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Zhang C, Zhou Y, Hu M, Pan Y, Chen X, Sun Q, Ma Z, Wang C, Zha Y, Zhu F, Xia H. PLOD1 promotes the malignancy of hepatocellular carcinoma by facilitating the NF-κB/IL-6/STAT3-dependent TCA cycle. JHEP Rep 2025; 7:101329. [PMID: 40290518 PMCID: PMC12023786 DOI: 10.1016/j.jhepr.2025.101329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 01/09/2025] [Accepted: 01/14/2025] [Indexed: 04/30/2025] Open
Abstract
Background & Aims Procollagen lysyl hydroxylase 1 (PLOD1) is crucial in regulating collagen synthesis and cross-linking. However, its roles and underlying mechanisms in the progression of hepatocellular carcinoma (HCC) remain unclear. Herein, we aimed to investigate the underlying biological functions and mechanisms of PLOD1 in HCC. Methods The expression levels of PLOD1 in HCC were measured by qPCR, Western blot, and immunohistochemistry. Cell proliferation, apoptosis, and stemness were examined by CCK8, flow cytometry, sphere formation, and aldehyde dehydrogenase activity assays. The subcutaneous tumorigenicity model, orthotopic tumorigenicity model, and hepatotoxin-induced HCC model were used for in vivo experiments. RNA-sequence and untargeted metabolomics analysis were performed to identify underlying mechanisms. Results PLOD1 is found to be highly expressed in both human (p <0.0001) and mouse HCC (p <0.01) and is associated with a poor prognosis (p = 0.047). In vitro and in vivo experiments reveal that overexpression of PLOD1 promotes the proliferation and stemness of HCC cells. Meanwhile, the depletion of PLOD1 attenuates the occurrence and growth of HCC, leading to cell cycle arrest (p <0.01) and apoptosis (p <0.001) in HCC. Mechanistically, PLOD1 positively regulates the NF-κB/IL-6/STAT3 signaling pathway and accelerates TCA cycle metabolic reprogramming. Blocking the NF-κB/IL-6/STAT3 signaling pathway and TCA cycle can effectively mitigate PLOD1-induced proliferation and stemness of HCC cells. Conclusions Our study uncovers the PLOD1/NF-κB/IL-6/STAT3 axis as a therapeutic target for inhibiting the progression and stemness of HCC. Impact and implications The roles and underlying mechanisms of PLOD1 in the progression of HCC remain unclear. In this study, we report that PLOD1 is highly expressed in patients with HCC and promotes the proliferation and stemness of HCC cells by activating the NF-κB/IL-6/STAT3-dependent TCA cycle. Knocking down hepatic PLOD1 using adeno-associated virus results in reduced progression of HCC in mice, suggesting that PLOD1 may serve as a potential therapeutic target for HCC.
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Affiliation(s)
- Chengfei Zhang
- Department of General Surgery, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
- Zhongda Hospital, School of Medicine, Advanced Institute for Life and Health, Southeast University, Nanjing, China
- Department of Pathology, Nanjing Drum Tower Hospital & National Health Commission Key Laboratory of Antibody Techniques & School of Basic Medical Sciences of Nanjing Medical University, Nanjing, China
| | - Yangchun Zhou
- Department of General Surgery, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Minghua Hu
- Department of Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, China
| | - Yue Pan
- Department of General Surgery, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Xin Chen
- Department of General Surgery, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Qi Sun
- Department of Pathology, Nanjing Drum Tower Hospital & National Health Commission Key Laboratory of Antibody Techniques & School of Basic Medical Sciences of Nanjing Medical University, Nanjing, China
| | - Zhijie Ma
- Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Cheng Wang
- Department of Pathology, Nanjing Drum Tower Hospital & National Health Commission Key Laboratory of Antibody Techniques & School of Basic Medical Sciences of Nanjing Medical University, Nanjing, China
| | - Yong Zha
- Hepatobiliary Pancreatic Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, China
| | - Feng Zhu
- Department of General Surgery, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Hongping Xia
- Zhongda Hospital, School of Medicine, Advanced Institute for Life and Health, Southeast University, Nanjing, China
- Department of Pathology, Nanjing Drum Tower Hospital & National Health Commission Key Laboratory of Antibody Techniques & School of Basic Medical Sciences of Nanjing Medical University, Nanjing, China
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Bauer TM, Moon J, Shadiow J, Buckley S, Gallagher KA. Mechanisms of Impaired Wound Healing in Type 2 Diabetes: The Role of Epigenetic Factors. Arterioscler Thromb Vasc Biol 2025; 45:632-642. [PMID: 40109262 PMCID: PMC12018132 DOI: 10.1161/atvbaha.124.321446] [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] [Indexed: 03/22/2025]
Abstract
Despite decades of research, impaired extremity wound healing in type 2 diabetes remains a significant driver of patient morbidity, mortality, and health care costs. Advances in surgical and medical therapies, including the advent of endovascular interventions for peripheral artery disease and topical therapies developed to promote wound healing, have not reduced the frequency of lower leg amputations for nonhealing wounds in type 2 diabetes. This brief report is aimed at reviewing the roles of various cell types in tissue repair and summarizing the known dysfunctions of these cell types in diabetic foot ulcers. Recent advances in our understanding of the epigenetic regulation in immune cells identified to be altered in type 2 diabetes are summarized, and particular attention is paid to the developing research defining the epigenetic regulation of structural cells, including keratinocytes, fibroblasts, and endothelial cells. Gaps in knowledge are highlighted, and potential future directions are suggested based on the current state of the field.
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Affiliation(s)
- Tyler M. Bauer
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Jadie Moon
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | - James Shadiow
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Sam Buckley
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Katherine A. Gallagher
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA
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Yue Z, Zhang W, Zhu G, Sun H, Jiang C. Lysine hydroxylase 1 (PLOD1) regulates glucose metabolism and promotes Th17 cell differentiation in psoriasis. Allergol Immunopathol (Madr) 2025; 53:74-81. [PMID: 40088025 DOI: 10.15586/aei.v53i2.1269] [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: 11/19/2024] [Accepted: 11/07/2025] [Indexed: 03/17/2025]
Abstract
Psoriasis is a common and chronic inflammatory skin disease. To treat psoriasis, more effective molecular targets still need to be developed and the mechanisms elucidated. PLOD1, as one of the genes related to glycolysis, can promote the glycolysis of cells. However, it is not clear whether upregulation of PLOD1 plays a causal role or is directly involved in psoriasis. Herein, we have examined the PLOD1 expression in patients with psoriasis and analyzed its effect on the progression of psoriasis. We found that PLOD1 is highly expressed in psoriasis. Also, the role of PLOD1 in promoting Th17 cell differentiation was further revealed, and PLOD1 promotes T cell glycolysis. Mechanically, PLOD1 activates the PI3K/AKT/mTOR pathway and thereby affects the progression of psoriasis. In conclusion, PLOD1 regulates glucose metabolism and promotes Th17 cell differentiation, which affects the progression of psoriasis.
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Affiliation(s)
- Zhen Yue
- Department of Dermatology, The First Affiliated Hospital of Bengbu Medical University, Bengbu City, Anhui Province, China
| | - Wanlu Zhang
- Department of Dermatology, The First Affiliated Hospital of Bengbu Medical University, Bengbu City, Anhui Province, China
| | - Gege Zhu
- Department of Dermatology, The First Affiliated Hospital of Bengbu Medical University, Bengbu City, Anhui Province, China
| | - Huiya Sun
- Department of Dermatology, The First Affiliated Hospital of Bengbu Medical University, Bengbu City, Anhui Province, China
| | - Congjun Jiang
- Department of Dermatology, The First Affiliated Hospital of Bengbu Medical University, Bengbu City, Anhui Province, China;
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Yang C, Lian H, Luo H, Song C, Lin J, Liang Z, Yang Y, Hong X, Li S, Chen Y, Wu L, Yan L, Chen S, Ren M. The Diminution of R-Loops Generated by LncRNA DSP-AS1 Inhibits DSP Gene Transcription to Impede the Re-Epithelialization During Diabetic Wound Healing. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2406021. [PMID: 39921255 PMCID: PMC11948065 DOI: 10.1002/advs.202406021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 11/26/2024] [Indexed: 02/10/2025]
Abstract
Re-epithelialization constitutes a critical stage in the intricate process of wound healing, yet its mechanisms in the context of diabetic wounds remain elusive. In this study, the role of the mesenchymal-epithelial transition (MET) vis-à-vis the epithelial-mesenchymal transition (EMT) of keratinocytes in diabetic wound re-epithelialization is investigated. The findings reveal an impediment in the MET process, rather than EMT, which significantly compromised re-epithelialization in diabetic wounds. Furthermore, Desmoplakin (DSP) gene expression, encoding a key desmosome protein, is down-regulated in diabetic rats. This down-regulation coincided with aberrant hypo-demethylation of the DSP promoter. The inhibition of DSP expression is linked to reduced occupancy of Ten-eleven translocation 3 (TET3) at the DSP promoter, consequently suppressing TET3-dependent DNA demethylation. Additionally, a novel lncRNA termed DSP-AS1is identified, which is antisense to DSP. Notably, DSP-AS1 expression is down-regulated in diabetic skin wounds, and it interacted with TET3, a DNA demethylase. Notably, DSP-AS1 is found to form R-loops, triple-stranded DNA:RNA hybrids, at the DSP promoter, facilitating TET3 localization to the DSP promoter. Collectively, the findings suggest that reduced R-loop formation by DSP-AS1 impairs DSP gene transcription by repressing TET3-mediated DNA demethylation. This disruption of the orchestrated re-epithelialization process contributes to refractory diabetic wound healing.
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Affiliation(s)
- Chen Yang
- Department of EndocrinologySun Yat‐sen Memorial HospitalSun Yat‐sen University107 Yanjiang West RoadGuangzhou510120China
- Guang Dong Clinical Research Center for Metabolic DiseasesGuangzhou510120China
- Department of Endocrinology and MetabolismZhuhai People's Hospital (The Affiliated Hospital of Beijing Institute of Technology, Zhuhai Clinical Medical College of Jinan University)Zhuhai519000China
| | - Hong Lian
- Department of EndocrinologySun Yat‐sen Memorial HospitalSun Yat‐sen University107 Yanjiang West RoadGuangzhou510120China
- Guang Dong Clinical Research Center for Metabolic DiseasesGuangzhou510120China
| | - Hengli Luo
- Department of EndocrinologySun Yat‐sen Memorial HospitalSun Yat‐sen University107 Yanjiang West RoadGuangzhou510120China
- Guang Dong Clinical Research Center for Metabolic DiseasesGuangzhou510120China
| | - Chenlin Song
- Department of Chemical and Systems BiologyStanford UniversityStanfordCA94305USA
| | - Jianghong Lin
- Department of EndocrinologySun Yat‐sen Memorial HospitalSun Yat‐sen University107 Yanjiang West RoadGuangzhou510120China
- Guang Dong Clinical Research Center for Metabolic DiseasesGuangzhou510120China
| | - Zhuoxian Liang
- Department of EndocrinologySun Yat‐sen Memorial HospitalSun Yat‐sen University107 Yanjiang West RoadGuangzhou510120China
- Guang Dong Clinical Research Center for Metabolic DiseasesGuangzhou510120China
| | - Yulin Yang
- Department of EndocrinologySun Yat‐sen Memorial HospitalSun Yat‐sen University107 Yanjiang West RoadGuangzhou510120China
- Guang Dong Clinical Research Center for Metabolic DiseasesGuangzhou510120China
| | - Xiaosi Hong
- Department of EndocrinologySun Yat‐sen Memorial HospitalSun Yat‐sen University107 Yanjiang West RoadGuangzhou510120China
- Guang Dong Clinical Research Center for Metabolic DiseasesGuangzhou510120China
| | - Shaohua Li
- Wards of CadresZhuhai People's Hospital (The Affiliated Hospital of Beijing Institute of Technology, Zhuhai Clinical Medical College of Jinan University)Zhuhai519000China
| | - Yanbo Chen
- Department of EndocrinologySun Yat‐sen Memorial HospitalSun Yat‐sen University107 Yanjiang West RoadGuangzhou510120China
- Guang Dong Clinical Research Center for Metabolic DiseasesGuangzhou510120China
| | - Liangyan Wu
- Department of EndocrinologySun Yat‐sen Memorial HospitalSun Yat‐sen University107 Yanjiang West RoadGuangzhou510120China
- Guang Dong Clinical Research Center for Metabolic DiseasesGuangzhou510120China
| | - Li Yan
- Department of EndocrinologySun Yat‐sen Memorial HospitalSun Yat‐sen University107 Yanjiang West RoadGuangzhou510120China
- Guang Dong Clinical Research Center for Metabolic DiseasesGuangzhou510120China
| | - Sifan Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene RegulationGuangdong‐Hong Kong Joint Laboratory for RNA MedicineMedical Research CenterSun Yat‐sen Memorial HospitalSun Yat‐sen UniversityGuangzhou510120China
- Nanhai Translational Innovation Center of Precision ImmunologySun Yat‐sen Memorial HospitalFoshan528200China
| | - Meng Ren
- Department of EndocrinologySun Yat‐sen Memorial HospitalSun Yat‐sen University107 Yanjiang West RoadGuangzhou510120China
- Guang Dong Clinical Research Center for Metabolic DiseasesGuangzhou510120China
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Morabbi A, Karimian M. Therapeutic potential of exosomal lncRNAs derived from stem cells in wound healing: focusing on mesenchymal stem cells. Stem Cell Res Ther 2025; 16:62. [PMID: 39934913 PMCID: PMC11816792 DOI: 10.1186/s13287-025-04200-0] [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: 07/12/2024] [Accepted: 01/30/2025] [Indexed: 02/13/2025] Open
Abstract
The self-renewal ability and multipotency of stem cells give them great potential for use in wound healing. Stem cell-derived exosomes, owing to their close biological resemblance to their parent cells, offer a more efficient, safer, and economical approach for facilitating cellular communication and interactions within different environments. This potential makes them particularly valuable in the treatment of both acute and chronic wounds, such as lacerations, burns, and diabetic ulcers. Long non-coding RNAs (lncRNAs) enclosed in exosomes, as one of the leading actors of these extracellular microvesicles, through interaction with miRNAs and regulation of various signaling pathways involved in inflammation, angiogenesis, cell proliferation, and migration, could heal the wounds. Exosome-derived lncRNAs from stem cells facilitate extracellular matrix remodeling through interaction between macrophages and fibroblasts. Moreover, alongside regulating the expression of inflammatory cytokines, controlling reactive oxygen species levels, and enhancing autophagic activity, they also modulate immune responses to support wound healing. Regulating the expression of genes and signaling pathways related to angiogenesis, by increasing blood supply and accelerating the delivery of essential substances to the wound environment, is another effect exosomal lncRNAs derived from stem cells for wound healing. These lncRNAs can also enhance skin wound healing by regulating homeostasis, increasing the proliferation and differentiation of cells involved in the wound-healing process, and enhancing fibroblast viability and migration to the injury site. Ultimately, exosome-derived lncRNAs from stem cells offer valuable and novel insights into the molecular mechanisms underlying improved wound healing. They can pave the way for potential therapeutic strategies, fostering further research for a better future. Meanwhile, exosomes derived from mesenchymal stem cells, due to their exceptional regenerative properties, as well as the lncRNAs derived from these exosomes, have emerged as one of the innovative tools in wound healing. This review article aims to narrate the cellular and molecular roles of exosome-derived lncRNAs from stem cells in enhancing wound healing with a focus on mesenchymal stem cells.
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Affiliation(s)
- Ali Morabbi
- Department of Molecular and Cell Biology, Faculty of Basic Sciences, University of Mazandaran, Babolsar, 47416-95447, Iran
| | - Mohammad Karimian
- Department of Molecular and Cell Biology, Faculty of Basic Sciences, University of Mazandaran, Babolsar, 47416-95447, Iran.
