Pathogenesis & prognosis of diabetic foot ulcer | DMSO – Dove Medical Press
Javascript is at present disabled in your browser. A number of options of this website won’t perform while javascript is disabled.
open entry to scientific and medical analysis
Papers Printed
Open entry peer-reviewed scientific and medical journals.
Learn more
Dove Medical Press is a member of the OAI.
Learn more
Bulk reprints for the pharmaceutical trade.
Learn more
We provide actual advantages to our authors, together with fast-track processing of papers.
Learn more
Register your particular particulars and particular medicine of curiosity and we’ll match the knowledge you present to articles from our in depth database and e-mail PDF copies to you promptly.
Learn more
Again to Journals » Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy » Volume 15
Authors Xu M , Li Y , Tang Y, Zhao X , Xie D, Chen M
Obtained 30 Might 2022
Accepted for publication 19 July 2022
Printed 3 November 2022 Quantity 2022:15 Pages 3415—3428
DOI https://doi.org/10.2147/DMSO.S376292
Checked for plagiarism Sure
Evaluate by Single anonymous peer review
Peer reviewer feedback 2
Editor who accepted publication: Prof. Dr. Antonio Brunetti
Murong Xu, Yutong Li, Ying Tang, Xiaotong Zhao, Dandan Xie, Mingwei Chen
Division of Endocrinology, The First Affiliated Hospital of Anhui Medical College, Hefei, Anhui, 230032, Individuals’s Republic of China
Correspondence: Mingwei Chen, Division of Endocrinology, The First Affiliated Hospital of Anhui Medical College, No. 218 Jixi Highway, Hefei, Anhui, 230032, Individuals’s Republic of China, Tel +86-551-2923631, Fax +86-551-2922160, E mail [email protected]
Goal: To research the correlations of miR-155 expression within the peripheral blood and wound margin tissue of sufferers with diabetic foot ulcer (DFU) and discover the scientific worth of miR-155 as a possible biomarker for the analysis and remedy outcomes of DFU.
Strategies: Sixty newly identified T2DM sufferers with out DFU (T2DM group), 112 T2DM sufferers with DFU (DFU group), and 60 wholesome controls (NC group) have been included. MiR-155 ranges within the peripheral blood and wound margin tissue have been decided by quantitative real-time PCR, whereas scientific options and danger elements of DFU have been explored. A number of stepwise logistic regression evaluation was used to find out whether or not miR-155 expression was an unbiased danger issue for DFU. The diagnostic effectiveness of miR-155 degree on DFU was evaluated utilizing ROC curve evaluation.
Outcomes: A big lower within the expression degree of miR-155 was noticed in T2DM group in contrast with NC group (P < 0.05), whereas a markedly elevated miR-155 expression degree was famous in DFU group in contrast with T2DM group (P < 0.01). Furthermore, there was a detrimental correlation between the expression ranges of miR-155 with therapeutic fee of DFU. Kaplan-Meier survival curve evaluation confirmed that the cumulative fee of unhealed DFU in miR-155 excessive expression group is increased than that in miR-155 low expression group, each in peripheral blood and wound margin tissue (log rank, P = 0.004, P < 0.001, respectively). The multivariate logistic regression evaluation confirmed {that a} excessive expression of miR-155 was an unbiased danger issue for DFU. The ROC curve evaluation indicated that the AUC of miR-155 for the analysis of DFU was 0.794, with the optimum sensitivity being 96.82% and the optimum specificity of 95.93%.
Conclusion: The elevated expression of miR-155 in peripheral blood of T2DM sufferers is carefully associated to the prevalence of DFU. MiR-155 is a probably priceless biomarker for analysis and prognosis of DFU.
Key phrases: miR-155, diabetic foot ulcer, sort 2 diabetes mellitus, microRNAs, biomarker
Diabetic foot is a critical power complication of diabetes. Diabetic foot ulcer (DFU) is the most typical manifestation of the diabetic foot and the most typical explanation for non-traumatic decrease limb amputation.1 The chance of a affected person with diabetes creating a foot ulcer throughout their lifetime has been estimated to be 19–34%.2 The pathogenesis of DFU is complicated and has not been absolutely clarified. Early analysis, scientific analysis and well timed standardized remedy can successfully enhance the prognosis of DFU.3
In recent times, an rising variety of research have proven that irregular expression of microRNAs (miRNAs) is carefully related to the prevalence and prognosis of DFU.4 MiRNAs are a category of endogenous non-coding RNAs with a size of roughly 18–25 nucleotides. They will regulate the expression of a goal gene by particularly binding to the three′ untranslated area of downstream goal mRNA to information the silencing complicated to degrade mRNA or inhibit protein translation.5,6 MiR-155 is extensively concerned in lots of organic processes, akin to the event and differentiation of immune cells,7,8 the inflammatory response,9 and it has vital results on the capabilities of keratinocytes, fibroblasts, dermal mesenchymal stem cells, and different cells concerned within the technique of wound therapeutic.10,11 Inhibition of miR-155 expression in native wound tissue can promote pores and skin wound therapeutic in diabetic rats.12,13 Knockout of microRNA-155 can ameliorate the Th17/Th9 immune response in mice and speed up wound therapeutic.14 As well as, latest research have proven that mesenchymal stem cell-derived exosomes loaded with miR-155 inhibitor can enhance diabetic wound therapeutic.15
Nonetheless, the scientific analysis on the correlation between miR-155 and DFU has not been reported. Accordingly, our research aimed to analyze the adjustments within the expression degree of miR-155 within the peripheral blood and wound tissue of DFU sufferers and its relationship with the pathogenesis and prognosis of DFU.
