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Wu Q, Xie Z, Cao X, Hu D, Sheng L, Guo X, Yan D, Ding C, Li C, Xiao J, Liu C, Wu K, Gong Y, Fan Q, Wang Q, Liu J, Liu Y. Chaihu-Shugan-San alleviates post-stroke depression in mice: Mechanistic insights into exosome-mediated neuroprotection. JOURNAL OF ETHNOPHARMACOLOGY 2025; 347:119700. [PMID: 40154896 DOI: 10.1016/j.jep.2025.119700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 03/19/2025] [Accepted: 03/24/2025] [Indexed: 04/01/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Post-stroke depression (PSD) is common among stroke survivors and negatively impacts recovery. Chaihu-Shugan-San (CSS), a traditional Chinese medicine, has shown therapeutic potential for mood disorders, particularly PSD. Recent studies suggest that CSS's effects may be mediated by exosomes, but the mechanisms remain unclear. AIM OF STUDY This study aimed to evaluate the therapeutic effects of CSS on PSD in mice and investigate the underlying mechanisms, particularly the role of exosomes. MATERIALS AND METHODS Active compounds in CSS were identified from rat serum using liquid chromatography-mass spectrometry (LC-MS) and analyzed through network pharmacology. In vitro, an oxygen-glucose deprivation/reperfusion (OGD/R) BV2 microglia model was used to assess the effects of CSS-containing serum (CSS-S). Exosomes from OGD/R-treated BV2 microglia were isolated, labeled with PKH26, and analyzed using transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). In vivo, a photothrombotic stroke (PT) model combined with chronic unpredictable mild stress (CUMS) was used to induce PSD in mice. Behavioral assessments and histological analysis were performed, along with immunofluorescence (IF), ELISA and q-PCR to measure key protein and miR-146 expression in the hippocampus. RESULTS CSS treatment significantly alleviated depressive-like behaviors in the PSD mouse model. Mice treated with high-dose CSS (4.2 g/kg) exhibited increased sucrose preference, reduced immobility in the tail suspension test (TST) and forced swimming test (FST), and enhanced exploratory activity in the open field test (OFT). Histological analysis demonstrated that CSS treatment improved brain tissue integrity, alleviating neuronal damage and reducing neuroinflammation. Exosome analysis revealed that CSS increased the expression of microglia-derived exosomes in the hippocampus, which were shown to carry miR-146. Further examination of miR-146 isoforms in the hippocampal tissue revealed significant changes: miR-146b-3p and miR-146a-5p were upregulated, while miR-146a-3p and miR-146b-5p were downregulated in PSD mice. Treatment with CSS reversed the altered miRNA expression, indicating a potential mechanism for its neuroprotective effects. Additionally, CSS treatment reduced the expression of inflammatory cytokines such as S100A8, IL1β, IL6, and TNF-α, while restoring the levels of angiogenic factors VEGFC and VEGFR3. ELISA measurements showed significant decreases in cyclic AMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), 5-hydroxytryptamine (5-HT), dopamine (DA), and noradrenaline (NE) in PSD mice; high-dose CSS notably elevated CREB and BDNF levels and showed comparable effects to fluoxetine in restoring 5-HT and DA levels. Additionally, the calcium signaling pathway was implicated, with altered mRNA expressions of CaMKIIα, CREB, phosphorylated CREB (p-CREB), PDE4D, and BDNF, although fluoxetine demonstrated stronger modulatory effects than CSS. CONCLUSIONS CSS alleviates PSD in mice by modulating exosome-mediated signaling, particularly through the regulation of miR-146. The treatment reversed abnormal miRNA expression, reduced neuroinflammation, and improved synaptic function. These findings highlight CSS's potential as an effective therapeutic strategy for PSD by targeting exosome-mediated neuroprotection and miR-146 regulation.
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Affiliation(s)
- Qiqing Wu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
| | - Zhouyuan Xie
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
| | - Xinyue Cao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
| | - Dan Hu
- Department of Neurology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu, 210017, China.
| | - Lei Sheng
- Department of Neurology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu, 210017, China.
| | - Xueyan Guo
- Department of Neurology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu, 210017, China.
| | - Dong Yan
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
| | - Caixia Ding
- Department of Neurology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu, 210017, China.
| | - Chuanyou Li
- Department of Neurology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu, 210017, China.
| | - Jing Xiao
- Department of Neurology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu, 210017, China.
| | - Chunyu Liu
- Department of Neurology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu, 210017, China.
| | - Ke Wu
- Department of Neurology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu, 210017, China.
| | - Yue Gong
- Department of Neurology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu, 210017, China.
| | - Qiqi Fan
- Central Laboratory, Affiliated Jiangmen TCM Hospital of Ji'nan University, Jiangmen, 529099, China.
| | - Qi Wang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
| | - Jinman Liu
- Central Laboratory, Affiliated Jiangmen TCM Hospital of Ji'nan University, Jiangmen, 529099, China.
| | - Yuanyue Liu
- Department of Neurology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu, 210017, China.
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Wang H, Wu S, Bai X, Pan D, Ning Y, Wang C, Guo L, Guo J, Gu Y. Mesenchymal Stem Cell-Derived Exosomes Hold Promise in the Treatment of Diabetic Foot Ulcers. Int J Nanomedicine 2025; 20:5837-5857. [PMID: 40351704 PMCID: PMC12065540 DOI: 10.2147/ijn.s516533] [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: 01/09/2025] [Accepted: 04/11/2025] [Indexed: 05/14/2025] Open
Abstract
Diabetic foot ulcers (DFU) represent one of the most common side effects of diabetes, significantly impacting patients' quality of life and imposing considerable financial burdens on families and society at large. Despite advancements in therapies targeting lower limb revascularization and various medications and dressings, outcomes for patients with severe lesions remain limited. A recent breakthrough in DFU treatment stems from the development of mesenchymal stem cells (MSCs). MSCs have shown promising results in treating various diseases and skin wounds due to their ability for multidirectional differentiation and immunomodulation. Recent studies highlight that MSCs primarily repair tissue through their paracrine activities, with exosomes playing a crucial role as the main biologically active components. These exosomes transport proteins, mRNA, DNA, and other substances, facilitating DFU treatment through immunomodulation, antioxidant effects, angiogenesis promotion, endothelial cell migration and proliferation, and collagen remodeling. Mesenchymal stem cell-derived exosomes (MSC-Exo) not only deliver comparable therapeutic effects to MSCs but also mitigate adverse reactions like immune rejection associated with MSCs transplantation. This article provides an overview of DFU pathophysiology and explores the mechanisms and research progress of MSC-Exo in DFU therapy.
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Affiliation(s)
- Hui Wang
- Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People’s Republic of China
| | - Sensen Wu
- Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People’s Republic of China
| | - Xinyu Bai
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, Jilin Province, 130033, People’s Republic of China
| | - Dikang Pan
- Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People’s Republic of China
| | - Yachan Ning
- Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People’s Republic of China
| | - Cong Wang
- Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People’s Republic of China
| | - Lianrui Guo
- Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People’s Republic of China
| | - Jianming Guo
- Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People’s Republic of China
| | - Yongquan Gu
- Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People’s Republic of China
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Han X, Ju L, Sands M, Zhao Y, Irudayaraj J. Oxygenated Exosome-Based Nanoeyedrop for Mitigating Hypoxia in Corneal Wound Healing: Impact on Healing Properties of Human Corneal Epithelial Cells. ACS Pharmacol Transl Sci 2025; 8:602-612. [PMID: 39974628 PMCID: PMC11833733 DOI: 10.1021/acsptsci.4c00724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/13/2025] [Accepted: 01/15/2025] [Indexed: 02/21/2025]
Abstract
The rapid and organized healing of the cornea, while maintaining optical clarity, is essential for patient health and quality of life following corneal injuries. Oxygen plays a critical role in regulating cell migration and proliferation during wound repair, and the application of stem cell-derived exosomes offers potential therapeutic benefits due to their antioxidant and antiscarring properties. In this study, we developed oxygenated exosome-coated hemoglobin nanoparticles (OExo NPs) designed for effective oxygen delivery to enhance corneal re-epithelialization, reduce inflammation, and mitigate scarring. These OExo NPs exhibit a uniform average diameter of 130 nm and demonstrate consistent oxygen release capabilities. In vitro assays using human corneal epithelial cells-transformed (HCE-T) revealed that OExo NPs significantly promote cell proliferation and accelerate migration in scratch wound assays. Fluorescence imaging confirmed the successful internalization of OExo NPs into HCE-T cells and increased intracellular oxygen levels under hypoxic conditions. Gene expression analyses indicated a downregulation of critical wound healing markers, including HIF-1α, VEGF, IL-8, and FAK, suggesting effective alleviation of hypoxia, inhibition of angiogenesis, suppression of inflammation, and reduction of scar formation. These results highlight the potential of OExo NPs as a promising therapeutic approach for topical treatment of corneal wounds.
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Affiliation(s)
- Xiaoxue Han
- Department of Bioengineering, University of Illinois at Urbana−Champaign, 1102 Everitt Lab, 1406 W. Green
St., Urbana, Illinois 61801, United States
- Biomedical Research Center, Mills Breast
Cancer Institute, Carle Foundation Hospital, Urbana, Illinois 61801, United States
- Cancer Center at Illinois, Beckman Institute, Urbana, Illinois 61801, United States
- Carle R. Woese Institute for Genomic Biology, Urbana, Illinois 61801, United States
| | - Leah Ju
- Department of Bioengineering, University of Illinois at Urbana−Champaign, 1102 Everitt Lab, 1406 W. Green
St., Urbana, Illinois 61801, United States
- Biomedical Research Center, Mills Breast
Cancer Institute, Carle Foundation Hospital, Urbana, Illinois 61801, United States
| | - Mia Sands
- Department of Bioengineering, University of Illinois at Urbana−Champaign, 1102 Everitt Lab, 1406 W. Green
St., Urbana, Illinois 61801, United States
- Biomedical Research Center, Mills Breast
Cancer Institute, Carle Foundation Hospital, Urbana, Illinois 61801, United States
| | - Yunlei Zhao
- Department of Electrical and Computer Engineering, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
| | - Joseph Irudayaraj
- Department of Bioengineering, University of Illinois at Urbana−Champaign, 1102 Everitt Lab, 1406 W. Green
St., Urbana, Illinois 61801, United States
- Biomedical Research Center, Mills Breast
Cancer Institute, Carle Foundation Hospital, Urbana, Illinois 61801, United States
- Cancer Center at Illinois, Beckman Institute, Urbana, Illinois 61801, United States
- Carle R. Woese Institute for Genomic Biology, Urbana, Illinois 61801, United States
- Carle
Illinois College of Medicine, University
of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
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Razavi ZS, Aliniay Sharafshadehi S, Yousefi MH, Javaheri F, Rahimi Barghani MR, Afkhami H, Heidari F. Application of novel strategies in chronic wound management with focusing on pressure ulcers: new perspective. Arch Dermatol Res 2025; 317:320. [PMID: 39888392 DOI: 10.1007/s00403-024-03790-8] [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: 11/10/2024] [Revised: 12/27/2024] [Accepted: 12/29/2024] [Indexed: 02/01/2025]
Abstract
Invading blood cells, extracellular tissue, and soluble mediators all play important roles in the wound-healing process. There is a substantial global burden of disease and mortality attributable to skin defects that do not heal. About 1% to 2% of the population in industrialized nations suffers from chronic wounds that don't heal, despite healthcare breakthroughs; this condition is very costly, costing about $25 billion each year in the US alone. Amputation, infection (affecting as many as 25% of chronic wounds), sepsis, and dermal replacements are all consequences of conventional therapeutic approaches like growth factor therapy and diabetic foot ulcers account for 85% of lower limb amputations. Despite these obstacles, scientists are constantly looking for new ways to speed healing and close wounds. The unique immunomodulatory capabilities and multipotency of mesenchymal stem cells (MSCs) have made them a potential therapeutic choice in tissue engineering and regenerative medicine. Animal models of wound healing have shown that MSCs can speed up the process by as much as 40% through enhancing angiogenesis, modulating inflammation, and promoting fibroblast migration. Clinical trials provide more evidence of their effectiveness; for instance, one RCT found that, after 12 weeks, patients treated with MSCs had a 72% smaller wound size than those in the control group. This review offers a thorough examination of MSCs by combining the latest research with preclinical evidence. Highlighting their potential to transform treatment paradigms, it delves into their biological properties, how they work during regeneration and healing, and therapeutic usefulness in controlling chronic wounds.
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Affiliation(s)
- Zahra Sadat Razavi
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Shahrzad Aliniay Sharafshadehi
- Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Hasan Yousefi
- Department of Tissue Engineering and Applied Cell Sciences, School of Medicine, Qom University of Medical Sciences, Qom, Iran
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
| | - Fatemeh Javaheri
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
| | | | - Hamed Afkhami
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran.
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran.
| | - Fatemeh Heidari
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
- Department of Anatomy, Faculty of Medicine, Qom University of Medical Sciences, Qom, Iran.
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Wang L, Wang C, Huang C, Zhou Z, Yang R, Huang Y, Chen Z, Zhang Y, Wang S, Feng K. Role of microRNAs in diabetic foot ulcers: Mechanisms and possible interventions. Diabetes Res Clin Pract 2024; 217:111858. [PMID: 39284457 DOI: 10.1016/j.diabres.2024.111858] [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: 06/29/2024] [Revised: 08/24/2024] [Accepted: 09/13/2024] [Indexed: 09/21/2024]
Abstract
Diabetic foot ulcer (DFU) is a common and serious complication among diabetic patients, and its incidence and difficulty in treatment have placed large burdens on patient health and quality of life. Diabetic foot tissue typically exhibits chronic wounds, ulcers, or necrosis that are difficult to heal, are prone to infection, and, in severe cases, may even lead to amputation. Recent studies have shown that microRNAs (miRNAs) play key roles in the development and healing of DFUs. miRNAs are a class of short noncoding RNA molecules that regulate gene expression to affect cellular functions and physiological processes. miRNAs may be involved in the development of DFUs by regulating cell growth, proliferation, differentiation and apoptosis. miRNAs can also participate in the healing and recovery of DFUs by regulating key steps, such as inflammation, angiogenesis, cell migration and proliferation, tissue repair and matrix remodeling. Therefore, altering the pathological processes of diabetic foot by modulating the expression of miRNAs could improve the recovery and treatment outcomes of patients. This review provides new insights and perspectives for the treatment of DFUs by summarizing the roles of miRNAs in the development and healing of DFUs and the mechanisms.
