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Anastasiou IA, Sarantis P, Rebelos E, Eleftheriadou I, Tentolouris KN, Katsaouni A, Koustas E, Kokala V, Karamouzis MV, Tentolouris N. l-Securinine Induces ROS-Dependent Apoptosis on Pancreatic Cancer Cells via the PI3K/AKT/mTOR Signaling Pathway. J Biochem Mol Toxicol 2024; 38:e70036. [PMID: 39467148 DOI: 10.1002/jbt.70036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 09/03/2024] [Accepted: 10/18/2024] [Indexed: 10/30/2024]
Abstract
Accumulating evidence has shown that l-securinine can, in certain circumstances, suppress tumor development by elevating reactive oxygen species (ROS) levels. The current work set out to examine l-securinine's apoptotic effects on HuP-T3 cells as well as any potential underlying molecular mechanism(s) that could explain its action as an anticancer agent. In this study, we used 1.2B4 cells as a control human cell line to verify our findings. Hup-T3 and 1.2B4 cells were cultured with a medium containing the following dilutions of l-securinine: 1-10 μΜ for up to 72 h. We examined the viability and proliferation levels of cells in both cell lines. Then, we measured only 1.2B4 insulin levels and content. We also quantified cell apoptosis, cell cycle levels, and the intracellular reactive oxygen species on HuP-T3 and 1.2B4. Afterwards, we performed a real-time quantitative polymerase chain reaction and western blot analysis. Our results demonstrated that l-securinine inhibited both proliferation and growth of Hup-T3 cells, showing inhibitory and antiproliferative activity in comparison with the control group. In addition, l-securinine had no impact on the proliferation and growth of 1.2B4 cells, nor on their insulin levels and content. By boosting ROS production, and inhibiting the PI3K/AKT/mTOR signaling pathway, l-securinine induced apoptosis on HuP-T3 cells. Pancreatic cancer was successfully inhibited by l-securinine in vitro. l-securinine triggers ROS-dependent apoptosis on pancreatic cancer cells while inhibiting the PI3K/AKT/mTOR signaling pathway. These findings suggest that l-securinine holds promise as a potential lead for future drug development in the fight against pancreatic adenocarcinoma.
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Affiliation(s)
- Ioanna A Anastasiou
- First Department of Propaedeutic Internal Medicine, Diabetes Center, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Greece
| | - Eleni Rebelos
- First Department of Propaedeutic Internal Medicine, Diabetes Center, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
- Turku PET Centre, University of Turku, Turku, Finland
| | - Ioanna Eleftheriadou
- First Department of Propaedeutic Internal Medicine, Diabetes Center, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Konstantinos N Tentolouris
- First Department of Propaedeutic Internal Medicine, Diabetes Center, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Athanasia Katsaouni
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Evangelos Koustas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Greece
| | - Vasileia Kokala
- First Department of Propaedeutic Internal Medicine, Diabetes Center, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Michalis V Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Greece
| | - Nikolaos Tentolouris
- First Department of Propaedeutic Internal Medicine, Diabetes Center, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
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Fakhlaei R, Selamat J, Abdull Razis AF, Sukor R, Ahmad S, Khatib A, Zou X. Development of a zebrafish model for toxicity evaluation of adulterated Apis mellifera honey. CHEMOSPHERE 2024; 356:141736. [PMID: 38554873 DOI: 10.1016/j.chemosphere.2024.141736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 03/09/2024] [Accepted: 03/15/2024] [Indexed: 04/02/2024]
Abstract
Since ancient times, honey has been used for medical purposes and the treatment of various disorders. As a high-quality food product, the honey industry is prone to fraud and adulteration. Moreover, limited experimental studies have investigated the impact of adulterated honey consumption using zebrafish as the animal model. The aims of this study were: (1) to calculate the lethal concentration (LC50) of acid-adulterated Apis mellifera honey on embryos, (2) to investigate the effect of pure and acid-adulterated A. mellifera honey on hatching rate (%) and heart rate of zebrafish (embryos and larvae), (3) to elucidate toxicology of selected adulterated honey based on lethal dose (LD50) using adult zebrafish and (4) to screen the metabolites profile of adulterated honey from blood serum of adult zebrafish. The result indicated the LC50 of 31.10 ± 1.63 (mg/ml) for pure A. mellifera honey, while acetic acid demonstrates the lowest LC50 (4.98 ± 0.06 mg/ml) among acid adulterants with the highest mortality rate at 96 hpf. The treatment of zebrafish embryos with adulterated A. mellifera honey significantly (p ≤ 0.05) increased the hatching rate (%) and decreased the heartbeat rate. Acute, prolong-acute, and sub-acute toxicology tests on adult zebrafish were conducted at a concentration of 7% w/w of acid adulterants. Furthermore, the blood serum metabolite profile of adulterated-honey-treated zebrafish was screened by LC-MS/MS analysis and three endogenous metabolites have been revealed: (1) Xanthotoxol or 8-Hydroxypsoralen, (2) 16-Oxoandrostenediol, and (3) 3,5-Dicaffeoyl-4-succinoylquinic acid. These results prove that employed honey adulterants cause mortality that contributes to higher toxicity. Moreover, this study introduces the zebrafish toxicity test as a new promising standard technique for the potential toxicity assessment of acid-adulterated honey in this study and hazardous food adulterants for future studies.
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Affiliation(s)
- Rafieh Fakhlaei
- School of Food and Biological Engineering, Jiangsu University, 301 Xuefu Rd, 212013, Zhenjiang, Jiangsu, China; Food Safety and Food Integrity (FOSFI), Institute of Tropical Agriculture and Food Security, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Jinap Selamat
- Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia.
| | - Ahmad Faizal Abdull Razis
- Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia; Natural Medicines and Products Research Laboratory, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia
| | - Rashidah Sukor
- Food Safety and Food Integrity (FOSFI), Institute of Tropical Agriculture and Food Security, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia; Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Syahida Ahmad
- Department of Biochemistry, Faculty of Biotechnology & Biomolecular Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Alfi Khatib
- Department of Pharmaceutical Chemistry, Kulliyyah of Pharmacy, International Islamic University Malaysia, 25200, Kuantan, Pahang, Malaysia
| | - Xiaobo Zou
- School of Food and Biological Engineering, Jiangsu University, 301 Xuefu Rd, 212013, Zhenjiang, Jiangsu, China
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Jones ZJM, Huang Y, Green KJ, Hammer KA. Changes in antibacterial activity, colour, and hydrogen peroxide content of Western Australian Jarrah and Marri honeys after storage at different temperatures over time. J Appl Microbiol 2023; 134:lxad164. [PMID: 37505452 DOI: 10.1093/jambio/lxad164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 06/08/2023] [Accepted: 07/28/2023] [Indexed: 07/29/2023]
Abstract
AIMS This study aimed to evaluate the effects of storage and different temperatures on the antibacterial activity and physicochemical characteristics of several types of honey. METHODS AND RESULTS Honeys stored for 16 weeks at 37 and 45°C showed significant declines in antibacterial activity determined by minimum inhibitory concentrations, the loss of hydrogen peroxide, decreases in honey pH, and increases in honey colour, with changes most pronounced at 45°C. In contrast, honeys stored for 16 weeks at ambient (∼22°C) and cold (4, -20, and -80°C) temperatures showed only minor changes. In a second set of 12 honeys stored for 16-32 months at ambient temperature and then 4°C, honeys showed minor changes in antibacterial activity, increases in colour, and decreases in pH. For a third set of 17 honeys stored for five years at ambient temperature, the honeys showed almost complete loss of hydrogen peroxide and were all significantly darker in colour, but showed varied changes in antibacterial activity. CONCLUSIONS Heat was detrimental to the antibacterial activity of honeys, as was long-term storage at ambient temperatures for some honeys but not others.
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Affiliation(s)
- Zachary J M Jones
- School of Biomedical Sciences, The University of Western Australia, Crawley WA 6009, Australia
| | - Yina Huang
- School of Biomedical Sciences, The University of Western Australia, Crawley WA 6009, Australia
| | - Kathryn J Green
- School of Biomedical Sciences, The University of Western Australia, Crawley WA 6009, Australia
- Cooperative Research Centre for Honey Bee Products Limited (CRC HBP), The University of Western Australia, Crawley 6009, Australia
| | - Katherine A Hammer
- School of Biomedical Sciences, The University of Western Australia, Crawley WA 6009, Australia
- Cooperative Research Centre for Honey Bee Products Limited (CRC HBP), The University of Western Australia, Crawley 6009, Australia
- The Marshall Centre for Infectious Diseases Research and Training, School of Biomedical Sciences, Crawley 6009, Australia
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Evidence for Natural Products as Alternative Wound-Healing Therapies. Biomolecules 2023; 13:biom13030444. [PMID: 36979379 PMCID: PMC10046143 DOI: 10.3390/biom13030444] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 02/13/2023] [Accepted: 02/15/2023] [Indexed: 03/02/2023] Open
Abstract
Chronic, non-healing wounds represent a significant area of unmet medical need and are a growing problem for healthcare systems around the world. They affect the quality of life for patients and are an economic burden, being difficult and time consuming to treat. They are an escalating problem across the developed world due to the increasing incidence of diabetes and the higher prevalence of ageing populations. Effective treatment options are currently lacking, and in some cases chronic wounds can persist for years. Some traditional medicines are believed to contain bioactive small molecules that induce the healing of chronic wounds by reducing excessive inflammation, thereby allowing re-epithelisation to occur. Furthermore, many small molecules found in plants are known to have antibacterial properties and, although they lack the therapeutic selectivity of antibiotics, they are certainly capable of acting as topical antiseptics when applied to infected wounds. As these molecules act through mechanisms of action distinct from those of clinically used antibiotics, they are often active against antibiotic resistant bacteria. Although there are numerous studies highlighting the effects of naturally occurring small molecules in wound-healing assays in vitro, only evidence from well conducted clinical trials can allow these molecules or the remedies that contain them to progress to the clinic. With this in mind, we review wound-healing natural remedies that have entered clinical trials over a twenty-year period to the present. We examine the bioactive small molecules likely to be in involved and, where possible, their mechanisms of action.
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Rayate AS, Nagoba BS, Mumbre SS, Mavani HB, Gavkare AM, Deshpande AS. Current scenario of traditional medicines in management of diabetic foot ulcers: A review. World J Diabetes 2023; 14:1-16. [PMID: 36684382 PMCID: PMC9850800 DOI: 10.4239/wjd.v14.i1.1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 11/04/2022] [Accepted: 12/06/2022] [Indexed: 01/10/2023] Open
Abstract
Diabetic foot infections and diabetic foot ulcers (DFU) cause significant suffering and are often recurring. DFU have three important pathogenic factors, namely, microangiopathy causing local tissue anoxia, neuropathy making the foot prone to injuries from trivial trauma, and local tissue hyperglycaemia favouring infection and delaying the wound healing. DFU have been the leading cause for non-traumatic amputations of part or whole of the limb. Western medicines focus mainly on euglycaemia, antimicrobials, debridement and wound cover with grafts, and off-loading techniques. Advances in euglycaemic control, foot care and footwear, systemic antimicrobial therapy, and overall health care access and delivery, have resulted in an overall decrease in amputations. However, the process of wound care after adequate debridement remains a major cost burden globally, especially in developing nations. This process revolves around two basic concerns regarding control/eradication of local infection and promotion of faster healing in a chronic DFU without recurrence. Wound modulation with various dressings and techniques are often a costly affair. Some aspects of the topical therapy with modern/Western medicines are frequently not addressed. Cost of and compliance to these therapies are important as both the wounds and their treatment are “chronic.” Naturally occurring agents/medications from traditional medicine systems have been used frequently in different cultures and nations, though without adequate clinical base/relevance. Traditional Chinese medicine