|
1
|
Xu J, Gao J, Li H, Zhu Z, Liu J, Gao C. The risk factors in diabetic foot ulcers and predictive value of prognosis of wound tissue vascular endothelium growth factor. Sci Rep 2024; 14:14120. [PMID: 38898068 PMCID: PMC11187195 DOI: 10.1038/s41598-024-64009-4] [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: 03/15/2024] [Accepted: 06/04/2024] [Indexed: 06/21/2024] Open
Abstract
Diabetic foot ulcer (DFU) is a leading cause of high-level amputation in DM patients, with a low wound healing rate and a high incidence of infection. Vascular endothelial growth factor (VEGF) plays an important role in diabetes mellitus (DM) related complications. This study aims to explore the VEGF expression and its predictive value for prognosis in DFU, in order to provide basis for the prevention of DFU related adverse events. We analyzed 502 patients, with 328 in healing group and 174 in non-healing/recurrent group. The general clinical data and laboratory indicators of patients were compared through Spearman correlation analysis, ROC analysis and logistic regression analysis. Finally, the independent risk factors for adverse prognosis in DFU patients were confirmed. Spearman analysis reveals a positive correlation between the DFU healing rate and ABI, VEGF in wound tissue, and positive rate of VEGF expression, and a negative correlation with DM duration, FPG, HbA1c, TC, Scr, BUN, and serum VEGF. Further logistic regression analysis finds that the DM duration, FPG, HbA1c, ABI, serum VEGF, VEGF in wound tissue, and positive rate of VEGF expression are the independent risk factors for adverse prognosis in DFU (p < 0.05). DM duration, FPG, HbA1c, ABI, serum VEGF, VEGF in wound tissue, and positive rate of VEGF expression are the independent risk factors for prognosis in DFU patients. Patients with these risk factors should be screened in time, which is of great significance to prevent DFU related adverse events and improve outcomes.
Collapse
Affiliation(s)
- Jing Xu
- Department of Oncology, The Second People's Hospital of Lianyungang, No. 41 Hailiandong Road, Haizhou District, Lianyungang, 222006, China
| | - Jian Gao
- Department of Orthopedics, The Sixth Affiliated Hospital of Xinjiang Medical University, No. 39 Wuxingnan Road, Tian Shan District, Urumqi, 830002, China
| | - Hui Li
- Department of Internal Medicine, Urumqi Maternal and Child Health Care Hospital, No. 3838, Convention and Exhibition Avenue, Midong District, Urumqi, 831400, China
| | - Zhoujun Zhu
- Department of Orthopedics, The Sixth Affiliated Hospital of Xinjiang Medical University, No. 39 Wuxingnan Road, Tian Shan District, Urumqi, 830002, China
| | - Junliang Liu
- Department of Orthopedics, Weihai Stomatological Hospital, No. 268, Tongyi South Road, Huancui District, Weihai, 264299, China
| | - Chong Gao
- Department of Orthopedics, The Second People's Hospital of Lianyungang, No. 41 Hailiandong Road, Haizhou District, Lianyungang, 222006, China.
| |
Collapse
|
|
2
|
Memarpour S, Raoufinia R, Saburi E, Razavi MS, Attaran M, Fakoor F, Rahimi HR. The future of diabetic wound healing: unveiling the potential of mesenchymal stem cell and exosomes therapy. AMERICAN JOURNAL OF STEM CELLS 2024; 13:87-100. [PMID: 38765803 PMCID: PMC11101987 DOI: 10.62347/ovbk9820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 03/18/2024] [Indexed: 05/22/2024]
Abstract
Diabetes mellitus (DM) is a significant public health problem and is one of the most challenging medical conditions worldwide. It is the severe complications that make this disease more intricate. A diabetic wound is one of these complications. Patients with diabetes are at higher risk of developing diabetic foot ulcers (DFU). Due to the ineffectiveness of Conventional treatments, growth in limb amputation, morbidity, and mortality have been recognized, which indicates the need for additional treatment. Mesenchymal stem cells (MSCs) can significantly improve wound healing. However, there are some risks related to stem cell therapy. Exosome therapy is a new treatment option for diabetic wounds that has shown promising results. However, an even more advanced form called cell-free therapy using exosomes has emerged. This upgraded version of stem cell therapy offers improved efficacy and eliminates the risk of cancer progression. Exosome therapy promotes wound healing from multiple angles, unlike traditional methods that primarily rely on the body's self-healing ability and only provide wound protection. Therefore, exosome therapy has the potential to replace conventional treatments effectively. However, further research is necessary to distinguish the optimal type of stem cells for therapy, ensure their safety, establish appropriate dosing, and identify the best management trail. The present study focused on the current literature on diabetic wound ulcers, their treatment, and mesenchymal stem cell and exosome therapy potential in DFU.
