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Rezaeiasl Z, Zavareh MS. Diabetic wounds and short-chain fatty acids. J Diabetes Metab Disord 2025; 24:45. [PMID: 39801685 PMCID: PMC11723878 DOI: 10.1007/s40200-025-01560-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Accepted: 01/01/2025] [Indexed: 01/16/2025]
Abstract
Diabetes mellitus is a debilitating and worrisome chronic disease with many complications such as cardiovascular disease, kidney damage, blindness and diabetic wounds. Despite advances in the treatment of diabetic wounds, there are still concerns regarding the management of diabetic wound healing, particularly the inflammatory phase. In addition to many treatments with successful effects on wound healing in diabetic patients, short-chain fatty acids (SCFA) acetate, propionate, butyrate, valproate and valerate and their by-products have recently been proposed as new treatments for wound healing in diabetic patients. We provide an overview of the most recent studies on the effectiveness of the above-mentioned SCFAs in the treatment of diabetic wounds as well as possible effects on cytokines in this area of study.
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Affiliation(s)
- Zahra Rezaeiasl
- Institute for Basic Sciences, Physiology Research Center, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
| | - Mahmoud Salami Zavareh
- Institute for Basic Sciences, Physiology Research Center, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
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2
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Aschen SZ, Zhang A, O'Connell GM, Salingaros S, Andy C, Rohde CH, Spector JA. Association of Perioperative Glucagon-like Peptide-1 Receptor Agonist Use and Postoperative Outcomes. Ann Surg 2025; 281:600-607. [PMID: 39704067 DOI: 10.1097/sla.0000000000006614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2024]
Abstract
OBJECTIVE To assess rates of surgical complications and postoperative readmission in diabetic patients with and without active perioperative prescriptions for glucagon-like peptide-1 receptor agonist (GLP-1 RA) medications. BACKGROUND With the rapid growth of GLP-1 RA use in the United States, it is important to understand the potential effect of these drugs on surgical outcomes broadly. METHODS In this retrospective, observational cohort analysis, patients with a diagnosis of type 1 or type 2 diabetes undergoing a surgical procedure at a multicenter quaternary-care health care system between February 2020 and July 2023 were included. Propensity score matching was performed between procedures in patients with and without an active GLP-1 RA prescription. The primary outcome was 30-day readmission, and secondary outcomes were documented dehiscence, infection, hematoma, and bleeding within 180 days after surgery. RESULTS Among 74,425 surgical procedures in 21,772 patients included in the analysis, 27.2% were performed in the setting of an active GLP-1 RA prescription. In 13,129 patients [48.0% men, 52.0% women; median (interquartile range) age, 67 (57, 75)], 35,020 procedures were propensity score matched. After matching, the active GLP-1 RA prescription group had a significantly reduced risk of 30-day readmission [relative risk (RR): 0.883; 95% CI: 0.789-0.987; P = 0.028; number needed to treat (NNT): 219; 95% CI: 191-257], postoperative wound dehiscence (RR: 0.711; 95% CI: 0.577-0.877; P = 0.001; NNT: 266; 95% CI: 202-391), and postoperative hematoma (RR: 0.440; 95% CI: 0.216-0.894; P = 0.023; NNT: 1786; 95% CI: 652-2416). No significant differences were seen in rates of infection and bleeding. CONCLUSIONS An active perioperative GLP-1 RA prescription in patients with diabetes was associated with significant reductions in risk-adjusted readmission, wound dehiscence, and hematoma, and no difference in infection and bleeding rates. Further study is warranted to elucidate any causal association.
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Affiliation(s)
- Seth Z Aschen
- Department of Surgery, Weill Cornell Medicine, New York, NY
| | - Ashley Zhang
- Department of Surgery, Columbia University Irving Medical Center, New York, NY
| | - Gillian M O'Connell
- Department of Surgery, Columbia University Irving Medical Center, New York, NY
| | | | - Caroline Andy
- Division of Biostatistics, Department of Population Health Sciences,Weill Cornell Medicine, New York, NY
| | - Christine H Rohde
- Department of Surgery, Columbia University Irving Medical Center, New York, NY
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Li X, Yi M, Song Z, Ni T, Tu L, Yu M, Zhang L, Shi J, Gao W, Zhang Q, Yan W. A calcitonin gene-related peptide co-crosslinked hydrogel promotes diabetic wound healing by regulating M2 macrophage polarization and angiogenesis. Acta Biomater 2025; 196:109-122. [PMID: 40020959 DOI: 10.1016/j.actbio.2025.02.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 02/07/2025] [Accepted: 02/21/2025] [Indexed: 03/03/2025]
Abstract
Delayed diabetic wound (DBW) healing is a severe complication of diabetes, characterized notably by peripheral sensory neuropathy. The underlying mechanism of sensory nerves and DBW remain unclear. Here, we demonstrate the role of calcitonin gene-related peptide (CGRP) in regulating epithelialization and angiogenesis in DBW. Subsequently, we design and synthesis a gelatin methacryloyl (GelMA-CGRP) hydrogel that slowly releases CGRP, and evaluated its effect on promoting DBW healing. The results show that CGRP is abnormally downregulated in DBW, and CGRP ablation further delays DBW healing. This is due to the reduced M2 polarization and decreased angiogenesis in the absence of CGRP, whereas local application of GelMA-CGRP accelerates DBW healing. Mechanistic studies indicate that CGRP promotes M2 macrophage polarization by inhibiting the p53 signaling pathway and enhances endothelial cell function, thereby accelerating DBW healing. These findings suggest that CGRP could provide a novel therapeutic approach for diabetic wound treatment. STATEMENT OF SIGNIFICANCE: Current methods for treating diabetic wounds have many limitations. Compared to conventional dressings, hydrogels combined with drugs or biological factors to promote diabetic wound healing have become an important research direction in recent years. This study reveals the key role of CGRP in the pathogenesis of diabetic wounds. The research found that CGRP promotes M2 macrophage polarization and angiogenesis by inhibiting the p53 signaling pathway, thereby promoting diabetic wound healing. We further utilized the carrier properties of GelMA hydrogel to develop a GelMA-CGRP hydrogel material that slowly delivers CGRP and effectively treats diabetic wounds. This material demonstrates strong biocompatibility and antimicrobial properties, offering a novel approach for the treatment of diabetic wounds.
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Affiliation(s)
- Xiangyu Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China
| | - Min Yi
- Department of Plastic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China
| | - Ziyan Song
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China
| | - Tianyi Ni
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China
| | - Liying Tu
- Department of Plastic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China
| | - Miao Yu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China
| | - Lantian Zhang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China
| | - Jingping Shi
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China
| | - Weicheng Gao
- Department of Plastic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China.
| | - Qian Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China.
| | - Wei Yan
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China.
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Xu JW, Ma L, Xiang Y, Dai MQ, Li QH, Jin XY, Ruan Y, Li Y, Wang JY, Shen X. Glabridin as a selective Kv2.1 inhibitor ameliorates DPN pathology by disrupting the Aβ/Kv2.1/JNK/NF-κB/NLRP3/p-Tau pathway. Acta Pharmacol Sin 2025:10.1038/s41401-025-01526-6. [PMID: 40113986 DOI: 10.1038/s41401-025-01526-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 02/25/2025] [Indexed: 03/22/2025]
Abstract
Diabetic peripheral neuropathy (DPN) is a common diabetic complication. DPN has a complicated pathogenesis, and the currently clinical drugs against this disease show only limited efficacy and undesirable side effects. Thus, it is of great challenges to discover effective targets and drugs against DPN. Glabridin (GLA) is a natural prenylated isoflavone from the roots of Glycyrrhiza glabra. It exhibits a wide range of pharmacological activities including anti-inflammatory, antioxidant, cardiovascular protective, neuroprotective, hepatoprotective, anti-obesity and anti-diabetic effects, etc. In this study we investigated the beneficial effects of GLA on late-stage DPN and the underlying mechanisms. Using electrophysiological recording from CHO-Kv2.1 cells, we identified GLA as a new Kv2.1-selective inhibitor with an IC50 value of 2.07 μM. We showed that oral administration of GLA (30, 60 mg·kg-1·d-1) for 4 weeks significantly improved all neurological dysfunctions and peripheral vascular dysfunctions in DPN mice. Furthermore, we demonstrated that GLA administration improved intraepidermal nerve fiber (IENF) density damage and myelin sheath injury, promoted neurite outgrowth of DRG neurons and alleviated the apoptosis of DRG neurons in DPN mice. All these beneficial effects of GLA were deprived in Kv2.1-knockdown DPN mice specifically in the DRG and sciatic nerve tissues by injection of adeno associated virus AAV8-Kv2.1-RNAi (AAV8-Kv2.1). We showed that the levels of Aβ and hyperphosphorylated tau proteins (p-Tau) were pathologically increased in serum of DPN patients. We demonstrated that Kv2.1 channels bridged Aβ to activate NLRP3 inflammasome in Schwann cells and promote p-Tau production in DRG neurons through Schwann cells/DRG neurons crosstalk. GLA interrupted Aβ/Kv2.1/NLRP3/p-Tau axis to ameliorate the DPN-like pathology in mice. Our results support that Kv2.1 inhibition is a therapeutic strategy for DPN and highlight the potential of GLA in treating this disease.
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Affiliation(s)
- Jia-Wen Xu
- School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong First People's Hospital, Medical School of Nantong University, Nantong, 226000, China
| | - Lin Ma
- School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yu Xiang
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Meng-Qing Dai
- School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Qiu-Hui Li
- School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Xiao-Yan Jin
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yuan Ruan
- School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yang Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China.
| | - Jia-Ying Wang
- School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Xu Shen
- School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
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Farid A, Mohsen A, Nasser B, Alaa H, Abdelaziz M, Mustafa M, Mansour M, Adel N, Magdy S, Mohsen S, Adel S, Ibrahim S, Abdel-Rahman S, Mohamed S, El-Karamany Y. Treatment of Staphylococcus aureus-infected diabetic wounds by melatonin loaded nanocarriers. AMB Express 2025; 15:46. [PMID: 40088373 PMCID: PMC11910460 DOI: 10.1186/s13568-025-01854-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Accepted: 02/20/2025] [Indexed: 03/17/2025] Open
Abstract
One of the complication of diabetes mellitus is chronic wounds. The healing of wounds in diabetic patients is retarded by the elevation in the pro-inflammatory cytokines secretion and free radicles accumulation. Wound management in diabetic patients requires preventing bacterial biofilm development. Due to the wound healing activity of chitosan (CS), lecithin (Le) and melatonin (M), the present study aimed to load melatonin on CS/Le NPs and examine their effect on diabetic wounds infected with Staphylococcus aureus. Melatonin loaded chitosan/lecithin nanoparticles (M-CS/Le NPs) were physically characterized and their antioxidant, anti-inflammatory and antimicrobial activities were examined in vitro. Male Sprague Dawley rats included two division (non-diabetic and diabetic) which were further divided in nine groups. Diabetes induction and follow up throughout the experimental period was confirmed by measuring the levels of fructosamine and blood glucose. Full-thickness wounds was induced in both non-diabetic and diabetic animals followed by infection with Staphylococcus aureus according to the experimental design. The wound healing effect of M-CS/Le NPs was evaluated through measurements of the oxidative stress, inflammatory cytokines and apoptotic proteins. Our results showed the anti-microbial, free radical scavenging and hemolysis inhibition effects of M-CS/Le NPs in vitro. Moreover, the preparation of M-CS/Le NPs decreased the dose of used melatonin (when compared to free melatonin). M-CS/Le NPs significantly decreased the wound area percent in treated infected wounds of both non-diabetic and diabetic rats more than free melatonin or unloaded CS/Le NPs. In conclusion, M-CS/Le NPs promoted the wound healing in Staphylococcus aureus-infected wounds in diabetic rats.
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Affiliation(s)
- Alyaa Farid
- Biotechnology Department, Faculty of Science, Cairo University, Giza, Egypt.
| | - Ayah Mohsen
- Biochemistry Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Bassant Nasser
- Biochemistry Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Habiba Alaa
- Biotechnology/Biomolecular chemistry program, Faculty of Science, Cairo University, Giza, Egypt
| | - Mariam Abdelaziz
- Biotechnology/Biomolecular chemistry program, Faculty of Science, Cairo University, Giza, Egypt
| | - Maryam Mustafa
- Biotechnology/Biomolecular chemistry program, Faculty of Science, Cairo University, Giza, Egypt
| | - Mustafa Mansour
- Biotechnology/Biomolecular chemistry program, Faculty of Science, Cairo University, Giza, Egypt
| | - Nourhan Adel
- Biochemistry Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Salma Magdy
- Biotechnology/Biomolecular chemistry program, Faculty of Science, Cairo University, Giza, Egypt
| | - Salma Mohsen
- Biotechnology/Biomolecular chemistry program, Faculty of Science, Cairo University, Giza, Egypt
| | - Samah Adel
- Biochemistry Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Sarah Ibrahim
- Biochemistry Department, Faculty of Science, Cairo University, Giza, Egypt
| | | | - Sohaila Mohamed
- Biochemistry Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Yomna El-Karamany
- Biotechnology/Biomolecular chemistry program, Faculty of Science, Cairo University, Giza, Egypt
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6
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Mackay K, Thompson R, Parker M, Pedersen J, Kelly H, Loynd M, Giffen E, Baker A. The role of hyperbaric oxygen therapy in the treatment of diabetic foot ulcers - A literature review. J Diabetes Complications 2025; 39:108973. [PMID: 39970800 DOI: 10.1016/j.jdiacomp.2025.108973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Revised: 02/10/2025] [Accepted: 02/12/2025] [Indexed: 02/21/2025]
Abstract
Diabetic Foot Ulcers (DFUs) are chronic foot wounds, in a person with diabetes, which are associated with peripheral arterial insufficiency and/or peripheral neuropathy of the lower limb. Recent UK audit figures report that approximately 50-60 % of DFUs remain unhealed after 12 weeks. Previous research has suggested that ischaemia plays a key role in the pathophysiology of many chronic wounds, including DFUs. For this reason, hyperbaric oxygen therapy (HOT) has been investigated. The study aimed to investigate 1) Current understanding of the physiology of normal wound healing and the pathological mechanisms that occur in DFUs to interrupt these processes; 2) Effectiveness of current DFU treatment approaches; 3) Effectiveness from clinical trials and meta-analyses for any demonstrated therapeutic benefits of HOT in the treatment of DFUs, 4) Patient selection criteria for HOT, and patients who stand to benefit most from treatment. The review found that wound healing is a complex process, involving many cells and signalling molecules, and it remains incompletely understood. However, current evidence suggests that hyperglycaemia, hypoxia, chronic inflammation (due to infection, immune-cell dysfunction or other causes), peripheral neuropathy, and macro- and micro-vascular dysfunction may all adversely affect DFU healing. The review found that current NICE guidelines do not approve HOT therapy in the UK for DFU's, despite encouraging clinical research findings. HOT shows theoretical promise and has been successfully used in the treatment of individual DFUs for several decades. Despite this, there remains a lack of strong clinical evidence of benefits to encourage HOT's wider use. The review found that there were four important patient selection criteria for HOT treatment, including glycaemic control, possible contraindications and complications associated with treatment, ulcer severity and resistance to first and second line treatments. The review concluded that further high-quality clinical research is needed to improve the evidence base.
