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K S, J O, N M, I T, A F, AR E. Perioperative Blood Glucose Optimization in Orthopaedic Trauma Patients. OPERATIVE TECHNIQUES IN ORTHOPAEDICS 2024; 34:101128. [DOI: 10.1016/j.oto.2024.101128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Yadav JP, Singh AK, Grishina M, Pathak P, Verma A, Kumar V, Kumar P, Patel DK. Insights into the mechanisms of diabetic wounds: pathophysiology, molecular targets, and treatment strategies through conventional and alternative therapies. Inflammopharmacology 2024; 32:149-228. [PMID: 38212535 DOI: 10.1007/s10787-023-01407-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 11/27/2023] [Indexed: 01/13/2024]
Abstract
Diabetes mellitus is a prevalent cause of mortality worldwide and can lead to several secondary issues, including DWs, which are caused by hyperglycemia, diabetic neuropathy, anemia, and ischemia. Roughly 15% of diabetic patient's experience complications related to DWs, with 25% at risk of lower limb amputations. A conventional management protocol is currently used for treating diabetic foot syndrome, which involves therapy using various substances, such as bFGF, pDGF, VEGF, EGF, IGF-I, TGF-β, skin substitutes, cytokine stimulators, cytokine inhibitors, MMPs inhibitors, gene and stem cell therapies, ECM, and angiogenesis stimulators. The protocol also includes wound cleaning, laser therapy, antibiotics, skin substitutes, HOTC therapy, and removing dead tissue. It has been observed that treatment with numerous plants and their active constituents, including Globularia Arabica, Rhus coriaria L., Neolamarckia cadamba, Olea europaea, Salvia kronenburgii, Moringa oleifera, Syzygium aromaticum, Combretum molle, and Myrtus communis, has been found to promote wound healing, reduce inflammation, stimulate angiogenesis, and cytokines production, increase growth factors production, promote keratinocyte production, and encourage fibroblast proliferation. These therapies may also reduce the need for amputations. However, there is still limited information on how to prevent and manage DWs, and further research is needed to fully understand the role of alternative treatments in managing complications of DWs. The conventional management protocol for treating diabetic foot syndrome can be expensive and may cause adverse side effects. Alternative therapies, such as medicinal plants and green synthesis of nano-formulations, may provide efficient and affordable treatments for DWs.
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Affiliation(s)
- Jagat Pal Yadav
- Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj, 211007, India.
- Pharmacology Research Laboratory, Faculty of Pharmaceutical Sciences, Rama University, Kanpur, 209217, India.
- Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj, 211007, India.
| | - Ankit Kumar Singh
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
| | - Maria Grishina
- Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University, Chelyabinsk, 454008, Russia
| | - Prateek Pathak
- Department of Pharmaceutical Analysis, Quality Assurance, and Pharmaceutical Chemistry, School of Pharmacy, GITAM (Deemed to Be University), Hyderabad, 502329, India
| | - Amita Verma
- Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj, 211007, India
| | - Vikas Kumar
- Natural Product Drug Discovery Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj, 211007, India
| | - Pradeep Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
| | - Dinesh Kumar Patel
- Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj, 211007, India.
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Mahmoud NN, Hamad K, Al Shibitini A, Juma S, Sharifi S, Gould L, Mahmoudi M. Investigating Inflammatory Markers in Wound Healing: Understanding Implications and Identifying Artifacts. ACS Pharmacol Transl Sci 2024; 7:18-27. [PMID: 38230290 PMCID: PMC10789122 DOI: 10.1021/acsptsci.3c00336] [Citation(s) in RCA: 46] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/08/2023] [Accepted: 12/13/2023] [Indexed: 01/18/2024]
Abstract
Understanding the complex interplay of pro-inflammatory and anti-inflammatory cytokines is crucial in the field of wound healing, as it holds the key to developing effective therapeutics. In the initial stages of wound healing, pro-inflammatory cytokines like IL-1β, IL-6, TNF-α, and various chemokines play vital roles in recruiting cells for debris clearance and the recruitment of growth factors. Careful regulation and timely resolution of this early inflammation are essential for optimal wound repair. As the healing process progresses, anti-inflammatory proteins such as IL-10 and IL-4 become instrumental in facilitating the transition to later stages where pro-inflammatory cytokines promote angiogenesis and wound remodeling. This Perspective underscores the complexity of inflammatory cytokines in wound healing research and emphasizes the need for comprehensive and unbiased methodologies in their evaluation. For robust and reliable results in wound-healing research, a more holistic approach is necessary-one that considers the roles, interactions, and timing of biological molecules, alongside careful sampling and evaluation strategies.
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Affiliation(s)
- Nouf N. Mahmoud
- Faculty
of Pharmacy, Al-Zaytoonah University of
Jordan, Amman 11733, Jordan
- Department
of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha 2713, Qatar
| | - Khawla Hamad
- School
of Medicine, Royal College of Surgeons in
Ireland-Bahrain, Busaiteen 228, Bahrain
| | - Aya Al Shibitini
- School
of Medicine, Royal College of Surgeons in
Ireland-Bahrain, Busaiteen 228, Bahrain
| | - Sarah Juma
- School
of Medicine, Royal College of Surgeons in
Ireland-Bahrain, Busaiteen 228, Bahrain
| | - Shahriar Sharifi
- Department
of Radiology and Precision Health Program, Michigan State University, East Lansing, Michigan 48824, United States
| | - Lisa Gould
- Warren
Alpert Medical School of Brown University, Providence, Rhode Island 02912, United
States
- South Shore
Health Center for Wound Healing, Weymouth, Massachusetts 02189, United States
| | - Morteza Mahmoudi
- Department
of Radiology and Precision Health Program, Michigan State University, East Lansing, Michigan 48824, United States
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Singh P, Sharma S, Sharma PK, Alam A. Topical Anti-ulcerogenic Effect of the Beta-adrenergic Blockers on Diabetic Foot Ulcers: Recent Advances and Future Prospectives. Curr Diabetes Rev 2024; 20:23-37. [PMID: 37867269 DOI: 10.2174/0115733998249061231009093006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 08/01/2023] [Accepted: 08/25/2023] [Indexed: 10/24/2023]
Abstract
BACKGROUND Patients with diabetes suffer from major complications like Diabetic Retinopathy, Diabetic Coronary Artery Disease, and Diabetic Foot ulcers (DFUs). Diabetes complications are a group of ailments whose recovery time is especially delayed, irrespective of the underlying reason. The longer duration of wound healing enhances the probability of problems like sepsis and amputation. The delayed healing makes it more critical for research focus. By understanding the molecular pathogenesis of diabetic wounds, it is quite easy to target the molecules involved in the healing of wounds. Recent research on beta-adrenergic blocking drugs has revealed that these classes of drugs possess therapeutic potential in the healing of DFUs. However, because the order of events in defective healing is adequately defined, it is possible to recognize moieties that are currently in the market that are recognized to aim at one or several identified molecular processes. OBJECTIVE The aim of this study was to explore some molecules with different therapeutic categories that have demonstrated favorable effects in improving diabetic wound healing, also called the repurposing of drugs. METHOD Various databases like PubMed/Medline, Google Scholar and Web of Science (WoS) of all English language articles were searched, and relevant information was collected regarding the role of beta-adrenergic blockers in diabetic wounds or diabetic foot ulcers (DFUs) using the relevant keywords for the literature review. RESULT The potential beta-blocking agents and their mechanism of action in diabetic foot ulcers were studied, and it was found that these drugs have a profound effect on diabetic foot ulcer healing as per reported literatures. CONCLUSION There is a need to move forward from preclinical studies to clinical studies to analyze clinical findings to determine the effectiveness and safety of some beta-antagonists in diabetic foot ulcer treatment.
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Affiliation(s)
- Prateek Singh
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Shweta Sharma
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Pramod Kumar Sharma
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Aftab Alam
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
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Zheng SY, Wan XX, Kambey PA, Luo Y, Hu XM, Liu YF, Shan JQ, Chen YW, Xiong K. Therapeutic role of growth factors in treating diabetic wound. World J Diabetes 2023; 14:364-395. [PMID: 37122434 PMCID: PMC10130901 DOI: 10.4239/wjd.v14.i4.364] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/16/2023] [Accepted: 03/21/2023] [Indexed: 04/12/2023] Open
Abstract
Wounds in diabetic patients, especially diabetic foot ulcers, are more difficult to heal compared with normal wounds and can easily deteriorate, leading to amputation. Common treatments cannot heal diabetic wounds or control their many complications. Growth factors are found to play important roles in regulating complex diabetic wound healing. Different growth factors such as transforming growth factor beta 1, insulin-like growth factor, and vascular endothelial growth factor play different roles in diabetic wound healing. This implies that a therapeutic modality modulating different growth factors to suit wound healing can significantly improve the treatment of diabetic wounds. Further, some current treatments have been shown to promote the healing of diabetic wounds by modulating specific growth factors. The purpose of this study was to discuss the role played by each growth factor in therapeutic approaches so as to stimulate further therapeutic thinking.
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Affiliation(s)
- Shen-Yuan Zheng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, Hunan Province, China
| | - Xin-Xing Wan
- Department of Endocrinology, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
| | - Piniel Alphayo Kambey
- Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
| | - Yan Luo
- Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Xi-Min Hu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, Hunan Province, China
| | - Yi-Fan Liu
- Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Jia-Qi Shan
- Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Yu-Wei Chen
- Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Kun Xiong
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, Hunan Province, China
- Key Laboratory of Emergency and Trauma, College of Emergency and Trauma, Hainan Medical University, Haikou 571199, Hainan Province, China
- Hunan Key Laboratory of Ophthalmology, Central South University, Changsha 410013, Hunan Province, China
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Herman A, Herman AP. Herbal Products and Their Active Constituents for Diabetic Wound Healing-Preclinical and Clinical Studies: A Systematic Review. Pharmaceutics 2023; 15:281. [PMID: 36678910 PMCID: PMC9865817 DOI: 10.3390/pharmaceutics15010281] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/06/2023] [Accepted: 01/12/2023] [Indexed: 01/19/2023] Open
Abstract
The purpose of this review is to provide verified data on the current knowledge acquired in preclinical and clinical studies regarding topically used herbal products and their active constituents (formulations and dressings) with diabetic wound healing activity. Moreover, herbal products and their active constituents used for diabetic wound infections, and various cellular and molecular mechanisms of their actions will also be described. The electronic databases were searched for articles published from 2012 to 2022. Publications with oral or systemic administration of herbal products in diabetic wound healing, published before 2012, available only as an abstract, or in languages other than English were excluded from the study. The 59 articles comparing topically used herbal products in diabetic wound healing treatment versus control treatments (placebo or active therapy) were selected. Herbal products through different mechanisms of action, including antimicrobial, anti-inflammatory, antioxidant activity, stimulation of angiogenesis, production of cytokines and growth factors, keratinocytes, and fibroblast migration and proliferation may be considered as an important support during conventional therapy or even as a substitute for synthetic drugs used for diabetic wound treatment.
