scholarly journals FOXO1 differentially regulates both normal and diabetic wound healing

2015 ◽  
Vol 209 (2) ◽  
pp. 289-303 ◽  
Author(s):  
Chenying Zhang ◽  
Bhaskar Ponugoti ◽  
Chen Tian ◽  
Fanxing Xu ◽  
Rohinton Tarapore ◽  
...  
Keyword(s):  
Wound Healing ◽  
High Glucose ◽  
Dependent Manner ◽  
Downstream Targets ◽  
Keratinocyte Migration ◽  
Normal Wound Healing ◽  
Normal Glucose ◽  
Enhanced Expression ◽  
Diabetic Wounds ◽  
The Impact

Healing is delayed in diabetic wounds. We previously demonstrated that lineage-specific Foxo1 deletion in keratinocytes interfered with normal wound healing and keratinocyte migration. Surprisingly, the same deletion of Foxo1 in diabetic wounds had the opposite effect, significantly improving the healing response. In normal glucose media, forkhead box O1 (FOXO1) enhanced keratinocyte migration through up-regulating TGFβ1. In high glucose, FOXO1 nuclear localization was induced but FOXO1 did not bind to the TGFβ1 promoter or stimulate TGFβ1 transcription. Instead, in high glucose, FOXO1 enhanced expression of serpin peptidase inhibitor, clade B (ovalbumin), member 2 (SERPINB2), and chemokine (C-C motif) ligand 20 (CCL20). The impact of high glucose on keratinocyte migration was rescued by silencing FOXO1, by reducing SERPINB2 or CCL20, or by insulin treatment. In addition, an advanced glycation end product and tumor necrosis factor had a similar regulatory effect on FOXO1 and its downstream targets and inhibited keratinocyte migration in a FOXO1-dependent manner. Thus, FOXO1 expression can positively or negatively modulate keratinocyte migration and wound healing by its differential effect on downstream targets modulated by factors present in diabetic healing.

scholarly journals High Glucose Enhances Cytotoxic T Lymphocyte-Mediated Cytotoxicity

2021 ◽  
Vol 12 ◽  
Author(s):  
Jie Zhu ◽  
Wenjuan Yang ◽  
Xiangda Zhou ◽  
Dorina Zöphel ◽  
Leticia Soriano-Baguet ◽  
...  
Keyword(s):  
High Glucose ◽  
Fas Ligand ◽  
Cytotoxic T Lymphocyte ◽  
Target Cells ◽  
Dependent Manner ◽  
Lytic Granules ◽  
Normal Glucose ◽  
Infected Cells ◽  
Killing Function ◽  
The Impact

Cytotoxic T lymphocytes (CTLs) are key players to eliminate tumorigenic or pathogen-infected cells using lytic granules (LG) and Fas ligand (FasL) pathways. Depletion of glucose leads to severely impaired cytotoxic function of CTLs. However, the impact of excessive glucose on CTL functions still remains largely unknown. Here we used primary human CD8+ T cells, which were stimulated by CD3/CD28 beads and cultured in medium either containing high glucose (HG, 25 mM) or normal glucose (NG, 5.6 mM). We found that in HG-CTLs, glucose uptake and glycolysis were enhanced, whereas proliferation remained unaltered. Furthermore, CTLs cultured in HG exhibited an enhanced CTL killing efficiency compared to their counterparts in NG. Unexpectedly, expression of cytotoxic proteins (perforin, granzyme A, granzyme B and FasL), LG release, cytokine/cytotoxic protein release and CTL migration remained unchanged in HG-cultured CTLs. Interestingly, additional extracellular Ca2+ diminished HG-enhanced CTL killing function. Our findings suggest that in an environment with excessive glucose, CTLs could eliminate target cells more efficiently, at least for a certain period of time, in a Ca2+-dependent manner.

scholarly journals Insights into Host–Pathogen Interactions in Biofilm-Infected Wounds Reveal Possibilities for New Treatment Strategies

Antibiotics ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 396
Author(s):  
Hannah Trøstrup ◽  
Anne Sofie Boe Laulund ◽  
Claus Moser
Keyword(s):  
Wound Healing ◽  
Host Response ◽  
Chronic Wounds ◽  
Therapeutic Potential ◽  
Recent Observation ◽  
Treatment Strategies ◽  
Normal Wound Healing ◽  
Inflammatory Phase ◽  
The Impact

