Relevance of Thoracic Adipose Tissue in Wound Healing Disorder of Diabetic Patients

AbstractAimsIn patients with cardiovascular disease, epicardial adipose tissue (EAT) is characterized by insulin resistance, high pro-inflammatory chemokines, and low differentiation ability. As dapagliflozin reduces body fat and cardiovascular events in diabetic patients, we would like to know its effect on EAT and subcutaneous adipose tissue (SAT).Methods and resultsAdipose samples were obtained from 52 patients undergoing heart surgery. Sodium-glucose cotransporter 2 (SGLT2) expression was determined by real-time polymerase chain reaction (n = 20), western blot, and immunohistochemistry. Fat explants (n = 21) were treated with dapagliflozin and/or insulin and glucose transporters expression measured. Glucose, free fatty acid, and adipokine levels (by array) were measured in the EAT secretomes, which were then tested on human coronary endothelial cells using wound healing assays. Glucose uptake was also measured using the fluorescent glucose analogue (6NBDG) in differentiated stromal vascular cells (SVCs) from the fat pads (n = 11). Finally, dapagliflozin-induced adipocyte differentiation was assessed from the levels of fat droplets (AdipoRed staining) and of perilipin. SGLT2 was expressed in EAT. Dapagliflozin increased glucose uptake (20.95 ± 4.4 mg/dL vs. 12.97 ± 4.1 mg/dL; P < 0.001) and glucose transporter type 4 (2.09 ± 0.3 fold change; P < 0.01) in EAT. Moreover, dapagliflozin reduced the secretion levels of chemokines and benefited wound healing in endothelial cells (0.21 ± 0.05 vs. 0.38 ± 0.08 open wound; P < 0.05). Finally, chronic treatment with dapagliflozin improved the differentiation of SVC, confirmed by AdipoRed staining [539 ± 142 arbitrary units (a.u.) vs. 473 ± 136 a.u.; P < 0.01] and perilipin expression levels (121 ± 10 vs. 84 ± 11 a.u.).ConclusionsDapagliflozin increased glucose uptake, reduced the secretion of pro-inflammatory chemokines (with a beneficial effect on the healing of human coronary artery endothelial cells), and improved the differentiation of EAT cells. These results suggest a new protective pathway for this drug on EAT from patients with cardiovascular disease.

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ID2019 Functional analysis of human type 2 diabetic adipose tissue-derived mesenchymal stem cells

Biomedical Research and Therapy ◽

10.15419/bmrat.v4is.262 ◽

2017 ◽

Vol 4 (S) ◽

pp. 52

Author(s):

Thuy Nhu Trinh

Keyword(s):

Stem Cells ◽

Wound Healing ◽

Mesenchymal Stem Cells ◽

Adipose Tissue ◽

Mouse Model ◽

Cell Therapy ◽

Diabetic Patients ◽

Hypoxic Conditions ◽

Ischemic Flap

Background: Stem cell therapy has recently shown promise in the prevention of diabetic complications due to its regenerative potential. The possible applications of human diabetic adipose tissue-derived mesenchymal stem cells (dAT-MSCs) in cell therapy are limited because their characteristics are still not fully understood. Aims: This study aimed to characterize dAT-MSCs in vitro and to investigate the potential application of dAT-MSCs in wound healing. Materials and Methods: dAT-MSCs were characterized under normoxic and hypoxic conditions in vitro and evaluated wound healing capacity in the ischemic flap mouse model. Results: Early growth response factor-1 (EGR-1) and its target genes were highly expressed in dAT-MSCs in comparison to nAT-MSCs, resulting in increasing of genes and protein associated with cell adhesion, insulin resistance, and impaired wound healing. Interestingly, under hypoxic conditions, hypoxia-inducible factor-1α (HIF-1α) can bind to the EGR-1 promoter in dAT-MSCs, but not in nAT-MSCs. The effects of EGR-1 were inhibited by shEGR-1 and PD98059. Mice injected with shEGR-1- dAT-MSCs were improved their wound healing capacity. Furthermore, we found that human nAT-MSC-derived microvesicles (nMVs) could improve dAT-MSC function by altering miRNA and mRNA expressions, which enhanced their migration ability in vitro and wound healing capacity in the ischemic flap mouse model. Conclusion: Our study suggests that dAT-MSCs may contribute to delay wound healing. Interrupting the expression of EGR-1 in dAT-MSCs or transfecting nMVs to dAT-MSCs may be a useful treatment for chronic wounds in diabetic patients.

