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Al Mamun A, Shao C, Geng P, Wang S, Xiao J. Recent advances in the role of neuroregulation in skin wound healing. BURNS & TRAUMA 2025; 13:tkae072. [PMID: 39872039 PMCID: PMC11770601 DOI: 10.1093/burnst/tkae072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 10/24/2024] [Accepted: 11/01/2024] [Indexed: 01/29/2025]
Abstract
Neuroregulation during skin wound healing involves complex interactions between the nervous system and intricate tissue repair processes. The skin, the largest organ, depends on a complex system of nerves to manage responses to injury. Recent research has emphasized the crucial role of neuroregulation in maximizing wound healing outcomes. Recently, researchers have also explained the interactive contact between the peripheral nervous system and skin cells during the different phases of wound healing. Neurotransmitters and neuropeptides, once observed as simple signalling molecules, have since been recognized as effective regulators of inflammation, angiogenesis, and cell proliferation. The significance of skin innervation and neuromodulators is underscored by the delayed wound healing observed in patients with diabetes and the regenerative capabilities of foetal skin. Foetal skin regeneration is influenced by the neuroregulatory environment, immature immune system, abundant growth factors, and increased pluripotency of cells. Foetal skin cells exhibit greater flexibility and specialized cell types, and the extracellular matrix composition promotes regeneration. The extracellular matrix composition of foetal skin promotes regeneration, making it more capable than adult skin because neuroregulatory signals affect skin regeneration. The understanding of these systems can facilitate the development of therapeutic strategies to alter the nerve supply to the skin to enhance the process of wound healing. Neuroregulation is being explored as a potential therapeutic strategy for enhancing skin wound repair. Bioelectronic strategies and neuromodulation techniques can manipulate neural signalling, optimize the neuroimmune axis, and modulate inflammation. This review describes the function of skin innervation in wound healing, emphasizing the importance of neuropeptides released by sensory and autonomic nerve fibres. This article discusses significant discoveries related to neuroregulation and its impact on skin wound healing.
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Affiliation(s)
- Abdullah Al Mamun
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Chuxiao Shao
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
| | - Peiwu Geng
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
| | - Shuanghu Wang
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
| | - Jian Xiao
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
- Department of Wound Healing, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
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Gavioli E, Mantelli F, Cesta MC, Sacchetti M, Allegretti M. The History of Nerve Growth Factor: From Molecule to Drug. Biomolecules 2024; 14:635. [PMID: 38927039 PMCID: PMC11201509 DOI: 10.3390/biom14060635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/12/2024] [Accepted: 05/23/2024] [Indexed: 06/28/2024] Open
Abstract
Nerve growth factor (NGF), the first neurotrophin to be discovered, has a long and eventful research journey with a series of turning points, setbacks, and achievements. Since the groundbreaking investigations led by Nobel Prize winner Rita Levi-Montalcini, advancements in the comprehension of NGF's functions have revolutionized the field of neuroscience, offering new insights and opportunities for therapeutic innovation. However, the clinical application of NGF has historically been hindered by challenges in determining appropriate dosing, administration strategies, and complications related to the production process. Recent advances in the production and scientific knowledge of recombinant NGF have enabled its clinical development, and in 2018, the United States Food and Drug Administration approved cenegermin-bkbj, a recombinant human NGF, for the treatment of all stages of neurotrophic keratitis. This review traces the evolutionary path that transformed NGF from a biological molecule into a novel therapy with potential research applications beyond the eye. Special emphasis is put on the studies that advanced NGF from discovery to the first medicinal product approved to treat a human disease.
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Affiliation(s)
| | - Flavio Mantelli
- Dompé farmaceutici S.p.A., Via Santa Lucia, 6, 20122 Milano, Italy; (F.M.); (M.C.C.); (M.S.)
| | - Maria Candida Cesta
- Dompé farmaceutici S.p.A., Via Santa Lucia, 6, 20122 Milano, Italy; (F.M.); (M.C.C.); (M.S.)
| | - Marta Sacchetti
- Dompé farmaceutici S.p.A., Via Santa Lucia, 6, 20122 Milano, Italy; (F.M.); (M.C.C.); (M.S.)
| | - Marcello Allegretti
- Dompé farmaceutici S.p.A., Via Santa Lucia, 6, 20122 Milano, Italy; (F.M.); (M.C.C.); (M.S.)
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Keykhaee M, Rahimifard M, Najafi A, Baeeri M, Abdollahi M, Mottaghitalab F, Farokhi M, Khoobi M. Alginate/gum arabic-based biomimetic hydrogel enriched with immobilized nerve growth factor and carnosine improves diabetic wound regeneration. Carbohydr Polym 2023; 321:121179. [PMID: 37739486 DOI: 10.1016/j.carbpol.2023.121179] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 07/05/2023] [Accepted: 07/06/2023] [Indexed: 09/24/2023]
Abstract
Diabetic foot ulcers (DFUs) often remain untreated because they are difficult to heal, caused by reduced skin sensitivity and impaired blood vessel formation. In this study, we propose a novel approach to manage DFUs using a multifunctional hydrogel made from a combination of alginate and gum arabic. To enhance the healing properties of the hydrogel, we immobilized nerve growth factor (NGF), within specially designed mesoporous silica nanoparticles (MSN). The MSNs were then incorporated into the hydrogel along with carnosine (Car), which further improves the hydrogel's therapeutic properties. The hydrogel containing the immobilized NGF (SiNGF) could control the sustain release of NGF for >21 days, indicating that the target hydrogel (AG-Car/SiNGF) can serve as a suitable reservoir managing diabetic wound regeneration. In addition, Car was able to effectively reduce inflammation and significantly increase angiogenesis compared to the control group. Based on the histological results obtained from diabetic rats, the target hydrogel (AG-Car/SiNGF) reduced inflammation and improved re-epithelialization, angiogenesis, and collagen deposition. Specific staining also confirmed that AG-Car/SiNGF exhibited improved tissue neovascularization, transforming growth factor-beta (TGFβ) expression, and nerve neurofilament. Overall, our research suggests that this newly developed composite system holds promise as a potential treatment for non-healing diabetic wounds.
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Affiliation(s)
- Maryam Keykhaee
- Department of Pharmaceutical Biomaterials and Medical Biomaterial Research Center (MBRC), Faculty of Pharmacy, Tehran University of Medical Science, Tehran, Iran
| | - Mahban Rahimifard
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Najafi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Baeeri
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Abdollahi
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran; Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Mottaghitalab
- Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Mehdi Farokhi
- National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Iran.
| | - Mehdi Khoobi
- Department of Pharmaceutical Biomaterials and Medical Biomaterial Research Center (MBRC), Faculty of Pharmacy, Tehran University of Medical Science, Tehran, Iran; Department of Radiopharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Biomaterials Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Science, Tehran, Iran.
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Luo P, Shu L, Huang Z, Huang Y, Wu C, Pan X, Hu P. Utilization of Lyotropic Liquid Crystalline Gels for Chronic Wound Management. Gels 2023; 9:738. [PMID: 37754419 PMCID: PMC10530416 DOI: 10.3390/gels9090738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 09/07/2023] [Accepted: 09/09/2023] [Indexed: 09/28/2023] Open
Abstract
Management of chronic wounds is becoming a serious health problem worldwide. To treat chronic wounds, a suitable healing environment and sustained delivery of growth factors must be guaranteed. Different therapies have been applied for the treatment of chronic wounds such as debridement and photodynamic therapy. Among them, growth factors are widely used therapeutic drugs. However, at present, growth factor delivery systems cannot meet the demand of clinical practice; therefore new methods should be developed to meet the emerging need. For this reason, researchers have tried to modify hydrogels through some methods such as chemical synthesis and molecule modifications to enhance their properties. However, there are still a large number of limitations in practical use like byproduct problems, difficulty to industrialize, and instability of growth factor. Moreover, applications of new materials like lyotropic liquid crystalline (LLC) on chronic wounds have emerged as a new trend. The structure of LLC is endowed with many excellent properties including low cost, ordered structure, and excellent loading efficiency. LLC can provide a moist local environment for the wound, and its lattice structure can embed the growth factors in the water channel. Growth factor is released from the high-concentration carrier to the low-concentration release medium, which can be precisely regulated. Therefore, it can provide sustained and stable delivery of growth factors as well as a suitable healing environment for wounds, which is a promising candidate for chronic wound healing and has a broad prospective application. In conclusion, more reliable and applicable drug delivery systems should be designed and tested to improve the therapy and management of chronic wounds.
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Affiliation(s)
- Peili Luo
- College of Pharmacy, Jinan University, Guangzhou 511443, China; (P.L.); (L.S.); (C.W.); (P.H.)
| | - Lei Shu
- College of Pharmacy, Jinan University, Guangzhou 511443, China; (P.L.); (L.S.); (C.W.); (P.H.)
| | - Zhengwei Huang
- College of Pharmacy, Jinan University, Guangzhou 511443, China; (P.L.); (L.S.); (C.W.); (P.H.)
| | - Ying Huang
- College of Pharmacy, Jinan University, Guangzhou 511443, China; (P.L.); (L.S.); (C.W.); (P.H.)
| | - Chuanbin Wu
- College of Pharmacy, Jinan University, Guangzhou 511443, China; (P.L.); (L.S.); (C.W.); (P.H.)
| | - Xin Pan
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China;
| | - Ping Hu
- College of Pharmacy, Jinan University, Guangzhou 511443, China; (P.L.); (L.S.); (C.W.); (P.H.)
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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: 31] [Impact Index Per Article: 15.5] [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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Abstract
BACKGROUND There are several possible interventions for managing pressure ulcers (sometimes referred to as pressure injuries), ranging from pressure-relieving measures, such as repositioning, to reconstructive surgery. The surgical approach is usually reserved for recalcitrant wounds (where the healing process has stalled, or the wound is not responding to treatment) or wounds with full-thickness skin loss and exposure of deeper structures such as muscle fascia or bone. Reconstructive surgery commonly involves wound debridement followed by filling the wound with new tissue. Whilst this is an accepted means of ulcer management, the benefits and harms of different surgical approaches, compared with each other or with non-surgical treatments, are unclear. This is an update of a Cochrane Review published in 2016. OBJECTIVES To assess the effects of different types of reconstructive surgery for treating pressure ulcers (category/stage II or above), compared with no surgery or alternative reconstructive surgical approaches, in any care setting. SEARCH METHODS We used standard, extensive Cochrane search methods. The latest search date was January 2022. SELECTION CRITERIA Published or unpublished randomised controlled trials (RCTs) that assessed reconstructive surgery in the treatment of pressure ulcers. DATA COLLECTION AND ANALYSIS Two review authors independently selected the studies, extracted study data, assessed the risk of bias and undertook GRADE assessments. We would have involved a third review author in case of disagreement. MAIN RESULTS We identified one RCT conducted in a hospital setting in the USA. It enrolled 20 participants aged between 20 and 70 years with stage IV ischial or sacral pressure ulcers (involving full-thickness skin and tissue loss). The study compared two reconstructive techniques for stage IV pressure ulcers: conventional flap surgery and cone of pressure flap surgery, in which a large portion of the flap tip is de-epithelialised and deeply inset to obliterate dead space. There were no clear data for any of our outcomes, although we extracted some information on complete wound healing, wound dehiscence, pressure ulcer recurrence and wound infection. We graded the evidence for these outcomes as very low-certainty. The study provided no data for any other outcomes. AUTHORS' CONCLUSIONS Currently there is very little randomised evidence on the role of reconstructive surgery in pressure ulcer management, although it is considered a priority area. More rigorous and robust research is needed to explore this intervention.
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Affiliation(s)
- Gill Norman
- Division of Nursing, Midwifery and Social Work, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Jason Kf Wong
- Blond McIndoe Laboratories, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medical and Health, University of Manchester, Manchester, UK
- Dept of Burns and Plastic Surgery, Manchester University Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Kavit Amin
- Blond McIndoe Laboratories, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medical and Health, University of Manchester, Manchester, UK
- Dept of Burns and Plastic Surgery, Manchester University Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Jo C Dumville
- Division of Nursing, Midwifery and Social Work, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Susy Pramod
- The Christie NHS Foundation Trust, Manchester, UK
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Compagnoni C, Zelli V, Bianchi A, Di Marco A, Capelli R, Vecchiotti D, Brandolini L, Cimini AM, Zazzeroni F, Allegretti M, Alesse E, Tessitore A. MicroRNAs Expression in Response to rhNGF in Epithelial Corneal Cells: Focus on Neurotrophin Signaling Pathway. Int J Mol Sci 2022; 23:ijms23073597. [PMID: 35408969 PMCID: PMC8998691 DOI: 10.3390/ijms23073597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/21/2022] [Accepted: 03/21/2022] [Indexed: 11/16/2022] Open
Abstract
PURPOSE Nerve growth factor efficacy was demonstrated for corneal lesions treatment, and recombinant human NGF (rhNGF) was approved for neurotrophic keratitis therapy. However, NGF-induced molecular responses in cornea are still largely unknown. We analyzed microRNAs expression in human epithelial corneal cells after time-dependent rhNGF treatment. METHODS Nearly 700 microRNAs were analyzed by qRT-PCR. MicroRNAs showing significant expression differences were examined by DIANA-miRpath v.3.0 to identify target genes and pathways. Immunoblots were performed to preliminarily assess the strength of the in silico results. RESULTS Twenty-one microRNAs (miR-26a-1-3p, miR-30d-3p, miR-27b-5p, miR-146a-5p, miR-362-5p, mir-550a-5p, mir-34a-3p, mir-1227-3p, mir-27a-5p, mir-222-5p, mir-151a-5p, miR-449a, let7c-5p, miR-337-5p, mir-29b-3p, miR-200b-3p, miR-141-3p, miR-671-3p, miR-324-5p, mir-411-3p, and mir-425-3p) were significantly regulated in response to rhNGF. In silico analysis evidenced interesting target genes and pathways, including that of neurotrophin, when analyzed in depth. Almost 80 unique target genes (e.g., PI3K, AKT, MAPK, KRAS, BRAF, RhoA, Cdc42, Rac1, Bax, Bcl2, FasL) were identified as being among those most involved in neurotrophin signaling and in controlling cell proliferation, growth, and apoptosis. AKT and RhoA immunoblots demonstrated congruence with microRNA expression, providing preliminary validation of in silico data. CONCLUSIONS MicroRNA levels in response to rhNGF were for the first time analyzed in corneal cells. Novel insights about microRNAs, target genes, pathways modulation, and possible biological responses were provided. Importantly, given the putative role of microRNAs as biomarkers or therapeutic targets, our results make available data which might be potentially exploitable for clinical applications.
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Affiliation(s)
- Chiara Compagnoni
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Via Vetoio, 67100 L’Aquila, Italy; (C.C.); (V.Z.); (R.C.); (D.V.); (F.Z.); (E.A.)
| | - Veronica Zelli
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Via Vetoio, 67100 L’Aquila, Italy; (C.C.); (V.Z.); (R.C.); (D.V.); (F.Z.); (E.A.)
- Center for Molecular Diagnostics and Advanced Therapies, University of L’Aquila, Via Petrini, 67100 L’Aquila, Italy
| | - Andrea Bianchi
- Department of Information Engineering, Computer Science and Mathematics, University of L’Aquila, Via Vetoio, 67100 L’Aquila, Italy; (A.B.); (A.D.M.)
| | - Antinisca Di Marco
- Department of Information Engineering, Computer Science and Mathematics, University of L’Aquila, Via Vetoio, 67100 L’Aquila, Italy; (A.B.); (A.D.M.)
| | - Roberta Capelli
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Via Vetoio, 67100 L’Aquila, Italy; (C.C.); (V.Z.); (R.C.); (D.V.); (F.Z.); (E.A.)
| | - Davide Vecchiotti
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Via Vetoio, 67100 L’Aquila, Italy; (C.C.); (V.Z.); (R.C.); (D.V.); (F.Z.); (E.A.)
- Center for Molecular Diagnostics and Advanced Therapies, University of L’Aquila, Via Petrini, 67100 L’Aquila, Italy
| | - Laura Brandolini
- Dompé Farmaceutici Spa, via Campo di Pile, 1, 67100 L’Aquila, Italy; (L.B.); (M.A.)
| | - Anna Maria Cimini
- Department of Life, Health and Environmental Sciences, University of L’Aquila, P.zza S. Tommasi, 67100 L’Aquila, Italy;
| | - Francesca Zazzeroni
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Via Vetoio, 67100 L’Aquila, Italy; (C.C.); (V.Z.); (R.C.); (D.V.); (F.Z.); (E.A.)
| | - Marcello Allegretti
- Dompé Farmaceutici Spa, via Campo di Pile, 1, 67100 L’Aquila, Italy; (L.B.); (M.A.)
| | - Edoardo Alesse
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Via Vetoio, 67100 L’Aquila, Italy; (C.C.); (V.Z.); (R.C.); (D.V.); (F.Z.); (E.A.)
| | - Alessandra Tessitore
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Via Vetoio, 67100 L’Aquila, Italy; (C.C.); (V.Z.); (R.C.); (D.V.); (F.Z.); (E.A.)
- Center for Molecular Diagnostics and Advanced Therapies, University of L’Aquila, Via Petrini, 67100 L’Aquila, Italy
- Correspondence: ; Tel.: +39-086-243-3518; Fax: +39-0862433131
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Gragnani A, Tonarelli E, Chomiski V, Piccolo Daher R, Ferreira LM. Fibroblast growth factor in the treatment of burns: A systematic review. Burns 2022; 48:104-110. [PMID: 33933306 DOI: 10.1016/j.burns.2021.04.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 03/06/2021] [Accepted: 04/06/2021] [Indexed: 11/24/2022]
Abstract
INTRODUCTION A burn is a trauma that breaks the skin barrier, causing local and systemic responses. Treatment is complex, multiprofessional and expensive. In addition to surgical treatment, topical dressings can be used to keep the wound moist, reduce the risk of infection and stimulate healing. Clinical studies show that topical use of fibroblast growth factors may accelerate healing. An assessment of the quality of the available evidence and its strength of recommendation is necessary. OBJECTIVE This study aimed to evaluate the effectiveness and safety of topical use of fibroblast growth factor, compared to other topical treatments or placebo, in the healing of burns, to determine the strength of recommendation. METHOD Based on a defined search strategy, randomized and quasi-randomized clinical trials, available in electronic databases, were gathered. These compare the topical use of FGF versus other topical or non-treatment. The primary outcome was healing and as adverse effects: pain, infection and mortality. The systematic review protocol was registered on the PROSPERO platform (CRD42018089556), developed in accordance with the "Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) 2015" and within the "SWiM guideline 2019". GRADEpro was used for the critical analysis of the methodology of the studies. RESULTS Four clinical trials were found, in which FGF reduced the healing time and improved the appearance of the scar. Two trials were determined to be of low strength, while two others have a moderate recommendation strength. CONCLUSION This review gathered available evidence, between low and moderate recommendation strength for the use of FGF as a topical dressing. Further rigorous trials are needed to improve the strength of recommendation for topical use of FGF for burns.
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Affiliation(s)
- A Gragnani
- Discipline of Plastic Surgery, Surgery Department, (UNIFESP/EPM), Brazil.
| | - E Tonarelli
- Universidade Federal de São Paulo/Escola Paulista de Medicina (UNIFESP/EPM), Brazil
| | - V Chomiski
- Universidade Federal de São Paulo/Escola Paulista de Medicina (UNIFESP/EPM), Brazil
| | - R Piccolo Daher
- Universidade Federal de São Paulo/Escola Paulista de Medicina (UNIFESP/EPM), Brazil
| | - L M Ferreira
- Discipline of Plastic Surgery, Surgery Department, (UNIFESP/EPM), Brazil
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Liu Z, Wu H, Huang S. Role of NGF and its receptors in wound healing (Review). Exp Ther Med 2021; 21:599. [PMID: 33884037 PMCID: PMC8056114 DOI: 10.3892/etm.2021.10031] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 03/08/2021] [Indexed: 12/17/2022] Open
Abstract
Wound healing is an important and complicated process that includes four highly integrated and overlapping phases, haemostasis, inflammation, proliferation and tissue remodelling. Nerve growth factor (NGF) was the first member of a family of neurotrophic factors to be discovered, and is an essential neurotrophic factor for the development and maintenance of the central and peripheral nervous systems. Several studies have proposed that NGF and its receptors, tropomyosin-related kinase receptor 1 and NGF receptor, are involved in the wound healing process, and are important components of the healing of several wounds both in vivo and in vitro. Topical application of NGF significantly promotes the healing of different types of wounds, including diabetic foot ulcers, pressure ulcers and corneal wounds. The present review summarizes the status of NGF and its receptors in current literature, and discusses data obtained in the last few years on the healing action of NGF in cutaneous, corneal and oral wounds.
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Affiliation(s)
- Zhenxing Liu
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, P.R. China
| | - Haiwei Wu
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, P.R. China
| | - Shengyun Huang
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, P.R. China
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Kanu LN, Ciolino JB. Nerve Growth Factor as an Ocular Therapy: Applications, Challenges, and Future Directions. Semin Ophthalmol 2021; 36:224-231. [PMID: 33641595 DOI: 10.1080/08820538.2021.1890793] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Nerve growth factor (NGF), the prototypical neurotrophin first discovered in the 1950s, has recently garnered increased interest as a therapeutic agent promoting neuronal health and regeneration. After gaining orphan drug status within the last decade, NGF-related research and drug development has accelerated. The purpose of this article is to review the preclinical and clinical evidence of NGF in various applications, including central and peripheral nervous system, skin, and ophthalmic disorders. We focus on the ophthalmic applications including not only the FDA-approved indication of neurotrophic keratitis but also retinal disease and glaucoma. NGF represents a promising therapy whose therapeutic profile is evolving. The challenges related to this therapy are reviewed, along with possible solutions and future directions.
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Affiliation(s)
- Levi N Kanu
- 1. Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
| | - Joseph B Ciolino
- 1. Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
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Giuliani A, Lorenzini L, Baldassarro VA, Pannella M, Cescatti M, Fernandez M, Alastra G, Flagelli A, Villetti G, Imbimbo BP, Giardino L, Calzà L. Effects of Topical Application of CHF6467, a Mutated Form of Human Nerve Growth Factor, on Skin Wound Healing in Diabetic Mice. J Pharmacol Exp Ther 2020; 375:317-331. [PMID: 32948647 DOI: 10.1124/jpet.120.000110] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 08/26/2020] [Indexed: 12/16/2022] Open
Abstract
Nerve growth factor (NGF) is the protein responsible for the development and maintenance of sensory skin innervation. Given the role of appropriate innervation in skin healing, NGF has been indicated as a possible prohealing treatment in pathologic conditions characterized by nerve-ending loss, such as chronic ulcers in diabetes; however, its use as a therapeutic agent is limited by its hyperalgesic effect. We tested the effect of topical application of the nonalgogenic NGF derivative hNGFP61S/R100E in two models of skin ulcer induced in dbdb diabetic mice, investigating healing time, skin histology, reinnervation, and angiogenesis using morphologic and molecular approaches. We showed that the topical administration of CHF6467, a recombinant human NGF in which an amino acid substitution (R100E) abolished the hyperalgesic effect usually associated with NGF, accelerated skin repair in experimental wounds (full-excision and pressure-ulcer) induced in diabetic mice (dbdb). CHF6467-induced acceleration of wound healing was accompanied by increased re-epithelization, reinnervation, and revascularization as assessed by histology, immunohistochemistry, and image analysis. Bioinformatic analysis of differentially expressed genes and signaling pathways in the wound tissues showed that protein kinase B-mammalian target of rapamycin was the most regulated pathway. In spite of the transdermal absorption leading to measurable, dose-dependent increases in CHF6467 plasma levels, no systemic thermal or local mechanical hyperalgesia was observed in treated mice. When tested in vitro in human cell lines, CHF6467 stimulated keratinocyte and fibroblast proliferation and tube formation by endothelial cells. Collectively, these results support a possible use of CHF6467 as a prohealing agent in skin lesions in diabetes. SIGNIFICANCE STATEMENT: Topical application of CHF6467 accelerates reinnervation, neoangiogenesis, and wound healing in diabetic mice in both full-thickness skin-excision and pressure-ulcer models through the protein kinase B/mammalian target of rapamycin pathway and does not induce hyperalgesia.
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Affiliation(s)
- A Giuliani
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
| | - L Lorenzini
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
| | - V A Baldassarro
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
| | - M Pannella
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
| | - M Cescatti
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
| | - M Fernandez
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
| | - G Alastra
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
| | - A Flagelli
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
| | - G Villetti
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
| | - B P Imbimbo
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
| | - L Giardino
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
| | - L Calzà
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
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Weshahy RH, Aly DG, Shalaby S, Mohammed FN, Sayed KS. Clinical and Histological Assessment of Combined Fractional CO
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Laser and Growth Factors Versus Fractional CO
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Laser Alone in the Treatment of Facial Mature Burn Scars: A Pilot Split‐Face Study. Lasers Surg Med 2020; 52:952-958. [DOI: 10.1002/lsm.23252] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 04/09/2020] [Accepted: 04/10/2020] [Indexed: 01/13/2023]
Affiliation(s)
- Ragia H. Weshahy
- Department of Dermatology and Venereology National Research Centre Giza Egypt
| | - Dalia G. Aly
- Department of Dermatology and Venereology National Research Centre Giza Egypt
| | - Suzan Shalaby
- Department of Dermatology, Faculty of medicine Cairo University Cairo Egypt
| | - Faisal N. Mohammed
- Department of Dermatology and Venereology National Research Centre Giza Egypt
| | - Khadiga S. Sayed
- Department of Dermatology, Faculty of medicine Cairo University Cairo Egypt
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Anti-Aging Effects of GDF11 on Skin. Int J Mol Sci 2020; 21:ijms21072598. [PMID: 32283613 PMCID: PMC7177281 DOI: 10.3390/ijms21072598] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 04/02/2020] [Accepted: 04/07/2020] [Indexed: 12/24/2022] Open
Abstract
Human skin is composed of three layers: the epidermis, the dermis, and the hypodermis. The epidermis has four major cell layers made up of keratinocytes in varying stages of progressive differentiation. Skin aging is a multi-factorial process that affects every phase of its biology and function. The expression profiles of inflammation-related genes analyzed in resident immune cells demonstrated that these cells have a strong ability to regenerate adult skin stem cells and to produce endogenous substances such as growth differentiation factor 11 (GDF11). GDF11 appears to be the key to progenitor proliferation and/or differentiation. The preservation of youthful phenotypes has been tied to the presence of GDF11 in different human tissues, and, in the skin, this factor inhibits inflammatory responses. The protective role of GDF11 depends on a multi-factorial process implicating various types of skin cells such as keratinocytes, fibroblasts and inflammatory cells. GDF11 should be further studied for the purpose of developing novel therapies for the treatment of skin diseases.
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Liu Z, Cao Y, Liu G, Yin S, Ma J, Liu J, Zhang M, Wang Y. p75 neurotrophin receptor regulates NGF-induced myofibroblast differentiation and collagen synthesis through MRTF-A. Exp Cell Res 2019; 383:111504. [PMID: 31325438 DOI: 10.1016/j.yexcr.2019.111504] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 07/02/2019] [Accepted: 07/15/2019] [Indexed: 02/09/2023]
Abstract
Myofibroblasts are characterized by de novo expression of α-smooth muscle actin (α-SMA) and play a key role in tissue repair and remodeling. In addition to TGF-β1, recent studies have shown that nerve growth factor (NGF) has effects on myofibroblast differentiation and collagen synthesis. However, the regulatory mechanism remains poorly defined. NGF effects are mediated by the specific expression of the NGF neurotrophic tropomyosin-receptor kinase A (TrkA) and p75 neurotrophin receptor (p75NTR). Using NIH/3T3 fibroblast cell lines, we examined the induction of myofibroblast differentiation stimulated by NGF. Our findings showed that p75NTR was in keeping with the expression of α-SMA. Herein, we investigated the role of p75NTR in NGF-induced myofibroblast differentiation and collagen synthesis in these cells using lentivirus transfection to overexpress and knock down. Our results showed that p75NTR was preferentially expressed and was sufficient to induce actin cytoskeleton remodeling, which was required for NGF-induced α-SMA expression. Furthermore, NGF induced nuclear translocation of MRTF-A, an effect that was regulated by p75NTR, and required for α-SMA and collagen-I expression in myofibroblasts. Using a novel MRTF-A pathway inhibitor, CCG-203971, we further demonstrated the requirement of MRTF-A nuclear localization and activity in NGF-induced α-SMA expression. In conclusion, we conclude that p75NTR regulates NGF-induced myofibroblast differentiation and collagen synthesis through MRTF-A. Regulation of NGF-p75NTR interactions represents a promising therapy for fibrotic disorders.
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Affiliation(s)
- Zhenxing Liu
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China
| | - Yongqian Cao
- Department of Burns and Plastic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, Shandong, China
| | - Guijun Liu
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China
| | - Siyuan Yin
- Department of Burns and Plastic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, Shandong, China
| | - Jiaxu Ma
- Department of Burns and Plastic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, Shandong, China
| | - Jian Liu
- Department of Burns and Plastic Surgery, Yantai Yuhuangding Hospital, Yantai, 264000, Shandong, China
| | - Min Zhang
- Department of Burns and Plastic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, Shandong, China
| | - Yibing Wang
- Department of Burns and Plastic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, Shandong, China.
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Furuya-Kanamori L, Walker RM, Gillespie BM, Clark J, Doi SAR, Thalib L. Effectiveness of Different Topical Treatments in the Healing of Pressure Injuries: A Network Meta-analysis. J Am Med Dir Assoc 2019; 20:399-407. [PMID: 30471948 DOI: 10.1016/j.jamda.2018.10.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 10/05/2018] [Accepted: 10/05/2018] [Indexed: 11/12/2022]
Abstract
OBJECTIVES Pressure injuries (PIs) are one of the most common types of complex wounds and impose a huge economic burden on the healthcare system and the patients. A plethora of topical treatments is widely available for PI treatment, yet there is a paucity of evidence with regard to the most effective treatment. The objective of this study was to compare the effect of various topical treatments and identify the best treatment choice(s) for PI healing. DESIGN Systematic review and network meta-analysis. SETTING AND PARTICIPANTS All published randomized controlled trials that compared the effectiveness of 2 or more of the following dressing groups: basic, foam, active, hydroactive, and other wound dressings. MEASURES The outcome was the relative risk (RR) of complete healing following treatment and the generalized pairwise modeling framework was used to generate mixed treatment effects against hydroactive wound dressing, currently the standard of treatment for PIs. All treatments were then ranked by their point estimates. RESULTS 40 studies (1757 participants) comparing 5 dressing groups were included in the analysis. All dressings groups ranked better than basic (ie, saline gauze or similar inert dressing). The foam [RR 1.18; 95% confidence interval (CI) 0.95-1.48] and active wound dressing (RR 1.16; 95% CI 0.92-1.47) ranked better than hydroactive wound dressing in terms of healing of PIs when the latter was used as the reference group. CONCLUSIONS/IMPLICATIONS There was substantial uncertainty around the point estimates; however, evidence from our analysis supports the use of hydroactive wound dressings to replace basic dressings. Foam and active wound dressing groups seem promising and therefore need further investigation. High-quality, rigorously conducted research about the clinical effectiveness of the topical treatments in these 2 groups developed in consultation with health professionals, patients, and their carers is needed to identify if indeed foam and active wound dressings provide advantages over hydroactive dressings.
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Affiliation(s)
- Luis Furuya-Kanamori
- Department of Population Medicine, College of Medicine, Qatar University, Doha, Qatar
| | - Rachel M Walker
- School of Nursing and Midwifery, Griffith University, Gold Coast, Australia; Division of Surgery, Princess Alexandra Hospital, Metro South Health, Brisbane, Australia.
| | - Brigid M Gillespie
- School of Nursing and Midwifery, Griffith University, Gold Coast, Australia; Gold Coast University Hospital, Gold Coast Health, Gold Coast, Australia
| | - Justin Clark
- Centre for Research in Evidence Based Practice, Bond University, Gold Coast, Australia
| | - Suhail A R Doi
- Department of Population Medicine, College of Medicine, Qatar University, Doha, Qatar
| | - Lukman Thalib
- Department of Public Health, College of Health Sciences, Qatar University, Doha, Qatar
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Yin G, Wang Z, Wang Z, Wang X. Topical application of quercetin improves wound healing in pressure ulcer lesions. Exp Dermatol 2018; 27:779-786. [PMID: 29733461 DOI: 10.1111/exd.13679] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/25/2018] [Indexed: 01/10/2023]
Affiliation(s)
- Guimei Yin
- Nursing Department; Cangzhou Central Hospital; Cangzhou City Hebei Province China
| | - Zhijing Wang
- Department of Anesthesiology; Cangzhou Central Hospital Brain Branch; Cangzhou City Hebei Province China
| | - Zhaoxia Wang
- Nursing Department; Cangzhou Central Hospital; Cangzhou City Hebei Province China
| | - Xirui Wang
- The Third Department of Neurosurgery; Cangzhou Central Hospital Brain Branch; Cangzhou City Hebei Province China
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Ziaei M, Greene C, Green CR. Wound healing in the eye: Therapeutic prospects. Adv Drug Deliv Rev 2018; 126:162-176. [PMID: 29355667 DOI: 10.1016/j.addr.2018.01.006] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 10/06/2017] [Accepted: 01/10/2018] [Indexed: 02/07/2023]
Abstract
In order to maintain a smooth optical surface the corneal epithelium has to continuously renew itself so as to maintain its function as a barrier to fluctuating external surroundings and various environmental insults. After trauma, the cornea typically re-epithelializes promptly thereby minimizing the risk of infection, opacification or perforation. A persistent epithelial defect (PED) is usually referred to as a non-healing epithelial lesion after approximately two weeks of treatment with standard therapies to no avail. They occur following exposure to toxic agents, mechanical injury, and ocular surface infections and are associated with significant clinical morbidity in patients, resulting in discomfort or visual loss. In the case of deeper corneal injury and corneal pathology the wound healing cascade can also extend to the corneal stroma, the layer below the epithelium. Although significant progress has been made in recent years, pharmaco-therapeutic agents that promote corneal healing remain limited. This article serves as a review of current standard therapies, recently introduced alternative therapies gaining in popularity, and a look into the newest developments into ocular wound healing.
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NGF protects corneal, retinal, and cutaneous tissues/cells from phototoxic effect of UV exposure. Graefes Arch Clin Exp Ophthalmol 2018; 256:729-738. [DOI: 10.1007/s00417-018-3931-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Revised: 12/30/2017] [Accepted: 02/02/2018] [Indexed: 01/25/2023] Open
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Rocco ML, Soligo M, Manni L, Aloe L. Nerve Growth Factor: Early Studies and Recent Clinical Trials. Curr Neuropharmacol 2018; 16:1455-1465. [PMID: 29651949 PMCID: PMC6295934 DOI: 10.2174/1570159x16666180412092859] [Citation(s) in RCA: 149] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 03/23/2018] [Accepted: 04/04/2018] [Indexed: 12/02/2022] Open
Abstract
Since its discovery, nerve growth factor (NGF) has long occupied a critical role in developmental and adult neurobiology for its many important regulatory functions on the survival, growth and differentiation of nerve cells in the peripheral and central nervous system. NGF is the first discovered member of a family of neurotrophic factors, collectively indicated as neurotrophins, (which include brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin 4/5). NGF was discovered for its action on the survival and differentiation of selected populations of peripheral neurons. Since then, an enormous number of basic and human studies were undertaken to explore the role of purified NGF to prevent the death of NGF-receptive cells. These studies revealed that NGF possesses important therapeutic properties, after topical administration, on human cutaneous pressure ulcer, corneal ulcers, glaucoma, retinal maculopathy, Retinitis Pigmentosa and in pediatric optic gliomas and brain traumas. The aim of this review is to present our previous, recent and ongoing clinical studies on the therapeutic properties of NGF.
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Affiliation(s)
| | | | | | - Luigi Aloe
- Address correspondence to this author at the Fondazione IRET ONLUS, Via Tolara di Sopra 41/E, 40064 Ozzano Emilia (BO), Italy; Tel: +39-051-798776; Fax: +39-051-799673; E-mail:
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Westby MJ, Dumville JC, Soares MO, Stubbs N, Norman G, Cochrane Wounds Group. Dressings and topical agents for treating pressure ulcers. Cochrane Database Syst Rev 2017; 6:CD011947. [PMID: 28639707 PMCID: PMC6481609 DOI: 10.1002/14651858.cd011947.pub2] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Pressure ulcers, also known as bedsores, decubitus ulcers and pressure injuries, are localised areas of injury to the skin or the underlying tissue, or both. Dressings are widely used to treat pressure ulcers and promote healing, and there are many options to choose from including alginate, hydrocolloid and protease-modulating dressings. Topical agents have also been used as alternatives to dressings in order to promote healing.A clear and current overview of all the evidence is required to facilitate decision-making regarding the use of dressings or topical agents for the treatment of pressure ulcers. Such a review would ideally help people with pressure ulcers and health professionals assess the best treatment options. This review is a network meta-analysis (NMA) which assesses the probability of complete ulcer healing associated with alternative dressings and topical agents. OBJECTIVES To assess the effects of dressings and topical agents for healing pressure ulcers in any care setting. We aimed to examine this evidence base as a whole, determining probabilities that each treatment is the best, with full assessment of uncertainty and evidence quality. SEARCH METHODS In July 2016 we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses, guidelines and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA Published or unpublished randomised controlled trials (RCTs) comparing the effects of at least one of the following interventions with any other intervention in the treatment of pressure ulcers (Stage 2 or above): any dressing, or any topical agent applied directly to an open pressure ulcer and left in situ. We excluded from this review dressings attached to external devices such as negative pressure wound therapies, skin grafts, growth factor treatments, platelet gels and larval therapy. DATA COLLECTION AND ANALYSIS Two review authors independently performed study selection, risk of bias assessment and data extraction. We conducted network meta-analysis using frequentist mega-regression methods for the efficacy outcome, probability of complete healing. We modelled the relative effectiveness of any two treatments as a function of each treatment relative to the reference treatment (saline gauze). We assumed that treatment effects were similar within dressings classes (e.g. hydrocolloid, foam). We present estimates of effect with their 95% confidence intervals for individual treatments compared with every other, and we report ranking probabilities for each intervention (probability of being the best, second best, etc treatment). We assessed the certainty (quality) of the body of evidence using GRADE for each network comparison and for the network as whole. MAIN RESULTS We included 51 studies (2947 participants) in this review and carried out NMA in a network of linked interventions for the sole outcome of probability of complete healing. The network included 21 different interventions (13 dressings, 6 topical agents and 2 supplementary linking interventions) and was informed by 39 studies in 2127 participants, of whom 783 had completely healed wounds.We judged the network to be sparse: overall, there were relatively few participants, with few events, both for the number of interventions and the number of mixed treatment contrasts; most studies were small or very small. The consequence of this sparseness is high imprecision in the evidence, and this, coupled with the (mainly) high risk of bias in the studies informing the network, means that we judged the vast majority of the evidence to be of low or very low certainty. We have no confidence in the findings regarding the rank order of interventions in this review (very low-certainty evidence), but we report here a summary of results for some comparisons of interventions compared with saline gauze. We present here only the findings from evidence which we did not consider to be very low certainty, but these reported results should still be interpreted in the context of the very low certainty of the network as a whole.It is not clear whether regimens involving protease-modulating dressings increase the probability of pressure ulcer healing compared with saline gauze (risk ratio (RR) 1.65, 95% confidence interval (CI) 0.92 to 2.94) (moderate-certainty evidence: low risk of bias, downgraded for imprecision). This risk ratio of 1.65 corresponds to an absolute difference of 102 more people healed with protease modulating dressings per 1000 people treated than with saline gauze alone (95% CI 13 fewer to 302 more). It is unclear whether the following interventions increase the probability of healing compared with saline gauze (low-certainty evidence): collagenase ointment (RR 2.12, 95% CI 1.06 to 4.22); foam dressings (RR 1.52, 95% CI 1.03 to 2.26); basic wound contact dressings (RR 1.30, 95% CI 0.65 to 2.58) and polyvinylpyrrolidone plus zinc oxide (RR 1.31, 95% CI 0.37 to 4.62); the latter two interventions both had confidence intervals consistent with both a clinically important benefit and a clinically important harm, and the former two interventions each had high risk of bias as well as imprecision. AUTHORS' CONCLUSIONS A network meta-analysis (NMA) of data from 39 studies (evaluating 21 dressings and topical agents for pressure ulcers) is sparse and the evidence is of low or very low certainty (due mainly to risk of bias and imprecision). Consequently we are unable to determine which dressings or topical agents are the most likely to heal pressure ulcers, and it is generally unclear whether the treatments examined are more effective than saline gauze.More research is needed to determine whether particular dressings or topical agents improve the probability of healing of pressure ulcers. The NMA is uninformative regarding which interventions might best be included in a large trial, and it may be that research is directed towards prevention, leaving clinicians to decide which treatment to use on the basis of wound symptoms, clinical experience, patient preference and cost.
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Affiliation(s)
- Maggie J Westby
- University of Manchester, Manchester Academic Health Science CentreDivision of Nursing, Midwifery & Social Work, School of Health Sciences, Faculty of Biology, Medicine & HealthJean McFarlane BuildingOxford RoadManchesterUKM13 9PL
| | - Jo C Dumville
- University of Manchester, Manchester Academic Health Science CentreDivision of Nursing, Midwifery & Social Work, School of Health Sciences, Faculty of Biology, Medicine & HealthJean McFarlane BuildingOxford RoadManchesterUKM13 9PL
| | - Marta O Soares
- University of YorkCentre for Health EconomicsAlcuin 'A' BlockHeslingtonYorkUKYO10 5DD
| | - Nikki Stubbs
- Leeds Community Healthcare NHS Trust, St Mary's HospitalWound Prevention and Management Service3 Greenhill RoadLeedsUKLS12 3QE
| | - Gill Norman
- University of Manchester, Manchester Academic Health Science CentreDivision of Nursing, Midwifery & Social Work, School of Health Sciences, Faculty of Biology, Medicine & HealthJean McFarlane BuildingOxford RoadManchesterUKM13 9PL
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Severini C, Petrocchi Passeri P, Ciotti M, Florenzano F, Petrella C, Malerba F, Bruni B, D'Onofrio M, Arisi I, Brandi R, Possenti R, Calissano P, Cattaneo A. Nerve growth factor derivative NGF61/100 promotes outgrowth of primary sensory neurons with reduced signs of nociceptive sensitization. Neuropharmacology 2017; 117:134-148. [DOI: 10.1016/j.neuropharm.2017.01.035] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Revised: 01/09/2017] [Accepted: 01/29/2017] [Indexed: 12/16/2022]
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Abstract
BACKGROUND The management of pressure ulcers involves several interventions ranging from pressure-relieving measures such as repositioning, to treatments that can include reconstructive surgery. Such surgery may be considered for recalcitrant wounds when full thickness skin loss arises and deeper structures such as muscle fascia and even bone are exposed. The surgery commonly involves wound debridement followed by the addition of new tissue into the wound. Whilst reconstructive surgery is an accepted means of ulcer management, the benefits and harms of surgery compared with non-surgical treatments, or alternative surgical approaches are not clear. OBJECTIVES To assess the effects of reconstructive surgery for healing pressure ulcers (stage II or above), comparing surgery with no surgery or comparing alternative forms of surgery in any care setting. SEARCH METHODS We searched the following electronic databases to identify reports of relevant randomised clinical trials (searched 26 September 2016): the Cochrane Wounds Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL. We also searched three clinical trials registers and reference lists of relevant systematic reviews, meta-analyses and health technology assessment reports. SELECTION CRITERIA Published or unpublished randomised controlled trials that assessed reconstructive surgery in the treatment of pressure ulcers. DATA COLLECTION AND ANALYSIS Two review authors independently performed study selection. We planned that two review authors would also assess the risk of bias and extract study data. MAIN RESULTS We did not identify any studies that met the review eligibility criteria nor any registered studies investigating the role of reconstructive surgery in the management of pressure ulcers. AUTHORS' CONCLUSIONS Currently there is no randomised evidence that supports or refutes the role of reconstructive surgery in pressure ulcer management. This is a priority area and there is a need to explore this intervention with more rigorous and robust research.
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Affiliation(s)
- Jason KF Wong
- University Hospital South ManchesterPlastic and Reconstructive SurgerySouthmoor Road, WythenshaweManchesterUKM23 9LT
| | - Kavit Amin
- University Hospital South ManchesterPlastic and Reconstructive SurgerySouthmoor Road, WythenshaweManchesterUKM23 9LT
| | - Jo C Dumville
- University of ManchesterDivision of Nursing, Midwifery & Social Work, School of Health Sciences, Faculty of Biology, Medicine & HealthManchesterUKM13 9PL
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Bezdjian A, Kraaijenga VJC, Ramekers D, Versnel H, Thomeer HGXM, Klis SFL, Grolman W. Towards Clinical Application of Neurotrophic Factors to the Auditory Nerve; Assessment of Safety and Efficacy by a Systematic Review of Neurotrophic Treatments in Humans. Int J Mol Sci 2016; 17:ijms17121981. [PMID: 27898033 PMCID: PMC5187781 DOI: 10.3390/ijms17121981] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 11/11/2016] [Accepted: 11/21/2016] [Indexed: 01/31/2023] Open
Abstract
Animal studies have evidenced protection of the auditory nerve by exogenous neurotrophic factors. In order to assess clinical applicability of neurotrophic treatment of the auditory nerve, the safety and efficacy of neurotrophic therapies in various human disorders were systematically reviewed. Outcomes of our literature search included disorder, neurotrophic factor, administration route, therapeutic outcome, and adverse event. From 2103 articles retrieved, 20 randomized controlled trials including 3974 patients were selected. Amyotrophic lateral sclerosis (53%) was the most frequently reported indication for neurotrophic therapy followed by diabetic polyneuropathy (28%). Ciliary neurotrophic factor (50%), nerve growth factor (24%) and insulin-like growth factor (21%) were most often used. Injection site reaction was a frequently occurring adverse event (61%) followed by asthenia (24%) and gastrointestinal disturbances (20%). Eighteen out of 20 trials deemed neurotrophic therapy to be safe, and six out of 17 studies concluded the neurotrophic therapy to be effective. Positive outcomes were generally small or contradicted by other studies. Most non-neurodegenerative diseases treated by targeted deliveries of neurotrophic factors were considered safe and effective. Hence, since local delivery to the cochlea is feasible, translation from animal studies to human trials in treating auditory nerve degeneration seems promising.
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Affiliation(s)
- Aren Bezdjian
- Department of Otorhinolaryngology and Head & Neck Surgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
| | - Véronique J C Kraaijenga
- Department of Otorhinolaryngology and Head & Neck Surgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
| | - Dyan Ramekers
- Department of Otorhinolaryngology and Head & Neck Surgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
| | - Huib Versnel
- Department of Otorhinolaryngology and Head & Neck Surgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
| | - Hans G X M Thomeer
- Department of Otorhinolaryngology and Head & Neck Surgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
| | - Sjaak F L Klis
- Department of Otorhinolaryngology and Head & Neck Surgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
| | - Wilko Grolman
- Department of Otorhinolaryngology and Head & Neck Surgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
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Aloe L, Rocco ML, Balzamino BO, Micera A. Nerve Growth Factor: A Focus on Neuroscience and Therapy. Curr Neuropharmacol 2016; 13:294-303. [PMID: 26411962 PMCID: PMC4812798 DOI: 10.2174/1570159x13666150403231920] [Citation(s) in RCA: 162] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
Abstract
Nerve growth factor (NGF) is the firstly discovered and best characterized neurotrophic factor, known to play a critical protective role in the development and survival of sympathetic, sensory and forebrain cholinergic neurons. NGF promotes neuritis outgrowth both in vivo and in vitro and nerve cell recovery after ischemic, surgical or chemical injuries. Recently, the therapeutic property of NGF has been demonstrated on human cutaneous and corneal ulcers, pressure ulcer, glaucoma, maculopathy and retinitis pigmentosa. NGF eye drops administration is well tolerated, with no detectable clinical evidence of systemic or local adverse effects. The aim of this review is to summarize these biological properties and the potential clinical development of NGF.
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Affiliation(s)
- Luigi Aloe
- Institute of Cell Biology and Neurobiology, National Research Council (CNR); NGF Section, Via Fosso di Fiorano, 64/65 - 00143 Rome, Italy.
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25
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The neglected role of copper ions in wound healing. J Inorg Biochem 2016; 161:1-8. [DOI: 10.1016/j.jinorgbio.2016.02.012] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Revised: 01/19/2016] [Accepted: 02/10/2016] [Indexed: 12/30/2022]
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Aloe L, Rocco ML, Balzamino BO, Micera A. Nerve growth factor: role in growth, differentiation and controlling cancer cell development. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2016; 35:116. [PMID: 27439311 PMCID: PMC4955168 DOI: 10.1186/s13046-016-0395-y] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Accepted: 07/12/2016] [Indexed: 02/01/2023]
Abstract
Recent progress in the Nerve Growth Factor (NGF) research has shown that this factor acts not only outside its classical domain of the peripheral and central nervous system, but also on non-neuronal and cancer cells. This latter observation has led to divergent hypothesis about the role of NGF, its specific distribution pattern within the tissues and its implication in induction as well as progression of carcinogenesis. Moreover, other recent studies have shown that NGF has direct clinical relevance in certain human brain neuron degeneration and a number of human ocular disorders. These studies, by suggesting that NGF is involved in a plethora of physiological function in health and disease, warrant further investigation regarding the true role of NGF in carcinogenesis. Based on our long-lasting experience in the physiopathology of NGF, we aimed to review previous and recent in vivo and in vitro NGF studies on tumor cell induction, progression and arrest. Overall, these studies indicate that the only presence of NGF is unable to generate cell carcinogenesis, both in normal neuronal and non-neuronal cells/tissues. However, it cannot be excluded the possibility that the co-expression of NGF and pro-carcinogenic molecules might open to different consequence. Whether NGF plays a direct or an indirect role in cell proliferation during carcinogenesis remains to demonstrate.
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Affiliation(s)
- Luigi Aloe
- Institute of Cell Biology and Neurobiology, CNR, Via Del Fosso di Fiorano, 64 I-00143, Rome, Italy.
| | - Maria Luisa Rocco
- Institute of Cell Biology and Neurobiology, CNR, Via Del Fosso di Fiorano, 64 I-00143, Rome, Italy
| | | | - Alessandra Micera
- IRCCS - G.B. Bietti Foundation, Via Santo Stefano Rotondo, 6 I-00184, Rome, Italy
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27
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Malerba F, Paoletti F, Bruni Ercole B, Materazzi S, Nassini R, Coppi E, Patacchini R, Capsoni S, Lamba D, Cattaneo A. Functional Characterization of Human ProNGF and NGF Mutants: Identification of NGF P61SR100E as a "Painless" Lead Investigational Candidate for Therapeutic Applications. PLoS One 2015; 10:e0136425. [PMID: 26371475 PMCID: PMC4570711 DOI: 10.1371/journal.pone.0136425] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 08/04/2015] [Indexed: 11/21/2022] Open
Abstract
Background Nerve Growth Factor (NGF) holds a great therapeutic promise for Alzheimer's disease, diabetic neuropathies, ophthalmic diseases, dermatological ulcers. However, the necessity for systemic delivery has hampered the clinical applications of NGF due to its potent pro-nociceptive action. A “painless” human NGF (hNGF R100E) mutant has been engineered. It has equal neurotrophic potency to hNGF but a lower nociceptive activity. We previously described and characterized the neurotrophic and nociceptive properties also of the hNGF P61S and P61SR100E mutants, selectively detectable against wild type hNGF. However, the reduced pain-sensitizing potency of the “painless” hNGF mutants has not been quantified. Objectives and Results Aiming at the therapeutic application of the “painless” hNGF mutants, we report on the comparative functional characterization of the precursor and mature forms of the mutants hNGF R100E and hNGF P61SR100E as therapeutic candidates, also in comparison to wild type hNGF and to hNGF P61S. The mutants were assessed by a number of biochemical, biophysical methods and assayed by cellular assays. Moreover, a highly sensitive ELISA for the detection of the P61S-tagged mutants in biological samples has been developed. Finally, we explored the pro-nociceptive effects elicited by hNGF mutants in vivo, demonstrating an expanded therapeutic window with a ten-fold increase in potency. Conclusions This structure-activity relationship study has led to validate the concept of developing painless NGF as a therapeutic, targeting the NGF receptor system and supporting the choice of hNGF P61S R100E as the best candidate to advance in clinical development. Moreover, this study contributes to the identification of the molecular determinants modulating the properties of the hNGF “painless” mutants.
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Affiliation(s)
- Francesca Malerba
- Neurotrophic Factors and Neurodegenerative Diseases Unit, European Brain Research Institute, “Rita Levi-Montalcini” Foundation, Rome, Italy
- Neurobiology Laboratory of Biology, Scuola Normale Superiore, Pisa, Italy
| | - Francesca Paoletti
- Neurotrophic Factors and Neurodegenerative Diseases Unit, European Brain Research Institute, “Rita Levi-Montalcini” Foundation, Rome, Italy
- Neurobiology Laboratory of Biology, Scuola Normale Superiore, Pisa, Italy
| | - Bruno Bruni Ercole
- Neurotrophic Factors and Neurodegenerative Diseases Unit, European Brain Research Institute, “Rita Levi-Montalcini” Foundation, Rome, Italy
| | - Serena Materazzi
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy
| | - Romina Nassini
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy
| | - Elisabetta Coppi
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy
| | | | - Simona Capsoni
- Neurobiology Laboratory of Biology, Scuola Normale Superiore, Pisa, Italy
| | - Doriano Lamba
- Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Area Science Park–Basovizza, Trieste, Italy
| | - Antonino Cattaneo
- Neurotrophic Factors and Neurodegenerative Diseases Unit, European Brain Research Institute, “Rita Levi-Montalcini” Foundation, Rome, Italy
- Neurobiology Laboratory of Biology, Scuola Normale Superiore, Pisa, Italy
- * E-mail:
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Wirostko B, Rafii M, Sullivan DA, Morelli J, Ding J. Novel Therapy to Treat Corneal Epithelial Defects: A Hypothesis with Growth Hormone. Ocul Surf 2015; 13:204-212.e1. [PMID: 26045234 DOI: 10.1016/j.jtos.2014.12.005] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Revised: 12/01/2014] [Accepted: 12/01/2014] [Indexed: 10/23/2022]
Abstract
Impaired corneal wound healing that occurs with ocular surface disease, trauma, systemic disease, or surgical intervention can lead to persistent corneal epithelial defects (PCED), which result in corneal scarring, ulceration, opacification, corneal neovascularization, and, ultimately, visual compromise and vision loss. The current standard of care can include lubricants, ointments, bandage lenses, amniotic membranes, autologous serum eye drops, and corneal transplants. Various inherent problems exist with application and administration of these treatments, which often may not result in a completely healed surface. A topically applicable compound capable of promoting corneal epithelial cell proliferation and/or migration would be ideal to accelerate healing. We hypothesize that human growth hormone (HGH) is such a compound. In a recent study, HGH was shown to activate signal transducer and activators of transcription-5 (STAT5) signaling and promote corneal wound healing by enhancing corneal epithelial migration in a co-culture system of corneal epithelial cells and fibroblasts. These effects require an intact communication between corneal epithelia and fibroblasts. Further, HGH promotes corneal wound healing in a rabbit debridement model, thus demonstrating the effectiveness of HGH in vivo as well. In conclusion, HGH may represent an exciting and effective topical therapeutic to promote corneal wound healing.