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Affiliation(s)
- Ken Mackay
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, United Kingdom
| | - Rhiannon Thompson
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, United Kingdom
| | - Matthew Parker
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, United Kingdom.
| | - James Pedersen
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, United Kingdom
| | - Hayden Kelly
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, United Kingdom
| | - Mairi Loynd
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, United Kingdom
| | - Emily Giffen
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, United Kingdom
| | - Angus Baker
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, United Kingdom
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Cariba S, Srivastava A, Bronsema K, Kouthouridis S, Zhang B, Payne SL. Innervated Coculture Device to Model Peripheral Nerve-Mediated Fibroblast Activation. ACS Biomater Sci Eng 2024; 10:7566-7576. [PMID: 39601321 PMCID: PMC11633653 DOI: 10.1021/acsbiomaterials.4c01482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 11/06/2024] [Accepted: 11/20/2024] [Indexed: 11/29/2024]
Abstract
Cutaneous wound healing is a complex process involving various cellular and molecular interactions, resulting in the formation of a collagen-rich scar with imperfect function and morphology. Dermal fibroblasts are crucial to successful wound healing, migrating to the wound site where they are activated to provide extracellular matrix remodeling and wound closure. Peripheral nerves have been shown to play an important role in wound healing, with loss or damage to these nerves often leading to impaired healing and the formation of chronic nonhealing wounds. Previous research has suggested that sensory nerves secrete trophic factors that can regulate wound healing, including fibroblast activation; however, the direct cell-cell interaction between nerves and fibroblasts has not been extensively studied. To address this knowledge gap, we developed an in vitro co-culture model using a device called the IFlowPlate. This model supports the long-term viability of multiple cell types while allowing for direct contact between sensory nerve cells and dermal fibroblasts. Using the IFlowPlate, we demonstrate that co-culture of dorsal root ganglia with dermal fibroblasts increases fibroblast proliferation, collagen and α-smooth muscle actin expression, and secretion of pro-wound healing factors, suggesting that nerves can promote wound healing by modulating fibroblast activation. The IFlowPlate offers a user-friendly and high-throughput platform to study the in vitro interactions between nerves and a variety of cell types that can be applied to wound healing and other important biological processes.
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Affiliation(s)
- Solsa Cariba
- Department
of Biomedical Sciences, University of Guelph, Guelph N1G 2W1, Canada
| | - Avika Srivastava
- Department
of Biomedical Sciences, University of Guelph, Guelph N1G 2W1, Canada
| | - Kendra Bronsema
- Department
of Biomedical Sciences, University of Guelph, Guelph N1G 2W1, Canada
| | - Sonya Kouthouridis
- Department
of Chemical Engineering, McMaster University, Hamilton L8S 4L8, Canada
| | - Boyang Zhang
- Department
of Chemical Engineering, McMaster University, Hamilton L8S 4L8, Canada
- School
of Biomedical Engineering, McMaster University, Hamilton L8S 4L8, Canada
| | - Samantha L. Payne
- Department
of Biomedical Sciences, University of Guelph, Guelph N1G 2W1, Canada
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Zeng R, Xiong Y, Lin Z, Chu X, Lv B, Lu L, Lin C, Liao J, Ouyang L, Sun Y, Dai G, Cao F, Liu G. Novel cocktail therapy based on multifunctional supramolecular hydrogel targeting immune-angiogenesis-nerve network for enhanced diabetic wound healing. J Nanobiotechnology 2024; 22:749. [PMID: 39623443 PMCID: PMC11613776 DOI: 10.1186/s12951-024-03038-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Accepted: 11/25/2024] [Indexed: 12/06/2024] Open
Abstract
Diabetes-associated chronic skin wounds present a formidable challenge due to inadequate angiogenesis and nerve regeneration during the healing process. In the present study, we introduce a groundbreaking approach in the form of a novel cocktail therapy utilizing a multifunctional supramolecular hydrogel. Formulated through the photo-crosslinking of gelatinized aromatic residues and β-cyclodextrin (β-CD), this injectable hydrogel fosters weak host-guest interactions, offering a promising solution. The therapeutic efficacy of the hydrogel is realized through its integration with adipose-derived stem cells (ADSCs) and lipid nanoparticles encapsulating ginsenoside RG1 and Stromal cell-derived factor-1 (SDF-1). This strategic combination directs ADSCs to the injury site, guiding them toward neurogenic specialization while establishing an advantageous immunomodulatory environment through macrophage reprogramming. The synergistic effects of the newly differentiated nerve cells and the regenerative cytokines secreted by ADSCs contribute significantly to enhanced angiogenesis, ultimately expediting the diabetic wound healing process. To summarize, this innovative hydrogel-based therapeutic system represents a novel perspective for the management of diabetic wounds by concurrently targeting immune response, angiogenesis, and nerve regeneration-a pivotal advancement in the quest for effective solutions in diabetic wound care.
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Affiliation(s)
- Ruiyin Zeng
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yuan Xiong
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ze Lin
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiangyu Chu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Bin Lv
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Li Lu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chuanlu Lin
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jiewen Liao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Lizhi Ouyang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yun Sun
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Guandong Dai
- Department of Orthopaedics, Pingshan District People's Hospital of Shenzhen, Pingshan General Hospital of Southern Medical University, Shenzhen, 518118, Guangdong, China.
| | - Faqi Cao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Guohui Liu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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9
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Xing L, Chen B, Qin Y, Li X, Zhou S, Yuan K, Zhao R, Qin D. The role of neuropeptides in cutaneous wound healing: a focus on mechanisms and neuropeptide-derived treatments. Front Bioeng Biotechnol 2024; 12:1494865. [PMID: 39539691 PMCID: PMC11557334 DOI: 10.3389/fbioe.2024.1494865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024] Open
Abstract
An extensive network of cutaneous nerves, neuropeptides, and specific receptors richly innervates the skin and influences a variety of physiological and pathological processes. The sensory and autonomic nerve fibers secrete a variety of neuropeptides that are essential to the different phases of wound healing. In addition to initiating a neurogenic inflammatory response in the early stages of healing, neuropeptides also control wound healing by influencing immune cells, repair cells, and the growth factor network. However, the precise mechanism by which they accomplish these roles in the context of cutaneous wound healing is still unknown. Investigating the mechanisms of action of neuropeptides in wound healing and potential therapeutic applications is therefore urgently necessary. The present review discusses the process of wound healing, types of neuropeptides, potential mechanisms underlying the role of neuropeptides in cutaneous wound healing, as well as some neuropeptide-derived treatment strategies, such as hydrogels, new dressings, electro stimulation, and skin-derived precursors. Future in-depth mechanistic studies of neuropeptides in cutaneous wound healing may provide opportunities to develop therapeutic technologies that harness the roles of neuropeptides in the wound healing process.
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Affiliation(s)
- Liwei Xing
- First Clinical Medical College, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| | - Bing Chen
- School of Medicine, Kunming University, Kunming, China
| | - Yuliang Qin
- Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Neuropsychiatric Diseases, Yunnan University of Chinese Medicine, Kunming, China
| | - Xinyao Li
- Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Neuropsychiatric Diseases, Yunnan University of Chinese Medicine, Kunming, China
| | - Sitong Zhou
- Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Neuropsychiatric Diseases, Yunnan University of Chinese Medicine, Kunming, China
| | - Kai Yuan
- Second Clinical Medical College, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| | - Rong Zhao
- First Clinical Medical College, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| | - Dongdong Qin
- Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Neuropsychiatric Diseases, Yunnan University of Chinese Medicine, Kunming, China
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10
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Britten-Jones AC, Wu M, Roberts LJ, MacIsaac RJ, Jiao H, Craig JP, Chinnery HR, Downie LE. Tear neuropeptide Y as a non-invasive marker of peripheral microvascular complications in type 1 diabetes. Ocul Surf 2024; 34:309-316. [PMID: 39153598 DOI: 10.1016/j.jtos.2024.08.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 07/30/2024] [Accepted: 08/13/2024] [Indexed: 08/19/2024]
Abstract
AIMS To investigate tear neuropeptide Y (NPY) and substance P concentrations in individuals with type 1 diabetes, comparing those with and without both diabetic retinopathy (DR) and peripheral neuropathy. METHODS This cross-sectional study involved 41 participants with type 1 diabetes and none to moderate DR, and 22 healthy controls. Assessments included clinical ocular surface parameters, quantification of corneal nerve attributes (based on in vivo confocal microscopy imaging), DR grading, and evaluation for small and large fibre neuropathy. Concentrations of NPY and substance P in tear samples were measured using enzyme-linked immunosorbent assay. RESULTS Mean (± standard deviation) tear NPY concentrations in participants with type 1 diabetes and length-dependent small fibre neuropathy (SFN) was lower than in controls (10.84 ± 4.10 ng/mL vs 14.72 ± 3.12 ng/mL; p=0.004), but not significantly different from type 1 diabetes participants without SFN (13.39 ± 4.66 ng/mL; p=0.11). Tear NPY levels were lower in individuals with type 1 diabetes and mild/moderate non-proliferative DR (10.44 ± 3.46 ng/mL) compared to none/minimal DR (13.79 ± 4.76 ng/mL; p=0.0005) and controls. In separate linear regression models, both the presence of SFN (β = -0.75, p=0.02) and the presence of mild/moderate DR (β = -0.84, p=0.009) were significantly associated with tear NPY levels relative to controls, after adjusting for participant age, sex, and dry eye disease. There were no inter-group differences for tear substance P concentrations. CONCLUSIONS Tear NPY has potential utility as an indicator of peripheral microvascular complications associated with type 1 diabetes.
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Affiliation(s)
| | - Mengliang Wu
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, VIC, Australia
| | - Leslie J Roberts
- Department of Medicine, St Vincent's Hospital Melbourne, University of Melbourne, Fitzroy, VIC, Australia; Centre for Clinical Neurosciences and Neurological Research, St Vincent's Hospital Melbourne, Fitzroy, Australia
| | - Richard J MacIsaac
- Department of Medicine, St Vincent's Hospital Melbourne, University of Melbourne, Fitzroy, VIC, Australia; Department of Diabetes & Endocrinology, St Vincent's Hospital Melbourne, Fitzroy, VIC, Australia; Australian Centre for Accelerating Diabetes Innovations (ACADI), University of Melbourne, Parkville, VIC Australia
| | - Haihan Jiao
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, VIC, Australia; Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, Australia
| | - Jennifer P Craig
- Department of Ophthalmology, Aotearoa New Zealand National Eye Centre, The University of Auckland, Auckland, New Zealand
| | - Holly R Chinnery
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, VIC, Australia
| | - Laura E Downie
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, VIC, Australia.
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11
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Kuhn PM, Chen S, Venkatraman A, Abadir PM, Walston JD, Kokkoli E. Co-Delivery of Valsartan and Metformin from a Thermosensitive Hydrogel-Nanoparticle System Promotes Collagen Production in Proliferating and Senescent Primary Human Dermal Fibroblasts. Biomacromolecules 2024; 25:5702-5717. [PMID: 39186039 DOI: 10.1021/acs.biomac.3c01461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/27/2024]
Abstract
Aging negatively impacts skin health, notably through the senescent cell phenotype, which reduces collagen production and leads to thinner, more fragile skin prone to injuries and chronic wounds. We designed a drug delivery system that addresses these age-related issues using a hybrid hydrogel-nanoparticle system that utilizes a poly(δ-valerolactone-co-lactide)-b-poly(ethylene-glycol)-b-poly(δ-valerolactone-co-lactide) (PVLA-PEG-PVLA) hydrogel. This hydrogel allows for the local, extended release of therapeutics targeting both proliferating and senescent cells. The PVLA-PEG-PVLA hydrogel entrapped valsartan, and metformin-loaded liposomes functionalized with a fibronectin-mimetic peptide, PR_b. Metformin acts as a senomorphic, reversing aspects of cellular senescence, and valsartan, an angiotensin receptor blocker, promotes collagen production. This combination treatment partially reversed the senescent phenotype and improved collagen production in senescent dermal fibroblasts from both young and old adults. Our codelivery hydrogel-nanoparticle system offers a promising treatment for improving age-related dermal pathologies.
