The Treatment of Impaired Wound Healing in Diabetes: Looking among Old Drugs
Abstract
:1. Introduction
2. The Problem of Wound Healing and Its Incidence in Diabetes
3. The Physiology of Wound Healing
3.1. The First Phase: Inflammatory Response
3.2. The Second and Third Phases: Proliferation and Remodeling
4. What Goes Wrong in Wound Repair in Diabetes?
5. Current Available Treatments
5.1. Dressings
5.2. Antidiabetic Drugs
5.3. Growth Factors
5.4. Stem Cells
6. Drug Repurposing in The Treatment of Wound Healing
6.1. Statins
6.2. Phenytoin
6.3. Metformin
6.4. Dipeptidyl Peptidase 4 (DPP4) Inhibitors
7. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Maffi, P.; Secchi, A. The Burden of Diabetes: Emerging Data. Dev. Ophthalmol. 2017, 60, 1–5. [Google Scholar]
- Dinh, T.; Elder, S.; Veves, A. Delayed wound healing in diabetes: Considering future treatments. Diabetes Manag. 2011, 1, 509–519. [Google Scholar] [CrossRef]
- Greenhalgh, D.G. Wound healing and diabetes mellitus. Clin. Plast. Surg. 2003, 30, 37–45. [Google Scholar] [CrossRef]
- Geraghty, T.; LaPorta, G. Current health and economic burden of chronic diabetic osteomyelitis. Expert Rev. Pharmacoecon. Outcomes Res. 2019, 19, 279–286. [Google Scholar] [CrossRef]
- Zhang, P.; Lu, J.; Jing, Y.; Tang, S.; Zhu, D.; Bi, Y. Global epidemiology of diabetic foot ulceration: A systematic review and meta-analysis (dagger). Ann. Med. 2017, 49, 106–116. [Google Scholar] [CrossRef] [PubMed]
- Boulton, A.J.; Vileikyte, L.; Ragnarson-Tennvall, G.; Apelqvist, J. The global burden of diabetic foot disease. Lancet 2005, 366, 1719–1724. [Google Scholar] [CrossRef]
- Raghav, A.; Khan, Z.A.; Labala, R.K.; Ahmad, J.; Noor, S.; Mishra, B.K. Financial burden of diabetic foot ulcers to world: A progressive topic to discuss always. Ther. Adv. Endocrinol. Metab. 2018, 9, 29–31. [Google Scholar] [CrossRef] [PubMed]
- Ragnarson Tennvall, G.; Apelqvist, J. Health-economic consequences of diabetic foot lesions. Clin. Infect. Dis. 2004, 39 (Suppl. 2), S132–S139. [Google Scholar] [CrossRef] [PubMed]
- Schreml, S.; Berneburg, M. The global burden of diabetic wounds. Br. J. Dermatol. 2017, 176, 845–846. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Eming, S.A.; Martin, P.; Tomic-Canic, M. Wound repair and regeneration: Mechanisms, signaling, and translation. Sci. Transl. Med. 2014, 6, 265sr6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Stadelmann, W.K.; Digenis, A.G.; Tobin, G.R. Physiology and healing dynamics of chronic cutaneous wounds. Am. J. Surg. 1998, 176 (Suppl. 2A), 26S–38S. [Google Scholar] [CrossRef]
- Singer, A.J.; Clark, R.A. Cutaneous wound healing. N. Engl. J. Med. 1999, 341, 738–746. [Google Scholar] [CrossRef] [PubMed]
- Falanga, V. Wound healing and its impairment in the diabetic foot. Lancet 2005, 366, 1736–1743. [Google Scholar] [CrossRef]
- Falanga, V. The chronic wound: Impaired healing and solutions in the context of wound bed preparation. Blood Cells Mol. Dis. 2004, 32, 88–94. [Google Scholar] [CrossRef] [PubMed]
- Liu, L.; Marti, G.P.; Wei, X.; Zhang, X.; Zhang, H.; Liu, Y.V.; Nastai, M.; Semenza, G.L.; Harmon, J.W. Age-dependent impairment of HIF-1alpha expression in diabetic mice: Correction with electroporation-facilitated gene therapy increases wound healing, angiogenesis, and circulating angiogenic cells. J. Cell Physiol. 2008, 217, 319–327. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Okonkwo, U.A.; DiPietro, L.A. Diabetes and Wound Angiogenesis. Int. J. Mol. Sci. 2017, 18, 1419. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hirschi, K.K.; D’Amore, P.A. Pericytes in the microvasculature. Cardiovasc. Res. 1996, 32, 687–698. [Google Scholar] [CrossRef] [Green Version]