involves restoring yin-yang balance, regulating the ‘chi’, and promoting local blood circulation. Traditional medicines from India have been emphasizing on ‘naturally’ available products to control wound infection and promote all the aspects of wound healing. There is one more group of chemicals which are not pharmaceutical agents but can create acidic milieu in the wound to satisfy the above-mentioned basic concerns. Various natural and plant derived products (e.g., honey, aloe vera, oils, and calendula) and maggots are also used for wound healing purposes. We believe that patients with a chronic wound are so tired physically, emotionally, and financially that they usually accept native traditional medicine which has the same cultural base, belief, and faith. Many of these products have never been tested in accordance to “evidence-based medicine.” There are usually case reports and experience-based reports about these products. Recently, there have been some trials (in vitro and in vivo) to verify the claims of usage of traditional medicines in management of DFU. Such studies show that these natural products enhance the healing process by controlling infection, stimulating granulation tissue, antimicrobial action, promoting fibroblastic activity and collagen deposition, etc. In this review, we attempt to study and analyse the available literature on results of topical traditional medicines, which are usually advocated in the management of DFU. An integrated and ‘holistic’ approach of both modern and traditional medicine may be more acceptable to the patient, cost effective, and easy to administer and monitor. This may also nevertheless lead to further improvement in quality of life and decrease in the rates of amputations for DFU.
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Affiliation(s)
- Abhijit S Rayate
- Department of Surgery, Maharashtra Institute of Medical Sciences & Research (Medical College), Latur 413531, India
| | - Basavraj S Nagoba
- Department of Microbiology, Maharashtra Institute of Medical Sciences & Research (Medical College), Latur 413531, India
| | - Sachin S Mumbre
- Department of Community Medicine, Ashwini Rural Medical College, Solapur 413006, India
| | - Hardi B Mavani
- Department of Surgery, Maharashtra Institute of Medical Sciences & Research (Medical College), Latur 413531, India
| | - Ajay M Gavkare
- Department of Physiology, Maharashtra Institute of Medical Sciences & Research (Medical College), Latur 413531, India
| | - Advait S Deshpande
- Department of Surgery, Maharashtra Institute of Medical Sciences & Research (Medical College), Latur 413531, India
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Sethuram L, Thomas J. Therapeutic applications of electrospun nanofibers impregnated with various biological macromolecules for effective wound healing strategy - A review. Biomed Pharmacother 2023; 157:113996. [PMID: 36399827 DOI: 10.1016/j.biopha.2022.113996] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/31/2022] [Accepted: 11/09/2022] [Indexed: 11/17/2022] Open
Abstract
A Non-healing infected wound is an ever-growing global epidemic, with increasing burden of mortality rates and management costs. The problems of chronic wound infections and their outcomes will continue as long as their underlying causes like diabetic wounds grow and spread. Commercial wound therapies employed have limited potential that inhibits pivotal functions and tissue re-epithelialization properties resulting in wound infections. Nanomaterial based drug delivery formulations involving biological macromolecules are developing areas of interest in wound healing applications which are utilized in the re-epithelialization of skin with cost-effective preparations. Research conducted on nanofibers has shown enhanced skin establishment with improved cell proliferation and growth and delivery of bioactive organic molecules at the wound site. However, drug targeted delivery with anti-scarring properties and tissue regeneration aspects have not been updated and discussed in the case of macromolecule impregnated nanofibrous mats. Hence, this review focuses on the brief concepts of wound healing and wound management, therapeutic commercialized wound dressings currently available in the field of wound care, effective electrospun nanofibers impregnated with different biological macromolecules and advancement of nanomaterials for tissue engineering have been discussed. These new findings will pave the way for producing anti-scarring high effective wound scaffolds for drug delivery.
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Affiliation(s)
- Lakshimipriya Sethuram
- School of Bio Sciences & Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India; Centre for Nanobiotechnology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - John Thomas
- Centre for Nanobiotechnology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.