The members for this research have been chosen from the topics described in a earlier research16 and included 112 sufferers with sort 2 diabetes mellitus (T2DM) having DFU issues (DFU group) who have been hospitalized within the Division of Endocrinology on the First Affiliated Hospital of Anhui Medical College from January 2018 to December 2019. In these 112 instances, the period of foot ulcer was greater than 4 weeks, the ulcer space was 2–20 cm2, the Wagner grade was 2–4, the ankle-brachial index (ABI) was 0.7–1.3. Sixty sufferers with newly identified T2DM with out DFU within the Division of Endocrinology at our hospital in the identical interval have been chosen as a diabetic group (T2DM group). These sufferers had a course of T2DM starting from one week to 5 months with no decrease extremity atherosclerosis illness, and no diabetic peripheral neuropathy. As well as, sixty wholesome topics who underwent bodily examination within the Well being Administration Heart of our hospital in the identical interval have been chosen as a standard management group (NC group). All the topics within the NC group underwent a 75 g oral glucose tolerance check to substantiate regular glucose tolerance. All topics had no extreme coronary heart, liver, or renal insufficiency; no autoimmune ailments; no extreme sepsis; and no cancerous ulcer wounds. This research was accepted by the Medical Ethics Committee of the First Affiliated Hospital of Anhui Medical College, and we obtained the knowledgeable consent of the topics.
All sufferers with DFU got routine systemic remedy beforehand reported,16 together with anti-infection, lowering blood strain, lowering blood glucose, correcting hypoproteinemia, nourishing nerves, enhancing blood provide of decrease limb wounds, and so on. Wound debridement was carried out to take away blackened necrotic comfortable tissue and bone tissue. The complete-sickness pores and skin tissue inside 0.5 cm of the wound margin was minimize by expert surgeons utilizing tissue scissors in line with the sampling protocol and saved in a fridge at −80°C. In line with the particular circumstances of every DFU, decompression or steady detrimental strain wound remedy was given. The course of the DFU was monitored, and the diabetic foot multidisciplinary workforce determined whether or not amputation ought to be carried out. All sufferers with DFU have been adopted up till the wound healed fully, and the therapeutic time was recorded. Full wound therapeutic after 8 weeks was outlined as spontaneous full closure, ie, 100% reepithelization,17 and recorded after eight weeks of remedy.
Venous blood from the elbow was drawn from all topics into anticoagulation tubes (the anticoagulant was sodium fluoride/EDTA/heparin, chosen in line with completely different examination objects) or non-anticoagulant tubes at 8:00–8:30 a.m. after fasting for 10 hours. Serum albumin (ALB), blood glucose, blood lipids, glycosylated hemoglobin A1c (HbA1c), white blood cell (WBC) rely, hemoglobin (Hb), C-reactive protein (CRP), erythrocyte sedimentation fee (ESR), and different indicators have been measured. Blood glucose, blood lipid, and ALB have been measured by an computerized biochemical analyzer (Module P800, Roche, Switzerland). Fasting plasma glucose (FPG) was decided utilizing the glucose oxidase methodology. Complete ldl cholesterol (TCH), triglycerides (TG), high-density lipoprotein ldl cholesterol (HDL-C), and low-density lipoprotein ldl cholesterol (LDL-C) have been assayed by the oxidase colorimetric methodology. HbA1c was detected by high-pressure liquid chromatography, CRP by latex enhanced immunoturbidimetry, and ESR by the Wechsler methodology. The realm of pores and skin ulcers was measured by digital images mixed with ImageJ (Picture J-ij133-jdk15, Nationwide Institutes of Well being, Bethesda, USA) medical picture evaluation software program, ABI was measured by a Doppler blood circulation detector (DPL-03, Hangzhou Yuanxiang Medical, China), and transcutaneous oxygen partial strain (TcPO2) was measured by a transcutaneous oxygen partial strain detector (TCM400, Ledu, Denmark).
The expressions of miR-155 in peripheral venous blood (P-miR-155) and the expressions of miR-155 in wound margin tissue (T-miR-155) have been measured by real-time quantitative reverse transcription PCR (qRT-PCR). RNA was extracted from 2-mL EDTA anticoagulant blood samples or 50 mg of wound margin tissue in line with the directions of the miRcute miRNA extraction and separation package (TIANGEN, Beijing, China). cDNA was then synthesized in line with the directions of miRcute miRNA cDNA synthesis package (TIANGEN, Beijing, China). The primer sequences of miR-155 have been as follows: ahead primer 5′-CGGCGGTTAATGCTAATTGTGAT-3′, reverse primer 5′-GTGCAGGGTCCGAGGT-3′; The primer sequences of the endogenous management U6 have been as follows: ahead primer 5’-GCTTCGGCAGCACATATACTAAAA-3’, reverse primer 5’-CGCTTCACGAATTTGCCTGTCAT-3’. qRT-PCR was carried out in line with the directions of the miRcute miRNA fluorescence quantitative detection package (TIANGEN, Beijing, China). The biking circumstances have been pre-denaturation at 95°C for five min, denaturation at 95°C for 20s, annealing at 58°C for 15s, and extension at 72°C for 10s, for a complete of 42 cycles. Utilizing U6 as the inner reference, the relative expression of miR-155 was calculated by the two−ΔΔCt methodology. Every pattern was repeated thrice, and the typical worth was taken because the end result.