- Haukipuro, K.; Melkko, J.; Risteli, L.; Kairaluoma, M.; Risteli, J. Synthesis of type I collagen in healing wounds in humans. Ann. Surg. 1991, 213, 75–80. [Google Scholar] [CrossRef]
- Gurtner, G.C.; Werner, S.; Barrandon, Y.; Longaker, M.T. Wound repair and regeneration. Nature 2008, 453, 314–321. [Google Scholar] [CrossRef]
- Han, G.; Ceilley, R. Chronic Wound Healing: A Review of Current Management and Treatments. Adv. Ther. 2017, 34, 599–610. [Google Scholar] [CrossRef] [Green Version]
- Wetzler, C.; Kampfer, H.; Stallmeyer, B.; Pfeilschifter, J.; Frank, S. Large and sustained induction of chemokines during impaired wound healing in the genetically diabetic mouse: Prolonged persistence of neutrophils and macrophages during the late phase of repair. J. Invest. Dermatol. 2000, 115, 245–253. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Brown, D.L.; Kane, C.D.; Chernausek, S.D.; Greenhalgh, D.G. Differential expression and localization of insulin-like growth factors I and II in cutaneous wounds of diabetic and nondiabetic mice. Am. J. Pathol. 1997, 151, 715–724. [Google Scholar] [PubMed]
- Roberts, A.B. Transforming growth factor-beta: Activity and efficacy in animal models of wound healing. Wound Repair Regen. 1995, 3, 408–418. [Google Scholar] [CrossRef] [PubMed]
- Semenza, G.L. HIF-1: Mediator of physiological and pathophysiological responses to hypoxia. J. Appl. Physiol. 2000, 88, 1474–1480. [Google Scholar] [CrossRef] [Green Version]
- Khanna, S.; Biswas, S.; Shang, Y.; Collard, E.; Azad, A.; Kauh, C.; Bhasker, V.; Gordillo, G.M.; Sen, C.K.; Roy, S. Macrophage dysfunction impairs resolution of inflammation in the wounds of diabetic mice. PLoS ONE 2010, 5, e9539. [Google Scholar] [CrossRef] [Green Version]
- Seitz, O.; Schürmann, C.; Hermes, N.; Müller, E.; Pfeilschifter, J.; Frank, S.; Goren, I. Wound healing in mice with high-fat diet- or ob gene-induced diabetes-obesity syndromes: A comparative study. Exp. Diabetes Res. 2010, 2010, 476969. [Google Scholar] [CrossRef] [Green Version]
- Galiano, R.D.; Tepper, O.M.; Pelo, C.R.; Bhatt, K.A.; Callaghan, M.; Bastidas, N.; Bunting, S.; Steinmetz, H.G.; Gurtner, G.C. Topical vascular endothelial growth factor accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrow-derived cells. Am. J. Pathol. 2004, 164, 1935–1947. [Google Scholar] [CrossRef] [Green Version]
- Drela, E.; Stankowska, K.; Kulwas, A.; Rosc, D. Endothelial progenitor cells in diabetic foot syndrome. Adv. Clin. Exp. Med. Off. Organ Wroc. Med. Univ. 2012, 21, 249–254. [Google Scholar]
- Sangiorgi, S.; Manelli, A.; Reguzzoni, M.; Ronga, M.; Protasoni, M.; Dell’Orbo, C. The cutaneous microvascular architecture of human diabetic toe studied by corrosion casting and scanning electron microscopy analysis. Anat. Record 2010, 293, 1639–1645. [Google Scholar] [CrossRef]
- Beer, H.D.; Longaker, M.T.; Werner, S. Reduced expression of PDGF and PDGF receptors during impaired wound healing. J. Investig. Dermatol. 1997, 109, 132–138. [Google Scholar] [CrossRef] [Green Version]