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Affiliation(s)
- Paul M Kuhn
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland 21218, United States
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland 21218, United States
| | - Siwei Chen
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland 21218, United States
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland 21218, United States
| | - Aditya Venkatraman
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland 21218, United States
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland 21218, United States
| | - Peter M Abadir
- Division of Geriatrics and Gerontology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, United States
| | - Jeremy D Walston
- Division of Geriatrics and Gerontology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, United States
| | - Efrosini Kokkoli
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland 21218, United States
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland 21218, United States
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12
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Miranda MB, Barbosa da Rocha R, Alves RF, Cardoso VS. Effect of Using Photobiomodulation (660 Nanometers) for the Treatment of Diabetic Ulcers: Protocol for a Randomized Controlled Trial. INT J LOW EXTR WOUND 2024:15347346241266732. [PMID: 39033377 DOI: 10.1177/15347346241266732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/23/2024]
Abstract
Diabetic foot ulcers (DFUs) result in tissue damage or impairment of deeper structures that affect quality of life. The impacts are numerous, and even after a long treatment period, 65% of patients experience recurrence. Among the interventions used to accelerate the healing process of DFUs, photobiomodulation therapy (PBMT) is a painless, noninvasive, and low-cost treatment. To achieve effective therapeutic results optimal PBMT parameters are necessary. The positive effect of PBMT on diabetic cells may be dependent on fluence (J/cm2) and wavelength (nm). This double-blind, randomized clinical trial will be conducted at the University Clinic of Physical Therapy. One hundred patients will be randomly placed in 4 groups. A Laserpulse Ibramed (Helium-Neon, HeNe, 660 nm) with 20 W power will be used (continuous mode), with doses stipulated for each treatment group (GL1, 4 J/cm2; GL2, 8 J/cm2; GL3, 12 J/cm2) and Endophoton KLD GaAs 904 nm (ST, 10 J/cm2) for 2 nonconsecutive days per week for 10 weeks, for a total of 20 sessions. The primary outcomes will be ulcer healing rate and University of Texas classification scores. Patients' DFUs will be assessed on the 1st day, 5 weeks, and 10 weeks of treatment then 1 month after the end of treatment. This study may aid effective clinical decision-making for the management of DFUs.
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Affiliation(s)
- Mariana Bezerra Miranda
- Integrated Center for Medical Specialties, Parnaíba, PI, Brazil
- Master's Degree Program in Biomedical Sciences, Universidade Federal do Delta do Parnaíba, Parnaíba, PI, Brazil
| | - Rebeca Barbosa da Rocha
- Integrated Center for Medical Specialties, Parnaíba, PI, Brazil
- Doctoral Program in Biotechnology, Universidade Federal do Delta do Parnaíba, Parnaíba, PI, Brazil
- Department of Physical Therapy, Federal University of Delta do Parnaíba, Parnaíba, PI, Brazil
| | | | - Vinicius Saura Cardoso
- Integrated Center for Medical Specialties, Parnaíba, PI, Brazil
- Master's Degree Program in Biomedical Sciences, Universidade Federal do Delta do Parnaíba, Parnaíba, PI, Brazil
- Department of Physical Therapy, Federal University of Delta do Parnaíba, Parnaíba, PI, Brazil
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13
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Liu C, Yang QQ, Zhou YL. Peptides and Wound Healing: From Monomer to Combination. Int J Pept Res Ther 2024; 30:46. [DOI: 10.1007/s10989-024-10627-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2024] [Indexed: 01/02/2025]
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14
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Benchaprathanphorn K, Muangman P, Chinaroonchai K, Namviriyachote N, Ampawong S, Angkhasirisap W, Kengkoom K, Viravaidya-Pasuwat K. Translational application of human keratinocyte-fibroblast cell sheets for accelerated wound healing in a clinically relevant type 2 diabetic rat model. Cytotherapy 2024; 26:360-371. [PMID: 38363247 DOI: 10.1016/j.jcyt.2024.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 12/27/2023] [Accepted: 01/20/2024] [Indexed: 02/17/2024]
Abstract
BACKGROUND AIMS Despite advancements in wound care, wound healing remains a challenge, especially in individuals with type 2 diabetes. Cell sheet technology has emerged as an efficient and promising therapy for tissue regeneration and wound repair. Among these, bilayered human keratinocyte-fibroblast cell sheets constructed using temperature-responsive culture surfaces have been shown to mimic a normal tissue-like structure and secrete essential cytokines and growth factors that regulate the wound healing process. METHODS This study aimed to evaluate the safety and therapeutic potential of human skin cell sheets to treat full-thickness skin defects in a rat model of type 2 diabetes. RESULTS Our findings demonstrate that diabetic wounds transplanted with bilayered cell sheets resulted in accelerated re-epithelialization, increased angiogenesis, enhanced macrophage polarization and regeneration of tissue that closely resembled healthy skin. In contrast, the control group that did not receive cell sheet transplantation presented characteristic symptoms of impaired and delayed wound healing associated with type 2 diabetes. CONCLUSIONS The secretory cytokines and the upregulation of Nrf2 expression in response to cell sheet transplantation are believed to have played a key role in the improved wound healing observed in diabetic rats. Our study suggests that human keratinocyte-fibroblast cell sheets hold great potential as a therapeutic alternative for diabetic ulcers.
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Affiliation(s)
- Kanokaon Benchaprathanphorn
- Biological Engineering Program, Faculty of Engineering, King Mongkut's University of Technology Thonburi, Bangkok, Thailand
| | - Pornprom Muangman
- Trauma Surgery Division, Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Kusuma Chinaroonchai
- Trauma Surgery Division, Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Nantaporn Namviriyachote
- Trauma Surgery Division, Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Sumate Ampawong
- Department of Tropical Pathology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Wannee Angkhasirisap
- Research and Academic Support Office, National Laboratory Animal Center, Mahidol University, Nakorn Pathom, Thailand
| | - Kanchana Kengkoom
- Research and Academic Support Office, National Laboratory Animal Center, Mahidol University, Nakorn Pathom, Thailand
| | - Kwanchanok Viravaidya-Pasuwat
- Biological Engineering Program, Faculty of Engineering, King Mongkut's University of Technology Thonburi, Bangkok, Thailand; Chemical Engineering, Faculty of Engineering, King Mongkut's University of Technology Thonburi, Bangkok, Thailand.
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15
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Sechovcová H, Mahayri TM, Mrázek J, Jarošíková R, Husáková J, Wosková V, Fejfarová V. Gut microbiota in relationship to diabetes mellitus and its late complications with a focus on diabetic foot syndrome: A review. Folia Microbiol (Praha) 2024; 69:259-282. [PMID: 38095802 DOI: 10.1007/s12223-023-01119-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 12/05/2023] [Indexed: 04/11/2024]
Abstract
Diabetes mellitus is a chronic disease affecting glucose metabolism. The pathophysiological reactions underpinning the disease can lead to the development of late diabetes complications. The gut microbiota plays important roles in weight regulation and the maintenance of a healthy digestive system. Obesity, diabetes mellitus, diabetic retinopathy, diabetic nephropathy and diabetic neuropathy are all associated with a microbial imbalance in the gut. Modern technical equipment and advanced diagnostic procedures, including xmolecular methods, are commonly used to detect both quantitative and qualitative changes in the gut microbiota. This review summarises collective knowledge on the role of the gut microbiota in both types of diabetes mellitus and their late complications, with a particular focus on diabetic foot syndrome.
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Affiliation(s)
- Hana Sechovcová
- Laboratory of Anaerobic Microbiology, Institute of Animal Physiology and Genetics, CAS, Vídeňská, 1083, 142 20, Prague, Czech Republic
- Faculty of Agrobiology, Food and Natural Resources, Department of Microbiology, Nutrition and Dietetics, Czech University of Life Sciences, Prague, Czech Republic
| | - Tiziana Maria Mahayri
- Laboratory of Anaerobic Microbiology, Institute of Animal Physiology and Genetics, CAS, Vídeňská, 1083, 142 20, Prague, Czech Republic.
- Department of Veterinary Medicine, University of Sassari, 07100, Sassari, Italy.
| | - Jakub Mrázek
- Laboratory of Anaerobic Microbiology, Institute of Animal Physiology and Genetics, CAS, Vídeňská, 1083, 142 20, Prague, Czech Republic
| | - Radka Jarošíková
- Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- Second Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Jitka Husáková
- Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Veronika Wosková
- Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Vladimíra Fejfarová
- Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- Second Faculty of Medicine, Charles University, Prague, Czech Republic
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16
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Sang P, Zhao J, Yang H. The efficacy of electroacupuncture in among early diabetic patients with lower limb arteriosclerotic wounds. Int Wound J 2024; 21:e14526. [PMID: 38093499 PMCID: PMC10961040 DOI: 10.1111/iwj.14526] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 11/15/2023] [Accepted: 11/16/2023] [Indexed: 03/25/2024] Open
Abstract
Diabetic foot ulcers are the prevalent complication of diabetes mellitus, frequently culminating in arteriosclerosis of the lower extremities and consequent development of chronic wounds. The effectiveness of electroacupuncture (EA) as therapeutic intervention for promoting wound healing in this particular group of patients has been comprehensively assessed in this study. A randomized controlled trial involving 380 early diabetic patients with arteriosclerotic lesions of the lower limbs was conducted. Standard wound care plus EA was administered to the treatment group, while standard wound care alone was administered to the control group. The principal outcome assessed was the reduction in lesion size following the 8-week treatment period. Pain scores, recuperation time, and quality of life (QoL) evaluations constituted secondary outcomes. In comparison to the control group, the treatment group exhibited a significantly greater reduction in wound size (p < 0.05). The treatment group exhibited significantly reduced pain scores and significantly higher QoL scores (p < 0.05). The duration of recovery did not vary substantially among the groups (p > 0.05). Electroacupuncture thus appeared to be an effective adjunctive treatment for early diabetic patients with lower limb arteriosclerotic lesions, promoting pain relief and quality of life. Additional investigation is necessary to validate these results and delve into the underlying mechanisms of action.
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Affiliation(s)
- Peng Sang
- Department of AcupunctureHeilongjiang Academy of Chinese Medicine SciencesHarbinHeilongjiangChina
| | - Jiahui Zhao
- Department of AcupunctureHeilongjiang Academy of Chinese Medicine SciencesHarbinHeilongjiangChina
| | - Hui Yang
- Department of AcupunctureHeilongjiang Academy of Chinese Medicine SciencesHarbinHeilongjiangChina
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17
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Lu YZ, Nayer B, Singh SK, Alshoubaki YK, Yuan E, Park AJ, Maruyama K, Akira S, Martino MM. CGRP sensory neurons promote tissue healing via neutrophils and macrophages. Nature 2024; 628:604-611. [PMID: 38538784 PMCID: PMC11023938 DOI: 10.1038/s41586-024-07237-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 02/26/2024] [Indexed: 04/06/2024]
Abstract
The immune system has a critical role in orchestrating tissue healing. As a result, regenerative strategies that control immune components have proved effective1,2. This is particularly relevant when immune dysregulation that results from conditions such as diabetes or advanced age impairs tissue healing following injury2,3. Nociceptive sensory neurons have a crucial role as immunoregulators and exert both protective and harmful effects depending on the context4-12. However, how neuro-immune interactions affect tissue repair and regeneration following acute injury is unclear. Here we show that ablation of the NaV1.8 nociceptor impairs skin wound repair and muscle regeneration after acute tissue injury. Nociceptor endings grow into injured skin and muscle tissues and signal to immune cells through the neuropeptide calcitonin gene-related peptide (CGRP) during the healing process. CGRP acts via receptor activity-modifying protein 1 (RAMP1) on neutrophils, monocytes and macrophages to inhibit recruitment, accelerate death, enhance efferocytosis and polarize macrophages towards a pro-repair phenotype. The effects of CGRP on neutrophils and macrophages are mediated via thrombospondin-1 release and its subsequent autocrine and/or paracrine effects. In mice without nociceptors and diabetic mice with peripheral neuropathies, delivery of an engineered version of CGRP accelerated wound healing and promoted muscle regeneration. Harnessing neuro-immune interactions has potential to treat non-healing tissues in which dysregulated neuro-immune interactions impair tissue healing.
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Affiliation(s)
- Yen-Zhen Lu
- European Molecular Biology Laboratory Australia, Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria, Australia
| | - Bhavana Nayer
- European Molecular Biology Laboratory Australia, Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria, Australia
| | - Shailendra Kumar Singh
- Laboratory of Host Defense, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Yasmin K Alshoubaki
- European Molecular Biology Laboratory Australia, Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria, Australia
| | - Elle Yuan
- European Molecular Biology Laboratory Australia, Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria, Australia
| | - Anthony J Park
- European Molecular Biology Laboratory Australia, Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria, Australia
| | - Kenta Maruyama
- Laboratory of Host Defense, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Department of Pharmacology, School of Medicine, Aichi Medical University, Aichi, Japan
| | - Shizuo Akira
- Laboratory of Host Defense, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Mikaël M Martino
- European Molecular Biology Laboratory Australia, Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria, Australia.
- Laboratory of Host Defense, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Osaka, Japan.
- Victorian Heart Institute, Monash University, Melbourne, Victoria, Australia.
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18
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Al Shehhi YI, Elemam NM, Alsaegh MA. The response of salivary proinflammatory biomarkers to tooth extraction in individuals with type II diabetes mellitus. BMC Oral Health 2024; 24:250. [PMID: 38373910 PMCID: PMC10875873 DOI: 10.1186/s12903-024-04006-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 02/08/2024] [Indexed: 02/21/2024] Open
Abstract
PURPOSE This study investigated the levels of salivary proinflammatory cytokines in the saliva of patients living with type II diabetes mellitus (DM) compared to those in healthy individuals three times: before tooth extraction and at 2 hours and 2 days after tooth extraction. METHODS The study included 27 participants. Among them, 20 (n = 20; 74%) had type II DM, and seven (n = 7; 26%) were healthy control subjects. Saliva samples were collected at three time intervals: before tooth extraction and 2 hours and 2 days after tooth extraction. The salivary biomarkers were investigated using a Luminex multiplex assay. These salivary biomarkers included tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), interleukin 1-beta (IL-1β), and interferon-gamma (IFN-γ). RESULTS At baseline, patients with type II DM had significantly lower levels of IL-1β (P = 0.016). Moreover, 2 hours after extraction, patients with type II DM had significantly lower levels of IL-1β and TNF-α than did healthy control subjects (P = 0.046 and P = 0.020, respectively). In addition, 2 days after tooth extraction, the DM group had significantly greater IL-6 levels (P = 0.010) than the control group. CONCLUSIONS In patients with type II DM, salivary proinflammatory biomarker levels are generally comparable or lower than those in healthy control subjects. Proinflammatory cytokines manifest differently in patients with type II DM after tooth extraction than in normal healthy individuals. There is generally a delayed early response of salivary proinflammatory markers in patients living with type II DM who undergo tooth extraction.
