scholarly journals PPARα Agonist Stimulated Angiogenesis by Improving Endothelial Precursor Cell Function Via a NLRP3 Inflammasome Pathway

2017 ◽  
Vol 42 (6) ◽  
pp. 2255-2266 ◽  
Author(s):  
Yaping Deng ◽  
Xue Han ◽  
Zheng Yao ◽  
Yuannan Sun ◽  
Jiawen Yu ◽  
...  
Keyword(s):  
Wound Healing ◽  
Nlrp3 Inflammasome ◽  
High Glucose ◽  
Wound Closure ◽  
Precursor Cell ◽  
Diabetic Mice ◽  
Impaired Wound Healing ◽  
Caspase 1 ◽  
Endothelial Precursor Cell ◽  
Pparα Agonist

Background: Impaired wound healing is a common complication of diabetes and is the leading cause of lower extremity amputation. Treatment with fenofibrate, a peroxisome proliferators–activated receptor α (PPARα) agonist, was associated with a lower risk of amputations, particularly minor amputations without known large-vessel diseases, probably through non-lipid mechanisms. The current study aimed to test our hypothesis that fenofibrate stimulates angiogenesis and restores endothelial precursor cell (EPC) function via inhibiting Nod-like receptor protein 3 (NLRP3) inflammasome in streptozotocin (STZ)-induced diabetic mice. Methods: Male C57BL/6 mice were randomly divided into three groups: control, STZ-induced diabetic mice and fenofibrate treated diabetic group. Wound closure was assessed by wound area and CD31 positive capillaries. Both the migration and tube formation capacities of EPCs were measured. Intracellular nitric oxide (NO) and superoxide (O2-) levels were determined. Activity of NLRP3 inflammasome in EPCs was assessed by measuring thioredoxin-interacting protein (TXNIP), NLRP3, and caspase-1 expression. Results: Compared with the untreated diabetic mice, wound closure and capillary densities were significantly increased in fenofibrate treated group. Fenofibrate treatment restored EPC function, increased NO production, and decreased O2- level in EPCs of diabetic mice. Furthermore, fenofibrate deregulated the activity of NLRP3 inflammasome by reducing TXNIP, NLRP3 and caspase-1 expression in EPCs of diabetic mice. In vitro, fenofibrate prevented high glucose induced EPC dysfunction, deregulated NLRP3 inflammasome activity. In addition, fenofibrate inhibited IL-1β expression caused by combination use of high glucose and lipopolysaccharide. Conclusion: Fenofibrate can accelerate wound healing in diabetic mice, which at least in part was mediated by improving the impaired EPC function via a NLRP3 inflammasome pathway, suggesting the significance of PPARα agonists in the treatment of diabetes.

scholarly journals Rosiglitazone accelerates wound healing by improving endothelial precursor cell function and angiogenesis in db/db mice

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7815
Author(s):  
Guoliang Zhou ◽  
Xue Han ◽  
Zhiheng Wu ◽  
Qiaojuan Shi ◽  
Xiaogang Bao
Keyword(s):  
Wound Healing ◽  
Cell Viability ◽  
Insulin Signaling ◽  
Tube Formation ◽  
Precursor Cell ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Positive Effects ◽  
And Migration ◽  
Endothelial Precursor Cell