- Balaji, S.; Han, N.; Moles, C.; Shaaban, A.F.; Bollyky, P.L.; Crombleholme, T.M.; Keswani, S.G. Angiopoietin-1 improves endothelial progenitor cell-dependent neovascularization in diabetic wounds. Surgery 2015, 158, 846–856. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lobmann, R.; Zemlin, C.; Motzkau, M.; Reschke, K.; Lehnert, H. Expression of matrix metalloproteinases and growth factors in diabetic foot wounds treated with a protease absorbent dressing. J. Diabetes Complicat. 2006, 20, 329–335. [Google Scholar] [CrossRef] [PubMed]
- Liu, Y.; Min, D.; Bolton, T.; Nubé, V.; Twigg, S.M.; Yue, D.K.; McLennan, S.V. Increased matrix metalloproteinase-9 predicts poor wound healing in diabetic foot ulcers. Diabetes Care 2009, 32, 117–119. [Google Scholar] [CrossRef] [Green Version]
- Moura, L.I.; Dias, A.M.; Carvalho, E.; de Sousa, H.C. Recent advances on the development of wound dressings for diabetic foot ulcer treatment—A review. Acta Biomater. 2013, 9, 7093–7114. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gianino, E.; Miller, C.; Gilmore, J. Smart Wound Dressings for Diabetic Chronic Wounds. Bioengineering 2018, 5, 51. [Google Scholar] [CrossRef] [Green Version]
- Dhivya, S.; Padma, V.V.; Santhini, E. Wound dressings—A review. Biomedicine 2015, 5, 22. [Google Scholar] [CrossRef]
- Salazar, J.J.; Ennis, W.J.; Koh, T.J. Diabetes medications: Impact on inflammation and wound healing. J. Diabetes Complicat. 2016, 30, 746–752. [Google Scholar] [CrossRef] [Green Version]
- Barrientos, S.; Stojadinovic, O.; Golinko, M.S.; Brem, H.; Tomic-Canic, M. Growth factors and cytokines in wound healing. Wound Repair Regen. 2008, 16, 585–601. [Google Scholar] [CrossRef]
- Martí-Carvajal, A.J.; Gluud, C.; Nicola, S.; Simancas-Racines, D.; Reveiz, L.; Oliva, P.; Cedeño-Taborda, J. Growth factors for treating diabetic foot ulcers. Cochrane Database Syst. Rev. 2015. [Google Scholar] [CrossRef]
- Fang, R.C.; Galiano, R.D. A review of becaplermin gel in the treatment of diabetic neuropathic foot ulcers. Biologics 2008, 2, 1–12. [Google Scholar]
- Gainza, G.; Villullas, S.; Pedraz, J.L.; Hernandez, R.M.; Igartua, M. Advances in drug delivery systems (DDSs) to release growth factors for wound healing and skin regeneration. Nanomedicine 2015, 11, 1551–1573. [Google Scholar] [CrossRef] [PubMed]
- Laiva, A.L.; O’Brien, F.J.; Keogh, M.B. Innovations in gene and growth factor delivery systems for diabetic wound healing. J. Tissue Eng. Regen. Med. 2018, 12, e296–e312. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Isakson, M.; de Blacam, C.; Whelan, D.; McArdle, A.; Clover, A.J. Mesenchymal Stem Cells and Cutaneous Wound Healing: Current Evidence and Future Potential. Stem Cells Int. 2015, 2015, 831095. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cao, Y.; Gang, X.; Sun, C.; Wang, G. Mesenchymal Stem Cells Improve Healing of Diabetic Foot Ulcer. J. Diabetes Res. 2017, 2017, 9328347. [Google Scholar] [CrossRef] [PubMed]
- Lu, D.; Chen, B.; Liang, Z.; Deng, W.; Jiang, Y.; Li, S.; Xu, J.; Wu, Q.; Zhang, Z.; Xie, B.; et al. Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: A double-blind, randomized, controlled trial. Diabetes Res. Clin. Pract. 2011, 92, 26–36. [Google Scholar] [CrossRef]
- Kirana, S.; Stratmann, B.; Prante, C.; Prohaska, W.; Koerperich, H.; Lammers, D.; Gastens, M.H.; Quast, T.; Negrean, M.; Stirban, O.A.; et al. Autologous stem cell therapy in the treatment of limb ischaemia induced chronic tissue ulcers of diabetic foot patients. Int. J. Clin. Pract. 2012, 66, 384–393. [Google Scholar] [CrossRef]