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Affiliation(s)
- Lin Wang
- Pingshan District People's Hospital of Shenzhen, Pingshan General Hospital of Southern Medical University, Shenzhen 518118, Guangdong, China
| | - Cong Wang
- Pingshan District People's Hospital of Shenzhen, Pingshan General Hospital of Southern Medical University, Shenzhen 518118, Guangdong, China
| | - Caiyan Huang
- Pingshan District People's Hospital of Shenzhen, Pingshan General Hospital of Southern Medical University, Shenzhen 518118, Guangdong, China
| | - Zhongyu Zhou
- Pingshan District People's Hospital of Shenzhen, Pingshan General Hospital of Southern Medical University, Shenzhen 518118, Guangdong, China
| | - Ruihong Yang
- Pingshan District People's Hospital of Shenzhen, Pingshan General Hospital of Southern Medical University, Shenzhen 518118, Guangdong, China
| | - Ying Huang
- Pingshan District People's Hospital of Shenzhen, Pingshan General Hospital of Southern Medical University, Shenzhen 518118, Guangdong, China
| | - Zhuangsen Chen
- Pingshan District People's Hospital of Shenzhen, Pingshan General Hospital of Southern Medical University, Shenzhen 518118, Guangdong, China
| | - Yanrong Zhang
- Pingshan District People's Hospital of Shenzhen, Pingshan General Hospital of Southern Medical University, Shenzhen 518118, Guangdong, China
| | - Shanshan Wang
- Pingshan District People's Hospital of Shenzhen, Pingshan General Hospital of Southern Medical University, Shenzhen 518118, Guangdong, China
| | - Kun Feng
- Pingshan District People's Hospital of Shenzhen, Pingshan General Hospital of Southern Medical University, Shenzhen 518118, Guangdong, China.
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Wang HJ, Sin CH, Yang SH, Hsueh HM, Lo WY. miR-200b-3p accelerates diabetic wound healing through anti-inflammatory and pro-angiogenic effects. Biochem Biophys Res Commun 2024; 731:150388. [PMID: 39024974 DOI: 10.1016/j.bbrc.2024.150388] [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: 04/01/2024] [Revised: 06/20/2024] [Accepted: 07/09/2024] [Indexed: 07/20/2024]
Abstract
The poor healing characteristics of diabetic foot ulcers are partially attributed to diabetes-induced pro-inflammatory wounds. Our previous study reported that both miR-146a-5p and miR-200b-3p decrease endothelial inflammation in human aortic endothelial cells and db/db diabetic mice. Although miR-146a-5p has been reported to improve diabetic wound healing, the role of miR-200b-3p is not clear. This study compared the roles of these miRNAs in diabetic wound healing. Two 8-mm full-thickness wounds were created in 12-week-old male db/db mice on the left and right back. After surgery, 100 ng miR-146a-5p, miR-200b-3p, or miR-negative control (NC) was injected in each wound. Full-thickness skin samples were harvested from mice at the 14th day for real-time polymerase chain reaction and immunohistochemistry analyses. At the 14th day, the miR-200b-3p group showed better wound healing and greater granulation tissue thickness than the miR-146a-5p group. The miR-200b-3p group showed a significant decrease of IL-6 and IL-1β gene expression and a significant increase of Col3α1 gene expression compared to those in the miR-NC group. The miR-200b-3p group had the lowest gene expression of TGF-β1, followed by the miR-146a-5p and miR-NC groups. Our findings suggest that the miR-200b-3p group had better healing characteristics than the other two groups. Immunohistochemical staining revealed that CD68 immunoreactivity was significantly decreased in both the miR-146a-5p and miR-200b-3p groups compared with that in the miR-NC group. In addition, CD31 immunoreactivity was significantly higher in the miR-200b-3p group than in the miR-146a-5p group. In conclusion, these results suggest that miR-200b-3p is more effective than miR-146a-5p in promoting diabetic wound healing through its anti-inflammatory and pro-angiogenic effects.
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MESH Headings
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Animals
- Wound Healing/genetics
- Male
- Mice
- Transforming Growth Factor beta1/metabolism
- Transforming Growth Factor beta1/genetics
- Diabetic Foot/genetics
- Diabetic Foot/metabolism
- Diabetic Foot/pathology
- Neovascularization, Physiologic/genetics
- Interleukin-6/metabolism
- Interleukin-6/genetics
- Antigens, Differentiation, Myelomonocytic/metabolism
- Antigens, Differentiation, Myelomonocytic/genetics
- Interleukin-1beta/metabolism
- Interleukin-1beta/genetics
- Diabetes Mellitus, Experimental/complications
- Diabetes Mellitus, Experimental/genetics
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Experimental/pathology
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Skin/metabolism
- Skin/pathology
- Inflammation/genetics
- Inflammation/pathology
- Inflammation/metabolism
- Mice, Inbred C57BL
- CD68 Molecule
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Affiliation(s)
- Huang-Joe Wang
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, No. 2, Yude Rd., North Dist., Taichung City 404327, Taiwan; School of Medicine, China Medical University, No. 91, Xueshi Rd., North Dist., Taichung City 404328, Taiwan
| | - Cian-Huei Sin
- Department of Life Science, National Chung Hsing University, No. 145, Xingda Rd., South Dist., Taichung City 402202, Taiwan
| | - Shang-Hsuan Yang
- Shiny Brands Group, 7F, No. 311, Fuxing N. Rd., Songshan Dist., Taipei, 10544, Taiwan
| | - Hsiang-Ming Hsueh
- Shiny Brands Group, 7F, No. 311, Fuxing N. Rd., Songshan Dist., Taipei, 10544, Taiwan
| | - Wan-Yu Lo
- Cardiovascular & Translational Medicine Laboratory, Department of Food Science and Technology, Hungkuang University, No. 1018, Sec. 6, Taiwan Blvd., Shalu Dist., Taichung City 43302, Taiwan.
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Tsai HC, Chang GRL, Tung MC, Tu MY, Chen IC, Liu YH, Cidem A, Chen CM. MicroRNA Signature in an In Vitro Keratinocyte Model of Diabetic Wound Healing. Int J Mol Sci 2024; 25:10125. [PMID: 39337611 PMCID: PMC11432929 DOI: 10.3390/ijms251810125] [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: 08/11/2024] [Revised: 09/12/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
Treating diabetic wounds effectively remains a significant clinical challenge. Emerging studies suggest that microRNAs (miRNAs) play crucial roles in various physiological and pathological processes and hold promise as therapeutic tools. This study investigates the miRNA expression profile in keratinocytes using a cell model of diabetic wounds. Microarray analysis revealed that 43 miRNAs from wounded keratinocytes incubated under diabetic conditions (high glucose/hypoxia) exhibited a two-fold change in expression compared to those incubated under normal conditions (low glucose/normoxia). Quantitative RT-PCR confirmed significant differences in the expression of eight miRNAs, with miR-3138 and miR-3679-5p being further analyzed for their roles in keratinocyte migration. Transfection with a miR-3138 mimic and a miR-3679-5p inhibitor indicated that upregulation of miR-3138 and downregulation of miR-3679-5p enhance keratinocyte migration in both normal and diabetic wounds. Pathway and gene ontology (GO) analyses identified potential pathways and functional annotations associated with miR-3138 and miR-3679-5p in diabetic wound healing. Potential human gene targets of miR-3138 and miR-3679-5p were predicted using a three-way comparison of the TargetScan, miRDB, and DIANA databases. This study elucidates the miRNA expression signature of human keratinocytes in a diabetes-like environment, providing deeper insights into the pathogenesis of diabetic wounds.
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Affiliation(s)
- Hsin-Chung Tsai
- Department of Life Sciences, Doctorial Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
- Department of Surgery, Taichung Hospital, Ministry of Health and Welfare, Taichung 403, Taiwan
| | - Gary Ro-Lin Chang
- Department of Life Sciences, Doctorial Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
| | - Min-Che Tung
- Department of Surgery, Tungs' Taichung Metro Harbor Hospital, Taichung 435, Taiwan
| | - Min-Yu Tu
- Department of Life Sciences, Doctorial Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
- Department of Orthopedic Surgery, Taichung Armed Forces General Hospital, Taichung 411, Taiwan
| | - I-Chien Chen
- Department of Life Sciences, Doctorial Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
| | - Yu-Hsien Liu
- Department of Life Sciences, Doctorial Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
- Department of Internal Medicine, Jen-Ai Hospital, Dali Branch, Taichung 402, Taiwan
| | - Abdulkadir Cidem
- Department of Life Sciences, Doctorial Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
- Department of Molecular Biology and Genetics, Erzurum Technical University, Erzurum 25250, Turkey
| | - Chuan-Mu Chen
- Department of Life Sciences, Doctorial Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
- The iEGG and Animal Biotechnology Research Center, National Chung Hsing University, Taichung 402, Taiwan
- Rong Hsing Research Center for Translational Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan
- Center for General Educational, National Quemoy University, Kinmen 892, Taiwan
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Wu S, Zhou Z, Li Y, Jiang J. Advancements in diabetic foot ulcer research: Focus on mesenchymal stem cells and their exosomes. Heliyon 2024; 10:e37031. [PMID: 39286219 PMCID: PMC11403009 DOI: 10.1016/j.heliyon.2024.e37031] [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: 06/18/2024] [Revised: 08/11/2024] [Accepted: 08/26/2024] [Indexed: 09/19/2024] Open
Abstract
Diabetes represents a widely acknowledged global public health concern. Diabetic foot ulcer (DFU) stands as one of the most severe complications of diabetes, its occurrence imposing a substantial economic burden on patients, profoundly impacting their quality of life. Despite the deepening comprehension regarding the pathophysiology and cellular as well as molecular responses of DFU, the current therapeutic arsenal falls short of efficacy, failing to offer a comprehensive remedy for deep-seated chronic wounds and microvascular occlusions. Conventional treatments merely afford symptomatic alleviation or retard the disease's advancement, devoid of the capacity to effectuate further restitution of compromised vasculature and nerves. An escalating body of research underscores the prominence of mesenchymal stem cells (MSCs) owing to their paracrine attributes and anti-inflammatory prowess, rendering them a focal point in the realm of chronic wound healing. Presently, MSCs have been validated as a highly promising cellular therapeutic approach for DFU, capable of effectuating cellular repair, epithelialization, granulation tissue formation, and neovascularization by means of targeted differentiation, angiogenesis promotion, immunomodulation, and paracrine activities, thereby fostering wound healing. The secretome of MSCs comprises cytokines, growth factors, chemokines, alongside exosomes harboring mRNA, proteins, and microRNAs, possessing immunomodulatory and regenerative properties. The present study provides a systematic exposition on the etiology of DFU and elucidates the intricate molecular mechanisms and diverse functionalities of MSCs in the context of DFU treatment, thereby furnishing pioneering perspectives aimed at harnessing the therapeutic potential of MSCs for DFU management and advancing wound healing processes.
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Affiliation(s)
- ShuHui Wu
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - ZhongSheng Zhou
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yang Li
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jinlan Jiang
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
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Vikraman PP, Amin K, Mohandas S, Umapathy D, Kesavan R, Ramkumar KM. Dysregulation of miR-146a is associated with exacerbated inflammation, oxidative and endoplasmic reticulum stress in the progression of diabetic foot ulcer. Wound Repair Regen 2024; 32:464-474. [PMID: 38656652 DOI: 10.1111/wrr.13186] [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: 01/25/2024] [Revised: 03/20/2024] [Accepted: 04/09/2024] [Indexed: 04/26/2024]
Abstract
Recent evidence has implicated the role of microRNA-146a (miR-146a) in regulating inflammatory responses. In the present study, we investigated the role of miRNA-146a in the progression of diabetic foot ulcer (DFU) in type 2 diabetes mellitus patients (T2DM) and studied its correlation with stress mediators such as Endoplasmic Reticulum (ER) and oxidative stress. Ninety subjects were enrolled and evenly distributed among three groups: Controls (n = 30), T2DM without complications (n = 30) and T2DM with foot ulcers (n = 30). Subsequently, each group was further subdivided based on the University of Texas classification. Peripheral blood was collected from all the study subjects, while tissue biopsies were taken only from DFU patients. Total RNA from both PBMCs and wound tissues were isolated using miRNA isolation kit and qPCR was performed to check the expression of miR-146a, ER stress and oxidative stress markers. Our findings revealed a significant decrease in miR-146a expression among T2DM patients with Grade 2 and Grade 3 DFUs compared with those with Grade 0 and Grade 1 DFUs. Notably, inflammatory genes regulated by miR-146a, including TRAF6, IRAK-1 and ADAM, were all upregulated in T2DM patients with Grade 2 and Grade 3 DFUs. Moreover, reduced miR-146a levels were correlated with increased markers of ER stress and oxidative stress in Grade 2 and Grade 3 DFU patients. Furthermore, our in vitro experiment using mouse 3T3 fibroblasts demonstrated a downregulation of miR-146a following induction of hyperglycaemia, ER stress and oxidative stress in these cells. These findings suggest a potential link between diminished miR-146a expression and heightened oxidative and ER stress in T2DM patients with more severe grades of DFUs. Our results imply that targeting miR-146a may hold therapeutic promise for managing disease progression in DFU patients, as it could help alleviate oxidative and ER stress associated with diabetic complications.
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Affiliation(s)
- Pooja Prathyushaa Vikraman
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
| | - Karan Amin
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
| | - Sundhar Mohandas
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
| | - Dhamodharan Umapathy
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
| | - Rajesh Kesavan
- Department of Podiatry, Hycare Super Speciality Hospital, Chennai, Tamilnadu, India
| | - Kunka Mohanram Ramkumar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
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10
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Zhang L, Wang IC, Meng S, Xu J. miR-146a Decreases Inflammation and ROS Production in Aged Dermal Fibroblasts. Int J Mol Sci 2024; 25:6821. [PMID: 38999931 PMCID: PMC11241687 DOI: 10.3390/ijms25136821] [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: 05/23/2024] [Revised: 06/17/2024] [Accepted: 06/19/2024] [Indexed: 07/14/2024] Open
Abstract
Aging is associated with a decline in the functionality of various cell types, including dermal fibroblasts, which play a crucial role in maintaining skin homeostasis and wound healing. Chronic inflammation and increased reactive oxygen species (ROS) production are hallmark features of aging, contributing to impaired wound healing. MicroRNA-146a (miR-146a) has been implicated as a critical regulator of inflammation and oxidative stress in different cell types, yet its role in aged dermal fibroblasts and its potential relevance to wound healing remains poorly understood. We hypothesize that miR-146a is differentially expressed in aged dermal fibroblasts and that overexpression of miR-146a will decrease aging-induced inflammatory responses and ROS production. Primary dermal fibroblasts were isolated from the skin of 17-week-old (young) and 88-week-old (aged) mice. Overexpression of miR-146a was achieved through miR-146a mimic transfection. ROS were detected using a reliable fluorogenic marker, 2,7-dichlorofluorescin diacetate. Real-time PCR was used to quantify relative gene expression. Our investigation revealed a significant reduction in miR-146a expression in aged dermal fibroblasts compared to their younger counterparts. Moreover, aged dermal fibroblasts exhibited heightened levels of inflammatory responses and increased ROS production. Importantly, the overexpression of miR-146a through miR-146a mimic transfection led to a substantial reduction in inflammatory responses through modulation of the NF-kB pathway in aged dermal fibroblasts. Additionally, the overexpression of miR-146a led to a substantial decrease in ROS production, achieved through the downregulation of NOX4 expression in aged dermal fibroblasts. These findings underscore the pivotal role of miR-146a in mitigating both inflammatory responses and ROS production in aged dermal fibroblasts, highlighting its potential as a therapeutic target for addressing age-related skin wound healing.
