Gene expression analysis of diabetic foot ulcers reveals the potential impact of Levofloxacin on wound healing

1. Agidigbi, T. S. et al. Transcriptomic identification of genes expressed in invasive S. aureus diabetic foot ulcer infection. Front.Cellular Infect. Microbiol. 13, 1198115. https://doi.org/10.3389/fcimb.2023.1198115 (2023).

   Google Scholar 

2. Mohsin, F., Javaid, S., Tariq, M. & Mustafa, M. Molecular immunological mechanisms of impaired wound healing in diabetic foot ulcers (DFU), current therapeutic strategies and future directions. Int. Immunopharmacol. 139, 112713. https://doi.org/10.1016/j.intimp.2024.112713 (2024).

   Google Scholar 

3. McDermott, K., Fang, M., Boulton, A. J. M., Selvin, E. & Hicks, C. W. Etiology, epidemiology, and disparities in the burden of diabetic foot ulcers. Diabetes Care 46(1), 209–221. https://doi.org/10.2337/dci22-0043 (2023).

   Google Scholar 

4. Akhtar, S. et al. The prevalence of foot ulcers in diabetic patients in Pakistan: A systematic review and meta-analysis. Front. Public Health 10, 1017201. https://doi.org/10.3389/fpubh.2022.1017201 (2022).

   Google Scholar 

5. Gorecka, J. et al. The potential and limitations of induced pluripotent stem cells to achieve wound healing. Stem Cell Res. Ther. 10(1), 87. https://doi.org/10.1186/s13287-019-1185-1 (2019).

   Google Scholar 

6. Davis, F. M., Kimball, A., Boniakowski, A. & Gallagher, K. Dysfunctional wound healing in diabetic foot ulcers: New crossroads. Curr. Diab.Rep. 18(1), 2. https://doi.org/10.1007/s11892-018-0970-z (2018).

   Google Scholar 

7. Boniakowski, A. E., Kimball, A. S., Jacobs, B. N., Kunkel, S. L. & Gallagher, K. A. Macrophage-mediated inflammation in normal and diabetic wound healing. J. Immunol. (Baltimore, Md.: 1950) 199(1), 17–24. https://doi.org/10.4049/jimmunol.1700223 (2017).

   Google Scholar 

8. Rosique, R. G., Rosique, M. J. & Farina Junior, J. A. Curbing inflammation in skin wound healing: A review. Int. J. Inflamm. 2015, 316235. https://doi.org/10.1155/2015/316235 (2015).

   Google Scholar 

9. Dasari, N. et al. Updates in diabetic wound healing, inflammation, and scarring. Semin. Plast. Surg. 35(3), 153–158. https://doi.org/10.1055/s-0041-1731460 (2021).

   Google Scholar 

10. Patel, S., Srivastava, S., Singh, M. R. & Singh, D. Mechanistic insight into diabetic wounds: Pathogenesis, molecular targets and treatment strategies to pace wound healing. Biomed. Pharm. Biomed. Pharm. 112, 108615. https://doi.org/10.1016/j.biopha.2019.108615 (2019).

    Google Scholar 

11. Al, S. H. Macrophage phenotypes in normal and diabetic wound healing and therapeutic interventions. Cells 11(15), 2430. https://doi.org/10.3390/cells11152430 (2022).

    Google Scholar 

12. Holl, J. et al. Chronic diabetic wounds and their treatment with skin substitutes. Cells 10(3), 655. https://doi.org/10.3390/cells10030655 (2021).

    Google Scholar 

13. Ivanov, E., Akhmetshina, M., Erdiakov, A. & Gavrilova, S. Sympathetic system in wound healing: Multistage control in normal and diabetic skin. Int. J. Mol. Sci. 24(3), 2045. https://doi.org/10.3390/ijms24032045 (2023).

    Google Scholar 

14. Polaka, S. et al. Emerging ROS-modulating technologies for augmentation of the wound healing process. ACS Omega 7(35), 30657–30672. https://doi.org/10.1021/acsomega.2c02675 (2022).