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Gomes MLNP, Krijnen PAJ, Middelkoop E, Niessen HWM, Boekema BKHL. Fetal Skin Wound Healing: Key Extracellular Matrix Components and Regulators in Scarless Healing. J Invest Dermatol 2025; 145:280-302. [PMID: 39152955 DOI: 10.1016/j.jid.2024.05.027] [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: 09/26/2023] [Revised: 05/28/2024] [Accepted: 05/30/2024] [Indexed: 08/19/2024]
Abstract
Fetal skin at early gestational stage is able to regenerate and heal rapidly after wounding. The exact mechanisms and molecular pathways involved in this process are however still largely unknown. The numerous differences in the skin of the early fetus versus skin in later developmental stages might provide clues for the mechanisms of scarless healing. This review summarizes the differences between mammalian fetal skin and the skin at later developmental phases in healthy and wounded conditions, focusing on extracellular matrix components, which are crucial factors in the microenvironment that direct cells and tissue functions and hence the wound healing process.
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Affiliation(s)
- Madalena Lopes Natário Pinto Gomes
- Department of Plastic, Reconstructive and Hand Surgery, Amsterdam UMC (Location VUmc), Amsterdam, The Netherlands; Preclinical Research, Association of Dutch Burn Centres (ADBC), Beverwijk, The Netherlands; Department of Pathology, Amsterdam UMC Location AMC, Amsterdam, The Netherlands; Tissue Function & Regeneration, Amsterdam Movement Sciences, Amsterdam UMC (Location VUmc), Amsterdam, The Netherlands
| | - Paul A J Krijnen
- Department of Pathology, Amsterdam UMC Location AMC, Amsterdam, The Netherlands; Amsterdam Cardiovascular Sciences Institute, Amsterdam UMC, Amsterdam, The Netherlands
| | - Esther Middelkoop
- Department of Plastic, Reconstructive and Hand Surgery, Amsterdam UMC (Location VUmc), Amsterdam, The Netherlands; Preclinical Research, Association of Dutch Burn Centres (ADBC), Beverwijk, The Netherlands; Tissue Function & Regeneration, Amsterdam Movement Sciences, Amsterdam UMC (Location VUmc), Amsterdam, The Netherlands; Burn Centre, Red Cross Hospital, Beverwijk, The Netherlands
| | - Hans W M Niessen
- Department of Pathology, Amsterdam UMC Location AMC, Amsterdam, The Netherlands; Amsterdam Cardiovascular Sciences Institute, Amsterdam UMC, Amsterdam, The Netherlands; Department of Cardio-thoracic Surgery, Amsterdam UMC (Location VUmc), Amsterdam, The Netherlands
| | - Bouke K H L Boekema
- Department of Plastic, Reconstructive and Hand Surgery, Amsterdam UMC (Location VUmc), Amsterdam, The Netherlands; Preclinical Research, Association of Dutch Burn Centres (ADBC), Beverwijk, The Netherlands.
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Yue K, Zhang T, Wang H, Wang B, Mu Y, Li H. MAGI2-AS3 hypermethylated in promoter region promotes migration and invasion of head and neck squamous cell carcinoma via miRNA-31-5p/AR axis. Transl Oncol 2025; 52:102223. [PMID: 39644822 PMCID: PMC11667182 DOI: 10.1016/j.tranon.2024.102223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 11/18/2024] [Accepted: 11/28/2024] [Indexed: 12/09/2024] Open
Abstract
Molecular regulatory mechanism of MAGI2-AS3 in HNSCC is not yet mature.In this study, we analyzed the methylation level of MAGI2-AS3 promoter and its downstream miR-31-5p/AR axis by bioinformatics methods. qRT-PCR was used to detect the mRNA expression level of each gene, and western blot was used to detect the expression level of AR proteins in tissues and cells. CCK-8, colony formation, wound healing, and cellular invasion assays were used to detect the HNSCC cell proliferation, migration, and invasion. Dual luciferase and RIP assays were performed to validate the binding relationship between genes. The effect of MAGI2-AS3 on HNSCC progression was verified in nude mice in vivo. The low expression of MAGI2-AS3 in HNSCC was caused by hypermethylation of MAGI2-AS3, which could regulate the target of miR-31-5p by sponge adsorption of miR-31-5p, and miR-31-5p could inhibit the expression of AR by directly targeting AR. Thus, MAGI2-AS3 could inhibit the proliferation, migration, and invasion of HNSCC through the miR-31-5p/AR axis. This provided a theoretical basis that MAGI2-AS3 was a potential therapeutic target for HNSCC.
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Affiliation(s)
- Kai Yue
- Department of Oncology, Nanyang Central Hospital, Nanyang 473005, China
| | - Ting Zhang
- Department of Oncology, Nanyang Central Hospital, Nanyang 473005, China
| | - Huanhuan Wang
- Department of Oncology, Nanyang Central Hospital, Nanyang 473005, China
| | - Bo Wang
- Department of Oncology, Nanyang Central Hospital, Nanyang 473005, China
| | - Yalin Mu
- Department of Oncology, Nanyang Central Hospital, Nanyang 473005, China
| | - Hui Li
- Department of Scientific Research, Nanyang Central Hospital, Nanyang 473005, China.
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8
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Aghayants S, Zhu J, Yu J, Tao R, Li S, Zhou S, Zhou Y, Zhu Z. The emerging modulators of non-coding RNAs in diabetic wound healing. Front Endocrinol (Lausanne) 2024; 15:1465975. [PMID: 39439564 PMCID: PMC11493653 DOI: 10.3389/fendo.2024.1465975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 09/23/2024] [Indexed: 10/25/2024] Open
Abstract
Diabetic wound healing is a complex physiological process often hindered by the underlying metabolic dysfunctions associated with diabetes. Despite existing treatments, there remains a critical need to explore innovative therapeutic strategies to improve patient outcomes. This article comprehensively examines the roles of non-coding RNAs (ncRNAs), specifically microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), in regulating key phases of the wound healing process: inflammation, angiogenesis, re-epithelialization, and tissue remodeling. Through a deep review of current literature, we discuss recent discoveries of ncRNAs that have been shown to either promote or impair the wound healing process in diabetic wound healing, which were not covered in earlier reviews. This review highlights the specific mechanisms by which these ncRNAs impact cellular behaviors and pathways critical to each healing stage. Our findings indicate that understanding these recently identified ncRNAs provides new insights into their potential roles in diabetic wound healing, thereby contributing valuable knowledge for future research directions in this field.
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Affiliation(s)
- Sis Aghayants
- Department of Plastic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Jinjin Zhu
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China
| | - Jing Yu
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rui Tao
- Department of Plastic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Sicheng Li
- Department of Plastic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Shengzhi Zhou
- Department of Plastic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yunhua Zhou
- Department of Wound Repair Surgery, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhanyong Zhu
- Department of Plastic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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Wang J, Wang X, Chen F, Ning Q, Liu Y, Zhu Y, Wei W, Leng M, Wang Z, Jin P, Li Q. N6-Methyladenosine Modification of lncCCKAR-5 Regulates Autophagy in Human Umbilical Cord Mesenchymal Stem Cells by Destabilizing LMNA and Inhibits Diabetic Wound Healing. J Invest Dermatol 2024; 144:1148-1160.e15. [PMID: 38242315 DOI: 10.1016/j.jid.2023.11.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 10/24/2023] [Accepted: 11/09/2023] [Indexed: 01/21/2024]
Abstract
Long noncoding RNAs are pivotal contributors to the development of human diseases. However, their significance in the context of diabetic wound healing regulated by human umbilical cord mesenchymal stem cells (hUCMSCs) remains unclear. This study sheds light on the involvement of lncCCKAR5 in this process. We found that hUCMSCs exposed to high glucose conditions exhibited a significant downregulation of lncCCKAR5 expression, and lncCCKAR5 played a critical role in modulating autophagy, thus inhibiting apoptosis in hUCMSCs. In addition, the reduction of lncCCKAR5 in cells exposed to high glucose effectively thwarted cellular senescence and facilitated filopodium formation. Mechanistically, lncCCKAR5 served as a scaffold that facilitated the interaction between MKRN2 and LMNA, a key regulator of cytoskeletal function and autophagy. The lncCCKAR5/LMNA/MKRN2 complex played a pivotal role in promoting the ubiquitin-mediated degradation of LMNA, with this effect being further augmented by N6-adenosine methylation of lncCCKAR5. Consequently, our findings underscore the critical role of lncCCKAR5 in regulating the autophagic process in hUCMSCs, particularly through protein ubiquitination and degradation. This intricate regulatory network presents a promising avenue for potential therapeutic interventions in the context of diabetic wound healing involving hUCMSCs.