- Gorecka, J.; Kostiuk, V.; Fereydooni, A.; Gonzalez, L.; Luo, J.; Dash, B.; Isaji, T.; Ono, S.; Liu, S.; Lee, S.R.; et al. The potential and limitations of induced pluripotent stem cells to achieve wound healing. Stem Cell Res Ther. 2019, 10, 87. [Google Scholar] [CrossRef] [Green Version]
- Ashcroft, G.S.; Dodsworth, J.; van Boxtel, E.; Tarnuzzer, R.W.; Horan, M.A.; Schultz, G.S.; Ferguson, M.W. Estrogen accelerates cutaneous wound healing associated with an increase in TGF-beta1 levels. Nat. Med. 1997, 3, 1209–1215. [Google Scholar] [CrossRef]
- Zhuge, Y.; Regueiro, M.M.; Tian, R.; Li, Y.; Xia, X.; Vazquez-Padron, R.; Elliot, S.; Thaller, S.R.; Liu, Z.J.; Velazquez, O.C. The effect of estrogen on diabetic wound healing is mediated through increasing the function of various bone marrow-derived progenitor cells. J. Vasc. Surg. 2018, 68, 127S–135S. [Google Scholar] [CrossRef] [Green Version]
- Merlo, S.; Frasca, G.; Canonico, P.L.; Sortino, M.A. Differential involvement of estrogen receptor alpha and estrogen receptor beta in the healing promoting effect of estrogen in human keratinocytes. J. Endocrinol. 2009, 200, 189–197. [Google Scholar] [CrossRef] [Green Version]
- Eo, H.; Lee, H.J.; Lim, Y. Ameliorative effect of dietary genistein on diabetes induced hyper-inflammation and oxidative stress during early stage of wound healing in alloxan induced diabetic mice. Biochem. Biophys. Res. Commun. 2016, 478, 1021–1027. [Google Scholar] [CrossRef] [PubMed]
- Zheng, Z.; Liu, Y.; Yang, Y.; Tang, J.; Cheng, B. Topical 1% propranolol cream promotes cutaneous wound healing in spontaneously diabetic mice. Wound Repair Regen. 2017, 25, 389–397. [Google Scholar] [CrossRef] [PubMed]
- Zandifar, E.; Sohrabi Beheshti, S.; Zandifar, A.; Haghjooy Javanmard, S. The effect of captopril on impaired wound healing in experimental diabetes. Int. J. Endocrinol. 2012, 2012, 785247. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Valachova, K.; Svik, K.; Biro, C.; Soltes, L. Skin wound healing with composite biomembranes loaded by tiopronin or captopril. J. Biotechnol. 2020, 310, 49–53. [Google Scholar] [CrossRef] [PubMed]
- Kavalipati, N.; Shah, J.; Ramakrishan, A.; Vasnawala, H. Pleiotropic effects of statins. Indian J. Endocrinol. Metab. 2015, 19, 554–562. [Google Scholar] [PubMed]
- Dimmeler, S.; Aicher, A.; Vasa, M.; Mildner-Rihm, C.; Adler, K.; Tiemann, M.; Rütten, H.; Fichtlscherer, S.; Martin, H.; Zeiher, A.M. HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J. Clin. Investig. 2001, 108, 391–397. [Google Scholar] [CrossRef]
- Bitto, A.; Minutoli, L.; Altavilla, D.; Polito, F.; Fiumara, T.; Marini, H.; Galeano, M.; Calò, M.; Cascio, P.L.; Bonaiuto, M.; et al. Simvastatin enhances VEGF production and ameliorates impaired wound healing in experimental diabetes. Pharmacol. Res. 2008, 57, 159–169. [Google Scholar] [CrossRef]
- Farsaei, S.; Khalili, H.; Farboud, E.S. Potential role of statins on wound healing: Review of the literature. Int. Wound J. 2012, 9, 238–247. [Google Scholar] [CrossRef]
- Asai, J.; Takenaka, H.; Hirakawa, S.; Sakabe, J.I.; Hagura, A.; Kishimoto, S.; Maruyama, K.; Kajiya, K.; Kinoshita, S.; Tokura, Y.; et al. Topical simvastatin accelerates wound healing in diabetes by enhancing angiogenesis and lymphangiogenesis. Am. J. Pathol. 2012, 181, 2217–2224. [Google Scholar] [CrossRef]
- Sawaya, A.P.; Jozic, I.; Stone, R.C.; Pastar, I.; Egger, A.N.; Stojadinovic, O.; Glinos, G.D.; Kirsner, R.S.; Tomic-Canic, M. Mevastatin promotes healing by targeting caveolin-1 to restore EGFR signaling. JCI Insight 2019, 4. [Google Scholar] [CrossRef] [Green Version]