    Google Scholar 

15. Dunnill, C. et al. Reactive oxygen species (ROS) and wound healing: the functional role of ROS and emerging ROS-modulating technologies for augmentation of the healing process. Int. Wound J. 14(1), 89–96. https://doi.org/10.1111/iwj.12557 (2017).

    Google Scholar 

16. Hunt, M., Torres, M., Bachar-Wikstrom, E. & Wikstrom, J. D. Cellular and molecular roles of reactive oxygen species in wound healing. Commun. Biol. 7(1), 1534. https://doi.org/10.1038/s42003-024-07219-w (2024).

    Google Scholar 

17. Wang, G. et al. The initiation of oxidative stress and therapeutic strategies in wound healing. Biomed. Pharm. Biomed. Pharma. 157, 114004. https://doi.org/10.1016/j.biopha.2022.114004 (2023).

    Google Scholar 

18. Deng, L. et al. The role of oxidative stress and antioxidants in diabetic wound healing. Oxid. Med. Cell. Longev. 2021, 8852759. https://doi.org/10.1155/2021/8852759 (2021).

    Google Scholar 

19. André-Lévigne, D., Modarressi, A., Pepper, M. S. & Pittet-Cuénod, B. Reactive oxygen species and NOX Enzymes are emerging as key players in cutaneous wound repair. Int. J. Mol. Sci. 18(10), 2149. https://doi.org/10.3390/ijms18102149 (2017).

    Google Scholar 

20. Assar, S. et al. A Review of Immunomodulatory Effects of Fluoroquinolones. Immunol. Invest. 50(8), 1007–1026. https://doi.org/10.1080/08820139.2020.1797778 (2021).

    Google Scholar 

21. Rais, N., Ved, A., Ahmad, R. & Parveen, A. Oxidative stress and diabetes mellitus: unravelling the intricate connection: A comprehensive review. J.Pharma. Res. Int. 36(1), 13–30. https://doi.org/10.9734/jpri/2024/v36i17493 (2024).

    Google Scholar 

22. Waibel, F. W. A., Uçkay, I., Soldevila-Boixader, L., Sydler, C. & Gariani, K. Current knowledge of morbidities and direct costs related to diabetic foot disorders: a literature review. Front. Endocrinol. 14, 1323315. https://doi.org/10.3389/fendo.2023.1323315 (2024).

    Google Scholar 

23. Caputo, W. J., Monterosa, P. & Beggs, D. antibiotic misuse in wound care: Can bacterial localization through fluorescence imaging help?. Diagnostics (Basel, Switzerland) 12(12), 3207. https://doi.org/10.3390/diagnostics12123207 (2022).

    Google Scholar 

24. Rao, X., Huang, X., Zhou, Z. & Lin, X. An improvement of the 2ˆ(-delta delta CT) method for quantitative real-time polymerase chain reaction data analysis. Biostat. Bioinform. Biomath. 3(3), 71–85 (2013).

    Google Scholar 

25. Kanehisa, M., Furumichi, M., Sato, Y., Matsuura, Y. & Ishiguro-Watanabe, M. KEGG: biological systems database as a model of the real world. Nucleic Acids Res. 53(D1), D672–D677. https://doi.org/10.1093/nar/gkae909 (2025).

    Google Scholar 

26. Huang, F. et al. Analysis and prediction of protein stability based on interaction network, gene ontology, and KEGG pathway enrichment scores. Biochim. Biophys. Acta 1871(3), 140889. https://doi.org/10.1016/j.bbapap.2023.140889 (2023).

    Google Scholar 

27. Szklarczyk, D. et al. The STRING database in 2021: Customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 49(D1), D605–D612. https://doi.org/10.1093/nar/gkaa1074 (2021).