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Affiliation(s)
- Jian Wang
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | | | - Feifei Chen
- Institute of Oncology, Xuzhou Medical University, Xuzhou, China
| | - Qianqian Ning
- Institute of Oncology, Xuzhou Medical University, Xuzhou, China
| | - YuTing Liu
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Yun Zhu
- Xuzhou Medical University, Xuzhou, China
| | - Wuhan Wei
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | | | - Ziyi Wang
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Peisheng Jin
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
| | - Qiang Li
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
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Ju CC, Liu XX, Liu LH, Guo N, Guan LW, Wu JX, Liu DW. Epigenetic modification: A novel insight into diabetic wound healing. Heliyon 2024; 10:e28086. [PMID: 38533007 PMCID: PMC10963386 DOI: 10.1016/j.heliyon.2024.e28086] [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: 07/05/2023] [Revised: 03/04/2024] [Accepted: 03/12/2024] [Indexed: 03/28/2024] Open
Abstract
Wound healing is an intricate and fine regulatory process. In diabetic patients, advanced glycation end products (AGEs), excessive reactive oxygen species (ROS), biofilm formation, persistent inflammation, and angiogenesis regression contribute to delayed wound healing. Epigenetics, the fast-moving science in the 21st century, has been up to date and associated with diabetic wound repair. In this review, we go over the functions of epigenetics in diabetic wound repair in retrospect, covering transcriptional and posttranscriptional regulation. Among these, we found that histone modification is widely involved in inflammation and angiogenesis by affecting macrophages and endothelial cells. DNA methylation is involved in factors regulation in wound repair but also affects the differentiation phenotype of cells in hyperglycemia. In addition, noncodingRNA regulation and RNA modification in diabetic wound repair were also generalized. The future prospects for epigenetic applications are discussed in the end. In conclusion, the study suggests that epigenetics is an integral regulatory mechanism in diabetic wound healing.
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Affiliation(s)
- Cong-Cong Ju
- Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, PR China
- Huankui Academy, Nanchang University, Nanchang, Jiangxi, PR China
| | - Xiao-Xiao Liu
- Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, PR China
| | - Li-hua Liu
- Huankui Academy, Nanchang University, Nanchang, Jiangxi, PR China
| | - Nan Guo
- Nanchang University, Nanchang, Jiangxi, PR China
| | - Le-wei Guan
- Huankui Academy, Nanchang University, Nanchang, Jiangxi, PR China
| | - Jun-xian Wu
- Nanchang University, Nanchang, Jiangxi, PR China
| | - De-Wu Liu
- Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, PR China
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11
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Cheng P, Xie X, Hu L, Zhou W, Mi B, Xiong Y, Xue H, Zhang K, Zhang Y, Hu Y, Chen L, Zha K, Lv B, Lin Z, Lin C, Dai G, Hu Y, Yu T, Hu H, Liu G, Zhang Y. Hypoxia endothelial cells-derived exosomes facilitate diabetic wound healing through improving endothelial cell function and promoting M2 macrophages polarization. Bioact Mater 2024; 33:157-173. [PMID: 38034500 PMCID: PMC10681882 DOI: 10.1016/j.bioactmat.2023.10.020] [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: 08/03/2023] [Revised: 10/19/2023] [Accepted: 10/19/2023] [Indexed: 12/02/2023] Open
Abstract
It is imperative to develop and implement newer, more effective strategies to address refractory diabetic wounds. As of now, there is currently no optimal solution for these wounds. Hypoxic human umbilical vein endothelial cells (HUVECs)-derived exosomes have been postulated to promote diabetic wound healing, however, its effect and molecular mechanism need further study. In this study, we aimed to investigate whether hypoxic exosomes enhance wound healing in diabetics. Based on our high-throughput sequencing, differentially expressed lncRNAs (including 64 upregulated lncRNAs and 94 downregulated lncRNAs) were found in hypoxic exosomes compared to normoxic exosomes. Interestingly, lncHAR1B was one of the prominently upregulated lncRNAs in hypoxic exosomes, showing a notable correlation with diabetic wound healing. More specifically, hypoxic exosomes were transmitted to surrounding cells, which resulted in a significant increase in lncHAR1B level, thereby relieving the dysfunction of endothelial cells and promoting the switch from M1 to M2 macrophages under high glucose conditions. Mechanistically, lncHAR1B directly interacted with the transcription factor basic helix-loop-helix family member e23 (BHLHE23), which subsequently led to its binding to the KLF transcription factor 4 (KLF4) and promoted KLF4 expression. In our in vivo experiments, the use of hypoxic exosomes-loaded HGM-QCS hydrogels (Gel-H-Exos) resulted in rapid wound healing compared to that of normoxic exosomes-loaded HGM-QCS hydrogels (Gel-N-Exos) and diabetic groups. Consequently, our study provides potentially novel therapeutic approaches aimed at accelerating wound healing and developing a practical exosomes delivery platform.
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Affiliation(s)
- Peng Cheng
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Xudong Xie
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Liangcong Hu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Wu Zhou
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Bobin Mi
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Yuan Xiong
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Hang Xue
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Kunyu Zhang
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, 511442, China
| | - Yuxiao Zhang
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, 511442, China
| | - Yiqiang Hu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Lang Chen
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Kangkang Zha
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Bin Lv
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Ze Lin
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Chuanlu Lin
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Guandong Dai
- Department of Orthopaedics, Pingshan District People's Hospital of Shenzhen, Pingshan General Hospital of Southern Medical University, Shenzhen, Guangdong, 518118, China
| | - Yixin Hu
- Hubei Micro-explore Innovative Pharmaceutical Research Co, Ltd, Wuhan, Hubei, 430071, China
- Suzhou Organ-on-a-Chip System Science and Technology Co, Ltd, Suzhou, Jiangsu, 215000, China
| | - Tengbo Yu
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hankun Hu
- Hubei Micro-explore Innovative Pharmaceutical Research Co, Ltd, Wuhan, Hubei, 430071, China
- Suzhou Organ-on-a-Chip System Science and Technology Co, Ltd, Suzhou, Jiangsu, 215000, China
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China
| | - Guohui Liu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Yingze Zhang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, NO.139 Ziqiang Road, Shijiazhuang, 050051, China
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12
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Xiao Y, Zhang C, Liu X, Yang Y, Landén NX, Zhang Z, Li D. Single-cell profiling and functional screening reveal crucial roles for lncRNAs in the epidermal re-epithelialization of human acute wounds. Front Surg 2024; 11:1349135. [PMID: 38468869 PMCID: PMC10925684 DOI: 10.3389/fsurg.2024.1349135] [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: 12/04/2023] [Accepted: 01/30/2024] [Indexed: 03/13/2024] Open
Abstract
Objectives Re-epithelialization is an important physiological process for repairing skin barrier function during wound healing. It is primarily mediated by coordinated migration, proliferation, and differentiation of keratinocytes. Long noncoding RNAs (lncRNAs) are essential components of the noncoding genome and participate in various biological processes; however, their expression profiles and function in re-epithelialization during wound healing have not been established. Methods We investigated the distribution of lncRNAs during wound re-epithelialization by comparing the genomic profiles of uninjured skin and acute wound (AW) from healthy donors. We performed functional screening of differentially expressed lncRNAs to identify the important lncRNAs for re-epithelialization. Results The expression of multiple lncRNAs is changed during human wound re-epithelialization process. We identified VIM-AS1, SMAD5-AS1, and LINC02581 as critical regulators involved in keratinocyte migration, proliferation, and differentiation, respectively. Conclusion LncRNAs play crucial regulatory roles in wound re-epithelialization. We established lncRNA expression profile in human acute wounds compared with intact skin, offering valuable insights into the physiological mechanisms underlying wound healing and potential therapeutic targets.
