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Miceli G, Basso MG, Pennacchio AR, Cocciola E, Pintus C, Cuffaro M, Profita M, Rizzo G, Sferruzza M, Tuttolomondo A. The Potential Impact of SGLT2-I in Diabetic Foot Prevention: Promising Pathophysiologic Implications, State of the Art, and Future Perspectives-A Narrative Review. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1796. [PMID: 39596981 PMCID: PMC11596194 DOI: 10.3390/medicina60111796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 10/24/2024] [Accepted: 10/30/2024] [Indexed: 11/29/2024]
Abstract
The impact of diabetic foot (DF) on the healthcare system represents a major public health problem, leading to a considerable clinical and economic burden. The factors contributing to DF's development and progression are strongly interconnected, including metabolic causes, neuropathy, arteriopathy, and inflammatory changes. Sodium-glucose cotransporter 2 inhibitors (SGLT2-i), novel oral hypoglycemic drugs used as an adjunct to standard treatment, have recently changed the pharmacological management of diabetes. Nevertheless, data about the risk of limb amputation, discordant and limited to canagliflozin, which is currently avoided in the case of peripheral artery disease, have potentially discouraged the design of specific studies targeting DF. There is good evidence for the single immunomodulatory, neuroprotective, and beneficial vascular effects of SGLT2-i. Still, there is no clinical evidence about the early use of SGLT2-i in diabetic foot due to the lack of longitudinal and prospective studies proving the effect of these drugs without confounders. This narrative review aims to discuss the main evidence about the impact of SGLT2-i on the three complications of diabetes implicated in the development of DF, the state of the art, and the potential future implications.
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Affiliation(s)
- Giuseppe Miceli
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (M.G.B.); (A.R.P.); (E.C.); (C.P.); (M.C.); (M.P.); (G.R.); (M.S.); (A.T.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Maria Grazia Basso
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (M.G.B.); (A.R.P.); (E.C.); (C.P.); (M.C.); (M.P.); (G.R.); (M.S.); (A.T.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Andrea Roberta Pennacchio
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (M.G.B.); (A.R.P.); (E.C.); (C.P.); (M.C.); (M.P.); (G.R.); (M.S.); (A.T.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Elena Cocciola
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (M.G.B.); (A.R.P.); (E.C.); (C.P.); (M.C.); (M.P.); (G.R.); (M.S.); (A.T.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Chiara Pintus
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (M.G.B.); (A.R.P.); (E.C.); (C.P.); (M.C.); (M.P.); (G.R.); (M.S.); (A.T.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Mariagiovanna Cuffaro
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (M.G.B.); (A.R.P.); (E.C.); (C.P.); (M.C.); (M.P.); (G.R.); (M.S.); (A.T.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Martina Profita
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (M.G.B.); (A.R.P.); (E.C.); (C.P.); (M.C.); (M.P.); (G.R.); (M.S.); (A.T.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Giuliana Rizzo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (M.G.B.); (A.R.P.); (E.C.); (C.P.); (M.C.); (M.P.); (G.R.); (M.S.); (A.T.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Mariachiara Sferruzza
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (M.G.B.); (A.R.P.); (E.C.); (C.P.); (M.C.); (M.P.); (G.R.); (M.S.); (A.T.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Antonino Tuttolomondo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (M.G.B.); (A.R.P.); (E.C.); (C.P.); (M.C.); (M.P.); (G.R.); (M.S.); (A.T.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
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Raja JM, Maturana MA, Kayali S, Khouzam A, Efeovbokhan N. Diabetic foot ulcer: A comprehensive review of pathophysiology and management modalities. World J Clin Cases 2023; 11:1684-1693. [PMID: 36970004 PMCID: PMC10037283 DOI: 10.12998/wjcc.v11.i8.1684] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 01/08/2023] [Accepted: 02/17/2023] [Indexed: 03/07/2023] Open
Abstract
Diabetic foot ulcer (DFU) is a debilitating and severe manifestation of uncontrolled and prolonged diabetes that presents as ulceration, usually located on the plantar aspect of the foot. Approximately 15% of individuals with diabetes will eventually develop DFU, and 14%-24% of them will require amputation of the ulcerated foot due to bone infection or other ulcer-related complications. The pathologic mechanisms underlying DFU are comprise a triad: Neuropathy, vascular insufficiency, and secondary infection due to trauma of the foot. Standard local and invasive care along with novel approaches like stem cell therapy pave the way to reduce morbidity, decrease amputations, and prevent mortality from DFU. In this manuscript, we review the current literature with focus on the pathophysiology, preventive options, and definitive management of DFU.