- Sawaya, A.P.; Pastar, I.; Stojadinovic, O.; Lazovic, S.; Davis, S.C.; Gil, J.; Kirsner, R.S.; Tomic-Canic, M. Topical mevastatin promotes wound healing by inhibiting the transcription factor c-Myc via the glucocorticoid receptor and the long non-coding RNA Gas5. J. Biol. Chem. 2018, 293, 1439–1449. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, C.; Zhu, J.; Hai, B.; Zhang, W.; Wang, H.; Leng, H.; Xu, Y.; Song, C. Single Intraosseous Injection of Simvastatin Promotes Endothelial Progenitor Cell Mobilization, Neovascularization, and Wound Healing in Diabetic Rats. Plast. Reconstr. Surg. 2020, 145, 433–443. [Google Scholar] [CrossRef]
- Yang, Y.; Yin, D.; Wang, F.; Hou, Z.; Fang, Z. In situ eNOS/NO up-regulation—A simple and effective therapeutic strategy for diabetic skin ulcer. Sci. Rep. 2016, 6, 30326. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Keppel Hesselink, J.M. Phenytoin repositioned in wound healing: Clinical experience spanning 60 years. Drug Discov. Today. 2018, 23, 402–408. [Google Scholar] [CrossRef] [PubMed]
- Talas, G.; Brown, R.A.; McGrouther, D.A. Role of phenytoin in wound healing—a wound pharmacology perspective. Biochem. Pharmacol. 1999, 57, 1085–1094. [Google Scholar] [PubMed]
- Moy, L.S.; Tan, E.M.; Holness, R.; Uitto, J. Phenytoin modulates connective tissue metabolism and cell proliferation in human skin fibroblast cultures. Arch. Dermatol. 1985, 121, 79–83. [Google Scholar] [CrossRef]
- Bhatia, A.; Prakash, S. Topical phenytoin for wound healing. Dermatol. Online J. 2004, 10, 5. [Google Scholar]
- Vijayasingham, S.M.; Dykes, P.J.; Marks, R. Phenytoin has little effect on in-vitro models of wound healing. Br. J. Dermatol. 1991, 125, 136–139. [Google Scholar] [CrossRef]
- Patil, M.M.; Sahoo, J.; Kamalanathan, S.; Pillai, V. Phenytoin Induced Osteopathy-Too Common to be Neglected. J. Clin. Diagn. Res. 2015, 9, OD11. [Google Scholar] [CrossRef]
- Pereira, C.A.; Alchorne Ade, O. Assessment of the effect of phenytoin on cutaneous healing from excision of melanocytic nevi on the face and on the back. BMC Dermatol. 2010, 10, 7. [Google Scholar] [CrossRef] [Green Version]
- Bansal, N.K. Comparison of topical phenytoin with normal saline in the treatment of chronic trophic ulcers in leprosy. Int. J. Dermatol. 1993, 32, 210–213. [Google Scholar] [CrossRef] [PubMed]
- Rena, G.; Hardie, D.G.; Pearson, E.R. The mechanisms of action of metformin. Diabetologia 2017, 60, 1577–1585. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Anabtawi, A.; Miles, J.M. Metformin: Nonglycemic Effects and Potential Novel Indications. Endocr. Pract. 2016, 22, 999–1007. [Google Scholar] [CrossRef]
- Chen, L.L.; Liao, Y.F.; Zeng, T.S.; Yu, F.; Li, H.Q.; Feng, Y. Effects of metformin plus gliclazide compared with metformin alone on circulating endothelial progenitor cell in type 2 diabetic patients. Endocrine 2010, 38, 266–275. [Google Scholar] [CrossRef] [PubMed]
- Lin, J.T.; Chen, H.M.; Chiu, C.H.; Liang, Y.J. AMP-activated protein kinase activators in diabetic ulcers: From animal studies to Phase II drugs under investigation. Expert Opin. Investig. Drugs. 2014, 23, 1253–1265. [Google Scholar] [CrossRef]
- Owen, M.R.; Doran, E.; Halestrap, A.P. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J. 2000, 348 Pt 3, 607–614. [Google Scholar] [CrossRef]