Background & Aims Endothelial precursor cell (EPC) dysfunction is one of the risk factors for diabetes mellitus (DM) which results in delayed wound healing. Rosiglitazone (RSG) is a frequently prescribed oral glucose-lowering drug. Previous studies have shown the positive effects of RSG on ameliorating EPC dysfunction in diabetic patients. Interestingly, knowledge about RSG with regard to the wound healing process caused by DM is scarce. Therefore, in this study, we investigated the possible actions of RSG on wound healing and the related mechanisms involved in db/db diabetic mice. Methods Db/db mice with spontaneous glucose metabolic disorder were used as a type 2 DM model. RSG (20 mg/kg/d, i.g.,) was administered for 4 weeks before wound creation and bone marrow derived EPC (BM-EPC) isolation. Wound closure was assessed by wound area and CD31 staining. Tubule formation and migration assays were used to judge the function of the BM-EPCs. The level of vascular endothelial growth factor (VEGF), stromal cell derived factor-1α (SDF-1α) and insulin signaling was determined by ELISA. Cell viability of the BM-EPCs was measured by CCK-8 assay. Results RSG significantly accelerated wound healing and improved angiogenesis in db/db mice. Bioactivities of tube formation and migration were decreased in db/db mice but were elevated by RSG. Level of both VEGF and SDF-1α was increased by RSG in the BM-EPCs of db/db mice. Insulin signaling was elevated by RSG reflected in the phosphorylated-to-total AKT in the BM-EPCs. In vitro, RSG improved impaired cell viability and tube formation of BM-EPCs induced by high glucose, but this was prevented by the VEGF inhibitor avastin. Conclusion Our data demonstrates that RSG has benefits for wound healing and angiogenesis in diabetic mice, and was partially associated with improvement of EPC function through activation of VEGF and stimulation of SDF-1α in db/db mice.

Abstract 18933: Regulation of Impaired Angiogenesis in Diabetes by Microrna26a

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Basak Icli ◽  
Christoph Nabzdyk ◽  
Jorge Lujan Hernandez ◽  
Megan Cahi ◽  
Dennis Orgill ◽  
...  
Keyword(s):  
Wound Healing ◽  
Endothelial Cells ◽  
High Glucose ◽  
Chronic Wounds ◽  
Cellular Migration ◽  
M2 Macrophage ◽  
Diabetic Mice ◽  
Impaired Wound Healing ◽  
Matrix Deposition ◽  
Wide Range

Wound healing is a physiological reparative response to injury that involves hemostasis, cellular migration, proliferation, angiogenesis, extracellular matrix deposition, wound contraction and re-epithelialization. However, patients with type 2 diabetes mellitus (T2D) are frequently afflicted with impaired wound healing that progresses into chronic wounds or diabetic ulcers, and may lead to complications including limb amputation. In recent years, microRNAs (miRNAs) has been implicated in a wide-range of disease states. We have investigated the potential role of microRNA-26a (miR-26a) in a diabetic model of wound healing. Expression of miR-26a is rapidly induced in response to diabetic stimuli (e.g. high glucose, PKC activation) in endothelial cells (ECs). Punch skin biopsy wounding of db/db mice revealed increased expression of miR-26a (~2-fold) four days post wounding compared to that of WT mice. Local administration of a miR-26a inhibitor, LNA-anti-miR-26a, induced angiogenesis (up to 80%), increased granulation tissue thickness (by 2.5 fold) and accelerated wound closure (by 50% after nine days) compared to scrambled anti-miR controls using a db/db mouse model of diabetes. These effects were independent of altered M1/M2 macrophage ratios. Mechanistically, inhibition of miR-26a increased its target gene, SMAD1, both at the mRNA and protein levels in ECs. In addition, increased SMAD1 levels correlated with increased ID1, a downstream modulator or SMAD1, and decreased expression of the cell cycle inhibitor p27 nine days post-wounding of diabetic mice. Interestingly, inhibition of miR-26a increased migration and growth of both human microvascular ECs (HMVECs), human umbilical endothelial cells (HUVECs), and fibroblasts under normal glucose conditions. However, in the presence of high glucose, anti-miR-26a functional effects were abolished in fibroblasts, but not in HUVECs or HMVECs, suggesting cell-specific miR-26a regulated effects under diabetic conditions. These findings establish miR-26a as an important regulator on the progression of skin wounds of diabetic mice by specifically regulating the angiogenic response after injury, and demonstrate that neutralization of miR-26a may serve as a novel approach for therapy.