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Affiliation(s)
- Yunting Xiao
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
- Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China
| | - Chenyang Zhang
- MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xiuping Liu
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yong Yang
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
- Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China
| | - Ning Xu Landén
- Dermatology and Venereology Division, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Zhao Zhang
- MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Dongqing Li
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
- Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China
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13
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Priyadarshini A, Madan R, Das S. Genetics and epigenetics of diabetes and its complications in India. Hum Genet 2024; 143:1-17. [PMID: 37999799 DOI: 10.1007/s00439-023-02616-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 10/17/2023] [Indexed: 11/25/2023]
Abstract
Diabetes mellitus (DM) has become a significant health concern with an increasing rate of morbidity and mortality worldwide. India ranks second in the number of diabetes cases in the world. The increasing burden of DM can be explained by genetic predisposition of Indians to type 2 diabetes mellitus (T2DM) coupled with rapid urbanization and socio-economic development in the last 3 decades leading to drastic changes in lifestyle. Environment and lifestyle changes contribute to T2DM development by altering epigenetic processes such as DNA methylation, histone post-translational modifications, and long non-coding RNAs, all of which regulate chromatin structure and gene expression. Although the genetic predisposition of Indians to T2DM is well established, how environmental and genetic factors interact and lead to T2DM is not well understood. In this review, we discuss the prevalence of diabetes and its complications across different states in India and how various risk factors contribute to its pathogenesis. The review also highlights the role of genetic predisposition among the Indian population and epigenetic factors involved in the etiology of diabetes. Lastly, we review current treatments and emphasize the knowledge gap with respect to genetic and epigenetic factors in the Indian context. Further understanding of the genetic and epigenetic determinants will help in risk prediction and prevention as well as therapeutic interventions, which will improve the clinical management of diabetes and associated macro- and micro-vascular complications.
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Affiliation(s)
- Ankita Priyadarshini
- Diabetic Vascular Complications Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Mohali, Punjab, 140306, India
| | - Riya Madan
- Diabetic Vascular Complications Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Mohali, Punjab, 140306, India
| | - Sadhan Das
- Diabetic Vascular Complications Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Mohali, Punjab, 140306, India.
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14
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Shaorong Z, Xiaodong L, Qiong P, Zhaodong X, Zhuo L, Hechen H, Yuancheng W. SNHG12/NFYC-AS1 Acted as the Sponge for hsa-miR-199a-5p to Promote the Expression of S100A8/S100A7/XDH and was Involved in the Progression of Diabetic Foot Ulcers. Mol Biotechnol 2023; 65:2038-2048. [PMID: 36920714 DOI: 10.1007/s12033-023-00692-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2023] [Indexed: 03/16/2023]
Abstract
Traditional Chinese medicine has been used to treat diabetic foot ulcer (DFU) for a long time. However, the underlying mechanism of Radix arnebiae seu lithospermi ointment (RAS-ointment) has not been revealed. Effects of RAS-ointment treatment were observed in DFU patients. The endogenous competitive RNA mechanism was constructed based on micro-array sequencing and bioinformatics analysis. RT-PCR was used to detected the expression of genes in DFU ulcerated skins and non-ulcerated skins. Dual luciferase and RT-PCR experiments were used to investigate the endogenous competitive RNA mechanism. Based on micro-array sequencing and bioinformatics analysis, we found that SNHG12/NFYC-AS1, hsa-miR-199a-5p and S100A8/S100A7/XDH might form an endogenous competitive RNA mechanism. RT-PCR assay shown that SNHG12, NFYC-AS1, S100A8, S100A7 and XDH were significantly up-regulated, while hsa-miR-199a-5p was significantly down-regulated in DFU ulcerated skins (N = 10) compared with non-ulcerated skins (N = 10). Dual luciferase and RT-PCR experiments showed that SNHG12 or NFYC-AS1 up-regulated the expression of S100A8, S100A7 and XDH by inhibiting hsa-miR-199a-5p in a direct binding way. After 35 days of RAS-ointment treatment, the wound healing of DFU patients was substantially improved and the expression of S100A7 and XDH were reduced expression in DFU patients. In addition, the monomer composition of RAS-ointment, 49070_FLUKA or auraptenol inhibited the expression of S100A7 and XDH in Te317.sk cells. In conclusion, RAS-ointment may be used as an adjunctive therapy for DFU patients.
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Affiliation(s)
- Zhou Shaorong
- Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Liu Xiaodong
- Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Pan Qiong
- Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xu Zhaodong
- Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Li Zhuo
- Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Huang Hechen
- Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wang Yuancheng
- Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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15
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Xiong Y, Chu X, Yu T, Knoedler S, Schroeter A, Lu L, Zha K, Lin Z, Jiang D, Rinkevich Y, Panayi AC, Mi B, Liu G, Zhao Y. Reactive Oxygen Species-Scavenging Nanosystems in the Treatment of Diabetic Wounds. Adv Healthc Mater 2023; 12:e2300779. [PMID: 37051860 DOI: 10.1002/adhm.202300779] [Citation(s) in RCA: 70] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 04/07/2023] [Indexed: 04/14/2023]
Abstract
Diabetic wounds are characterized by drug-resistant bacterial infections, biofilm formation, impaired angiogenesis and perfusion, and oxidative damage to the microenvironment. Given their complex nature, diabetic wounds remain a major challenge in clinical practice. Reactive oxygen species (ROS), which have been shown to trigger hyperinflammation and excessive cellular apoptosis, play a pivotal role in the pathogenesis of diabetic wounds. ROS-scavenging nanosystems have recently emerged as smart and multifunctional nanomedicines with broad synergistic applicability. The documented anti-inflammatory and pro-angiogenic ability of ROS-scavenging treatments predestines these nanosystems as promising options for the treatment of diabetic wounds. Yet, in this context, the therapeutic applicability and efficacy of ROS-scavenging nanosystems remain to be elucidated. Herein, the role of ROS in diabetic wounds is deciphered, and the properties and strengths of nanosystems with ROS-scavenging capacity for the treatment of diabetic wounds are summarized. In addition, the current challenges of such nanosystems and their potential future directions are discussed through a clinical-translational lens.