Collapse
Affiliation(s)
- Sara Memarpour
- Medical Genetics Research Center, Mashhad University of Medical SciencesMashhad, Iran
| | - Ramin Raoufinia
- Medical Genetics Research Center, Mashhad University of Medical SciencesMashhad, Iran
- Department of Basic Medical Sciences, Neyshabur University of Medical SciencesNeyshabur, Iran
| | - Ehsan Saburi
- Medical Genetics Research Center, Mashhad University of Medical SciencesMashhad, Iran
| | - Masoud Sharifian Razavi
- Department of Internal Medicine, Ghaem Hospital, Mashhad University of Medical SciencesMashhad, Iran
| | - Matin Attaran
- Department of Obstetrics and Gynecology, Mashhad University of Medical SciencesMashhad, Iran
| | - Farhad Fakoor
- Department of Paramedical Sciences, Iran University of Medical SciencesTehran, Iran
| | - Hamid Reza Rahimi
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical SciencesMashhad, Iran
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical SciencesMashhad, Iran
| |
Collapse
|
|
3
|
Del Cuore A, Pipitone RM, Casuccio A, Mazzola MM, Puleo MG, Pacinella G, Riolo R, Maida C, Di Chiara T, Di Raimondo D, Zito R, Lupo G, Agnello L, Di Maria G, Ciaccio M, Grimaudo S, Tuttolomondo A. Metabolic memory in diabetic foot syndrome (DFS): MICRO-RNAS, single nucleotide polymorphisms (SNPs) frequency and their relationship with indices of endothelial function and adipo-inflammatory dysfunction. Cardiovasc Diabetol 2023; 22:148. [PMID: 37365645 PMCID: PMC10294440 DOI: 10.1186/s12933-023-01880-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 06/06/2023] [Indexed: 06/28/2023] Open
Abstract
BACKGROUND Diabetic foot is a significant cause of morbidity in diabetic patients, with a rate that is approximately twice that of patients without foot ulcers. "Metabolic memory" represents the epigenetic changes induced by chronic hyperglycaemia, despite the correction of the glucose levels themselves. These epigenetic modifications appear to perpetuate the damage caused by persistently elevated glucose levels even in their absence, acting at various levels, mostly affecting the molecular processes of diabetic ulcer healing. METHODS The aim of our cross-sectional study was to analyse a cohort of patients with diabetes with and without lower limb ulcers. We examined the effects of epigenetic changes on miRNA 126, 305, and 217 expression and the frequency of the SNPs of genes encoding inflammatory molecules (e.g., IL-6 and TNF-alpha) and their correlations with serum levels of proangiogenic molecules (e.g., ENOS, VEGF and HIF-1alpha) and several adipokines as well as with endothelial dysfunction, assessed noninvasively by reactive hyperaemia peripheral artery tonometry. Between March 2021 and June 2022, 110 patients were enrolled into the study: 50 diabetic patients with diabetic foot injuries, 40 diabetic patients without ulcerative complications and 20 nondiabetic patients as the control group. RESULTS Diabetic subjects with lower limb ulcerative lesions exhibited higher levels of inflammatory cytokines, such as VEGF (191.40 ± 200 pg/mL vs. 98.27 ± 56.92 pg/mL vs. 71.01 ± 52.96 pg/mL; p = 0.22), HIF-1alpha (40.18 ± 10.80 ng/mL vs. 33.50 ± 6.16 ng/mL vs. 33.85 ± 6.84 ng/mL; p = 0.10), and Gremlin-1 (1.72 ± 0.512 ng/mL vs. 1.31 ± 0.21 ng/mL vs. 1.11 ± 0.19 ng/mL; p < 0.0005), than those without lower limb ulcers and healthy controls. Furthermore, we observed that miR-217-5p and miR-503-5p were 2.19-fold (p < 0.05) and 6.21-fold (p = 0.001) more highly expressed in diabetic foot patients than in healthy controls, respectively. Additionally, diabetic patients without lower limb ulcerative complications showed 2.41-fold (p = 0) and 2.24-fold (p = 0.029) higher expression of miR-217-5p and miR-503-5p, respectively, than healthy controls. Finally, diabetic patients with and without ulcerative complications of the lower limbs showed higher expression of the VEGFC2578A CC polymorphism (p = 0.001) and lower expression of the VEGFC2578A AC polymorphism (p < 0.005) than the healthy control population. We observed a significant increase in Gremlin-1 levels in patients with diabetic foot, suggesting that this inflammatory adipokine may serve as a predictive marker for the diagnosis of diabetic foot. CONCLUSIONS Our results highlighted that patients with diabetic foot showed predominant expression of the VEGF C2578A CC polymorphism and reduced expression of the AC allele. Additionally, we found an overexpression of miR-217-5p and miR-503-5p in diabetic patients with and without diabetic foot syndrome compared with healthy controls. These results align with those reported in the literature, in which the overexpression of miR-217-5p and miR-503-5p in the context of diabetic foot is reported. The identification of these epigenetic modifications could therefore be helpful in the early diagnosis of diabetic foot and the treatment of risk factors. However, further studies are necessary to confirm this hypothesis.