    Google Scholar 

28. Lin, C., Liu, J. & Sun, H. Risk factors for lower extremity amputation in patients with diabetic foot ulcers: A meta-analysis. PLoS ONE 15(9), e0239236. https://doi.org/10.1371/journal.pone.0239236 (2020).

    Google Scholar 

29. Boyko, E. J. et al. Risk of foot ulcer and lower-extremity amputation among participants in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care 45(2), 357–364. https://doi.org/10.2337/dc21-1816 (2022).

    Google Scholar 

30. Rossboth, S., Rossboth, B., Schoenherr, H., Lechleitner, M. & Oberaigner, W. Risk factors for diabetic foot complications among patients with type 2 diabetes in Austria-A registry-based retrospective cohort study. Endocrinol. Diabetes Metabolism 4(4), e00286. https://doi.org/10.1002/edm2.286 (2021).

    Google Scholar 

31. Abuhay, H. W., Yenit, M. K. & Wolde, H. F. Incidence and predictor of diabetic foot ulcer and its association with change in fasting blood sugar among diabetes mellitus patients at referral hospitals in Northwest Ethiopia, 2021. PLoS ONE 17(10), e0274754. https://doi.org/10.1371/journal.pone.0274754 (2022).

    Google Scholar 

32. Ghanbari, A., Nouri, M., & Darvishi, M. Evaluation of relationship between serum hemoglobin A1C level and severity of diabetic foot ulcers based on Wagner criteria. (2023).

33. Yin, K. et al. Unraveling shared risk factors for diabetic foot ulcer: a comprehensive Mendelian randomization analysis. BMJ Open Diabetes Res. Care 11(6), e003523. https://doi.org/10.1136/bmjdrc-2023-003523 (2023).

    Google Scholar 

34. Suárez-Rivero, J. M. et al. Mitochondria and Antibiotics: For Good or for Evil?. Biomolecules 11(7), 1050. https://doi.org/10.3390/biom11071050 (2021).

    Google Scholar 

35. Miller, M. & Singer, M. Do antibiotics cause mitochondrial and immune cell dysfunction? A literature review. J. Antimicrob. Chemother. 77(5), 1218–1227. https://doi.org/10.1093/jac/dkac025 (2022).

    Google Scholar 

36. Kalghatgi, S. et al. Bactericidal antibiotics induce mitochondrial dysfunction and oxidative damage in Mammalian cells. Sci. Trans. Med. 5(192), 19ra285. https://doi.org/10.1126/scitranslmed.3006055 (2013).

    Google Scholar 

37. Cai, F., Chen, W., Zhao, R. & Liu, Y. Mechanisms of Nrf2 and NF-κB pathways in diabetic wound and potential treatment strategies. Mol. Biol. Rep. 50(6), 5355–5367. https://doi.org/10.1007/s11033-023-08392-7 (2023).

    Google Scholar 

38. Guillouzo, A. & Guguen-Guillouzo, C. Antibiotics-induced oxidative stress. Current Opinion Toxicol. 20, 23–28. https://doi.org/10.1016/j.cotox.2020.03.004 (2020).

    Google Scholar 

39. Song, J. et al. The emerging role of immune cells and targeted therapeutic strategies in diabetic wounds healing. J. Inflamm. Res. 15, 4119–4138. https://doi.org/10.2147/JIR.S371939 (2022).

    Google Scholar 

40. Liu, Y. et al. NRF2 signalling pathway: New insights and progress in the field of wound healing. J. Cellular Mol. Med. 25(13), 5857–5868. https://doi.org/10.1111/jcmm.16597 (2021).

    Google Scholar 

41. Imdad, S., Lim, W., Kim, J. H. & Kang, C. Intertwined relationship of mitochondrial metabolism, gut microbiome and exercise potential. Int. J. Mol. Sci. 23(5), 2679. https://doi.org/10.3390/ijms23052679 (2022).

    Google Scholar 

42. Bhatti, J. S. et al. Oxidative stress in the pathophysiology of type 2 diabetes and related complications: Current therapeutics strategies and future perspectives. Free Radical. Biol. Med. 184, 114–134. https://doi.org/10.1016/j.freeradbiomed.2022.03.019 (2022).