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Affiliation(s)
- Anna Herman
- Chair of Drug and Cosmetics Biotechnology, Faculty of Chemistry, Warsaw University of Technology, Koszykowa 75 Street, 00-662 Warsaw, Poland
| | - Andrzej Przemysław Herman
- Department of Genetic Engineering, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3 Street, 05-110 Jabłonna, Poland
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Nasrullah MZ. Caffeic Acid Phenethyl Ester Loaded PEG-PLGA Nanoparticles Enhance Wound Healing in Diabetic Rats. Antioxidants (Basel) 2022; 12:antiox12010060. [PMID: 36670922 PMCID: PMC9854644 DOI: 10.3390/antiox12010060] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/21/2022] [Accepted: 12/26/2022] [Indexed: 12/29/2022] Open
Abstract
Delayed wound healing is a serious complication of diabetes and a main reason for foot amputation. Caffeic acid phenethyl ester (CAPE) is a main active constituent of honeybee propolis with reported appealing pharmacological activities. In the current study, CAPE was loaded onto PEG-PLGA nanoparticles and showed a particle size of 198 ± 7.3 nm and polydispersity index of 0.43 ± 0.04. An in vivo study was performed to appraise the wound-healing activity of CAPE-loaded PEG-PLGA nanoparticles (CAPE-NPs) in diabetic rats. Wound closure was significantly accelerated in rats treated with CAPE-NPs. This was confirmed via histological examinations of skin tissues that indicated expedited healing and enhanced collagen deposition. This was accompanied by observed antioxidant activity as evidenced by the prevention of lipid peroxidation and the exhaustion of superoxide dismutase (SOD) and catalase (CAT) activities. In addition, CAPE-NPs showed superior anti-inflammatory activity as compared with the regular formula of CAPE, as they prevented the expression of interleukin-6 (IL-6) as well as tumor necrosis-alpha (TNF-α). The pro-collagen actions of CAPE-NPs were highlighted by the enhanced hyroxyproline content and up-regulation of Col 1A1 mRNA expression. Furthermore, the immunohistochemial assessment of skin tissues indicated that CAPE-NPs enhance proliferation and angiogenesis, as shown by the increased expression of transforming growth factor β1 (TGF-β1) and platelet-derived growth factor subunit B (PDGF-B). In conclusion, CAPE-loaded PEG-PLGA nanoparticles possess potent healing effects in diabetic wounds. This is mediated, at least partially, by its antioxidant, anti-inflammatory, and pro-collagen as well as angiogenic activities.
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Affiliation(s)
- Mohammed Z Nasrullah
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
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Bhadauria SS, Malviya R. Advancement in Nanoformulations for the Management of Diabetic Wound Healing. Endocr Metab Immune Disord Drug Targets 2022; 22:911-926. [PMID: 35249512 DOI: 10.2174/1871530322666220304214106] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 12/01/2021] [Accepted: 01/07/2022] [Indexed: 11/22/2022]
Abstract
People with diabetes have a very slow tendency for wound healing. Wound healing is a vast process where several factors inhibit the sequence of healing. Nano formulation plays a major role during acute and chronic wound healing. The present manuscript aims to discuss the role of nanoformulation in the treatment of diabetic wound healing. Diabetes is a common disease that has harmful consequences which lead to bad health. During the literature survey, it was observed that nanotechnology has significant advantages in the treatment of diabetic wound healing. The present manuscript summarized the role of nanomaterials in wound healing, challenges in diabetic wound healing, physiology of wound healing, a limitation that comes during wound repair, and treatments available for wound healing. After a comprehensive literature survey, it can be concluded that health worker needs more focus on the area of wound healing in diabetic patients. Medical practitioners, pharmaceutical and biomedical researchers need more attention towards the utilization of nanoformulations for the treatment of wound healing, specifically in the case of diabetes.
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Affiliation(s)
- Shailendra Singh Bhadauria
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Rishabha Malviya
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
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9
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Chattopadhyay S, Teixeira LBC, Kiessling LL, McAnulty JF, Raines RT. Bifunctional Peptide that Anneals to Damaged Collagen and Clusters TGF-β Receptors Enhances Wound Healing. ACS Chem Biol 2022; 17:314-321. [PMID: 35084170 DOI: 10.1021/acschembio.1c00745] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Transforming growth factor-β (TGF-β) plays important roles in wound healing. The activity of TGF-β is initiated upon the binding of the growth factor to the extracellular domains of its receptors. We sought to facilitate the activation by clustering these extracellular domains. To do so, we used a known peptide that binds to TGF-β receptors without diminishing their affinity for TGF-β. We conjugated this peptide to a collagen-mimetic peptide that can anneal to the damaged collagen in a wound bed. We find that the conjugate enhances collagen deposition and wound closure in mice in a manner consistent with the clustering of TGF-β receptors. This strategy provides a means to upregulate the TGF-β signaling pathway without adding exogenous TGF-β and could inspire means to treat severe wounds.
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Affiliation(s)
- Sayani Chattopadhyay
- Department of Chemistry, University of Wisconsin−Madison, Madison, Wisconsin 53706, United States
| | - Leandro B. C. Teixeira
- Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin−Madison, Madison, Wisconsin 53706, United States
| | - Laura L. Kiessling
- Department of Chemistry, University of Wisconsin−Madison, Madison, Wisconsin 53706, United States
- Department of Biochemistry, University of Wisconsin−Madison, Madison, Wisconsin 53706, United States
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - Jonathan F. McAnulty
- Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin−Madison, Madison, Wisconsin 53706, United States
| | - Ronald T. Raines
- Department of Chemistry, University of Wisconsin−Madison, Madison, Wisconsin 53706, United States
- Department of Biochemistry, University of Wisconsin−Madison, Madison, Wisconsin 53706, United States
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
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Zannotti A, Greco S, Pellegrino P, Giantomassi F, Delli Carpini G, Goteri G, Ciavattini A, Ciarmela P. Macrophages and Immune Responses in Uterine Fibroids. Cells 2021; 10:cells10050982. [PMID: 33922329 PMCID: PMC8146588 DOI: 10.3390/cells10050982] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/19/2021] [Accepted: 04/20/2021] [Indexed: 12/12/2022] Open
Abstract
Uterine fibroids represent the most common benign tumors of the uterus. They are considered a typical fibrotic disorder. In fact, the extracellular matrix (ECM) proteins—above all, collagen 1A1, fibronectin and versican—are upregulated in this pathology. The uterine fibroids etiology has not yet been clarified, and this represents an important matter about their resolution. A model has been proposed according to which the formation of an altered ECM could be the result of an excessive wound healing, in turn driven by a dysregulated inflammation process. A lot of molecules act in the complex inflammatory response. Macrophages have a great flexibility since they can assume different phenotypes leading to the tissue repair process. The dysregulation of macrophage proliferation, accumulation and infiltration could lead to an uncontrolled tissue repair and to the consequent pathological fibrosis. In addition, molecules such as monocyte chemoattractant protein-1 (MCP-1), granulocyte macrophage-colony-stimulating factor (GM-CSF), transforming growth factor-beta (TGF-β), activin A and tumor necrosis factor-alfa (TNF-α) were demonstrated to play an important role in the macrophage action within the uncontrolled tissue repair that contributes to the pathological fibrosis that represents a typical feature of the uterine fibroids.
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Affiliation(s)
- Alessandro Zannotti
- Department of Specialist and Odontostomatological Clinical Sciences, Università Politecnica delle Marche, 60126 Ancona, Italy; (A.Z.); (G.D.C.); (A.C.)
- Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, 60126 Ancona, Italy; (S.G.); (P.P.)
| | - Stefania Greco
- Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, 60126 Ancona, Italy; (S.G.); (P.P.)
| | - Pamela Pellegrino
- Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, 60126 Ancona, Italy; (S.G.); (P.P.)
| | - Federica Giantomassi
- Department of Biomedical Sciences and Public Health, Università Politecnica delle Marche, 60126 Ancona, Italy; (F.G.); (G.G.)
| | - Giovanni Delli Carpini
- Department of Specialist and Odontostomatological Clinical Sciences, Università Politecnica delle Marche, 60126 Ancona, Italy; (A.Z.); (G.D.C.); (A.C.)
| | - Gaia Goteri
- Department of Biomedical Sciences and Public Health, Università Politecnica delle Marche, 60126 Ancona, Italy; (F.G.); (G.G.)
| | - Andrea Ciavattini
- Department of Specialist and Odontostomatological Clinical Sciences, Università Politecnica delle Marche, 60126 Ancona, Italy; (A.Z.); (G.D.C.); (A.C.)
| | - Pasquapina Ciarmela
- Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, 60126 Ancona, Italy; (S.G.); (P.P.)
- Correspondence: ; Tel.:+39-071-220-6270
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The Treatment of Impaired Wound Healing in Diabetes: Looking among Old Drugs. Pharmaceuticals (Basel) 2020; 13:ph13040060. [PMID: 32244718 PMCID: PMC7243111 DOI: 10.3390/ph13040060] [Citation(s) in RCA: 217] [Impact Index Per Article: 43.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 03/27/2020] [Accepted: 03/29/2020] [Indexed: 12/19/2022] Open
Abstract
Chronic wounds often occur in patients with diabetes mellitus due to the impairment of wound healing. This has negative consequences for both the patient and the medical system and considering the growing prevalence of diabetes, it will be a significant medical, social, and economic burden in the near future. Hence, the need for therapeutic alternatives to the current available treatments that, although various, do not guarantee a rapid and definite reparative process, appears necessary. We here analyzed current treatments for wound healing, but mainly focused the attention on few classes of drugs that are already in the market with different indications, but that have shown in preclinical and few clinical trials the potentiality to be used in the treatment of impaired wound healing. In particular, repurposing of the antiglycemic agents dipeptidylpeptidase 4 (DPP4) inhibitors and metformin, but also, statins and phenyotin have been analyzed. All show encouraging results in the treatment of chronic wounds, but additional, well designed studies are needed to allow these drugs access to the clinics in the therapy of impaired wound healing.
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12
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Patel S, Srivastava S, Singh MR, Singh D. Mechanistic insight into diabetic wounds: Pathogenesis, molecular targets and treatment strategies to pace wound healing. Biomed Pharmacother 2019; 112:108615. [PMID: 30784919 DOI: 10.1016/j.biopha.2019.108615] [Citation(s) in RCA: 554] [Impact Index Per Article: 92.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 01/19/2019] [Accepted: 01/23/2019] [Indexed: 12/15/2022] Open
Abstract
Wound management in diabetic patient is of an extreme clinical and social concern. The delayed and impaired healing makes it more critical for research focus. The research on impaired healing process is proceeding hastily evident by new therapeutic approaches other than conventional such as single growth factor, dual growth factor, skin substitutes, cytokine stimulators, cytokine inhibitors, matrix metalloproteinase inhibitors, gene and stem cell therapy, extracellular matrix and angiogenesis stimulators. Although numerous studies are available that support delayed wound healing in diabetes but detailed mechanistic insight including factors involved and their role still needs to be revealed. This review mainly focuses on the molecular cascades of cytokines (with growth factors) and erstwhile factors responsible for delayed wound healing, molecular targets and recent advancements in complete healing and its cure. Present article briefed recent pioneering information on possible molecular targets and treatment strategies including clinical trials to clinicians and researchers working in similar area.
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Affiliation(s)
- Satish Patel
- University Institute of Pharmacy, Pt. Ravishankar Shukla University, 492010, Raipur, C.G., India
| | - Shikha Srivastava
- University Institute of Pharmacy, Pt. Ravishankar Shukla University, 492010, Raipur, C.G., India
| | - Manju Rawat Singh
- University Institute of Pharmacy, Pt. Ravishankar Shukla University, 492010, Raipur, C.G., India
| | - Deependra Singh
- University Institute of Pharmacy, Pt. Ravishankar Shukla University, 492010, Raipur, C.G., India.
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Allameh M, Khalesi S, Khozeimeh F, Faghihian E. Comparative Evaluation of the Efficacy of Laser Therapy and Fibroblastic Growth Factor Injection on Mucosal Wound Healing in Rat Experimental Model. J Lasers Med Sci 2018; 9:194-199. [PMID: 30809331 DOI: 10.15171/jlms.2018.35] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Introduction: The aim of the present study was to compare the effects of laser and basic fibroblastic growth factor (bFGF) treatment on operative wound healing in a rat model. Methods: Sixty-six male Wistar rats were employed in this study. A 10-mm surgical wound was created on the buccal mucosa of each rat, under anesthesia, and then the rats were divided into 3 groups of 22: (1) GF group (received subcutaneous injection of bFGF), (2) laser group (treated with low-level laser irradiation), and (3) control group (received no treatment). On day 5, half of the rats in each group and on day 10 the other half, were sacrificed. Afterward, samples were taken from rats' buccal mucosa for histological assay and scoring. The data were analyzed using MannWhitney test (α =5%). Results: On day 5 there was not any significant difference between GF and control groups; however, the laser group showed clinically delayed wound coverage, compared to other groups (P<0.05). On day 10, histological examination demonstrated marked vascular granulation tissue ( GT) in GF group. Collagen production was significantly prominent in laser group compared to GF treated samples (P=0.004). Inflammation of GT in GF and laser groups was significantly less than that in control samples (P=0.005 and P=0.001, respectively). Conclusion: The components of wound matrix induced by GF and laser treatment were significantly different. Although bFGF or laser treatment of oral wounds, under the conditions of the present study, did not accelerate wound healing, they showed some other notable effects on the quality of healing.
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Affiliation(s)
- Maryam Allameh
- Dental Research Center, Department of Oral Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Saeedeh Khalesi
- Dental Material Research Center, Department of Oral and Maxillofacial Pathology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Faezeh Khozeimeh
- Dental Research Center, Department of Oral Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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14
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Abadir P, Hosseini S, Faghih M, Ansari A, Lay F, Smith B, Beselman A, Vuong D, Berger A, Tian J, Rini D, Keenahan K, Budman J, Inagami T, Fedarko N, Marti G, Harmon J, Walston J. Topical Reformulation of Valsartan for Treatment of Chronic Diabetic Wounds. J Invest Dermatol 2018; 138:434-443. [PMID: 29078982 PMCID: PMC10941026 DOI: 10.1016/j.jid.2017.09.030] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 09/05/2017] [Accepted: 09/07/2017] [Indexed: 02/07/2023]
Abstract
Chronic wounds are among the most devastating and difficult to treat consequences of diabetes. Dysregulation of the skin renin-angiotensin system is implicated in abnormal wound healing in diabetic and older adults. Given this, we sought to determine the effects of topical reformulations of the angiotensin type 1 receptor blockers losartan and valsartan and the angiotensin-converting enzyme inhibitor captopril on wound healing in diabetic and aged mice with further validation in older diabetic pigs. The application of 1% valsartan gel compared with other tested formulations and placebo facilitated and significantly accelerated closure time and increased tensile strength in mice, and was validated in the porcine model. One percent of valsartan gel-treated wounds also exhibited higher mitochondrial content, collagen deposition, phosphorylated mothers against decapentaplegic homologs 2 and 3 and common mothers against decapentaplegic homolog 4, alpha-smooth muscle actin, CD31, phospho-vascular endothelial growth factor receptor 2, and p42/44 mitogen-activated protein kinase. Knockout of the angiotensin subtype 2 receptors abolished the beneficial effects of angiotensin type 1 receptor blockers, suggesting a role for angiotensin subtype 2 receptors in chronic wound healing.
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Affiliation(s)
- Peter Abadir
- Division of Geriatrics Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
| | - Sayed Hosseini
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Mahya Faghih
- Division of Geriatrics Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Amir Ansari
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Frank Lay
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Barbara Smith
- Cell Biology Imaging Facility, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Aleksandra Beselman
- Investigational Drug Service Pharmacy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Diep Vuong
- Division of Geriatrics Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Alan Berger
- Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jing Tian
- Department of Biostatistics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - David Rini
- Art as Applied to Medicine, Division of Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Kevin Keenahan
- Department of Bioengineering Innovation, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Joshua Budman
- Department of Bioengineering Innovation, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Tadashi Inagami
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Neal Fedarko
- Division of Geriatrics Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Guy Marti
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Clinique Saint Jean, Melun, France
| | - John Harmon
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jeremy Walston
- Division of Geriatrics Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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15
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Chegini N, Rong H, Bennett B, Stone IK. Peritoneal Fluid Cytokine and Eicosanoid Levels and Their Relation to the Incidence of Peritoneal Adhesion. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/107155769900600307] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Nasser Chegini
- Department of Obstetrics and Gynecology, The Institute for Wound Research, University of Florida College of Medicine, Gainesville, Florida
| | | | | | - I. Keith Stone
- Department of Obstetrics and Gynecology, The Institute for Wound Research, University of Florida College of Medicine, Gainesville, Florida
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16
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Tang E, Khan I, Andreana S, Arany PR. Laser-activated transforming growth factor-β1 induces human β-defensin 2: implications for laser therapies for periodontitis and peri-implantitis. J Periodontal Res 2016; 52:360-367. [PMID: 27396269 DOI: 10.1111/jre.12399] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/25/2016] [Indexed: 12/20/2022]
Abstract
BACKGROUND There is increasing popularity of high-power lasers for surgical debridement and antimicrobial therapy in the management of peri-implantitis and periodontal therapy. Removal of the noxious foci would naturally promote tissue healing directly. However, there are also anecdotal reports of better healing around routine high-power laser procedures. The precise mechanisms mediating these effects remain to be fully elucidated. This work examines these low-dose laser bystander effects on oral human epithelial and fibroblasts, particularly focusing on the role of human β-defensin 2 (HBD-2 or DEFB4A), a potent factor capable of antimicrobial effects and promoting wound healing. MATERIAL AND METHODS Laser treatments were performed using a near-infrared laser (810 nm diode) at low doses. Normal human oral keratinocytes and fibroblast cells were used and HBD-2 mRNA and protein expression was assessed with real time polymerase chain reaction, western blotting and immunostaining. Role of transforming growth factor (TGF)-β1 signaling in this process was dissected using pathway-specific small molecule inhibitors. RESULTS We observed laser treatments robustly induced HBD-2 expression in an oral fibroblast cell line compared to a keratinocyte cell line. Low-dose laser treatments results in activation of the TGF-β1 pathway that mediated HBD-2 expression. The two arms of TGF-β1 signaling, Smad and non-Smad are involved in laser-mediated HBD-2 expression. CONCLUSIONS Laser-activated TGF-β1 signaling and induced expression of HBD-2, both of which are individually capable of promoting healing in tissues adjacent to high-power surgical laser applications. Moreover, the use of low-dose laser therapy itself can provide additional therapeutic benefits for effective clinical management of periodontal or peri-implant disease.
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Affiliation(s)
- E Tang
- Cell Regulation and Control Unit, NIDCR, National Institutes of Health, Bethesda, MD, USA
| | - I Khan
- Cell Regulation and Control Unit, NIDCR, National Institutes of Health, Bethesda, MD, USA
| | - S Andreana
- Restorative and Implant Dentistry, School of Dental Medicine, University at Buffalo, Buffalo, NY, USA
| | - P R Arany
- Cell Regulation and Control Unit, NIDCR, National Institutes of Health, Bethesda, MD, USA.,Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, NY, USA
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17
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The Discovery and Early Days of TGF-β: A Historical Perspective. Cold Spring Harb Perspect Biol 2016; 8:cshperspect.a021865. [PMID: 27328871 DOI: 10.1101/cshperspect.a021865] [Citation(s) in RCA: 143] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Transforming growth factors (TGFs) were discovered as activities that were secreted by cancer cells, and later by normal cells, and had the ability to phenotypically and reversibly transform immortalized fibroblasts. TGF-β distinguished itself from TGF-α because it did not bind to the same epidermal growth factor (EGF) receptor as TGF-α and, therefore, acted through different cell-surface receptors and signaling mediators. This review summarizes the discovery of TGF-β, the early developments in its molecular and biological characterization with its many biological activities in different cell and tissue contexts and its roles in disease, the realization that there is a family of secreted TGF-β-related proteins with many differentiation functions in development and activities in normal cell and tissue physiology, and the subsequent identification and characterization of the receptors and effectors that mediate TGF-β family signaling responses.
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18
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Chen N, Guo D, Guo Y, Sun Y, Bi H, Ma X. Paclitaxel inhibits cell proliferation and collagen lattice contraction via TGF-β signaling pathway in human tenon's fibroblasts in vitro. Eur J Pharmacol 2016; 777:33-40. [DOI: 10.1016/j.ejphar.2016.02.059] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Revised: 02/25/2016] [Accepted: 02/26/2016] [Indexed: 12/30/2022]
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19
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Li B, Clemons TD, Agarwal V, Kretzmann J, Bradshaw M, Toshniwal P, Smith NM, Li S, Fear M, Wood FM, Swaminathan Iyer K. Regulation of collagen expression using nanoparticle mediated inhibition of TGF-β activation. NEW J CHEM 2016. [DOI: 10.1039/c5nj03115j] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Polymeric nanoparticle for delivery of an effective anti-fibrotic agent in an in vitro model of scarring.
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20
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Arndt S, Landthaler M, Zimmermann JL, Unger P, Wacker E, Shimizu T, Li YF, Morfill GE, Bosserhoff AK, Karrer S. Effects of cold atmospheric plasma (CAP) on ß-defensins, inflammatory cytokines, and apoptosis-related molecules in keratinocytes in vitro and in vivo. PLoS One 2015; 10:e0120041. [PMID: 25768736 PMCID: PMC4359157 DOI: 10.1371/journal.pone.0120041] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2014] [Accepted: 01/26/2015] [Indexed: 11/18/2022] Open
Abstract
Cold atmospheric plasma (CAP) has been gaining increasing interest as a new approach for the treatment of skin diseases or wounds. Although this approach has demonstrated promising antibacterial activity, its exact mechanism of action remains unclear. This study explored in vitro and in vivo whether CAP influences gene expression and molecular mechanisms in keratinocytes. Our results revealed that a 2 min CAP treatment using the MicroPlaSter ß in analogy to the performed clinical studies for wound treatment induces expression of IL-8, TGF-ß1, and TGF-ß2. In vitro and in vivo assays indicated that keratinocyte proliferation, migration, and apoptotic mechanisms were not affected by the CAP treatment under the applied conditions. Further, we observed that antimicrobial peptides of the ß-defensin family are upregulated after CAP treatment. In summary, our results suggest that a 2 min application of CAP induces gene expression of key regulators important for inflammation and wound healing without causing proliferation, migration or cell death in keratinocytes. The induction of ß-defensins in keratinocytes describes an absolutely new plasma strategy. Activation of antimicrobial peptides supports the well-known antibacterial effect of CAP treatment, whereas the mechanism of ß-defensin activation by CAP is not investigated so far.
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Affiliation(s)
- Stephanie Arndt
- Institute of Pathology, University Regensburg, D-93042 Regensburg, Germany
| | - Michael Landthaler
- Department of Dermatology, University Hospital Regensburg, D-93042 Regensburg, Germany
| | - Julia L. Zimmermann
- Max Planck Institute for Extraterrestrial Physics, D-85748 Garching, Germany
| | - Petra Unger
- Department of Dermatology, University Hospital Regensburg, D-93042 Regensburg, Germany
| | - Eva Wacker
- Institute of Pathology, University Regensburg, D-93042 Regensburg, Germany
| | - Tetsuji Shimizu
- Max Planck Institute for Extraterrestrial Physics, D-85748 Garching, Germany
| | - Yang-Fang Li
- Max Planck Institute for Extraterrestrial Physics, D-85748 Garching, Germany
| | - Gregor E. Morfill
- Max Planck Institute for Extraterrestrial Physics, D-85748 Garching, Germany
| | - Anja-Katrin Bosserhoff
- Institute of Biochemistry and Molecular Medicine, University Erlangen, D-91054—Erlangen, Germany
| | - Sigrid Karrer
- Department of Dermatology, University Hospital Regensburg, D-93042 Regensburg, Germany
- * E-mail:
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21
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FOXO1, TGF-β regulation and wound healing. Int J Mol Sci 2014; 15:16257-69. [PMID: 25226535 PMCID: PMC4200873 DOI: 10.3390/ijms150916257] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Revised: 08/13/2014] [Accepted: 08/14/2014] [Indexed: 01/10/2023] Open
Abstract
Re-epithelialization is a complex process that involves migration and proliferation of keratinocytes, in addition to the production of cytokines and growth factors that affect other cells. The induction of transcription factors during these processes is crucial for successful wound healing. The transcription factor forkhead boxO-1 (FOXO1) has recently been found to be an important regulator of wound healing. In particular, FOXO1 has significant effects through regulation of transforming growth factor-beta (TGF-β) expression and protecting keratinocytes from oxidative stress. In the absence of FOXO1, there is increased oxidative damage, reduced TGF-β1 expression, reduced migration and proliferation of keratinocytes and increased keratinocytes apoptosis leading to impaired re-epithelialization of wounds.
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22
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Park JY, Lee J, Jeong M, Min S, Kim SY, Lee H, Lim Y, Park HJ. Effect of Hominis Placenta on cutaneous wound healing in normal and diabetic mice. Nutr Res Pract 2014; 8:404-9. [PMID: 25110560 PMCID: PMC4122712 DOI: 10.4162/nrp.2014.8.4.404] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 01/16/2014] [Accepted: 01/25/2014] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND/OBJECTIVES The number of diabetic patients has recently shown a rapid increase, and delayed wound healing is a major clinical complication in diabetes. In this study, the wound healing effect of Hominis placenta (HP) treatment was investigated in normal and streptozotocin-induced diabetic mice. MATERIALS/METHODS Four full thickness wounds were created using a 4 mm biopsy punch on the dorsum. HP was injected subcutaneously at the middle region of the upper and lower wounds. Wounds were digitally photographed and wound size was measured every other day until the 14th day. Wound closure rate was analyzed using CANVAS 7SE software. Wound tissues were collected on days 2, 6, and 14 after wounding for H/E, immunohistochemistry for FGF2, and Masson's trichrome staining for collagen study. RESULTS Significantly faster wound closure rates were observed in the HP treated group than in normal and diabetes control mice on days 6 and 8. Treatment with HP resulted in reduced localization of inflammatory cells in wounded skin at day 6 in normal mice and at day 14 in diabetic mice (P < 0.01). Expression of fibroblast growth factor (FGF) 2 showed a significant increase in the HP treated group on day 14 in both normal (P < 0.01) and diabetic mice (P < 0.05). In addition, HP treated groups showed a thicker collagen layer than no treatment groups, which was remarkable on the last day, day 14, in both normal and diabetic mice. CONCLUSIONS Taken together, HP treatment has a beneficial effect on acceleration of cutaneous wound healing via regulation of the entire wound healing process, including inflammation, proliferation, and remodeling.
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Affiliation(s)
- Ji-Yeun Park
- Studies of Translational Acupuncture Research, Acupuncture and Meridian Science Research Center, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Korea. ; Department of Korean Medical Science, Graduate School of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Korea
| | - Jiyoung Lee
- Studies of Translational Acupuncture Research, Acupuncture and Meridian Science Research Center, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Korea
| | - Minsu Jeong
- Happy Kyung Hee Korean Medicine Clinic, Banrim-dong, Sungsan-gu, Changwon, Kyungbuk 642-180, Korea
| | - Seorim Min
- Studies of Translational Acupuncture Research, Acupuncture and Meridian Science Research Center, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Korea. ; Department of Korean Medical Science, Graduate School of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Korea
| | - Song-Yi Kim
- Studies of Translational Acupuncture Research, Acupuncture and Meridian Science Research Center, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Korea
| | - Hyejung Lee
- Studies of Translational Acupuncture Research, Acupuncture and Meridian Science Research Center, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Korea. ; Department of Korean Medical Science, Graduate School of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Korea
| | - Yunsook Lim
- Department of Food and Nutrition, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Korea
| | - Hi-Joon Park
- Studies of Translational Acupuncture Research, Acupuncture and Meridian Science Research Center, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Korea. ; Department of Korean Medical Science, Graduate School of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Korea
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23
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Liao Y, Itoh M, Yang A, Zhu H, Roberts S, Highet AM, Latshaw S, Mitchell K, Van De Ven C, Christiano A, Cairo MS. Human Cord Blood-Derived Unrestricted Somatic Stem Cells Promote Wound Healing and have Therapeutic Potential for Patients with Recessive Dystrophic Epidermolysis Bullosa. Cell Transplant 2014; 23:303-17. [DOI: 10.3727/096368913x663569] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Human umbilical cord blood (CB)-derived unrestricted somatic stem cells (USSCs) have previously been demonstrated to have a broad differentiation potential and regenerative beneficial effects when administered in animal models of multiple degenerative diseases. Here we demonstrated that USSCs could be induced to express genes that hallmark keratinocyte differentiation. We also demonstrated that USSCs express type VII collagen (C7), a protein that is absent or defective in patients with an inherited skin disease, recessive dystrophic epidermolysis bullosa (RDEB). In mice with full-thickness excisional wounds, a single intradermal injection of USSCs at a 1-cm distance to the wound edge resulted in significantly accelerated wound healing. USSC-treated wounds displayed a higher density of CD31+ cells, and the wounds healed with a significant increase in skin appendages. These beneficial effects were demonstrated without apparent differentiation of the injected USSCs into keratinocytes or endothelial cells. In vivo bioluminescent imaging (BLI) revealed specific migration of USSCs modified with a luciferase reporter gene, from a distant intradermal injection site to the wound, as well as following systemic injection of USSCs. These data suggest that CB-derived USSCs could significantly contribute to wound repair and be potentially used in cell therapy for patients with RDEB.
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Affiliation(s)
- Yanling Liao
- Department of Pediatrics, New York Medical College, Valhalla, NY, USA
| | - Munenari Itoh
- Department of Dermatology, Jikei University School of Medicine, Tokyo, Japan
| | - Albert Yang
- Department of Pediatrics, New York Medical College, Valhalla, NY, USA
| | - Hongwen Zhu
- Department of Pediatrics, New York Medical College, Valhalla, NY, USA
| | - Samantha Roberts
- Department of Pediatrics, New York Medical College, Valhalla, NY, USA
| | | | - Shaun Latshaw
- Department of Pediatrics, New York Medical College, Valhalla, NY, USA
| | - Kelly Mitchell
- Department of Pediatrics, New York Medical College, Valhalla, NY, USA
| | | | - Angela Christiano
- Department of Dermatology, Columbia University Medical Center, New York, NY, USA
| | - Mitchell S. Cairo
- Department of Pediatrics, New York Medical College, Valhalla, NY, USA
- Department of Medicine, New York Medical College, Valhalla, NY, USA
- Department of Pathology, New York Medical College, Valhalla, NY, USA
- Immunology and Microbiology, New York Medical College, Valhalla, NY, USA
- Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA
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24
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Slovák M, Štibrániová I, Hajnická V, Nuttall PA. Antiplatelet-derived growth factor (PDGF) activity in the saliva of ixodid ticks is linked with their long mouthparts. Parasite Immunol 2014; 36:32-42. [PMID: 24102426 DOI: 10.1111/pim.12075] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Accepted: 09/12/2013] [Indexed: 12/31/2022]
Abstract
The saliva of blood-feeding arthropods modulates their vertebrate hosts' haemostatic, inflammatory and immune responses to facilitate blood feeding. In a previous study, we showed that salivary gland products from ixodid tick species also manipulate the wound-healing response by targeting at least four different mammalian growth factors: transforming growth factor β1, hepatocyte growth factor, fibroblast growth factor 2 and platelet-derived growth factor (PDGF). In addition, species that showed PDGF-binding activity also inhibited cell proliferation in vitro and induced changes in cell morphology accompanied by disruption of the actin cytoskeleton. Here, we show a correlation between the length of the tick hypostome, the sclerotized feeding tube of the mouthparts inserted into the host's skin and anti-PDGF activity. This apparent link between hypostome length, and hence the potential depth of skin damage, and PDGF-binding activity was not apparent for the other growth factors or for other cytokines important in wound healing (keratinocyte growth factor, interleukin 6 and stromal cell-derived factor 1). However, PDGF-binding activity was no longer correlated with anti-cell activities, indicating that an additional as yet unidentified activity in tick saliva may affect cellular changes in wound repair.
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Affiliation(s)
- M Slovák
- Institute of Zoology, Slovak Academy of Sciences, Bratislava, Slovakia
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25
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Gómez-Gil V, Pascual G, Pérez-Köhler B, Cifuentes A, Buján J, Bellón JM. Involvement of transforming growth factor-β3 and betaglycan in the cytoarchitecture of postoperative omental adhesions. J Surg Res 2013; 187:699-711. [PMID: 24332552 DOI: 10.1016/j.jss.2013.11.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Revised: 11/06/2013] [Accepted: 11/07/2013] [Indexed: 01/03/2023]
Abstract
BACKGROUND Adhesions commonly appear in patients after abdominal surgery, with considerable individual variation in adhesion composition and severity of the repair process. Here, we address the influence of transforming growth factor (TGF)-β3 and betaglycan in this response, in relation to TGF-β1, in an adhesiogenic rabbit model. MATERIALS AND METHODS Omental adhesions were recovered 3, 7, 14, and 90 d after the implantation of a polypropylene mesh on the parietal peritoneum in New Zealand White rabbits. Omentum from nonoperated animals served as control. Tissue specimens were examined for TGF-β3 and TGF-β1 (Western blotting, reverse transcription-polymerase chain reaction), and TGF-β1:TGF-β3 messenger RNA and protein expression ratios were analyzed. Immunohistochemical detection of TGF-β3 and betaglycan was performed. RESULTS Injury to the omentum led to mobilization of TGF-β3 and betaglycan-expressing cells from milky spots. Fibrous zones in adhesions were simultaneous to the presence of TGF-β1 and the membrane-bound form of betaglycan (7-d adhesions), whereas soluble betaglycan appeared in TGF-β1-positive areas showing limited fibrosis (3-d adhesions). The elevated expression of TGF-β3 concurrent with the presence of membrane-bound form of betaglycan was observed in zones of adipose regeneration (14-d adhesions), whereas zones of fibrous consistency were negative for TGF-β3. CONCLUSIONS Milky spots on the omentum contain inflammatory/immune cells positive for TGF-β3, TGF-β1, and betaglycan, playing a role in the damaged omentum repair. Our observations support the contribution of TGF-β3 to tissue repair through adipose tissue regeneration and the profibrotic role of TGF-β1 and suggest that these effects on the local wound repair response could be driven by the expression of betaglycan in its soluble or membrane-bound form.
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Affiliation(s)
- Verónica Gómez-Gil
- Department of Medicine and Medical Specialties, Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, Madrid, Spain
| | - Gemma Pascual
- Department of Medicine and Medical Specialties, Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, Madrid, Spain
| | - Bárbara Pérez-Köhler
- Department of Surgery, Medical and Social Sciences, Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, Madrid, Spain
| | - Alberto Cifuentes
- Department of Medicine and Medical Specialties, Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, Madrid, Spain
| | - Julia Buján
- Department of Medicine and Medical Specialties, Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, Madrid, Spain
| | - Juan M Bellón
- Department of Surgery, Medical and Social Sciences, Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, Madrid, Spain.
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Lee J, Han SY, Ji AR, Park JK, Hong IH, Ki MR, Lee EM, Kim AY, Lee EJ, Hwang JS, Lee J, Lee DG, Jeong KS. Antimicrobial effects of coprisin on wounds infected with Staphylococcus aureus in rats. Wound Repair Regen 2013; 21:876-82. [PMID: 24134388 DOI: 10.1111/wrr.12112] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2013] [Accepted: 08/12/2013] [Indexed: 12/30/2022]
Abstract
Antimicrobial peptides (AMPs) are naturally produced antibiotics that play important roles in host defense mechanisms. These proteins are found in variety of animal and plant species. The antibiotic effects of AMPs are gaining attention for use in human medicine. In this study, the antimicrobial effects of coprisin, a novel AMP isolated from the dung beetle (Copris tripartitus), were evaluated. The peptide was used to treat rats with wounds infected with Staphylococcus aureus. Coprisin accelerated wound closure both grossly and microscopically compared with the untreated group. Additionally, treatment with this peptide decreased phosphorylated-Smad2/3 (p-Smad2/3) levels, a downstream factor of the transforming growth factor-β signaling pathway which is believed to inhibit reepithelization, in the nucleus and cytoplasm of regenerating cells. Moreover, increased cell populations and angiogenesis were observed in lesions treated with coprisin, suggesting that this peptide promotes wound healing via its antimicrobial activity against S. aureus. Our results demonstrated that coprisin is a potential therapeutic agent that can possibly replace traditional antibiotics and overcome microbial resistance.
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Affiliation(s)
- Jingoo Lee
- Department of Pathology, College of Veterinary Medicine, Daegu, Gyenonggi-do, Republic of Korea
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Enhancement of wound closure in diabetic mice by ex vivo expanded cord blood CD34+ cells. Cell Mol Biol Lett 2013; 18:263-83. [PMID: 23666595 PMCID: PMC6275982 DOI: 10.2478/s11658-013-0089-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Accepted: 04/18/2013] [Indexed: 12/11/2022] Open
Abstract
Diabetes can impair wound closure, which can give rise to major clinical problems. Most treatments for wound repair in diabetes remain ineffective. This study aimed to investigate the influence on wound closure of treatments using expanded human cord blood CD34+ cells (CB-CD34+ cells), freshly isolated CB-CD34+ cells and a cytokine cocktail. The test subjects were mice with streptozotocin-induced diabetes. Wounds treated with fresh CB-CD34+ cells showed more rapid repair than mice given the PBS control. Injection of expanded CB-CD34+ cells improved wound closure significantly, whereas the injection of the cytokine cocktail alone did not improve wound repair. The results also demonstrated a significant decrease in epithelial gaps and advanced re-epithelialization over the wound bed area after treatment with either expanded CB-CD34+ cells or freshly isolated cells compared with the control. In addition, treatments with both CB-CD34+ cells and the cytokine cocktail were shown to promote recruitment of CD31+-endothelial cells in the wounds. Both the CB-CD34+ cell population and the cytokine treatments also enhanced the recruitment of CD68-positive cells in the early stages (day 3) of treatment compared with PBS control, although the degree of this enhancement was found to decline in the later stages (day 9). These results demonstrated that expanded CB-CD34+ cells or freshly isolated CB-CD34+ cells could accelerate wound repair by increasing the recruitment of macrophages and capillaries and the reepithelialization over the wound bed area. Our data suggest an effective role in wound closure for both ex vivo expanded CB-CD34+ cells and freshly isolated cells, and these may serve as therapeutic options for wound treatment for diabetic patients. Wound closure acceleration by expanded CB-CD34+ cells also breaks the insufficient quantity obstacle of stem cells per unit of cord blood and other stem cell sources, which indicates a broader potential for autologous transplantation.
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Lee DM, Bhat AR, Kim YW, Shin DH, Kim JY, Kim KJ, Lee KH, Cheon YP, Chun T, Choi I. Effects of porcine testis extract on wound healing in rat. Anim Cells Syst (Seoul) 2012. [DOI: 10.1080/19768354.2012.726645] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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Alves CC, Torrinhas RS, Giorgi R, Brentani MM, Logullo AF, Waitzberg DL. TGF-β1 expression in wound healing is acutely affected by experimental malnutrition and early enteral feeding. Int Wound J 2012. [PMID: 23194083 DOI: 10.1111/j.1742-481x.2012.01120.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Malnutrition is associated with the delay or failure of healing. We assessed the effect of experimental malnutrition and early enteral feeding with standard diet or diet supplemented with arginine and antioxidants on the levels of mRNA encoding growth factors in acute, open wound healing. Standardised cutaneous dorsal wounds and gastrostomies for enteral feeding were created in malnourished (M, n = 27) and eutrophic control (E, n = 30) Lewis male adult rats. Both M and E rats received isocaloric and isonitrogenous regimens with oral chow and saline (C), standard (S) or supplemented (A) enteral diets. On post-trauma day 7, mRNA levels of growth factor genes were analysed in wound granulation tissue by reverse transcription polymerase chain reaction (RT-PCR). M(C) rats had significantly lower transforming growth factor β(TGF-β1 ) mRNA levels than E(C) rats (2·58 ± 0·83 versus 3·53 ± 0·57, P < 0·01) and in comparison with M(S) and M(A) rats (4·66 ± 2·49 and 4·61 ± 2·11, respectively; P < 0·05). VEGF and KGF-7 mRNA levels were lower in M(A) rats than in E(A) rats (0·74 ± 0·16 versus 1·25 ± 0·66; and 1·07 ± 0·45 versus 1·79 ± 0·89, respectively; P≤ 0·04), but did not differ from levels in E(C) and M(C) animals. In experimental open acute wound healing, previous malnutrition decreased local mRNA levels of TGF-β1 genes, which was minimised by early enteral feeding with standard or supplemented diets.
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Affiliation(s)
- Claudia Cristina Alves
- Laboratory of Nutrition and Metabolic Surgery of the Digestive System (LIM 35), Gastroenterology Department, University of São Paulo Medical School (FMUSP), São Paulo, Brazil; University of São Paulo, NAPAN, Food and Nutrition Research Center, São Paulo, Brazil
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Rafehi H, Ververis K, Balcerczyk A, Ziemann M, Ooi J, Hu S, Kwa FAA, Loveridge SJ, Georgiadis GT, El-Osta A, Karagiannis TC. Investigation of the biological properties of Cinnulin PF in the context of diabetes: mechanistic insights by genome-wide mRNA-Seq analysis. PATHOBIOLOGY OF AGING & AGE RELATED DISEASES 2012; 2:PBA-2-11905. [PMID: 22953038 PMCID: PMC3417697 DOI: 10.3402/pba.v2i0.11905] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2011] [Revised: 01/17/2012] [Accepted: 02/01/2012] [Indexed: 01/20/2023]
Abstract
The accumulating evidence of the beneficial effects of cinnamon (Cinnamomum burmanni) in type-2 diabetes, a chronic age-associated disease, has prompted the commercialisation of various supplemental forms of the spice. One such supplement, Cinnulin PF®, represents the water soluble fraction containing relatively high levels of the double-linked procyanidin type-A polymers of flavanoids. The overall aim of this study was to utilize genome-wide mRNA-Seq analysis to characterise the changes in gene expression caused by Cinnulin PF in immortalised human keratinocytes and microvascular endothelial cells, which are relevant with respect to diabetic complications. In summary, our findings provide insights into the mechanisms of action of Cinnulin PF in diabetes and diabetic complications. More generally, we identify relevant candidate genes which could provide the basis for further investigation.
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Affiliation(s)
- Haloom Rafehi
- Epigenomic Medicine, Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, VIC., Australia
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Regenerative phenotype in mice with a point mutation in transforming growth factor beta type I receptor (TGFBR1). Proc Natl Acad Sci U S A 2011; 108:14560-5. [PMID: 21841138 DOI: 10.1073/pnas.1111056108] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Regeneration of peripheral differentiated tissue in mammals is rare, and regulators of this process are largely unknown. We carried out a forward genetic screen in mice using N-ethyl-N-nitrosourea mutagenesis to identify genetic mutations that affect regenerative healing in vivo. More than 400 pedigrees were screened for closure of a through-and-through punch wound in the mouse ear. This led to the identification of a single pedigree with a heritable, fast, and regenerative wound-healing phenotype. Within 5 wk after ear-punch, a threefold decrease in the diameter of the wound was observed in the mutant mice compared with the wild-type mice. At 22 wk, new cartilage, hair follicles, and sebaceous glands were observed in the newly generated tissue. This trait was mapped to a point mutation in a receptor for TGF-β, TGFBR1. Mouse embryonic fibroblasts from the affected mice had increased expression of a subset of TGF-β target genes, suggesting that the mutation caused partial activation of the receptor. Further, bone marrow stromal cells from the mutant mice more readily differentiated to chondrogenic precursors, providing a plausible explanation for the enhanced development of cartilage islands in the regenerated ears. This mutant mouse strain provides a unique model to further explore regeneration in mammals and, in particular, the role of TGFBR1 in chondrogenesis and regenerative wound healing.
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Rustad KC, Sorkin M, Levi B, Longaker MT, Gurtner GC. Strategies for organ level tissue engineering. Organogenesis 2011; 6:151-7. [PMID: 21197216 DOI: 10.4161/org.6.3.12139] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2010] [Revised: 04/16/2010] [Accepted: 04/21/2010] [Indexed: 01/22/2023] Open
Abstract
The field of tissue engineering has made considerable strides since it was first described in the late 1980s. The advent and subsequent boom in stem cell biology, emergence of novel technologies for biomaterial development and further understanding of developmental biology have contributed to this accelerated progress. However, continued efforts to translate tissue-engineering strategies into clinical therapies have been hampered by the problems associated with scaling up laboratory methods to produce large, complex tissues. The significant challenges faced by tissue engineers include the production of an intact vasculature within a tissue-engineered construct and recapitulation of the size and complexity of a whole organ. Here we review the basic components necessary for bioengineering organs-biomaterials, cells and bioactive molecules-and discuss various approaches for augmenting these principles to achieve organ level tissue engineering. Ultimately, the successful translation of tissue-engineered constructs into everyday clinical practice will depend upon the ability of the tissue engineer to "scale up" every aspect of the research and development process.
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Affiliation(s)
- Kristine C Rustad
- Stanford University, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford, CA, USA
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Abiko Y, Selimovic D. The mechanism of protracted wound healing on oral mucosa in diabetes. Review. Bosn J Basic Med Sci 2011; 10:186-91. [PMID: 20846123 DOI: 10.17305/bjbms.2010.2683] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Diabetic patients increase their body's susceptibility to infection and diabetes is a risk factor for periodontal diseases and oral infection. Although many studies showed the mechanism of impaired wound healing in diabetes, there are still arguments to shed light on what kind of factors, including local and systemic factors are involved in the protracted wound healing. This review article summarizes reports on the wound healing in diabetes and discusses the mechanism of the protracted wound healing of the oral mucosa in diabetes. Delayed vascularization, reduction in blood flow, decline in innate immunity, decreases in growth factor production, and psychological stresses may be involved in the protracted wound healing of the oral mucosa in diabetics.
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Affiliation(s)
- Yoshihiro Abiko
- Department of Dental Science, Division of Oral Medicine and Pathology, Institute of Personalized Medical Science, Health Sciences University of Hokkaido, 2-5 Ainosato, Kita-ku, Sapporo, Hokkaido, 0028072, Japan
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Li Z, Sun Y, Min W, Zhang D. Correlation between overexpression of transforming growth factor-beta 1 in occluded fallopian tubes and postsurgical pregnancy among infertile women. Int J Gynaecol Obstet 2010; 112:11-4. [PMID: 20837351 DOI: 10.1016/j.ijgo.2010.07.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2010] [Revised: 07/15/2010] [Accepted: 08/13/2010] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To compare the expression profiles of transforming growth factor-beta 1 (TGF-β1) and its receptors in occluded tubes of infertile women with those of control patients and to evaluate the potential correlation with postsurgical pregnancy outcome. METHODS The expression profiles of TGF-β1, TGF-β1R1, and TGF-β1R2 in occluded fallopian tubes were compared using immunohistochemistry between 60 infertile patients with adhered tubes and 60 control patients with normal tubes; potential correlations with postsurgical fertility were evaluated at 2-year follow up. RESULTS Immunostainings of TGF-β1, TGF-β1R1, and TGF-β1R2 were all significantly elevated in patients with adhered tubes compared with normal specimens (P<0.001). In adhered specimens, correlation analyses showed positive correlations between TGF-β1 and TGF-β1R1 (P=0.008), and TGF-β1 and TGF-β1R2 (P=0.035). At 2-year follow up, 32 of the 60 infertile women had achieved normal pregnancies, 5 had had ectopic pregnancies, and 23 remained infertile. Correlation analysis showed that TGF-β1 expression level was negatively correlated with pregnancy outcome (r=-0.445, P<0.001), independent of adhesion severity or patient age. CONCLUSION TGF-β1 expression was independently correlated with the postsurgical pregnancy outcome among infertile women.
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Affiliation(s)
- Zhengyu Li
- Department of Gynecology and Obstetrics, West China Second Hospital, Sichuan University, Chengdu, China
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Jo Y, Han SU, Kim YJ, Kim JH, Kim ST, Kim SJ, Hahm KB. Suppressed Gastric Mucosal TGF-beta1 Increases Susceptibility to H. pylori-Induced Gastric Inflammation and Ulceration: A Stupid Host Defense Response. Gut Liver 2010; 4:43-53. [PMID: 20479912 DOI: 10.5009/gnl.2010.4.1.43] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2009] [Accepted: 11/12/2009] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND/AIMS Loss of transforming growth factor beta1 (TGF-beta1) exhibits a similar pathology to that seen in a subset of individuals infected with Helicobacter pylori, including propagated gastric inflammation, oxidative stress, and autoimmune features. We thus hypothesized that gastric mucosal TGF-beta1 levels could be used to determine the outcome after H. pylori infection. METHODS Northern blot for the TGF-beta1 transcript, staining of TGF-beta1 expression, luciferase reporter assay, and enzyme-linked immunosorbent assay for TGF-beta1 levels were performed at different times after H. pylori infection. RESULTS The TGF-beta1 level was markedly lower in patients with H. pylori-induced gastritis than in patients with a similar degree of gastritis induced by nonsteroidal anti-inflammatory drugs. There was a significant negative correlation between the severity of inflammation and gastric mucosal TGF-beta1 levels. SNU-16 cells showing intact TGF-beta signaling exhibited a marked decrease in TGF-beta1 expression, whereas SNU-638 cells defective in TGF-beta signaling exhibited no such decrease after H. pylori infection. The decreased expressions of TGF-beta1 in SNU-16 cells recovered to normal after 24 hr of H. pylori infection, but lasted very spatial times, suggesting that attenuated expression of TGF-beta1 is a host defense mechanism to avoid attachment of H. pylori. CONCLUSIONS H. pylori infection was associated with depressed gastric mucosal TGF-beta1 for up to 24 hr, but this apparent strategy for rescuing cells from H. pylori attachment exacerbated the gastric inflammation.
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Affiliation(s)
- Yunjeong Jo
- Laboratory of Cell Regulation and Carcinogenesis, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Korea
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Beyond epithelial to mesenchymal transition: a novel role for the transcription factor Snail in inflammation and wound healing. J Gastrointest Surg 2010; 14:388-97. [PMID: 19856033 DOI: 10.1007/s11605-009-1068-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2009] [Accepted: 10/06/2009] [Indexed: 01/31/2023]
Abstract
INTRODUCTION Snail, a transcription factor linked to epithelial to mesenchymal transition (EMT) during embryonic development and tumor progression, is associated with migration of cells. During inflammation and tissue injury, cell movement is also observed to provide the first line of defense against bacteria and to promote wound healing. Therefore, we studied the function of Snail in activated macrophages in a variety of inflammatory processes. MATERIALS AND METHODS In this study, we examined the expression and localization of Snail during inflammation and tissue injury in rats and human tissue specimens, by immunohistochemistry, Western blot, and real-time PCR. We investigated Snail expression after stimulation of macrophages with TGF-beta1, LPS, Interleukin-8, and MMP-3 in vitro. To further understand the role of Snail in activated macrophages, we used Stealth siRNA against Snail, transfected the human macrophage cell line THP-1, and measured migration of cells in an in vitro invasion assay. RESULTS AND DISCUSSION We found a strong, transient, and time-dependent activation of Snail in migrating macrophages at the sites of injury in vivo and in vitro, as well as in patients with inflammatory bowel disease. Furthermore, we showed that induction of Snail in macrophages is dependent on TGF-beta1 signaling pathway. Downregulation of Snail by Stealth siRNA led to impaired migration of THP-1 cells in an invasion assay after stimulation with TGF-beta1. CONCLUSION We conclude that TGF-beta1 induced migration of activated macrophages during inflammation and wound healing is mediated by snail. These results give insights in a novel EMT-like mechanism present in immune cell movement during tissue injury.
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Martinez-Ferrer M, Afshar-Sherif AR, Uwamariya C, de Crombrugghe B, Davidson JM, Bhowmick NA. Dermal transforming growth factor-beta responsiveness mediates wound contraction and epithelial closure. THE AMERICAN JOURNAL OF PATHOLOGY 2009; 176:98-107. [PMID: 19959810 DOI: 10.2353/ajpath.2010.090283] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Stromal-epithelial interactions are important during wound healing. Transforming growth factor-beta (TGF-beta) signaling at the wound site has been implicated in re-epithelization, inflammatory infiltration, wound contraction, and extracellular matrix deposition and remodeling. Ultimately, TGF-beta is central to dermal scarring. Because scarless embryonic wounds are associated with the lack of dermal TGF-beta signaling, we studied the role of TGF-beta signaling specifically in dermal fibroblasts through the development of a novel, inducible, conditional, and fibroblastic TGF-beta type II receptor knockout (Tgfbr2(dermalKO)) mouse model. Full thickness excisional wounds were studied in control and Tgfbr2(dermalKO) back skin. The Tgfbr2(dermalKO) wounds had accelerated re-epithelization and closure compared with controls, resurfacing within 4 days of healing. The loss of TGF-beta signaling in the dermis resulted in reduced collagen deposition and remodeling associated with a reduced extent of wound contraction and elevated macrophage infiltration. Tgfbr2(dermalKO) and control skin had similar numbers of myofibroblastic cells, suggesting that myofibroblastic differentiation was not responsible for reduced wound contraction. However, several mediators of cell-matrix interaction were reduced in the Tgfbr2(dermalKO) fibroblasts, including alpha1, alpha2, and beta1 integrins, and collagen gel contraction was diminished. There were associated deficiencies in actin cytoskeletal organization of vasodilator-stimulated phosphoprotein-containing lamellipodia. This study indicated that paracrine and autocrine TGF-beta dermal signaling mechanisms mediate macrophage recruitment, re-epithelization, and wound contraction.
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Affiliation(s)
- Magaly Martinez-Ferrer
- Vanderbilt-Ingram Cancer Center and Department of Urologic Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
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Abstract
Dysregulated wound healing and pathologic fibrosis cause abnormal scarring, leading to poor functional and aesthetic results in hand burns. Understanding the underlying biologic mechanisms involved allows the hand surgeon to better address these issues, and suggests new avenues of research to improve patient outcomes. In this article, the authors review the biology of scar and contracture by focusing on potential causes of abnormal wound healing, including depth of injury, cytokines, cells, the immune system, and extracellular matrix, and explore therapeutic measures designed to target the various biologic causes of poor scar.
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Affiliation(s)
- Peter Kwan
- Division of Plastic and Reconstructive Surgery, Department of Surgery, 2D2.28 WMC, University of Alberta, 8440-112 Street, Edmonton, AB T6G 2B7, Canada
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Abstract
The continuously increasing worldwide prevalence of diabetes will be accompanied by a greater incidence of diabetic foot ulcer, a complication in which many of the morphological processes involved in normal wound healing are disrupted. The highly complex and integrated process of wound healing is regulated by a large array of molecular factors. These often have overlapping functions, ensuring a certain degree of tolerance through redundancy. In diabetes, changes to the expression of a large number of molecular factors have been observed, overwhelming this inbuilt redundancy. This results in delayed healing or incomplete healing as in ulceration. Understanding the relationship between altered levels of molecular factors and the inhibited healing process in such ulcers will permit the development of targeted treatments aimed to greatly improve the quality of life of patients, at the same time helping to reduce the huge costs associated with treating this diabetic condition and its long-term consequences. This short review examines how changes in the expression of molecular factors are related to altered morphology in diabetic foot ulceration and very briefly considers treatment strategies at molecular level.
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Affiliation(s)
- Robert Blakytny
- Institute of Orthopaedic Research and Biomechanics, University of Ulm, Germany
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40
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Effect of pravastatin on experimental diabetic wound healing. J Surg Res 2009; 161:336-40. [PMID: 20031169 DOI: 10.1016/j.jss.2009.01.024] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2008] [Revised: 01/13/2009] [Accepted: 01/16/2009] [Indexed: 12/24/2022]
Abstract
BACKGROUND Impaired wound healing in diabetes has been associated with abnormalities in wound nitric oxide (NO) and nitric oxide synthase (NOS) availability. Efforts to alter the profile of NO expression in the wound microenvironment have proven to be successful in partially restoring wound healing deficits. We investigated the effects of pravastatin, a HMG Co A reductase inhibitor on endothelial nitric oxide synthase (eNOS) expression, NO production, and wound healing in a diabetic acute wound healing model. MATERIALS AND METHODS Of 70 male Sprague Dawley rats injected with streptozocin, 62 were confirmed diabetic after 1 wk. Animals were randomized into two groups: (1) diabetic control and (2) diabetic treated with pravastatin. Pravastatin sodium was gavaged at 0.4 mg/kg/d for 5 d, after which all animals underwent dorsal incision with insertion of subcutaneous sponges. Breaking strengths and hydroxyproline were measured on days 1, 3, and 10 post-wounding. Wound fluid was analyzed for nitrate/nitrite production. Tissue samples were analyzed for eNOS expression. RESULTS We demonstrated enhanced wound breaking strengths, hydroxyproline accumulation, an up-regulation in eNOS expression, and elevated NO levels in the pravastatin treated group. CONCLUSION We have shown that pravastatin, in an experimental model of diabetes may through up-regulation of eNOS and NO expression improve wound healing.
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Prevention and management of hypertrophic scars and keloids after burns in children. J Craniofac Surg 2008; 19:989-1006. [PMID: 18650721 DOI: 10.1097/scs.0b013e318175f3a7] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Hypertrophic scars and keloids are challenging to manage, particularly as sequelae of burns in children in whom the psychologic burden and skin characteristics differ substantially from adults. Prevention of hypertrophic scars and keloids after burns is currently the best strategy in their management to avoid permanent functional and aesthetical alterations. Several actions can be taken to prevent their occurrence, including parental and children education regarding handling sources of fire and flammable materials, among others. Combination of therapies is the mainstay of current burn scar management, including surgical reconstruction, pressure therapy, silicon gels and sheets, and temporary garments. Other adjuvant therapies such as topical imiquimod, tacrolimus, and retinoids, as well as intralesional corticosteroids, 5-fluorouracil, interferons, and bleomycin, have been used with relative success. Cryosurgery and lasers have also been reported as alternatives. Newer treatments aimed at molecular targets such as cytokines, growth factors, and gene therapy, currently in developing stages, are considered the future of the treatment of postburn hypertrophic scars and keloids in children.
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van Kaam K, Schouten J, Nap A, Dunselman G, Groothuis P. Fibromuscular differentiation in deeply infiltrating endometriosis is a reaction of resident fibroblasts to the presence of ectopic endometrium. Hum Reprod 2008; 23:2692-700. [DOI: 10.1093/humrep/den153] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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Velander P, Theopold C, Hirsch T, Bleiziffer O, Zuhaili B, Fossum M, Hoeller D, Gheerardyn R, Chen M, Visovatti S, Svensson H, Yao F, Eriksson E. Impaired wound healing in an acute diabetic pig model and the effects of local hyperglycemia. Wound Repair Regen 2008; 16:288-93. [PMID: 18318812 DOI: 10.1111/j.1524-475x.2008.00367.x] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Diabetic wounds result in significant morbidity, prolonged hospitalization, and enormous health-care expenses. Pigs have been shown to have wound healing resembling that in humans. The aim of this study was to develop a large-animal model for diabetic wound healing. Diabetes was induced by streptozotocin injection in Yorkshire pigs. Full-thickness wounds were created and dressed with a sealed chamber. Nondiabetic pigs with or without high glucose wound fluid concentration served as controls. Glucose concentration in serum and wound fluid was measured and collected. Wound contraction was monitored, and biopsies were obtained for measurement of reepithelialization. Wound fluid was analyzed for insulin-like growth factor-1 (IGF-1), platelet-derived growth factor, and transforming growth factor. Glucose concentration in wound fluid initially followed serum levels and then decreased to undetectable on day 9. Reepithelialization was significantly delayed in diabetic pigs. In nondiabetic pigs, wounds treated in a local hyperglycemic environment, and thus excluding the effects of systemic hyperglycemia, showed no difference in wound closure compared with controls. This suggests that delayed wound healing in diabetes is not induced by local high-glucose concentration itself. Analysis of growth factor expression showed a marked reduction in IGF-1 in the diabetic wounds. Diabetic pigs have impaired healing that is accompanied by a reduction of IGF-1 in the healing wound and is not due to the local hyperglycemia condition itself.
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Affiliation(s)
- Patrik Velander
- Laboratory of Tissue Repair and Gene Transfer, Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
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Abstract
Abdominal wall hernias occur when tissue structure and function are lost at the load-bearing muscle, tendon, and fascial layer. The fundamental biologic mechanisms are primary fascial pathology or surgical wound failure. In both cases, cellular and extracellular molecular matrix defects occur. Primary abdominal wall hernias have been associated with extracellular matrix diseases. Incisional hernias and recurrent inguinal hernias more often involve a combination of technical and biologic limitations. Defects in wound healing and extracellular matrix synthesis contribute to the high incidence of incisional hernia formation following laparotomy.
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Affiliation(s)
- Michael G Franz
- Division of Minimally Invasive Surgery, Department of Surgery, University of Michigan School of Medicine, 2922H Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0331, USA.