Collapse
Affiliation(s)
- Alessandro Del Cuore
- Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialized Medicine (PROMISE) G. D'Alessandro, University of Palermo, Piazza Delle Cliniche N.2, 90127, Palermo, Italy
- Internal Medicine and Stroke Care Ward, Policlinico "P. Giaccone", Palermo, Italy
| | - Rosaria Maria Pipitone
- Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialized Medicine (PROMISE) G. D'Alessandro, University of Palermo, Piazza Delle Cliniche N.2, 90127, Palermo, Italy
| | - Alessandra Casuccio
- Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialized Medicine (PROMISE) G. D'Alessandro, University of Palermo, Piazza Delle Cliniche N.2, 90127, Palermo, Italy
| | - Marco Maria Mazzola
- Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialized Medicine (PROMISE) G. D'Alessandro, University of Palermo, Piazza Delle Cliniche N.2, 90127, Palermo, Italy
- Internal Medicine and Stroke Care Ward, Policlinico "P. Giaccone", Palermo, Italy
| | - Maria Grazia Puleo
- Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialized Medicine (PROMISE) G. D'Alessandro, University of Palermo, Piazza Delle Cliniche N.2, 90127, Palermo, Italy
- Internal Medicine and Stroke Care Ward, Policlinico "P. Giaccone", Palermo, Italy
| | - Gaetano Pacinella
- Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialized Medicine (PROMISE) G. D'Alessandro, University of Palermo, Piazza Delle Cliniche N.2, 90127, Palermo, Italy
- Internal Medicine and Stroke Care Ward, Policlinico "P. Giaccone", Palermo, Italy
| | - Renata Riolo
- Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialized Medicine (PROMISE) G. D'Alessandro, University of Palermo, Piazza Delle Cliniche N.2, 90127, Palermo, Italy
- Internal Medicine and Stroke Care Ward, Policlinico "P. Giaccone", Palermo, Italy
| | - Carlo Maida
- Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialized Medicine (PROMISE) G. D'Alessandro, University of Palermo, Piazza Delle Cliniche N.2, 90127, Palermo, Italy
- Internal Medicine and Stroke Care Ward, Policlinico "P. Giaccone", Palermo, Italy
| | - Tiziana Di Chiara
- Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialized Medicine (PROMISE) G. D'Alessandro, University of Palermo, Piazza Delle Cliniche N.2, 90127, Palermo, Italy
- Internal Medicine and Stroke Care Ward, Policlinico "P. Giaccone", Palermo, Italy
| | - Domenico Di Raimondo
- Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialized Medicine (PROMISE) G. D'Alessandro, University of Palermo, Piazza Delle Cliniche N.2, 90127, Palermo, Italy
- Internal Medicine and Stroke Care Ward, Policlinico "P. Giaccone", Palermo, Italy
| | - Rossella Zito
- Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialized Medicine (PROMISE) G. D'Alessandro, University of Palermo, Piazza Delle Cliniche N.2, 90127, Palermo, Italy
| | - Giulia Lupo
- Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialized Medicine (PROMISE) G. D'Alessandro, University of Palermo, Piazza Delle Cliniche N.2, 90127, Palermo, Italy
| | - Luisa Agnello
- Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, Department of Biomedicine, Neurosciences, and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Gabriele Di Maria
- Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialized Medicine (PROMISE) G. D'Alessandro, University of Palermo, Piazza Delle Cliniche N.2, 90127, Palermo, Italy
| | - Marcello Ciaccio
- Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, Department of Biomedicine, Neurosciences, and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Stefania Grimaudo
- Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialized Medicine (PROMISE) G. D'Alessandro, University of Palermo, Piazza Delle Cliniche N.2, 90127, Palermo, Italy
| | - Antonino Tuttolomondo
- Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialized Medicine (PROMISE) G. D'Alessandro, University of Palermo, Piazza Delle Cliniche N.2, 90127, Palermo, Italy.
- Internal Medicine and Stroke Care Ward, Policlinico "P. Giaccone", Palermo, Italy.
| |
Collapse
|
|
4
|
Mahmoudvand G, Karimi Rouzbahani A, Razavi ZS, Mahjoor M, Afkhami H. Mesenchymal stem cell therapy for non-healing diabetic foot ulcer infection: New insight. Front Bioeng Biotechnol 2023; 11:1158484. [PMID: 37122856 PMCID: PMC10133463 DOI: 10.3389/fbioe.2023.1158484] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 03/31/2023] [Indexed: 05/02/2023] Open
Abstract
Diabetic foot ulcer (DFU) is considered the most catastrophic complication of diabetes mellitus (DM), leading to repeated hospitalizations, infection, gangrene, and finally amputation of the limb. In patients suffering from diabetes mellitus, the wound-healing process is impaired due to various factors such as endothelial dysfunction and synthesis of advanced glycation end-products, hence, conventional therapeutic interventions might not be effective. With increasing therapeutic applications of mesenchymal stem cells (MSCs) in recent years, their potential as a method for improving the wound-healing process has gained remarkable attention. In this field, mesenchymal stem cells exert their beneficial effects through immunomodulation, differentiation into the essential cells at the site of ulcers, and promoting angiogenesis, among others. In this article, we review cellular and molecular pathways through which mesenchymal stem cell therapy reinforces the healing process in non-healing Diabetic foot ulcers.
