in diabetic foot ulcers. J Invest Dermatol 2018; 138(5): 1187-96.
[http://dx.doi.org/10.1016/j.jid.2017.11.038] [PMID: 29273315]
[44]
Sawaya AP, Stone RC, Brooks SR, et al. Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing. Nat Commun 2020; 11(1): 4678.
[http://dx.doi.org/10.1038/s41467-020-18276-0] [PMID: 32938916]
[45]
Li S, Zhang B. Traditional Chinese medicine network pharmacology: Theory, methodology and application. Chin J Nat Med 2013; 11(2): 110-20.
[http://dx.doi.org/10.1016/S1875-5364(13)60037-0] [PMID: 23787177]
[46]
Kanehira T, Takekoshi S, Nagata H, et al. A novel and potent biological antioxidant, Kinobeon A, from cell culture of safflower. Life Sci 2003; 74(1): 87-97.
[http://dx.doi.org/10.1016/j.lfs.2003.06.033] [PMID: 14575815]
[47]
Wei X, Zhang L, Zhang R, et al. Targeting the TLR2 receptor with a novel thymopentin-derived peptide modulates immune responses. Front Immunol 2021; 12: 620494.
[http://dx.doi.org/10.3389/fimmu.2021.620494] [PMID: 34122400]
[48]
Peng SJ, Feng Y, Li X, et al. Thymopentin (TP-5) prevents lipopolysaccharide-induced neuroinflammation and dopaminergic neuron injury by inhibiting the NF-κB/NLRP3 signaling pathway. Int Immunopharmacol 2023; 119: 110109.
[http://dx.doi.org/10.1016/j.intimp.2023.110109] [PMID: 37121113]
[49]
Zhang D, Chen Q, Yao L. Geniposide alleviates neuropathic pain in CCI rats by inhibiting the EGFR/PI3K/AKT pathway and Ca2+ channels. Neurotox Res 2022; 40(4): 1057-69.
[http://dx.doi.org/10.1007/s12640-022-00531-5] [PMID: 35699893]
[50]
Lee JG, Lee S, Jeon J, et al. Host tp53 mutation induces gut dysbiosis eliciting inflammation through disturbed sialic acid metabolism. Microbiome 2022; 10(1): 3.
[http://dx.doi.org/10.1186/s40168-021-01191-x] [PMID: 34991725]
[51]
Wang X, Dai S, Zheng W, et al. Identification and verification of ferroptosis-related genes in diabetic foot using bioinformatics analysis. Int Wound J 2023; 20(8): 3191-203.
[http://dx.doi.org/10.1111/iwj.14198] [PMID: 37249237]
[52]
Pastar I, Sawaya AP, Marjanovic J, et al. Intracellular Staphylococcus aureus triggers pyroptosis and contributes to inhibition of healing due to perforin-2 suppression. J Clin Invest 2021; 131(24): e133727.
[http://dx.doi.org/10.1172/JCI133727] [PMID: 34730110]
[53]
Gan MS, Yang B, Fang DL, Wu BL. IL-1B can serve as a healing process and is a critical regulator of diabetic foot ulcer. Ann Transl Med 2022; 10(4): 179.
[http://dx.doi.org/10.21037/atm-22-75] [PMID: 35280410]
[54]
Kay AM, Simpson CL, Stewart JA. The role of AGE/RAGE signaling in diabetes-mediated vascular calcification. J Diabet Res 2016; 2016
[55]
Mai L, Zhu X, Huang F, He H, Fan W. p38 mitogen-activated protein kinase and pain. Life Sci 2020; 256: 117885.
[http://dx.doi.org/10.1016/j.lfs.2020.117885] [PMID: 32485175]
[56]
Jere SW, Houreld NN, Abrahamse H. Photobiomodulation and the expression of genes related to the JAK/STAT signalling pathway in wounded and diabetic wounded cells. J Photochem Photobiol B 2020; 204: 111791.
[http://dx.doi.org/10.1016/j.jphotobiol.2020.111791] [PMID: 31981991]
[57]
Audu CO, Melvin WJ, Joshi AD, et al. Macrophage-specific inhibition of the histone demethylase JMJD3 decreases STING and pathologic inflammation in diabetic wound repair. Cell Mol Immunol 2022; 19(11): 1251-62.
[http://dx.doi.org/10.1038/s41423-022-00919-5] [PMID: 36127466]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy