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Cai Z, Wang Y, Hu S, Yuan Q, Liu J, Luo C, Jiang L, Huang Y. The efficacy of platelet-derived extracellular vesicles in the treatment of diabetic wounds: a systematic review and meta-analysis of animal studies. Arch Dermatol Res 2025; 317:244. [PMID: 39812853 DOI: 10.1007/s00403-024-03781-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 12/27/2024] [Accepted: 12/29/2024] [Indexed: 01/16/2025]
Abstract
Platelet-derived extracellular vesicles (PEVs) are rich in growth factors and have significant potential for facilitating tissue repair and regeneration. Therefore, we conducted this meta-analysis to assess the efficacy of PEVs in treating diabetic wounds. To assess the efficacy and safety of PEVs in treating diabetic wounds, we conducted a systematic review of several databases and performed a meta-analysis using a random effects model. Nine studies (n = 128 animals) meeting the inclusion criteria for this review were identified. The pooled analysis revealed that compared to the control group, wounds treated with PEVs had a higher healing rate (SMD = 4.43, 95% CI = 2.85-6.01, P < 0.00001). In subgroup analysis, PEVs combined with hydrogel showed better efficacy than PEVs alone (SMD = 7.96, 95% CI = 5.05-10.87, P < 0.00001). Additionally, the PEVs treatment group outperformed the control group in other outcomes, such as vessel density and number, re-epithelialization rate, and collagen deposition. PEVs have the potential to promote angiogenesis at diabetic wound sites and alleviate inflammatory responses, ultimately aiding in wound healing, especially when combined with hydrogels or other medications.
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Affiliation(s)
- Zhi Cai
- Department of Transfusion, The Affiliated Hospital of Southwest Medical University, Sichuan, 646000, Luzhou, People's Republic of China
| | - Yuhan Wang
- Department of Clinical Laboratory, Longmatan District People's Hospital of Luzhou, Luzhou, People's Republic of China
| | - Shan Hu
- Department of Transfusion, Guanghan People's Hospital, Deyang, People's Republic of China
| | - Qiong Yuan
- Department of Transfusion, Zigong First People's Hospital, Zigong, People's Republic of China
| | - Jusong Liu
- Department of Transfusion, Zigong First People's Hospital, Zigong, People's Republic of China
| | - Chengcen Luo
- Department of Transfusion, Zigong Fourth People's Hospital, Zigong, People's Republic of China
| | - Ling Jiang
- Department of Transfusion, The Affiliated Hospital of Southwest Medical University, Sichuan, 646000, Luzhou, People's Republic of China.
- Department of Transfusion, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People's Republic of China.
| | - Yuanshuai Huang
- Department of Transfusion, The Affiliated Hospital of Southwest Medical University, Sichuan, 646000, Luzhou, People's Republic of China.
- Department of Transfusion, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People's Republic of China.
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2
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Yang J, Li S. Application of self-assembled antibacterial nanofiber loaded oriented artificial skin in infected diabetic-related wound regeneration. J Biomater Appl 2025; 39:661-668. [PMID: 39297741 DOI: 10.1177/08853282241267253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Diabetic patients develop wounds that exhibit delayed healing, prolonged inflammatory responses, and slower epithelialization kinetics compared to non-diabetic patients. Diabetic foot ulcers(DFUs) affect approximately 18.6 million people worldwide. The presence of a high glucose microenvironment in DFUs results in the significant accumulation of bacterial infection and advanced glycation end products (AGEs). To solve this, a self-assemble antibacterial nanofiber(ANF) loaded oriential artificial skin (ANF@OAS) was introduced in this research, which is consisted of L/D-phenylalanine derivatives coupled the natural antimicrobial peptides. The ANF@OAS can effectively reduce AGEs production and suppress multiple resistant bacteria. Additionally, the ANF@OAS can suppress infection and stimulate wound healing in infected diabetic mice.
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Affiliation(s)
- Jie Yang
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration, Translational Research of Zhejiang Province, Hangzhou, China
| | - Shengyun Li
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration, Translational Research of Zhejiang Province, Hangzhou, China
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Chai M, Zhang CY, Chen S, Xu DH. Application of autophagy in mesenchymal stem cells. World J Stem Cells 2024; 16:990-1001. [PMID: 39734481 PMCID: PMC11669988 DOI: 10.4252/wjsc.v16.i12.990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 11/05/2024] [Accepted: 12/02/2024] [Indexed: 12/13/2024] Open
Abstract
In this editorial, we have taken an in-depth look at the article published by Wan et al. The study showed that preconditioning mesenchymal stem cells (MSCs) protected them against programmed cell death, and increased their survival rate and therapeutic potential. Autophagy, a type of programmed cell death, is a major intracellular degradation and recycling pathway that is crucial for maintaining cellular homeostasis, self-renewal, and pluripotency. We have explored the relationship between autophagy and MSCs to determine the role of autophagy in the therapeutic applications of MSCs.
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Affiliation(s)
- Min Chai
- Department of Emergency Medicine, The First Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Chun-Yan Zhang
- Department of Rehabilitation Medicine, The First Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Shuai Chen
- Department of Emergency Surgery, The First Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Da-Hai Xu
- Department of Emergency Medicine, The First Hospital of Jilin University, Changchun 130000, Jilin Province, China.
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4
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MENG J, ZHANG H, CAO Y, ZHANG Y, WANG X, SHENG B, AN J, CHEN Y. Zuyangping formula promotes skin wound healing in diabetic rats. J TRADIT CHIN MED 2024; 44:1194-1203. [PMID: 39617705 PMCID: PMC11589546 DOI: 10.19852/j.cnki.jtcm.2024.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 12/19/2023] [Indexed: 12/17/2024]
Abstract
OBJECTIVE To evaluate the effects of Zuyangping (, ZYP) formula on wound healing in diabetic rats, as well as the molecular mechanisms involved. METHODS The main compounds in ZYP formula were identified by the Liquid chromatography-tandem mass spectrometry. Sprague-Dawley rats, injected with streptozotocin (STZ) to establish diabetes model, then, formed a defective skin trauma in the back, and each group was treated with corresponding drugs once a day. Granulation was taken from each time node for histological analysis. The Western blotting was used to measured protein expression of advanced glycation end products receptor (RAGE) and hypoxia-inducible factor-1α (HIF-1α) axis-related proteins. The relative expression levels of inflammatory cytokines and growth factors were measured by the enzyme-linked immunosorbent assay method. RESULTS The main ingredients were identified in the ZYP formula. Histological analysis showed that the ZYP formula could inhibit the expression of inflammation, promote angiogenesis and collagen deposition. In addition, the ZYP formula could regulate the expression of RAGE and HIF1-α axis-related proteins, thus promoting the wound healing in diabetic rats. CONCLUSION The ZYP formula could accelerate wound healing in diabetic rats.
