Network pharmacology-based approach for exploring the biotargets and mechanisms of vitamin A for the treatment of diabetic foot ulcers

Abstract

Background: In some developing countries, people have little knowledge about the causes of diabetic foot ulcers. Therefore, public health education for patients on these conditions is a prerequisite for effective pharmacological treatment. Diabetic foot ulcers are a complex symptom of diabetes and are hard to cure due to the lack of efficacious medicine and alternative treatment approaches. Vitamin A (VA) is known to have potent biological functions, including skin repair and immunoregulation. However, the potential pharmacological effects and molecular mechanisms of VA on foot ulcers are still to be discovered. Methods: By using bioinformatic/computational analyses, including network pharmacology, gene ontology and the Kyoto Encyclopedia of Genes and Genomes enrichment analysis, we aimed to identify and reveal the pharmacological targets, molecular mechanisms, biological functions, and signaling pathways of VA in the treatment of diabetic foot ulcers. Results: A total of 66 intersection genes were identified as candidate targets of VA, which are related to diabetic foot ulcers. Therein, 18 core genes/targets, namely JUN, MAPK1, THRB, MAPK14, MTNR1B, CXCR3, ESR1, AR, HDAC1, IL-10, CNR1, DRD2, EGFR, ADRA2A, CCND1, RXRB, RARA, and RXRA, were further identified. Furthermore, the biological processes, cell components, and molecular functions which may underlie the effects of VA against diabetic foot ulcers were characterized. Conclusion: Based on our findings, we concluded that the pharmacological effects of VA on diabetic foot ulcers primarily involve the promotion of cellular regeneration and proliferation and the inhibition of inflammatory response. The core genes/targets may potentially serve as promising biomarkers for the diagnosis of diabetic foot ulcers.

Keywords

diabetic foot ulcers / vitamin A / network pharmacology / core genes / mechanisms

References

[[1]] Zheng Y, Ley S H, Hu F B. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol, 2018; 14(2): 88-98.

[[2]] Yang L, Shao J, Bian Y, et al. Prevalence of type 2 diabetes mellitus among inland residents in China (2000-2014): A meta-analysis. J Diabetes Investig, 2016; 7(6): 845-852.

[[3]] Malemute C L, Shultz J A, Ballejos M, et al. Goal setting education and counseling practices of diabetes educators. Diabetes Educ, 2011; 37(4): 549-563.

[[4]] Wheeler L A, Wheeler M L, Ours P, et al. Evaluation of computer-based diet education in persons with diabetes mellitus and limited educational background. Diabetes Care, 1985; 8(6): 537-544.

[[5]] Armstrong D G, Boulton A J M, Bus S A. Diabetic foot ulcers and their recurrence. N Engl J Med, 2017; 376(24): 2367-2375.

[[6]] Sen P, Demirdal T. Evaluation of mortality risk factors in diabetic foot infections. Int Wound J, 2020; 17(4): 880-889.

[[7]] Lim J Z, Ng N S, Thomas C. Prevention and treatment of diabetic foot ulcers. J R Soc Med, 2017; 110(3): 104-109.

[[8]] Everett E, Mathioudakis N. Update on management of diabetic foot ulcers. Ann N Y Acad Sci, 2018; 1411(1): 153-165.

[[9]] Braun L R, Fisk W A, Lev-Tov H, et al. Diabetic foot ulcer: an evidence-based treatment update. Am J Clin Dermatol, 2014; 15(3): 267-281.

[[10]] Pena G, Kuang B, Cowled P, et al. Micronutrient status in diabetic patients with foot ulcers. Adv Wound Care (New Rochelle), 2020; 9(1): 9-15.

[[11]] Bar-El Dadon S, Reifen R. Vitamin A and the epigenome. Crit Rev Food Sci Nutr, 2017; 57(11): 2404-2411.

[[12]] Iskakova M, Karbyshev M, Piskunov A, et al. Nuclear and extranuclear effects of vitamin A. Can J Physiol Pharmacol, 2015; 93(12): 1065-1075.

[[13]] Blaner W S. Vitamin A signaling and homeostasis in obesity, diabetes, and metabolic disorders. Pharmacol Ther, 2019; 197: 153-178.

[[14]] Olsen T, Blomhoff R. Retinol, retinoic acid, and retinol-binding protein 4 are differentially associated with cardiovascular disease, type 2 diabetes, and obesity: An overview of human studies. Adv Nutr, 2020; 11(3): 644-666.

[[15]] Chen Q, Feng Y, Yang H, et al. A vitamin pattern diet is associated with decreased risk of gestational diabetes mellitus in chinese women: Results from a case control study in Taiyuan, China. J Diabetes Res, 2019; 2019: 5232308.