Normal wound healing occurs in three phases—the inflammatory, the proliferative, and the remodeling phase. Chronic wounds are, for unknown reasons, arrested in the inflammatory phase. Bacterial biofilms may cause chronicity by arresting healing in the inflammatory state by mechanisms not fully understood. Pseudomonas aeruginosa, a common wound pathogen with remarkable abilities in avoiding host defense and developing microbial resistance by biofilm formation, is detrimental to wound healing in clinical studies. The host response towards P. aeruginosa biofilm-infection in chronic wounds and impact on wound healing is discussed and compared to our own results in a chronic murine wound model. The impact of P. aeruginosa biofilms can be described by determining alterations in the inflammatory response, growth factor profile, and count of leukocytes in blood. P. aeruginosa biofilms are capable of reducing the host response to the infection, despite a continuously sustained inflammatory reaction and resulting local tissue damage. A recent observation of in vivo synergism between immunomodulatory and antimicrobial S100A8/A9 and ciprofloxacin suggests its possible future therapeutic potential.

scholarly journals Intracellular Ca2+-Mediated AE2 Is Involved in the Vectorial Movement of HaCaT Keratinocyte

2020 ◽  
Vol 21 (22) ◽  
pp. 8429
Author(s):  
Soyoung Hwang ◽  
Dong Min Shin ◽  
Jeong Hee Hong
Keyword(s):  
Wound Healing ◽  
Anion Exchanger ◽  
Skin Barrier ◽  
Chelating Agent ◽  
Hacat Keratinocytes ◽  
Keratinocyte Migration ◽  
Enhanced Expression ◽  
Hacat Keratinocyte ◽  
Stimulation Of ◽  
Exchange Activity

Keratinocyte migration is initiated toward the wound skin barrier as a crucial process in wound healing. However, the migratory machinery used by keratinocytes is relatively unknown. Histamine signaling, including an increase in the Ca2+ signal, mediated the enhanced protein expression and chloride/bicarbonate exchange activity of anion exchanger AE2 in keratinocytes. In this study, we applied an agarose spot assay to induce a vectorial motion. The vectorial stimulation of the histamine-containing agarose spot enhanced the HaCaT keratinocyte migration, compared to non-directional stimulation. AE2 is associated with the vectorial movement of HaCaT keratinocytes. Enhanced expression of AE2 was mainly associated with an increase in Ca2+ and was abolished by the treatment with the Ca2+ chelating agent BAPTA-AM. These findings revealed that the directionality of Ca2+-exerted stimulation can play a prominent role in facilitating migration through the involvement of AE2 as a migratory machinery in HaCaT keratinocytes.

scholarly journals Mathematical Model Predicts that Acceleration of Diabetic Wound Healing is Dependent on Spatial Distribution of VEGF-A mRNA (AZD8601)

2021 ◽  
Author(s):  
S. Michaela Rikard ◽  
Paul J. Myers ◽  
Joachim Almquist ◽  
Peter Gennemark ◽  
Anthony C. Bruce ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Wound Healing ◽  
Spatial Distribution ◽  
Surrounding Tissue ◽  
Diabetic Patients ◽  
Model Parameters ◽  
Diabetic Wound ◽  
Diabetic Wound Healing ◽  
Diabetic Wounds ◽  
The Impact

Abstract Introduction Pharmacologic approaches for promoting angiogenesis have been utilized to accelerate healing of chronic wounds in diabetic patients with varying degrees of success. We hypothesize that the distribution of proangiogenic drugs in the wound area critically impacts the rate of closure of diabetic wounds. To evaluate this hypothesis, we developed a mathematical model that predicts how spatial distribution of VEGF-A produced by delivery of a modified mRNA (AZD8601) accelerates diabetic wound healing. Methods We modified a previously published model of cutaneous wound healing based on coupled partial differential equations that describe the density of sprouting capillary tips, chemoattractant concentration, and density of blood vessels in a circular wound. Key model parameters identified by a sensitivity analysis were fit to data obtained from an in vivo wound healing study performed in the dorsum of diabetic mice, and a pharmacokinetic model was used to simulate mRNA and VEGF-A distribution following injections with AZD8601. Due to the limited availability of data regarding the spatial distribution of AZD8601 in the wound bed, we performed simulations with perturbations to the location of injections and diffusion coefficient of mRNA to understand the impact of these spatial parameters on wound healing. Results When simulating injections delivered at the wound border, the model predicted that injections delivered on day 0 were more effective in accelerating wound healing than injections delivered at later time points. When the location of the injection was varied throughout the wound space, the model predicted that healing could be accelerated by delivering injections a distance of 1–2 mm inside the wound bed when compared to injections delivered on the same day at the wound border. Perturbations to the diffusivity of mRNA predicted that restricting diffusion of mRNA delayed wound healing by creating an accumulation of VEGF-A at the wound border. Alternatively, a high mRNA diffusivity had no effect on wound healing compared to a simulation with vehicle injection due to the rapid loss of mRNA at the wound border to surrounding tissue. Conclusions These findings highlight the critical need to consider the location of drug delivery and diffusivity of the drug, parameters not typically explored in pre-clinical experiments, when designing and testing drugs for treating diabetic wounds.