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Affiliation(s)
- Yousuf Ibrahim Al Shehhi
- Department of Oral and Craniofacial Health Sciences, College of Dental Medicine, University of Sharjah, Sharjah, UAE
| | - Noha M Elemam
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, UAE
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, UAE
| | - Mohammed Amjed Alsaegh
- Department of Oral and Craniofacial Health Sciences, College of Dental Medicine, University of Sharjah, Sharjah, UAE.
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19
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Voza FA, Huerta CT, Le N, Shao H, Ribieras A, Ortiz Y, Atkinson C, Machuca T, Liu ZJ, Velazquez OC. Fibroblasts in Diabetic Foot Ulcers. Int J Mol Sci 2024; 25:2172. [PMID: 38396848 PMCID: PMC10889208 DOI: 10.3390/ijms25042172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 02/01/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
Fibroblasts are stromal cells ubiquitously distributed in the body of nearly every organ tissue. These cells were previously considered to be "passive cells", solely responsible for ensuring the turnover of the extracellular matrix (ECM). However, their versatility, including their ability to switch phenotypes in response to tissue injury and dynamic activity in the maintenance of tissue specific homeostasis and integrity have been recently revealed by the innovation of technological tools such as genetically modified mouse models and single cell analysis. These highly plastic and heterogeneous cells equipped with multifaceted functions including the regulation of angiogenesis, inflammation as well as their innate stemness characteristics, play a central role in the delicately regulated process of wound healing. Fibroblast dysregulation underlies many chronic conditions, including cardiovascular diseases, cancer, inflammatory diseases, and diabetes mellitus (DM), which represent the current major causes of morbidity and mortality worldwide. Diabetic foot ulcer (DFU), one of the most severe complications of DM affects 40 to 60 million people. Chronic non-healing DFU wounds expose patients to substantial sequelae including infections, gangrene, amputation, and death. A complete understanding of the pathophysiology of DFU and targeting pathways involved in the dysregulation of fibroblasts are required for the development of innovative new therapeutic treatments, critically needed for these patients.
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Affiliation(s)
- Francesca A. Voza
- DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (F.A.V.); (C.T.H.); (H.S.); (A.R.); (Y.O.); (T.M.)
| | - Carlos Theodore Huerta
- DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (F.A.V.); (C.T.H.); (H.S.); (A.R.); (Y.O.); (T.M.)
| | - Nga Le
- Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Hongwei Shao
- DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (F.A.V.); (C.T.H.); (H.S.); (A.R.); (Y.O.); (T.M.)
- Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Antoine Ribieras
- DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (F.A.V.); (C.T.H.); (H.S.); (A.R.); (Y.O.); (T.M.)
| | - Yulexi Ortiz
- DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (F.A.V.); (C.T.H.); (H.S.); (A.R.); (Y.O.); (T.M.)
- Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Carl Atkinson
- Department of Internal Medicine, Division of Pulmonary Critical Care & Sleep Medicine, University of Florida, Gainesville, FL 32611, USA;
| | - Tiago Machuca
- DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (F.A.V.); (C.T.H.); (H.S.); (A.R.); (Y.O.); (T.M.)
| | - Zhao-Jun Liu
- DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (F.A.V.); (C.T.H.); (H.S.); (A.R.); (Y.O.); (T.M.)
- Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Omaida C. Velazquez
- DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (F.A.V.); (C.T.H.); (H.S.); (A.R.); (Y.O.); (T.M.)
- Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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20
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Singh P, Sharma S, Sharma PK, Alam A. Topical Anti-ulcerogenic Effect of the Beta-adrenergic Blockers on Diabetic Foot Ulcers: Recent Advances and Future Prospectives. Curr Diabetes Rev 2024; 20:23-37. [PMID: 37867269 DOI: 10.2174/0115733998249061231009093006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 08/01/2023] [Accepted: 08/25/2023] [Indexed: 10/24/2023]
Abstract
BACKGROUND Patients with diabetes suffer from major complications like Diabetic Retinopathy, Diabetic Coronary Artery Disease, and Diabetic Foot ulcers (DFUs). Diabetes complications are a group of ailments whose recovery time is especially delayed, irrespective of the underlying reason. The longer duration of wound healing enhances the probability of problems like sepsis and amputation. The delayed healing makes it more critical for research focus. By understanding the molecular pathogenesis of diabetic wounds, it is quite easy to target the molecules involved in the healing of wounds. Recent research on beta-adrenergic blocking drugs has revealed that these classes of drugs possess therapeutic potential in the healing of DFUs. However, because the order of events in defective healing is adequately defined, it is possible to recognize moieties that are currently in the market that are recognized to aim at one or several identified molecular processes. OBJECTIVE The aim of this study was to explore some molecules with different therapeutic categories that have demonstrated favorable effects in improving diabetic wound healing, also called the repurposing of drugs. METHOD Various databases like PubMed/Medline, Google Scholar and Web of Science (WoS) of all English language articles were searched, and relevant information was collected regarding the role of beta-adrenergic blockers in diabetic wounds or diabetic foot ulcers (DFUs) using the relevant keywords for the literature review. RESULT The potential beta-blocking agents and their mechanism of action in diabetic foot ulcers were studied, and it was found that these drugs have a profound effect on diabetic foot ulcer healing as per reported literatures. CONCLUSION There is a need to move forward from preclinical studies to clinical studies to analyze clinical findings to determine the effectiveness and safety of some beta-antagonists in diabetic foot ulcer treatment.
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Affiliation(s)
- Prateek Singh
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Shweta Sharma
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Pramod Kumar Sharma
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Aftab Alam
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
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21
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Raghav SS, Kumar B, Sethiya NK, Lal DK. Diabetic Foot Ulcer Management and Treatment: An Overview of Published Patents. Curr Diabetes Rev 2024; 20:e120623217906. [PMID: 37309771 DOI: 10.2174/1573399820666230612161846] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 03/24/2023] [Accepted: 05/15/2023] [Indexed: 06/14/2023]
Abstract
BACKGROUND One of the most challenging effects of diabetes is diabetic foot ulceration (DFU). DFU may occur in up to one-third of individuals with diabetes mellitus (D.M.) at some point in their lives. The major cause of morbidity in D.M. patients is DFU. The length of treatment is difficult, and DFU recurrence is common. OBJECTIVE The most crucial element for the treatment and prevention of DFUs require a multidisciplinary approach. Patients who are at risk should be identified, depending on the type of risk, prophylactic actions etc. It is imperative to identify at-risk patients and take preventative measures accordingly. METHOD The at-risk diabetes-related foot ulcer was identified based on the risk category classification, while the foot ulcers were evaluated using Wagner's classification system. RESULTS Literature reported that patients with lower limb vascular insufficiency, loss of vibratory sensation, or protective sensation loss have an increased risk of developing foot ulcers. Proper categorization and therapeutic measures will be implemented after the DFU has been formed. The appropriate assessment and management of general health status should include glycemic control, the diagnosis and treatment of vascular disease, standard care for wounds, diagnosis, and infection treatments. CONCLUSION The review reflects the updated awareness of the treatment and management of DFU based on the current and past literature and patent analysis.
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Affiliation(s)
| | - Bhavna Kumar
- Faculty of Pharmacy, DIT University, Dehradun 248009, Uttarakhand, India
| | | | - Diwya Kumar Lal
- Faculty of Pharmacy, DIT University, Dehradun 248009, Uttarakhand, India
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22
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Fu Z, Jiang Z, Liao X, Liu M, Guo G, Wang X, Yang G, Zhou Z, Hu L, Xiong Z. Upregulation of circ_0080968 in diabetic foot ulcer inhibits wound healing via repressing the migration and promoting proliferation of keratinocytes. Gene 2023; 883:147669. [PMID: 37500023 DOI: 10.1016/j.gene.2023.147669] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 07/13/2023] [Accepted: 07/24/2023] [Indexed: 07/29/2023]
Abstract
BACKGROUND Diabetic foot ulcer (DFU) is a serious chronic complication of diabetes mellitus whose pathogenesis remains unclear. Circular RNA (circRNA) refers to a group of covalently closed non-coding RNAs that are reported to be dysregulated in patients with DFU. However, the mechanism whereby dysregulation in circRNAs contributes to DFU remains unclear. In this study, we investigated the role of dysregulated circRNAs in DFU. MATERIALS AND METHODS A gene expression dataset was downloaded from the Gene Expression Omnibus portal and analyzed by the limma package of R. The levels of 24 upregulated circRNAs were detected in two independent cohorts by RT-qPCR. Interactions between miRNAs and circRNAs were predicted through bioinformatics and confirmed using a dual luciferase assay. The circularity and subcellular localization of circRNA-080968 was examined by northern blotting after digestion with RNase-R and in situ hybridization. Cell migration and proliferation were examined using Transwell and MTT assays. The apoptotic cells were detected by flow cytometry. RESULTS The level of circRNA-080968 was upregulated in DFU tissues compared to that of non-DFU samples and normal human wounds. CircRNA-080968 was mainly localized in the cytoplasm and its overexpression inhibited the migration and promoted the proliferation of keratinocytes. MiR-326 and miR-766-3p were identified to interact with and be negatively correlated with circRNA-080968 levels. Increased glucose upregulated circRNA-080968, and its overexpression accelerated the degradation of both miR-326 and miR-766-3p. Reduced levels of miR-326 and miR-766-3p upregulated the expression of several genes controlling cell adhesion and proliferation which are related to the pathogenesis of DFU. CONCLUSIONS The upregulation of circRNA-080968 in DFU induced the degradation of miR-326 and miR-766-3p, which further repressed the migration and increased the proliferation of keratinocytes.
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Affiliation(s)
- Zhonghua Fu
- Burn Plastic and Wound Restorative Medicine Center, The First Affilicated Hospital of Nanchang University, 330006 Jiangxi, China
| | - Zhengying Jiang
- Burn Plastic and Wound Restorative Medicine Center, The First Affilicated Hospital of Nanchang University, 330006 Jiangxi, China
| | - Xincheng Liao
- Burn Plastic and Wound Restorative Medicine Center, The First Affilicated Hospital of Nanchang University, 330006 Jiangxi, China
| | - Mingzhuo Liu
- Burn Plastic and Wound Restorative Medicine Center, The First Affilicated Hospital of Nanchang University, 330006 Jiangxi, China
| | - Guanghua Guo
- Burn Plastic and Wound Restorative Medicine Center, The First Affilicated Hospital of Nanchang University, 330006 Jiangxi, China
| | - Xin Wang
- Burn Plastic and Wound Restorative Medicine Center, The First Affilicated Hospital of Nanchang University, 330006 Jiangxi, China
| | - Guangping Yang
- Burn Plastic and Wound Restorative Medicine Center, The First Affilicated Hospital of Nanchang University, 330006 Jiangxi, China
| | - Zhiyu Zhou
- College of Traditional Chinese Medicine, Jiangxi University of Chinese Medicine, 330004 Jiangxi, China
| | - Long Hu
- Department of Pathology, The First Affilicated Hospital of Nanchang University, 330006 Jiangxi, China.
| | - Zhenfang Xiong
- Department of Pathology, The First Affilicated Hospital of Nanchang University, 330006 Jiangxi, China.
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Tan M, Xu W, Yan G, Xu Y, Xiao Q, Liu A, Peng L. Oriented artificial niche provides physical-biochemical stimulations for rapid nerve regeneration. Mater Today Bio 2023; 22:100736. [PMID: 37521524 PMCID: PMC10374615 DOI: 10.1016/j.mtbio.2023.100736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 07/08/2023] [Accepted: 07/19/2023] [Indexed: 08/01/2023] Open
Abstract
Skin wound is always accompanied with nerve damage, leading to significant sensory function loss. Currently, the functional matrix material based stem cell transplantation and in situ nerve regeneration are thought to be effective strategies, of which, how to recruit stem cells, retard senescence, and promote neural differentiation has been obstacle to be overcome. However, the therapeutic efficiency of the reported systems has yet to be improved and side effect reduced. Herein, a conduit matrix with three-dimensional ordered porous structures, regular porosity, appropriate mechanical strength, and conductive features was prepared by orienting the freezing technique, which was further filled with neural-directing exosomes to form a neural-stimulating matrix for providing hybrid physical-biochemical stimulations. This neural-stimulating matrix was then compacted with methacrylate gelatin (GelMA) hydrogel thin coat that loaded with chemokines and anti-senescence drugs, forming a multi-functional artificial niche (termed as GCr-CSL) that promotes MSCs recruitment, anti-senescence, and neural differentiation. GCr-CSL was shown to rapidly enhances in situ nerve regeneration in skin wound therapy, and with great potential in promoting sensory function recovery. This study demonstrates proof-of-concept in building a biomimetic niche to organize endogenous MSCs recruitment, differentiation, and functionalization for fast neurological and sensory recovery.