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

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.

scholarly journals Keratin Scaffolds Containing Casomorphin Stimulate Macrophage Infiltration and Accelerate Full-Thickness Cutaneous Wound Healing in Diabetic Mice

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2554
Author(s):  
Marek Konop ◽  
Anna K. Laskowska ◽  
Mateusz Rybka ◽  
Ewa Kłodzińska ◽  
Dorota Sulejczak ◽  
...  
Keyword(s):  
Wound Healing ◽  
Wound Dressing ◽  
Healing Process ◽  
Skin Wound ◽  
Wound Healing Process ◽  
Diabetic Mice ◽  
Full Thickness ◽  
Skin Wound Healing ◽  
Impaired Wound Healing

Impaired wound healing is a major medical challenge, especially in diabetics. Over the centuries, the main goal of tissue engineering and regenerative medicine has been to invent biomaterials that accelerate the wound healing process. In this context, keratin-derived biomaterial is a promising candidate due to its biocompatibility and biodegradability. In this study, we evaluated an insoluble fraction of keratin containing casomorphin as a wound dressing in a full-thickness surgical skin wound model in mice (n = 20) with iatrogenically induced diabetes. Casomorphin, an opioid peptide with analgesic properties, was incorporated into keratin and shown to be slowly released from the dressing. An in vitro study showed that keratin-casomorphin dressing is biocompatible, non-toxic, and supports cell growth. In vivo experiments demonstrated that keratin-casomorphin dressing significantly (p < 0.05) accelerates the whole process of skin wound healing to the its final stage. Wounds covered with keratin-casomorphin dressing underwent reepithelization faster, ending up with a thicker epidermis than control wounds, as confirmed by histopathological and immunohistochemical examinations. This investigated dressing stimulated macrophages infiltration, which favors tissue remodeling and regeneration, unlike in the control wounds in which neutrophils predominated. Additionally, in dressed wounds, the number of microhemorrhages was significantly decreased (p < 0.05) as compared with control wounds. The dressing was naturally incorporated into regenerating tissue during the wound healing process. Applied keratin dressing favored reconstruction of more regular skin structure and assured better cosmetic outcome in terms of scar formation and appearance. Our results have shown that insoluble keratin wound dressing containing casomorphin supports skin wound healing in diabetic mice.

scholarly journals Chitosan from Lucilia cuprina (Diptera: Calliphoridae) enhances sensitization to insulin treatment in a diabetic burn mice of wound healing

2020 ◽  
Vol 1 (1) ◽  
pp. 1-15
Author(s):  
Lamia M. El-Samad ◽  
◽  
Azza A. Attia ◽  
Basant A. Bakr ◽  
◽  
...  
Keyword(s):  
Wound Healing ◽  
Wound Closure ◽  
Lucilia Cuprina ◽  
Diabetic Mice ◽  
Burn Wound ◽  
Time Intervals ◽  
Burn Wound Healing ◽  
High Degree

Chitosan is recognized as a multipurpose biomaterial because of its low allergenicity, non-toxicity, biodegradability and biocompatibility. The present study was designed to estimate the role of chitosan derived from Lucilia cuprina on burn healing in diabetic mice; using histopathological and microbiological studies at different time intervals. Chitosan was prepared from L. cuprina with high molecular weight (MW) and high degree of deacetylation (DD) to evaluate its burn wound healing potential; skin burn closure assessment, histological and microbiological studies in vivo in male diabetic mice. Chitosan topical treatment was superior in wound closure acceleration; mainly in insulin injected group at all the time intervals. Additionally, earlier epidermal remodelling with mature and intense collagen deposition was encountered in all chitosan treated animals as well as non-diabetic burned animals. There was a significant delay in hair growth and poor epidermal remodelling with impairment of wound closure in diabetic groups. Moreover, chitosan treated groups assert the chitosan antibacterial effects with protecting the burn against contamination that hinders healing especially in this diabetic condition. Further researches needed to interpret effects of possible synergistic combination therapy.

scholarly journals Astragaloside IV Suppresses High Glucose-Induced NLRP3 Inflammasome Activation by Inhibiting TLR4/NF-κB and CaSR

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Bin Leng ◽  
Yingjie Zhang ◽  
Xinran Liu ◽  
Zhen Zhang ◽  
Yang Liu ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
High Glucose ◽  
Inflammasome Activation ◽  
Astragaloside Iv ◽  
Caspase 1 ◽  
Endothelial Inflammation ◽  
Nlrp3 Inflammasome Activation ◽  
Anti Inflammatory