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Enhanced Healing of Diabetic Wounds by Topical Administration of Adipose Tissue-Derived Stromal Cells Overexpressing Stromal-Derived Factor-1: Biodistribution and Engraftment Analysis by Bioluminescent Imaging

Stem Cells International ◽

10.4061/2011/304562 ◽

2011 ◽

Vol 2011 ◽

pp. 1-11 ◽

Cited By ~ 15

Author(s):

Giuliana Di Rocco ◽

Antonietta Gentile ◽

Annalisa Antonini ◽

Francesca Ceradini ◽

Joseph C. Wu ◽

...

Keyword(s):

Wound Healing ◽

Adipose Tissue ◽

Progenitor Cells ◽

Stromal Cells ◽

Topical Administration ◽

Diabetic Patients ◽

Bioluminescent Imaging ◽

Major Health Problem ◽

Wound Site ◽

Cellular Recruitment

Chronic ulcers represent a major health problem in diabetic patients resulting in pain and discomfort. Conventional therapy does not guarantee adequate wound repair. In diabetes, impaired healing is partly due to poor endothelial progenitor cells mobilisation and homing, with altered levels of the chemokine stromal-derived factor-1 (SDF-1) at the wound site. Adipose tissue-associated stromal cells (AT-SCs) can provide an accessible source of progenitor cells secreting proangiogenic factors and differentiating into endothelial-like cells. We demonstrated that topical administration of AT-SCs genetically modifiedex vivoto overexpress SDF-1, promotes wound healing into diabetic mice. In particular, byin vivobioluminescent imaging analysis, we monitored biodistribution and survival after transplantation of luciferase-expressing cells. In conclusion, this study indicates the therapeutic potential of AT-SCs administration in wound healing, through cell differentiation, enhanced cellular recruitment at the wound site, and paracrine effects associated with local growth-factors production.

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Comparison of the Effect of Adipocyte-derived Stem Cells and Curcumin Nanoliposomes with Phenytoin on Open Cutaneous Wound Healing in Rats

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320999200817172200 ◽

2020 ◽

Vol 20 ◽

Author(s):

Mohammadreza Ebrahimzade ◽

Mohammad Mirdoraghi ◽

Ameneh Alikarami ◽

Sahar Heidari ◽

Tayebeh Rastegar ◽

...

Keyword(s):

Stem Cells ◽

Wound Healing ◽

Adipose Tissue ◽

Healing Time ◽

Daily Work ◽

Expression Of Genes ◽

Skin Ulcers ◽

Immobility Time ◽

Liposomal Nanoparticles ◽

Chromosome Staining

Background: Reducing the healing time of wounds can decrease the patient`s immobility time and their medical costs,leading a faster return of the patients to daily work. Objective: To compare the effect of adipose-derived stem cells and curcumin-containing liposomal nanoparticles with phenytoin on wound healing. Method: After anesthesia of the rats, open skin ulcers were made by a bistoury blade.Subsequently,stem cells were re-moved from the adipose tissue of theupper border of the epididymis. Then,the originality of stem cells was confirmed by the flow cytometry. The fusion method was used to prepare the liposome;and also nanoliposomal particles wereconfirmedby using the DLS microscope.The percentage of recovery and the cell count was measured with IMAGEJ.The expression of genes was assessed by PCR. The number of fibro blasts was counted by immuno histo chemistry techniques.The amount of collagen was determined by Tri-chromosome staining and the number of capillaries was enumerated byH & E staining. Results: The expression of TGF-β1 gene, vascular number, wound healing rate and the numberof fibroblasts increased significantly in adipose tissue-derived stem cells and curcumin nanoliposome groups(p<0.05);the wound surface was also decreased significantly(p<0.05). Conclusion: Based on the results of our research, adipose tissue-derived stem cells and curcumin nanoliposomescan heal wounds efficiently.