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Affiliation(s)
- Junhua MENG
- 1 Department of Pharmacy, Wuhan University Tongren Hospital (the Third Hospital of Wuhan), Wuhan 430060, China
| | - Hong ZHANG
- 2 Department of Pharmacy, the First People’s Hospital of Jiangxia District, Wuhan 430200, China
| | - Yuling CAO
- 3 Department of Pharmacy, Wuhan ASIA General Hospital, Wuhan 430065, China
| | - Yu ZHANG
- 1 Department of Pharmacy, Wuhan University Tongren Hospital (the Third Hospital of Wuhan), Wuhan 430060, China
| | - Xiong WANG
- 1 Department of Pharmacy, Wuhan University Tongren Hospital (the Third Hospital of Wuhan), Wuhan 430060, China
| | - Bi SHENG
- 1 Department of Pharmacy, Wuhan University Tongren Hospital (the Third Hospital of Wuhan), Wuhan 430060, China
| | - Jing AN
- 1 Department of Pharmacy, Wuhan University Tongren Hospital (the Third Hospital of Wuhan), Wuhan 430060, China
| | - Yonggang CHEN
- 4 Laboratory Department, Wuhan Center for Clinical Laboratory, Wuhan 430015, China
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Liu S, Zhao H, Jiang T, Wan G, Yan C, Zhang C, Yang X, Chen Z. The Angiogenic Repertoire of Stem Cell Extracellular Vesicles: Demystifying the Molecular Underpinnings for Wound Healing Applications. Stem Cell Rev Rep 2024; 20:1795-1812. [PMID: 39001965 DOI: 10.1007/s12015-024-10762-y] [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] [Accepted: 07/06/2024] [Indexed: 07/15/2024]
Abstract
Stem cells-derived extracellular vesicles (SC-EVs) have emerged as promising therapeutic agents for wound repair, recapitulating the biological effects of parent cells while mitigating immunogenic and tumorigenic risks. These EVs orchestrate wound healing processes, notably through modulating angiogenesis-a critical event in tissue revascularization and regeneration. This study provides a comprehensive overview of the multifaceted mechanisms underpinning the pro-angiogenic capacity of EVs from various stem cell sources within the wound microenvironment. By elucidating the molecular intricacies governing their angiogenic prowess, we aim to unravel the mechanistic repertoire underlying their remarkable potential to accelerate wound healing. Additionally, methods to enhance the angiogenic effects of SC-EVs, current limitations, and future perspectives are highlighted, emphasizing the significant potential of this rapidly advancing field in revolutionizing wound healing strategies.
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Affiliation(s)
- Shuoyuan Liu
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Huayuan Zhao
- Department of Urology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Tao Jiang
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Gui Wan
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Chengqi Yan
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chi Zhang
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiaofan Yang
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Zhenbing Chen
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Huang F, Gao T, Feng Y, Xie Y, Tai C, Huang Y, Ling L, Wang B. Bioinspired Collagen Scaffold Loaded with bFGF-Overexpressing Human Mesenchymal Stromal Cells Accelerating Diabetic Skin Wound Healing via HIF-1 Signal Pathway Regulated Neovascularization. ACS APPLIED MATERIALS & INTERFACES 2024; 16:45989-46004. [PMID: 39165237 PMCID: PMC11378764 DOI: 10.1021/acsami.4c08174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/22/2024]
Abstract
The healing of severe chronic skin wounds in chronic diabetic patients is still a huge clinical challenge due to complex regeneration processes and control signals. Therefore, a single approach is difficult in obtaining satisfactory therapeutic efficacy for severe diabetic skin wounds. In this study, we adopted a composite strategy for diabetic skin wound healing. First, we fabricated a collagen-based biomimetic skin scaffold. The human basic fibroblast growth factor (bFGF) gene was electrically transduced into human umbilical cord mesenchymal stromal cells (UC-MSCs), and the stable bFGF-overexpressing UC-MSCs (bFGF-MSCs) clones were screened out. Then, an inspired collagen scaffold loaded with bFGF-MSCs was applied to treat full-thickness skin incision wounds in a streptozotocin-induced diabetic rat model. The mechanism of skin damage repair in diabetes mellitus was investigated using RNA-Seq and Western blot assays. The bioinspired collagen scaffold demonstrated good biocompatibility for skin-regeneration-associated cells such as human fibroblast (HFs) and endothelial cells (ECs). The bioinspired collagen scaffold loaded with bFGF-MSCs accelerated the diabetic full-thickness incision wound healing including cell proliferation enhancement, collagen deposition, and re-epithelialization, compared with other treatments. We also showed that the inspired skin scaffold could enhance the in vitro tube formation of ECs and the early angiogenesis process of the wound tissue in vivo. Further findings revealed enhanced angiogenic potential in ECs stimulated by bFGF-MSCs, evidenced by increased AKT phosphorylation and elevated HIF-1α and HIF-1β levels, indicating the activation of HIF-1 pathways in diabetic wound healing. Based on the superior biocompatibility and bioactivity, the novel bioinspired skin healing materials composed of the collagen scaffold and bFGF-MSCs will be promising for healing diabetic skin wounds and even other refractory tissue regenerations. The bioinspired collagen scaffold loaded with bFGF-MSCs could accelerate diabetic wound healing via neovascularization by activating HIF-1 pathways.
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Affiliation(s)
- Feifei Huang
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, China
| | - Tianyun Gao
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, China
| | - Yirui Feng
- School of Life Science, Nanjing University, Nanjing 210008, Jiangsu Province, China
| | - Yuanyuan Xie
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, China
| | - Chenxu Tai
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, China
| | - Yahong Huang
- School of Life Science, Nanjing University, Nanjing 210008, Jiangsu Province, China
| | - Li Ling
- Department of Endocrinology, The Sixth Affiliated Hospital of Shenzhen University Medical School and Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen 518020, China
| | - Bin Wang
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, China
- Jiangsu Key Laboratory for Molecular Medicine, Nanjing University, Nanjing 210008, Jiangsu Province, China
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7
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Dong L, Li Y, Chen Q, Liu Y, Wu Z, Pan D, Yan N, Liu L. Cereal polyphenols inhibition mechanisms on advanced glycation end products and regulation on type 2 diabetes. Crit Rev Food Sci Nutr 2024; 64:9495-9513. [PMID: 37222572 DOI: 10.1080/10408398.2023.2213768] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Advanced glycation end products (AGEs), the products of non-enzymatic browning reactions between the active carbonyl groups of reducing sugars and the free amines of amino acids, are largely considered oxidative derivatives resulting from diabetic hyperglycemia, which are further recognized as a potential risk for insulin resistance (IR) and type 2 diabetes (T2D). The accumulation of AGEs can trigger numerous negative effects such as oxidative stress, carbonyl stress, inflammation, autophagy dysfunction and imbalance of gut microbiota. Recently, studies have shown that cereal polyphenols have the ability to inhibit the formation of AGEs, thereby preventing and alleviating T2D. In the meanwhile, phenolics compounds could produce different biological effects due to the quantitative structure activity-relationship. This review highlights the effects of cereal polyphenols as a nonpharmacologic intervention in anti-AGEs and alleviating T2D based on the effects of oxidative stress, carbonyl stress, inflammation, autophagy, and gut microbiota, which also provides a new perspective on the etiology and treatment of diabetes.