    Google Scholar 

43. Chen, Y., Zhang, Y., Jiang, M., Ma, H. & Cai, Y. HMOX1 as a therapeutic target associated with diabetic foot ulcers based on single-cell analysis and machine learning. Int. Wound J. 21(3), e14815. https://doi.org/10.1111/iwj.14815 (2024).

    Google Scholar 

44. Cabral-Pacheco, G. A. et al. The roles of matrix metalloproteinases and their inhibitors in human diseases. Int. J. Mol. Sci. 21(24), 9739. https://doi.org/10.3390/ijms21249739 (2020).

    Google Scholar 

45. Shi, X., Li, H., Guo, F., Li, D. & Xu, F. Novel ray of hope for diabetic wound healing: Hydrogen sulfide and its releasing agents. J. Adv. Res. 58, 105–115. https://doi.org/10.1016/j.jare.2023.05.009 (2024).

    Google Scholar 

46. Heydarpour, F. et al. Involvement of TGF-β and autophagy pathways in pathogenesis of diabetes: A comprehensive review on biological and pharmacological insights. Front. Pharmacol. 11, 498758. https://doi.org/10.3389/fphar.2020.498758 (2020).

    Google Scholar 

47. Du, G., Chen, J., Zhu, X. & Zhu, Z. Bioinformatics analysis identifies TGF-β signaling pathway-associated molecular subtypes and gene signature in diabetic foot. iScience 27(3), 109094. https://doi.org/10.1016/j.isci.2024.109094 (2024).

    Google Scholar 

48. Long, M. et al. An essential role of NRF2 in diabetic wound healing. Diabetes 65(3), 780–793. https://doi.org/10.2337/db15-0564 (2016).

    Google Scholar 

49. Xiaojie, W. et al. Scarless wound healing: Current insights from the perspectives of TGF-β, KGF-1, and KGF-2. Cytokine Growth Factor Rev. 66, 26–37. https://doi.org/10.1016/j.cytogfr.2022.03.001 (2022).

    Google Scholar 

50. Kamal, R., Awasthi, A., Pundir, M. & Thakur, S. Healing the diabetic wound: Unlocking the secrets of genes and pathways. Eur. J. Pharmacol. 975, 176645. https://doi.org/10.1016/j.ejphar.2024.176645 (2024).

    Google Scholar 

51. Liu, W., Xu, Y. & Slaveykova, V. I. Oxidative stress induced by sub-lethal exposure to copper as a mediator in development of bacterial resistance to antibiotics. Sci. Tot. Environ. 860, 160516. https://doi.org/10.1016/j.scitotenv.2022.160516 (2023).

    Google Scholar 

52. Khaliq, Y. & Zhanel, G. G. Fluoroquinolone-associated tendinopathy: a critical review of the literature. Clinic. Infect. Diseases: Official Public. Infect. Diseases Soc. America 36(11), 1404–1410. https://doi.org/10.1086/375078 (2003).

    Google Scholar 

53. Liu, P. et al. Antibiotic-induced dysbiosis of the gut microbiota impairs gene expression in gut-liver axis of mice. Genes 14(7), 1423. https://doi.org/10.3390/genes14071423 (2023).

    Google Scholar 

54. Kohanski, M. A., Dwyer, D. J. & Collins, J. J. How antibiotics kill bacteria: from targets to networks. Nat. Rev. Microbiol. 8(6), 423–435. https://doi.org/10.1038/nrmicro2333 (2010).

    Google Scholar 

55. Liao, Y. et al. Antibiotic intervention exacerbated oxidative stress and inflammatory responses in SD rats under hypobaric hypoxia exposure. Free Radical. Biol. Med. 209(Pt 1), 70–83. https://doi.org/10.1016/j.freeradbiomed.2023.10.002 (2023).

    Google Scholar 

Download references