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Affiliation(s)
- Barbara Wirostko
- Jade Therapeutics, Inc., University of Utah Research Park, Salt Lake City, UT; Moran Eye Center, University of Utah, Salt Lake City, UT, USA
| | - MaryJane Rafii
- Jade Therapeutics, Inc., University of Utah Research Park, Salt Lake City, UT
| | - David A Sullivan
- Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary, and Department of Ophthalmology, Harvard Medical School, Boston, MA
| | - Julia Morelli
- Jade Therapeutics, Inc., University of Utah Research Park, Salt Lake City, UT
| | - Juan Ding
- Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary, and Department of Ophthalmology, Harvard Medical School, Boston, MA.
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29
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Paoletti F, Malerba F, Ercole BB, Lamba D, Cattaneo A. A comparative analysis of the structural, functional and biological differences between Mouse and Human Nerve Growth Factor. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2014; 1854:187-97. [PMID: 25496838 DOI: 10.1016/j.bbapap.2014.12.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2014] [Revised: 12/02/2014] [Accepted: 12/05/2014] [Indexed: 11/19/2022]
Abstract
NGF is the prototype member of the neurotrophin family of proteins that promote the survival and growth of selected neurons in the central and peripheral nervous systems. As for all neurotrophins, NGF is translated as a pre-pro-protein. Over the years, NGF and proNGF of either human or mouse origin, given their high degree of homology, have been exploited for numerous applications in biomedical sciences. The mouse NGF has been considered the golden-standard for bioactivity. Indeed, due to evolutionary relatedness to human NGF and to its ready availability and by assuming identical properties to its human counterpart, the mouse NGF, isolated and purified from sub-maxillary glands, has been tested not only in laboratory practice and in preclinical models, but it has also been evaluated in several human clinical trials. Aiming to validate this assumption, widely believed, we performed a comparative study of the biochemical and biophysical properties of the mouse and human counterparts of NGF and proNGF. The mature and the precursor proteins of either species strikingly differ in their biophysical profiles and, when tested for ligand binding to their receptors, in their in vitro biological activities. We provide a structural rationale that accounts for their different functional behaviors. Despite being highly conserved during evolution, NGF and proNGF of mouse and human origins show distinct properties and therefore special care must be taken in performing experiments with cross-species systems in the laboratory practice, in developing immunoassays, in clinical trials and in pharmacological treatments.
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Affiliation(s)
- Francesca Paoletti
- Neurotrophic Factors and Neurodegenerative Diseases Unit, European Brain Research Institute, "Rita Levi-Montalcini" Foundation, Via del Fosso di Fiorano 64, Rome 00143, Italy
| | - Francesca Malerba
- Neurotrophic Factors and Neurodegenerative Diseases Unit, European Brain Research Institute, "Rita Levi-Montalcini" Foundation, Via del Fosso di Fiorano 64, Rome 00143, Italy; Neurobiology Laboratory of Biology, Scuola Normale Superiore, Piazza dei Cavalieri 7, Pisa 56126, Italy
| | - Bruno Bruni Ercole
- Neurotrophic Factors and Neurodegenerative Diseases Unit, European Brain Research Institute, "Rita Levi-Montalcini" Foundation, Via del Fosso di Fiorano 64, Rome 00143, Italy
| | - Doriano Lamba
- Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Area Science Park-Basovizza, S.S. 14 Km 163.5, Trieste I-34149, Italy
| | - Antonino Cattaneo
- Neurotrophic Factors and Neurodegenerative Diseases Unit, European Brain Research Institute, "Rita Levi-Montalcini" Foundation, Via del Fosso di Fiorano 64, Rome 00143, Italy; Neurobiology Laboratory of Biology, Scuola Normale Superiore, Piazza dei Cavalieri 7, Pisa 56126, Italy.
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Zhang Y, Wang T, He J, Dong J. Growth factor therapy in patients with partial-thickness burns: a systematic review and meta-analysis. Int Wound J 2014; 13:354-66. [PMID: 25040572 DOI: 10.1111/iwj.12313] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2014] [Revised: 05/05/2014] [Accepted: 05/14/2014] [Indexed: 12/29/2022] Open
Abstract
Growth factor (GF) therapy has shown promise in treating a variety of refractory wounds. However, evidence supporting its routine use in burn injury remains uncertain. We performed this systematic review and meta-analysis assessing randomised controlled trials (RCTs) to investigate efficacy and safety of GFs in the management of partial-thickness burns. Electronic searches were conducted in PubMed and the Cochrane databases. Endpoint results analysed included wound healing and scar formation. Thirteen studies comprising a total of 1924 participants with 2130 wounds (1131 GF receiving patients versus 999 controls) were identified and included, evaluating the effect of fibroblast growth factor (FGF), epidermal growth factor (EGF) and granulocyte macrophage-colony stimulating factor (GM-CSF) on partial-thickness burns. Topical application of these agents significantly reduced healing time by 5·02 (95% confidence interval, 2·62 to 7·42), 3·12 (95% CI, 1·11 to 5·13) and 5·1 (95% CI, 4·02 to 6·18) days, respectively, compared with standard wound care alone. In addition, scar improvement following therapy with FGF and EGF was evident in terms of pigmentation, pliability, height and vascularity. No significant increase in adverse events was observed in patients receiving GFs. These results suggested that GF therapy could be an effective and safe add-on to standard wound care for partial-thickness burns. High-quality, adequately powered trials are needed to further confirm the conclusion.
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Affiliation(s)
- Yi Zhang
- Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tao Wang
- Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinguang He
- Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiasheng Dong
- Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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NGF accelerates cutaneous wound healing by promoting the migration of dermal fibroblasts via the PI3K/Akt-Rac1-JNK and ERK pathways. BIOMED RESEARCH INTERNATIONAL 2014; 2014:547187. [PMID: 25006578 PMCID: PMC4055427 DOI: 10.1155/2014/547187] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/06/2014] [Accepted: 04/12/2014] [Indexed: 11/18/2022]
Abstract
As a well-known neurotrophic factor, nerve growth factor (NGF) has also been extensively recognized for its acceleration of healing in cutaneous wounds in both animal models and randomized clinical trials. However, the underlying mechanisms accounting for the therapeutic effect of NGF on skin wounds are not fully understood. NGF treatment significantly accelerated the rate of wound healing by promoting wound reepithelialization, the formation of granulation tissue, and collagen production. To explore the possible mechanisms of this process, the expression levels of CD68, VEGF, PCNA, and TGF-β1 in wounds were detected by immunohistochemical staining. The levels of these proteins were all significantly raised in NGF-treated wounds compared to untreated controls. NGF also significantly promoted the migration, but not the proliferation, of dermal fibroblasts. NGF induced a remarkable increase in the activity of PI3K/Akt, JNK, ERK, and Rac1, and blockade with their specific inhibitors significantly impaired the NGF-induced migration. In conclusion, NGF significantly accelerated the healing of skin excisional wounds in rats and the fibroblast migration induced by NGF may contribute to this healing process. The activation of PI3K/Akt, Rac1, JNK, and ERK were all involved in the regulation of NGF-induced fibroblast migration.
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Nerve growth factor and its receptor in schizophrenia. BBA CLINICAL 2014; 1:24-9. [PMID: 26675984 PMCID: PMC4633968 DOI: 10.1016/j.bbacli.2014.05.001] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2014] [Revised: 05/03/2014] [Accepted: 05/08/2014] [Indexed: 01/18/2023]
Abstract
Promising studies suggest that defects in synaptic plasticity detected in schizophrenia may be linked to neurodevelopmental and neurodegenerative abnormalities and contribute to disease-associated cognitive impairment. We aimed to clarify the role of the synaptic plasticity regulatory proteins, nerve growth factor (NGF) and its receptor (NGFR) in the pathogenesis of schizophrenia by comparative analysis of their blood levels and functional single nucleotide polymorphisms (SNPs) in genes encoding these proteins (NGF and NGFR) in schizophrenia-affected and healthy subjects. Relationships between the selected SNPs' genotypes and NGF and NGFR plasma levels were also assessed. Our results demonstrated a positive association between schizophrenia and the NGF rs6330 as well as the NGFR rs11466155 and rs2072446 SNPs. Also, a negative association between this disorder and NGF rs4839435 as well as NGFR rs734194 was found. In both, haloperidol-treated and antipsychotic-free patients decreased blood levels of the NGF and NGFR were found, and a positive interrelation between rs6330 and rs2072446 carriage and decreased NGF and NGFR levels, respectively, was revealed. In conclusion, our results demonstrate association of schizophrenia with the rs6330, rs4839435 and rs734194, rs11466155, rs2072446 as well as with the decreased blood levels of corresponding proteins. Our findings indicate the implication of alterations in NGFR and NGFR genes in schizophrenia, particularly, in defects of synaptic plasticity. Furthermore, the data obtained suggests that at least in Armenian population the NGF rs6330*T and NGFR rs11466155*T, rs2072446*T alleles might be nominated as risk factors, whereas the NGF rs4839435*A and NGFR rs734194*G alleles might be protective against developing schizophrenia.
The NGF and NGFR functional polymorphisms in schizophrenia-affected and healthy subjects were studied. Blood plasma levels of these proteins were also evaluated. Decreased NGF and NGFR levels in schizophrenia patients were detected. The rs6330*T and rs2072446*T carriage was interrelated with low NGF and NGFR levels, respectively. The NGF rs6330*T and NGFR rs11466155*T, rs2072446*T alleles might be nominated as risk factors.
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Manni L, Rocco ML, Bianchi P, Soligo M, Guaragna M, Barbaro SP, Aloe L. Nerve growth factor: basic studies and possible therapeutic applications. Growth Factors 2013; 31:115-22. [PMID: 23777359 DOI: 10.3109/08977194.2013.804073] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The nerve growth factor (NGF) belongs to a family of neurotrophic factors called neurotrophins. It was discovered as a molecule that stimulates the survival and maturation of developing neurons in the peripheral nervous system and has later been shown to protect adult neurons in the degenerating mammalian brain. Basic and clinical studies have been undertaken to use NGF as a therapeutic agent aimed at restoring and maintaining neuronal function in the central nervous system and to determine the mechanisms to safely deliver the molecule into the brain. Recent studies have also recognized that the role of NGF extends far beyond the horizon of nerve cells and even beyond the peripheral and central nervous system. Studies published from our laboratory have shown that topical application of NGF possesses a protective action on human pressure ulcer, corneal ulcer and glaucoma. Here, we will review these studies, supporting the therapeutic potential of NGF.
