Analyzing the Intrinsic Links and Common Therapeutic Targets between Diabetic Foot Ulcers and Liver Disease through Bioinformatics
DOI:
https://doi.org/10.70088/gsnekc48Keywords:
Diabetic foot ulcer, NAFLD, LC, bioinformatics, mendelian randomization studies, hub genes, medication prediction, immune cell infiltrationAbstract
Background. Diabetic foot ulcer (DFU) is a critical and prolonged complication of diabetes associated with high disability and mortality rates. Lipid metabolism disorders resulting from liver diseases are a key etiology in the development of diabetes mellitus and diabetic foot. Currently, there are no effective therapeutic targets or medications for treating DFU in combination with liver diseases such as nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) and liver cirrhosis (LC). The intrinsic links between the pathogenesis of DFU and these liver conditions have yet to be fully elucidated. Methods. We explored the molecular networks associated with DFU and NASH, as well as DFU and LC. Datasets were downloaded from the Gene Expression Omnibus (GEO) database and differentially expressed genes (DEGs) were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. Protein-protein interaction (PPI) networks were constructed using the STRING database, and hub genes were identified. The co-expression framework of hub genes was analyzed, and a mRNA-miRNA-TF regulatory network was constructed. The hub genes were validated, and medication prediction and molecular docking analyses were conducted. The causal link between NAFLD and DFU was studied utilizing Mendelian randomization. Results. In DFU and NASH, 294 common DEGs were identified, with four hub genes (FOS, PTGS2, SOCS3, and CD274) associated with inflammatory, immune, and metabolic responses. In DFU and LC, 347 common DEGs were identified, with six hub genes (FOS, PTGS2, CD8A, CD44, CXCL8, and SPP1) linked to inflammatory responses, metabolic processes, and cytokine receptor interactions. Our study suggests that oxygen therapy could serve as a viable therapeutic approach for managing DFU in patients with concurrent NASH. Simvastatin, a classic lipid-lowering medication, shows potential as an effective treatment for combined with NASH or LC due to its strong binding affinity with identified hub genes. Discussion. Understanding the networks and central genes is essential for advancing our comprehension of the diverse complexities associated with diabetes and promoting the advancement of potential therapeutic strategies. Targeting these hub genes and their associated signaling pathways could provide new treatment strategies for DFU combined with NASH or LC, offering a solid theoretical foundation for future therapies.References
K. McDermott, M. Fang, A. Boulton, et al., "Etiology, epidemiology, and disparities in the burden of diabetic foot ulcers," Diabetes Care, vol. 46, no. 1, pp. 209–221, Jan. 2023.
X. Xu, K. L. Poulsen, L. Wu, et al., "Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH)," Signal Transduction and Targeted Therapy, vol. 7, no. 1, p. 287, 2022.
B. Kim, E. Ban, and A. Kim, "Gelatin-alginate coacervates optimized by DOE to improve delivery of bFGF for wound healing," Pharmaceutics, vol. 13, no. 12, 2021.
X. Chen, Y. Xu, X. Meng, et al., "Analysis of the association between serum levels of 25(OH)D, retinol binding protein, and cyclooxygenase-2 and the disease severity in patients with diabetic foot ulcers," International Wound Journal, vol. 21, no. 3, p. e14502, Mar. 2023.
J. Gauthier, A. T. Vincent, S. J. Charette, et al., "A brief history of bioinformatics," Briefings in Bioinformatics, vol. 20, no. 6, pp. 1981–1996, Nov. 2019.
J. C. Navarro-Muñoz, N. Selem-Mojica, M. W. Mullowney, et al., "A computational framework to explore large-scale biosynthetic diversity," Nature Chemical Biology, vol. 16, no. 1, pp. 60–68, Jan. 2020.
R. Edgar, M. Domrachev, and A. E. Lash, "Gene Expression Omnibus: NCBI gene expression and hybridization array data repository," Nucleic Acids Research, vol. 30, no. 1, pp. 207–210, Jan. 2002.
H. A. Ramirez, I. Pastar, I. Jozic, et al., "Staphylococcus aureus triggers induction of miR-15b-5p to diminish DNA repair and deregulate inflammatory response in diabetic foot ulcers," Journal of Investigative Dermatology, vol. 138, no. 5, pp. 1187–1196, May 2018.