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Affiliation(s)
- Joel M Raja
- Department of Internal Medicine, University of Tennessee Health Science Center, Memphis, TN 38119, United States
| | - Miguel A Maturana
- Department of Internal Medicine, University of Tennessee Health Science Center, Memphis, TN 38119, United States
| | - Sharif Kayali
- Department of Internal Medicine, University of Tennessee Health Science Center, Memphis, TN 38119, United States
| | - Amir Khouzam
- Department of Internal Medicine, University of Tennessee Health Science Center, Memphis, TN 38119, United States
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Savitri C, Kwon JW, Drobyshava V, Ha SS, Park K. M2 Macrophage-Derived Concentrated Conditioned Media Significantly Improves Skin Wound Healing. Tissue Eng Regen Med 2021; 19:617-628. [PMID: 34962626 PMCID: PMC9130431 DOI: 10.1007/s13770-021-00414-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Macrophages, with many different phenotypes play a major role during wound healing process, secreting the cytokines crucial to angiogenesis, cell recruitment and ECM remodeling. Therefore, macrophage-derived cytokines may be attractive therapeutic resource for wound healing. METHODS To obtain a conditioned media (CM) from macrophages, human monocyte THP-1 cells were seeded on TCP or human fibroblast-derived matrix (hFDM) and they were differentiated into M1 or M2 phenotype using distinct protocols. A combination of different substrates and macrophage phenotypes produced M1- and M2-CM or M1-hFDM- and M2-hFDM-CM, respectively. Proteome microarray determines the cytokine contents in those CMs. CMs-treated human dermal fibroblast (hDFB) was analyzed using collagen synthesis and wound scratch assay. Concentrated form of the CM (CCM), obtained by high-speed centrifugation, was administered to a murine full-thickness wound model using alginate patch, where alginate patch was incubated in the M2-CCM overnight at 4 °C before transplantation. On 14 day post-treatment, examination was carried out through H&E and Herovici staining. Keratinocyte and M2 macrophages were also evaluated via immunofluorescence staining. RESULTS Cytokine analysis of CMs found CCL1, CCL5, and G-CSF, where CCL5 is more dominant. We found increased collagen synthesis and faster wound closure in hDFB treated with M2-CM. Full-thickness wounds treated by M2-hFDM-CCM containing alginate patch showed early wound closure, larger blood vessels, increased mature collagen deposition, enhanced keratinocyte maturation and more M2-macrophage population. CONCLUSION Our study demonstrated therapeutic potential of the CM derived from M2 macrophages, where the cytokines in the CM may have played an active role for enhanced wound healing.
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Affiliation(s)
- Cininta Savitri
- Center for Biomaterials, Korea Institute of Science and Technology (KIST), Seoul, 02792 Republic of Korea ,Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul, 02792 Republic of Korea
| | - Jae Won Kwon
- Center for Biomaterials, Korea Institute of Science and Technology (KIST), Seoul, 02792 Republic of Korea ,Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul, 02792 Republic of Korea
| | - Valeryia Drobyshava
- Center for Biomaterials, Korea Institute of Science and Technology (KIST), Seoul, 02792 Republic of Korea ,Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul, 02792 Republic of Korea
| | - Sang Su Ha
- Center for Biomaterials, Korea Institute of Science and Technology (KIST), Seoul, 02792 Republic of Korea
| | - Kwideok Park
- Center for Biomaterials, Korea Institute of Science and Technology (KIST), Seoul, 02792 Republic of Korea ,Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul, 02792 Republic of Korea
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Tripathi S, Singh BN, Singh D, kumar G, Srivastava P. Optimization and evaluation of ciprofloxacin-loaded collagen/chitosan scaffolds for skin tissue engineering. 3 Biotech 2021; 11:160. [PMID: 33758738 PMCID: PMC7937002 DOI: 10.1007/s13205-020-02567-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Accepted: 11/24/2020] [Indexed: 01/24/2023] Open
Abstract
A novel ciprofloxacin-loaded collagen-chitosan scaffold was developed for the treatment of wound using freeze drying method. The average pore size and porosity of developed scaffold was found to be around 125 µm and 91 ± 0.56%. Moreover, swelling, degradation and mechanical tests profile supported the suitability of scaffold for wound healing process. The scaffold has high degree of hemocompatibility towards the blood and promotes the growth, migration and proliferation of fibroblast. The developed scaffold exhibits antibacterial properties and was found to be efficient against the Gram-negative (E.coli) and Gram-positive (Staphylococcus aureus) bacteria hence can be used for wound healing applications. In vivo study demonstrated that the scaffold not only escalated the tissue regeneration time but also accelerated the wound healing process compared to control. The histological studies revealed better granulation, vascularization, and remodeling of extracellular matrix along with regeneration of epidermal and dermal layer of skin. Overall, the obtained results suggested that the developed skin tissue constructs possess the enormous potential for tissue regeneration and might be a suitable biomaterial for skin tissue engineering applications.