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Affiliation(s)
- Luigi Manni
- Institute of Translational Pharmacology, National Research Council, Rome, Italy
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Farsaei S, Khalili H, Farboud ES, Khazaeipour Z. Sildenafil in the treatment of pressure ulcer: a randomised clinical trial. Int Wound J 2013; 12:111-7. [PMID: 23731453 DOI: 10.1111/iwj.12104] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Accepted: 04/29/2013] [Indexed: 12/12/2022] Open
Abstract
Pressure ulcer (PrU)-related hospitalisation and mortality are critical issues in medical and surgical patients. Although animal studies have suggested the beneficial effects of sildenafil on wound healing, related clinical data are lacking. This is the first clinical study that has evaluated the effects of topical sildenafil on PrU healing in human subjects. Enrolled patients were randomly allocated to receive topical sildenafil (10%) ointment or placebo daily. Wound healing was assessed visually and photographically by the change in wound score according to two-digit Stirling scale. Decreases in grades of the PrUs were significantly higher in sildenafil group compared with placebo group (P < 0·001). In addition, surface areas of ulcers in sildenafil group were significantly reduced compared to the control group at day 14 of intervention (P = 0·007). It appears that these effects may be mediated by improvement of microvascular reperfusion in the skin and soft tissue. Further study to emphasise the role of topical sildenafil in the prevention or treatment of PrUs in hospitalised patients is required.
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Affiliation(s)
- Shadi Farsaei
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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Kant V, Gopal A, Kumar D, Bag S, Kurade NP, Kumar A, Tandan SK, Kumar D. Topically applied substance P enhanced healing of open excision wound in rats. Eur J Pharmacol 2013; 715:345-53. [PMID: 23684543 DOI: 10.1016/j.ejphar.2013.04.042] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Revised: 04/23/2013] [Accepted: 04/26/2013] [Indexed: 12/13/2022]
Abstract
Significant social and financial burden due to wounds need newer drugs/formulations to speed up the healing process. Substance P (SP), a neuropeptide, is associated with release of various cytokines and growth factors from inflammatory, epithelial and endothelial cells. In the present study, temporal effects of topically applied SP (10(-7)M in normal saline) were evaluated in the modulation of various cytokines and growth factors that participate in cutaneous wound healing. Gross examination of full thickness open excision wound in rats revealed that once daily topical application of SP significantly increased the wound closure, as compared to control group. SP treatment significantly increased tumor necrosis factor-α (TNF-α) and decreased interleukin 10 (IL-10) levels on day 3. On the contrary, on day 7 level of TNF-α decreased and that of IL-10 increased. The mRNA and protein expressions of vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1) increased on days 3 and 7, and decreased on day 14 in SP-treated wounds. Histopathological evaluation of hematoxylin and eosin stained wound sections showed that SP treatment produced increased early leukocytes infiltration, fibroblast proliferation, angiogenesis, collagen deposition and re-epithelialization. Results of the present study demonstrate that topical application of SP enhanced wound healing by modulating cytokines, growth factors and cells. Based on the results, it is suggested that SP could be of beneficial use in diabetic wounds where levels of VEGF, TGF-β1 and SP decrease along with impairment of inflammatory reaction.
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Affiliation(s)
- Vinay Kant
- Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243 122, U.P., India
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Aloe L, Chaldakov GN. Homage to Rita Levi-Montalcini, the queen of modern neuroscience. Cell Biol Int 2013; 37:761-5. [PMID: 23520136 DOI: 10.1002/cbin.10098] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2013] [Accepted: 03/11/2013] [Indexed: 11/08/2022]
Abstract
The first cell growth factor, nerve growth factor (NGF), was discovered by Rita Levi-Montalcini (RLM) in the early 1950s. Originally identified as neurite outgrowth-stimulating factor, later studies revealed that non-neuronal cells, including immune cells, endothelial cells, cardiomyocytes, pancreatic beta cells, prostate epithelial and adipose tissue cells, were also targets for and/or sources of NGF. Nerve growth factor is well recognised as mediating multiple biological phenomena, ranging from the neurotrophic through immunotrophic and epitheliotrophic to metabotrophic effects. Consequently, NGF and other members of the neurotrophin family are implicated in the pathogenesis of a large spectrum of neuronal and non-neuronal diseases, ranging from Alzheimer's and other neurodegenerative diseases to atherosclerosis and cardiometabolic disorders. Recent studies have demonstrated the therapeutic potentials of NGF in these conditions, including ocular and cutaneous diseases. NGF TrkA receptor antagonists emerged as novel drugs for pain, prostate and breast cancer, melanoma and urinary bladder syndromes. Here, we briefly describe the 'unpredictable' ideogenesis of the discovery of NGF, a eureka in the neuroscience.
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Affiliation(s)
- Luigi Aloe
- Institute of Cell Biology and Neurobiology, National Research Council (CNR), Rome, Italy.
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Aloe L, Chaldakov GN. The multiple life of nerve growth factor: tribute to rita levi-montalcini (1909-2012). Balkan Med J 2013; 30:4-7. [PMID: 25207059 DOI: 10.5152/balkanmedj.2013.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2013] [Accepted: 03/06/2013] [Indexed: 12/12/2022] Open
Abstract
At the end of the 19(th) century, it was envisaged by Santiago Ramon y Cajal, but not, proven, that life at the neuronal level requires trophic support. The proof was obtained in the early 1950's by work initiated by Rita Levi-Montalcini (RLM) discovering the nerve growth factor (NGF). Today, NGF and its relatives, collectively designated neurotrophins, are well recognized as mediators of multiple biological phenomena in health and disease, ranging from the neurotrophic through immunotrophic and epitheliotrophic to metabotrophic effects. Consequently, NGF and other neurotrophins are implicated in the pathogenesis of a large spectrum of neuronal and non-neuronal diseases, from Alzheimer's and other neurodegenerative diseases to atherosclerosis and other cardiometabolic diseases. Recent studies demonstrated the therapeutic potentials of NGF in these diseases, including ocular and cutaneous diseases. Furthermore, NGF TrkA receptor antagonists emerged as novel drugs for pain, prostate and breast cancer, melanoma, and urinary bladder syndromes. Altogether, NGF's multiple potential in health and disease is briefly described here.
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Affiliation(s)
- Luigi Aloe
- Institute of Cell Biology and Neurobiology, National Research Council (CNR), Rome, Italy
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Aloe L, Rocco ML, Bianchi P, Manni L. Nerve growth factor: from the early discoveries to the potential clinical use. J Transl Med 2012. [PMID: 23190582 PMCID: PMC3543237 DOI: 10.1186/1479-5876-10-239] [Citation(s) in RCA: 326] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The physiological role of the neurotrophin nerve growth factor (NGF) has been characterized, since its discovery in the 1950s, first in the sensory and autonomic nervous system, then in central nervous, endocrine and immune systems. NGF plays its trophic role both during development and in adulthood, ensuring the maintenance of phenotypic and functional characteristic of several populations of neurons as well as immune cells. From a translational standpoint, the action of NGF on cholinergic neurons of the basal forebrain and on sensory neurons in dorsal root ganglia first gained researcher's attention, in view of possible clinical use in Alzheimer's disease patients and in peripheral neuropathies respectively. The translational and clinical research on NGF have, since then, enlarged the spectrum of diseases that could benefit from NGF treatment, at the same time highlighting possible limitations in the use of the neurotrophin as a drug. In this review we give a comprehensive account for almost all of the clinical trials attempted until now by using NGF. A perspective on future development for translational research on NGF is also discussed, in view of recent proposals for innovative delivery strategies and/or for additional pathologies to be treated, such as ocular and skin diseases, gliomas, traumatic brain injuries, vascular and immune diseases.
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Affiliation(s)
- Luigi Aloe
- Cellular Biology and Neurobiology Institute, CNR, via del Fosso di Fiorano 64, 00143, Rome, Italy
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Bito S, Mizuhara A, Oonishi S, Takeuchi K, Suzuki M, Akiyama K, Kobayashi K, Matsunaga K. Randomised controlled trial evaluating the efficacy of wrap therapy for wound healing acceleration in patients with NPUAP stage II and III pressure ulcer. BMJ Open 2012; 2:e000371. [PMID: 22223842 PMCID: PMC3253421 DOI: 10.1136/bmjopen-2011-000371] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Objectives To evaluate if 'wrap therapy' using food wraps, which is widely used in Japanese clinical sites, is not inferior when compared to guideline adhesion treatments. Design Multicentre, prospective, randomised, open, blinded endpoint clinical trial. Setting 15 hospitals in Japan. Patients 66 older patients with new National Pressure Ulcer Advisory Panel stage II or III pressure ulcers. Interventions Of these 66 patients, 31 were divided into the conventional treatment guidelines group and 35 into the wrap therapy group. Main outcome measures The primary end point was the period until the pressure ulcers were cured. The secondary end point was a comparison of the speed of change in the Pressure Ulcer Scale for Healing score. Results 64 of the 66 patients were analysed. The estimated mean period until healing was 57.5 days (95% CI 45.2 to 69.8) in the control group as opposed to 59.8 days (95% CI 49.7 to 69.9) in the wrap therapy group. By the extent of pressure ulcer infiltration, the mean period until healing was 16.0 days (95% CI 8.1 to 23.9) in the control group as opposed to 18.8 days (95% CI 10.3 to 27.2) in the wrap therapy group with National Pressure Ulcer Advisory Panel stage II ulcers, and 71.8 days (95% CI 61.4 to 82.3) as opposed to 63.2 days (95% CI 53.0 to 73.4), respectively, with stage III ulcers. There is no statistical significance in difference in Pressure Ulcer Scale for Healing scores. Conclusions It might be possible to consider wrap therapy as an alternative choice in primary care settings as a simple and inexpensive dressing care. Clinical Trial registration UMIN Clinical Trials Registry UMIN000002658. Summary protocol is available on https://upload.umin.ac.jp/cgi-bin/ctr/ctr.cgi?function=brows&action=brows&type=detail&recptno=R000003235&admin=0&language=J.