Collapse
Affiliation(s)
- Golnaz Mahmoudvand
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Arian Karimi Rouzbahani
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Zahra Sadat Razavi
- Physiology Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohamad Mahjoor
- Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Afkhami
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
- *Correspondence: Hamed Afkhami,
| |
Collapse
|
|
5
|
Ganapathy P, Devanatha Desikan Sheshadri V, Sarkar R, Jones S, Gunasekaran K, Feysia TO, Umapathy D, Basha S. Vascular Endothelial Growth Factor Single Nucleotide Polymorphism +405 G/C (rs2010963) is associated with Levels, Infection Severity, and Amputation among South Indian Diabetic Foot Ulcer Patients. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2023; 2023:2059426. [PMID: 37089713 PMCID: PMC10118891 DOI: 10.1155/2023/2059426] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 01/02/2023] [Accepted: 01/23/2023] [Indexed: 04/25/2023]
Abstract
Background The regulation of vascular endothelial growth factor (VEGF) by genetic factors in T2DM and DFU still requires thorough investigation. Hence, the present study aimed to investigate the association of VEGF +405 G/C in DFU subjects and correlate it with its circulatory levels, infection severity, and amputation rate. Materials and Methods This study registered a total of 754 participants of which group I: healthy controls (n = 297), group II: T2DM subjects (n = 242), and group III: DFU subjects (n = 215). Genotyping and levels of rs2010963 were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and ELISA, respectively. Results Results of the current study showed a clear decline in circulatory VEGF-A levels in DFU subjects. VEGF-A was decreased in DFU subjects with the mutant "CC" genotype. The mutant "CC" of VEGF +405G/C was also found to be more susceptible to ulcer grade (III and IV) and major amputations. Conclusion VEGF +405G/C SNP is associated with levels, infection severity, and amputation amongst South Indian DFU patients.
Collapse
Affiliation(s)
- Priyanka Ganapathy
- Department of Physiology, Sree Balaji Medical College and Hospital, Chennai, Tamilnadu, India
| | - Vidya Devanatha Desikan Sheshadri
- Department of Pharmacology and Toxicology, College of Pharmacy (Women's Campus), Prince Sattam Bin Abdul Aziz University, Al-Kharj, Saudi Arabia
| | - Rajesh Sarkar
- Department of Medical Microbiology, College of Health and Medical Sciences, Haramaya University, Dire Dawa, Ethiopia
| | - Sumathi Jones
- Department of Pharmacology and Therapeutics, Sree Balaji Dental College and Hospital, Chennai, Tamilnadu, India
| | - Krishnamoorthy Gunasekaran
- Department of Medical Biochemistry, College of Medical and Health Sciences, Dambi Dollo University, Oromia Region, Ethiopia
| | - Teka Obsa Feysia
- Department of Medical Biochemistry, College of Health and Medical Sciences, Haramaya University, Dire Dawa, Ethiopia
| | - Dhamodharan Umapathy
- Department of Biotechnology, D.K.M. College for Women, Vellore, Tamil Nadu, India
- Department of Research, APRAISE, Adhiparasakthi Dental College and Hospital, Melmaruvathur, Tamilnadu, India
| | - Saleem Basha
- Department of Medical Biochemistry, College of Health and Medical Sciences, Haramaya University, Dire Dawa, Ethiopia
| |
Collapse
|
|
6
|
Hu YJ, Song CS, Jiang N. Single nucleotide variations in the development of diabetic foot ulcer: A narrative review. World J Diabetes 2022; 13:1140-1153. [PMID: 36578869 PMCID: PMC9791576 DOI: 10.4239/wjd.v13.i12.1140] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 11/24/2022] [Accepted: 12/05/2022] [Indexed: 12/15/2022] Open
Abstract
Diabetes mellitus has become a global health problem, and the number of patients with diabetic foot ulcers (DFU) is rapidly increasing. Currently, DFU still poses great challenges to physicians, as the treatment is complex, with high risks of infection, recurrence, limb amputation, and even death. Therefore, a comprehensive understanding of DFU pathogenesis is of great importance. In this review, we summarized recent findings regarding the DFU development from the perspective of single-nucleotide variations (SNVs). Studies have shown that SNVs located in the genes encoding C-reactive protein, interleukin-6, tumor necrosis factor-alpha, stromal cell-derived factor-1, vascular endothelial growth factor, nuclear factor erythroid-2-related factor 2, sirtuin 1, intercellular adhesion molecule 1, monocyte chemoattractant protein-1, endothelial nitric oxide synthase, heat shock protein 70, hypoxia inducible factor 1 alpha, lysyl oxidase, intelectin 1, mitogen-activated protein kinase 14, toll-like receptors, osteoprotegerin, vitamin D receptor, and fibrinogen may be associated with the development of DFU. However, considering the limitations of the present investigations, future multi-center studies with larger sample sizes, as well as in-depth mechanistic research are warranted.
Collapse
Affiliation(s)
- Yan-Jun Hu
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Southern Medical University Nanfang Hospital, Guangzhou 510515, Guangdong Province, China
| | - Chen-Sheng Song
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Southern Medical University Nanfang Hospital, Guangzhou 510515, Guangdong Province, China
| | - Nan Jiang
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Southern Medical University Nanfang Hospital, Guangzhou 510515, Guangdong Province, China
| |
Collapse
|
|
7
|
Bassar IK, Jamsari J, Nasrul E, Humaryanto H. Relationship between Gene Polymorphism of Vascular Endothelial Growth Factor (VEGF) rs699947 with VEGF and Matrix Metalloproteinase-14 Protein Levels in Patient with Diabetic Foot Ulcer. Open Access Maced J Med Sci 2022. [DOI: 10.3889/oamjms.2022.9562] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND: Vascular endothelial growth factor (VEGF) protein levels in diabetes mellitus (DM) patients with ulcerative foot will tend to decrease. Matrix metalloproteinases (MMPs) and their inhibitors have also been identified in regulating capillary tubes formation (morphogenesis) with the collagen matrix, associated with the formation and regression of granulation tissue during the wound healing process.
AIM: This study was aimed to determine the relationship between gene polymorphism VEGF rs699947 with VEGF and MMP-14 protein levels in cases of diabetic foot ulcers (DFUs).
METHODS: This study was an observational research with cross-sectional comparative study design. The population in this study were type-2 DM patients who met the inclusion criteria. According to the Meggitt-Wagner classification, the study sample was divided into two groups: Type 2 DM group without DFU and type 2 DM group with DFU Grades 1–3.
RESULTS: In this study, there were differences in the protein levels of MMP-14 (p = 0.039) VEGF (p = 0.002) between type-2 DM patients with and without FDU. However, there was no difference in the VEGF gene polymorphism rs6999947 between type-2 DM patients with and without FDU (p = 0.099). In addition, the results showed that type-2 DM patients with MMP-14 protein levels ≤ 3.864 had a 3.6 times greater risk of suffer FDU compared to type-2 DM patients with MMP-14 protein levels > 3.864 but not significant (PR = 3.600 (IK 5 % 1.142–11.346); p = 0.052). Meanwhile, type 2 DM patients with VEGF protein levels ≤567.42 were significantly more at risk of 9048 times to suffer FDU compared to type 2 DM patients with VEGF protein levels > 567.42 (PR = 9.048 (CI 5% 2.571–31.842); p = 0.001).
CONCLUSION: In type 2 DM patients with FDU, there were lower levels of MMP-14 and VEGF compared to patients without FDU. There is a significant relationship between VEGF protein levels and the incidence of FDU in type 2 DM patients, but there is no relationship between MMP-14 and the gene polymorphism VEGF rs6999947 with the incidence of FDU in type 2 DM patients.
Collapse
|
|
8
|
Elfaki I, Mir R, Duhier FMA, Alotaibi MA, Alalawy AI, Barnawi J, Babakr AT, Mir MM, Altayeb F, Mirghani H, Frah EAM. Clinical Implications of MiR128, Angiotensin I Converting Enzyme and Vascular Endothelial Growth Factor Gene Abnormalities and Their Association with T2D. Curr Issues Mol Biol 2021; 43:1859-1875. [PMID: 34889890 PMCID: PMC8928978 DOI: 10.3390/cimb43030130] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 10/25/2021] [Accepted: 10/27/2021] [Indexed: 02/07/2023] Open
Abstract
Type 2 DM (T2D) results from the interaction of the genetic and environmental risk factors. Vascular endothelial growth factor (VEGF), angiotensin I-converting enzyme (ACE), and MicroRNAs (MiRNAs) are involved in important physiological processes. Gene variations in VEGF, ACE and MiRNA genes are associated with diseases. In this study we investigated the associations of the VEGF-2578 C/A (rs699947), VEGF-2549 insertion/deletion (I/D), and ACE I/D rs4646994 and Mir128a (rs11888095) gene variations with T2D using the amplification refractory mutation system PCR (ARMS-PCR) and mutation specific PCR (MSP). We screened 122 T2D cases and 126 healthy controls (HCs) for the rs699947, and 133 T2D cases and 133 HCs for the VEGF I/D polymorphism. For the ACE I/D we screened 152 cases and 150 HCs, and we screened 129 cases and 112 HCs for the Mir128a (rs11888095). The results showed that the CA genotype of the VEGF rs699947 and D allele of the VEGF I/D polymorphisms were associated with T2D with OR =2.01, p-value = 0.011, and OR = 2.42, p-value = 0.010, respectively. The result indicated the D allele of the ACE ID was protective against T2D with OR = 0.10, p-value = 0.0001, whereas the TC genotype and the T allele of the Mir128a (rs11888095) were associated with increased risk to T2D with OR = 3.16, p-value = 0.0001, and OR = 1.68, p-value = 0.01, respectively. We conclude that the VEGF (rs699947), VEGF I/D and Mir128a (rs11888095) are potential risk loci for T2D, and that the D allele of the ACE ID polymorphism may be protective against T2D. These results help in identification and stratification for the individuals that at risk for T2D. However, future well-designed studies in different populations and with larger sample sizes are required. Moreover, studies to examine the effects of these polymorphisms on VEGF and ACE proteins are recommended.