- Zoncu, R.; Efeyan, A.; Sabatini, D.M. mTOR: From growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 2011, 12, 21–35. [Google Scholar] [CrossRef] [Green Version]
- Ursini, F.; Russo, E.; Pellino, G.; D’Angelo, S.; Chiaravalloti, A.; De Sarro, G.; Manfredini, R.; De Giorgio, R. Metformin and Autoimmunity: A “New Deal” of an Old Drug. Front. Immunol. 2018, 9, 1236. [Google Scholar] [CrossRef] [Green Version]
- Wang, T.; Zhao, J.; Zhang, J.; Mei, J.; Shao, M.; Pan, Y.; Yang, W.; Jiang, Y.; Liu, F.; Jia, W. Heparan sulfate inhibits inflammation and improves wound healing by downregulating the NLR family pyrin domain containing 3 (NLRP3) inflammasome in diabetic rats. J. Diabetes 2018, 10, 556–563. [Google Scholar] [CrossRef] [Green Version]
- Qing, L.; Fu, J.; Wu, P.; Zhou, Z.; Yu, F.; Tang, J. Metformin induces the M2 macrophage polarization to accelerate the wound healing via regulating AMPK/mTOR/NLRP3 inflammasome singling pathway. Am. J. Transl. Res. 2019, 11, 655–668. [Google Scholar]
- Han, X.; Tao, Y.; Deng, Y.; Yu, J.; Sun, Y.; Jiang, G. Metformin accelerates wound healing in type 2 diabetic db/db mice. Mol. Med. Rep. 2017, 16, 8691–8698. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhao, P.; Sui, B.D.; Liu, N.; Lv, Y.J.; Zheng, C.X.; Lu, Y.B.; Huang, W.T.; Zhou, C.H.; Chen, J.; Pang, D.L.; et al. Anti-aging pharmacology in cutaneous wound healing: Effects of metformin, resveratrol, and rapamycin by local application. Aging Cell 2017, 16, 1083–1093. [Google Scholar] [CrossRef] [PubMed]
- Tawfeek, H.M.; Abou-Taleb, D.A.E.; Badary, D.M.; Ibrahim, M.; Abdellatif, A.A.H. Pharmaceutical, clinical, and immunohistochemical studies of metformin hydrochloride topical hydrogel for wound healing application. Arch. Dermatol. Res. 2020, 312, 113–121. [Google Scholar] [CrossRef] [PubMed]
- El Gazaerly, H.; Elbardisey, D.M.; Eltokhy, H.M.; Teaama, D. Effect of transforming growth factor Beta 1 on wound healing in induced diabetic rats. Int. J. Health Sci. 2013, 7, 160–172. [Google Scholar] [CrossRef]
- Bagheri, M.; Mostafavinia, A.; Abdollahifar, M.A.; Amini, A.; Ghoreishi, S.K.; Chien, S.; Hamblin, M.R.; Bayat, S.; Bayat, M. Combined effects of metformin and photobiomodulation improve the proliferation phase of wound healing in type 2 diabetic rats. Biomed. Pharmacother. 2020, 123, 109776. [Google Scholar] [CrossRef]
- Drucker, D.J. The biology of incretin hormones. Cell Metab. 2006, 3, 153–165. [Google Scholar] [CrossRef] [Green Version]
- Boonacker, E.; Van Noorden, C.J. The multifunctional or moonlighting protein CD26/DPPIV. Eur. J. Cell Biol. 2003, 82, 53–73. [Google Scholar] [CrossRef] [Green Version]
- Marathe, P.H.; Gao, H.X.; Close, K.L. American Diabetes Association Standards of Medical Care in Diabetes 2017. J. Diabetes 2017, 9, 320–324. [Google Scholar] [CrossRef]
- Ku, H.C.; Liang, Y.J. Incretin-based therapy for diabetic ulcers: From bench to bedside. Expert Opin. Investig. Drugs 2018, 27, 989–996. [Google Scholar] [CrossRef] [PubMed]
- Sortino, M.A.; Sinagra, T.; Canonico, P.L. Linagliptin: A thorough Characterization beyond Its Clinical Efficacy. Front. Endocrinol. 2013, 4, 16. [Google Scholar] [CrossRef] [Green Version]
- Hattori, Y.; Jojima, T.; Tomizawa, A.; Satoh, H.; Hattori, S.; Kasai, K.; Hayashi, T. A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells. Diabetologia 2010, 53, 2256–2263. [Google Scholar] [CrossRef] [PubMed]