High glucose abolishes the antiproliferative effect of 17β-estradiol in human vascular smooth muscle cells

2002 ◽  
Vol 282 (4) ◽  
pp. E746-E751 ◽  
Author(s):  
Shanhong Ling ◽  
Peter J. Little ◽  
Maro R. I. Williams ◽  
Aozhi Dai ◽  
Kazuhiko Hashimura ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Dna Synthesis ◽  
High Glucose ◽  
Antiproliferative Effect ◽  
Dependent Manner ◽  
Vsmc Proliferation ◽  
Normal Glucose ◽  
17Β Estradiol ◽  
Pkc Β

We examined effects of 17β-estradiol (E2) on human vascular smooth muscle cell (VSMC) proliferation under normal (5 mmol/l) and high (25 mmol/l) glucose concentrations. Platelet-derived growth factor (PDGF) BB (20 ng/ml)-induced increases in DNA synthesis and proliferation were greater in high than normal glucose concentrations; the difference in DNA synthesis was abolished by a protein kinase C (PKC)-β inhibitor, LY-379196 (30 nmol/l). Western blotting showed that PKC-β1 protein increased in cells exposed to high glucose, whereas PKC-α protein and total PKC activity remained unchanged, compared with normal glucose cultures. In normal glucose, E2 (1–100 nmol/l) inhibited PDGF-induced DNA synthesis by 18–37% and cell proliferation by 16–22% in a concentration-dependent manner. The effects of E2 were blocked by the estrogen receptor (ER) antagonist ICI-182780, indicating ER dependence. In high glucose, the inhibitory effect of E2on VSMC proliferation was abolished but was restored in the presence of the PKC-β inhibitor LY-379196. Thus high glucose enhances human VSMC proliferation and attenuates the antiproliferative effect of E2 in VSMC via activation of PKC-β.

scholarly journals Diabetic Wound Care: A Concise Review of Diabetic Wound and Skincare Ingredients

2020 ◽  
Vol 8 (2) ◽  
Author(s):  
Mohammad Afsahi ◽  
Hamid Reza Ahmadi Ashtiani ◽  
Amir Hosein Askari Pour ◽  
Ebrahim Hazrati
Keyword(s):  
Wound Healing ◽  
Wound Care ◽  
Healing Process ◽  
Topical Administration ◽  
The Body ◽  
Wound Healing Process ◽  
Diabetic Wound ◽  
Normal Wound Healing ◽  
Healing Wounds ◽  
Diabetic Wounds

: Chronic wound healing remains a complicated issue in the world's scientific health society. Alterations in the human body conditions such as biochemical, immunological, and physiological states may lead to non-healing wounds, making the treatment an insurmountably long and expensive procedure. Diabetes mellitus disposes the body to many complicated conditions while preventing diabetic wounds away from the normal wound-healing process. As topical administration is a favorable route of treating wounds, here, in this article, different topical materials and their roles are briefly reviewed.

scholarly journals The Impact of Curcumin on Bone Osteogenic Promotion of MC3T3 Cells under High Glucose Conditions and Enhanced Bone Formation in Diabetic Mice

Coatings ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 258
Author(s):  
Jia He ◽  
Xiaofeng Yang ◽  
Fan Liu ◽  
Duo Li ◽  
Bowen Zheng ◽  
...  
Keyword(s):  
Bone Density ◽  
Bone Formation ◽  
High Glucose ◽  
Optimal Concentration ◽  
Dependent Manner ◽  
Diabetic Mice ◽  
Related Gene ◽  
Gene Expressions ◽  
Diabetic Osteoporosis ◽  
The Impact