SPSS 19.0 software program was used for statistical evaluation. The measurement information are expressed by the imply ± customary deviation (
±S), whereas the non-normal measurement information are expressed by the median (quartile interval) [M (P25, P75)]. X2 check or t-test was used for comparability between the 2 teams; evaluation of variance check was used for comparability between a number of teams; and LSD-t check was used for additional pairwise comparability. Spearman correlation evaluation was used to judge the correlation between the expression of miR-155 in each peripheral blood and wound margin tissue and different scientific variables. A number of stepwise logistic regression evaluation was used to find out whether or not miR-155 in peripheral blood was an unbiased danger issue for DFU. Kaplan–Meier survival curve evaluation was used to review the correlation between the expression of miR-155 in peripheral blood and wound margin tissue and the wound therapeutic of DFU. ROC curve evaluation was used to discover the potential for miR-155 in peripheral blood as a possible biomarker for the analysis of DFU. The perfect sensitivity and specificity of ROC curve have been decided by frequent strategies.18 All assessments have been bilateral, P < 0.05 was thought of to be a statistically vital distinction.
There have been no vital variations in gender composition, age, TCH, or LDL-C ranges among the many three teams (P > 0.05). The degrees of FPG, HbA1c, and TG within the T2DM group and DFU group have been increased than these of the NC group, whereas the extent of HDL-C was decrease than that of the NC group, and the variations have been statistically vital (P < 0.05). The expression degree of miR-155 within the peripheral blood of the T2DM group was decrease than that of the NC group, and that of the DFU group was increased than that of the NC group and T2DM group, and the variations have been statistically vital (P < 0.05). As well as, there have been no vital variations in TcPO2, ABI, CRP, ESR, ALB, WBC, and Hb values between the NC group and the T2DM group (P > 0.05). Furthermore, the period of diabetes, FPG, HbA1c, CRP, ESR, WBC rely, and miR-155 expression ranges in peripheral blood within the DFU group have been increased than these within the T2DM group, whereas TcPO2, ABI, ALB, and Hb have been decrease within the DFU group than these within the T2DM group, and the variations have been statistically vital (P < 0.05). There was no vital distinction in TG and HDL-C ranges between the 2 teams (P > 0.05) (Table 1).
 |
Desk 1 Comparisons of Scientific Parameters Amongst NC Group, T2DM Group, and DFU Group [n (%), ( |
Desk 1 Comparisons of Scientific Parameters Amongst NC Group, T2DM Group, and DFU Group [n (%), (
±S), M (P25, P75)]
The 112 sufferers with DFU have been divided into two subgroups in line with the median degree of miR-155 expression in peripheral blood and wound margin tissue, respectively. The sufferers with miR-155 expression decrease than the median have been categorized because the low expression group and people with expression increased than or equal to the median have been categorized because the excessive expression group. The scientific traits of DFU between the excessive expression group and the low expression group have been in contrast. As proven in Tables 2 and 3, the expression ranges of miR-155 in each peripheral blood and wound margin tissue of sufferers with DFU have been negatively correlated with the therapeutic fee of foot ulcer after eight weeks (P = 0.037, P = 0.035, respectively), and positively correlated with the course of foot ulcer (P = 0.033, P = 0.034, respectively), and Wagner grade of foot ulcer (P = 0.010, P = 0.013, respectively). There was no correlation between miR-155 expression in each the peripheral blood and wound margin tissue and different scientific traits of foot ulcers. As a way to additional discover the impact of the change of miR-155 expression in peripheral blood and wound margin tissue on wound therapeutic, we used Kaplan–Meier survival curve evaluation methodology. The outcomes confirmed that the estimated time median of wound therapeutic in peripheral blood miR-155 excessive expression group and low expression group have been 10.23 weeks and 9.51 weeks, respectively; Equally, the estimated time median of wound therapeutic in wound margin tissue miR-155 excessive expression group and low expression group have been 10.12 weeks and eight.67 weeks, respectively. Whether or not in peripheral blood or wound margin tissue, the cumulative fee of unhealed DFU in miR-155 excessive expression group is increased than that in miR-155 low expression group (log rank, P = 0.004, P < 0.001, respectively). The wound therapeutic time of excessive expression group is longer than that of low expression group (P < 0.05) (Figure 1A and B).