Collapse
Affiliation(s)
- Imadeldin Elfaki
- Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Rashid Mir
- Prince and Fahd Bin Sultan Research Chair, Department of Medical Lab Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.M.); (F.M.A.D.); (J.B.); (F.A.)
| | - Faisel M. Abu Duhier
- Prince and Fahd Bin Sultan Research Chair, Department of Medical Lab Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.M.); (F.M.A.D.); (J.B.); (F.A.)
| | - Maeidh A. Alotaibi
- King Faisal Medical Complex Laboratory, Ministry of Health, Taif 26521, Saudi Arabia;
| | - Adel Ibrahim Alalawy
- Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Jameel Barnawi
- Prince and Fahd Bin Sultan Research Chair, Department of Medical Lab Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.M.); (F.M.A.D.); (J.B.); (F.A.)
| | - Abdullatif Taha Babakr
- Department of Medical Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah 57039, Saudi Arabia;
| | - Mohammad Muzaffar Mir
- Department of Basic Medical Sciences, College of Medicine, University of Bisha, Bisha 61992, Saudi Arabia;
| | - Faris Altayeb
- Prince and Fahd Bin Sultan Research Chair, Department of Medical Lab Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.M.); (F.M.A.D.); (J.B.); (F.A.)
| | - Hyder Mirghani
- Internal Medicine and Endocrine, Medical Department, Faculty of Medicine, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Ehab A. M. Frah
- Department of Statistics, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia;
| |
Collapse
|
|
9
|
Genetic Variation in the Vascular Endothelial Growth Factor (VEGFA) Gene at rs13207351 Is Associated with Overall Survival of Patients with Head and Neck Cancer. Cancers (Basel) 2021; 13:cancers13051163. [PMID: 33800431 PMCID: PMC7962814 DOI: 10.3390/cancers13051163] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/25/2021] [Accepted: 02/28/2021] [Indexed: 01/10/2023] Open
Abstract
Simple Summary Angiogenesis and apoptosis play a pivotal role in the pathogenesis and clinical course not only of nasopharyngeal cancer (NPC), but also of other subgroups of head and neck cancer (HNC), such as laryngeal cancer. Thus, the aim of this study was to investigate the clinical significance of genetic polymorphisms in four pivotal angiogenesis- and apoptosis-related genes (VEGFA, FAS, EDNRA and NBS1) in HNC patients. Thirty-four genetic variants located in the studied genes were assessed. Two of them (VEGFA rs13207351 and FAS rs2234768) were associated with overall survival for patients with laryngeal cancer and NPC, respectively, with VEGFA rs13207351 showing the most promise for its prognostic value in the subgroup of laryngeal cancer patients. This study suggests that genetic variations in angiogenesis- and apoptosis-related genes may be useful in the management of HNC patients. Abstract Head and neck cancer (HNC) is a significantly heterogeneous disease and includes malignancies arising from different anatomical sites, such as nasopharyngeal cancer (NPC) and laryngeal cancer (LC). In the current study, polymorphisms located in angiogenesis- and apoptosis-related genes (VEGFA, FAS, EDNRA and NBS1) were evaluated regarding their clinical significance in HNC patients. In total, 333 HNC patients were enrolled in this study and 34 variants located on the aforementioned genes were genotyped via Sanger sequencing. LC patients, homozygous A for VEGFA rs13207351, had shorter overall survival (OS) as opposed to homozygous G (Hazard ratio (HR) = 2.06, Wald’s p = 0.017) upon adjustment for age, disease stage, and surgery. Following the dominant model, LC patients carrying the A allele had a marginally significantly higher risk for death (HR = 1.72, p = 0.059). NPC patients heterozygous (CT) for FAS rs2234768 had a marginal but significantly higher risk of death compared to those with homozygosity for the T allele (HR = 2.22, p = 0.056). In conclusion, rs13207351 (VEGFA) and rs2234768 (FAS) polymorphisms seem to have prognostic significance in HNC, with VEGFA rs13207351 showing the most promise in this subgroup of LC patients.
Collapse
|
|
10
|
Zhao J, Zhang LX, Wang YT, Li Y, Chen Md HL. Genetic Polymorphisms and the Risk of Diabetic Foot: A Systematic Review and Meta-Analyses. INT J LOW EXTR WOUND 2020; 21:574-587. [PMID: 33327826 DOI: 10.1177/1534734620977599] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Diabetic foot (DF) is a dangerous complication of diabetes. The aim of the study was to synthesize all the published single nucleotide polymorphisms (SNPs) of DF to objectively evaluate the relationship of SNPs and DF risks. METHODS The HuGE database and CNKI were searched for eligible publications on genetic polymorphisms and the risk of DF systematically. The quality of literatures was evaluated by the Newcastle-Ottawa scale. Pooled odds ratios with a 95% confidence interval for SNPs were evaluated through 3 genetic models. RESULTS Citing 29 different polymorphisms from 24 articles and the study met our selection criteria. There were 24 polymorphisms summarized systematically, and 5 merged polymorphisms for a meta-analysis: 9 positively associated with DF: HIF-1α rs11549465, TNF-α rs1800629, TLR-9 rs5743836, FIB rs6056, HSP70-2437C/T, VDR rs2228570, LOX rs1800449, ITLN1 rs2274907, and OPG rs2073617, but OPG rs3134069 was not a risk factor in DF; 6 negatively associated with DF: VEGF rs833061 and rs2010963, MCP-1 rs1024611, SDF-1 rs1801157, SIRT1 rs12778366, and OPG rs2073617. In addition, 13 polymorphisms were not associated with DF: MMP-9 rs3918242, eNOS rs1799983, VEGF rs3025039, -7C/T, rs1570360, rs13207351, and rs699947, IL-6 rs1800795, HIF-1α rs11549467, TNF-α rs361525, TLR-2 rs3804100, SIRT1 rs3758391, and TIMP-1 rs2070584. CONCLUSIONS The study provided some evidence for SNPs to the development of diabetic foot. The meta-analysis showed that rs1024611 of MCP-1 may be regarded as a protective factor, especially in Asian populations. Other loci indicated inconsistent results.