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Affiliation(s)
- Liping Zhang
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA; (L.Z.); (I.C.W.); (S.M.)
| | - Iris C. Wang
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA; (L.Z.); (I.C.W.); (S.M.)
- Division of Applied Mathematics, Brown University, Providence, RI 02912, USA
| | - Songmei Meng
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA; (L.Z.); (I.C.W.); (S.M.)
| | - Junwang Xu
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA; (L.Z.); (I.C.W.); (S.M.)
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Da Silva J, Santos D, Vilaça M, Carvalho A, Carvalho R, Jesus Dantas MD, Pereira MG, Carvalho E. Impact of Psychological Distress on Physiological Indicators of Healing Prognosis in Patients with Chronic Diabetic Foot Ulcers: A Longitudinal Study. Adv Wound Care (New Rochelle) 2024; 13:308-321. [PMID: 37756373 DOI: 10.1089/wound.2023.0043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/29/2023] Open
Affiliation(s)
- Jessica Da Silva
- PDBEB-Ph.D. Program in Experimental Biology and Biomedicine, Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
- CNC-UC-Center for Neuroscience and Cell Biology, CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Diana Santos
- PDBEB-Ph.D. Program in Experimental Biology and Biomedicine, Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
- CNC-UC-Center for Neuroscience and Cell Biology, CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Margarida Vilaça
- CIPsi-Psychology Research Center, School of Psychology, University of Minho, Braga, Portugal
| | - André Carvalho
- Centro Hospitalar e Universitário de Santo António, E.P.E., Unidade de Pé Diabético, Porto, Portugal
| | - Rui Carvalho
- Centro Hospitalar e Universitário de Santo António, E.P.E., Unidade de Pé Diabético, Porto, Portugal
| | - Maria de Jesus Dantas
- Centro Hospitalar do Tâmega e Sousa, E.P.E., Clínica do Pé Diabético, Penafiel, Portugal
| | - M Graça Pereira
- CIPsi-Psychology Research Center, School of Psychology, University of Minho, Braga, Portugal
| | - Eugénia Carvalho
- CNC-UC-Center for Neuroscience and Cell Biology, CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
- Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
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12
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Zheng J, Yang B, Liu S, Xu Z, Ding Z, Mo M. Applications of Exosomal miRNAs from Mesenchymal Stem Cells as Skin Boosters. Biomolecules 2024; 14:459. [PMID: 38672475 PMCID: PMC11048182 DOI: 10.3390/biom14040459] [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: 03/19/2024] [Revised: 04/04/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
The skin is the outer layer of the human body, and it is crucial in defending against injuries and damage. The regenerative capacity of aging and damaged skin caused by exposure to external stimuli is significantly impaired. Currently, the rise in average life expectancy and the modern population's aesthetic standards have sparked a desire for stem-cell-based therapies that can address skin health conditions. In recent years, mesenchymal stem cells (MSCs) as therapeutic agents have provided a promising and effective alternative for managing skin regeneration and rejuvenation, attributing to their healing capacities that can be applied to damaged and aged skin. However, it has been established that the therapeutic effects of MSC may be primarily mediated by paracrine mechanisms, particularly the release of exosomes (Exos). Exosomes are nanoscale extracellular vesicles (EVs) that have lipid bilayer and membrane structures and can be naturally released by different types of cells. They influence the physiological and pathological processes of recipient cells by transferring a variety of bioactive molecules, including lipids, proteins, and nucleic acids such as messenger RNAs (mRNAs) and microRNAs (miRNAs) between cells, thus playing an important role in intercellular communication and activating signaling pathways in target cells. Among them, miRNAs, a type of endogenous regulatory non-coding RNA, are often incorporated into exosomes as important signaling molecules regulating protein biosynthesis. Emerging evidence suggests that exosomal miRNAs from MSC play a key role in skin regeneration and rejuvenation by targeting multiple genes and regulating various biological processes, such as participating in inflammatory responses, cell migration, proliferation, and apoptosis. In this review, we summarize the recent studies and observations on how MSC-derived exosomal miRNAs contribute to the regeneration and rejuvenation of skin tissue, with particular attention to the applications of bioengineering methods for manipulating the miRNA content of exosome cargo to improve their therapeutic potential. This review can provide new clues for the diagnosis and treatment of skin damage and aging, as well as assist investigators in exploring innovative therapeutic strategies for treating a multitude of skin problems with the aim of delaying skin aging, promoting skin regeneration, and maintaining healthy skin.
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Affiliation(s)
- Jinmei Zheng
- Department of Biotechnology, Guangdong Medical University, Dongguan 523808, China; (J.Z.); (B.Y.); (S.L.); (Z.X.); (Z.D.)
| | - Beibei Yang
- Department of Biotechnology, Guangdong Medical University, Dongguan 523808, China; (J.Z.); (B.Y.); (S.L.); (Z.X.); (Z.D.)
| | - Siqi Liu
- Department of Biotechnology, Guangdong Medical University, Dongguan 523808, China; (J.Z.); (B.Y.); (S.L.); (Z.X.); (Z.D.)
| | - Zhenfeng Xu
- Department of Biotechnology, Guangdong Medical University, Dongguan 523808, China; (J.Z.); (B.Y.); (S.L.); (Z.X.); (Z.D.)
| | - Zhimeng Ding
- Department of Biotechnology, Guangdong Medical University, Dongguan 523808, China; (J.Z.); (B.Y.); (S.L.); (Z.X.); (Z.D.)
| | - Miaohua Mo
- Department of Biotechnology, Guangdong Medical University, Dongguan 523808, China; (J.Z.); (B.Y.); (S.L.); (Z.X.); (Z.D.)
- Institute of Aging Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan 523808, China
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Architha TCA, Juanitaa GR, Vijayalalitha R, Jayasuriya R, Athira G, Balamurugan R, Ganesan K, Ramkumar KM. LncRNA NEAT1/miR-146a-5p Axis Restores Normal Angiogenesis in Diabetic Foot Ulcers by Targeting mafG. Cells 2024; 13:456. [PMID: 38474419 PMCID: PMC10931324 DOI: 10.3390/cells13050456] [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: 01/12/2024] [Revised: 02/23/2024] [Accepted: 02/28/2024] [Indexed: 03/14/2024] Open
Abstract
Non-healing lesions in diabetic foot ulcers are a significant effect of poor angiogenesis. Epigenetic regulators, mainly lncRNA and miRNA, are recognized for their important roles in disease progression. We deciphered the regulation of lncRNA NEAT1 through the miR-146a-5p/mafG axis in the progression of DFU. A lowered expression of lncRNA NEAT1 was associated with dysregulated angiogenesis through the reduced expression of mafG, SDF-1α, and VEGF in chronic ulcer subjects compared to acute DFU. This was validated by silencing NEAT1 by SiRNA in the endothelial cells which resulted in the transcriptional repression of target genes. Our in silico analysis identified miR-146a-5p as a potential target of lncRNA NEAT1. Further, silencing NEAT1 led to an increase in the levels of miR-146a-5p in chronic DFU subjects. This research presents the role of the lncRNA NEAT1/miR-146a-5p/mafG axis in enhancing angiogenesis in DFU.
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Affiliation(s)
- TCA Architha
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Chengalpattu Dt., Tamil Nadu, India; (T.A.); (G.R.J.); (R.V.); or (R.J.)
| | - George Raj Juanitaa
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Chengalpattu Dt., Tamil Nadu, India; (T.A.); (G.R.J.); (R.V.); or (R.J.)
| | - Ramanarayanan Vijayalalitha
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Chengalpattu Dt., Tamil Nadu, India; (T.A.); (G.R.J.); (R.V.); or (R.J.)
| | - Ravichandran Jayasuriya
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Chengalpattu Dt., Tamil Nadu, India; (T.A.); (G.R.J.); (R.V.); or (R.J.)
| | - Gopinathan Athira
- SRM Medical Hospital and Research Centre, SRM Institute of Science and Technology, Kattankulathur 603 203, Chengalpattu Dt., Tamil Nadu, India; (G.A.); (R.B.)
| | - Ramachandran Balamurugan
- SRM Medical Hospital and Research Centre, SRM Institute of Science and Technology, Kattankulathur 603 203, Chengalpattu Dt., Tamil Nadu, India; (G.A.); (R.B.)
| | - Kumar Ganesan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong 999077, China
| | - Kunka Mohanram Ramkumar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Chengalpattu Dt., Tamil Nadu, India; (T.A.); (G.R.J.); (R.V.); or (R.J.)
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14
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Gao M, Guo H, Dong X, Wang Z, Yang Z, Shang Q, Wang Q. Regulation of inflammation during wound healing: the function of mesenchymal stem cells and strategies for therapeutic enhancement. Front Pharmacol 2024; 15:1345779. [PMID: 38425646 PMCID: PMC10901993 DOI: 10.3389/fphar.2024.1345779] [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: 11/30/2023] [Accepted: 02/05/2024] [Indexed: 03/02/2024] Open
Abstract
A wound takes a long time to heal and involves several steps. Following tissue injury, inflammation is the primary cause of tissue regeneration and repair processes. As a result, the pathophysiological processes involving skin damage, healing, and remodeling depend critically on the control of inflammation. The fact that it is a feasible target for improving the prognosis of wound healing has lately become clear. Mesenchymal stem cells (MSCs) are an innovative and effective therapeutic option for wound healing due to their immunomodulatory and paracrine properties. By controlling the inflammatory milieu of wounds through immunomodulation, transplanted MSCs have been shown to speed up the healing process. In addition to other immunomodulatory mechanisms, including handling neutrophil activity and modifying macrophage polarization, there may be modifications to the activation of T cells, natural killer (NK) cells, and dendritic cells (DCs). Furthermore, several studies have shown that pretreating MSCs improves their ability to modulate immunity. In this review, we summarize the existing knowledge about how MSCs influence local inflammation in wounds by influencing immunity to facilitate the healing process. We also provide an overview of MSCs optimizing techniques when used to treat wounds.
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Affiliation(s)
| | | | | | | | | | | | - Qiying Wang
- Department of Plastic Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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15
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Bestepe F, Ghanem GF, Fritsche CM, Weston J, Sahay S, Mauro AK, Sahu P, Tas SM, Ruemmele B, Persing S, Good ME, Chatterjee A, Huggins GS, Salehi P, Icli B. MicroRNA-409-3p/BTG2 signaling axis improves impaired angiogenesis and wound healing in obese mice. FASEB J 2024; 38:e23459. [PMID: 38329343 DOI: 10.1096/fj.202302124rr] [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: 10/27/2023] [Revised: 01/09/2024] [Accepted: 01/18/2024] [Indexed: 02/09/2024]
Abstract
Wound healing is facilitated by neoangiogenesis, a complex process that is essential to tissue repair in response to injury. MicroRNAs are small, noncoding RNAs that can regulate the wound healing process including stimulation of impaired angiogenesis that is associated with type-2 diabetes (T2D). Expression of miR-409-3p was significantly increased in the nonhealing skin wounds of patients with T2D compared to the non-wounded normal skin, and in the skin of a murine model with T2D. In response to high glucose, neutralization of miR-409-3p markedly improved EC growth and migration in human umbilical vein endothelial cells (HUVECs), promoted wound closure and angiogenesis as measured by increased CD31 in human skin organoids, while overexpression attenuated EC angiogenic responses. Bulk mRNA-Seq transcriptomic profiling revealed BTG2 as a target of miR-409-3p, where overexpression of miR-409-3p significantly decreased BTG2 mRNA and protein expression. A 3' untranslated region (3'-UTR) luciferase assay of BTG2 revealed decreased luciferase activity with overexpression of miR-409-3p, while inhibition had opposite effects. Mechanistically, in response to high glucose, miR-409-3p deficiency in ECs resulted in increased mTOR phosphorylation, meanwhile BTG-anti-proliferation factor 2 (BTG2) silencing significantly decreased mTOR phosphorylation. Endothelial-specific and tamoxifen-inducible miR-409-3p knockout mice (MiR-409IndECKO ) with hyperglycemia that underwent dorsal skin wounding showed significant improvement of wound closure, increased blood flow, granulation tissue thickness (GTT), and CD31 that correlated with increased BTG2 expression. Taken together, our results show that miR-409-3p is a critical mediator of impaired angiogenesis in diabetic skin wound healing.
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Affiliation(s)
- Furkan Bestepe
- Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
| | - George F Ghanem
- Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
| | - Colette M Fritsche
- Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
| | - James Weston
- Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
| | - Sumedha Sahay
- Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
| | - Amanda K Mauro
- Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
| | - Parul Sahu
- Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
| | - Sude M Tas
- Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
| | - Brooke Ruemmele
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Tufts Medical Center, Boston, Massachusetts, USA
| | - Sarah Persing
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Tufts Medical Center, Boston, Massachusetts, USA
| | - Miranda E Good
- Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
| | - Abhishek Chatterjee
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Tufts Medical Center, Boston, Massachusetts, USA
| | - Gordon S Huggins
- Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
| | - Payam Salehi
- Division of Vascular Surgery, Cardiovascular Center, Tufts Medical Center, Boston, Massachusetts, USA
| | - Basak Icli
- Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
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16
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Anuradha U, Mehra NK, Khatri DK. Understanding molecular mechanisms and miRNA-based targets in diabetes foot ulcers. Mol Biol Rep 2024; 51:82. [PMID: 38183502 DOI: 10.1007/s11033-023-09074-0] [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: 07/10/2023] [Accepted: 11/21/2023] [Indexed: 01/08/2024]
Abstract
In today's culture, obesity and overweight are serious issues that have an impact on how quickly diabetes develops and how it causes complications. For the development of more effective therapies, it is crucial to understand the molecular mechanisms underlying the chronic problems of diabetes. The most prominent effects of diabetes are microvascular abnormalities such as retinopathy, nephropathy, and neuropathy, especially diabetes foot ulcers, as well as macrovascular abnormalities such as heart disease and atherosclerosis. MicroRNAs (miRNAs), which are highly conserved endogenous short non-coding RNA molecules, have been implicated in several physiological functions recently, including the earliest stages of the disease. By binding to particular messenger RNAs (mRNAs), which cause mRNA degradation, translation inhibition, or even gene activation, it primarily regulates posttranscriptional gene expression. These molecules exhibit considerable potential as diagnostic biomarkers for disease and are interesting treatment targets. This review will provide an overview of the latest findings on the key functions that miRNAs role in diabetes and its complications, with an emphasis on the various stages of diabetic wound healing.