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Affiliation(s)
- Lezhen Dong
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Animal Protein Deep Processing Technology of Zhejiang, School of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang, China
| | - Ying Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Animal Protein Deep Processing Technology of Zhejiang, School of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang, China
| | - Qin Chen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Animal Protein Deep Processing Technology of Zhejiang, School of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang, China
| | - Yahui Liu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Animal Protein Deep Processing Technology of Zhejiang, School of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang, China
| | - Zufang Wu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Animal Protein Deep Processing Technology of Zhejiang, School of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang, China
| | - Daodong Pan
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Animal Protein Deep Processing Technology of Zhejiang, School of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang, China
| | - Ning Yan
- Plant Functional Component Research Center, Tobacco Research Institute of Chinese Academy of Agricultural Sciences, Qingdao, China
| | - Lianliang Liu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Animal Protein Deep Processing Technology of Zhejiang, School of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang, China
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8
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Sun Y, Zhang X, Nie X, Yang R, Zhao X, Cui C, Liu W. Dough-Kneading-Inspired Design of an Adhesive Cardiac Patch to Attenuate Cardiac Fibrosis and Improve Cardiac Function via Regulating Glycometabolism. Adv Healthc Mater 2024; 13:e2303685. [PMID: 38386972 DOI: 10.1002/adhm.202303685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 02/19/2024] [Indexed: 02/24/2024]
Abstract
Recently, hydrogel adhesive patches have been explored for treating myocardial infarction. However, achieving secure adhesion onto the wet beating heart and local regulation of pathological microenvironment remains challenging. Herein, a dough-kneading-inspired design of hydrogel adhesive cardiac patch is reported, aiming to improve the strength of prevalent powder-formed patch and retain wet adhesion. In mimicking the polysaccharide and protein components of natural flour, methacrylated polyglutamic acid (PGAMA) is electrostatically interacted with hydroxypropyl chitosan (HPCS) to form PGAMA/HPCS coacervate hydrogel. The PGAMA/HPCS hydrogel is freeze-dried and ground into powders, which are further rehydrated with two aqueous solutions of functional drug, 3-acrylamido phenylboronic acid (APBA)/rutin (Rt) complexes for protecting the myocardium from advanced glycation end product (AGEs) injury by reactive oxygen species (ROS) -responsive Rt release, and hypoxanthine-loaded methacrylated hyaluronic acid (HAMA) nanogels for enhancing macrophage targeting ability to regulate glycometabolism for combating inflammation. The rehydrated powders bearing APBA/Rt complexes and HAMA-hypoxanthine nanogels are repeatedly kneaded into a dough-like gel, which is further subjected to thermal-initiated crosslinking to form a stabilized and sticky patch. This biofunctional patch is applied onto the rats' infarcted myocardium, and the outcomes at 28 days post-surgery indicate efficient restoration of cardiac functions and attenuation of cardiac fibrosis.
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Affiliation(s)
- Yage Sun
- School of Materials Science and Engineering, Tianjin Key Laboratory of Composite and Functional Materials, Tianjin University, Tianjin, 300350, China
| | - Xiaoping Zhang
- School of Materials Science and Engineering, Tianjin Key Laboratory of Composite and Functional Materials, Tianjin University, Tianjin, 300350, China
| | - Xiongfeng Nie
- School of Materials Science and Engineering, Tianjin Key Laboratory of Composite and Functional Materials, Tianjin University, Tianjin, 300350, China
| | - Rong Yang
- School of Materials Science and Engineering, Tianjin Key Laboratory of Composite and Functional Materials, Tianjin University, Tianjin, 300350, China
| | - Xinrui Zhao
- School of Materials Science and Engineering, Tianjin Key Laboratory of Composite and Functional Materials, Tianjin University, Tianjin, 300350, China
| | - Chunyan Cui
- School of Materials Science and Engineering, Tianjin Key Laboratory of Composite and Functional Materials, Tianjin University, Tianjin, 300350, China
| | - Wenguang Liu
- School of Materials Science and Engineering, Tianjin Key Laboratory of Composite and Functional Materials, Tianjin University, Tianjin, 300350, China
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9
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Sayed AH, Mahmoud NS, Mohawed OAM, Ahmed HH. Combined effect of pantoprazole and mesenchymal stem cells on experimentally induced gastric ulcer: implication of oxidative stress, inflammation and apoptosis pathways. Inflammopharmacology 2024; 32:1961-1982. [PMID: 38652367 PMCID: PMC11136780 DOI: 10.1007/s10787-024-01469-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 03/21/2024] [Indexed: 04/25/2024]
Abstract
Gastric ulcer (GU) is one of the most common diseases of the upper gastrointestinal tract that affects millions of people worldwide. This study aimed to investigate the possible alleviating effect of a combined treatment of pantoprazole (PANTO) and adipose tissue-derived mesenchymal stem cells (ADSCs) in comparison with each treatment alone on the healing process of the experimentally induced GU in rats, and to uncover the involved pathways. Rats were divided into five groups: (1) Control, (2) GU, (3) PANTO, (4) ADSCs and (5) ADSCs + PANTO. Markers of oxidative stress, inflammation and apoptosis were assessed. The current data indicated that PANTO-, ADSCs- and ADSCs + PANTO-treated groups showed significant drop (p < 0.05) in serum advanced oxidation protein products (AOPPs) and advanced glycation end products (AGEPs) along with significant elevation (p < 0.05) in serum TAC versus the untreated GU group. Moreover, the treated groups (PANTO, ADSCs and ADSCs + PANTO) displayed significant down-regulation (p < 0.05) in gastric nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor alpha (TNF-α), cyclooxygenase-2 (COX-2), intercellular adhesion molecule-1 (ICAM-1), matrix metallopeptidase 9 (MMP-9) and caspase-3 along with significant up-regulation (p < 0.05) in vascular endothelial growth factor (VEGF) and peroxisome proliferator-activated receptor gamma (PPARγ) genes expression compared to the untreated GU group. Immunohistochemical examination of gastric tissue for transforming growth factor β1 (TGF-β1), epidermal growth factor (EGF) and proliferating cell nuclear antigen (PCNA) showed moderate to mild and weak immune reactions, respectively in the PANTO-, ADSCs- and ADSCs + PANTO-treated rat. Histopathological investigation of gastric tissue revealed moderate to slight histopathological alterations and almost normal histological features of the epithelial cells, gastric mucosal layer, muscularis mucosa and submucosa in PANTO-, ADSCs- and ADSCs + PANTO-treated rats, respectively. Conclusively, the co-treatment with ADSCs and PANTO evidenced sententious physiological protection against GU by suppressing oxidative stress, inhibiting inflammation and reducing apoptosis with consequent acceleration of gastric tissue healing process.
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Affiliation(s)
- Alaa H Sayed
- Hormones Department, Medical Research and Clinical Studies Institute, National Research Centre, Dokki 12622, Giza, Egypt.
| | - Nadia S Mahmoud
- Hormones Department, Medical Research and Clinical Studies Institute, National Research Centre, Dokki 12622, Giza, Egypt
- Stem Cell Lab, Center of Excellence for Advanced Sciences, National Research Centre, Dokki, Giza, Egypt
| | - Ola A M Mohawed
- Hormones Department, Medical Research and Clinical Studies Institute, National Research Centre, Dokki 12622, Giza, Egypt
| | - Hanaa H Ahmed
- Hormones Department, Medical Research and Clinical Studies Institute, National Research Centre, Dokki 12622, Giza, Egypt
- Stem Cell Lab, Center of Excellence for Advanced Sciences, National Research Centre, Dokki, Giza, Egypt
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10
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Wu Z, Liu C, Yin S, Ma J, Sun R, Cao G, Lu Y, Liu J, Su L, Song R, Wang Y. P75NTR regulates autophagy through the YAP-mTOR pathway to increase the proliferation of interfollicular epidermal cells and promote wound healing in diabetic mice. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167012. [PMID: 38176461 DOI: 10.1016/j.bbadis.2023.167012] [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: 07/29/2023] [Revised: 12/27/2023] [Accepted: 12/27/2023] [Indexed: 01/06/2024]
Abstract
Wound healing is delayed in diabetic patients. Increased autophagy and dysfunction of interfollicular epidermal (IFE) cells are closely associated with delayed healing of diabetic wounds. Autophagy plays an important role in all stages of wound healing, but its role in diabetic wound healing and the underlying molecular mechanisms are not clear. Here, we found that diabetic mice had delayed wound healing and increased autophagy in wounds compared with normal mice and that chloroquine, an inhibitor of autophagy, decreased the level of autophagy, improved the function of IFE cells, and accelerated wound healing in diabetic mice. Treatment of IFE cells with advanced glycosylation end products (AGEs) resulted in increased microtubule-associated protein chain (LC3) expression and decreased prostacyclin-62 (P62) expression, indicating increased autophagy in AGE-treated IFE cells. Moreover, P75NTR reduced autophagy in IFE cells in the presence of AGEs and significantly increased the proliferation of IFE cells. In addition, P75NTR participated in regulating autophagy in IFE cells and in wounds in diabetic mice through the YAP-mTOR signalling pathway, which increased the functional activity of the cells and the healing rate of wounds in diabetic mice. Thus, our study suggests that P75NTR protects IFE cells against AGEs by affecting autophagy and accelerating wound healing in diabetic mice, providing a basis for understanding the role of autophagy in diabetic wound healing.
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Affiliation(s)
- Zhenjie Wu
- Department of Plastic Surgery, The First Affiliated Hospital of Shandong First, Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, PR China; Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, Jinan, Shandong 250014, PR China
| | - Chunyan Liu
- Department of Plastic Surgery, The First Affiliated Hospital of Shandong First, Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, PR China; Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, Jinan, Shandong 250014, PR China
| | - Siyuan Yin
- Department of Plastic Surgery, The First Affiliated Hospital of Shandong First, Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, PR China; Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, Jinan, Shandong 250014, PR China
| | - Jiaxu Ma
- Department of Plastic Surgery, The First Affiliated Hospital of Shandong First, Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, PR China; Department of Plastic Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, 250012, PR China
| | - Rui Sun
- Department of Plastic Surgery, The First Affiliated Hospital of Shandong First, Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, PR China; Department of Plastic Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, 250012, PR China
| | - Guoqi Cao
- Department of Plastic Surgery, The First Affiliated Hospital of Shandong First, Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, PR China; Department of Plastic Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, 250012, PR China
| | - Yongpan Lu
- Department of Plastic Surgery, The First Affiliated Hospital of Shandong First, Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, PR China; First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, PR China
| | - Jian Liu
- Department of Plastic Surgery, The First Affiliated Hospital of Shandong First, Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, PR China; Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, Jinan, Shandong 250014, PR China
| | - Linqi Su
- Department of Plastic Surgery, The First Affiliated Hospital of Shandong First, Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, PR China; Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, Jinan, Shandong 250014, PR China
| | - Ru Song
- Department of Plastic Surgery, The First Affiliated Hospital of Shandong First, Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, PR China; Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, Jinan, Shandong 250014, PR China.
| | - Yibing Wang
- Department of Plastic Surgery, The First Affiliated Hospital of Shandong First, Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, PR China; Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, Jinan, Shandong 250014, PR China; Department of Plastic Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, 250012, PR China; First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, PR China.
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Panda D, Nayak S. Stem Cell-Based Tissue Engineering Approaches for Diabetic Foot Ulcer: a Review from Mechanism to Clinical Trial. Stem Cell Rev Rep 2024; 20:88-123. [PMID: 37867186 DOI: 10.1007/s12015-023-10640-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/05/2023] [Indexed: 10/24/2023]
Abstract
Diabetic foot ulcer (DFU) is a complication from incomplete or prolonged wound healing, at times requires amputation, putting substantial health and socioeconomic burden. Wound healing is a dynamic overlapping process that can be regulated by arrays of molecular factors showing redundancy in function. However, dysregulation in the mechanism of angiogenesis, extra cellular matrix (ECM) formation and immune modulation are the major causes for impair wound healing in hyperglycaemic patients. Despite development of wound care research, there is a lack of well-accepted targeted therapy with multidisciplinary approach for DFU treatment. Stem cell therapy holds a promising outcome both in preclinical and clinical trials because of its ability to promote healing via regeneration and specialized tissue differentiation. Among different types of stem cells, regenerative potential of mesenchymal stem cell (MSC) is well demonstrated in both experimental and clinical trial. Still there is a huge knowledge gap among medical practitioners for deciding the best stem cell source, administration route, and safety. This review strengthens the fact that why stem cell therapy is a promising candidate to treat DFU and cited multiple tissue engineering and biomaterial-based approaches for delivering stem cells and their aftermath paracrine events. Based on the pre-clinical and clinical studies, the review tried to come up with optimum stem cell source and delivery route for the treatment of DFU. At last, the review glances on possible direction to enhance therapeutics strategy for the same, including different approaches like: phytocompounds, exosomes, scaffold geometry, cell preconditioning and licensing etc.
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Affiliation(s)
- Debarchan Panda
- Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Sunita Nayak
- Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.
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Xing C, Zhu H, Dou X, Gao L, Baddi S, Zou Y, Zhao C, Peng Y, Fang Y, Feng CL. Infected Diabetic Wound Regeneration Using Peptide-Modified Chiral Dressing to Target Revascularization. ACS NANO 2023; 17:6275-6291. [PMID: 36946387 DOI: 10.1021/acsnano.2c10039] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
Revascularization plays a critical role in the healing of diabetic wounds. Accumulation of advanced glycation end products (AGEs) and refractory multidrug resistant bacterial infection are the two major barriers to revascularization, directly leading to impaired healing of diabetic wounds. Here, an artfully designed chiral gel dressing is fabricated (named as HA-LM2-RMR), which consists of l-phenylalanine and cationic hexapeptide coassembled helical nanofibers cross-linked with hyaluronic acid via hydrogen bonding. This chiral gel possesses abundant chiral and cationic sites, not only effectively reducing AGEs via stereoselective interaction but also specifically killing multidrug resistant bacteria rather than host cells since cationic hexapeptides selectively interact with negatively charged microbial membrane. Surprisingly, the HA-LM2-RMR fibers present an attractive ability to activate sprouted angiogenesis of Human Umbilical Vein Endothelial Cells by upregulating VEGF and OPA1 expression. In comparison with clinical Prontosan Wound Gel, the HA-LM2-RMR gel presents superior healing efficiency in the infected diabetic wound with respect to angiogenesis and re-epithelialization, shortening the healing period from 21 days to 14 days. These findings for chiral wound dressing provide insights for the design and construction of diabetic wound dressings that target revascularization, which holds great potential to be utilized in tissue regenerative medicine.
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Affiliation(s)
- Chao Xing
- State Key Lab of Metal Matrix Composites, Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs School of Pharmacy, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Hanting Zhu
- Department of Burns and Plastic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201900, China
- Institute of Traumatic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 201900, China
| | - Xiaoqiu Dou
- State Key Lab of Metal Matrix Composites, Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs School of Pharmacy, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Laiben Gao
- State Key Lab of Metal Matrix Composites, Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs School of Pharmacy, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Sravan Baddi
- State Key Lab of Metal Matrix Composites, Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs School of Pharmacy, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Yunqing Zou
- State Key Lab of Metal Matrix Composites, Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs School of Pharmacy, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Changli Zhao
- State Key Lab of Metal Matrix Composites, Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs School of Pharmacy, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Yinbo Peng
- Department of Burns and Plastic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201900, China
- Institute of Traumatic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 201900, China
| | - Yong Fang
- Department of Burns and Plastic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201900, China
- Institute of Traumatic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 201900, China
| | - Chuan-Liang Feng
- State Key Lab of Metal Matrix Composites, Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs School of Pharmacy, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
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13
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Adipose-Derived Stem Cell Extracellular Vesicles Improve Wound Closure and Angiogenesis in Diabetic Mice. Plast Reconstr Surg 2023; 151:331-342. [PMID: 36696316 DOI: 10.1097/prs.0000000000009840] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND Currently, there is a lack in therapy that promotes the reepithelialization of diabetic wounds as an alternative to skin grafting. Here, the authors hypothesized that extracellular vesicles from adipose-derived stem cells (ADSC-EVs) could accelerate wound closure through rescuing the function of keratinocytes in diabetic mice. METHODS The effect of ADSC-EVs on the biological function of human keratinocyte cells was assayed in vitro. In vivo, 81 male severe combined immune deficiency mice aged 8 weeks were divided randomly into the extracellular vesicle-treated diabetes group (n = 27), the phosphate-buffered saline-treated diabetes group (n = 27), and the phosphate-buffered saline-treated normal group (n = 27). A round, 8-mm-diameter, full-skin defect was performed on the back skin of each mouse. The wound closure kinetics, average healing time, reepithelialization rate, and neovascularization were evaluated by histological staining. RESULTS In vitro, ADSC-EVs improved proliferation, migration, and proangiogenic potential, and inhibited the apoptosis of human keratinocyte cells by suppressing Fasl expression with the optimal dose of 40 μg/mL. In vivo, postoperative dripping of ADSC-EVs at the dose of 40 μg/mL accelerated diabetic wound healing, with a 15.8% increase in closure rate and a 3.3-day decrease in average healing time. ADSC-EVs improved reepithelialization (18.2%) with enhanced epithelial proliferation and filaggrin expression, and suppressed epithelial apoptosis and Fasl expression. A 2.7-fold increase in the number of CD31-positive cells was also observed. CONCLUSION ADSC-EVs improve diabetic wound closure and angiogenesis by enhancing keratinocyte-mediated reepithelialization and vascularization. CLINICAL RELEVANCE STATEMENT ADSC-EVs could be developed as a regenerative medicine for diabetic wound care.
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Zhang J, Li L, Yu J, Zhang F, Shi J, LI M, Liu J, Li H, Gao J, Wu Y. Autophagy-Modulated Biomaterial: A Robust Weapon for Modulating the Wound Environment to Promote Skin Wound Healing. Int J Nanomedicine 2023; 18:2567-2588. [PMID: 37213350 PMCID: PMC10198186 DOI: 10.2147/ijn.s398107] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 03/28/2023] [Indexed: 05/23/2023] Open
Abstract
Autophagy, a self-renewal mechanism, can help to maintain the stability of the intracellular environment of organisms. Autophagy can also regulate several cellular functions and is strongly related to the onset and progression of several diseases. Wound healing is a biological process that is coregulated by different types of cells. However, it is troublesome owing to prolonged treatment duration and poor recovery. In recent years, biomaterials have been reported to influence the skin wound healing process by finely regulating autophagy. Biomaterials that regulate autophagy in various cells involved in skin wound healing to regulate the differentiation, proliferation and migration of cells, inflammatory responses, oxidative stress and formation of the extracellular matrix (ECM) have emerged as a key method for improving the tissue regeneration ability of biomaterials. During the inflammatory phase, autophagy enhances the clearance of pathogens from the wound site and leads to macrophage polarization from the M1 to the M2 phenotype, thus preventing enhanced inflammation that can lead to further tissue damage. Autophagy plays important roles in facilitating the formation of extracellular matrix (ECM) during the proliferative phase, removing excess intracellular ROS, and promoting the proliferation and differentiation of endothelial cells, fibroblasts, and keratinocytes. This review summarizes the close association between autophagy and skin wound healing and discusses the role of biomaterial-based autophagy in tissue regeneration. The applications of recent biomaterials designed to target autophagy are highlighted, including polymeric materials, cellular materials, metal nanomaterials, and carbon-based materials. A better understanding of biomaterial-regulated autophagy and skin regeneration and the underlying molecular mechanisms may open new possibilities for promoting skin regeneration. Moreover, this can lay the foundation for the development of more effective therapeutic approaches and novel biomaterials for clinical applications.
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Affiliation(s)
- Jin Zhang
- College of Life Science, Mudanjiang Medical University, Mudanjiang, People’s Republic of China
| | - Luxin Li
- College of Life Science, Mudanjiang Medical University, Mudanjiang, People’s Republic of China
| | - Jing Yu
- Department of Endocrinology, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, 157011, People’s Republic of China
| | - Fan Zhang
- College of Life Science, Mudanjiang Medical University, Mudanjiang, People’s Republic of China
| | - Jiayi Shi
- College of Life Science, Mudanjiang Medical University, Mudanjiang, People’s Republic of China
| | - Meiyun LI
- College of Life Science, Mudanjiang Medical University, Mudanjiang, People’s Republic of China
| | - Jianyong Liu
- Department of Vascular Surgery, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Haitao Li
- Department of Vascular Surgery, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Jie Gao
- Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, People’s Republic of China
- Jie Gao, Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, People’s Republic of China, Tel/Fax +86 21-31166666, Email
| | - Yan Wu
- College of Life Science, Mudanjiang Medical University, Mudanjiang, People’s Republic of China
- Correspondence: Yan Wu, College of Life Science, Mudanjiang Medical University, Mudanjiang, Heilongjiang, 157001, People’s Republic of China, Tel/Fax +86-453-6984647, Email
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15
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Huang JN, Cao H, Liang KY, Cui LP, Li Y. Combination therapy of hydrogel and stem cells for diabetic wound healing. World J Diabetes 2022; 13:949-961. [PMID: 36437861 PMCID: PMC9693739 DOI: 10.4239/wjd.v13.i11.949] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 09/25/2022] [Accepted: 11/02/2022] [Indexed: 11/11/2022] Open
Abstract
Diabetic wounds (DWs) are a common complication of diabetes mellitus; DWs have a low cure rate and likely recurrence, thus affecting the quality of patients’ lives. As traditional therapy cannot effectively improve DW closure, DW has become a severe clinical medical problem worldwide. Unlike routine wound healing, DW is difficult to heal because of its chronically arrested inflammatory phase. Although mesenchymal stem cells and their secreted cytokines can alleviate oxidative stress and stimulate angiogenesis in wounds, thereby promoting wound healing, the biological activity of mesenchymal stem cells is compromised by direct injection, which hinders their therapeutic effect. Hydro-gels form a three-dimensional network that mimics the extracellular matrix, which can provide shelter for stem cells in the inflammatory microenvironment with reactive oxygen species in DW, and maintains the survival and viability of stem cells. This review summarizes the mechanisms and applications of stem cells and hydrogels in treating DW; additionally, it focuses on the different applications of therapy combining hydrogel and stem cells for DW treatment.