Collapse
Affiliation(s)
- Jun Zhao
- Nantong University, Nantong City, People's Republic of China
| | - Le-Xuan Zhang
- Nantong University, Nantong City, People's Republic of China
| | - Yu-Ting Wang
- Nantong University, Nantong City, People's Republic of China
| | - Yang Li
- Nantong University, Nantong City, People's Republic of China
| | | |
Collapse
|
|
11
|
Xiong XF, Wei L, Xiao Y, Han YC, Yang J, Zhao H, Yang M, Sun L. Family history of diabetes is associated with diabetic foot complications in type 2 diabetes. Sci Rep 2020; 10:17056. [PMID: 33051498 PMCID: PMC7555504 DOI: 10.1038/s41598-020-74071-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Accepted: 09/18/2020] [Indexed: 12/20/2022] Open
Abstract
To investigate the relationship between diabetic foot complications (DFCs) and clinical characteristics, especially the number and types of first-degree family members with diabetes. A total of 8909 type 2 diabetes patients were enrolled. The clinical characteristics of these patients, including DFCs and family history of diabetes (FHD), were collected from medical records. Multiple regression was used to investigate the association between FHD and DFCs after adjusting for confounding factors. The patients with one and more than one first-degree family member with diabetes accounted for 18.7% and 12.8%, respectively. The proportions of the participants with a father with diabetes, a mother with diabetes, both parents with diabetes, siblings with diabetes, father and siblings with diabetes, mother and siblings with diabetes, and both parents and siblings with diabetes were 3.5%, 6.2%, 1.1%, 14.4%, 1.5%, 4%, and 0.7%, respectively. The multiple regression analysis showed that the number of family members with diabetes was positively associated with DFCs. However, among the different types of FHD, only the patients with a mother with diabetes showed a statistical association with DFCs. In addition to FHD, other factors, including gender, body mass index, platelet count, hemoglobin levels, albumin levels, high-density cholesterol levels, diabetic peripheral neuropathy, and the use of lipid-lowering agents, oral hypoglycemic agents, and insulin, were also associated with DFCs. DFCs were associated with different numbers of family members with diabetes and types of FHD. This association reveals the importance of genetic and environmental factors in DFCs and highlights the importance of adding FHD to public health strategies targeting detecting and preventing the disease.
Collapse
Affiliation(s)
- Xiao-Fen Xiong
- Department of Nephrology, The Second Xiangya Hospital at Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Ling Wei
- Department of Nephrology, The Second Xiangya Hospital at Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Ying Xiao
- Department of Nephrology, The Second Xiangya Hospital at Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Ya-Chun Han
- Department of Nephrology, The Second Xiangya Hospital at Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Jinfei Yang
- Department of Nephrology, The Second Xiangya Hospital at Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Hao Zhao
- Department of Nephrology, The Second Xiangya Hospital at Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Ming Yang
- Department of Nephrology, The Second Xiangya Hospital at Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Lin Sun
- Department of Nephrology, The Second Xiangya Hospital at Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China.
| |
Collapse
|
|
12
|
The association of vascular endothelial growth factor polymorphism (rs699947) with diabetic foot ulcer and oxidative status. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
|
|
13
|
The role of circulating soluble fms-like tyrosine kinase-1 in patients with diabetic foot ulcer: A possible mechanism of pathogenesis via a novel link between oxidative stress, inflammation and angiogenesis. Microvasc Res 2020; 130:103987. [PMID: 32035919 DOI: 10.1016/j.mvr.2020.103987] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Revised: 01/24/2020] [Accepted: 02/05/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Diabetic foot ulcer (DFU) is one of the most devastating diabetic consequences leading to amputations. Oxidative stress, inflammation, vascular insufficiency and neuropathy have been linked to DFU development. Since soluble fms-like tyrosine kinase-1 (sFlt-1) is one of the anti-angiogenic factors regulating vascular endothelial growth factor (VEGF) biological activity. So, we aimed to evaluate its role in pathogenesis of DFU and its correlation with oxidative stress and inflammatory markers. METHODS 60 type 2 diabetic patients: 30 without DFU and 30 with DFU in addition to 20 healthy controls were enrolled in the study. sFlt-1 and VEGF mRNA relative gene expressions and levels and sFlt-1/VEGF ratio were assessed. Also, Advanced oxidation protein products (AOPPs), malondialdhyde (MDA), Total thiol and, tumor necrosis factor alpha (TNF-α) levels were measured. RESULTS sFlt-1 expression and level, AOPPs, MDA and TNF-α were significantly higher in diabetic patients as compared with the control group with highest levels in DFU patients. However, there were significant decrease in total thiol level and VEGF expression and level in diabetic patients with DFU. CONCLUSION This study revealed that sFlt-1 is a major player in DFU pathogenesis and may be considered as a novel diagnostic biomarker for early detection of DFU.