B. M. Arendt, E. M. Comelli, D. W. Ma, et al., "Altered hepatic gene expression in nonalcoholic fatty liver disease is associated with lower hepatic n-3 and n-6 polyunsaturated fatty acids," Hepatology, vol. 61, no. 5, pp. 1565–1578, May 2015.
V. R. Mas, D. G. Maluf, K. J. Archer, et al., "Genes involved in viral carcinogenesis and tumor initiation in hepatitis C virus-induced hepatocellular carcinoma," Molecular Medicine, vol. 15, no. 3–4, pp. 85–94, Mar.–Apr. 2009.
M. Kanehisa, M. Furumichi, Y. Sato, et al., "KEGG for taxonomy-based analysis of pathways and genomes," Nucleic Acids Research, vol. 51, no. D1, pp. D587–D592, Jan. 2023.
M. Kanehisa, "Toward understanding the origin and evolution of cellular organisms," Protein Science, vol. 28, no. 11, pp. 1947–1951, Nov. 2019.
M. Kanehisa and S. Goto, "KEGG: Kyoto Encyclopedia of Genes and Genomes," Nucleic Acids Research, vol. 28, no. 1, pp. 27–30, Jan. 2000.
A. Franceschini, D. Szklarczyk, S. Frankild, et al., "STRING v9.1: Protein–protein interaction networks, with increased coverage and integration," Nucleic Acids Research, vol. 41, no. Database issue, pp. D808–D815, Jan. 2013.
M. E. Smoot, K. Ono, J. Ruscheinski, et al., "Cytoscape 2.8: New features for data integration and network visualization," Bioinformatics, vol. 27, no. 3, pp. 431–432, Feb. 2011.
H. Han, J. W. Cho, S. Lee, et al., "TRRUST v2: An expanded reference database of human and mouse transcriptional regulatory interactions," Nucleic Acids Research, vol. 46, no. D1, pp. D380–D386, Jan. 2018.
C. Sticht, C. De La Torre, A. Parveen, et al., "miRWalk: An online resource for prediction of microRNA binding sites," PLoS ONE, vol. 13, no. 10, p. e0206239, Oct. 2018.
M. V. Kuleshov, M. R. Jones, A. D. Rouillard, et al., "Enrichr: A comprehensive gene set enrichment analysis web server 2016 update," Nucleic Acids Research, vol. 44, no. W1, pp. W90–W97, Jul. 2016.
X. Chen, Y. Xu, X. Meng, et al., "Analysis of the association between serum levels of 25(OH)D, retinol binding protein, and cyclooxygenase-2 and the disease severity in patients with diabetic foot ulcers," International Wound Journal, vol. 21, no. 3, p. e14502, Mar. 2023.
C. Y. Zhang, X. H. Tan, H. H. Yang, et al., "COX-2/sEH dual inhibitor alleviates hepatocyte senescence in NAFLD mice by restoring autophagy through Sirt1/PI3K/AKT/mTOR," International Journal of Molecular Sciences, vol. 23, no. 15, 2022.
J. H. Cha, L. C. Chan, C. W. Li, et al., "Mechanisms controlling PD-L1 expression in cancer," Molecular Cell, vol. 76, no. 3, pp. 359–370, Nov. 2019.
L. A. Orci, M. Kreutzfeldt, N. Gossens, et al., "Tolerogenic properties of liver macrophages in non-alcoholic steatohepatitis," Liver International, vol. 40, no. 3, pp. 609–621, Mar. 2020.
B. Carow and M. E. Rottenberg, "SOCS3, a major regulator of infection and inflammation," Frontiers in Immunology, vol. 5, p. 58, 2014.
L. Xu, Y. Li, L. Yin, et al., "miR-125a-5p ameliorates hepatic glycolipid metabolism disorder in type 2 diabetes mellitus through targeting of STAT3," Theranostics, vol. 8, no. 20, pp. 5593–5609, 2018.
F. Soysouvanh, D. Rousseau, S. Bonnafous, et al., "Osteopontin-driven T-cell accumulation and function in adipose tissue and liver promoted insulin resistance and MAFLD," Obesity, vol. 31, no. 10, pp. 2568–2582, Oct. 2023.