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Affiliation(s)
- Jia-Na Huang
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Hao Cao
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Kai-Ying Liang
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Li-Ping Cui
- Endocrinology Department, Panyu Central Hospital, Guangzhou 511400, Guangdong Province, China
| | - Yan Li
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
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16
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Teng L, Maqsood M, Zhu M, Zhou Y, Kang M, Zhou J, Chen J. Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Accelerate Diabetic Wound Healing via Promoting M2 Macrophage Polarization, Angiogenesis, and Collagen Deposition. Int J Mol Sci 2022; 23:ijms231810421. [PMID: 36142334 PMCID: PMC9498995 DOI: 10.3390/ijms231810421] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/05/2022] [Accepted: 08/07/2022] [Indexed: 11/16/2022] Open
Abstract
Some scholars have suggested that the clinical application of exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs-exo) might represent a novel strategy to improve diabetic wound healing. However, the mechanisms underlying the effects of hucMSCs-exo on wound healing remain poorly understood. This study aimed to identify the mechanism of hucMSCs-exo in treating diabetic wounds. HucMSCs-exo were isolated from human umbilical cord mesenchymal stem cells (hucMSCs) and subcutaneously injected into full-thickness wounds in diabetic rats. Wound healing closure rates and histological analysis were performed. The levels of tumor necrosis factor-α (TNF-α), macrophage mannose receptor (MMR/CD206), platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31), and vascular endothelial growth factor (VEGF) were detected by immunohistochemistry. The degree of collagen deposition was examined using Masson’s trichrome staining. Gross evaluation of wound healing was carried out from day 0 to 14 post-surgery, and the wound site was harvested for histology on days 3, 7, and 14 post-wounding. HucMSCs-exo transplantation increased diabetic wound healing. In vitro, hucMSCs-exo promoted the proliferation of human umbilical vein endothelial cells (HUVECs) and NIH-3T3 cells. In vivo, hucMSCs-exo reduced wound area and inflammatory infiltration and increased collagen fibers. In addition, wound tissues in the hucMSCs-exo group had higher CD206, CD31, and VEGF expressions and lower TNF-α levels than those in the control group on day 14. Our results demonstrated that hucMSCs-exo facilitated diabetic wound repair by inducing anti-inflammatory macrophages and promoting angiogenesis and collagen deposition.
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Affiliation(s)
- Liping Teng
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China
| | - Maria Maqsood
- School of Life Sciences and Heath Engineering, Jiangnan University, Wuxi 214122, China
| | - Min Zhu
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China
| | - Yuting Zhou
- School of Life Sciences and Heath Engineering, Jiangnan University, Wuxi 214122, China
| | - Mingzhu Kang
- School of Life Sciences and Heath Engineering, Jiangnan University, Wuxi 214122, China
| | - Juan Zhou
- School of Life Sciences and Heath Engineering, Jiangnan University, Wuxi 214122, China
| | - Jinghua Chen
- School of Life Sciences and Heath Engineering, Jiangnan University, Wuxi 214122, China
- Correspondence:
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17
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Tu ZL, Lin C. [Research advances on the effects and mechanism of curcumin in promoting diabetic wound healing]. ZHONGHUA SHAO SHANG ZA ZHI = ZHONGHUA SHAOSHANG ZAZHI = CHINESE JOURNAL OF BURNS 2021; 37:391-394. [PMID: 33887887 PMCID: PMC11917206 DOI: 10.3760/cma.j.cn501120-20200224-00089] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Diabetic wound is a common complication of diabetes, and the effect of current treatment is still poor. Curcumin has many pharmacological effects, such as anti-inflammatory, anti-oxidation, antimicrobial, anti-cancer, and improving insulin resistance. In this paper, the research advances on the effects and mechanism of curcumin in promoting diabetic wound healing were mainly reviewed.
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Affiliation(s)
- Z L Tu
- Department of Burns, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - C Lin
- Department of Burns, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
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19
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Sruthi CR, Raghu KG. Advanced glycation end products and their adverse effects: The role of autophagy. J Biochem Mol Toxicol 2021; 35:e22710. [PMID: 33506967 DOI: 10.1002/jbt.22710] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 11/27/2020] [Accepted: 01/09/2021] [Indexed: 12/14/2022]
Abstract
The critical roles played by advanced glycation endproducts (AGEs) accumulation in diabetes and diabetic complications have gained intense recognition. AGEs interfere with the normal functioning of almost every organ with multiple actions like apoptosis, inflammation, protein dysfunction, mitochondrial dysfunction, and oxidative stress. However, the development of a potential treatment strategy is yet to be established. Autophagy is an evolutionarily conserved cellular process that maintains cellular homeostasis with the degradation and recycling systems. AGEs can activate autophagy signaling, which could be targeted as a therapeutic strategy against AGEs induced problems. In this review, we have provided an overview of the adverse effects of AGEs, and we put forth the notion that autophagy could be a promising targetable strategy against AGEs.
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Affiliation(s)
- C R Sruthi
- Biochemistry and Molecular Mechanism Laboratory, Agro-processing and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (NIIST), Thiruvananthapuram, Kerala, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - K G Raghu
- Biochemistry and Molecular Mechanism Laboratory, Agro-processing and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (NIIST), Thiruvananthapuram, Kerala, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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20
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Wang H, Xu Z, Zhao M, Liu G, Wu J. Advances of hydrogel dressings in diabetic wounds. Biomater Sci 2021; 9:1530-1546. [DOI: 10.1039/d0bm01747g] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The hydrogel dressings with various functions for diabetic wound treatment.