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Affiliation(s)
- Minhong Tan
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
- College of Materials Science and Engineering, Zhejiang University, Hangzhou, 310027, PR China
| | - Weizhong Xu
- Key Laboratory of Optical Field Manipulation of Zhejiang Province, Zhejiang Sci-Tech University, PR China
| | - Ge Yan
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Yang Xu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Qiyao Xiao
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Aiping Liu
- Key Laboratory of Optical Field Manipulation of Zhejiang Province, Zhejiang Sci-Tech University, PR China
| | - Lihua Peng
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, PR China
- Jinhua Institute of Zhejiang University, Jinhua 321299, Zhejiang, PR China
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24
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Lu T, Cong L, Jiang T, Dong X, Song L. Neuropeptide Y Promotes the Treatment of Adipose Stem Cells on Type 2 Diabetic Wounds. Tissue Eng Regen Med 2023; 20:683-694. [PMID: 37084169 PMCID: PMC10352478 DOI: 10.1007/s13770-023-00540-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 02/27/2023] [Accepted: 03/21/2023] [Indexed: 04/22/2023] Open
Abstract
BACKGROUND Type 2 diabetes (T2D) is a common metabolic disorder. Due to insufficient insulin secretion or insulin resistance, increased blood glucose often leads to impaired wound healing in T2D patients. Our previous research showed that adipose-derived stem cells (ASCs) from normal mice and T2D mice improved the cutaneous wound healing of diabetic mice. We also found that the expression of neuropeptide Y (NPY) in T2D ASCs was significantly decreased. METHODS In order to explore the effects of NPY on ASCs and diabetic wound healing, we investigated the effects of NPY on ASCs proliferation and growth factors expression and secretion, the effects of NPY on skin fibroblasts, and the effects of NPY combined with ASCs on T2D wound healing. RESULTS The results showed that a certain concentration of NPY could promote the proliferation and the growth factors expression and secretion of ASCs, and promote the proliferation and migration of fibroblasts. At the same time, NPY and ASCs have a synergistic effect, which can promote wound healing and decrease inflammation in T2D wounds. NPY may regulate ASCs through the ERK pathway. These results are conducive to promoting ASCs and NPY in the treatment of diabetic wounds. CONCLUSIONS NPY can promote the effect of ASCs in the treatment of diabetic wounds.
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Affiliation(s)
- Tinghuan Lu
- College of Life Science, Qingdao Agricultural University, No. 700, Changcheng Road, Chengyang District, Qingdao, 266109, Shandong, People's Republic of China
| | - Lu Cong
- Department of Neurology, Peking University People's Hospital, Beijing, 100044, People's Republic of China
| | - Tong Jiang
- College of Life Science, Qingdao Agricultural University, No. 700, Changcheng Road, Chengyang District, Qingdao, 266109, Shandong, People's Republic of China
| | - Xiao Dong
- College of Life Science, Qingdao Agricultural University, No. 700, Changcheng Road, Chengyang District, Qingdao, 266109, Shandong, People's Republic of China.
| | - Lili Song
- College of Life Science, Qingdao Agricultural University, No. 700, Changcheng Road, Chengyang District, Qingdao, 266109, Shandong, People's Republic of China.
- School of Life Science, Shandong University, No. 72, Binhai Road, Qingdao, 266237, Shandong, People's Republic of China.
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25
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El-Senduny FF, Elgazar AA, Alwasify HA, Abed A, Foda M, Abouzeid S, Lewerenz L, Selmar D, Badria F. Bio-evaluation of Untapped Alkaloids from Vinca minor Enriched by Methyl-jasmonate-induced Stress: an Integrated Approach. PLANTA MEDICA 2023; 89:964-978. [PMID: 36940927 DOI: 10.1055/a-2058-3863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]
Abstract
The low amount of metabolites isolated from natural products is one of the challenges preventing their biological evaluation. The modulation of biosynthetic pathways by stimulating stress-induced responses in plants was proven to be a valuable tool for diversification of already known natural products. Recently, we reported the dramatic effect of methyl jasmonate (MeJA) on Vinca minor alkaloids distribution. In this study, three compounds identified as 9-methoxyvincamine, minovincinine, and minovincine are successfully isolated in good yield and subjected to several bioassays based on a network pharmacology study. The extracts and isolated compounds show weak to moderate antimicrobial and cytotoxic activities. Also, they are found to significantly promote wound healing in scratch assay, and transforming growth factor-β (TGF-β) modulation is suggested to be the potential pathway based on bioinformatic analysis. Hence, Western blotting is used to assess the expression of several markers related to this pathway and wound healing. The extracts and isolated compounds are able to increase the expression of Smad3 and Phosphatidylinositol-3-kinase (PI3K), while downregulating the levels of cyclin D1 and the mammalian target of rapamycin (mTOR) except for minovincine, which increases the mTOR expression, inferring that it might act through a different mechanism. Molecular docking is used to give insights on the ability of isolated compounds to bind with different active sites in mTOR. Collectively, the integrated phytochemical, in silico, and molecular biology approach reveal that V. minor and its metabolite could be repurposed for the management of dermatological disorders where these markers are dysregulated, which opens the gate to develop new therapeutics in the future.
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Affiliation(s)
- Fardous F El-Senduny
- Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt
- Department of Pathology & Laboratory Medicine, Sylvester Comprehensive Cancer Center, Miami, FL, United States
| | - Abdullah A Elgazar
- Department of Pharmacognosy, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt
| | - Heba Allah Alwasify
- Zoology Department, Faculty of Science, Mansoura University, Mansoura, Egypt
| | - Alaa Abed
- Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt
| | - Mohamed Foda
- Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt
| | - Sara Abouzeid
- Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
- Institute for Plant Biology, Technische Universität Braunschweig, Braunschweig, Germany
| | - Laura Lewerenz
- Institute for Plant Biology, Technische Universität Braunschweig, Braunschweig, Germany
| | - Dirk Selmar
- Institute for Plant Biology, Technische Universität Braunschweig, Braunschweig, Germany
| | - Farid Badria
- Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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26
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Nirenjen S, Narayanan J, Tamilanban T, Subramaniyan V, Chitra V, Fuloria NK, Wong LS, Ramachawolran G, Sekar M, Gupta G, Fuloria S, Chinni S, Selvaraj S. Exploring the contribution of pro-inflammatory cytokines to impaired wound healing in diabetes. Front Immunol 2023; 14:1216321. [PMID: 37575261 PMCID: PMC10414543 DOI: 10.3389/fimmu.2023.1216321] [Citation(s) in RCA: 54] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 06/26/2023] [Indexed: 08/15/2023] Open
Abstract
Background Impaired wound healing is the most common and significant complication of Diabetes. While most other complications of Diabetes have better treatment options, diabetic wounds remain a burden as they can cause pain and suffering in patients. Wound closure and repair are orchestrated by a sequence of events aided by the release of pro-inflammatory cytokines, which are dysregulated in cases of Diabetes, making the wound environment unfavorable for healing and delaying the wound healing processes. This concise review provides an overview of the dysregulation of pro-inflammatory cytokines and offers insights into better therapeutic outcomes. Purpose of review Although many therapeutic approaches have been lined up nowadays to treat Diabetes, there are no proper treatment modalities proposed yet in treating diabetic wounds due to the lack of understanding about the role of inflammatory mediators, especially Pro-inflammatory mediators- Cytokines, in the process of Wound healing which we mainly focus on this review. Recent findings Although complications of Diabetes mellitus are most reported after years of diagnosis, the most severe critical complication is impaired Wound Healing among Diabetes patients. Even though Trauma, Peripheral Artery Disease, and Peripheral Neuropathy are the leading triggering factors for the development of ulcerations, the most significant issue contributing to the development of complicated cutaneous wounds is wound healing impairment. It may even end up with amputation. Newer therapeutic approaches such as incorporating the additives in the present dressing materials, which include antimicrobial molecules and immunomodulatory cytokines is of better therapeutic value. Summary The adoption of these technologies and the establishment of novel therapeutic interventions is difficult since there is a gap in terms of a complete understanding of the pathophysiological mechanisms at the cellular and molecular level and the lack of data in terms of the assessment of safety and bioavailability differences in the individuals' patients. The target-specific pro-inflammatory cytokines-based therapies, either by upregulation or downregulation of them, will be helpful in the wound healing process and thereby enhances the Quality of life in patients, which is the goal of drug therapy.
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Affiliation(s)
- S. Nirenjen
- Department of Pharmacology, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
| | - J. Narayanan
- Department of Pharmacology, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
| | - T. Tamilanban
- Department of Pharmacology, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
| | - Vetriselvan Subramaniyan
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University, Jalan Lagoon Selatan, Bandar Sunway, Petaling Jaya, Selangor, Malaysia
- Center for Transdisciplinary Research, Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India
| | - V. Chitra
- Department of Pharmacology, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
| | | | - Ling Shing Wong
- Faculty of Health and Life Sciences, INTI International University, Nilai, Malaysia
| | - Gobinath Ramachawolran
- Department of Foundation, RCSI & UCD Malaysia Campus, Jalan Sepoy Lines, Georgetown, Pulau Pinang, Malaysia
| | - Mahendran Sekar
- School of Pharmacy, Monash University Malaysia, Subang Jaya, Selangor, Malaysia
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Mahal Road, Jaipur, India
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | | | - Suresh V. Chinni
- Department of Biochemistry, Faculty of Medicine, Bioscience, and Nursing, MAHSA University, Jenjarom, Selangor, Malaysia
- Department of Periodontics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
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Abdalla MMI, Mohanraj J, Somanath SD. Adiponectin as a therapeutic target for diabetic foot ulcer. World J Diabetes 2023; 14:758-782. [PMID: 37383591 PMCID: PMC10294063 DOI: 10.4239/wjd.v14.i6.758] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/25/2023] [Accepted: 04/24/2023] [Indexed: 06/14/2023] Open
Abstract
The global burden of diabetic foot ulcers (DFUs) is a significant public health concern, affecting millions of people worldwide. These wounds cause considerable suffering and have a high economic cost. Therefore, there is a need for effective strategies to prevent and treat DFUs. One promising therapeutic approach is the use of adiponectin, a hormone primarily produced and secreted by adipose tissue. Adiponectin has demonstrated anti-inflammatory and anti-atherogenic properties, and researchers have suggested its potential therapeutic applications in the treatment of DFUs. Studies have indicated that adiponectin can inhibit the production of pro-inflammatory cytokines, increase the production of vascular endothelial growth factor, a key mediator of angiogenesis, and inhibit the activation of the intrinsic apoptotic pathway. Additionally, adiponectin has been found to possess antioxidant properties and impact glucose metabolism, the immune system, extracellular matrix remodeling, and nerve function. The objective of this review is to summarize the current state of research on the potential role of adiponectin in the treatment of DFUs and to identify areas where further research is needed in order to fully understand the effects of adiponectin on DFUs and to establish its safety and efficacy as a treatment for DFUs in the clinical setting. This will provide a deeper understanding of the underlying mechanisms of DFUs that can aid in the development of new and more effective treatment strategies.
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Affiliation(s)
- Mona Mohamed Ibrahim Abdalla
- Department of Physiology, Human Biology Division, School of Medicine, International Medical University, Kuala Lumpur 57000, Malaysia
| | - Jaiprakash Mohanraj
- Department of Biochemistry, Human Biology Division, School of Medicine, International Medical University, Kuala Lumpur 57000, Malaysia
| | - Sushela Devi Somanath
- Department of Microbiology, School of Medicine, International Medical University, Kuala Lumpur 57000, Malaysia
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Jing S, Li H, Xu H. Mesenchymal Stem Cell Derived Exosomes Therapy in Diabetic Wound Repair. Int J Nanomedicine 2023; 18:2707-2720. [PMID: 37250470 PMCID: PMC10216860 DOI: 10.2147/ijn.s411562] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 05/15/2023] [Indexed: 05/31/2023] Open
Abstract
Nowadays, refractory diabetic wounds cause a worldwide medical burden. Mesenchymal stem cells derived exosomes (MSC-Exos) show promise as a solid alternative to existing therapeutics in the latest researches, since MSC-Exos share similar biologic activity but less immunogenicity when compared with MSCs. To facilitate further understanding and application, it is essential to summarize the current progress and limitations of MSC-Exos in the treatment of diabetic wounds. In this review, we introduce the effects of different MSC-Exos on diabetic wounds according to their origins and contents and discuss the specific experimental conditions, target wound cells/pathways, and specific mechanisms. In addition, this paper focuses on the combination of MSC-Exos and biomaterials, which improves the efficacy and utilization of MSC-Exos therapy. Together, exosome therapy has high clinical value and application prospects, both in its role and in combination with biomaterials, while novel drugs or molecules loaded into exosomes as carriers targeting wound cells will be development trends.
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Affiliation(s)
- Shengyu Jing
- Department of Vascular Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China
- Xiangya School of Medicine, Central South University, Changsha, Hunan, People’s Republic of China
| | - Hongjie Li
- Department of Vascular Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China
- Xiangya School of Medicine, Central South University, Changsha, Hunan, People’s Republic of China
| | - Hongbo Xu
- Department of Vascular Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China
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Chappidi S, Buddolla V, Ankireddy SR, Lakshmi BA, Kim YJ. Recent trends in diabetic wound healing with nanofibrous scaffolds. Eur J Pharmacol 2023; 945:175617. [PMID: 36841285 DOI: 10.1016/j.ejphar.2023.175617] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 02/03/2023] [Accepted: 02/03/2023] [Indexed: 02/26/2023]
Abstract
There is an emphasis in this review on nanofibrous scaffolds (NFSs) in diabetic wound healing, as well as their mechanisms and recent advancements. Diabetes-related complex wounds pose an important problem to humanity, due to the fact that their chronic nature can lead to serious complications including sepsis and amputations. Despite the fact that there are certain therapy options available for diabetic wound healing, these options are either ineffective or intrusive, making clinical intervention difficult. Clinical research is also challenged by the emergence of bacterial resistance to standard antibiotics. However, research into nanotechnology, in particular NFSs, is growing swiftly and has a positive impact on the treatment of diabetic wounds. For instance, SpinCare™, developed by Nanomedic Technologies Ltd, has successfully finished clinical testing and can re-epithelialize second-degree burns and chronic diabetic wounds in 7 and 14 days, respectively. In this review, we discussed homologous studies as well as other recent research studies on diabetic wound healing using NFSs.
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Affiliation(s)
| | - Viswanath Buddolla
- Dr. Buddolla's Institute of Life Sciences, Tirupati, 517503, Andhra Pradesh, India
| | | | - Buddolla Anantha Lakshmi
- Department of Electronic Engineering, Gachon University, 1342 Seongnam-Daero, Seongnam, Gyeonggi-Do, 13120, Republic of Korea.
| | - Young-Joon Kim
- Department of Electronic Engineering, Gachon University, 1342 Seongnam-Daero, Seongnam, Gyeonggi-Do, 13120, Republic of Korea.