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Franz MG, Steed DL, Robson MC. Optimizing healing of the acute wound by minimizing complications. Curr Probl Surg 2007; 44:691-763. [PMID: 18036992 DOI: 10.1067/j.cpsurg.2007.07.001] [Citation(s) in RCA: 101] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Michael G Franz
- University of Michigan School of Medicine, Ann Arbor, Michigan, USA
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Lévesque M, Gatien S, Finnson K, Desmeules S, Villiard É, Pilote M, Philip A, Roy S. Transforming growth factor: beta signaling is essential for limb regeneration in axolotls. PLoS One 2007; 2:e1227. [PMID: 18043735 PMCID: PMC2082079 DOI: 10.1371/journal.pone.0001227] [Citation(s) in RCA: 114] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2007] [Accepted: 10/31/2007] [Indexed: 11/23/2022] Open
Abstract
Axolotls (urodele amphibians) have the unique ability, among vertebrates, to perfectly regenerate many parts of their body including limbs, tail, jaw and spinal cord following injury or amputation. The axolotl limb is the most widely used structure as an experimental model to study tissue regeneration. The process is well characterized, requiring multiple cellular and molecular mechanisms. The preparation phase represents the first part of the regeneration process which includes wound healing, cellular migration, dedifferentiation and proliferation. The redevelopment phase represents the second part when dedifferentiated cells stop proliferating and redifferentiate to give rise to all missing structures. In the axolotl, when a limb is amputated, the missing or wounded part is regenerated perfectly without scar formation between the stump and the regenerated structure. Multiple authors have recently highlighted the similarities between the early phases of mammalian wound healing and urodele limb regeneration. In mammals, one very important family of growth factors implicated in the control of almost all aspects of wound healing is the transforming growth factor-beta family (TGF-β). In the present study, the full length sequence of the axolotl TGF-β1 cDNA was isolated. The spatio-temporal expression pattern of TGF-β1 in regenerating limbs shows that this gene is up-regulated during the preparation phase of regeneration. Our results also demonstrate the presence of multiple components of the TGF-β signaling machinery in axolotl cells. By using a specific pharmacological inhibitor of TGF-β type I receptor, SB-431542, we show that TGF-β signaling is required for axolotl limb regeneration. Treatment of regenerating limbs with SB-431542 reveals that cellular proliferation during limb regeneration as well as the expression of genes directly dependent on TGF-β signaling are down-regulated. These data directly implicate TGF-β signaling in the initiation and control of the regeneration process in axolotls.
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Affiliation(s)
- Mathieu Lévesque
- Department of Biochemistry, Université de Montréal, Montréal, Québec, Canada
| | - Samuel Gatien
- Department of Biochemistry, Université de Montréal, Montréal, Québec, Canada
| | - Kenneth Finnson
- Department of Surgery, Faculty of Medicine, McGill University, Montréal, Québec, Canada
| | - Sophie Desmeules
- Faculty of Dentistry, Université de Montréal, Montréal, Québec, Canada
| | - Éric Villiard
- Faculty of Dentistry, Université de Montréal, Montréal, Québec, Canada
| | - Mireille Pilote
- Department of Biochemistry, Université de Montréal, Montréal, Québec, Canada
| | - Anie Philip
- Department of Surgery, Faculty of Medicine, McGill University, Montréal, Québec, Canada
| | - Stéphane Roy
- Department of Biochemistry, Université de Montréal, Montréal, Québec, Canada
- Faculty of Dentistry, Université de Montréal, Montréal, Québec, Canada
- * To whom correspondence should be addressed. E-mail:
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van Kaam KJAF, Romano A, Dunselman GAJ, Groothuis PG. Transforming growth factor beta1 gene polymorphism 509C/T in deep infiltrating endometriosis. Reprod Sci 2007; 14:367-73. [PMID: 17644809 DOI: 10.1177/1933719107303436] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Deep infiltrating endometriosis is characterized by the presence of nodular lesions largely composed of fibromuscular tissue. Transforming growth factor beta 1 (TGF-beta1) is the cytokine most causatively associated with disorders characterized by fibrosis throughout the body. Therefore, the hypothesis was tested that mechanisms increasing the fraction of biologically active TGF-beta1, such as TGF-beta 1 gene polymorphisms, lead to an increased risk of developing deep infiltrating endometriosis. The frequency of the -509C/T polymorphism of the TGF-beta 1 gene was tested in women with deep infiltrating endometriosis (n = 72), gynecological patients without symptoms of endometriosis (n = 95) and healthy females (n = 93). Detection of the -509C/T polymorphisms was performed using PCR-restriction fragment length polymorphism analysis. We did not observe statistically significant differences in the frequency of the -509C/T polymorphism between the groups. Our study does not support an association between the -509C/T polymorphism of the TGF-beta 1 gene and an increased risk of deep infiltrating endometriosis.
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Affiliation(s)
- K J A F van Kaam
- Research Institute GROW, University Hospital of Maastricht, Maastricht, Netherlands.
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Koo KT, Susin C, Wikesjö UME, Choi SH, Kim CK. Transforming Growth Factor-β1Accelerates Resorption of a Calcium Carbonate Biomaterial in Periodontal Defects. J Periodontol 2007; 78:723-9. [PMID: 17397321 DOI: 10.1902/jop.2007.060336] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND In a previous study, recombinant human transforming growth factor-beta1 (rhTGF-beta(1)) in a calcium carbonate carrier was implanted into critical-size, supraalveolar periodontal defects under conditions for guided tissue regeneration (GTR) to study whether rhTGF-beta(1) would enhance or accelerate periodontal regeneration. The results showed minimal benefits of rhTGF-beta(1), and a clear account for this could not be offered. One potential cause may be that the rhTGF-beta(1) formulation was biologically inactive. Several growth or differentiation factors have been suggested to accelerate degradation of biomaterials used as carriers. The objective of this study was to evaluate possible activity of rhTGF-beta(1) on biodegradation of the calcium carbonate carrier. METHODS rhTGF-beta(1) in a putty-formulated particulate calcium carbonate carrier was implanted into critical-size, supraalveolar periodontal defects under conditions for GTR in five beagle dogs. Contralateral defects received the calcium carbonate carrier combined with GTR without rhTGF-beta(1) (control). The animals were euthanized at week 4 post-surgery and block biopsies of the defect sites were collected for histologic and histometric analysis. Radiographs were obtained at defect creation and weeks 2 and 4 after defect creation. RESULTS No statistically significant differences were observed in new bone formation (bone height and area) among the treatments. However, total residual carrier was significantly reduced in sites receiving rhTGF-beta(1) compared to control (P = 0.04). Similarly, carrier density was considerably reduced in sites receiving rhTGF-beta(1) compared to control; the difference was borderline statistically significant (P = 0.06). CONCLUSION Within the limitations of the study, it may be concluded that rhTGF-beta(1) accelerates biodegradation of a particulate calcium carbonate biomaterial, indicating a biologic activity of the rhTGF-beta(1) formulation apparently not encompassing enhanced or accelerated periodontal regeneration.
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Affiliation(s)
- Ki-Tae Koo
- Department of Periodontology, Research Institute for Periodontal Regeneration, College of Dentistry, Yonsei University, Seoul, Korea
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Mei J, Xu RJ. Transient changes of transforming growth factor-β expression in the small intestine of the pig in association with weaning. Br J Nutr 2007; 93:37-45. [PMID: 15705223 DOI: 10.1079/bjn20041302] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
It is well known that early weaning causes marked changes in intestinal structure and function, and transforming growth factor-β (TGF-β) is believed to play an important regulatory role in post-weaning adaptation of the small intestine. The present study examined the distribution and expression intensity of TGF-β in the small intestinal mucosa of pre- and post-weaning pigs using a specific immunostaining technique and Western blot analysis. The level of TGF-β in the intestinal mucosa, as estimated by Western blot analysis, did not change significantly during weaning. However, when examined by the immunostaining technique, TGF-β1 (one of the TGF-β isoforms dominantly expressed in the tissue) at the intestinal villus epithelium, particularly at the apical membrane of the epithelium, decreased significantly 4 d after weaning, while the staining intensity increased significantly at the intestinal crypts compared with that in pre-weaning pigs. These changes were transient, with the immunostaining intensity for TGF-β1 at the intestinal villi and the crypts returning to the pre-weaning level by 8 d post-weaning. The transient decrease in TGF-β1 level at the intestinal villus epithelium was associated with obvious intestinal villus atrophy and marked reduction of mucosal digestive enzyme activities. Furthermore, the number of leucocytes staining positively for TGF-β1 increased significantly in the pig intestinal lamina propria 4 d after weaning. These findings strongly suggest that TGF-β plays an important role in the post-weaning adaptation process in the intestine of the pig.
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Affiliation(s)
- Jie Mei
- Department of Zoology, The University of Hong Kong, Pokfulam Road, Hong Kong
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Chung JY, Do SH, Jeong WI, Jeong DH, Park SJ, Ki MR, Kwak DM, Kim SB, Choi MS, Jeong KS. Effects of bio-active ceramic resources in cutaneous wound healing and the role of TGF-β signaling. Mol Cell Biochem 2006; 295:137-44. [PMID: 16871359 DOI: 10.1007/s11010-006-9283-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2006] [Accepted: 07/10/2006] [Indexed: 01/08/2023]
Abstract
The wound healing process is a highly orchestrated process, which includes inflammation, re-epithelialization, granulation tissue formation, matrix formation and re-modeling. In this paper, we attempt to determine if bio-active ceramic resource powder particles had an effect on cutaneous wound healing. Furthermore, we investigated its related mechanism and the expression of Smads of cutaneous wound healing, which can be accelerated by bio-active ceramic ointment. Topically applied lesions of 5%, 10% and 15% bio-active ceramic ointment (AO) showed accelerated wound closure, re-epithelialization, and the related immediate down stream of TGF-beta (p-Smad2/3 and Smad3) was suppressed. In particular, 10% and 15% AO lesions became closed faster at Days 3 and 4 of post-wound and p-Smad2/3 was also suppressed. All AO lesions showed accelerated mild wound closure at Day 6, but there were no significant difference. Several papers reported that Smad3 may mediate the signaling pathways that is inhibitory to wound healing, as the deletion of Smad3 leads to enhanced re-epithelialization and contraction of the wound area. This study showed that topical, bio-active ceramic ointment applications accelerated wound closure, re-epithelialization and the suppression of Smad proteins (p-Smad2/3, Smad3). The data revealed that the suppression of Smad3, which was induced by bio-active ceramic resources powder particles affected re-epithelialization and cutaneous wound closure. At the end of this paper, we concluded that bio-active ceramic resources affect cutaneous wound healing by accelerating the re-epithelialization of keratinocytes and that is mediated by the suppression of related protein, Smad3.
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Affiliation(s)
- Jae-Yong Chung
- Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, 702-701, Republic of Korea
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