Long-term exposure to high glucose induces vascular endothelial inflammation that can result in cardiovascular disease. Astragaloside IV (As-IV) is widely used for anti-inflammatory treatment of cardiovascular diseases. However, its mechanism of action is still not fully understood. In this study, we investigated the effect of As-IV on high glucose-induced endothelial inflammation and explored its possible mechanisms. In vivo, As-IV (40 and 80 mg/kg/d) was orally administered to rats for 8 weeks after a single intraperitoneal injection of streptozotocin (STZ, 65 mg/kg). In vitro, human umbilical vein endothelial cells (HUVECs) were treated with high glucose (33 mM glucose) in the presence or absence of As-IV, NPS2143 (CaSR inhibitor), BAY 11-7082 (NF-κB p65 inhibitor), and INF39 (NLRP3 inhibitor), and overexpression of CaSR was induced by infection of CaSR-overexpressing lentiviral vectors to further discuss the anti-inflammatory property of As-IV. The results showed that high glucose increased the expression of interleukin-18 (IL-18), interleukin-1β (IL-1β), NLRP3, caspase-1, and ASC, as well as the protein level of TLR4, nucleus p65, and CaSR. As-IV can reverse these changes in vivo and in vitro. Meanwhile, NPS2143, BAY 11-7082, and INF39 could significantly abolish the high glucose-enhanced NLRP3, ASC, caspase-1, IL-18, and IL-1β expression in vitro. In addition, both NPS2143 and BAY 11-7082 attenuated high glucose-induced upregulation of NLRP3, ASC, caspase-1, IL-18, and IL-1β expression. In conclusion, this study suggested that As-IV could inhibit high glucose-induced NLRP3 inflammasome activation and subsequent secretion of proinflammatory cytokines via inhibiting TLR4/NF-κB signaling pathway and CaSR, which provides new insights into the anti-inflammatory activity of As-IV.

scholarly journals Specific PKC βII inhibitor: one stone two birds in the treatment of diabetic foot ulcers

2018 ◽  
Vol 38 (5) ◽  
Author(s):  
Sushant Kumar Das ◽  
Yi Feng Yuan ◽  
Mao Quan Li
Keyword(s):  
Wound Healing ◽  
Protein Kinase ◽  
Peripheral Blood ◽  
Wound Closure ◽  
Type I Diabetes ◽  
Healing Process ◽  
Wound Healing Process ◽  
Peripheral Blood Flow ◽  
Type I ◽  
Diabetic Mice

To explore whether or not inhibition of protein kinase C βII (PKC βII) stimulates angiogenesis as well as prevents excessive NETosis in diabetics thus accelerating wound healing. Streptozotocin (STZ, 60 mg/kg/day for 5 days, i.p.) was injected to induce type I diabetes in male ICR mice. Mice were treated with ruboxistaurin (30 mg/kg/day, orally) for 14 consecutive days. Wound closure was evaluated by wound area and number of CD31-stained capillaries. Peripheral blood flow cytometry was done to evaluate number of circulating endothelial progenitor cells (EPCs). NETosis assay and wound tissue immunofluorescence imaging were done to evaluate the percentage of neutrophils undergoing NETosis. Furthermore, the expression of PKC βII, protein kinase B (Akt), endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), and histone citrullation (H3Cit) were determined in the wound by Western blot analysis. Ruboxistaurin accelerated wound closure and stimulated angiogenesis in diabetic mice. The number of circulating EPCs was increased significantly in ruboxistaurin-treated diabetic mice. Moreover, ruboxistaurin treatment significantly decreases the percentages of H3Cit+ cells in both peripheral blood and wound areas. This prevented excess activated neutrophils forming an extracellular trap (NETs) formation. The expressions of phospho-Akt (p-Akt), phospho-eNOS (p-eNOS), and VEGF increased significantly in diabetic mice on ruboxistaurin treatment. The expressions of PKC βII and H3Cit+, on the other hand, decreased with ruboxistaurin treatment. The results of the present study suggest that ruboxistaurin by inhibiting PKC βII activation, reverses EPCs dysfunction as well as prevents exaggerated NETs formation in a diabetic mouse model; thereby accelerating the wound healing process.

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