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Affiliation(s)
- Yuan Xiong
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore, 637371, Singapore
| | - Xiangyu Chu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Tao Yu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Samuel Knoedler
- Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02152, USA
- Institute of Regenerative Biology and Medicine, Helmholtz Zentrum München, Max-Lebsche-Platz 31, 81377, Munich, Germany
| | - Andreas Schroeter
- Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Hannover Medical School, 30625, Hanover, Lower Saxony, Germany
| | - Li Lu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Kangkang Zha
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Ze Lin
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Dongsheng Jiang
- Institute of Regenerative Biology and Medicine, Helmholtz Zentrum München, Max-Lebsche-Platz 31, 81377, Munich, Germany
| | - Yuval Rinkevich
- Institute of Regenerative Biology and Medicine, Helmholtz Zentrum München, Max-Lebsche-Platz 31, 81377, Munich, Germany
| | - Adriana C Panayi
- Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02152, USA
- Department of Hand, Plastic and Reconstructive Surgery, Microsurgery, Burn Center, BG Trauma Center Ludwigshafen, University of Heidelberg, Ludwig-Guttmann-Strasse 13, 67071, Ludwigshafen, Germany
| | - Bobin Mi
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Guohui Liu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Yanli Zhao
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore, 637371, Singapore
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16
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Wu Y, Wu X, Wang J, Chen S, Chen H, Liu J, Zeng T, Hu M, Liang Y, Sun K, Yang C, Yan L, Ren M. Fibroblast-Derived Extracellular Vesicle-Packaged Long Noncoding RNA Upregulated in Diabetic Skin Enhances Keratinocyte MMP-9 Expression and Delays Diabetic Wound Healing. J Transl Med 2023; 103:100019. [PMID: 36925202 DOI: 10.1016/j.labinv.2022.100019] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 09/29/2022] [Accepted: 10/09/2022] [Indexed: 01/11/2023] Open
Abstract
Accurate communication between fibroblasts and keratinocytes is crucial for diabetic wound healing. Extracellular vesicles are being explored as essential mediators of intercellular communication in the skin. However, the mechanisms underlying wound healing mediated by fibroblast-derived extracellular vesicles (Fib-EVs) remain unclear. The present study evaluated the role of long noncoding RNA upregulated in diabetic skin (lnc-URIDS) packed in Fib-EVs in the wound healing of streptozotocin-induced diabetes and the potential mechanisms of the effects. We demonstrated that high glucose induced the enrichment of lnc-URIDS in Fib-EVs, facilitated the transfer of lnc-URIDS to primary rat epidermal keratinocytes, and increased the expression of matrix metalloproteinase-9. Mechanistically, the binding of lnc-URIDS to YTH domain family protein-2 enhanced the degradation of YTH domain family protein-2 in the lysosomes, which increased the translational activity of the messenger RNA of matrix metalloproteinase-9 and ultimately induced the degradation of collagen for wound healing. The results provided an insight into the crosstalk and cooperation between fibroblasts and keratinocytes in collagen homeostasis in diabetic wounds and clarified the mechanism by which lnc-URIDS degrades collagen for diabetic wound healing.
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Affiliation(s)
- Yuxi Wu
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoying Wu
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Department of Endocrinology, National Center of Gerontology, Beijing Hospital, Peking University Fifth School of Clinical Medicine, Beijing, China
| | - Jiahuan Wang
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Sifan Chen
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hongxing Chen
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jing Liu
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Tingting Zeng
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Mengdie Hu
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ying Liang
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Kan Sun
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Chuan Yang
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Li Yan
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
| | - Meng Ren
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
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17
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Tang YB, Uwimana MMP, Zhu SQ, Zhang LX, Wu Q, Liang ZX. Non-coding RNAs: Role in diabetic foot and wound healing. World J Diabetes 2022; 13:1001-1013. [PMID: 36578864 PMCID: PMC9791568 DOI: 10.4239/wjd.v13.i12.1001] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/26/2022] [Accepted: 11/18/2022] [Indexed: 12/15/2022] Open
Abstract
Diabetic foot ulcer (DFU) and poor wound healing are chronic complications in patients with diabetes. The increasing incidence of DFU has resulted in huge pressure worldwide. Diagnosing and treating this condition are therefore of great importance to control morbidity and improve prognosis. Finding new markers with potential diagnostic and therapeutic utility in DFU has gathered increasing interest. Wound healing is a process divided into three stages: Inflammation, proliferation, and regeneration. Non-coding RNAs (ncRNAs), which are small protected molecules transcribed from the genome without protein translation function, have emerged as important regulators of diabetes complications. The deregulation of ncRNAs may be linked to accelerated DFU development and delayed wound healing. Moreover, ncRNAs can be used for therapeutic purposes in diabetic wound healing. Herein, we summarize the role of microRNAs, long ncRNAs, and circular RNAs in diverse stages of DFU wound healing and their potential use as novel therapeutic targets.
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Affiliation(s)
- Yi-Bo Tang
- Department of Obstetrics, Women’s Hospital School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Muhuza Marie Parfaite Uwimana
- Department of Obstetrics, Women’s Hospital School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Shu-Qi Zhu
- Department of Obstetrics, Women’s Hospital School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Li-Xia Zhang
- Department of Obstetrics, Women’s Hospital School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Qi Wu
- Department of Obstetrics, Women’s Hospital School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Zhao-Xia Liang
- Department of Obstetrics, Women’s Hospital School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
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18
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Estimation of Early Postmortem Interval from Long Noncoding RNA Gene Expression in the Incised Cutaneous Wound: An Experimental Study. Biomedicines 2022; 10:biomedicines10112919. [PMID: 36428487 PMCID: PMC9687757 DOI: 10.3390/biomedicines10112919] [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: 09/08/2022] [Revised: 10/19/2022] [Accepted: 11/11/2022] [Indexed: 11/16/2022] Open
Abstract
The assessment of alteration of postmortem RNA expression has forensic significance in estimating postmortem interval. To evaluate wound healing progression and the effect of different postmortem intervals, histopathological changes, immunohistochemical matrix metalloproteinase-9 (MMP-9) expression, and long noncoding fatty acid oxidation (lncFAO), RNA expression was assessed in the incised cutaneous wound model. A full-thickness cutaneous wound was inflicted on 75 rats. All 15 rats were sacrificed at different post-infliction intervals (0, 2, 4, 8 and 10 days), and the cutaneous wounds (n = 5) were excised at different postmortem intervals (0, 5, and 24 h after euthanasia). The maximal inflammatory healing stage was detected at day 4 post-infliction, while near complete healing, thick mature collagen deposition was detected at day 10 post-infliction. LncFAO expression was significantly over-expressed with increasing wound age. MMP-9 was detectable on injury day with continuous elevation until 8 days post-wounding, which later decreased. Although histopathological and immunohistochemical examinations within 24 h postmortem did not show any remarkable changes, lncFAO RNA expression showed a significant negative correlation with hours passed since death. The combined use of histopathological changes, immunohistochemical expression of MMP-9, and molecular expression of lncFAO could be appropriate in wound dating verification. Among these factors, lncFAO could be a reliable indicator in postmortem interval estimation.
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19
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Glycation-Associated Diabetic Nephropathy and the Role of Long Noncoding RNAs. Biomedicines 2022; 10:biomedicines10102623. [PMID: 36289886 PMCID: PMC9599575 DOI: 10.3390/biomedicines10102623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/12/2022] [Accepted: 10/14/2022] [Indexed: 11/16/2022] Open
Abstract
The glycation of various biomolecules is the root cause of many pathological conditions associated with diabetic nephropathy and end-stage kidney disease. Glycation imbalances metabolism and increases renal cell injury. Numerous therapeutic measures have narrowed down the adverse effects of endogenous glycation, but efficient and potent measures are miles away. Recent advances in the identification and characterization of noncoding RNAs, especially the long noncoding RNAs (lncRNAs), have opened a mammon of new biology to explore the mitigations for glycation-associated diabetic nephropathy. Furthermore, tissue-specific distribution and condition-specific expression make lncRNA a promising key for second-generation therapeutic interventions. Though the techniques to identify and exemplify noncoding RNAs are rapidly evolving, the lncRNA study encounters multiple methodological constraints. This review will discuss lncRNAs and their possible involvement in glycation and advanced glycation end products (AGEs) signaling pathways. We further highlight the possible approaches for lncRNA-based therapeutics and their working mechanism for perturbing glycation and conclude our review with lncRNAs biology-related future opportunities.
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20
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Proteomic Analysis of Exudates from Chronic Ulcer of Diabetic Foot Treated with Scorpion Antimicrobial Peptide. Mediators Inflamm 2022; 2022:5852786. [PMID: 36225537 PMCID: PMC9550419 DOI: 10.1155/2022/5852786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 08/26/2022] [Accepted: 09/15/2022] [Indexed: 11/17/2022] Open
Abstract
Scorpion peptides have good therapeutic effect on chronic ulcer of diabetic foot, but the related pharmacological mechanism has remained unclear. The different proteins and bacteria present in ulcer exudates from chronic diabetic foot patients, treated with scorpion antimicrobial peptide at different stages, were analyzed using isobaric tags for quantification-labeled proteomics and bacteriological methods. According to the mass spectrometry data, a total of 1865 proteins were identified qualitatively, and the number of the different proteins was 130 (mid/early), 401 (late/early), and 310 (mid, late/early). In addition, functional annotation, cluster analysis of effects and the analysis of signal pathway, transcription regulation, and protein-protein interaction network were carried out. The results showed that the biochemical changes of wound microenvironment during the treatment involved activated biological functions such as protein synthesis, cell proliferation, differentiation, migration, movement, and survival. Inhibited biological functions such as cell death, inflammatory response, immune diseases, and bacterial growth were also involved. Bacteriological analysis showed that Burkholderia cepacia was the main bacteria in the early and middle stage of ulcer exudate and Staphylococcus epidermidis in the late stage. This study provides basic data for further elucidation of the molecular mechanism of diabetic foot.