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Affiliation(s)
- Urati Anuradha
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Hyderabad, Telangana, 500037, India
| | - Neelesh Kumar Mehra
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Hyderabad, Telangana , 500037, India.
| | - Dharmendra Kumar Khatri
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Hyderabad, Telangana, 500037, India.
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17
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Sun D, Chang Q, Lu F. Immunomodulation in diabetic wounds healing: The intersection of macrophage reprogramming and immunotherapeutic hydrogels. J Tissue Eng 2024; 15:20417314241265202. [PMID: 39071896 PMCID: PMC11283672 DOI: 10.1177/20417314241265202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 06/12/2024] [Indexed: 07/30/2024] Open
Abstract
Diabetic wound healing presents a significant clinical challenge due to the interplay of systemic metabolic disturbances and local inflammation, which hinder the healing process. Macrophages undergo a phenotypic shift from M1 to M2 during wound healing, a transition pivotal for effective tissue repair. However, in diabetic wounds, the microenvironment disrupts this phenotypic polarization, perpetuating inflammation, and impeding healing. Reprograming macrophages to restore their M2 phenotype offers a potential avenue for modulating the wound immune microenvironment and promoting healing. This review elucidates the mechanisms underlying impaired macrophage polarization toward the M2 phenotype in diabetic wounds and discusses novel strategies, including epigenetic and metabolic interventions, to promote macrophage conversion to M2. Hydrogels, with their hydrated 3D cross-linked structure, closely resemble the physiological extracellular matrix and offer advantageous properties such as biocompatibility, tunability, and versatility. These characteristics make hydrogels promising candidates for developing immunomodulatory materials aimed at addressing diabetic wounds. Understanding the role of hydrogels in immunotherapy, particularly in the context of macrophage reprograming, is essential for the development of advanced wound care solutions. This review also highlights recent advancements in immunotherapeutic hydrogels as a step toward precise and effective treatments for diabetic wounds.
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Affiliation(s)
- Dan Sun
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qiang Chang
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Feng Lu
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
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18
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Zhou X, Ye C, Jiang L, Zhu X, Zhou F, Xia M, Chen Y. The bone mesenchymal stem cell-derived exosomal miR-146a-5p promotes diabetic wound healing in mice via macrophage M1/M2 polarization. Mol Cell Endocrinol 2024; 579:112089. [PMID: 37863468 DOI: 10.1016/j.mce.2023.112089] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 10/10/2023] [Accepted: 10/12/2023] [Indexed: 10/22/2023]
Abstract
A diabetic wound is a refractory disease that afflicts patients globally. MicroRNA-146a-5p (miR-146a-5p) is reported to represent a potential therapeutic target for diabetic wounds. However, microRNA easily degrades in the wound microenvironment. This study extracted bone marrow mesenchymal stem cell (BMSC)-derived exosomes (EXO). Electroporation technology was used to load miR-146a-5p into EXO (labeled as EXO-miR-146a). The endothelial cells (human umbilical vein endothelial cells [HUVECs]) and macrophages were cocultured in transwell chambers in the presence of high glucose. Cell proliferation, migration, and angiogenesis were measured with cell counting kit 8, scratch, and tube forming assays, respectively. Flow cytometry was introduced to validate the biomarker of macrophages and BMSCs. The expression level of macrophage polarization-related proteins and tumor necrosis factor receptor-associated factor 6 (TRAF6) was assessed with western blotting analysis. The full-thickness skin wound model was developed to verify the in vitro results. EXO-miR-146a promoted the proliferation, migration, and angiogenesis of HUVECs in the hyperglycemic state by suppressing the TRAF6 expression in vitro. Additionally, EXO-miR-146a treatment facilitated M2 but inhibited M1 macrophage polarization. Furthermore, EXO-miR-146a enhances reepithelialization, angiogenesis, and M2 macrophage polarization, thereby accelerating diabetic wound healing in vivo. The EXO-miR-146a facilitated M2 macrophage polarization, proliferation, migration, and angiogenesis of HUVECs through TRAF6, thereby ameliorating intractable diabetic wound healing. These results established the basis for using EXO to deliver drugs and revealed mediators for diabetic wound treatment.
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Affiliation(s)
- Xijie Zhou
- Department of Hand and Microsurgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Chenhao Ye
- Department of Hand and Microsurgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Liangfu Jiang
- Department of Hand and Microsurgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Xuwei Zhu
- Department of Hand and Microsurgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Feiya Zhou
- Department of Hand and Microsurgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Meizi Xia
- Department of Nephrology, Wenzhou Geriatric Hospital, Wenzhou, 325000, China.
| | - Yiheng Chen
- Department of Hand and Microsurgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
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19
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Teh HX, Phang SJ, Looi ML, Kuppusamy UR, Arumugam B. Molecular pathways of NF-ĸB and NLRP3 inflammasome as potential targets in the treatment of inflammation in diabetic wounds: A review. Life Sci 2023; 334:122228. [PMID: 37922981 DOI: 10.1016/j.lfs.2023.122228] [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: 06/15/2023] [Revised: 10/23/2023] [Accepted: 10/29/2023] [Indexed: 11/07/2023]
Abstract
Diabetic wounds are slow healing wounds characterized by disordered healing processes and frequently take longer than three months to heal. One of the defining characteristics of impaired diabetic wound healing is an abnormal and unresolved inflammatory response, which is primarily brought on by abnormal macrophage innate immune signaling activation. The persistent inflammatory state in a diabetic wound may be attributed to inflammatory pathways such as nuclear factor kappa B (NF-ĸB) and nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, which have long been associated with inflammatory diseases. Despite the available treatments for diabetic foot ulcers (DFUs) that include debridement, growth factor therapy, and topical anti-bacterial agents, successful wound healing is still hampered. Further understanding of the molecular mechanism of these pathways could be useful in designing potential therapeutic targets for diabetic wound healing. This review provides an update and novel insights into the roles of NF-ĸB and NLRP3 pathways in the molecular mechanism of diabetic wound inflammation and their potential as therapeutic targets in diabetic wound healing.
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Affiliation(s)
- Huey Xhin Teh
- Department of Biomedical Science, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Shou Jin Phang
- Department of Biomedical Science, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Mee Lee Looi
- Centre for Future Learning, Taylor's University Lakeside Campus, 47500 Subang Jaya, Selangor, Malaysia
| | - Umah Rani Kuppusamy
- Department of Biomedical Science, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Bavani Arumugam
- Department of Biomedical Science, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia.
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20
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Chen Md G, Wu Md Y, Zou Md L, Zeng Md Y. Effect of MicroRNA-146a Modified Adipose-Derived Stem Cell Exosomes on Rat Back Wound Healing. INT J LOW EXTR WOUND 2023; 22:704-712. [PMID: 34459668 DOI: 10.1177/15347346211038092] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Objective: To investigate the effect of MicroRNA-146a modified adipose-derived stem cell exosomes on the proliferation and migration of fibroblasts and the therapeutic effect on wound healing. Methods: Culture and identification of human adipose-derived stem cells (hASCs), miRNA-146a minic vector was constructed and transfected into hASCs, the exosomes of the empty group and overexpression group were extracted, identified, and quantitatively analyzed after 24 h of successful transfection. The exosomes were added into National Institute of Health Mouse Embryonic Fibroblasts (NIH/3T3) and cultured for 48 h, the proliferation and migration ability of NIH/3T3 fibroblasts was detected. The expression of serpin family H member 1 (SERPINH1) and phosphorylated extracellular regulated protein kinase (p-ERK) was detected by Western blot. The model of back wound was established. The exosomes were injected into 4 different sites with the shape of "cross" around the wound, and the scar diameter of the skin defect was measured at 3, 7, and 11 days, the skin of the defect was taken on the 14th day. platelet endothelial cell adhesion molecule-1 (CD31) was detected by immunofluorescence staining to evaluate angiogenesis, and Western blot was used to detect the expression of SERPINH1 and p-ERK. Results: The miR-146a mimic-exosome promoted the proliferation and migration of fibroblasts, and the expression of SERPINH1 and p-ERK2 was up-regulated. After the rats were treated with exosomes, the wound area decreased rapidly, neovascularization was promoted, and the expression of SERPINH1 and p-ERK2 was up-regulated. Conclusions: MicroRNA-146a modified adipose stem cell exosomes could regulate the expression of SERPINH1 and p-ERK, promote the migration and proliferation of fibroblasts, and neovascularization to promote the wound healing of rat back.
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Affiliation(s)
- Gangquan Chen Md
- The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Yaling Wu Md
- Jiangxi Health Vocational College, Nanchang, China
| | - Lijin Zou Md
- The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Yuanlin Zeng Md
- The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, P.R. China
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21
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Peddibhotla S, Caples K, Mehta A, Chen QY, Hu J, Idlett-Ali S, Zhang L, Zgheib C, Xu J, Liechty KW, Malany S. Triazolothiadiazine derivative positively modulates CXCR4 signaling and improves diabetic wound healing. Biochem Pharmacol 2023; 216:115764. [PMID: 37634595 PMCID: PMC11115308 DOI: 10.1016/j.bcp.2023.115764] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 08/17/2023] [Accepted: 08/21/2023] [Indexed: 08/29/2023]
Abstract
Development of specific therapies that target and accelerate diabetic wound repair is an urgent need to alleviate pain and suffering and the huge socioeconomic burden of this debilitating disease. C-X-C Motif Chemokine Ligand 12 (CXCL12) also know an stromal cell-derived factor 1α (SDF-1α) is a chemokine that binds the CXC chemokine receptor type 4 (CXCR4) and activates downstream signaling resulting in recruitment of hematopoietic cells to locations of tissue injury and promotes tissue repair. In diabetes, low expression of CXCL12 correlates with impaired wound healing. Activation of CXCR4 receptor signaling with agonists or positive allosteric modulators (PAMs) provides a potential for small molecule therapeutic discovery and development. We recently reported high throughput screening and identification of the CXCR4 partial agonist UCUF-728, characterization of in vitro activity and reduced wound closure time in diabetic mice at 100 μM as a proof-of-concept study. We report here, the discovery of a second chemical scaffold demonstrating increased agonist potency and represented by thiadiazine derivative, UCUF-965. UCUF-965 is a potent partial agonist of β-arrestin recruitment in CXCR4 receptor overexpressing cell line. Furthermore, UCUF-965 potentiates the CXCL12 maximal response in cAMP signaling pathway, activates CXCL12 stimulated migration in lymphoblast cells and modulates the levels of specific microRNA involved in the complex wound repair process, specifically in mouse fibroblasts. Our results indicate that UCUF-965 acts as a PAM agonist of the CXCR4 receptor. Furthermore, UCUF-965 enhanced angiogenesis markers and reduced wound healing time by 36% at 10.0 μM in diabetic mice models compared to untreated control.
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Affiliation(s)
| | - Karly Caples
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA
| | - Alka Mehta
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA
| | - Qi-Yin Chen
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA
| | - Junyi Hu
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA
| | - Shaquia Idlett-Ali
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver - Anschutz Medical Campus and Children's Hospital Colorado, Aurora, CO 80045, USA
| | - Liping Zhang
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Carlos Zgheib
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver - Anschutz Medical Campus and Children's Hospital Colorado, Aurora, CO 80045, USA
| | - Junwang Xu
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver - Anschutz Medical Campus and Children's Hospital Colorado, Aurora, CO 80045, USA; Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Kenneth W Liechty
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver - Anschutz Medical Campus and Children's Hospital Colorado, Aurora, CO 80045, USA.
| | - Siobhan Malany
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
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22
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Song X, Chen Y, Chen X, Zhao X, Zou Y, Li L, Zhou X, Li M, Zhang D, Ye G, Jia R, Yin Z. Exosomes from tannic acid-stimulated macrophages accelerate wound healing through miR-221-3p mediated fibroblasts migration by targeting CDKN1b. Int J Biol Macromol 2023; 244:125088. [PMID: 37270133 DOI: 10.1016/j.ijbiomac.2023.125088] [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: 02/27/2023] [Revised: 05/06/2023] [Accepted: 05/22/2023] [Indexed: 06/05/2023]
Abstract
Tannic acid (TA) and its extraction were traditionally used for treatment of traumatic bleeding in China, and in the previous study we have demonstrated that TA could accelerate cutaneous wound healing in rats. We attempted to decipher the mechanism of TA in promoting wound healing. In this study, we found that TA could enhance the growth of macrophages and inhibit the release of inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-8 and IL-10) through inhibition of NF-κB/JNK pathway. TA activated Erk1/2 pathway, leading to increased expressions of growth factors, bFGF and HGF. Scratch study revealed that TA did not directly regulate the migration function of fibroblasts, but could indirectly enhance fibroblasts migration by the supernatant of TA-treated macrophages. Transwell study further proved that TA stimulates macrophages to secrete exosomes enriched in miR-221-3p by activating the p53 signaling pathway, and the exosomes entered into the fibroblast cytoplasm and bound to 3'UTR of target gene CDKN1b which induced decreased expression level of CDKN1b, leading to promoting fibroblast migration. This study provided new insights into how TA accelerates wound healing in the inflammatory and proliferative phases of wound healing.
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Affiliation(s)
- Xu Song
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Yaqin Chen
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Xiangxiu Chen
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Xinghong Zhao
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Yuanfeng Zou
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Lixia Li
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Xun Zhou
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Mingyue Li
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Dongmei Zhang
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Gang Ye
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Renyong Jia
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China.
| | - Zhongqiong Yin
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China.