Diabetic osteoporosis (DOP) is characterized by impaired bone microstructure and reduced bone density resulting from high glucose levels. Curcumin (CURC) is extensively applied in the treatment of inflammation-associated diseases. However, the effect of curcumin on bone metabolism in diabetic osteoporosis is unclear. Therefore, this study investigated the optimal concentration of curcumin on enhancing osteogenesis in diabetic osteoporosis. Osteoblasts were treated with a high or low concentration of curcumin under a series of concentrations of high-glucose conditions. Type 2 diabetic mice were intervened with curcumin. Cell proliferation, apoptosis, and osteogenesis-related gene expressions were evaluated by CCK-8, flow cytometry, and real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). Bone formation was evaluated by histological staining. The findings revealed that curcumin suppressed apoptosis and enhanced proliferation and osteogenesis-related gene expressions of osteoblasts under high glucose concentrations (p < 0.05). The histological sections displayed reduced bone destruction and increased the growth rate of trabecular bone and the bone density of diabetic mice treated with curcumin, compared to diabetic mice. These results showed that curcumin could reverse the harmful effects of diabetic osteoporosis in a dose-dependent manner, and 10 μmol/L was regarded as the optimal concentration, which supports the potential use of curcumin for bone regeneration under high glucose concentrations.

Hard-to-heal wounds, biofilm and wound healing: an intricate interrelationship

2020 ◽  
Vol 29 (5) ◽  
pp. S6-S13 ◽  
Author(s):  
Maria-Manuel Azevedo ◽  
Carmen Lisboa ◽  
Luís Cobrado ◽  
Cidália Pina-Vaz ◽  
Acácio Rodrigues
Keyword(s):  
Wound Healing ◽  
Healing Process ◽  
Public Health Problem ◽  
Wound Healing Process ◽  
Major Public Health Problem ◽  
Normal Wound Healing ◽  
Efficient Management ◽  
Acute Wound ◽  
Reparative Process ◽  
The Impact

Hard-to-heal wounds are a major public health problem that incur high economic costs. A major source of morbidity, they can have an overwhelming impact on patients, caregivers and society. In contrast to acute wound healing, which follows an ‘orderly and timely reparative process', the healing of hard-to-heal wounds is delayed because the usual biological progression is interrupted. This article discusses hard-to-heal wounds, the impact they have on patients and healthcare systems, and how biofilms and other factors affect the wound-healing process. Controlling and preventing infection is of utmost importance for normal wound healing. Rational use of anti-infectious agents is crucial and is particularly relevant in the context of rising healthcare costs. Knowledge of the complex relationship between hard-to-heal wounds, biofilm formation and wound healing is vital for efficient management of hard-to-heal wounds.

scholarly journals Rosiglitazone enhances the apoptotic effect of 5-fluorouracil in colorectal cancer cells with high-glucose-induced glutathione

2019 ◽  
Vol 103 (1) ◽  
pp. 003685041988644
Author(s):  
Meng-Fei Lau ◽  
Kek-Heng Chua ◽  
Vikineswary Sabaratnam ◽  
Umah Rani Kuppusamy
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
High Glucose ◽  
Reduced Glutathione ◽  
Control Cell ◽  
Dependent Manner ◽  
Normal Glucose ◽  
Apoptotic Effect ◽  
Hct 116 ◽  
Ht 29

Colorectal cancer is one of the most prevalent noncommunicable diseases worldwide. 5-Fluorouracil is the mainstay of chemotherapy for colorectal cancer. Previously, we have demonstrated that high glucose diminishes the cytotoxicity of 5-fluorouracil by promoting cell cycle progression. The synergistic impact of rosiglitazone on 5-fluorouracil-induced apoptosis was further investigated in this study. Besides control cell lines (CCD-18Co), two human colonic carcinoma cell lines (HCT 116 and HT 29) were exposed to different treatments containing 5-fluorouracil, rosiglitazone or 5-fluorouracil/rosiglitazone combination under normal glucose (5.5 mM) and high-glucose (25 mM) conditions. The cellular oxidative stress level was evaluated with biomarkers of nitric oxide, advanced oxidation protein products, and reduced glutathione. The cell apoptosis was assessed using flow cytometry technique. High glucose caused the production of reduced glutathione in HCT 116 and HT 29 cells. Correspondingly, high glucose suppressed the apoptotic effect of 5-fluorouracil and rosiglitazone. As compared to 5-fluorouracil alone (2 µg/mL), addition of rosiglitazone significantly enhanced the apoptosis (increment rate of 5–20%) in a dose-dependent manner at normal glucose and high glucose levels. This study indicates that high-glucose-induced reduced glutathione confers resistance to apoptosis, but it can be overcome upon treatment of 5-fluorouracil and 5-fluorouracil/rosiglitazone combination. Rosiglitazone may be a promising antidiabetic drug to reduce the chemotherapeutic dose of 5-fluorouracil for colorectal cancer complicated with hyperglycemia.

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