 |
Desk 2 Relationship Between miR-155 Expression Ranges in Peripheral Blood and Scientific Traits of DFU [n (%)] |
 |
Desk 3 Relationship Between miR-155 Expression Ranges in Wound Margin Tissue and Scientific Traits of DFU [n (%)] |
 |
Determine 1 Curve of wound full therapeutic fee of DFU between miR-155 excessive expression group and low expression group by Kaplan-Meier survival curve evaluation. (A) The cumulative fee of unhealed DFU within the excessive expression group of peripheral blood miR-155 was increased than that within the low expression group of peripheral blood miR-155 (log rank, P = 0.004). The estimated time median of wound full therapeutic in peripheral blood miR-155 excessive expression group and low expression group have been 10.23 weeks and 9.51 weeks, respectively (P < 0.05). (B) The cumulative fee of unhealed DFU within the excessive expression group of wound margin tissue miR-155 was increased than that within the low expression group of wound margin tissue miR-155 (log rank, P < 0.001). The estimated time median of wound full therapeutic in wound margin tissue miR-155 excessive expression group and low expression group have been 10.12 weeks and eight.67 weeks, respectively (P < 0.05). |
Desk 2 Relationship Between miR-155 Expression Ranges in Peripheral Blood and Scientific Traits of DFU [n (%)]
Desk 3 Relationship Between miR-155 Expression Ranges in Wound Margin Tissue and Scientific Traits of DFU [n (%)]
Determine 1 Curve of wound full therapeutic fee of DFU between miR-155 excessive expression group and low expression group by Kaplan-Meier survival curve evaluation. (A) The cumulative fee of unhealed DFU within the excessive expression group of peripheral blood miR-155 was increased than that within the low expression group of peripheral blood miR-155 (log rank, P = 0.004). The estimated time median of wound full therapeutic in peripheral blood miR-155 excessive expression group and low expression group have been 10.23 weeks and 9.51 weeks, respectively (P < 0.05). (B) The cumulative fee of unhealed DFU within the excessive expression group of wound margin tissue miR-155 was increased than that within the low expression group of wound margin tissue miR-155 (log rank, P < 0.001). The estimated time median of wound full therapeutic in wound margin tissue miR-155 excessive expression group and low expression group have been 10.12 weeks and eight.67 weeks, respectively (P < 0.05).
Within the NC group, no vital correlation was noticed between the expression of miR-155 in peripheral blood and different scientific parameters (P > 0.05). Within the T2DM group, the expression of miR-155 in peripheral blood was negatively correlated with the degrees of FPG and HbA1c (P < 0.05) and had no vital correlation with different indicators (P > 0.05). Within the DFU group, the expression of miR-155 in each peripheral blood and wound margin tissue was positively correlated with the course of foot ulcer, Wagner grade, CRP, and WBC rely (P < 0.05), and had no vital correlation with different indicators (P > 0.05). As well as, the expression of miR-155 in peripheral blood was positively correlated with that in wound margin tissue within the DFU group (Tables 4 and 5).
 |
Desk 4 Correlations Between miR-155 Expression in Peripheral Blood and Different Scientific Parameters in NC Group, T2DM Group, and DFU Group (r) |
 |
Desk 5 Correlation Between miR-155 Expression in Wound Margin Tissue and Different Scientific Parameters within the DFU Group (r) |
Desk 4 Correlations Between miR-155 Expression in Peripheral Blood and Different Scientific Parameters in NC Group, T2DM Group, and DFU Group (r)
Desk 5 Correlation Between miR-155 Expression in Wound Margin Tissue and Different Scientific Parameters within the DFU Group (r)
In diabetic sufferers, DFU was used as a dependent variable, and intercourse, age, and different variables with P < 0.1 obtained from univariate logistic regression evaluation (together with the course of diabetes, FPG, HbA1c, TG, LDL-C, HDL-C, ALB, Hb, TcPO2, ABI, CRP, WBC, ESR, P-miR-155) have been used as unbiased variables for multivariate stepwise logistic regression evaluation. The course of diabetes, HbA1c, CRP, low TcPO2, excessive expression of P-miR-155 have been unbiased danger elements for DFU (Table 6).
 |
Desk 6 The Multivariate Stepwise Logistic Regression Evaluation of Danger Components for Diabetic Foot Ulcer |
Desk 6 The Multivariate Stepwise Logistic Regression Evaluation of Danger Components for Diabetic Foot Ulcer
To additional discover the potential worth of miR-155 within the analysis of DFU, the expression degree of miR-155 within the peripheral blood was assessed on an unbiased group of 172 peripheral blood samples together with 60 instances of T2DM and 112 instances of DFU. The ROC curve was decided to judge the sensitivity and specificity of peripheral blood miR-155 in diagnosing DFU. The outcomes confirmed that the AUC of peripheral blood miR-155 for diagnosing DFU was 0.794 (95% CI, 0.726–0.863, P < 0.001), one of the best cut-off level of miR-155 was 1.01, the sensitivity was 96.82%, and the specificity was 95.93% (Figure 2).
 |
Determine 2 The biomarker potential of circulating miR-155 for DFU and management. ROC evaluation was used to judge the power of circulating miR-155 to differentiate between two teams. MiR-155 distinguished DFU sufferers from controls with space below curve (AUC) of 0.794 (95% CI, 0.726–0.863, P < 0.001), one of the best cut-off level of miR-155 was 1.01, the sensitivity was 96.82%, and the specificity was 95.93%. DFU: diabetic foot ulcer. |
Determine 2 The biomarker potential of circulating miR-155 for DFU and management. ROC evaluation was used to judge the power of circulating miR-155 to differentiate between two teams. MiR-155 distinguished DFU sufferers from controls with space below curve (AUC) of 0.794 (95% CI, 0.726–0.863, P < 0.001), one of the best cut-off level of miR-155 was 1.01, the sensitivity was 96.82%, and the specificity was 95.93%. DFU: diabetic foot ulcer.