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Affiliation(s)
- Satyavrat Tripathi
- School of Biochemical Engineering, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005 India
| | - Bhisham Narayan Singh
- School of Biochemical Engineering, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005 India
| | - Divakar Singh
- School of Biochemical Engineering, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005 India
| | - Gaurav kumar
- School of Biomedical Engineering, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005 India
| | - Pradeep Srivastava
- School of Biochemical Engineering, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005 India
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Huang Y, Kyriakides TR. The role of extracellular matrix in the pathophysiology of diabetic wounds. Matrix Biol Plus 2020; 6-7:100037. [PMID: 33543031 PMCID: PMC7852307 DOI: 10.1016/j.mbplus.2020.100037] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 04/13/2020] [Accepted: 04/14/2020] [Indexed: 12/29/2022] Open
Abstract
Impaired healing leading to the formation of ulcerated wounds is a critical concern in patients with diabetes. Abnormalities in extracellular matrix (ECM) production and remodeling contribute to tissue dysfunction and delayed healing. Specifically, diabetes-induced changes in the expression and/or activity of structural proteins, ECM-modifying enzymes, proteoglycans, and matricellular proteins have been reported. In this review, we provide a summary of the key ECM molecules and associated changes in skin and diabetic wounds. Such information should allow for new insights in the understanding of impaired wound healing and lead to the development of ECM-based therapeutic strategies.
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Affiliation(s)
- Yaqing Huang
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT 06519, USA.,Department of Pathology, Yale University, New Haven, CT 06519, USA
| | - Themis R Kyriakides
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT 06519, USA.,Department of Pathology, Yale University, New Haven, CT 06519, USA.,Department of Biomedical Engineering, Yale University, New Haven, CT 06519, USA
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Kim DU, Chung HC, Choi J, Sakai Y, Lee BY. Oral Intake of Low-Molecular-Weight Collagen Peptide Improves Hydration, Elasticity, and Wrinkling in Human Skin: A Randomized, Double-Blind, Placebo-Controlled Study. Nutrients 2018; 10:nu10070826. [PMID: 29949889 PMCID: PMC6073484 DOI: 10.3390/nu10070826] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 06/20/2018] [Accepted: 06/21/2018] [Indexed: 11/29/2022] Open
Abstract
Collagen-peptide supplementation could be an effective remedy to improve hydration, elasticity, and wrinkling in human skin. The aim of this study was to conduct a double-blind, randomized, placebo-controlled trial to clinically evaluate the effect on human skin hydration, wrinkling, and elasticity of Low-molecular-weight Collagen peptide (LMWCP) with a tripetide (Gly-X-Y) content >15% including 3% Gly-Pro-Hyp. Individuals (n = 64) were randomly assigned to receive either placebo or 1000 mg of LMWCP once daily for 12 weeks. Parameters of skin hydration, wrinkling, and elasticity were assessed at baseline and after 6 weeks and 12 weeks. Compared with the placebo group, skin-hydration values were significantly higher in the LMWCP group after 6 weeks and 12 weeks. After 12 weeks in the LMWCP group, visual assessment score and three parameters of skin wrinkling were significantly improved compared with the placebo group. In case of skin elasticity, one parameter out of three was significantly improved in the LMWCP group from the baseline after 12 weeks, while, compared with the placebo group, two parameters out of three in the LMWCP group were higher with significance after 12 weeks. In terms of the safety of LMWCP, none of the subjects presented adverse symptoms related to the test material during the study period. These results suggest that LMWCP can be used as a health functional food ingredient to improve human skin hydration, elasticity, and wrinkling.
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Affiliation(s)
- Do-Un Kim
- Newtree, Seongnam 13207, Gyeonggi, Korea.
| | | | - Jia Choi
- Department of Food Science and Biotechnology, College of Life Science, CHA University, Seongnam 13488, Gyeonggi, Korea.
| | - Yasuo Sakai
- Central Research Institute, Jellice, Sakae, Tagajo 985-0833, Japan.
| | - Boo-Yong Lee
- Department of Food Science and Biotechnology, College of Life Science, CHA University, Seongnam 13488, Gyeonggi, Korea.
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Abstract
The second article in a series on the biology of wound healing looks at the regulatory mechanisms in the wound-healing process.
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Affiliation(s)
- I Hopkinson
- Director, Wound Biology Laboratory and lecturer in wound healing, University of Wales College of Medicine, Cardiff
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