[[16]] Rostamkhani H, Mellati A A, Tabaei B S, et al. Association of serum zinc and vitamin A levels with severity of retinopathy in type 2 diabetic patients: a cross-sectional study. Biol Trace Elem Res, 2019; 192(2): 123-128.

[[17]] Nogales C, Mamdouh Z M, List M, et al. Network pharmacology: curing causal mechanisms instead of treating symptoms. Trends Pharmacol Sci, 2022; 43(2): 136-150.

[[18]] Liu J, Guo C, Wang Y, et al. Preclinical insights into fucoidan as a nutraceutical compound against perfluorooctanoic acid-associated obesity via targeting endoplasmic reticulum stress. Front Nutr, 2022; 9: 950130.

[[19]] Liang X, Pan Q, Liao Y, et al. In silico analysis and experimental validation to exhibit anti-nasopharyngeal carcinoma effects of plumbagin, an anti-cancer compound. J Sci Food Agric, 2022; 102(12): 5460-5467.

[[20]] Pundir S, Martin M J, O’Donovan C, et al. UniProt tools. Curr Protoc Bioinformatics, 2016; 53: 1.29.1-1.29.15.

[[21]] Fonseka P, Pathan M, et al. FunRich enables enrichment analysis of OMICs datasets. J Mol Biol, 2021; 433(11): 166747.

[[22]] Szklarczyk D, Gable A L, Lyon D, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res, 2019; 47(D1): D607-D613.

[[23]] Doncheva N T, Morris J H, Gorodkin J, et al. Cytoscape StringApp: network analysis and visualization of proteomics data. J Proteome Res, 2019; 18(2): 623-632.

[[24]] Everett E, Mathioudakis N. Update on management of diabetic foot ulcers. Ann N Y Acad Sci, 2018; 1411(1): 153-165.

[[25]] Sanz-Corbalán I, Lázaro-Martínez J L, García-Morales E, et al. Advantages of early diagnosis of diabetic neuropathy in the prevention of diabetic foot ulcers. Diabetes Res Clin Pract, 2018; 146: 148-154.

[[26]] Zinder R, Cooley R, Vlad L G, et al. Vitamin A and wound healing. Nutr Clin Pract, 2019; 34(6): 839-849.

[[27]] Bar-El Dadon S, Reifen R. Vitamin A and the epigenome. Crit Rev Food Sci Nutr, 2017; 57(11): 2404-2411.

[[28]] Pena G, Kuang B, Cowled P, et al. Micronutrient status in diabetic patients with foot ulcers. Adv Wound Care (New Rochelle), 2020; 9(1): 9-15.

[[29]] Schonthaler H B, Guinea-Viniegra J, Wagner E F. Targeting inflammation by modulating the Jun/AP-1 pathway. Ann Rheum Dis, 2011; 70(Suppl 1): i109-12.

[[30]] Lang J, Yang C, Liu L, et al. High glucose activates ERK1/ 2 to stabilize AP1 and increase MMP9 expression in diabetic foot ulcers. Exp Cell Res, 2021; 403(1): 112550.

[[31]] Xu S, Weng X, Wang Y, et al. Screening and preliminary validation of T lymphocyte immunoregulation associated long non coding RNAs in diabetic foot ulcers. Mol Med Rep, 2019; 19(3): 2368-2376.

[[32]] Laimer M. MAPK14 as candidate for genetic susceptibility to diabetic foot ulcer. Br J Dermatol, 2017; 177(6): 1482-1483.

[[33]] Meng W, Veluchamy A, Hébert H L, et al. A genome-wide association study suggests that MAPK 14 is associated with diabetic foot ulcers. Br J Dermatol, 2017; 177(6): 1664-1670.

[[34]] Izquierdo M C, Shanmugarajah N, Lee S X, et al. Hepatic FoxOs link insulin signaling with plasma lipoprotein metabolism through an apolipoprotein M/sphingosine-1-phosphate pathway. J Clin Invest, 2022; 132(7): e146219.

[[35]] Liao S, Lin X, Mo C. Integrated analysis of circRNA-miRNA-mRNA regulatory network identifies potential diagnostic biomarkers in diabetic foot ulcer. Noncoding RNA Res, 2020; 5(3): 116-124.

[[36]] Fang Z, Deng Q, Hu H, et al. Characteristics of immunogenic and tolerogenic dendritic cells within the arterial wall in atherosclerosis and in vitro. Int J Clin Exp Med, 2014; 7(12): 4846-4856.