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Rangwala US, Tashrifwala F, Egbert NN, Asif AA. The Potential of Topical Therapy for Diabetic Wounds: A Narrative Review. Cureus 2023; 15:e36887. [PMID: 37128530 PMCID: PMC10147563 DOI: 10.7759/cureus.36887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/29/2023] [Indexed: 03/31/2023] Open
Abstract
The rising prevalence of diabetes mellitus brings with it a rise in the occurrence of several complications of the disease such as chronic non-healing wounds. Diabetics are more prone to developing chronic wounds due to complications like peripheral neuropathy, poor foot care, hyperglycaemia and peripheral vascular diseases. The aim of this review is to discuss the various imbalances in the cytokine environment of diabetic wounds and to explore the developments in their management with an emphasis on agents that may be used topically to aid the healing process of chronic wounds. A systematic search was conducted on Scopus, PubMed and Google Scholar and relevant articles were shortlisted. We conclude that increased blood sugar impairs most phases of wound healing in several ways. Supplementary therapy with either topical or systemic cytokines is shown to promote wound healing in a diabetic wound.
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Role of Innate Immune Cells in Chronic Diabetic Wounds. J Indian Inst Sci 2023. [DOI: 10.1007/s41745-022-00355-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/17/2023]
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Karnam K, Sedmaki K, Sharma P, Mahale A, Ghosh B, Kulkarni OP. Pharmacological blockade of HDAC3 accelerates diabetic wound healing by regulating macrophage activation. Life Sci 2023; 321:121574. [PMID: 36931496 DOI: 10.1016/j.lfs.2023.121574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 03/08/2023] [Accepted: 03/10/2023] [Indexed: 03/17/2023]
Abstract
AIMS Here, we report the effect of histone deacetylase 3 (HDAC3) inhibition associated with macrophage activation, IL-1β expression, angiogenesis and wound healing in diabetic mice. MAIN METHODS To determine the expression of HDAC3 in diabetic mice wounds, hyperglycemia was induced in C57BL/6 mice with streptozotocin followed by induction of 6 mm wounds. To understand the effect of HDAC3 selective inhibitor, BG45, wound tissues were isolated for analysing M1/M2 markers expression, immune cells infiltration, angiogenesis and healing factors expression. CD11b+F4/80+ cells were sorted from the wound tissues and analysed for the expression of M1/M2 markers using RT-qPCR and flow cytometer. In cell based assays, HDAC3 expression was measured in macrophages stimulated with high glucose (HG) plus LPS. Macrophages treated with BG45 and HG + LPS were analysed for the expression of pro-IL-1β, mature IL-1β, oxidative stress and pro-inflammatory (M1) and anti-inflammatory (M2) factors. KEY FINDINGS HDAC3 was found to be upregulated in impaired diabetic mice wounds and in macrophages stimulated with HG + LPS. Topical application of BG45 loaded gel accelerated the wound healing in diabetic mice and was evident by improved expression of Collagen-1A, IL-10, TGF-β, and angiogenesis (CD31, VEGF). BG45 treatment decreased the expression of IL-1β, TNF-α, and IL-6 (M1 phenotype), reduced oxidative stress and promoted the expression of Arginase-1 and YM1/2 (M2 phenotype) in macrophages treated with HG + LPS. BG45 also improved the expression of CD11b+F4/80+CD206+ cells in wound tissues and reduced expression of inflammatory markers. SIGNIFICANCE HDAC3 is upregulated in diabetic mice wounds and HDAC3 selective inhibitor promotes the wound healing by regulating macrophage activation, angiogenesis and IL-1β.
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Affiliation(s)
- Kalyani Karnam
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, India
| | - Kavitha Sedmaki
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, India
| | - Pravesh Sharma
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, India
| | - Ashutosh Mahale
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, India
| | - Balaram Ghosh
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, India; Epigenetic Research Laboratory, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, India
| | - Onkar Prakash Kulkarni
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, India.
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Yao Y, Zhang W, Li S, Xie H, Zhang Z, Jia B, Huang S, Li W, Ma L, Gao Y, Song J, Wang R. Development of Neuropeptide Hemokinin-1 Analogues with Antimicrobial and Wound-Healing Activity. J Med Chem 2023; 66:6617-6630. [PMID: 36893465 DOI: 10.1021/acs.jmedchem.2c02021] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/11/2023]
Abstract
Wound healing is a complex process that can be delayed in some pathological conditions, such as infection and diabetes. Following skin injury, the neuropeptide substance P (SP) is released from peripheral neurons to promote wound healing by multiple mechanisms. Human hemokinin-1 (hHK-1) has been identified as an SP-like tachykinin peptide. Surprisingly, hHK-1 shares similar structural features with antimicrobial peptides (AMPs), but it does not display efficient antimicrobial activity. Therefore, a series of hHK-1 analogues were designed and synthesized. Among these analogues, AH-4 was found to display the greatest antimicrobial activity against a broad spectrum of bacteria. Furthermore, AH-4 rapidly killed bacteria by membrane disruption, similar to most AMPs. More importantly, AH-4 showed favorable healing activity in all tested mouse full-thickness excisional wound models. Overall, this study suggests that the neuropeptide hHK-1 can be used as a desirable template for developing promising therapeutics with multiple functions for wound healing.
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Affiliation(s)
- Yufan Yao
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Wei Zhang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Sisi Li
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Huan Xie
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Zhengzheng Zhang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Bo Jia
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Sujie Huang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Wenyuan Li
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Ling Ma
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Yuxuan Gao
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Jingjing Song
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Rui Wang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Sciences, 2019RU066, Lanzhou University, Lanzhou, Gansu 730000, China.,State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
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Di Cristo F, Valentino A, De Luca I, Peluso G, Bonadies I, Di Salle A, Calarco A. Polylactic Acid/Poly(vinylpyrrolidone) Co-Electrospun Fibrous Membrane as a Tunable Quercetin Delivery Platform for Diabetic Wounds. Pharmaceutics 2023; 15:pharmaceutics15030805. [PMID: 36986666 PMCID: PMC10054567 DOI: 10.3390/pharmaceutics15030805] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 02/23/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Diabetic wound infections (DWI) represent one of the most costly and disruptive complications in diabetic mellitus. The hyperglycemic state induces a persistent inflammation with immunological and biochemical impairments that promotes delayed wound healing processes and wound infection that often results in extended hospitalization and limb amputations. Currently, the available therapeutic options for the management of DWI are excruciating and expensive. Hence, it is essential to develop and improve DWI-specific therapies able to intervene on multiple fronts. Quercetin (QUE) exhibits excellent anti-inflammatory, antioxidant, antimicrobial and wound healing properties, which makes it a promising molecule for the management of diabetic wounds. In the present study, Poly-lactic acid/poly(vinylpyrrolidone) (PP) co-electrospun fibers loaded with QUE were developed. The results demonstrated a bimodal diameter distribution with contact angle starting from 120°/127° and go to 0° in less than 5 s indicating the hydrophilic nature of fabricated samples. The release QUE kinetics, analyzed in simulated wound fluid (SWF), revealed a strong initial burst release, followed by a constant and continuous QUE release. Moreover, QUE-loaded membranes present excellent antibiofilm and anti-inflammatory capacity and significantly reduce the gene expression of M1 markers tumor necrosis factor (TNF)-α, and IL-1β in differentiated macrophages. In conclusion, the results suggested that the prepared mats loaded with QUE could be a hopeful drug-delivery system for the effective treatment of diabetic wound infections.
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Affiliation(s)
| | - Anna Valentino
- Research Institute on Terrestrial Ecosystems (IRET)—CNR, Via Pietro Castellino, 111, 80131 Naples, Italy
| | - Ilenia De Luca
- Research Institute on Terrestrial Ecosystems (IRET)—CNR, Via Pietro Castellino, 111, 80131 Naples, Italy
| | - Gianfranco Peluso
- Research Institute on Terrestrial Ecosystems (IRET)—CNR, Via Pietro Castellino, 111, 80131 Naples, Italy
- Faculty of Medicine and Surgery, Saint Camillus International University of Health and Medical Sciences, Via di Sant’Alessandro, 8, 00131 Rome, Italy
| | - Irene Bonadies
- Institute of Polymers, Composites and Biomaterials (IPCB-CNR), Via Campi Flegrei, 34, 80078 Pozzuoli, Italy
- Correspondence: (I.B.); (A.C.)
| | - Anna Di Salle
- Research Institute on Terrestrial Ecosystems (IRET)—CNR, Via Pietro Castellino, 111, 80131 Naples, Italy
| | - Anna Calarco
- Research Institute on Terrestrial Ecosystems (IRET)—CNR, Via Pietro Castellino, 111, 80131 Naples, Italy
- Correspondence: (I.B.); (A.C.)
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Frugtniet BA, Ruge F, Sanders AJ, Owen S, Harding KG, Jiang WG, Martin TA. nWASP Inhibition Increases Wound Healing via TrKb/PLCγ Signalling. Biomolecules 2023; 13:biom13020379. [PMID: 36830748 PMCID: PMC9953671 DOI: 10.3390/biom13020379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/18/2022] [Accepted: 02/07/2023] [Indexed: 02/19/2023] Open
Abstract
(1) Background: Chronic wounds represent a major burden to patients and healthcare systems and identifying new therapeutic targets to encourage wound healing is a significant challenge. This study evaluated nWASP as a new therapeutic target in human wound healing and determined how this can be regulated. (2) Methods: Clinical cohorts from patients with chronic wounds were tested for the expression of nWASP and cell models were employed to evaluate the influence of nWASP on cellular functions that are key to the healing process following knockdown and/or the use of nWASP-specific inhibitors. (3) Results: nWASP was significantly elevated at transcript levels in human non-healing chronic wounds versus healing tissues. nWASP inhibitors, wiskostatin and 187-1, along with the knockdown of nWASP, modified both HaCaT and HECV cell behaviour. We then identified two signalling pathways affected by nWASP inhibition: TrkB signalling and downstream PLCγ1 phosphorylation were impaired by nWASP inhibition in HaCaT cells. The healing of wounds in a diabetic murine model was significantly improved with an nWASP inhibitor treatment. (4) Conclusions: This study showed that nWASP activity was related to the non-healing behaviour of chronic wounds and together with the findings in the in vivo models, it strongly suggested nWASP as a therapeutic target in non-healing wounds that are regulated via TrkB and PLCγ1 signalling.
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Affiliation(s)
- Bethan A. Frugtniet
- Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
| | - Fiona Ruge
- Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
| | - Andrew J. Sanders
- Institute of Biomedical Science, University of Gloucestershire, Cheltenham GL50 2RH, UK
| | - Sioned Owen
- School of Applied Sciences, University of South Wales, Pontypridd CF37 4AT, UK
| | - Keith G. Harding
- Wound Healing Research Unit, Cardiff University School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
| | - Wen G. Jiang
- Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
| | - Tracey A. Martin
- Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
- Correspondence: ; Tel.: +44-(0)202-068-7209
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Hao Z, Qi W, Sun J, Zhou M, Guo N. Review: Research progress of adipose-derived stem cells in the treatment of chronic wounds. Front Chem 2023; 11:1094693. [PMID: 36860643 PMCID: PMC9968763 DOI: 10.3389/fchem.2023.1094693] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 01/25/2023] [Indexed: 02/15/2023] Open
Abstract
Although methods are used to treat wounds clinically, there are still many challenges in the treatment of chronic wounds due to excessive inflammatory response, difficulties in epithelialization, vascularization, and other factors. With the increasing research on adipose-derived stem cells (ADSCs) in recent years, accumulating evidence has shown that ADSCs scan promotes the healing of chronic wounds by regulating macrophage function and cellular immunity and promoting angiogenesis and epithelialization. The present study reviewed the difficulties in the treatment of chronic wounds, as well as the advantages and the mechanism of ADSCs in promoting the healing of chronic wounds, to provide a reference for the stem cell therapy of chronic wounds.
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Affiliation(s)
| | | | - Jiaming Sun
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Muran Zhou
- *Correspondence: Muran Zhou, ; Nengqiang Guo,
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Abstract
Nerves not only regulate the homeostasis and energetic metabolism of normal epithelial cells but also are critical for cancer, as cancer recapitulates the biology of neural regulation of epithelial tissues. Cancer cells rarely develop in denervated organs, and denervation affects tumorigenesis, in vivo and in humans. Axonogenesis occurs to supply the new malignant epithelial growth with nerves. Neurogenesis happens later, first in ganglia around organs or the spinal column and subsequently through recruitment of neuroblasts from the central nervous system. The hallmark of this stage is regulation of homeostasis and energetic metabolism. Perineural invasion is the most efficient interaction between cancer cells and nerves. The hallmark of this stage is increased proliferation and decreased apoptosis. Finally, carcinoma cells transdifferentiate into a neuronal profile in search of neural independence. The latter is the last stage in neuroepithelial interactions. Treatments for cancer must address the biology of neural regulation of cancer.
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Affiliation(s)
- Gustavo Ayala
- Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston, McGovern School of Medicine, Houston, Texas, USA;
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Sympathetic System in Wound Healing: Multistage Control in Normal and Diabetic Skin. Int J Mol Sci 2023; 24:ijms24032045. [PMID: 36768369 PMCID: PMC9916402 DOI: 10.3390/ijms24032045] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/14/2023] [Accepted: 01/18/2023] [Indexed: 01/22/2023] Open
Abstract
In this review, we discuss sympathetic regulation in normal and diabetic wound healing. Experimental denervation studies have confirmed that sympathetic nerve endings in skin have an important and complex role in wound healing. Vasoconstrictor neurons secrete norepinephrine (NE) and neuropeptide Y (NPY). Both mediators decrease blood flow and interact with inflammatory cells and keratinocytes. NE acts in an ambiguous way depending on receptor type. Beta2-adrenoceptors could be activated near sympathetic endings; they suppress inflammation and re-epithelialization. Alpha1- and alpha2-adrenoceptors induce inflammation and activate keratinocytes. Sudomotor neurons secrete acetylcholine (ACh) and vasoactive intestinal peptide (VIP). Both induce vasodilatation, angiogenesis, inflammation, keratinocytes proliferation and migration. In healthy skin, all effects are important for successful healing. In treatment of diabetic ulcers, mediator balance could be shifted in different ways. Beta2-adrenoceptors blockade and nicotinic ACh receptors activation are the most promising directions in treatment of diabetic ulcers with neuropathy, but they require further research.