Based mostly on the above analysis, it’s simple to seek out that the miR-155 expression degree in peripheral blood of newly identified T2DM sufferers is considerably decrease than that of topics with regular glucose tolerance. Conversely, the expression degree of miR-155 in DFU sufferers was dramatically increased than that of sufferers with out DFU. A number of logistic regression evaluation confirmed that prime expression of peripheral blood miR-155 was an unbiased danger issue for DFU. Additional evaluation revealed that the expression ranges of miR-155 within the peripheral blood and wound margin tissue of sufferers with DFU have been carefully associated to the Wagner grade, the therapeutic fee of foot ulcers. The sufferers with excessive expression of miR-155 within the peripheral blood and wound margin tissue had extra critical DFU standing, decrease therapeutic fee, and longer therapeutic time, indicating that the excessive expression of miR-155 is just not solely a powerful danger issue for the pathogenesis of DFU but in addition a possible biomarker for the analysis, remedy, and prognosis of DFU. To our data, that is the primary research to analyze the connection between adjustments in miR-155 expression and the onset and remedy consequence of DFU in sufferers with T2DM.
Within the current research, peripheral blood miR-155 ranges have been notably decreased in sufferers with T2DM in contrast with management people with regular glucose tolerance. Correlation evaluation revealed that in sufferers with T2DM, the expression of miR-155 was negatively correlated with FPG and HbA1c. Animal research discover that overexpression of miR-155 transgenes can enhance glucose tolerance and insulin sensitivity in mice, resulting in hypoglycemia; in distinction, miR-155 deficiency in mice can impair islet perform and result in hyperglycemia, impaired glucose tolerance, and insulin resistance within the liver, muscle, and adipocytes.19,20 Scientific research present that the expression degree of miR-155 within the peripheral plasma and monocytes of T2DM sufferers is considerably decrease than that of sex-age-matched regular glucose tolerance topics.21,22 These findings assist the outcomes of the current research. Notably, in line with the outcomes of this research, we can’t clarify the rationale for the down-regulation of miR-155 expression in T2DM sufferers. Nonetheless, a earlier research demonstrated that prime blood sugar probably downregulates the expression of miR-24 by inducing the activation of c-Myc.23 As for whether or not hyperglycemia straight downregulates the expression of miR-155, it’s nonetheless unsure. Due to this fact, extra research are wanted to make clear the mechanism of miR-155 expression change in excessive glucose setting. Nonetheless, within the DFU group, there was no vital correlation between the expression degree of miR-155 in peripheral blood and wound margin tissue and FPG or HbA1c. We speculate that the reason being that different elements in DFU sufferers might have extra affect on the expression of miR-155 than FPG and HbA1c.
As well as, our research additionally demonstrated that in DFU group, each the expression degree of miR-155 in peripheral blood and wound margin tissue was positively correlated with the index of inflammatory state, together with CRP, ESR, and WBC rely, suggesting that the excessive expression of miR-155 within the peripheral blood and wound margin tissue of sufferers with DFU could also be associated to the state of infectious irritation. Liu et al discovered that sepsis sufferers exhibited a considerably elevated miR-155 degree, which was positively associated to better severity of sepsis.24 Chen et al revealed that serum miR-155 degree was up-regulated in community-acquired pneumonia sufferers, and lipopolysaccharides might induce the up-regulation of miR-155 in RAW264.7 cells in vitro.25 These outcomes strengthened our findings. Furthermore, though there was a big distinction in the middle of diabetes between the DFU group and the T2DM group, additional evaluation discovered that there was no correlation between miR155 and the course of diabetes in both the DFU group or the T2DM group. Due to this fact, the numerous distinction in the middle of illness between the DFU group and the T2DM group may need little impact on the distinction of miR-155 expression between the 2 teams.
On this research, the course of foot ulcers within the DFU group was a minimum of 4 weeks, which could be categorized as a power refractory wound.26 The scientific options of the DFU group are a protracted course of diabetes, poor management of blood glucose for a very long time, irregular lipid metabolism, peripheral angiopathy, and infectious irritation. Multivariate regression evaluation confirmed that the course of diabetes, HbA1c, TcPO2, and CRP have been unbiased elements affecting the prevalence of foot ulcers, which was in step with the outcomes of earlier research.27,28 Additional evaluation confirmed that the degrees of miR-155 within the peripheral blood and wound margin tissue of the DFU group have been considerably increased than that of the T2DM group; the expression degree of miR-155 in each peripheral blood and wound margin tissue of the DFU group was positively correlated with the course of foot ulcer and Wagner grade, and negatively correlated with the therapeutic fee of foot ulcer after 8 weeks, the upper the expression of miR-155, the tougher and longer the time required for full therapeutic of DFU wound. A number of regression evaluation confirmed that the excessive expression of miR-155 in each peripheral blood and wound margin tissue was an unbiased danger issue for foot ulcer. These outcomes prompt that miR-155 could also be concerned within the prevalence of diabetic foot ulcers and can be utilized as a biomarker for the severity and the prognosis of DFU.