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The Effects of Silver-Releasing Foam Dressings on Diabetic Foot Ulcer Healing

Journal of Clinical Medicine ◽

10.3390/jcm10071495 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1495

Author(s):

Yu-Chi Wang ◽

Hsiao-Chen Lee ◽

Chien-Lin Chen ◽

Ming-Chun Kuo ◽

Savitha Ramachandran ◽

...

Keyword(s):

Wound Healing ◽

Diabetic Foot ◽

Healing Rate ◽

Early Period ◽

Foot Ulcer ◽

Diabetic Foot Ulcer ◽

Wound Management ◽

Control Group ◽

Diabetic Patients ◽

High Morbidity

Diabetic foot ulcers (DFUs) are a serious complication in diabetic patients and lead to high morbidity and mortality. Numerous dressings have been developed to facilitate wound healing of DFUs. This study investigated the wound healing efficacy of silver-releasing foam dressings versus silver-containing cream in managing outpatients with DFUs. Sixty patients with Wagner Grade 1 to 2 DFUs were recruited. The treatment group received silver-releasing foam dressing (Biatain® Ag Non-Adhesive Foam dressing; Coloplast, Humlebaek, Denmark). The control group received 1% silver sulfadiazine (SSD) cream. The ulcer area in the silver foam group was significantly reduced compared with that in the SSD group after four weeks of treatment (silver foam group: 76.43 ± 7.41%, SSD group: 27.00 ± 4.95%, p < 0.001). The weekly wound healing rate in the silver foam group was superior to the SSD group during the first three weeks of treatment (p < 0.05). The silver-releasing foam dressing is more effective than SSD in promoting wound healing of DFUs. The effect is more pronounced in the initial three weeks of the treatment. Thus, silver-releasing foam could be an effective wound dressing for DFUs, mainly in the early period of wound management.

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A small molecule HIF-1α stabilizer that accelerates diabetic wound healing

Nature Communications ◽

10.1038/s41467-021-23448-7 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Guodong Li ◽

Chung-Nga Ko ◽

Dan Li ◽

Chao Yang ◽

Wanhe Wang ◽

...

Keyword(s):

Wound Healing ◽

Small Molecule ◽

Hypoxia Inducible Factor ◽

Diabetic Patients ◽

Diabetic Mice ◽

Impaired Wound Healing ◽

Von Hippel Lindau ◽

Design And Synthesis

AbstractImpaired wound healing and ulcer complications are a leading cause of death in diabetic patients. In this study, we report the design and synthesis of a cyclometalated iridium(III) metal complex 1a as a stabilizer of hypoxia-inducible factor-1α (HIF-1α). In vitro biophysical and cellular analyses demonstrate that this compound binds to Von Hippel-Lindau (VHL) and inhibits the VHL–HIF-1α interaction. Furthermore, the compound accumulates HIF-1α levels in cellulo and activates HIF-1α mediated gene expression, including VEGF, GLUT1, and EPO. In in vivo mouse models, the compound significantly accelerates wound closure in both normal and diabetic mice, with a greater effect being observed in the diabetic group. We also demonstrate that HIF-1α driven genes related to wound healing (i.e. HSP-90, VEGFR-1, SDF-1, SCF, and Tie-2) are increased in the wound tissue of 1a-treated diabetic mice (including, db/db, HFD/STZ and STZ models). Our study demonstrates a small molecule stabilizer of HIF-1α as a promising therapeutic agent for wound healing, and, more importantly, validates the feasibility of treating diabetic wounds by blocking the VHL and HIF-1α interaction.