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Alka, Verma A, Mishra N, Singh N, Singh P, Nisha R, Pal RR, Saraf SA. Polymeric Gel Scaffolds and Biomimetic Environments for Wound Healing. Curr Pharm Des 2023; 29:3221-3239. [PMID: 37584354 DOI: 10.2174/1381612829666230816100631] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/16/2023] [Accepted: 07/14/2023] [Indexed: 08/17/2023]
Abstract
Infected wounds that do not heal are a worldwide problem that is worsening, with more people dying and more money being spent on care. For any disease to be managed effectively, its root cause must be addressed. Effective wound care becomes a bigger problem when various traditional wound healing methods and products may not only fail to promote good healing. Still, it may also hinder the healing process, causing wounds to stay open longer. Progress in tissue regeneration has led to developing three-dimensional scaffolds (3D) or constructs that can be leveraged to facilitate cell growth and regeneration while preventing infection and accelerating wound healing. Tissue regeneration uses natural and fabricated biomaterials that encourage the growth of tissues or organs. Even though the clinical need is urgent, the demand for polymer-based therapeutic techniques for skin tissue abnormalities has grown quickly. Hydrogel scaffolds have become one of the most imperative 3D cross-linked scaffolds for tissue regeneration because they can hold water perfectly and are porous, biocompatible, biodegradable, and biomimetic. For damaged organs or tissues to heal well, the porosity topography of the natural extracellular matrix (ECM) should be imitated. This review details the scaffolds that heal wounds and helps skin tissue to develop. After a brief overview of the bioactive and drug-loaded polymeric hydrogels, the discussion moves on to how the scaffolds are made and what they are made of. It highlights the present uses of in vitro and in-vivo employed biomimetic scaffolds. The prospects of how well bioactiveloaded hydrogels heal wounds and how nanotechnology assists in healing and regeneration have been discussed.
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Affiliation(s)
- Alka
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University Lucknow (A Central University), Uttar Pradesh, Vidya Vihar, Raebareli Road, Lucknow, 226025, Uttar Pradesh, India
| | - Abhishek Verma
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University Lucknow (A Central University), Uttar Pradesh, Vidya Vihar, Raebareli Road, Lucknow, 226025, Uttar Pradesh, India
| | - Nidhi Mishra
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University Lucknow (A Central University), Uttar Pradesh, Vidya Vihar, Raebareli Road, Lucknow, 226025, Uttar Pradesh, India
| | - Neelu Singh
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University Lucknow (A Central University), Uttar Pradesh, Vidya Vihar, Raebareli Road, Lucknow, 226025, Uttar Pradesh, India
| | - Priya Singh
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University Lucknow (A Central University), Uttar Pradesh, Vidya Vihar, Raebareli Road, Lucknow, 226025, Uttar Pradesh, India
| | - Raquibun Nisha
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University Lucknow (A Central University), Uttar Pradesh, Vidya Vihar, Raebareli Road, Lucknow, 226025, Uttar Pradesh, India
| | - Ravi Raj Pal
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University Lucknow (A Central University), Uttar Pradesh, Vidya Vihar, Raebareli Road, Lucknow, 226025, Uttar Pradesh, India
| | - Shubhini A Saraf
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University Lucknow (A Central University), Uttar Pradesh, Vidya Vihar, Raebareli Road, Lucknow, 226025, Uttar Pradesh, India
- National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, Bijnor-Sisendi Road, Sarojini Nagar, Lucknow, 226002, Uttar Pradesh, India
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Papi M, Fiscarelli E. The Fascinating History of Wound Healing Through Fine Arts. INT J LOW EXTR WOUND 2022:15347346221102642. [PMID: 35585699 DOI: 10.1177/15347346221102642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Visual art images narrate the evolution of humankind including different and specific wound managing strategies. Through the observation of some notable art works we explore the empiric historical progress in wound healing and the main reasons they may have been represented. We briefly examine the cultural, symbolic, magical or religious beliefs that have conditioned the approach to a fundamental vital need of humanity: to heal a wound.