At current, the mechanism of miR-155 concerned in wound therapeutic has not been absolutely clarified. It’s extensively believed that the persistent and extreme inflammatory state within the wound and the practical impairment of quite a lot of cells within the dermis concerned in wound therapeutic are essential elements within the issue of DFU therapeutic.3,29 Research12 present that the expression of miR-155 is elevated in pores and skin wounds of diabetic rats. The up regulation of miR-155 not solely performs a task in selling irritation but in addition can have an effect on the migration and proliferation of keratinocytes and injury the re-epithelialization of wounds by down-regulating the expression of fibroblast progress factor-7. Nonetheless, after the knockout of miR-155, M1-like macrophages in wound tissue of mice lower, M2-like macrophages and sort I collagen deposition considerably enhance, wound irritation is alleviated, and repairability is enhanced.30 One other research additionally discovered that flattening miR-155 in mice may also lower the expression of inflammatory cytokines Th17/Th9 in wound tissue and promote wound restoration.14 As well as, within the pores and skin wound mannequin of diabetic rats, after native injection of miR-155 inhibitor interferes with miR-155 expression, the variety of inflammatory cells, akin to T lymphocytes, neutrophils, and macrophages in wound tissue lower, the degrees of interleukin-1β and tumor necrosis factor-α lower, the inflammatory response is alleviated, neovascularization considerably will increase, the collagen content material in granulation tissue will increase and is organized extra commonly, and wound therapeutic is accelerated.12,13 Moreover, angiogenesis in wound tissue performs an essential function in DFU wound therapeutic and endothelial progenitor cells (EPC) migrate to the peripheral circulation and differentiate into mature cells to take part in angiogenesis.31 Research present that miR-155 in M1-like macrophage-derived exosomes can scale back the angiogenesis of endothelial cells,32 and goal PTCH1 to mediate EPC dysfunction brought on by excessive glucose.33
It turned out that the expression degree of exosomal miR-155 in peripheral blood may very well be used as a non-invasive biomarker for the analysis and development of hepatic fibrosis34 in addition to a possible biomarker for the detection of lung most cancers.35 Within the current research, in line with the outcomes of ROC curve evaluation, we additionally discovered that the expression degree of miR-155 in peripheral blood of T2DM sufferers might function a possible biomarker for the prediction DFU. Furthermore, we additionally found that the expression degree of miR-155 in each peripheral blood and wound margin tissue was positively correlated with the course of DFU, and negatively correlated with the therapeutic fee of DFU after eight weeks and the entire therapeutic time. Due to this fact, the abovementioned outcomes prompt the performance of the expression degree of miR-155 in each peripheral blood and wound margin tissue for the analysis and prognosis of DFU. Nonetheless, additional research are wanted to establish the explanations for the elevated expression of miR-155 in each peripheral blood and wound margin tissue of sufferers with DFU. Considerably, within the current research, miR-155 in peripheral blood and in wound margin tissue exhibited a superb consistency when it comes to their expression and predictive worth for wound therapeutic. Sampling of peripheral blood carries a small danger of trauma, and the willpower of miR-155 in peripheral blood is comparatively easy and handy. Due to this fact, based mostly on our findings and former research,36 our analysis group recommends that the remedy consequence of DFU could be predicted by detecting the expression of miR-155 in peripheral blood.
This research finds that the elevated degree of miR-155 expression in peripheral blood of sort 2 diabetes sufferers is carefully associated to the prevalence of DFU, and could be a biomarker for analysis of DFU (Figure 3). As well as, the elevated degree of miR-155 expression in peripheral blood and wound margin tissue is carefully associated to the poor prognosis of DFU. The shortcomings of this research embrace that it’s a single-center research, the pattern dimension is comparatively small, and choice bias might exist. Due to this fact, additional research are wanted to substantiate these findings. As well as, this research additionally can’t make clear the causal relationship between miR-155 and DFU. Sooner or later, we have to additional discover the mechanism of motion of miR-155 and consider whether or not miR-155 can grow to be a brand new therapeutic goal for DFU.
 |
Determine 3 MiR-155 is a probably priceless biomarker for analysis and prognosis of DFU. ↑: enhance; ↓: lower. |
Determine 3 MiR-155 is a probably priceless biomarker for analysis and prognosis of DFU. ↑: enhance; ↓: lower.
T2DM, sort 2 diabetes mellitus; DFU, diabetic foot ulcer; AUC, space below the curves; FPG, fasting plasma glucose; HbA1c, glycosylated hemoglobin A1c; TCH, complete ldl cholesterol; TG, triacylglycerol; HDL-C, high-density lipoprotein ldl cholesterol; LDL-C, low-density lipoprotein ldl cholesterol; ALB, serum albumin; Hb, hemoglobin; WBC, white blood cell; CRP, C-reactive protein; ESR, erythrocyte sedimentation fee; TcPO2, transcutaneous oxygen strain; ABI, ankle brachial index; qRT-PCR, quantitative real-time PCR assays.
The datasets used and/or analysed in the course of the present research can be found from the corresponding creator on cheap request. Inquiries for information entry could also be despatched to the next e-mail handle: [email protected]
This research was accepted by the Medical Ethics Committee of the First Affiliated Hospital of Anhui Medical College, and we obtained the knowledgeable consent of the topics. All procedures have been carried out in research involving human members in accordance with the moral requirements of the institutional and/or nationwide analysis committee and with the 1964 Helsinki declaration and its later amendments or comparable moral requirements.
We’re grateful to all sufferers for taking part within the research. We thank the members of this research together with the docs, nurses, and researchers from the Division of Endocrinology and the Burns Division within the First Affiliated Hospital of Anhui Medical College.
All authors made a big contribution to the work reported, whether or not that’s within the conception, research design, execution, acquisition of knowledge, evaluation and interpretation, or in all these areas; took half in drafting, revising or critically reviewing the article; gave remaining approval of the model to be revealed; have agreed on the journal to which the article has been submitted; and comply with be accountable for all elements of the work.
This research was supported by the Pure Science Basis of Anhui Province in China (2108085MH269) and the Pure Science Analysis Venture of Schools and Universities in Anhui Province (KJ2021A0274). The funding physique had no function within the design of the research, or the gathering, evaluation, and interpretation of knowledge, or in writing the manuscript.
The authors report no conflicts of curiosity on this work.