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Kokabi F, Ebrahimi S, Mirzavi F, Ghiasi Nooghabi N, Hashemi SF, Hashemy SI. The neuropeptide substance P/neurokinin-1 receptor system and diabetes: From mechanism to therapy. Biofactors 2023. [PMID: 36651605 DOI: 10.1002/biof.1935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 12/22/2022] [Indexed: 01/19/2023]
Abstract
Diabetes is a significant public health issue known as the world's fastest-growing disease condition. It is characterized by persistent hyperglycemia and subsequent chronic complications leading to organ dysfunction and, ultimately, the failure of target organs. Substance P (SP) is an undecapeptide that belongs to the family of tachykinin (TK) peptides. The SP-mediated activation of the neurokinin 1 receptor (NK1R) regulates many pathophysiological processes in the body. There is also a relation between the SP/NK1R system and diabetic processes. Importantly, deregulated expression of SP has been reported in diabetes and diabetes-associated chronic complications. SP can induce both diabetogenic and antidiabetogenic effects and thus affect the pathology of diabetes destructively or protectively. Here, we review the current knowledge of the functional relevance of the SP/NK1R system in diabetes pathogenesis and its exploitation for diabetes therapy. A comprehensive understanding of the role of the SP/NK1R system in diabetes is expected to shed further light on developing new therapeutic possibilities for diabetes and its associated chronic conditions.
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Affiliation(s)
- Fariba Kokabi
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Safieh Ebrahimi
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farshad Mirzavi
- Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | | | | | - Seyed Isaac Hashemy
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Srivastava P, Sondak T, Sivashanmugam K, Kim KS. A Review of Immunomodulatory Reprogramming by Probiotics in Combating Chronic and Acute Diabetic Foot Ulcers (DFUs). Pharmaceutics 2022; 14:2436. [PMID: 36365254 PMCID: PMC9699442 DOI: 10.3390/pharmaceutics14112436] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/02/2022] [Accepted: 11/08/2022] [Indexed: 08/29/2023] Open
Abstract
Diabetic foot ulcers (DFUs) are characterized by a lack of angiogenesis and distal limb diabetic neuropathy. This makes it possible for opportunistic pathogens to protect the biofilm-encased micro-communities, causing a delay in wound healing. The acute and chronic phases of DFU-associated infections are distinguished by the differential expression of innate proinflammatory cytokines and tumor necrosis factors (TNF-α and -β). Efforts are being made to reduce the microbial bioburden of wounds by using therapies such as debridement, hyperbaric oxygen therapy, shock wave therapy, and empirical antibiotic treatment. However, the constant evolution of pathogens limits the effectiveness of these therapies. In the wound-healing process, continuous homeostasis and remodeling processes by commensal microbes undoubtedly provide a protective barrier against diverse pathogens. Among commensal microbes, probiotics are beneficial microbes that should be administered orally or topically to regulate gut-skin interaction and to activate inflammation and proinflammatory cytokine production. The goal of this review is to bridge the gap between the role of probiotics in managing the innate immune response and the function of proinflammatory mediators in diabetic wound healing. We also highlight probiotic encapsulation or nanoformulations with prebiotics and extracellular vesicles (EVs) as innovative ways to tackle target DFUs.
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Affiliation(s)
- Prakhar Srivastava
- Department of Chemistry and Chemistry Institute of Functional Materials, Pusan National University, Busan 46241, Korea
| | - Tesalonika Sondak
- Department of Chemistry and Chemistry Institute of Functional Materials, Pusan National University, Busan 46241, Korea
| | - Karthikeyan Sivashanmugam
- School of Biosciences and Technology, High Throughput Screening Lab, Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India
| | - Kwang-sun Kim
- Department of Chemistry and Chemistry Institute of Functional Materials, Pusan National University, Busan 46241, Korea
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Wang L, Yu Y, Zhao X, Zhang Z, Yuan X, Cao J, Meng W, Ye L, Lin W, Wang G. A Biocompatible Self-Powered Piezoelectric Poly(vinyl alcohol)-Based Hydrogel for Diabetic Wound Repair. ACS APPLIED MATERIALS & INTERFACES 2022; 14:46273-46289. [PMID: 36195572 DOI: 10.1021/acsami.2c13026] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Acute and chronic wounds, caused by trauma, tumors, diabetic foot ulcers, etc., are usually difficult to heal, while applying exogenous electrical stimulation to enhance the endogenous electric field in the wound has been proven to significantly accelerate wound healing. However, traditional electrical stimulation devices require an additional external power supply, making them poor in portability and comfort. In this work, a self-powered piezoelectric poly(vinyl alcohol) (PVA)/polyvinylidene fluoride (PVDF) composite hydrogel is constructed by establishing a distinctive preparation process of freezing/thawing-solvent replacement-annealing-swelling. The hydrogen bonding in the hydrogel is remarkably enhanced by the annealing-swelling process, which is stronger between PVA/PVDF molecules than that between PVA molecules, promoting transformation of the α-phase into the electroactive β-phase PVDF and facilitating formation of a much more crystalline structure with high cross-linking density. Hence, an obvious piezoelectric response with high piezoelectric coefficient and electrical signal output with superior stability and sensitivity and excellent mechanical strength and stretchability was achieved for hydrogels. PVA/PVDF composite hydrogels with good cytocompatibility significantly promote proliferation, migration, and secretion of extracellular matrix proteins and growth factors of fibroblasts, possibly through activating the AKT and ERK1/2 signaling pathways. In a wound model of diabetic rats, piezoelectric hydrogels could not only rapidly attract wound exudate and maintain the wet environment of the wound bed but also convert the mechanical energy generated by rats' physical activities into electrical energy, so as to provide local piezoelectric stimulation to the wound bed evenly and symmetrically in real time. Such an effect significantly promotes re-epithelialization and collagen deposition and increases angiogenesis and secretion of growth factors in wound tissue. Besides, it regulates the macrophage phenotype from the M1 subtype (pro-inflammatory subtype) to the M2 subtype (anti-inflammatory subtype) and reduces the expression levels of inflammatory factors, thus accelerating wound healing. The development of such a novel piezoelectric hydrogel provides new therapeutic strategies for chronic wound healing.
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Affiliation(s)
- Limin Wang
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu610065, China
| | - Yaru Yu
- State Key Laboratory of Polymer Materials Engineering, Polymer Research Institute of Sichuan University, Chengdu610065, China
| | - Xiaowen Zhao
- State Key Laboratory of Polymer Materials Engineering, Polymer Research Institute of Sichuan University, Chengdu610065, China
| | - Zhen Zhang
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu610065, China
| | - Xueling Yuan
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu610065, China
| | - Jinlong Cao
- State Key Laboratory of Polymer Materials Engineering, Polymer Research Institute of Sichuan University, Chengdu610065, China
| | - Weikun Meng
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu610065, China
| | - Lin Ye
- State Key Laboratory of Polymer Materials Engineering, Polymer Research Institute of Sichuan University, Chengdu610065, China
| | - Wei Lin
- West China Women's and Children's Hospital, Chengdu610065, China
| | - Guanglin Wang
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu610065, China
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Guo Y, Schon L, Paudel S, Feltham T, Manandhar L, Zhang Z. Increased synovial expression of calcitonin gene-related peptide and its potential roles in Charcot Neuroarthropathy. Exp Mol Pathol 2022; 128:104835. [PMID: 36195300 DOI: 10.1016/j.yexmp.2022.104835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 09/19/2022] [Accepted: 09/28/2022] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Joint destruction in Charcot neuroarthropathy (CNA) is accompanied with abundant hyperplastic synovium. This study aimed to characterize the expression patterns of a group of neuropeptides in the CNA synovium. METHODS Synovial specimens were collected during surgery from the CNA (n = 6) and non-CNA joints (n = 14). Tissue samples were processed for protein extraction and western blot for vasoactive intestinal peptide (VIP), galanin, and calcitonin gene-related peptide (CGRP). Immunohistochemistry was performed to localize CGRP in the CNA synovium. Additionally, CGRP was applied to fibroblast-like synoviocytes (FLS) isolated from CNA synovium for its effects on cell proliferation and collagenolysis in vitro. RESULTS Western blot detected light bands of VIP in the CNA samples but abundant galanin in both CNA and non-CNA samples. Most of the CNA samples (5/6) increased expression of CGRP, with an average band density about 2 times that in the non-CNA group (p < .05). Immunohistochemistry of CGRP demonstrated intense staining in the intimal layer of the CNA synovium. In tissue culture, adding CGRP (10 nM) in the medium promoted FLS proliferation. In combination with TNF-α, CGRP enhanced FLS-mediated collagenolysis in vitro. CONCLUSION This study revealed an increased expression of CGRP in the CNA synovium and demonstrated that CGRP regulates FLS proliferation and collagenolytic activity, suggesting CGRP may contribute to the bone and cartilage destruction in CNA.
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Affiliation(s)
- Yi Guo
- Department of Orthopaedic Surgery, Montefiore Medical Center, Bronx, NY, USA
| | - Lew Schon
- Institute for Foot and Ankle Reconstruction, Mercy Medical Center, Baltimore, MD, USA; Center for Orthopaedic Innovation, Mercy Medical Center, Baltimore, MD, USA
| | - Sharada Paudel
- Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Tyler Feltham
- Philadelphia College of Osteopathic Medicine-GA, Suwanee, GA, USA
| | | | - Zijun Zhang
- Center for Orthopaedic Innovation, Mercy Medical Center, Baltimore, MD, USA.
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Zhang Z, Zhang Y, Yang D, Luo Y, Luo Y, Ru Y, Song J, Fei X, Chen Y, Li B, Jiang J, Kuai L. Characterisation of key biomarkers in diabetic ulcers via systems bioinformatics. Int Wound J 2022; 20:529-542. [PMID: 36181454 PMCID: PMC9885479 DOI: 10.1111/iwj.13900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 07/02/2022] [Accepted: 07/04/2022] [Indexed: 02/03/2023] Open
Abstract
Diabetic ulcers (DUs) are characterised by a high incidence and disability rate. However, its pathogenesis remains elusive. Thus, a deep understanding of the underlying mechanisms for the pathogenesis of DUs has vital implications. The weighted gene co-expression network analysis was performed on the main data from the Gene Expression Omnibus database. Gene Ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were adopted to analyse the potential biological function of the most relevant module. Furthermore, we utilised CytoHubba and protein-protein interaction network to identify the hub genes. Finally, the hub genes were validated by animal experiments in diabetic ulcer mice models. The expression of genes from the turquoise module was found to be strongly related to DUs. GO terms, KEGG analysis showed that biological functions are closely related to immune response. The hub genes included IFI35, IFIT2, MX2, OASL, RSAD2, and XAF1, which were higher in wounds of DUs mice than that in normal lesions. Additionally, we also demonstrated that the expression of hub genes was correlated with the immune response using immune checkpoint, immune cell infiltration, and immune scores. These data suggests that IFI35, IFIT2, MX2, OASL, RSAD2, and XAF1 are crucial for DUs.
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Affiliation(s)
- Zhan Zhang
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghaiChina,Institute of DermatologyShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Ying Zhang
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghaiChina,Institute of DermatologyShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Dan Yang
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghaiChina,Institute of DermatologyShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Yue Luo
- Department of Integrated TCM and Western Medicine, Shanghai Skin Disease HospitalTongji UniversityShanghaiChina
| | - Ying Luo
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghaiChina,Institute of DermatologyShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Yi Ru
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghaiChina,Institute of DermatologyShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Jiankun Song
- Department of Integrated TCM and Western Medicine, Shanghai Skin Disease HospitalTongji UniversityShanghaiChina
| | - Xiaoya Fei
- Department of Integrated TCM and Western Medicine, Shanghai Skin Disease HospitalTongji UniversityShanghaiChina
| | - Yiran Chen
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghaiChina,Institute of DermatologyShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Bin Li
- Institute of DermatologyShanghai Academy of Traditional Chinese MedicineShanghaiChina,Department of Integrated TCM and Western Medicine, Shanghai Skin Disease HospitalTongji UniversityShanghaiChina
| | - Jingsi Jiang
- Department of Skin and Cosmetics Research, Shanghai Skin Disease HospitalTongji UniversityShanghaiChina
| | - Le Kuai
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghaiChina,Institute of DermatologyShanghai Academy of Traditional Chinese MedicineShanghaiChina
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Scaffold-based delivery of mesenchymal stromal cells to diabetic wounds. Stem Cell Res Ther 2022; 13:426. [PMID: 35987712 PMCID: PMC9392335 DOI: 10.1186/s13287-022-03115-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 08/04/2022] [Indexed: 02/06/2023] Open
Abstract
AbstractFoot ulceration is a major complication of diabetes mellitus, which results in significant human suffering and a major burden on healthcare systems. The cause of impaired wound healing in diabetic patients is multifactorial with contributions from hyperglycaemia, impaired vascularization and neuropathy. Patients with non-healing diabetic ulcers may require amputation, creating an urgent need for new reparative treatments. Delivery of stem cells may be a promising approach to enhance wound healing because of their paracrine properties, including the secretion of angiogenic, immunomodulatory and anti-inflammatory factors. While a number of different cell types have been studied, the therapeutic use of mesenchymal stromal cells (MSCs) has been widely reported to improve delayed wound healing. However, topical administration of MSCs via direct injection has several disadvantages, including low cell viability and poor cell localization at the wound bed. To this end, various biomaterial conformations have emerged as MSC delivery vehicles to enhance cell viability and persistence at the site of implantation. This paper discusses biomaterial-based MSCs therapies in diabetic wound healing and highlights the low conversion rate to clinical trials and commercially available therapeutic products.