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Affiliation(s)
- Heni Wang
- Key Laboratory of Sensing Technology and Biomedical Instrument of Guangdong Province
- School of Biomedical Engineering
- Sun Yat-sen University
- Guangzhou
- PR China
| | - Zejun Xu
- Key Laboratory of Sensing Technology and Biomedical Instrument of Guangdong Province
- School of Biomedical Engineering
- Sun Yat-sen University
- Guangzhou
- PR China
| | - Meng Zhao
- Shenzhen Lansi Institute of Artificial Intelligence in Medicine
- Shenzhen
- China
| | - Guiting Liu
- Key Laboratory of Sensing Technology and Biomedical Instrument of Guangdong Province
- School of Biomedical Engineering
- Sun Yat-sen University
- Guangzhou
- PR China
| | - Jun Wu
- Key Laboratory of Sensing Technology and Biomedical Instrument of Guangdong Province
- School of Biomedical Engineering
- Sun Yat-sen University
- Guangzhou
- PR China
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21
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Sun Y, Song L, Zhang Y, Wang H, Dong X. Adipose stem cells from type 2 diabetic mice exhibit therapeutic potential in wound healing. Stem Cell Res Ther 2020; 11:298. [PMID: 32680569 PMCID: PMC7368682 DOI: 10.1186/s13287-020-01817-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 07/04/2020] [Accepted: 07/07/2020] [Indexed: 12/12/2022] Open
Abstract
Background Diabetic patients suffer from impaired wound healing. Mesenchymal stem cell (MSC) therapy represents a promising approach toward improving skin wound healing through the release of soluble growth factors and cytokines that stimulate new vessel formation and modulate inflammation. Whether adipose tissue-derived MSCs (ASCs) from type 2 diabetes (T2D) donors are suitable for skin damage repair remains largely unknown. Methods In this study, we compared the phenotype and functionality of ASCs harvested from high-fat diet (HFD) and streptozotocin (STZ)-induced T2D or control mice, and assessed their abilities to promote wound healing in an excisional wound splinting mouse model with T2D. Results T2D ASCs expressed similar cellular markers as control ASCs but secreted less hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and transforming growth factor β (TGF-β). T2D ASCs were somewhat less effective in promoting healing of the wound, as manifested by slightly reduced re-epithelialization, cutaneous appendage regeneration, and collagen III deposition in wound tissues. In vitro, T2D ASCs promoted proliferation and migration of skin fibroblasts to a comparable extent as control ASCs via suppression of inflammation and macrophage infiltration. Conclusions From these findings, we conclude that, although ASCs from T2D mice are marginally inferior to control ASCs, they possess comparable therapeutic effects in wound healing.
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Affiliation(s)
- Yongfa Sun
- College of Life Science, Qingdao Agricultural University, No. 700, Changcheng Road, Chengyang District, Qingdao, 266109, Shandong, People's Republic of China
| | - Lili Song
- College of Life Science, Qingdao Agricultural University, No. 700, Changcheng Road, Chengyang District, Qingdao, 266109, Shandong, People's Republic of China
| | - Yong Zhang
- College of Life Science, Qingdao Agricultural University, No. 700, Changcheng Road, Chengyang District, Qingdao, 266109, Shandong, People's Republic of China
| | - Hongjun Wang
- Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Xiao Dong
- College of Life Science, Qingdao Agricultural University, No. 700, Changcheng Road, Chengyang District, Qingdao, 266109, Shandong, People's Republic of China.
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22
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Wartchow KM, Rodrigues L, Lissner LJ, Federhen BC, Selistre NG, Moreira A, Gonçalves CA, Sesterheim P. Insulin-producing cells from mesenchymal stromal cells: Protection against cognitive impairment in diabetic rats depends upon implant site. Life Sci 2020; 251:117587. [PMID: 32224027 DOI: 10.1016/j.lfs.2020.117587] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 03/21/2020] [Accepted: 03/22/2020] [Indexed: 12/11/2022]
Abstract
Diabetes mellitus (DM) is a serious public health problem and can cause long-term damage to the brain, resulting in cognitive impairment in these patients. Insulin therapy for type 1 DM (DM1) can achieve overall blood glucose control, but glycemic variations can occur during injection intervals, which may contribute to some complications. Among the additional therapies available for DM1 treatment is the implantation of insulin-producing cells (IPCs) to attenuate hyperglycemia and even reverse diabetes. Here, we studied the strategy of implanting IPCs obtained from mesenchymal stromal cells (MSCs) from adipose tissue, comparing two different IPC implant sites, subcapsular renal (SR) and subcutaneous (SC), to investigate their putative protection against hippocampal damage, induced by STZ, in a rat DM1 model. Both implants improved hyperglycemia and reduced the serum content of advanced-glycated end products in diabetic rats, but serum insulin was not observed in the SC group. The SC-implanted group demonstrated ameliorated cognitive impairment (evaluated by novel object recognition) and modulation of hippocampal astroglial reactivity (evaluated by S100B and GFAP). Using GFP+ cell implants, the survival of cells at the implant sites was confirmed, as well as their migration to the pancreas and hippocampus. The presence of undifferentiated MSCs in our IPC preparation may explain the peripheral reduction in AGEs and subsequent cognitive impairment recovery, mediated by autophagic depuration and immunomodulation at the hippocampus, respectively. Together, these data reinforce the importance of MSCs for use in neuroprotective strategies, and highlight the logistic importance of the subcutaneous route for their administration.
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Affiliation(s)
- Krista Minéia Wartchow
- Federal University of Rio Grande do Sul (UFRGS), Biochemistry Post-Graduate Program, Porto Alegre, Brazil
| | - Leticia Rodrigues
- Federal University of Rio Grande do Sul (UFRGS), Biochemistry Post-Graduate Program, Porto Alegre, Brazil
| | - Lílian Juliana Lissner
- Federal University of Rio Grande do Sul (UFRGS), Biochemistry Post-Graduate Program, Porto Alegre, Brazil
| | - Barbara Carolina Federhen
- Federal University of Rio Grande do Sul (UFRGS), Biochemistry Post-Graduate Program, Porto Alegre, Brazil
| | - Nicholas Guerini Selistre
- Federal University of Rio Grande do Sul (UFRGS), Biochemistry Post-Graduate Program, Porto Alegre, Brazil
| | - Aline Moreira
- Federal University of Rio Grande do Sul (UFRGS), Biochemistry Post-Graduate Program, Porto Alegre, Brazil
| | - Carlos-Alberto Gonçalves
- Federal University of Rio Grande do Sul (UFRGS), Biochemistry Post-Graduate Program, Porto Alegre, Brazil.
| | - Patrícia Sesterheim
- Institute of Cardiology of Rio Grande do Sul, Experimental Center, Porto Alegre, Brazil
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Fei J, Ling YM, Zeng MJ, Zhang KW. Shixiang Plaster, a Traditional Chinese Medicine, Promotes Healing in a Rat Model of Diabetic Ulcer Through the receptor for Advanced Glycation End Products (RAGE)/Nuclear Factor kappa B (NF-κB) and Vascular Endothelial Growth Factor (VEGF)/Vascular Cell Adhesion Molecule-1 (VCAM-1)/Endothelial Nitric Oxide Synthase (eNOS) Signaling Pathways. Med Sci Monit 2019; 25:9446-9457. [PMID: 31825949 PMCID: PMC6925528 DOI: 10.12659/msm.918268] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background Shixiang plaster is a traditional Chinese medicine has been used to treat chronic ulcers, including diabetic ulcers. Aminoguanidine is a hydrazine derivative that inhibits the formation of advanced glycosylation end products (AGEs). This study aimed to investigate the effects of shixiang plaster and aminoguanidine on wound healing in the streptozotocin-induced rat model of diabetes and the molecular mechanisms involved. Material/Methods Sprague-Dawley rats treated with intraperitoneal streptozotocin and given surgical wounds were divided into the untreated chronic ulcer group (n=10), the aminoguanidine group (n=10), the shixiang plaster group (n=10), and the control group with sham surgery (n=10). Granulation tissue samples underwent light microscopy to evaluate angiogenesis and immunohistochemistry to identify AGE, vascular endothelial growth factor (VEGF), and CD34 expression. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot measured mRNA and protein expression of receptor for advanced glycation end products (RAGE), vascular cell adhesion molecule-1 (VCAM-1), nuclear factor kappa B (NF-κB) and endothelial nitric oxide synthase (eNOS). Results The shixiang plaster group showed a significant increase in angiogenesis in ulcer granulation tissue, significantly reduced expression of AGEs and increased expression of VEGF and CD34 expression in granulation tissue compared with the untreated chronic ulcer group (p<0.05). The shixiang plaster group showed significantly down-regulated expression of RAGE and VCAM-1 compared with the untreated chronic ulcer group (p<0.05). Shixiang plaster promoted angiogenesis by activating the NF-κB p65 associated pathway and eNOS activation. Conclusions Shixiang plaster promoted healing in a rat model of diabetic ulcer through the RAGE/NF-κB and VEGF/VCAM-1/eNOS signaling pathways.