- Erdogdu, O.; Nathanson, D.; Sjoholm, A.; Nystrom, T.; Zhang, Q. Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-, PKA- and PI3K/Akt-dependent pathways and requires GLP-1 receptor. Mol. Cell. Endocrinol. 2010, 325, 26–35. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Morimoto, C.; Schlossman, S.F. The structure and function of CD26 in the T-cell immune response. Immunol. Rev. 1998, 161, 55–70. [Google Scholar] [CrossRef] [PubMed]
- Ohnuma, K.; Yamochi, T.; Uchiyama, M.; Nishibashi, K.; Iwata, S.; Hosono, O.; Kawasaki, H.; Tanaka, H.; Dang, N.H.; Morimoto, C. CD26 mediates dissociation of Tollip and IRAK-1 from caveolin-1 and induces upregulation of CD86 on antigen-presenting cells. Mol. Cell. Biol. 2005, 25, 7743–7757. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Baticic Pucar, L.; Pernjak Pugel, E.; Detel, D.; Varljen, J. Involvement of DPP IV/CD26 in cutaneous wound healing process in mice. Wound Repair Regen. 2017, 25, 25–40. [Google Scholar] [CrossRef] [PubMed]
- Schürmann, C.; Linke, A.; Engelmann-Pilger, K.; Steinmetz, C.; Mark, M.; Pfeilschifter, J.; Klein, T.; Frank, S. The dipeptidyl peptidase-4 inhibitor linagliptin attenuates inflammation and accelerates epithelialization in wounds of diabetic ob/ob mice. J. Pharmacol. Exp. Ther. 2012, 342, 71–80. [Google Scholar] [CrossRef] [Green Version]
- Sinagra, T.; Merlo, S.; Spampinato, S.F.; Pasquale, R.D.; Sortino, M.A. High mobility group box 1 contributes to wound healing induced by inhibition of dipeptidylpeptidase 4 in cultured keratinocytes. Front. Pharmacol. 2015, 6, 126. [Google Scholar] [CrossRef] [Green Version]
- Straino, S.; Di Carlo, A.; Mangoni, A.; De Mori, R.; Guerra, L.; Maurelli, R.; Panacchia, L.; Di Giacomo, F.; Palumbo, R.; Di Campli, C.; et al. High-mobility group box 1 protein in human and murine skin: Involvement in wound healing. J. Investig. Dermatol. 2008, 128, 1545–1553. [Google Scholar] [CrossRef]
- Ranzato, E.; Patrone, M.; Pedrazzi, M.; Burlando, B. HMGb1 promotes scratch wound closure of HaCaT keratinocytes via ERK1/2 activation. Mol. Cell. Biochem. 2009, 332, 199–205. [Google Scholar] [CrossRef]
- Ranzato, E.; Patrone, M.; Pedrazzi, M.; Burlando, B. Hmgb1 promotes wound healing of 3T3 mouse fibroblasts via RAGE-dependent ERK1/2 activation. Cell Biochem. Biophys. 2010, 57, 9–17. [Google Scholar] [CrossRef]
- Long, M.; Cai, L.; Li, W.; Zhang, L.; Guo, S.; Zhang, R.; Zheng, Y.; Liu, X.; Wang, M.; Zhou, X.; et al. DPP-4 Inhibitors Improve Diabetic Wound Healing via Direct and Indirect Promotion of Epithelial-Mesenchymal Transition and Reduction of Scarring. Diabetes 2018, 67, 518–531. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gallagher, K.A.; Liu, Z.J.; Xiao, M.; Chen, H.; Goldstein, L.J.; Buerk, D.G.; Nedeau, A.; Thom, S.R.; Velazquez, O.C. Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1 alpha. J. Clin. Investig. 2007, 117, 1249–1259. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fadini, G.P.; Boscaro, E.; Albiero, M.; Menegazzo, L.; Frison, V.; De Kreutzenberg, S.; Agostini, C.; Tiengo, A.; Avogaro, A. The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes: Possible role of stromal-derived factor-1alpha. Diabetes Care 2010, 33, 1607–1609. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Roan, J.N.; Cheng, H.N.; Young, C.C.; Lee, C.J.; Yeh, M.L.; Luo, C.Y.; Tsai, Y.S.; Lam, C.F. Exendin-4, a glucagon-like peptide-1 analogue, accelerates diabetic wound healing. J. Surg. Res. 2017, 208, 93–103. [Google Scholar] [CrossRef] [Green Version]