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Affiliation(s)
- Seiji Bito
- Division of Clinical Epidemiology, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
| | - Akihiro Mizuhara
- Sanwa Medical Corporation Higashi-Washinomiya Hospital, Saitama, Japan
| | - Sandai Oonishi
- Nursing Health Services Facilities for the Elderly Hatta, Aichi, Japan
| | - Kensuke Takeuchi
- Sanwa Medical Corporation Higashi-Washinomiya Hospital, Saitama, Japan
| | - Masatsune Suzuki
- Department of General Internal Medicine, Tsukuba Medical Center Hospital, Tsukuba, Japan
| | | | | | - Kayoko Matsunaga
- Department of Dermatology, Fujita Health University School of Medicine, Toyoake, Japan
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Palazzo E, Marconi A, Truzzi F, Dallaglio K, Petrachi T, Humbert P, Schnebert S, Perrier E, Dumas M, Pincelli C. Role of neurotrophins on dermal fibroblast survival and differentiation. J Cell Physiol 2011; 227:1017-25. [DOI: 10.1002/jcp.22811] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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Truzzi F, Marconi A, Pincelli C. Neurotrophins in healthy and diseased skin. DERMATO-ENDOCRINOLOGY 2011; 3:32-6. [PMID: 21519407 PMCID: PMC3051851 DOI: 10.4161/derm.3.1.14661] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2010] [Revised: 12/22/2010] [Accepted: 12/23/2010] [Indexed: 12/16/2022]
Abstract
Neurotrophins (NT) belong to a family of structurally and functionally related proteins that, depending on the tissue context and the receptors involved, promote either neuronal cell survival and differentiation or cell death. NT, and in particular NGF, were first identified as neurotrophic factors supporting the synthesis and development of sensory neurons in the central and peripheral nervous system. It is now widely accepted that NT also act as growth factors in non-neuronal cells, including the skin. In the skin, most cell types are able to secrete and/or to respond to stimulation by NT, creating a unique network of molecular signaling in the cutaneous microenvironment. Moreover, many skin diseases have been associated with an involvement of a number of neural factors including NT, but less attention has been given to the role of NT as growth factors in the development of skin pathologies. This review summarizes currently data on the expression and function of NT and their receptors in several cell types in the skin. Moreover it focuses on the role of the skin NT network in two cutaneous conditions, melanoma and psoriasis where NT are clearly involved.
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Affiliation(s)
- Francesca Truzzi
- Institute of Dermatology; School of Biosciences and Biotechnologies; University of Modena and Reggio Emilia; Modena, Italy
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Analysis of nerve and neuropeptide patterns in vacuum-assisted closure-treated diabetic murine wounds. Plast Reconstr Surg 2010; 126:87-96. [PMID: 20595860 DOI: 10.1097/prs.0b013e3181da86d0] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND Reestablishment of the peripheral nervous system occurs in parallel with wound healing. With accelerated wound healing seen with the vacuum-assisted closure device, the authors studied its effects on nerve fiber regeneration, nerve sprouting, and the stimulation of neuropeptides and neurotrophins. METHODS A vacuum-assisted closure device was applied to a full-thickness diabetic mouse wound using continuous or cyclical modes and compared with foam dressing or occlusive dressing controls, using 10 mice per group. Nerve fibers, substance P, calcitonin gene-related peptide, and nerve growth factor were analyzed using two-dimensional immunohistochemistry and real-time reverse-transcriptase polymerase chain reaction. RESULTS A significant increase in dermal and epidermal nerve fiber densities and in substance P, calcitonin gene-related peptide, and nerve growth factor expression was seen in vacuum-assisted closure-treated wounds. Cyclical treatment mode correlated with the largest increase in granulation tissue production, wound surface microdeformations, and a slightly faster wound closure rate. CONCLUSIONS This study suggests that vacuum-assisted closure therapy can modulate nerve fiber and neuropeptide production in the wound. Optimized kinetics of vacuum-assisted closure application may provide an opportunity for clinicians to further improve wound healing in denervated wounds such as pressure sores and diabetic foot ulcerations.
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Abstract
Tumor necrosis factor alpha antagonists (e.g. etanercept) are now being extensively evaluated in the setting of chronic wound healing. Preliminary studies and case reports provide evidence of the clinical potential of these compounds in pyoderma gangrenosum, and further investigations are warranted. A clear rationale also exists for further detailed assessments of the potential efficacy of etanercept in patients with venous leg ulcers or hospital-acquired pressure ulcers.
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Affiliation(s)
- Robert S Kirsner
- Department and Cutaneous Surgery, University of Miami Miller School of Medicine, 1600 N.W. 10th Avenue, RMSB, Room 2023-A, Miami, FL 33136, USA.
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Scevola S, Nicoletti G, Brenta F, Isernia P, Maestri M, Faga A. Allogenic platelet gel in the treatment of pressure sores: a pilot study. Int Wound J 2010; 7:184-90. [PMID: 20455960 DOI: 10.1111/j.1742-481x.2010.00671.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Although platelet gel is considered one of the most popular tools in the treatment of chronic ulcers, current consensus on its use is not unanimous. A prospective randomised trial was carried out at the Plastic Surgery Unit of the 'Salvatore Maugeri' Foundation Hospital of Pavia (Italy). The study involved 13 patients affected by spinal cord injury with 16 pressure sores over a period of 20 months. The ulcer was considered the experimental unit of the study irrespective of the number of ulcers per patient. Each consecutive ulcer was randomised to be treated either with allogenic platelet gel or with current best practice approach to chronic wounds dressing protocol. At the end of the treatment 15 ulcers out of 16 improved clinically. No statistically significant difference was demonstrated in volume reduction between the two groups, although a statistically significant difference could be demonstrated in the onset time of granulation tissue proliferation as in the wounds treated with platelet gel the healing process was triggered earlier. Our study suggests that platelet gel is mostly effective within the first 2 weeks of treatment while a prolonged treatment does not provide any significant advantage versus the current best practice approach to chronic wounds protocols.
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Affiliation(s)
- Silvia Scevola
- Department of Plastic and Reconstructive Surgery, University of Pavia -Salvatore Maugeri Foundation Research and Care Institute, Pavia, Italy.
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Sun W, Lin H, Chen B, Zhao W, Zhao Y, Xiao Z, Dai J. Collagen scaffolds loaded with collagen-binding NGF-beta accelerate ulcer healing. J Biomed Mater Res A 2010; 92:887-95. [PMID: 19283824 DOI: 10.1002/jbm.a.32445] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Studies have shown that exogenous nerve growth factor (NGF) accelerates ulcer healing, but the inefficient growth factor delivery system limits its clinical application. In this report, we found that the native human NGF-beta fused with a collagen-binding domain (CBD) could form a collagen-based NGF targeting delivery system, and the CBD-fused NGF-beta could bind to collagen membranes efficiently. Using the rabbit dermal ischemic ulcer model, we have found that this targeting delivery system maintains a higher concentration and stronger bioactivity of NGF-beta on the collagen membranes by promoting peripheral nerve growth. Furthermore, it enhances the rate of ulcer healing through accelerating the re-epithelialization of dermal ulcer wounds and the formation of capillary lumens within the newly formed tissue area. Thus, collagen membranes loaded with collagen-targeting human NGF-beta accelerate ulcer healing efficiently.
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Affiliation(s)
- Wenjie Sun
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
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Lohi J, Sipponen A, Jokinen J. Local dressings for pressure ulcers: what is the best tool to apply in primary and second care? J Wound Care 2010; 19:123-7. [DOI: 10.12968/jowc.2010.19.3.47282] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- J. Lohi
- Institute of Health Sciences, University of Oulu, Oulu, Finland
| | - A. Sipponen
- Department of Surgery, Rheumatism Foundation Hospital, Heinola, Finland
| | - J.J. Jokinen
- Department of Cardiothoracic Surgery, Helsinki University Hospital, Helsinki, Finland
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Zuloff-Shani A, Adunsky A, Even-Zahav A, Semo H, Orenstein A, Tamir J, Regev E, Shinar E, Danon D. Hard to heal pressure ulcers (stage III-IV): efficacy of injected activated macrophage suspension (AMS) as compared with standard of care (SOC) treatment controlled trial. Arch Gerontol Geriatr 2010; 51:268-72. [PMID: 20034682 DOI: 10.1016/j.archger.2009.11.015] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2009] [Revised: 11/19/2009] [Accepted: 11/20/2009] [Indexed: 11/25/2022]
Abstract
The objective of this study was to compare local injections of AMS with SOC treatments for stage III and IV pressure ulcers in elderly patients. It was designed as historically prospective 2-arms non-parallel open controlled trial, and conducted in a department of geriatric medicine and rehabilitation of a university affiliated tertiary hospital. We studied 100 consecutive elderly patients with a total of 216 stage III or IV pressure ulcers, 66 patients were assigned to the AMS group and had their wounds injected, while 38 patients were assigned to the SOC group. Primary outcome was rate of complete wound closure. Time to complete wound closure and 1-year mortality served as secondary outcomes. Statistical analyses were performed at both patient and wound levels. Percentage of completely closed wounds (wound level and patient level) were significantly better (p<0.001/p<0.001, respectively) in all patients in favor of AMS, as well as in the subset of diabetic patients (p<0.001/p<0.001). Similarly, AMS proved significantly better for the subset of those with leg ulcers and with baseline wounds ≤15 cm(2), compared with SOC. There were no statistically significant differences with regard to time to complete closure or 1-year mortality rates in the two groups. It is concluded that there is a significant difference in favor of stage III and IV wound closure rates by AMS, as compared with SOC treatments.
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Affiliation(s)
- Adi Zuloff-Shani
- Research and Development Unit, Magen David Adom National Blood Services, Tel-Hashomer 52621, Ramat-Gan, Israel.
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Mao CL, Rivet AJ, Sidora T, Pasko MT. Update on Pressure Ulcer Management and Deep Tissue Injury. Ann Pharmacother 2010; 44:325-32. [DOI: 10.1345/aph.1m315] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Objective: To review recent literature regarding therapeutic management of pressure ulcers and to discuss the potential implications of the newly recognized entity, deep tissue injury (DTI). Data Sources: A MEDLINE search was conducted of pressure ulcer therapy published between January 2001 and October 2009. Key search terms included pressure ulcers, deep tissue injury, nutrition, antibiotics, and therapy. Study Selection and Data Extraction: Comparative clinical trials involving pharmacologic agents in the treatment of pressure ulcers and DTI were evaluated. Included trials were those with defined interventions and outcome parameters for wound healing. Data Synthesis: Pressure ulcers remain an important issue in the care of elderly and immobilized patients. DTI has been recently added by the National Pressure Ulcer Advisory Panel as a separate category in the staging of pressure ulcers. There is currently a lack of consensus on how to identify and treat DTI. but preventive measures typically employed in the management of all pressure ulcers have been recommended. Recent studies on topical phenytoin, silver preparations, and growth factors report benefit in the management of pressure ulcers. However, studies evaluating these treatment approaches often lack the sample size necessary to adequately support recommendations. Conclusions: Determining the extent of tissue damage in DTI is currently not possible. Therefore, management recommendations focus on limiting extension of the ulcer stage through preventive strategies. Routine use of topical phenytoin, silver preparations, or growth factors in therapy of pressure ulcers cannot be recommended until more data from rigorously designed studies are available.
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Affiliation(s)
- Cindy L Mao
- School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, NY; now, Pharmacist, Department of Pharmacy, Santa Rosa Memorial Hospital, Santa Rosa, CA
| | - Amanda J Rivet
- School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, NY; now, Pharmacist, Department of Pharmacy, St. Joseph's Hospital Health Center, Syracuse, NY
| | - Tara Sidora
- School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, NY; now, Pharmacist, Walgreens Pharmacy, Erie, PA
| | - Mary T Pasko
- Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY
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