L. Guo, Z. Zhu, C. Shi, et al., "Drug suspending during wound healing effectively weakens immunosuppression-related complications by preserving CD8(+) T cell function," Wound Repair and Regeneration, vol. 31, no. 4, pp. 489–499, Jul./Aug. 2023.
Z. Song, W. Chen, D. Athavale, et al., "Osteopontin takes center stage in chronic liver disease," Hepatology, vol. 73, no. 4, pp. 1594–1608, Apr. 2021.
P. Govindaraju, L. Todd, S. Shetye, et al., "CD44-dependent inflammation, fibrogenesis, and collagenolysis regulates extracellular matrix remodeling and tensile strength during cutaneous wound healing," Matrix Biology, vol. 75–76, pp. 314–330, Mar. 2019.
S. Mustika, H. Wijaya, and B. Pratomo, "The expressions of CD44, CD90 and alpha fetoprotein biomarkers in Indonesian patients with advanced liver disease: An observational study," Acta Medica Indonesiana, vol. 51, no. 2, pp. 137–144, Apr. 2019.
S. Cambier, M. Gouwy, and P. Proost, "The chemokines CXCL8 and CXCL12: Molecular and functional properties, role in disease and efforts towards pharmacological intervention," Cellular & Molecular Immunology, vol. 20, no. 3, pp. 217–251, Mar. 2023.
M. S. Agren, T. Litman, J. O. Erikksen, et al., "Gene expression linked to reepithelialization of human skin wounds," International Journal of Molecular Sciences, vol. 23, no. 24, 2022.
M. M. Langer, S. Sichelschmidt, A. Bauschen, et al., "Pathological neutrophil migration predicts adverse outcomes in hospitalized patients with liver cirrhosis," Liver International, vol. 43, no. 4, pp. 896–905, Apr. 2023.
L. Scisciola, U. Chianese, V. Caponigro, et al., "Multi-omics analysis reveals attenuation of cellular stress by empagliflozin in high glucose-treated human cardiomyocytes," Journal of Translational Medicine, vol. 21, no. 1, p. 1–662, 2023.
Y. Xi, D. Chen, Z. Dong, et al., "Multi-omics insights into potential mechanism of SGLT2 inhibitors cardiovascular benefit in diabetic cardiomyopathy," Frontiers in Cardiovascular Medicine, vol. 9, p. 999254, 2022.
Y. Zhang, Z. Zhang, C. Li, et al., "Metabolomics study reveals the alteration of fatty acid oxidation in the hearts of diabetic mice by empagliflozin," Molecular Omics, vol. 18, no. 7, pp. 643–651, Jul. 2022.
G. De Smet, L. F. Kroese, A. G. Menon, et al., "Oxygen therapies and their effects on wound healing," Wound Repair and Regeneration, vol. 25, no. 4, pp. 591–608, Jul./Aug. 2017.
E. Everett and N. Mathioudakis, "Update on management of diabetic foot ulcers," Annals of the New York Academy of Sciences, vol. 1411, no. 1, pp. 153–165, Jan. 2018.
R. J. Goldman, "Hyperbaric oxygen therapy for wound healing and limb salvage: A systematic review," PM&R, vol. 1, no. 5, pp. 471–489, May 2009.
M. Rezvanian, S. F. Ng, T. Alavi, et al., "In-vivo evaluation of alginate-pectin hydrogel film loaded with simvastatin for diabetic wound healing in streptozotocin-induced diabetic rats," International Journal of Biological Macromolecules, vol. 171, pp. 308–319, Mar. 2021.
E. Pereira, B. P. Araujo, K. L. Rodrigues, et al., "Simvastatin improves microcirculatory function in nonalcoholic fatty liver disease and downregulates oxidative and ALE-RAGE stress," Nutrients, vol. 14, no. 3, 2022.
H. Zhang, Q. Zhang, S. Li, et al., "Simvastatin is efficacious in treating cirrhosis: A meta-analysis," Journal of Clinical Gastroenterology, vol. 56, no. 8, pp. e303–e312, Aug. 2022.
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Wenbo Li, Xudong Xin, Tianyi Shen, Zhenhao Zhang, Jihua Wei (Author)
This work is licensed under a Creative Commons Attribution 4.0 International License.