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21
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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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22
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Shu L, Wang C, Ding Z, Tang J, Zhu Y, Wu L, Wang Z, Zhang T, Wang T, Xu Y, Sun L. A novel regulated network mediated by downregulation HIF1A-AS2 lncRNA impairs placental angiogenesis by promoting ANGPTL4 expression in preeclampsia. Front Cell Dev Biol 2022; 10:837000. [PMID: 36016656 PMCID: PMC9396278 DOI: 10.3389/fcell.2022.837000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 06/30/2022] [Indexed: 01/17/2023] Open
Abstract
Preeclampsia (PE) is the predominant medical condition leading to maternal and fetal mortality, and the lack of effective treatment increases its risk to the public health. Among the numerous predisposing factors, the ineffectual remodeling of the uterine spiral arteries, which can induce abnormal placental angiogenesis, has been focused to solve the pathogenesis of PE. According to the preceding research results, abnormal expression of long non-coding RNAs (lncRNA)s could be associated with the pathological changes inducing PE. To be more specific, lncRNA HIF1A-AS2 was proposed for its potential to participate in the molecular mechanisms underlying PE. In vitro, in trophoblast cell lines HTR-8/SVneo and human umbilical vein endothelial cells HUVECs, HIF1A-AS2 knockdown inhibited cell proliferation, migration and tube formation. Mechanistically, transcription factor FOXP1 could regulate the expression of HIF1A-AS2. Moreover, a series of assays, including RNA pull down and mass spectrometry, RNA immunoprecipitation and chromatin immunoprecipitation assay, revealed that HIF1A-AS2 interacted with Lamin A/C (LMNA) to inhibit ANGPTL4 expression in trophoblast cells, thus further participating in the progression of PE. Taken together, these findings suggested that further analysis on HIF1A-AS2 could contribute to the development of prospective therapeutic strategy for PE.
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Affiliation(s)
- Lijun Shu
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Nanjing Medical University, Nanjing, JS, China
| | - Cong Wang
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Nanjing Medical University, Nanjing, JS, China
| | - Zhengzheng Ding
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Nanjing Medical University, Nanjing, JS, China
| | - Jianjiao Tang
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Nanjing Medical University, Nanjing, JS, China
| | - Yuanyuan Zhu
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Nanjing Medical University, Nanjing, JS, China
| | - Liuxin Wu
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Nanjing Medical University, Nanjing, JS, China
| | - Zheyue Wang
- Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing, JS, China
| | - Tingting Zhang
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Nanjing Medical University, Nanjing, JS, China
| | - Tianjun Wang
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Nanjing Medical University, Nanjing, JS, China
| | - Yetao Xu
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Nanjing Medical University, Nanjing, JS, China
- *Correspondence: Lizhou Sun, ; Yetao Xu,
| | - Lizhou Sun
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Nanjing Medical University, Nanjing, JS, China
- *Correspondence: Lizhou Sun, ; Yetao Xu,
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23
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NEAT1 promotes keratinocyte migration and proliferation during wound healing by regulating miR-26a-5p/LGR4 axis. Mol Cell Toxicol 2022. [DOI: 10.1007/s13273-022-00275-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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24
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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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25
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Golledge J, Thanigaimani S. Novel therapeutic targets for diabetes-related wounds or ulcers: an update on preclinical and clinical research. Expert Opin Ther Targets 2021; 25:1061-1075. [PMID: 34873970 DOI: 10.1080/14728222.2021.2014816] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Diabetes-related wounds, particularly diabetes-related foot ulcers, are mainly caused by lack of foot sensation and high plantar tissue stress secondary to peripheral neuropathy, ischemia secondary to peripheral artery disease, and dysfunctional wound healing. Current management of diabetes-related wounds involves the offloading of high foot pressures and the treatment of ischemia through revascularization. Despite these treatments, the global burden of diabetes-related wounds is growing, and thus, novel therapies are needed. The normal wound healing process is a coordinated remodeling process orchestrated by fibroblasts, endothelial cells, phagocytes, and platelets, controlled by an array of growth factors. In diabetes-related wounds, these coordinated processes are dysfunctional. The past animal model and human research suggest that prolonged wound inflammation, failure to adequately correct ischemia, and impaired wound maturation are key therapeutic targets to improve diabetes-related wound healing. AREAS COVERED This review summarizes recent preclinical and clinical research on novel diabetes-related wound treatments. Animal models of diabetes-related wounds and recent studies testing novel therapeutic agents in these models are described. Findings from clinical trials are also discussed. Finally, challenges to identifying and implementing novel therapies are described. EXPERT OPINION Given the growing volume of promising drug therapies currently under investigation, it is expected within the next decade, that diabetes-related wound treatment will be transformed.
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Affiliation(s)
- Jonathan Golledge
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia.,The Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, Queensland, Australia.,The Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Queensland, Australia
| | - Shivshankar Thanigaimani
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia.,The Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Queensland, Australia
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26
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Xu M, Fang S, Xie A. Posttranscriptional control of PLOD1 in adipose-derived stem cells regulates scar formation through altering macrophage polarization. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1573. [PMID: 34790779 PMCID: PMC8576667 DOI: 10.21037/atm-21-4978] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 10/16/2021] [Indexed: 11/06/2022]
Abstract
Background The level of cutaneous scar formation is a critical parameter to determine the success of skin wound healing. Adipose-derived mesenchymal stem cells (AMSCs) have been applied to improve treatment of cutaneous injury with the purpose of reducing scar formation. Methods The levels of procollagen-lysine 1,2-oxoglutarate 5-dioxygenase 1 (PLOD1) were assessed at scar sites. Then, PLOD1 in AMSCs was depleted by either expression of a PLOD1-specific short-hair interfering RNA (shPLOD1) or by expression of microRNA-449 (miR-449) that targets and suppresses protein translation of PLOD1 through 3 prime untranslated region (3'-UTR) interfering. For induction of skin injury, a blade cut of 1.5-cm long and 2-mm thick was made on the middle back of the mice. Transplantation of either AMSCs-shPLOD1 or AMSCs-miR-449 into the injured region of the mice was performed via tail vein injection. The fibrosis as well as underlying mechanisms were assessed. Results The AMSCs expressed high levels of PLOD1, a potent stimulator of fibrosis. We knocked down PLOD1 in AMSCs by expression of either shPLOD1 or miR-449. Transplantation of either AMSCs-shPLOD1 or AMSCs-miR-449 significantly reduced the fibrotic process in the injured region of the mice to a similar degree. Mechanistically, transplantation of either AMSCs-shPLOD1 or AMSCs-miR-449 shifted macrophage polarization from M2 to M1-like and reduced both reactive oxygen species (ROS) and activation of myofibroblasts from fibroblasts. Conclusions Suppression of PLOD1 levels in AMSCs either directly by shPLOD1 or indirectly by miR-449 may substantially improve the anti-fibrotic potential of AMSCs during wound healing, likely through altering macrophage polarization.