1. Lim JZM, Ng NSL, Thomas C. Prevention and remedy of diabetic foot ulcers. J Roy Soc Med. 2017;110(3):104–109. doi:10.1177/0141076816688346
2. Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. New Engl J Med. 2017;376(24):2367–2375. doi:10.1056/NEJMra1615439
3. Bandyk DF. The diabetic foot: pathophysiology, analysis, and remedy. Semin Vasc Surg. 2018;31(2–4):43–48. doi:10.1053/j.semvascsurg.2019.02.001
4. Goodarzi G, Maniati M, Qujeq D. The function of microRNAs within the therapeutic of diabetic ulcers. Int Wound J. 2019;16(3):621–633. doi:10.1111/iwj.13070
5. Saliminejad Ok, Khorram Khorshid HR, Soleymani Fard S, Ghaffari SH. An summary of microRNAs: biology, capabilities, therapeutics, and evaluation strategies. J Cell Physiol. 2019;234(5):5451–5465. doi:10.1002/jcp.27486
6. Bartel DP. Metazoan microRNAs. Cell. 2018;173(1):20–51. doi:10.1016/j.cell.2018.03.006
7. Vigorito E, Kohlhaas S, Lu D, Leyland R. miR-155: an historic regulator of the immune system. Immunol Rev. 2013;253(1):146–157. doi:10.1111/imr.12057
8. Arbore G, Henley T, Biggins L, et al. MicroRNA-155 is important for the optimum proliferation and survival of plasmablast B cells. Life Sci Alliance. 2019;2(3):e201800244. doi:10.26508/lsa.201800244
9. Guo P, Qiao F, Huang D, et al. MiR-155-5p performs as a “janus” within the expression of inflammatory cytokines induced by T-2 toxin. Meals Chem Toxicol. 2020;140:111258. doi:10.1016/j.fct.2020.111258
10. Yang L, Zheng Z, Zhou Q, et al. miR-155 promotes cutaneous wound therapeutic by means of enhanced keratinocytes migration by MMP-2. J Mol Histol. 2017;48(2):147–155. doi:10.1007/s10735-017-9713-8
11. Hou RX, Liu RF, Zhao XC, et al. Elevated miR-155-5p expression in dermal mesenchymal stem cells of psoriatic sufferers: evaluating the microRNA expression profile by microarray. Genet Mol Res. 2016;15(3). doi:10.4238/gmr.15038631.
12. Moura J, Sørensen A, Leal EC, et al. microRNA-155 inhibition restores Fibroblast Progress Issue 7 expression in diabetic pores and skin and reduces wound irritation. Sci Rep. 2019;9(1):5836. doi:10.1038/s41598-019-42309-4
13. Ye J, Kang Y, Solar X, Ni P, Wu M, Lu S. MicroRNA-155 inhibition promoted wound therapeutic in diabetic rats. Int J Low Extrem Wounds. 2017;16(2):74–84. doi:10.1177/1534734617706636
14. Wang CR, Zhu HF, Zhu Y. Knockout of microRNA-155 ameliorates the Th17/Th9 immune response and promotes wound therapeutic. Curr Med Sci. 2019;39(6):954–964. doi:10.1007/s11596-019-2128-x
15. Gondaliya P, Sayyed AA, Bhat P, et al. Mesenchymal stem cell-derived exosomes loaded with miR-155 inhibitor ameliorate diabetic wound therapeutic. Mol Pharm. 2022;19(5):1294–1308. doi:10.1021/acs.molpharmaceut.1c00669
16. Li X, Tang Y, Jia Z, Zhao X, Chen M. Decreased expression of miR-24 in peripheral plasma of sort 2 diabetes mellitus sufferers related to diabetic foot ulcer. Wound Restore Regen. 2020;28(6):728–738. doi:10.1111/wrr.12850
17. Sharma D, Singh B, Jaswal KS, Thakur V, Nabh R. Effectiveness of detrimental strain wound remedy within the administration of power diabetic ulcers: a potential research. Int Surg J. 2017;4(4):1313. doi:10.18203/2349-2902.isj20171134
18. Perkins NJ, Schisterman EF. The inconsistency of “optimum” cut-points obtained utilizing two standards based mostly on the receiver working attribute curve. Am J Epidemiol. 2006;163(7):6. doi:10.1093/aje/kwj063
19. Lin X, Qin Y, Jia J, et al. MiR-155 enhances insulin sensitivity by coordinated regulation of a number of genes in mice. PLoS Genet. 2016;12(10):e1006308. doi:10.1371/journal.pgen.1006308
20. Zhu M, Wei Y, Geißler C, et al. Hyperlipidemia-induced microRNA-155-5p improves β-cell perform by focusing on Mafb. Diabetes. 2017;66(12):3072–3084. doi:10.2337/db17-0313
21. Corral-Fernández NE, Salgado-Bustamante M, Martínez-Leija ME, et al. Dysregulated miR-155 expression in peripheral blood mononuclear cells from sufferers with sort 2 diabetes. Exp Clin Endocrinol Diabetes. 2013;121(6):347–353. doi:10.1055/s-0033-1341516
22. Nunez Lopez YO, Garufi G, Seyhan AA. Altered ranges of circulating cytokines and microRNAs in lean and overweight people with prediabetes and sort 2 diabetes. Mol Biosyst. 2016;13(1):106–121. doi:10.1039/C6MB00596A
23. Xiang Y, Cheng J, Wang D, et al. Hyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand issue. Blood. 2015;125(22):3377–3387. doi:10.1182/blood-2015-01-620278
24. Liu J, Shi Ok, Chen M, et al. Elevated miR-155 expression induces immunosuppression by way of CD39(+) regulatory T-cells in sepsis affected person. Int J Infect Dis. 2015;40:135–141. doi:10.1016/j.ijid.2015.09.016
25. Chen CG, Luo BS, Wang C. Potential function of miR-425, miR-155 and miR-33 in Streptococcus pneumoniae pneumonia through the use of bioinformatics evaluation and experimental validation. J Biol Regul Homeost Brokers. 2021;35(3):953–964. doi:10.23812/21-120-A
26. Chinese language Diabetes Society, Chinese language Society of Infectious Ailments, Chinese language Society for Tissue Restore and Regeneration. Chinese language guideline on prevention and administration of diabetic foot. Chin J Diabetes Mellitus. 2019;11(2):92–108.