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23
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Berlanga-Acosta J, Garcia-Ojalvo A, Guillen-Nieto G, Ayala-Avila M. Endogenous Biological Drivers in Diabetic Lower Limb Wounds Recurrence: Hypothetical Reflections. Int J Mol Sci 2023; 24:10170. [PMID: 37373317 DOI: 10.3390/ijms241210170] [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: 04/24/2023] [Revised: 05/22/2023] [Accepted: 05/25/2023] [Indexed: 06/29/2023] Open
Abstract
An impaired healing response underlies diabetic foot wound chronicity, frequently translating to amputation, disability, and mortality. Diabetics suffer from underappreciated episodes of post-epithelization ulcer recurrence. Recurrence epidemiological data are alarmingly high, so the ulcer is considered in "remission" and not healed from the time it remains epithelialized. Recurrence may result from the combined effects of behavioral and endogenous biological factors. Although the damaging role of behavioral, clinical predisposing factors is undebatable, it still remains elusive in the identification of endogenous biological culprits that may prime the residual scar tissue for recurrence. Furthermore, the event of ulcer recurrence still waits for the identification of a molecular predictor. We propose that ulcer recurrence is deeply impinged by chronic hyperglycemia and its downstream biological effectors, which originate epigenetic drivers that enforce abnormal pathologic phenotypes to dermal fibroblasts and keratinocytes as memory cells. Hyperglycemia-derived cytotoxic reactants accumulate and modify dermal proteins, reduce scar tissue mechanical tolerance, and disrupt fibroblast-secretory activity. Accordingly, the combination of epigenetic and local and systemic cytotoxic signalers induce the onset of "at-risk phenotypes" such as premature skin cell aging, dysmetabolism, inflammatory, pro-degradative, and oxidative programs that may ultimately converge to scar cell demise. Post-epithelialization recurrence rate data are missing in clinical studies of reputed ulcer healing therapies during follow-up periods. Intra-ulcer infiltration of epidermal growth factor exhibits the most consistent remission data with the lowest recurrences during 12-month follow-up. Recurrence data should be regarded as a valuable clinical endpoint during the investigational period for each emergent healing candidate.
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Affiliation(s)
- Jorge Berlanga-Acosta
- Tissue Repair, Wound Healing and Cytoprotection Research Group, Biomedical Research Direction, Center for Genetic Engineering and Biotechnology, Playa, Havana 10600, Cuba
| | - Ariana Garcia-Ojalvo
- Tissue Repair, Wound Healing and Cytoprotection Research Group, Biomedical Research Direction, Center for Genetic Engineering and Biotechnology, Playa, Havana 10600, Cuba
| | - Gerardo Guillen-Nieto
- Tissue Repair, Wound Healing and Cytoprotection Research Group, Biomedical Research Direction, Center for Genetic Engineering and Biotechnology, Playa, Havana 10600, Cuba
| | - Marta Ayala-Avila
- Tissue Repair, Wound Healing and Cytoprotection Research Group, Biomedical Research Direction, Center for Genetic Engineering and Biotechnology, Playa, Havana 10600, Cuba
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24
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Wallbank AM, Vaughn AE, Niemiec S, Bilodeaux J, Lehmann T, Knudsen L, Kolanthai E, Seal S, Zgheib C, Nozik E, Liechty KW, Smith BJ. CNP-miR146a improves outcomes in a two-hit acute- and ventilator-induced lung injury model. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2023; 50:102679. [PMID: 37116556 PMCID: PMC10129905 DOI: 10.1016/j.nano.2023.102679] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 03/21/2023] [Accepted: 04/09/2023] [Indexed: 04/30/2023]
Abstract
Acute respiratory distress syndrome (ARDS) has high mortality (~40 %) and requires the lifesaving intervention of mechanical ventilation. A variety of systemic inflammatory insults can progress to ARDS, and the inflamed and injured lung is susceptible to ventilator-induced lung injury (VILI). Strategies to mitigate the inflammatory response while restoring pulmonary function are limited, thus we sought to determine if treatment with CNP-miR146a, a conjugate of novel free radical scavenging cerium oxide nanoparticles (CNP) to the anti-inflammatory microRNA (miR)-146a, would protect murine lungs from acute lung injury (ALI) induced with intratracheal endotoxin and subsequent VILI. Lung injury severity and treatment efficacy were evaluated via lung mechanical function, relative gene expression of inflammatory biomarkers, and lung morphometry (stereology). CNP-miR146a reduced the severity of ALI and slowed the progression of VILI, evidenced by improvements in inflammatory biomarkers, atelectasis, gas volumes in the parenchymal airspaces, and the stiffness of the pulmonary system.
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Affiliation(s)
- Alison M Wallbank
- Department of Bioengineering, University of Colorado Denver | Anschutz Medical Campus, Aurora, CO, USA
| | - Alyssa E Vaughn
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver School of Medicine and Children's Hospital Colorado, Aurora, CO, USA
| | - Steve Niemiec
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver School of Medicine and Children's Hospital Colorado, Aurora, CO, USA
| | - Jill Bilodeaux
- Department of Bioengineering, University of Colorado Denver | Anschutz Medical Campus, Aurora, CO, USA
| | - Tanner Lehmann
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver School of Medicine and Children's Hospital Colorado, Aurora, CO, USA
| | - Lars Knudsen
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Centre for Lung Research (DZL), Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research, Germany
| | - Elayaraja Kolanthai
- Advanced Materials Processing and Analysis Center, Department of Materials Science and Engineering, University of Central Florida, Orlando, FL, USA
| | - Sudipta Seal
- Advanced Materials Processing and Analysis Center, Department of Materials Science and Engineering, University of Central Florida, Orlando, FL, USA
| | - Carlos Zgheib
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver School of Medicine and Children's Hospital Colorado, Aurora, CO, USA; Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Arizona Tucson College of Medicine and Banner Children's at Diamond Children's Medical Center, Tucson, AZ, USA
| | - Eva Nozik
- Developmental Lung Biology, Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatric Critical Care, Departments of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA
| | - Kenneth W Liechty
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver School of Medicine and Children's Hospital Colorado, Aurora, CO, USA; Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Arizona Tucson College of Medicine and Banner Children's at Diamond Children's Medical Center, Tucson, AZ, USA
| | - Bradford J Smith
- Department of Bioengineering, University of Colorado Denver | Anschutz Medical Campus, Aurora, CO, USA; Department of Pediatric Pulmonary and Sleep Medicine, School of Medicine, University of Colorado, Aurora, CO, USA.
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25
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Cai F, Chen W, Zhao R, Liu Y. Mechanisms of Nrf2 and NF-κB pathways in diabetic wound and potential treatment strategies. Mol Biol Rep 2023; 50:5355-5367. [PMID: 37029875 DOI: 10.1007/s11033-023-08392-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 03/15/2023] [Indexed: 04/09/2023]
Abstract
The issue of delayed wound healing or nonhealing in diabetic patients presents a challenge for modern medicine. A number of attempts have been made to understand the mechanisms behind diabetic wound. In a hyperglycemic environment, increased intracellular reactive oxygen species (ROS) disturb the balance between oxidation and antioxidant, causing the wound environment to deteriorate. It has been established that the nuclear factor E2-related factor 2 (Nrf2) and nuclear factor-kappa B (NF-κB) pathways play an important role in regulating inflammation and oxidative stress. Several potential treatment strategies involving Nrf2 and/or NF-κB pathways have been explored in previous studies. Hence, we analyzed mechanisms and changes in Nrf2 and NF-κB pathways in response to oxidative stress and inflammation in diabetic environment. Additionally, we reviewed potential treatment strategies from the past five years for diabetic wound by Nrf2 and/or NF-κB pathways, including receptor agonists, vitamins, hormones, exosomes, drugs, plants, and biomaterials. It may be useful to develop drugs to promote diabetic wound healing.
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Affiliation(s)
- Feiyu Cai
- Department of Burns and Plastic Surgery & Wound Repair Surgery, the Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Wenjiao Chen
- Department of Burns and Plastic Surgery & Wound Repair Surgery, the Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Ruomei Zhao
- Department of Burns and Plastic Surgery & Wound Repair Surgery, the Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Yi Liu
- Department of Burns and Plastic Surgery & Wound Repair Surgery, the Lanzhou University Second Hospital, Lanzhou, Gansu, China.
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26
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Yu X, Liu P, Li Z, Zhang Z. Function and mechanism of mesenchymal stem cells in the healing of diabetic foot wounds. Front Endocrinol (Lausanne) 2023; 14:1099310. [PMID: 37008908 PMCID: PMC10061144 DOI: 10.3389/fendo.2023.1099310] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 03/06/2023] [Indexed: 03/18/2023] Open
Abstract
Diabetes has become a global public health problem. Diabetic foot is one of the most severe complications of diabetes, which often places a heavy economic burden on patients and seriously affects their quality of life. The current conventional treatment for the diabetic foot can only relieve the symptoms or delay the progression of the disease but cannot repair damaged blood vessels and nerves. An increasing number of studies have shown that mesenchymal stem cells (MSCs) can promote angiogenesis and re-epithelialization, participate in immune regulation, reduce inflammation, and finally repair diabetic foot ulcer (DFU), rendering it an effective means of treating diabetic foot disease. Currently, stem cells used in the treatment of diabetic foot are divided into two categories: autologous and allogeneic. They are mainly derived from the bone marrow, umbilical cord, adipose tissue, and placenta. MSCs from different sources have similar characteristics and subtle differences. Mastering their features to better select and use MSCs is the premise of improving the therapeutic effect of DFU. This article reviews the types and characteristics of MSCs and their molecular mechanisms and functions in treating DFU to provide innovative ideas for using MSCs to treat diabetic foot and promote wound healing.
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Affiliation(s)
- Xiaoping Yu
- School of Medicine and Nursing, Chengdu University, Chengdu, Sichuan, China
| | - Pan Liu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Zheng Li
- People’s Hospital of Jiulongpo District, Chongqing, China
| | - Zhengdong Zhang
- School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Orthopedics, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
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27
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Zhang L, Hung GCC, Meng S, Evans R, Xu J. LncRNA MALAT1 Regulates Hyperglycemia Induced EMT in Keratinocyte via miR-205. Noncoding RNA 2023; 9:14. [PMID: 36827547 PMCID: PMC9963368 DOI: 10.3390/ncrna9010014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 01/31/2023] [Accepted: 02/09/2023] [Indexed: 02/15/2023] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) is critical to cutaneous wound healing. When skin is injured, EMT activates and mobilizes keratinocytes toward the wound bed, therefore enabling re-epithelialization. This process becomes dysregulated in patients with diabetes mellitus (DM). Long non-coding RNAs (lncRNAs) regulate many biological processes. LncRNA-metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) influences numerous cellular processes, including EMT. The objective of the current study is to explore the role of MALAT1 in hyperglycemia (HG)-induced EMT. The expression of MALAT1 was found to be significantly upregulated, while the expression of miR-205 was downregulated in diabetic wounds and high-glucose-treated HaCaT cells. The initiation of EMT in HaCaT cells from hyperglycemia was confirmed by a morphological change, the increased expression of CDH2, KRT10, and ACTA2, and the downregulation of CDH1. The knockdown of MALAT1 was achieved by transfecting a small interfering RNA (SiRNA). MALAT1 and miR-205 were found to modulate HG-induced EMT. MALAT1 silencing or miR-205 overexpression appears to attenuate hyperglycemia-induced EMT. Mechanistically, MALAT1 affects HG-induced EMT through binding to miR-205 and therefore inducing ZEB1, a critical transcription factor for EMT. In summary, lncRNA MALAT1 is involved in the hyperglycemia-induced EMT of human HaCaT cells. This provides a new perspective on the pathogenesis of diabetic wounds.
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Affiliation(s)
- Liping Zhang
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - George Chu-Chih Hung
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Songmei Meng
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Robin Evans
- Division of Plastic Surgery, Department of Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Junwang Xu
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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28
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Xu ZH, Ma MH, Li YQ, Li LL, Liu GH. Progress and expectation of stem cell therapy for diabetic wound healing. World J Clin Cases 2023; 11:506-513. [PMID: 36793646 PMCID: PMC9923865 DOI: 10.12998/wjcc.v11.i3.506] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 11/08/2022] [Accepted: 01/09/2023] [Indexed: 01/22/2023] Open
Abstract
Impaired wound healing presents great health risks to diabetics. Encouragingly, the current clinical successfully found out meaningful method to repair wound tissue, and stem cell therapy could be an effective method for diabetic wound healing with its ability to accelerate wound closure and avoid amputation. This minireview aims at introducing stem cell therapy for facilitating tissue repair in diabetic wounds, discussing the possible therapeutic mechanism and clinical application status and problems.
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Affiliation(s)
- Zhen-Han Xu
- Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510610, Guangdong Province, China
| | - Meng-Hui Ma
- Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510610, Guangdong Province, China
| | - Yan-Qing Li
- Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510610, Guangdong Province, China
| | - Li-Lin Li
- Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510610, Guangdong Province, China
| | - Gui-Hua Liu
- Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510610, Guangdong Province, China
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29
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Chen C, Liu T, Tang Y, Luo G, Liang G, He W. Epigenetic regulation of macrophage polarization in wound healing. BURNS & TRAUMA 2023; 11:tkac057. [PMID: 36687556 PMCID: PMC9844119 DOI: 10.1093/burnst/tkac057] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 11/16/2022] [Indexed: 06/01/2023]
Abstract
The immune microenvironment plays a critical role in regulating skin wound healing. Macrophages, the main component of infiltrating inflammatory cells, play a pivotal role in shaping the immune microenvironment in the process of skin wound healing. Macrophages comprise the classic proinflammatory M1 subtype and anti-inflammatory M2 population. In the early inflammatory phase of skin wound closure, M1-like macrophages initiate and amplify the local inflammatory response to disinfect the injured tissue. In the late tissue-repairing phase, M2 macrophages are predominant in wound tissue and limit local inflammation to promote tissue repair. The biological function of macrophages is tightly linked with epigenomic organization. Transcription factors are essential for macrophage polarization. Epigenetic modification of transcription factors determines the heterogeneity of macrophages. In contrast, transcription factors also regulate the expression of epigenetic enzymes. Both transcription factors and epigenetic enzymes form a complex network that regulates the plasticity of macrophages. Here, we describe the latest knowledge concerning the potential epigenetic mechanisms that precisely regulate the biological function of macrophages and their effects on skin wound healing.