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Topical Application of Ozonated Oils for the Treatment of MRSA Skin Infection in an Animal Model of Infected Ulcer

Biology ◽

10.3390/biology10050372 ◽

2021 ◽

Vol 10 (5) ◽

pp. 372

Author(s):

Vanessa Silva ◽

Cecília Peirone ◽

Rosa Capita ◽

Carlos Alonso-Calleja ◽

José A Marques-Magallanes ◽

...

Keyword(s):

Wound Healing ◽

Animal Model ◽

Topical Application ◽

Early Stage ◽

Bacterial Load ◽

Ozone Treatment ◽

Diabetic Patients ◽

Colony Forming Units ◽

Group 2 ◽

Epidermal Regeneration

Diabetic foot ulcers are a common cause of morbidity in diabetic patients. One of the main pathogens found in these ulcers is methicillin-resistant Staphylococcus aureus (MRSA). MRSA often carries resistance to several classes of antibiotics and their infections are becoming harder to treat. Therefore, new alternatives are urgently needed. Thus, this study aimed to investigate the capacity of topical ozonated oil application on the treatment of early-stage skin infected with MRSA in an animal model. Ozonated oil was prepared from a mixture of oils subjected to a gas stream of O2/O3 mixture. Sixteen Wistar rats were inoculated by an intradermic injection of MRSA suspension, producing an abscess lesion. After 3 days, the skin epidermis was removed to open the wound. Group 1 received an application of oil mixture without ozone treatment and Group 2 received an application of ozonated oil. After the treatment period, skin was collected, colony-forming units (CFU) of bacteria were quantified and the histological analysis of the skin was carried out. Skin samples from the control 1 and 2 had a bacterial load was of 1.1 × 105 and 5.7 × 103 CFU/mL, respectively. Group 2 showed better wound healing from mild to moderate epidermal regeneration. Topical application of ozonated vegetable oil in MRSA-infected skin in rats showed a small reduction of the bacterial load and better wound healing.

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Migration and Proliferation Effects of Thymoquinone-Loaded Nanostructured Lipid Carrier (TQ-NLC) and Thymoquinone (TQ) on In Vitro Wound Healing Models

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/9725738 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 1

Author(s):

Henna Roshini Alexander ◽

Sharifah Sakinah Syed Alwi ◽

Latifah Saiful Yazan ◽

Fatin Hanani Zakarial Ansar ◽

Yong Sze Ong

Keyword(s):

Wound Healing ◽

Nigella Sativa ◽

Drug Carrier ◽

Healing Process ◽

Diabetic Patients ◽

Nanostructured Lipid Carrier ◽

Impaired Wound Healing ◽

And Migration ◽

Proliferation And Migration

Wound healing is a regulated biological event that involves several processes including infiltrating leukocyte subtypes and resident cells. Impaired wound healing is one of the major problems in diabetic patients due to the abnormal physiological changes of tissues and cells in major processes. Thymoquinone, a bioactive compound found in Nigella sativa has been demonstrated to possess antidiabetic, anti-inflammatory, and antioxidant effects. Today, the rapidly progressing nanotechnology sets a new alternative carrier to enhance and favour the speed of healing process. In order to overcome its low bioavailability, TQ is loaded into a colloidal drug carrier known as a nanostructured lipid carrier (NLC). This study aimed to determine the effect of TQ-NLC and TQ on cell proliferation and migration, mode of cell death, and the antioxidant levels in normal and diabetic cell models, 3T3 and 3T3-L1. Cytotoxicity of TQ-NLC and TQ was determined by MTT assay. The IC10 values obtained for 3T3-L1 treated with TQ-NLC and TQ for 24 hours were 4.7 ± 3.3 and 5.3 ± 0.6 μM, respectively. As for 3T3, the IC10 values obtained for TQ-NLC and TQ at 24 hours were 4.3 ± 0.17 and 3.9 ± 2.05 μM, respectively. TQ-NLC was observed to increase the number of 3T3 and 3T3-L1 healthy cells (87–95%) and gradually decrease early apoptotic cells in time- and dose-dependant manner compared with TQ. In the proliferation and migration assay, 3T3-L1 treated with TQ-NLC showed higher proliferation and migration rate (p<0.05) compared with TQ. TQ-NLC also acted as an antioxidant by reducing the ROS levels in both cells after injury at concentration as low as 3 μM. Thus, this study demonstrated that TQ-NLC has better proliferation and migration as well as antioxidant effect compared with TQ especially on 3T3-L1 which confirms its ability as a good antidiabetic and antioxidant agent.