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Affiliation(s)
- Ji Fei
- Department of Orthopedics, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China (mainland)
| | - Yi-Ming Ling
- Department of Orthopedics, Shaoxing Hospital of Traditional Chinese Medicine, Shaoxing, Zhejiang, China (mainland)
| | - Man-Jie Zeng
- Department of Orthopedics, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China (mainland)
| | - Kai-Wei Zhang
- Department of Orthopedics, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China (mainland)
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Han Y, Sun T, Han Y, Lin L, Liu C, Liu J, Yan G, Tao R. Human umbilical cord mesenchymal stem cells implantation accelerates cutaneous wound healing in diabetic rats via the Wnt signaling pathway. Eur J Med Res 2019; 24:10. [PMID: 30736851 PMCID: PMC6367839 DOI: 10.1186/s40001-019-0366-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2018] [Accepted: 01/23/2019] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE Difficulty in wound healing is one common complication of diabetes mellitus. The study explored whether the therapeutic effect of human umbilical cord mesenchymal stem cells (hUCMSCs) on diabetic ulcer wound was enhanced by the activation of the Wnt signaling pathway. METHODS Rat diabetic model was established by intraperitoneal injection of Streptozotocin (STZ). hUCMSCs were purified and seeded on the collagen-chitosan laser drilling acellular dermal matrix (CCLDADM) scaffold, which was subsequently implanted into the cutaneous wound of normal and diabetic rats, followed by daily injection of Wnt signaling pathway agonist (Wnt3a) or antagonist (sFRP3) at the edge of the scaffold. Wound healing was checked on days 7, 14, and 21, and the fibrous tissue deposition, capillaries, and epidermal regeneration at the wound were examined by hematoxylin-eosin staining. The hUCMSCs-CCLDADM scaffold was cultured in vitro and treated with Wnt3a or sFRP3, followed by evaluation of cell proliferation, cell proliferation rate, survival status, and altered protein levels in the Wnt signaling pathway using BrdU staining, CCK-8 assay, live/dead staining, and Western blotting, respectively. RESULTS On days 7 and 14 postoperatively, the speed of wound healing was significantly lower in diabetic rats than that in normal control rats. This phenomenon was significantly improved by the activation of the Wnt signaling pathway that also elevated the fibrous protein deposition and the abundance of capillary in the granulation tissue. Conversely, blockade of Wnt signaling slowed the healing of skin wound in diabetic rats. The activation of Wnt signaling pathway promoted the proliferation and differentiation and decreased the apoptosis of hUCMSCs, thereby elevating the number of living hUCMSCs on the CCLDADM scaffold, while the suppression exerted a contrary effect. CONCLUSION The activation of the Wnt signaling pathway promotes the healing of diabetic skin wound by the regulation of proliferation and differentiation of hUCMSCs on the CCLDADM scaffold.
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Affiliation(s)
- Yanfu Han
- Department of Plastic Surgery, Beijing Shijitan Hospital, Capital Medical University, 10 Tieyilu, Yangfangdian Haidian District, 100038, Beijing, People's Republic of China
| | - Tianjun Sun
- Department of Burn and Plastic Surgery, Hainan Branch of People's Liberation Army General Hospital, Haitangwan, Sanya, People's Republic of China
| | - Yanqing Han
- School of Electrical and Information Engineering, Wuhan Institute of Technology, 366 Huquan, Wuhan, People's Republic of China
| | - Lingling Lin
- Department of Burn and Plastic Surgery, Harrison International Peace Hospital, 180 Renmin East Road, Hengshui, Hebei, People's Republic of China
| | - Chang Liu
- Department of Plastic Surgery, Beijing Shijitan Hospital, Capital Medical University, 10 Tieyilu, Yangfangdian Haidian District, 100038, Beijing, People's Republic of China
| | - Jing Liu
- Department of Plastic Surgery, Beijing Shijitan Hospital, Capital Medical University, 10 Tieyilu, Yangfangdian Haidian District, 100038, Beijing, People's Republic of China
| | - Guangzhi Yan
- Department of Burn and Plastic Surgery, Harrison International Peace Hospital, 180 Renmin East Road, Hengshui, Hebei, People's Republic of China.
| | - Ran Tao
- Department of Plastic Surgery, PLA General Hospital, 28 Fuxing Road, Beijing, People's Republic of China.
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GRP78 protects CHO cells from ribosylation. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2018; 1865:629-637. [DOI: 10.1016/j.bbamcr.2018.02.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 01/29/2018] [Accepted: 02/01/2018] [Indexed: 12/28/2022]
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Alhusban A, Alkhazaleh E, El-Elimat T. Silymarin Ameliorates Diabetes-Induced Proangiogenic Response in Brain Endothelial Cells through a GSK-3 β Inhibition-Induced Reduction of VEGF Release. J Diabetes Res 2017; 2017:2537216. [PMID: 29209632 PMCID: PMC5676450 DOI: 10.1155/2017/2537216] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Accepted: 09/24/2017] [Indexed: 02/03/2023] Open
Abstract
Diabetes mellitus (DM) is a major risk factor for cardiovascular disease. Additionally, it was found to induce a dysfunctional angiogenic response in the brain that was attributed to oxidative stress. Milk thistle seed extract (silymarin) has potent antioxidant properties, though its potential use in ameliorating diabetes-induced aberrant brain angiogenesis is unknown. Glycogen synthase kinase-3β is a regulator of angiogenesis that is upregulated by diabetes. Its involvement in diabetes-induced angiogenesis is unknown. To evaluate the potential of silymarin to ameliorate diabetes-induced aberrant angiogenesis, human brain endothelial cells (HBEC-5i) were treated with 50 μg/mL advanced glycation end (AGE) products in the presence or absence of silymarin (50, 100 μM). The angiogenic potential of HBEC-5i was evaluated in terms of migration and in vitro tube formation capacities. The involvement of GSK-3β was also evaluated. AGE significantly increased the migration and tube formation rates of HBEC-5i by about onefold (p = 0.0001). Silymarin reduced AGE-induced migration in a dose-dependent manner where 50 μM reduced migration by about 50%, whereas the 100 μM completely inhibited AGE-induced migration. Similarly, silymarin 50 μg/mL blunted AGE-induced tube formation (p = 0.001). This effect was mediated through a GSK-3β-dependent inhibition of VEGF release. In conclusion, silymarin inhibits AGE-induced aberrant angiogenesis in a GSK-3β-mediated inhibition of VEGF release.
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Affiliation(s)
- Ahmed Alhusban
- Clinical Pharmacy Department, College of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan
| | - Enaam Alkhazaleh
- Clinical Pharmacy Department, College of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan
| | - Tamam El-Elimat
- Medicinal Chemistry & Pharmacognosy Department, College of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan
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