Collapse
|
|
14
|
Xu B, Zhan R, Mai H, Wu Z, Zhu P, Liang Y, Zhang Y. The association between vascular endothelial growth factor gene polymorphisms and stroke: A PRISMA-compliant meta-analysis. Medicine (Baltimore) 2019; 98:e14696. [PMID: 30882632 PMCID: PMC6426541 DOI: 10.1097/md.0000000000014696] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Numerous studies showed that vascular endothelial growth factor (VEGF) gene polymorphisms were linked with the regularity of stroke, but the results remained controversial. The aim of this meta-analysis was to determine the associations between VEGF gene polymorphisms and the risk of stroke. METHODS A systematic literature search of PubMed, Embase, Wed of Science, The Cochrane Library, Elsevier, China National Knowledge Infrastructure, China Biology Medicine disc, WanFang Data, VIP Database for Chinese Technical Periodicals, and Science paper Online was conducted. Two authors independently assessed trial quality and extracted data. The pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of associations. Begger funnel plot and Egger test were used to estimate the publication bias of included studies. Heterogeneity assumption was assessed by Cochran Chi-squared-based Q-statistic test and I test. RESULTS Thirteen publications including 23 trails with a total of 3794 stroke patients and 3094 control subjects were enrolled. About 3747 cases and 2868 controls for +936C/T, 2134 cases and 1424 controls for -2578C/A, and 2187 cases and 1650 controls for -1154G/A were examined, respectively. The results indicated that VEGF +936C/T (T vs C, OR = 1.19, 95% CI = 1.01-1.40) or -2578C/A (A vs C, OR = 1.13, 95% CI = 1.02-1.27) was positively associated with the risk of stroke, whereas there was no association between -1154G/A (A vs G, OR = 0.99, 95% CI = 0.87-1.11) polymorphism and stroke risk in our study. Among the subgroup analyses on ethnicity, the results showed that VEGF +936C/T was an increased risk of stroke in Asian population (T vs C, OR = 1.21, 95% CI = 1.01-1.44), but not -1154G/A. CONCLUSION Our findings suggest that VEGF +936C/T and -2578C/A might be related to the risk of stroke, especially in the Asian population, but not -1154G/A.
Collapse
Affiliation(s)
| | - Rui Zhan
- Department of Gastroenterology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | | | | | | | | | | |
Collapse
|
|
15
|
Viswanathan V, Dhamodharan U, Srinivasan V, Rajaram R, Aravindhan V. Single nucleotide polymorphisms in cytokine/chemokine genes are associated with severe infection, ulcer grade and amputation in diabetic foot ulcer. Int J Biol Macromol 2018; 118:1995-2000. [PMID: 30009916 DOI: 10.1016/j.ijbiomac.2018.07.083] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Revised: 06/29/2018] [Accepted: 07/12/2018] [Indexed: 12/15/2022]
Abstract
Compared to other complications the genetics of diabetic foot ulcer is poorly studied. The Interleukin (IL)-6 (-174G > C/rs1800795), Tumor Necrosis Factor (TNF)-α (-308G > A/rs1800629) and (-238G > A/rs361525) and Stromal cell Derived Factor (SDF)-1 (+801G > A/rs1801157) are well characterized single nucleotide polymorphisms (SNPs) which were previously shown to be associated with Diabetic Foot Ulcer (DFU). In the present study, we looked at the association of these SNPs with foot microbial infection, Wagner's ulcer grade and treatment procedure, along with serum levels of these cytokines (intermediate phenotype) and other serum biomarkers (adiponectin, leptin, CRP and HOMA-IR) in subjects with DFU. Subjects with DFU (n = 270) were genotyped by PCR-RFLP and the serum levels of IL-6, TNF-α and SDF-1 were determined by ELISA. Microbial infections were determined by standard microbiological methods. Ulcer grade and treatment procedures were recorded. IL-6 (-174G > C), TNF-α (-308G > A) and SDF-1 (+801G > A) SNPs were associated with severe microbial infections. TNF-α (-308G > A) and (-238G > A) SNPs were associated with severe ulcer grades. SDF-1 (+801G > A) SNP was associated with major amputation even after adjusting for confounding variables. Identification of these SNPs in DFU subjects would help in identifying high risk individuals who need better treatment care.
Collapse
Affiliation(s)
| | | | - Valarmathi Srinivasan
- Department of Epidemiology, Tamil Nadu Dr. M.G.R. Medical University, Chennai, India
| | - Rama Rajaram
- Department of Biochemistry, Central Leather Research Institute, Chennai, India
| | - Vivekanandhan Aravindhan
- Department of Genetics, Dr. A.L.M. Post Graduate Institute of Basic Medical Sciences, University of Madras, Chennai, India.
| |
Collapse
|