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Affiliation(s)
| | | | - Yuanyang Tang
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
- Academy of Biological Engineering, Chongqing University, Chongqing, China
| | - Gaoxing Luo
- Correspondence. Gaoxing Luo, ; Guangping Liang, ; Weifeng He,
| | - Guangping Liang
- Correspondence. Gaoxing Luo, ; Guangping Liang, ; Weifeng He,
| | - Weifeng He
- Correspondence. Gaoxing Luo, ; Guangping Liang, ; Weifeng He,
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Dama G, Du J, Zhu X, Liu Y, Lin J. Bone marrow-derived mesenchymal stem cells: A promising therapeutic option for the treatment of diabetic foot ulcers. Diabetes Res Clin Pract 2023; 195:110201. [PMID: 36493913 DOI: 10.1016/j.diabres.2022.110201] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 08/31/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022]
Abstract
Chronic wounds fail to heal through the three normal stages of healing (inflammatory, proliferative, and remodelling), resulting in a chronic tissue injury that is not repaired within the average time limit. Patients suffering from type 1 and type 2 diabetes are prone to develop diabetic foot ulcers (DFUs), which commonly develop into chronic wounds that are non treatable with conventional therapies. DFU develops due to various risk factors, such as peripheral neuropathy, peripheral vascular disease, arterial insufficiency, foot deformities, trauma and impaired resistance to infection. DFUs have gradually become a major problem in the health care system worldwide. In this review, we not only focus on the pathogenesis of DFU but also comprehensively summarize the outcomes of preclinical and clinical studies thus far and the potential therapeutic mechanism of bone marrow-derived mesenchymal stem cells (BMSCs) for the treatment of DFU. Based on the published results, BMSC transplantation can contribute to wound healing through growth factor secretion, anti-inflammation, differentiation into tissue-specific cells, neovascularization, re-epithelialization and angiogenesis in DFUs. Moreover, clinical trials showed that BMSC treatment in patients with diabetic ulcers improved ulcer healing and the ankle-brachial index, ameliorated pain scores, and enhanced claudication walking distances with no reported complications. In conclusion, although BMSC transplantation exhibits promising therapeutic potential in DFU treatment, additional studies should be performed to confirm their efficacy and long-term safety in DFU patients.
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Affiliation(s)
- Ganesh Dama
- Stem Cell and Biotherapy Engineering Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China; Department of Community Health, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas, Malaysia
| | - Jiang Du
- Stem Cell and Biotherapy Engineering Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China; College of Medical Engineering, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China
| | - Xinxing Zhu
- Stem Cell and Biotherapy Engineering Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China; College of Medical Engineering, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China
| | - Yanli Liu
- Stem Cell and Biotherapy Engineering Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China; College of Life Sciences and Technology, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China.
| | - Juntang Lin
- Stem Cell and Biotherapy Engineering Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China; College of Medical Engineering, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China; College of Life Sciences and Technology, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China.
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Ghaffari M, Razi S, Zalpoor H, Nabi-Afjadi M, Mohebichamkhorami F, Zali H. Association of MicroRNA-146a with Type 1 and 2 Diabetes and their Related Complications. J Diabetes Res 2023; 2023:2587104. [PMID: 36911496 PMCID: PMC10005876 DOI: 10.1155/2023/2587104] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 01/17/2023] [Accepted: 02/04/2023] [Indexed: 03/06/2023] Open
Abstract
Most medical investigations have found a reduced blood level of miR-146a in type 2 diabetes (T2D) patients, suggesting an important role for miR-146a (microRNA-146a) in the etiology of diabetes mellitus (DM) and its consequences. Furthermore, injection of miR-146a mimic has been confirmed to alleviate diabetes mellitus in diabetic animal models. In this line, deregulation of miR-146a expression has been linked to the progression of nephropathy, neuropathy, wound healing, olfactory dysfunction, cardiovascular disorders, and retinopathy in diabetic patients. In this review, besides a comprehensive review of the function of miR-146a in DM, we discussed new findings on type 1 (T1MD) and type 2 (T2DM) diabetes mellitus, highlighting the discrepancies between clinical and preclinical investigations and elucidating the biological pathways regulated through miR-146a in DM-affected tissues.
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Affiliation(s)
- Mahyar Ghaffari
- Department of Biology, Parand Branch, Islamic Azad University, Parand, Iran
| | - Sara Razi
- Vira Pioneers of Modern Science (VIPOMS), Tehran, Iran
| | - Hamidreza Zalpoor
- Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Mohsen Nabi-Afjadi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Hakimeh Zali
- Proteomics Research Center, Shahid Beheshti University of Medical Science, Tehram, Iran
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Lyttle BD, Vaughn AE, Bardill JR, Apte A, Gallagher LT, Zgheib C, Liechty KW. Effects of microRNAs on angiogenesis in diabetic wounds. Front Med (Lausanne) 2023; 10:1140979. [PMID: 37020673 PMCID: PMC10067680 DOI: 10.3389/fmed.2023.1140979] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 02/27/2023] [Indexed: 04/07/2023] Open
Abstract
Diabetes mellitus is a morbid condition affecting a growing number of the world population, and approximately one third of diabetic patients are afflicted with diabetic foot ulcers (DFU), which are chronic non-healing wounds that frequently progress to require amputation. The treatments currently used for DFU focus on reducing pressure on the wound, staving off infection, and maintaining a moist environment, but the impaired wound healing that occurs in diabetes is a constant obstacle that must be faced. Aberrant angiogenesis is a major contributor to poor wound healing in diabetes and surgical intervention is often necessary to establish peripheral blood flow necessary for healing wounds. Over recent years, microRNAs (miRNAs) have been implicated in the dysregulation of angiogenesis in multiple pathologies including diabetes. This review explores the pathways of angiogenesis that become dysregulated in diabetes, focusing on miRNAs that have been identified and the mechanisms by which they affect angiogenesis.
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Affiliation(s)
- Bailey D. Lyttle
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, School of Medicine, University of Colorado Denver—Anschutz Medical Campus, Aurora, CO, United States
- *Correspondence: Bailey D. Lyttle,
| | - Alyssa E. Vaughn
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, School of Medicine, University of Colorado Denver—Anschutz Medical Campus, Aurora, CO, United States
| | - James R. Bardill
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, School of Medicine, University of Colorado Denver—Anschutz Medical Campus, Aurora, CO, United States
| | - Anisha Apte
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, College of Medicine, University of Arizona Health Sciences College of Medicine—Tucson, Tucson, AZ, United States
| | - Lauren T. Gallagher
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, School of Medicine, University of Colorado Denver—Anschutz Medical Campus, Aurora, CO, United States
| | - Carlos Zgheib
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, College of Medicine, University of Arizona Health Sciences College of Medicine—Tucson, Tucson, AZ, United States
| | - Kenneth W. Liechty
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, College of Medicine, University of Arizona Health Sciences College of Medicine—Tucson, Tucson, AZ, United States
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Jasineviciute I, Hasan MN, Grigas J, Pautienius A, Stankevicius A, Zymantiene J, Miura N. microRNAs Are Abundant and Stable in Platelet-Rich Fibrin and Other Autologous Blood Products of Canines. Int J Mol Sci 2023; 24:ijms24010770. [PMID: 36614213 PMCID: PMC9821218 DOI: 10.3390/ijms24010770] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/14/2022] [Accepted: 12/29/2022] [Indexed: 01/03/2023] Open
Abstract
Various microRNAs (miRNAs) present in autologous blood products of canines have not been studied recently. We aimed to elucidate the existence of miRNAs in platelet-rich fibrin (PRF) and the stability of canine autologous blood products under various storage conditions. Total RNAs were isolated from PRF and other autologous blood products following newly adapted protocols used in commercial kits for plasma and tissue samples. Quantitative real-time polymerase chain reaction analysis (qPCR) was used to detect miRNAs in autologous blood products. The miR-16, miR-21, miR-155, and miR-146a were abundant in PRF and other autologous blood products of canines. Furthermore, we found they could maintain stability under protracted freezing temperatures of -30 °C for at least one month. Our findings revealed that PRF might be a stable resource for various canine miRNAs.
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Affiliation(s)
- Indre Jasineviciute
- Department of Anatomy and Physiology, Veterinary Faculty, Lithuanian University of Health Sciences, LT-47181 Kaunas, Lithuania
| | - Md Nazmul Hasan
- Joint Graduate School of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan
| | - Juozas Grigas
- Department of Anatomy and Physiology, Veterinary Faculty, Lithuanian University of Health Sciences, LT-47181 Kaunas, Lithuania
- Institute of Microbiology and Virology, Lithuanian University of Health Sciences, LT-47181 Kaunas, Lithuania
| | - Arnoldas Pautienius
- Department of Anatomy and Physiology, Veterinary Faculty, Lithuanian University of Health Sciences, LT-47181 Kaunas, Lithuania
- Institute of Microbiology and Virology, Lithuanian University of Health Sciences, LT-47181 Kaunas, Lithuania
| | - Arunas Stankevicius
- Department of Anatomy and Physiology, Veterinary Faculty, Lithuanian University of Health Sciences, LT-47181 Kaunas, Lithuania
| | - Judita Zymantiene
- Department of Anatomy and Physiology, Veterinary Faculty, Lithuanian University of Health Sciences, LT-47181 Kaunas, Lithuania
| | - Naoki Miura
- Joint Graduate School of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan
- Joint Faculty of Veterinary Medicine, Veterinary Teaching Hospital, Kagoshima University, Kagoshima 890-8580, Japan
- Correspondence:
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El Ghzaoui C, Neal CJ, Kolanthai E, Fu Y, Kumar U, Hu J, Zgheib C, Liechty KW, Seal S. Assessing the bio-stability of microRNA-146a conjugated nanoparticles via electroanalysis. NANOSCALE ADVANCES 2022; 5:191-207. [PMID: 36605803 PMCID: PMC9766199 DOI: 10.1039/d2na00600f] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 11/13/2022] [Indexed: 06/17/2023]
Abstract
The number of diabetics is increasing worldwide and is associated with significant instances of clinical morbidity. Increased amounts of reactive oxygen species (ROS) and proinflammatory cytokines are associated with the pathogenesis of diabetic wounds and result in a significant delay in healing. Our previous studies have shown the ability of a cerium oxide nanoparticle (CNP) formulation conjugated with the anti-inflammatory microRNA miR146a (CNP-miR146a) to enhance the healing of diabetic wounds. The observed therapeutic activity exceeded the combined efficacies of the individual conjugate components (CNPs and miR146a alone), suggesting a synergistic effect. The current study evaluates whether the previously observed enhanced activity arises from increased agent delivery (simple nanocarrier activity) or is specific to the CNP-miR146a formulation (functional, bio-active nanomaterial). Comparison with miR146a conjugated gold (bioactive, metal) and silica (bioinert, oxide) nanoparticles (AuNPs and SiO2NPs) was performed in the presence of H2O2, as an analogue to the high levels of ROS present in the diabetic wound environment. Electrochemical studies, materials characterization, and chemical assays showed limited interaction of AuNP-miR146a with H2O2 and instability of SiO2NP-miR146a over time. In contrast, and in support of our prior results, CNP-miR146a displayed chemical stability and persistent ROS scavenging ability. Furthermore, it was determined that CNPs protect miR146a from oxidative damage under prolonged exposure to H2O2, whereas AuNPs and SiO2NPs were shown to be ineffective. Overall, these results reinforce the ability of CNPs to stabilize and protect miRNA while exhibiting robust antioxidant properties, suggesting that therapeutic activity observed in related earlier studies is not limited to a facile nanocarrier function.
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Affiliation(s)
- Chaimae El Ghzaoui
- Advanced Materials Processing and Analysis Center, Dept. of Materials Science and Engineering, University of Central Florida Orlando FL USA
| | - Craig J Neal
- Advanced Materials Processing and Analysis Center, Dept. of Materials Science and Engineering, University of Central Florida Orlando FL USA
| | - Elayaraja Kolanthai
- Advanced Materials Processing and Analysis Center, Dept. of Materials Science and Engineering, University of Central Florida Orlando FL USA
| | - Yifei Fu
- Advanced Materials Processing and Analysis Center, Dept. of Materials Science and Engineering, University of Central Florida Orlando FL USA
| | - Udit Kumar
- Advanced Materials Processing and Analysis Center, Dept. of Materials Science and Engineering, University of Central Florida Orlando FL USA
| | - Junyi Hu
- Department of Surgery, School of Medicine, University of Colorado Denver Anschutz Medical Camps Aurora Colorado USA
| | - Carlos Zgheib
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, College of Medicine, University of Arizona Tucson AZ USA
| | - Kenneth W Liechty
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, College of Medicine, University of Arizona Tucson AZ USA
| | - Sudipta Seal
- Advanced Materials Processing and Analysis Center, Dept. of Materials Science and Engineering, University of Central Florida Orlando FL USA
- College of Medicine, Nanoscience Technology Center, University of Central Florida Biionix Cluster Orlando FL USA
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梁 渝, 李 艳, 高 芸, 王 莉, 冉 兴. [Experimental Study of Using Aloe Vera Gel to Treat Diabetic Chronic Cutaneous Ulcers in Bama Miniature Pigs]. SICHUAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF SICHUAN UNIVERSITY. MEDICAL SCIENCE EDITION 2022; 53:953-960. [PMID: 36443034 PMCID: PMC10408970 DOI: 10.12182/20221160503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Indexed: 06/16/2023]
Abstract
Objective To investigate the efficacy, safety, and mechanism of topical application of aloe vera gel (AVG) to treat diabetic chronic cutaneous ulcers in Bama miniature pigs. Methods The Bama miniature pig model of diabetic chronic skin wounds was constructed and the model pigs were randomly assigned to AVG daily administration group (AVG QD), aloe vera gel every-other-day administration group (AVG QOD), and diabetic control group (DC). A non-diabetic chronic skin wounds model pig was set as the non-diabetic control group (NDC). Treatment efficacy was evaluated based on the amount of time needed for complete healing of the wounds, healing rates, granulation growth rates, and skin histopathological changes. Safety was evaluated according to whether adverse reactions were observed. In addition, the dynamic changes of the relative expression levels of miR21, miR29a, miR126, miR146a, miR155, and miR210 in wound granulation tissues were examined. Results 1) Efficacy and safety: The amount of time needed for complete healing of the wounds was shorter in the NDC group than those of the three other groups, DC group, AVG QD group, and AVG QOD group (all P<0.05). The amount of time needed for complete healing of the wounds was shorter in the AVG QD group and AVG QOD group than that of DC group (all P<0.05). The amount of time needed for complete healing of the wounds was shorter in the AVG QOD group than that of AVG QD group (all P<0.05). No adverse reactions were detected in the whole process of AVG topical treatment. The granulation growth rate of NDC group was higher than those of DC group, AVG QD group, and AVG QOD group (all P<0.05). The wound healing rate of NDC group was higher than those of DC group, AVG QD group, and AVG QOD group (all P<0.05); the wound healing rate of AVG QOD group was higher than those of DC group and AVG QD group (all P<0.05). 2) Histopathology: The results of HE staining light microscopy showed that collagen fiber production increased, and that microvascular formation with slight inflammatory cell infiltration was observed in the dermal interstitium at the initial stage of wound healing after AVG treatment. One year of after complete healing, pathological examination results of wound healing skin showed that the epidermal keratinization was complete, that collagen was arranged neatly and orderly, and that many microvessels were found in the interstitium. The results of picric acid celestite scarlet staining showed that, after AVG treatment, type Ⅰ collagen mainly increased in the initial stage of wound healing, type Ⅲ collagen gradually increased when the wound healed completely, and the collagen was arranged neatly during the whole process. 3) The relative expression of microRNAs: The relative expression of miR21, miR126, and miR210 in NDC group, AVG QD group, and AVG QOD group were higher than that in DC group (all P<0.05). The relative expression of miR29a and miR155 in NDC group, AVG QD group, and AVG QOD group was lower than that in DC group (all P<0.05). The relative expression of miR146a in NDC group was higher than that in DC group ( P<0.05). Conclusion AVG topical application can shorten the time needed for complete healing of diabetic chronic wounds in Bama minipigs. The wound healing speed of the alternate-day treatment group was faster than that of the daily treatment group. No adverse reactions were observed over the course of the treatment. The mechanism may be related to the up-regulation of the expressions of miR21, miR126, and miR210 and the down-regulation of miR29a and miR155 in wound granulation tissue.