27. Tindong M, Palle JN, Nebongo D, et al. Prevalence, scientific presentation, and elements related to diabetic foot ulcer in two regional hospitals in Cameroon. Int J Low Extrem Wounds. 2018;17(1):42–47. doi:10.1177/1534734618764252
28. van Netten JJ, Worth PE, Lavery LA, et al.; Worldwide Working Group on the Diabetic Foot. Prevention of foot ulcers within the at-risk affected person with diabetes: a scientific overview. Diabetes Metab Res Rev. 2016;32(Suppl 1):84–98. doi:10.1002/dmrr.2701
29. Nickinson ATO, Bridgwood B, Houghton JSM, et al. A scientific overview investigating the identification, causes, and outcomes of delays within the administration of power limb-threatening ischemia and diabetic foot ulceration. J Vasc Surg. 2020;71(2):669–681.e2. doi:10.1016/j.jvs.2019.08.229
30. van Solingen C, Araldi E, Chamorro-Jorganes A, Fernández-Hernando C, Suárez Y. Improved restore of dermal wounds in mice missing microRNA-155. J Cell Mol Med. 2014;18(6):1104–1112. doi:10.1111/jcmm.12255
31. Catrina SB, Zheng X. Disturbed hypoxic responses as a pathogenic mechanism of diabetic foot ulcers. Diabetes Metab Res Rev. 2016;32(Suppl 1):179–185. doi:10.1002/dmrr.2742
32. Liu S, Chen J, Shi J, et al. M1-like macrophage-derived exosomes suppress angiogenesis and exacerbate cardiac dysfunction in a myocardial infarction microenvironment. Fundamental Res Cardiol. 2020;115(2):22. doi:10.1007/s00395-020-0781-7
33. Gao J, Zhao G, Li W, et al. MiR-155 targets PTCH1 to mediate endothelial progenitor cell dysfunction brought on by excessive glucose. Exp Cell Res. 2018;366(1):55–62. doi:10.1016/j.yexcr.2018.03.012
34. Niu LJ, Zhang YM, Huang T, Solar XF, Luo SX. Exosomal microRNA-155 as a biomarker for hepatic fibrosis analysis and development. Ann Transl Med. 2021;9(2):137. doi:10.21037/atm-20-7787
35. Shao C, Yang F, Qin Z, Jing X, Shu Y, Shen H. The worth of miR-155 as a biomarker for the analysis and prognosis of lung most cancers: a scientific overview with meta-analysis. BMC Most cancers. 2019;19(1):1103. doi:10.1186/s12885-019-6297-6
36. Liu L, Chen R, Jia Z, et al. Downregulation of hsa-miR-203 in peripheral blood and wound margin tissue by detrimental strain wound remedy contributes to wound therapeutic of diabetic foot ulcers. Microvasc Res. 2022;139:104275. doi:10.1016/j.mvr.2021.104275
© 2022 The Creator(s). This work is revealed and licensed by Dove Medical Press Restricted. The complete phrases of this license can be found at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License. By accessing the work you hereby settle for the Phrases. Non-commercial makes use of of the work are permitted with none additional permission from Dove Medical Press Restricted, supplied the work is correctly attributed. For permission for business use of this work, please see paragraphs 4.2 and 5 of our Terms.
Contact Us • Privacy Policy • Associations & Partners • Testimonials • Terms & Conditions • Recommend this site • Top
Contact Us • Privacy Policy
© Copyright 2022 • Dove Press Ltd • software program growth by maffey.com • Net Design by Adhesion
The opinions expressed in all articles revealed listed here are these of the particular creator(s), and don’t essentially mirror the views of Dove Medical Press Ltd or any of its workers.
Dove Medical Press is a part of Taylor & Francis Group, the Tutorial Publishing Division of Informa PLC
Copyright 2017 Informa PLC. All rights reserved. This website is owned and operated by Informa PLC ( “Informa”) whose registered workplace is 5 Howick Place, London SW1P 1WG. Registered in England and Wales. Quantity 3099067. UK VAT Group: GB 365 4626 36
As a way to present our web site guests and registered customers with a service tailor-made to their particular person preferences we use cookies to analyse customer visitors and personalise content material. You possibly can study our use of cookies by studying our Privacy Policy. We additionally retain information in relation to our guests and registered customers for inner functions and for sharing data with our enterprise companions. You possibly can study what information of yours we retain, how it’s processed, who it’s shared with and your proper to have your information deleted by studying our Privacy Policy.
If you happen to comply with our use of cookies and the contents of our Privateness Coverage please click on ‘settle for’.