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Liu Y, Liu Y, He W, Mu X, Wu X, Deng J, Nie X. Fibroblasts: Immunomodulatory factors in refractory diabetic wound healing. Front Immunol 2022; 13:918223. [PMID: 35990622 PMCID: PMC9391070 DOI: 10.3389/fimmu.2022.918223] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 07/15/2022] [Indexed: 12/15/2022] Open
Abstract
Diabetes is a systemic disease in which patients with diabetes may develop peripheral neuropathy of the lower extremities and peripheral vascular disease due to long-term continuous exposure to high glucose. Delayed wound healing in diabetes is one of the major complications of diabetes. Slow wound healing in diabetic patients is associated with high glucose toxicity. When the condition deteriorates, the patient needs to be amputated, which seriously affects the quality of life and even endangers the life of the patient. In general, the delayed healing of diabetes wound is due to the lack of chemokines, abnormal inflammatory response, lack of angiogenesis and epithelial formation, and fibroblast dysfunction. The incidence of several chronic debilitating conditions is increasing in patients with diabetes, such as chronic renal insufficiency, heart failure, and hepatic insufficiency. Fibrosis is an inappropriate deposition of extracellular matrix (ECM) proteins. It is common in diabetic patients causing organ dysfunction. The fibrotic mechanism of diabetic fibroblasts may involve direct activation of permanent fibroblasts. It may also involve the degeneration of fibers after hyperglycemia stimulates immune cells, vascular cells, or organ-specific parenchymal cells. Numerous studies confirm that fibroblasts play an essential role in treating diabetes and its complications. The primary function of fibroblasts in wound healing is to construct and reshape the ECM. Nowadays, with the widespread use of single-cell RNA sequencing (scRNA-seq), an increasing number of studies have found that fibroblasts have become the critical immune sentinel cells, which can detect not only the activation and regulation of immune response but also the molecular pattern related to the injury. By exploring the heterogeneity and functional changes of fibroblasts in diabetes, the manuscript discusses that fibroblasts may be used as immunomodulatory factors in refractory diabetic wound healing, providing new ideas for the treatment of refractory diabetic wound healing.
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Affiliation(s)
- Ye Liu
- College of Pharmacy, Zunyi Medical University, Zunyi, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi, China
| | - Yiqiu Liu
- College of Pharmacy, Zunyi Medical University, Zunyi, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi, China
| | - Wenjie He
- College of Pharmacy, Zunyi Medical University, Zunyi, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi, China
| | - Xingrui Mu
- College of Pharmacy, Zunyi Medical University, Zunyi, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi, China
| | - Xingqian Wu
- College of Pharmacy, Zunyi Medical University, Zunyi, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi, China
| | - Junyu Deng
- College of Pharmacy, Zunyi Medical University, Zunyi, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi, China
| | - Xuqiang Nie
- College of Pharmacy, Zunyi Medical University, Zunyi, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi, China
- *Correspondence: Xuqiang Nie,
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Zhu Z, Zhang X, Hao H, Xu H, Shu J, Hou Q, Wang M. Exosomes Derived From Umbilical Cord Mesenchymal Stem Cells Treat Cutaneous Nerve Damage and Promote Wound Healing. Front Cell Neurosci 2022; 16:913009. [PMID: 35846563 PMCID: PMC9279568 DOI: 10.3389/fncel.2022.913009] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 06/02/2022] [Indexed: 11/13/2022] Open
Abstract
Wound repair is a key step in the treatment of skin injury caused by burn, surgery, and trauma. Various stem cells have been proven to promote wound healing and skin regeneration as candidate seed cells. Therefore, exosomes derived from stem cells are emerging as a promising method for wound repair. However, the mechanism by which exosomes promote wound repair is still unclear. In this study, we reported that exosomes derived from umbilical cord mesenchymal stem cells (UC-MSCs) promote wound healing and skin regeneration by treating cutaneous nerve damage. The results revealed that UC-MSCs exosomes (UC-MSC-Exo) promote the growth and migration of dermal fibroblast cells. In in vitro culture, dermal fibroblasts could promote to nerve cells and secrete nerve growth factors when stimulated by exosomes. During the repair process UC-MSC-Exo accelerated the recruitment of fibroblasts at the site of trauma and significantly enhanced cutaneous nerve regeneration in vivo. Interestingly, it was found that UC-MSC-Exo could promote wound healing and skin regeneration by recruiting fibroblasts, stimulating them to secrete nerve growth factors (NGFs) and promoting skin nerve regeneration. Therefore, we concluded that UC-MSC-Exo promote cutaneous nerve repair, which may play an important role in wound repair and skin regeneration.
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Affiliation(s)
- Ziying Zhu
- College of Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing, China
- The First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
- *Correspondence: Ziying Zhu,
| | - Xiaona Zhang
- College of Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing, China
| | - Haojie Hao
- The First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
| | - Heran Xu
- College of Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing, China
| | - Jun Shu
- The First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
| | - Qian Hou
- The First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
- Medical Innovation Research Center, Chinese People’s Liberation Army General Hospital, Beijing, China
- Qian Hou,
| | - Min Wang
- College of Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing, China
- Min Wang,
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Polyherbal formulation exerts wound healing, anti-inflammatory, angiogenic and antimicrobial properties: Potential role in the treatment of diabetic foot ulcers. Saudi J Biol Sci 2022; 29:103330. [PMID: 35721231 PMCID: PMC9198379 DOI: 10.1016/j.sjbs.2022.103330] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 04/27/2022] [Accepted: 05/26/2022] [Indexed: 11/22/2022] Open
Abstract
Diabetic foot ulcer (DFU) is a common and devastating complication in diabetic patients and is associated with an elevated risk of amputation and mortality. DFU remains a major therapeutic challenge due to poor understanding of its underlying pathogenesis. This complication is characterized by impaired wound healing; however, mechanisms causing this impairment are complicated and involve interactions between many different cell types and infections. In addition to other conventional DFU treatments, herbal foot baths are also common, although little is known about their mechanisms of action, and they contain a wide variety of herbal ingredients. In this study, we aimed to examine the effects of three polyherbal formulations consisting of medicinal plants used in traditional Thai herbal foot baths on wound healing, anti-inflammation, angiogenesis, and extracellular matrix modulation using high-concentration glucose-treated human keratinocytes, in addition to antibacterial evaluation. Our results showed that formulation 3 (F3) possessed the greatest potential to restore the impairment of keratinocytes caused by high glucose concentrations. We found that F3 could inhibit the growth of Staphylococcus aureus, accelerate wound healing, and upregulate the expression of TIMP-1, VEGF, and TGF-β, and downregulate the expression of TNF-α, IL-6, and MMP-9. Collectively, these data support the potential of F3 for therapeutic development in the treatment of DFU.
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Alhakamy NA, Caruso G, Privitera A, Ahmed OAA, Fahmy UA, Md S, Mohamed GA, Ibrahim SRM, Eid BG, Abdel-Naim AB, Caraci F. Fluoxetine Ecofriendly Nanoemulsion Enhances Wound Healing in Diabetic Rats: In Vivo Efficacy Assessment. Pharmaceutics 2022; 14:1133. [PMID: 35745706 PMCID: PMC9227110 DOI: 10.3390/pharmaceutics14061133] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 05/20/2022] [Accepted: 05/23/2022] [Indexed: 02/04/2023] Open
Abstract
Impaired diabetic wound healing is a major concern for health care professionals worldwide, imposing an intense financial burden and reducing the quality of life of patients. A dysregulation of this process can be responsible for the development of intractable ulcers and the formation of excessive scars. Therefore, the identification of novel pharmacological strategies able to promote wound healing and restore the mechanical integrity of injured tissue becomes essential. In the present study, fluoxetine ecofriendly nanoemulsion (FLX-EFNE) was prepared and its potential efficacy in enhancing wound healing was tested in diabetic rats. The Box-Behnken response surface design was used to select the optimized formulation that was prepared by the high-shear homogenization-based technique. A Zetasizer was used for the characterization of the optimized formulation, providing a FLX-EFNE with a globule size of 199 nm. For the in vivo study, a wound was induced by surgical methods, and diabetic rats (streptozotocin-induced) were divided into five groups: untreated control, vehicle-treated, FLX, FLX-EFNE, and positive control receiving a commercially available formula. The treatment continued from the day of wound induction to day 21. Then, the animals were sacrificed and skin tissues were collected at the site of wounding and used for biochemical, histopathological, immunohistochemical, and mRNA expression assessments. In the FLX-EFNE treated group, the rate of wound contraction and signs of healing were significantly higher compared to all other groups. In addition, angiogenesis, proliferation, and collagen deposition were enhanced, while oxidative stress and inflammation decreased. The present data highlight the enhanced wound healing activity of the optimized FLX-EFNE formulation.
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Affiliation(s)
- Nabil A. Alhakamy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (O.A.A.A.); (U.A.F.); (S.M.)
- Advanced Drug Delivery Research Group, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Mohamed Saeed Tamer Chair for Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Giuseppe Caruso
- Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy; (A.P.); (F.C.)
- Unit of Neuropharmacology and Translational Neurosciences, Oasi Research Institute—IRCCS, 94018 Troina, Italy
| | - Anna Privitera
- Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy; (A.P.); (F.C.)
| | - Osama A. A. Ahmed
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (O.A.A.A.); (U.A.F.); (S.M.)
- Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Mohamed Saeed Tamer Chair for Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Usama A. Fahmy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (O.A.A.A.); (U.A.F.); (S.M.)
| | - Shadab Md
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (O.A.A.A.); (U.A.F.); (S.M.)
| | - Gamal A. Mohamed
- Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Sabrin R. M. Ibrahim
- Preparatory Year Program, Batterjee Medical College, Jeddah 21442, Saudi Arabia;
- Department of Pharmacognosy, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt
| | - Basma G. Eid
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (B.G.E.); (A.B.A.-N.)
| | - Ashraf B. Abdel-Naim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (B.G.E.); (A.B.A.-N.)
| | - Filippo Caraci
- Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy; (A.P.); (F.C.)
- Unit of Neuropharmacology and Translational Neurosciences, Oasi Research Institute—IRCCS, 94018 Troina, Italy
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Astragalus Polysaccharides/PVA Nanofiber Membranes Containing Astragaloside IV-Loaded Liposomes and Their Potential Use for Wound Healing. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:9716271. [PMID: 35600951 PMCID: PMC9117023 DOI: 10.1155/2022/9716271] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 04/13/2022] [Indexed: 12/24/2022]
Abstract
Delayed wound healing is a common and serious complication in diabetic patients, especially the slow healing of foot ulcers, which seriously affects the quality of life of patients and is also the most important risk factor for lower limb amputation. The multifunctional novel dressing prepared by loading the polymer nanofibers with anti-inflammatory and prohealing plant extracts can promote the wound repair of these ulcers by electrospinning technology. Liposomes are nanoparticles prepared from phospholipids and have been widely used as drug delivery systems. Liposomes can be combined with electrospun nanofibrous webs to facilitate local and sustained delivery of loaded bioactive substances. In this study, liposomes were prepared with astragaloside IV (AS) by employing a modified ethanol injection method and conducting the physical and chemical characterization (e.g., the particle size, polydispersity index, zeta potential, and entrapment efficiency). Astragalus polysaccharides were extracted from Astragalus membranaceus. Subsequently, we prepared the electrospun polyvinyl alcohol (PVA)/astragalus polysaccharide (APS)/astragaloside IV (AS) nanofibers. The morphology of the produced ASL/APS/PVA, APS/PVA, and PVA nanofibers were analyzed by scanning electron microscopy (SEM), and it turns out that the addition of astragalus extract made the fiber diameter smaller and the fibers arranged neatly with no dripping. An induced diabetic rat model was built, and a diabetic ulcer model was built by total cortical resection to assess the prorepair ability of the prepared nanofibers. According to in vivo animal experiments, the nanofibrous membrane loaded with APS and ASL was reported to inhibit the occurrence of wound inflammation, enhance the deposition of collagen fibers (P < 0.05) and the repair of regenerated epithelium (P < 0.05), and effectively strengthen the wound healing of diabetic rats (P < 0.05). In brief, PVA-loaded APS/ASL nanofibrous membranes refer to a prominent wound healing dressing material, which can effectively facilitate the healing of diabetic wounds, and they are demonstrated to be highly promising for application in diabetic wound dressings and tissue engineering.
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Gupta D, Kaushik D, Mohan V. Role of neurotransmitters in the regulation of cutaneous wound healing. Exp Brain Res 2022; 240:1649-1659. [PMID: 35488904 DOI: 10.1007/s00221-022-06372-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 04/13/2022] [Indexed: 11/04/2022]
Abstract
Wound healing is a highly coordinated and dynamic process of tissue repair after injury. The global burden of disease associated with wounds, both acute and chronic, is a significantly rising health concern. Upon skin wounding, neurons have the ability to sense the disruption to mediate the release of neurotransmitters into the wound microenvironment. Serotonin that has long been recognised as a potential vasoconstrictor is now also being contemplated to play a role in re-epithelialisation of wounds. While the role of neuropeptides in stimulating diabetic wound healing is being increasingly emphasised, on the other hand, dopamine is being widely studied for its dual role in mediating both pro- and antiangiogenic effects at the site of the wounds. Similarly, epinephrine levels that are known to be elevated during stress is now recognised as a contributing factor towards delayed wound closure, thereby serving as an inhibitor of wound healing. Thus, each neurotransmitter regulates wound repair and their active regeneration in a typical way. Strengthening our understanding of the molecular pathways via which the neurotransmitter modulates the immune system to control wound healing can yield potential therapeutic measures. Further investigations regarding the safety, efficacy, and cost-effectiveness of these processes are a prerequisite for their possible translation into clinical trials.
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Affiliation(s)
- Divya Gupta
- Department of Life Sciences, Neurosciences, Gurugram University, Sector-51, Gurugram, Haryana, India
| | - Dhirender Kaushik
- Department of Life Sciences, Neurosciences, Gurugram University, Sector-51, Gurugram, Haryana, India
| | - Vandana Mohan
- Department of Life Sciences, Neurosciences, Gurugram University, Sector-51, Gurugram, Haryana, India.
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