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Affiliation(s)
- 渝捷 梁
- 四川大学华西医院 内分泌代谢科 糖尿病足诊治中心 创面修复创新中心 （成都 610041）Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, China
| | - 艳 李
- 四川大学华西医院 内分泌代谢科 糖尿病足诊治中心 创面修复创新中心 （成都 610041）Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, China
| | - 芸艺 高
- 四川大学华西医院 内分泌代谢科 糖尿病足诊治中心 创面修复创新中心 （成都 610041）Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, China
| | - 莉 王
- 四川大学华西医院 内分泌代谢科 糖尿病足诊治中心 创面修复创新中心 （成都 610041）Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, China
| | - 兴无 冉
- 四川大学华西医院 内分泌代谢科 糖尿病足诊治中心 创面修复创新中心 （成都 610041）Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, China
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Lin CW, Hung CM, Chen WJ, Chen JC, Huang WY, Lu CS, Kuo ML, Chen SG. New Horizons of Macrophage Immunomodulation in the Healing of Diabetic Foot Ulcers. Pharmaceutics 2022; 14:pharmaceutics14102065. [PMID: 36297499 PMCID: PMC9606988 DOI: 10.3390/pharmaceutics14102065] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/22/2022] [Accepted: 09/23/2022] [Indexed: 11/16/2022] Open
Abstract
Diabetic foot ulcers (DFUs) are one of the most costly and troublesome complications of diabetes mellitus. The wound chronicity of DFUs remains the main challenge in the current and future treatment of this condition. Persistent inflammation results in chronic wounds characterized by dysregulation of immune cells, such as M1 macrophages, and impairs the polarization of M2 macrophages and the subsequent healing process of DFUs. The interactive regulation of M1 and M2 macrophages during DFU healing is critical and seems manageable. This review details how cytokines and signalling pathways are co-ordinately regulated to control the functions of M1 and M2 macrophages in normal wound repair. DFUs are defective in the M1-to-M2 transition, which halts the whole wound-healing machinery. Many pre-clinical and clinical innovative approaches, including the application of topical insulin, CCL chemokines, micro RNAs, stem cells, stem-cell-derived exosomes, skin substitutes, antioxidants, and the most recent Phase III-approved ON101 topical cream, have been shown to modulate the activity of M1 and M2 macrophages in DFUs. ON101, the newest clinically approved product in this setting, is designed specifically to down-regulate M1 macrophages and further modulate the wound microenvironment to favour M2 emergence and expansion. Finally, the recent evolution of macrophage modulation therapies and techniques will improve the effectiveness of the treatment of diverse DFUs.
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Affiliation(s)
| | | | | | | | | | | | - Ming-Liang Kuo
- Microbio Co., Ltd., Taipei 115, Taiwan
- Correspondence: (M.-L.K.); or (S.-G.C.); Tel.: +886-2-27031298 (ext. 550) (M.-L.K.); +886-2-27031098 (ext. 551) (S.-G.C.)
| | - Shyi-Gen Chen
- Oneness Biotech Co., Ltd., Taipei 106, Taiwan
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
- Correspondence: (M.-L.K.); or (S.-G.C.); Tel.: +886-2-27031298 (ext. 550) (M.-L.K.); +886-2-27031098 (ext. 551) (S.-G.C.)
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Malakoti F, Mohammadi E, Akbari Oryani M, Shanebandi D, Yousefi B, Salehi A, Asemi Z. Polyphenols target miRNAs as a therapeutic strategy for diabetic complications. Crit Rev Food Sci Nutr 2022; 64:1865-1881. [PMID: 36069329 DOI: 10.1080/10408398.2022.2119364] [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] [Indexed: 11/03/2022]
Abstract
MiRNAs are a large group of non-coding RNAs which participate in different cellular pathways like inflammation and oxidation through transcriptional, post-transcriptional, and epigenetic regulation. In the post-transcriptional regulation, miRNA interacts with the 3'-UTR of mRNAs and prevents their translation. This prevention or dysregulation can be a cause of pathological conditions like diabetic complications. A huge number of studies have revealed the association between miRNAs and diabetic complications, including diabetic nephropathy, cardiomyopathy, neuropathy, retinopathy, and delayed wound healing. To address this issue, recent studies have focused on the use of polyphenols as selective and safe drugs in the treatment of diabetes complications. In this article, we will review the involvement of miRNAs in diabetic complications' occurrence or development. Finally, we will review the latest findings on targeting miRNAs by polyphenols like curcumin, resveratrol, and quercetin for diabetic complications therapy.
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Affiliation(s)
- Faezeh Malakoti
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Erfan Mohammadi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahsa Akbari Oryani
- Department of Pathology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Darioush Shanebandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahman Yousefi
- Research Center for Integrative Medicine in Aging, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Azadeh Salehi
- Faculty of Pharmacy, Islamic Azad University of Tehran Branch, Tehran, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, I.R. Iran
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Yu H, Wang Y, Wang D, Yi Y, Liu Z, Wu M, Wu Y, Zhang Q. Landscape of the epigenetic regulation in wound healing. Front Physiol 2022; 13:949498. [PMID: 36035490 PMCID: PMC9403478 DOI: 10.3389/fphys.2022.949498] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 07/19/2022] [Indexed: 12/13/2022] Open
Abstract
Wound healing after skin injury is a dynamic and highly coordinated process involving a well-orchestrated series of phases, including hemostasis, inflammation, proliferation, and tissue remodeling. Epigenetic regulation refers to genome-wide molecular events, including DNA methylation, histone modification, and non-coding RNA regulation, represented by microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA). Epigenetic regulation is pervasively occurred in the genome and emerges as a new role in gene expression at the post-transcriptional level. Currently, it is well-recognized that epigenetic factors are determinants in regulating gene expression patterns, and may provide evolutionary mechanisms that influence the wound microenvironments and the entire healing course. Therefore, this review aims to comprehensively summarize the emerging roles and mechanisms of epigenetic remodeling in wound healing. Moreover, we also pose the challenges and future perspectives related to epigenetic modifications in wound healing, which would bring novel insights to accelerated wound healing.
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Affiliation(s)
| | | | | | | | | | - Min Wu
- *Correspondence: Min Wu, ; Yiping Wu, ; Qi Zhang,
| | - Yiping Wu
- *Correspondence: Min Wu, ; Yiping Wu, ; Qi Zhang,
| | - Qi Zhang
- *Correspondence: Min Wu, ; Yiping Wu, ; Qi Zhang,
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Awasthi A, Vishwas S, Gulati M, Corrie L, Kaur J, Khursheed R, Alam A, Alkhayl FF, Khan FR, Nagarethinam S, Kumar R, Arya K, Kumar B, Chellappan DK, Gupta G, Dua K, Singh SK. Expanding arsenal against diabetic wounds using nanomedicines and nanomaterials: Success so far and bottlenecks. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2022.103534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
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León-Sosa A, Castañeda V, Espinosa-Vallejo R, Gómez X, Díaz RF, Cabrera F, Caicedo A. Key points for translating wound regenerative agents from in vivo assays in mice to clinical validation. Cytotherapy 2022; 24:1074-1086. [DOI: 10.1016/j.jcyt.2022.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 06/07/2022] [Accepted: 07/16/2022] [Indexed: 11/29/2022]
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Gondaliya P, Sayyed AA, Bhat P, Mali M, Arya N, Khairnar A, Kalia K. Mesenchymal Stem Cell-Derived Exosomes Loaded with miR-155 Inhibitor Ameliorate Diabetic Wound Healing. Mol Pharm 2022; 19:1294-1308. [PMID: 35294195 DOI: 10.1021/acs.molpharmaceut.1c00669] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Diabetic wounds are one of the debilitating complications that affect up to 20% of diabetic patients. Despite the advent of extensive therapies, the recovery rate is unsatisfactory, and approximately, 25% of patients undergo amputation, thereby demanding alternative therapeutic strategies. On the basis of the individual therapeutic roles of the miR-155 inhibitor and mesenchymal stem cells (MSC)-derived exosomes, we conjectured that the combination of the miR-155 inhibitor and MSC-derived exosomes would have synergy in diabetic wound healing. Herein, miR-155-inhibitor-loaded MSC-derived exosomes showed synergistic effects in keratinocyte migration, restoration of FGF-7 levels, and anti-inflammatory action, leading to accelerated wound healing mediated by negative regulation of miR-155, using an in vitro co-culture model and in vivo mouse model of the diabetic wound. Furthermore, treatment with miR-155-inhibitor-loaded MSC-derived exosomes led to enhanced collagen deposition, angiogenesis, and re-epithelialization in diabetic wounds. This study revealed the therapeutic potential of miR-155-inhibitor-loaded MSC-derived exosomes in diabetic wound healing and opened the doors for encapsulating miRNAs along with antibiotics within the MSC-derived exosomes toward improved management of chronic, nonhealing diabetic wounds.
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Affiliation(s)
- Piyush Gondaliya
- Department of Biotechnology, National of Pharmaceutical Education and Research, Ahmedabad, Gujarat 382355, India
| | - Adil Ali Sayyed
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat 382355, India
| | - Palak Bhat
- Department of Biotechnology, National of Pharmaceutical Education and Research, Ahmedabad, Gujarat 382355, India
| | - Mukund Mali
- Department of Biotechnology, National of Pharmaceutical Education and Research, Ahmedabad, Gujarat 382355, India
| | - Neha Arya
- Department of Medical Devices, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat 382355, India
| | - Amit Khairnar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat 382355, India
| | - Kiran Kalia
- Department of Biotechnology, National of Pharmaceutical Education and Research, Ahmedabad, Gujarat 382355, India
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Silk Fibroin-Based Therapeutics for Impaired Wound Healing. Pharmaceutics 2022; 14:pharmaceutics14030651. [PMID: 35336024 PMCID: PMC8949428 DOI: 10.3390/pharmaceutics14030651] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/04/2022] [Accepted: 03/11/2022] [Indexed: 02/06/2023] Open
Abstract
Impaired wound healing can lead to local hypoxia or tissue necrosis and ultimately result in amputation or even death. Various factors can influence the wound healing environment, including bacterial or fungal infections, different disease states, desiccation, edema, and even systemic viral infections such as COVID-19. Silk fibroin, the fibrous structural-protein component in silk, has emerged as a promising treatment for these impaired processes by promoting functional tissue regeneration. Silk fibroin’s dynamic properties allow for customizable nanoarchitectures, which can be tailored for effectively treating several wound healing impairments. Different forms of silk fibroin include nanoparticles, biosensors, tissue scaffolds, wound dressings, and novel drug-delivery systems. Silk fibroin can be combined with other biomaterials, such as chitosan or microRNA-bound cerium oxide nanoparticles (CNP), to have a synergistic effect on improving impaired wound healing. This review focuses on the different applications of silk-fibroin-based nanotechnology in improving the wound healing process; here we discuss silk fibroin as a tissue scaffold, topical solution, biosensor, and nanoparticle.
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Zhu H, Luo H, Lin M, Li Y, Chen A, He H, Sheng F, Wu J. Methacrylated gelatin shape-memorable cryogel subcutaneously delivers EPCs and aFGF for improved pressure ulcer repair in diabetic rat model. Int J Biol Macromol 2022; 199:69-76. [PMID: 34973992 DOI: 10.1016/j.ijbiomac.2021.12.138] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 12/18/2021] [Accepted: 12/20/2021] [Indexed: 12/22/2022]
Abstract
Pressure ulcer (PU) in patients with diabetes mellitus (DM) is still a clinical intractable issue due to the complicated physiological characteristics by the prolonged high glucose level and impaired angiogenesis. The PU treatment includes surgical debridement, stem cell therapy and growth factors, leading to high cost and repeated professional involvement. Developing effective wound dressing combining the therapeutic cells and growth factors has become highly demanded. Herein, we reported the direct subcutaneous administration of endothelial progenitor cells (EPCs) and acid fibroblast growth factor (aFGF) with a shape-memorable methacrylated gelatin cryogel (EPCs/aFGF@GelMA) for the therapy of PU in rats with DM. This EPCs/aFGF@GelMA cryogel system presented microporous structure, elastic mechanical strength and enhanced cell migration property with controlled release of aFGF. Moreover, compared with EPCs/aFGF and GelMA alone, in vivo results showed that this EPCs/aFGF@GelMA system exhibited accelerated wound closure rate, enhanced granulation formation, collagen deposition as well as re-epithelization. Importantly, we found that the excellent positive performance of EPCs/aFGF@GelMA is due to its up-regulation of HIF-ɑ upon the wound site, modulating the microenvironment of wound site to initiate the impaired local angiogenesis. Collectively, this hybrid gelatin cryogels show great promise for biomedical applications, especially in tissue engineering and regenerative medicine.
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Affiliation(s)
- Hong Zhu
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, PR China
| | - Hangqi Luo
- School of Pharmaceutical Sciences, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, PR China
| | - Minjie Lin
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, PR China
| | - Yuan Li
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, PR China
| | - Anqi Chen
- School of Pharmaceutical Sciences, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, PR China
| | - Huacheng He
- College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, Zhejiang, PR China.
| | - Feixia Sheng
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, PR China
| | - Jiang Wu
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, PR China; School of Pharmaceutical Sciences, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, PR China.
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Li D, Niu G, Landén NX. Beyond the Code: Noncoding RNAs in Skin Wound Healing. Cold Spring Harb Perspect Biol 2022; 14:a041230. [PMID: 35197246 PMCID: PMC9438779 DOI: 10.1101/cshperspect.a041230] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
An increasing number of noncoding RNAs (ncRNAs) have been found to regulate gene expression and protein functions, playing important roles in diverse biological processes and diseases. Their crucial functions have been reported in almost every cell type and all stages of skin wound healing. Evidence of their pathogenetic roles in common wound complications, such as chronic nonhealing wounds and excessive scarring, is also accumulating. Given their unique expression and functional properties, ncRNAs are promising therapeutic and diagnostic entities. In this review, we discuss current knowledge about the functional roles of noncoding elements, such as microRNAs, long ncRNAs, and circular RNAs, in skin wound healing, focusing on in vivo evidence from studies of human wound samples and animal wound models. Finally, we provide a perspective on the outlook of ncRNA-based therapeutics in wound care.