- Seo, E.; Lim, J.S.; Jun, J.B.; Choi, W.; Hong, I.S.; Jun, H.S. Exendin-4 in combination with adipose-derived stem cells promotes angiogenesis and improves diabetic wound healing. J. Transl. Med. 2017, 15, 35. [Google Scholar] [CrossRef] [Green Version]
- Bacci, S.; Laurino, A.; Manni, M.E.; Landucci, E.; Musilli, C.; De Siena, G.; Mocali, A.; Raimondi, L. The pro-healing effect of exendin-4 on wounds produced by abrasion in normoglycemic mice. Eur. J. Pharmacol. 2015, 764, 346–352. [Google Scholar] [CrossRef]
- Whittam, A.J.; Maan, Z.N.; Duscher, D.; Barrera, J.A.; Hu, M.S.; Fischer, L.H.; Khong, S.; Kwon, S.H.; Wong, V.W.; Walmsley, G.G.; et al. Small molecule inhibition of dipeptidyl peptidase-4 enhances bone marrow progenitor cell function and angiogenesis in diabetic wounds. Transl. Res. J. Lab. Clin. Med. 2019, 205, 51–63. [Google Scholar] [CrossRef]
- Marfella, R.; Sasso, F.C.; Rizzo, M.R.; Paolisso, P.; Barbieri, M.; Padovano, V.; Carbonara, O.; Gualdiero, P.; Petronella, P.; Ferraraccio, F.; et al. Dipeptidyl peptidase 4 inhibition may facilitate healing of chronic foot ulcers in patients with type 2 diabetes. Exp. Diabetes Res. 2012, 2012, 892706. [Google Scholar] [CrossRef]
Name | Chemical Formula | Chemical Structure |
---|---|---|
Statins | C24H36O5 | |
Phenytoin | C15H11N2NaO2 | |
Metformin | C4H11N5 | |
DPP-4 inhibitors | C16H15F6N5O |
Drugs | Effect on Wound Healing | Evidence from Human Studies | Administration |
---|---|---|---|
DPP-4 inhibitors | anti-inflammatory, anti-oxidant endothelial cell precursors proliferation-> angiogenesis fibroblast and keratinocyte migration wound remodeling | Improved healing of wounds and chronic foot ulcers in patients with diabetes [101,108]. | systemic |
metformin | anti-inflammatory, anti-oxidant endothelial cell precursors proliferation-> angiogenesis collagen deposition ECM organization | Improved healing in traumatic wound or ulcers [82]. | topical |
phenytoin | antibacterial, fibroblast proliferation-> granulation tissue increased VEGF release -> angiogenesis | Improved healing in a variety of wounds. Several randomized clinical trials available but methodologically poor. Reviewed in [64]. | topical |
statins | anti-inflammatory, angiogenesis | Mevastatin reverses several altered molecular pathways in ex vivo specimens derived from non healing edge of foot ulcers from diabetic patients [60,61]. | topical |
β-blockers | angiogenesis, proliferation of keratinocytes ECM organization | Only data in animals | topical |
ACE-inhibitor | anti-oxidative | Only data in animals | topical |
Estrogen (ERβ) | angiogenesis, proliferation of keratinocytes | Only data in animals | topical/systemic |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Spampinato, S.F.; Caruso, G.I.; De Pasquale, R.; Sortino, M.A.; Merlo, S. The Treatment of Impaired Wound Healing in Diabetes: Looking among Old Drugs. Pharmaceuticals 2020, 13, 60. https://doi.org/10.3390/ph13040060
Spampinato SF, Caruso GI, De Pasquale R, Sortino MA, Merlo S. The Treatment of Impaired Wound Healing in Diabetes: Looking among Old Drugs. Pharmaceuticals. 2020; 13(4):60. https://doi.org/10.3390/ph13040060
Chicago/Turabian StyleSpampinato, Simona Federica, Grazia Ilaria Caruso, Rocco De Pasquale, Maria Angela Sortino, and Sara Merlo. 2020. "The Treatment of Impaired Wound Healing in Diabetes: Looking among Old Drugs" Pharmaceuticals 13, no. 4: 60. https://doi.org/10.3390/ph13040060