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Transcriptomic Analysis of a Diabetic Skin-Humanized Mouse Model Dissects Molecular Pathways Underlying the Delayed Wound Healing Response

Genes ◽

10.3390/genes12010047 ◽

2020 ◽

Vol 12 (1) ◽

pp. 47

Author(s):

Carlos León ◽

Francisco García-García ◽

Sara Llames ◽

Eva García-Pérez ◽

Marta Carretero ◽

...

Keyword(s):

Wound Healing ◽

Functional Enrichment ◽

Preclinical Model ◽

Published Data ◽

Diabetic Patients ◽

Ulcer Formation ◽

Histological Features ◽

Depth Analysis ◽

Wound Healing Model ◽

Healing Model

Defective healing leading to cutaneous ulcer formation is one of the most feared complications of diabetes due to its consequences on patients’ quality of life and on the healthcare system. A more in-depth analysis of the underlying molecular pathophysiology is required to develop effective healing-promoting therapies for those patients. Major architectural and functional differences with human epidermis limit extrapolation of results coming from rodents and other small mammal-healing models. Therefore, the search for reliable humanized models has become mandatory. Previously, we developed a diabetes-induced delayed humanized wound healing model that faithfully recapitulated the major histological features of such skin repair-deficient condition. Herein, we present the results of a transcriptomic and functional enrichment analysis followed by a mechanistic analysis performed in such humanized wound healing model. The deregulation of genes implicated in functions such as angiogenesis, apoptosis, and inflammatory signaling processes were evidenced, confirming published data in diabetic patients that in fact might also underlie some of the histological features previously reported in the delayed skin-humanized healing model. Altogether, these molecular findings support the utility of such preclinical model as a valuable tool to gain insight into the molecular basis of the delayed diabetic healing with potential impact in the translational medicine field.

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Updates in Diabetic Wound Healing, Inflammation, and Scarring

Seminars in Plastic Surgery ◽

10.1055/s-0041-1731460 ◽

2021 ◽

Author(s):

Nina Dasari ◽

Austin Jiang ◽

Anna Skochdopole ◽

Jayer Chung ◽

Edward Reece ◽

...

Keyword(s):

Wound Healing ◽

Disease Process ◽

Wound Dehiscence ◽

Diabetic Patients ◽

Wound Infections ◽

Diabetic Wound ◽

Complex Process ◽

Diabetic Wound Healing ◽

Almost All ◽

Diabetic Wounds

AbstractDiabetic patients can sustain wounds either as a sequelae of their disease process or postoperatively. Wound healing is a complex process that proceeds through phases of inflammation, proliferation, and remodeling. Diabetes results in several pathological changes that impair almost all of these healing processes. Diabetic wounds are often characterized by excessive inflammation and reduced angiogenesis. Due to these changes, diabetic patients are at a higher risk for postoperative wound healing complications. There is significant evidence in the literature that diabetic patients are at a higher risk for increased wound infections, wound dehiscence, and pathological scarring. Factors such as nutritional status and glycemic control also significantly influence diabetic wound outcomes. There are a variety of treatments available for addressing diabetic wounds.

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