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Affiliation(s)
- Dongqing Li
- Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Guanglin Niu
- Dermatology and Venereology Division, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden
| | - Ning Xu Landén
- Dermatology and Venereology Division, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden
- Ming Wai Lau Centre for Reparative Medicine, Stockholm Node, Karolinska Institute, 17177 Stockholm, Sweden
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Xu J, Hu J, Idlett-Ali S, Zhang L, Caples K, Peddibhotla S, Reeves M, Zgheib C, Malany S, Liechty KW. Discovery of Small Molecule Activators of Chemokine Receptor CXCR4 That Improve Diabetic Wound Healing. Int J Mol Sci 2022; 23:2196. [PMID: 35216311 PMCID: PMC8879702 DOI: 10.3390/ijms23042196] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/07/2022] [Accepted: 02/09/2022] [Indexed: 12/16/2022] Open
Abstract
Diabetes produces a chronic inflammatory state that contributes to the development of vascular disease and impaired wound healing. Despite the known individual and societal impacts of diabetic ulcers, there are limited therapies effective at improving healing. Stromal cell-derived factor 1α (SDF-1α) is a CXC chemokine that functions via activation of the CXC chemokine receptor type 4 (CXCR4) receptor to recruit hematopoietic cells to locations of tissue injury and promote tissue repair. The expression of SDF-1α is reduced in diabetic wounds, suggesting a potential contribution to wound healing impairment and presenting the CXCR4 receptor as a target for therapeutic investigations. We developed a high-throughput β-arrestin recruitment assay and conducted structure-activity relationship (SAR) studies to screen compounds for utility as CXCR4 agonists. We identified CXCR4 agonist UCUF-728 from our studies and further validated its activity in vitro in diabetic fibroblasts. UCUF-728 reduced overexpression of miRNA-15b and miRNA-29a, negative regulators of angiogenesis and type I collagen production, respectively, in diabetic fibroblasts. In vivo, UCUF-728 reduced the wound closure time by 36% and increased the evidence of angiogenesis in diabetic mice. Together, this work demonstrates the clinical potential of small molecule CXCR4 agonists as novel therapies for pathologic wound healing in diabetes.
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Affiliation(s)
- Junwang Xu
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA;
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, Anschutz Medical Campus, University of Colorado Denver Aurora, Denver, CO 80045, USA; (J.H.); (S.I.-A.); (L.Z.); (C.Z.)
| | - Junyi Hu
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, Anschutz Medical Campus, University of Colorado Denver Aurora, Denver, CO 80045, USA; (J.H.); (S.I.-A.); (L.Z.); (C.Z.)
| | - Shaquia Idlett-Ali
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, Anschutz Medical Campus, University of Colorado Denver Aurora, Denver, CO 80045, USA; (J.H.); (S.I.-A.); (L.Z.); (C.Z.)
| | - Liping Zhang
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, Anschutz Medical Campus, University of Colorado Denver Aurora, Denver, CO 80045, USA; (J.H.); (S.I.-A.); (L.Z.); (C.Z.)
| | - Karly Caples
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA; (K.C.); (S.P.); (M.R.)
| | - Satyamaheshwar Peddibhotla
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA; (K.C.); (S.P.); (M.R.)
| | - Morgan Reeves
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA; (K.C.); (S.P.); (M.R.)
| | - Carlos Zgheib
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, Anschutz Medical Campus, University of Colorado Denver Aurora, Denver, CO 80045, USA; (J.H.); (S.I.-A.); (L.Z.); (C.Z.)
| | - Siobhan Malany
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA; (K.C.); (S.P.); (M.R.)
| | - Kenneth W. Liechty
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, Anschutz Medical Campus, University of Colorado Denver Aurora, Denver, CO 80045, USA; (J.H.); (S.I.-A.); (L.Z.); (C.Z.)
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Stager MA, Bardill J, Raichart A, Osmond M, Niemiec S, Zgheib C, Seal S, Liechty KW, Krebs MD. Photopolymerized Zwitterionic Hydrogels with a Sustained Delivery of Cerium Oxide Nanoparticle-miR146a Conjugate Accelerate Diabetic Wound Healing. ACS APPLIED BIO MATERIALS 2022; 5:1092-1103. [PMID: 35167263 DOI: 10.1021/acsabm.1c01155] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
In the United States, $87 billion per year is spent on the care of diabetic ulcers alone. Although the pathophysiology of diabetic wound healing is multifaceted, high systemic levels of inflammation and increased reactive oxygen species are often implicated in the wound healing impairment. Zwitterionic materials have been demonstrated to reduce inflammation and increase extracellular matrix deposition in wound beds, and here, we demonstrate a fabrication method for photopolymerized zwitterionic hydrogels that also enables sustained drug delivery over time. A therapeutic molecule of interest that is examined in this work is cerium oxide nanoparticle tagged with microRNA-146a (CNP-miR146a) to combat both oxidative stress and inflammation. The hydrogels are composed of zwitterionic and nonzwitterionic monomers, and the hydrogel formation occurs in the absence of a crosslinker. The hydrogels exhibit a wide range of stiffness and mechanical properties depending on their monomer content. Additionally, these hydrogels exhibit sustained release of nanoparticles and proteins. Finally, when employed in an in vivo diabetic mouse wound healing model, the zwitterionic hydrogels alone and laden with the CNP-miR146a conjugate significantly improved the rate of diabetic wound healing. Overall, these materials have excellent potential to be used as a topical treatment for chronic diabetic wounds.
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Affiliation(s)
- Michael A Stager
- Department of Chemical and Biological Engineering, Colorado School of Mines, Golden, Colorado 80401, United States
| | - James Bardill
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver School of Medicine and Children's Hospital Colorado, Aurora, Colorado 80217, United States
| | - Alexandra Raichart
- Department of Chemical and Biological Engineering, Colorado School of Mines, Golden, Colorado 80401, United States
| | - Matthew Osmond
- Department of Chemical and Biological Engineering, Colorado School of Mines, Golden, Colorado 80401, United States
| | - Stephen Niemiec
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver School of Medicine and Children's Hospital Colorado, Aurora, Colorado 80217, United States
| | - Carlos Zgheib
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver School of Medicine and Children's Hospital Colorado, Aurora, Colorado 80217, United States
| | - Sudipta Seal
- Department of Materials Science and Engineering, AMPAC, Nanoscience Technology Center, Biionix Cluster, College of Medicine, University of Central Florida, Orlando, Florida 32816, United States
| | - Kenneth W Liechty
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver School of Medicine and Children's Hospital Colorado, Aurora, Colorado 80217, United States
| | - Melissa D Krebs
- Department of Chemical and Biological Engineering, Colorado School of Mines, Golden, Colorado 80401, United States
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Gouhar SA, Abo-Elfadl MT, Gamal-Eldeen AM, El-Daly SM. Involvement of miRNAs in response to oxidative stress induced by the steroidal glycoalkaloid α-solanine in hepatocellular carcinoma cells. ENVIRONMENTAL TOXICOLOGY 2022; 37:212-223. [PMID: 34655286 DOI: 10.1002/tox.23390] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 09/28/2021] [Accepted: 10/05/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND α-Solanine is a natural toxic glycoalkaloid produced in some species of the Solanaceae family with antiproliferative activity in various cancers. OBJECTIVE This study aimed to investigate the effect of α-solanine on the oxidative stress status in human hepatocellular carcinoma HepG2 cells and to evaluate its influence on microRNAs (miRNAs) associated with oxidative stress and NF-κB regulation. METHODS The prooxidant effect of α-solanine was tested by the decay rate of the fluorescent probe, β-phycoerythrin, and by measuring malondialdehyde, reduced Glutathione, catalase, and superoxide dismutase following treatment of HepG2 cells with low doses of α-solanine. Immunocytochemical techniques were used to detect mitochondrial membrane potential (ΔΨm) and NF-κB protein. The gene expression of NF-κB and miRNAs was evaluated by real-time PCR. RESULTS α-Solanine is a prooxidant that causes a rapid decay in the fluorescence intensity of β-phycoerythrin. It induces oxidative stress-related alterations such as increased lipid peroxidation and reduced antioxidant markers. Oxidative stress induced by α-solanine was mediated by decreased ΔΨm, increased NF-κB expression, upregulation of miRNAs that control oxidative stress by regulating the NF-κB pathway, and downregulation of oncogenic miRNAs that inhibit the NF-κB pathway. CONCLUSION α-Solanine-induced oxidative stress is mediated by alterations in the NF-κB pathway with a detected crosstalk between α-solanine treatment and the expression of oxidative stress-responsive miRNAs.
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Affiliation(s)
- Shaimaa A Gouhar
- Medical Biochemistry Department, Medical Research Division, National Research Centre, Cairo, Egypt
| | - Mahmoud T Abo-Elfadl
- Biochemistry Department, Genetic Engineering and Biotechnology Research Division, National Research Centre, Cairo, Egypt
- Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Cairo, Egypt
| | - Amira M Gamal-Eldeen
- Biochemistry Department, Genetic Engineering and Biotechnology Research Division, National Research Centre, Cairo, Egypt
- Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Cairo, Egypt
| | - Sherien M El-Daly
- Medical Biochemistry Department, Medical Research Division, National Research Centre, Cairo, Egypt
- Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Cairo, Egypt
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Dewberry LC, Niemiec SM, Hilton SA, Louiselle AE, Singh S, Sakthivel TS, Hu J, Seal S, Liechty KW, Zgheib C. Cerium oxide nanoparticle conjugation to microRNA-146a mechanism of correction for impaired diabetic wound healing. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2022; 40:102483. [PMID: 34748956 PMCID: PMC9153729 DOI: 10.1016/j.nano.2021.102483] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 09/05/2021] [Accepted: 10/11/2021] [Indexed: 02/03/2023]
Abstract
Diabetic wounds represent a significant healthcare burden and are characterized by impaired wound healing due to increased oxidative stress and persistent inflammation. We have shown that CNP-miR146a synthesized by the conjugation of cerium oxide nanoparticles (CNP) to microRNA (miR)-146a improves diabetic wound healing. CNP are divalent metal oxides that act as free radical scavenger, while miR146a inhibits the pro-inflammatory NFκB pathway, so CNP-miR146a has a synergistic role in modulating both oxidative stress and inflammation. In this study, we define the mechanism(s) by which CNP-miR146a improves diabetic wound healing by examining immunohistochemical and gene expression analysis of markers of inflammation, oxidative stress, fibrosis, and angiogenesis. We have found that intradermal injection of CNP-miR146a increases wound collagen, enhances angiogenesis, and lowers inflammation and oxidative stress, ultimately promoting faster closure of diabetic wounds.
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Affiliation(s)
- Lindel C Dewberry
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver School of Medicine and Children's Hospital Colorado, Aurora, CO
| | - Stephen M Niemiec
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver School of Medicine and Children's Hospital Colorado, Aurora, CO
| | - Sarah A Hilton
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver School of Medicine and Children's Hospital Colorado, Aurora, CO
| | - Amanda E Louiselle
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver School of Medicine and Children's Hospital Colorado, Aurora, CO
| | - Sushant Singh
- Department of Materials Science and Engineering, Advance Materials Processing Analysis Center, Nanoscience Technology Center, University of Central Florida, Orlando, FL; Amity Institute of Biotechnology, Amity University Chhattisgarh, Raipur, Chhattisgarh, India
| | - Tamil S Sakthivel
- Department of Materials Science and Engineering, Advance Materials Processing Analysis Center, Nanoscience Technology Center, University of Central Florida, Orlando, FL
| | - Junyi Hu
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver School of Medicine and Children's Hospital Colorado, Aurora, CO
| | - Sudipta Seal
- Department of Materials Science and Engineering, Advance Materials Processing Analysis Center, Nanoscience Technology Center, University of Central Florida, Orlando, FL
| | - Kenneth W Liechty
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver School of Medicine and Children's Hospital Colorado, Aurora, CO
| | - Carlos Zgheib
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver School of Medicine and Children's Hospital Colorado, Aurora, CO.
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Ranjbar R, Ghasemian M, Maniati M, Hossein Khatami S, Jamali N, Taheri-Anganeh M. Gastrointestinal disorder biomarkers. Clin Chim Acta 2022; 530:13-26. [DOI: 10.1016/j.cca.2022.02.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 02/11/2022] [Accepted: 02/15/2022] [Indexed: 01/19/2023]
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50
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Zhang HC, Wen T, Cai YZ. Overexpression of miR-146a promotes cell proliferation and migration in a model of diabetic foot ulcers by regulating the AKAP12 axis. Endocr J 2022; 69:85-94. [PMID: 34483150 DOI: 10.1507/endocrj.ej21-0177] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
In the current study, we aimed to study the effect of miR-146a on proliferation and migration in an in vitro diabetic foot ulcer (DFU) model by targeting A-kinase-anchoring protein 12 (AKAP12). An in vitro DFU model was initially established using HaCaT cells derived from human keratinocytes and induced by advanced glycation end products (AGEs). The effects of overexpression of miR-146a on proliferation and migration ability were analysed. The expression levels of miR-146a and AKAP12 were measured by quantitative real-time polymerase chain reaction (qRT-PCR), and AKAP12, hypoxia-inducible factor-1α (HIF-1α), Wnt3a and β-catenin protein levels were measured by western blotting. The cell proliferation ability was measured by MTT, and the migration ability was analysed by a cell scratch assay. The binding between miR-146a and AKAP12 was identified using a luciferase reporter assay. The results demonstrated that AGEs significantly suppressed cell proliferation and migration, while the expression of miR-146a decreased and the expression of AKAP12 increased. A luciferase reporter assay revealed that miR-146a could directly target AKAP12. Overexpression of miR-146a promoted cell proliferation and migration in an in vitro DFU model and also promoted the expression of HIF-1α, Wnt3a and β-catenin but suppressed the expression of AKAP12. Co-overexpression of miR-146a and AKAP12 reversed the effect of miR-146a on cell proliferation and migration. Our findings revealed that miR-146a directly targeted AKAP12 and promoted cell proliferation and migration in an in vitro DFU model. This study provides a new perspective for the study of miR-146a in the treatment of DFU.
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Affiliation(s)
- Han-Chong Zhang
- Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, P.R. China
- Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, P.R. China
| | - Tie Wen
- Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, P.R. China
- Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, P.R. China
| | - Yu-Zhong Cai
- Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, P.R. China
- Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, P.R. China
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