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Affiliation(s)
- Miao Xu
- Department of Plastic and Reconstructive Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shuo Fang
- Department of Plastic and Reconstructive Surgery, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Aiguo Xie
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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27
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Li X, Li N, Li B, Feng Y, Zhou D, Chen G. Noncoding RNAs and RNA-binding proteins in diabetic wound healing. Bioorg Med Chem Lett 2021; 50:128311. [PMID: 34438011 DOI: 10.1016/j.bmcl.2021.128311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 08/02/2021] [Accepted: 08/04/2021] [Indexed: 12/15/2022]
Abstract
Poor wound healing is a common complication in diabetic patients. It often leads to intractable infections and lower limb amputations and is associated with cardiovascular morbidity and mortality. NcRNAs, which can regulate gene expression, have emerged as important regulators of various physiological processes. Herein, we summarize the diverse roles of ncRNAs in the key stages of diabetic wound healing, including inflammation, angiogenesis, re-epithelialization, and extracellular matrix remodeling. Meanwhile, the potential use of ncRNAs as novel therapeutic targets for wound healing in diabetic patients is also discussed. In addition, we summarize the role of RNA-binding proteins (RBPs) in the regulation of gene expression and signaling pathways during skin repair, which may provide opportunities for therapeutic intervention for this potentially devastating disease. However, so far, research on the modulated drug based on ncRNAs that lead to significantly altered gene expression in diabetic patients is scarce. We have compiled some drugs that may be able to modulate ncRNAs, which significantly regulate the gene expression in diabetic patients.
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Affiliation(s)
- Xue Li
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Ning Li
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Bingxin Li
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Yuan Feng
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Di Zhou
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
| | - Gang Chen
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, People's Republic of China; Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, People's Republic of China.
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28
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Kuai L, Jiang JS, Li W, Li B, Yin SY. Long non-coding RNAs in diabetic wound healing: Current research and clinical relevance. Int Wound J 2021; 19:583-600. [PMID: 34337861 PMCID: PMC8874090 DOI: 10.1111/iwj.13655] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 05/15/2021] [Accepted: 06/21/2021] [Indexed: 01/23/2023] Open
Abstract
Diabetic wounds are a protracted complication of diabetes mainly characterised by chronic inflammation, obstruction of epithelialization, damaged blood vessels and collagen production (maturation), as well as neuropathy. As a non‐coding RNA (ncRNA) that lack coding potential, long non‐coding RNAs (lncRNAs) have recently been reported to play a salient role in diabetic wound healing. Here, this review summarises the roles of lncRNAs in the pathology and treatments of diabetic wounds, providing references for its potential clinical diagnostic criteria or therapeutic targets in the future.
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Affiliation(s)
- Le Kuai
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing-Si Jiang
- Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Wei Li
- Center for Translational Medicine, Huaihe Hospital of Henan University, Kaifeng, China
| | - Bin Li
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shuang-Yi Yin
- Center for Translational Medicine, Huaihe Hospital of Henan University, Kaifeng, China
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29
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Lang J, Yang C, Liu L, Li L, Wu L, Liu Y, Luo H, Yan L, Chen S, Ning J, Yang C. High glucose activates ERK1/2 to stabilize AP1 and increase MMP9 expression in diabetic foot ulcers. Exp Cell Res 2021; 403:112550. [PMID: 33675806 DOI: 10.1016/j.yexcr.2021.112550] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 02/25/2021] [Accepted: 02/27/2021] [Indexed: 12/17/2022]
Abstract
Increased matrix metalloproteinase 9 (MMP9) expression is involved in delayed wound healing in diabetic foot ulcers. We created skin wounds in normal SD rats and STZ-induced diabetic SD rats, then we found protein levels of activator protein-1 (AP1), a crucial transcription factor to increase MMP9 transcription, as well as MMP9 was up-regulated in epithelium of diabetic skin tissues. Then, we evaluated the mRNA and protein stability of AP1 subunits C-FOS/C-Jun in HaCaT cells after high glucose treatment. Results showed that high glucose could increase protein stability of C-FOS and C-Jun. Additionally, high glucose also activated extracellular signaling-related kinase 1/2 (ERK1/2). ERK1/2 inhibitor could rescue phosphorylation of C-FOS and C-Jun, increased protein stability of C-Jun, and increased MMP9 expressions. Thus, our study demonstrated that high glucose could activate ERK1/2 to stabilize AP1 and increase MMP9 expression in diabetic skin and HaCaT cells.
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Affiliation(s)
- Jiangli Lang
- Department of Endocrinology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Chen Yang
- Department of Endocrinology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Lixuan Liu
- Department of Endocrinology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Li Li
- Department of Emergency, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Liangyan Wu
- Department of Endocrinology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Yanyan Liu
- Department of Endocrinology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Hengli Luo
- Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Li Yan
- Department of Endocrinology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Sifan Chen
- Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Jie Ning
- Department of Endocrinology, Shenzhen Longhua District Central Hospital, Guangdong Medical University Affiliated Longhua Central Hospital, Shenzhen, People's Republic of China
| | - Chuan Yang
- Department of Endocrinology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.
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30
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Pastar I, Marjanovic J, Stone RC, Chen V, Burgess JL, Mervis JS, Tomic-Canic M. Epigenetic regulation of cellular functions in wound healing. Exp Dermatol 2021; 30:1073-1089. [PMID: 33690920 DOI: 10.1111/exd.14325] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 03/04/2021] [Accepted: 03/08/2021] [Indexed: 02/06/2023]
Abstract
Stringent spatiotemporal regulation of the wound healing process involving multiple cell types is associated with epigenetic mechanisms of gene regulation, such as DNA methylation, histone modification and chromatin remodelling, as well as non-coding RNAs. Here, we discuss the epigenetic changes that occur during wound healing and the rapidly expanding understanding of how these mechanisms affect healing resolution in both acute and chronic wound milieu. We provide a focussed overview of current research into epigenetic regulators that contribute to wound healing by specific cell type. We highlight the role of epigenetic regulators in the molecular pathophysiology of chronic wound conditions. The understanding of how epigenetic regulators can affect cellular functions during normal and impaired wound healing could lead to novel therapeutic approaches, and we outline questions that can provide guidance for future research on epigenetic-based interventions to promote healing. Dissecting the dynamic interplay between cellular subtypes involved in wound healing and epigenetic parameters during barrier repair will deepen our understanding of how to improve healing outcomes in patients affected by chronic non-healing wounds.
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Affiliation(s)
- Irena Pastar
- Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, Wound Healing and Regenerative Medicine Research Program, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Jelena Marjanovic
- Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, Wound Healing and Regenerative Medicine Research Program, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Rivka C Stone
- Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, Wound Healing and Regenerative Medicine Research Program, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Vivien Chen
- Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, Wound Healing and Regenerative Medicine Research Program, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Jamie L Burgess
- Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, Wound Healing and Regenerative Medicine Research Program, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Joshua S Mervis
- Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, Wound Healing and Regenerative Medicine Research Program, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Marjana Tomic-Canic
- Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, Wound Healing and Regenerative Medicine Research Program, University of Miami Miller School of Medicine, Miami, FL, USA
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31
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Yan C, Chen J, Yang X, Li W, Mao R, Chen Z. Emerging Roles of Long Non-Coding RNAs in Diabetic Foot Ulcers. Diabetes Metab Syndr Obes 2021; 14:2549-2560. [PMID: 34135607 PMCID: PMC8200159 DOI: 10.2147/dmso.s310566] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 05/13/2021] [Indexed: 12/13/2022] Open
Abstract
Diabetes mellitus is one of the most widespread metabolic diseases in the world, and diabetic foot ulcer (DFU), as one of its chronic complications, not only causes a large amount of physiological and psychological pain to patients but also places a tremendous burden on the entire economy and society. Despite significant advances in knowledge on the mechanism and in the treatment of DFU, clinical practice is still not satisfactory, and our understanding of its cellular and molecular pathogenesis is far from complete. Fortunately, progress in studying the roles of long non-coding RNAs (lncRNAs), which play important regulatory roles in the expression of genes at multiple levels, suggests that we can apply them in the early diagnosis and potential targeted intervention of DFU. In this review, we briefly summarize the current knowledge regarding the functional roles and potential mechanisms of reported lncRNAs in regulating DFU.
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Affiliation(s)
- Chengqi Yan
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
| | - Jing Chen
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
| | - Xiaofan Yang
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
| | - Wenqing Li
- Department of Hand and Foot Surgery, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - Renqun Mao
- Department of Hand and Foot Surgery, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - Zhenbing Chen
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
- Correspondence: Zhenbing Chen Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of ChinaTel +86 13871103730Fax +86 2785351628 Email
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