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Affiliation(s)
- Massimo Papi
- ADOI (National Study Group Vascular Dermatology and Vulnology), Rome, Italy
| | - Ersilia Fiscarelli
- Clinical management and technological innovations, Research Center S. Paolo, 586725Bambin Gesù Hospital, IRCCS, Rome, Italy
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Zhao Q, Xu J, Han X, Zhang Z, Qu J, Cheng Z. Growth differentiation factor 10 induces angiogenesis to promote wound healing in rats with diabetic foot ulcers by activating TGF-β1/Smad3 signaling pathway. Front Endocrinol (Lausanne) 2022; 13:1013018. [PMID: 36714584 PMCID: PMC9880151 DOI: 10.3389/fendo.2022.1013018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 11/23/2022] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Diabetic foot ulcer (DFU) represents a highly-prevalent complication of diabetes mellitus (DM). Herein, the current study sought to identify the role of growth differentiation factor 10 (GDF-10) in wound healing in DFU via regulation of the transforming growth factor-beta 1 (TGF-β1)/Smad3 pathway. METHODS DM- and DFU-related microarray datasets GSE29221 and GSE134431 were firstly retrieved, and weighted gene co-expression network analysis (WGCNA) was carried out to construct a co-expression network affecting wound healing in DFU, followed by differential analysis. A protein-protein interaction (PPI) network of the DFU-related genes was subsequently constructed, and the core genes and signaling pathways in DFU were screened with the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional analyses. A DFU rat model was constructed for mechanism verification of the effect of GDF-10 on wound healing in DFU. RESULTS WGCNA screened five co-expression modules, and the brown module was most closely-related to DM. Clustering analysis screened 4417 candidate genes, of which 175 differential genes were associated with wound healing, further involved in TGF-β1/Smad3 signaling pathway regulation of wound healing in DFU. The PPI network analysis predicted that GDF-10 might regulate the TGF-β1/Smad3 signaling pathway to participate in DFU development. Results of animal experimentation showed that the wound healing rates of NFU, DFU, DFU + GDF and GDF + SIS3 groups on the 22nd day were (87.66 ± 6.80)%, (56.31 ± 7.29)%, (71.64 ± 9.43)% and (55.09 ± 7.13)%, respectively. Besides, the expression of TGF-β1 in NFU, DFU, DFU + GDF and GDF + SIS3 groups was 0.988 ± 0.086, 0.297 ± 0.036, 0.447 ± 0.044, and 0.240 ± 0.050, respectively, and that of Smad3 was 1.009 ± 0.137, 0.145 ± 0.017, 0.368 ± 0.048, and 0.200 ± 0.028, respectively. Specifically, GDF-10 exerted a significant diminishing effect on fasting blood glucose level, and promoted wound healing in DFU rats, in addition to up-regulation of VEGF, FGF, Ang-1, TGF-β1, Smad3 and enhancement of IL-1b, IL-6, TNF-a and MMP-9, thereby promoting fibroblast proliferation, collagen deposition and angiogenesis. CONCLUSIONS Our findings highlight that GDF-10 may promote angiogenesis by activating TGF-β1/Smad3 signaling, thereby promoting wound healing in DFU rats.
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Papanas N, Papi M, Rerkasem K. Fighting Against a sea of Troubles. INT J LOW EXTR WOUND 2021; 20:289-290. [PMID: 34705591 DOI: 10.1177/15347346211055713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Nikolaos Papanas
- Diabetes Centre-Diabetic Foot Clinic, Democritus University of Thrace, Alexandroupolis, Greece
| | - Massimo Papi
- National Institute for Health, Migration and Poverty (NIHMP), Rome, Italy
| | - Kittipan Rerkasem
- Environmental - Occupational Health Sciences and Non Communicable Diseases Research Group. Research Institute for Health Science, Chiang Mai University, Chiang Mai, Thailand.,Department of Surgery, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
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