High Glucose-Mediated Oxidative Stress Impairs Cell Migration

Lamers, Marcelo Lazzaron; Almeida, Maíra Estanislau Soares de; Vicente‐Manzanares, Miguel; Horwitz, Alan F.; Santos, Marinilce Fagundes dos

doi:10.1371/journal.pone.0022865

Cited by 138 publications

(126 citation statements)

References 45 publications

(54 reference statements)

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“…To simulate diabetes, HG was utilized to study its effects on the fibroblasts (22). To analyze the effects of different concentrations of HG on fibroblasts, cell proliferation was monitored in different concentrations of glucose-containing media with 10% fetal bovine serum.…”

Section: Hg Induces Apoptosis and Inflammatory Responses In Fibro-mentioning

confidence: 99%

Transcriptomic study of high-glucose effects on human skin fibroblast cells

Pang

Wang

Zheng

et al. 2016

Molecular Medicine Reports

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Abstract. Skin ulcers are a common complication of diabetes mellitus (DM). Fibroblasts are located within the dermis of skin tissue and can be damaged by diabetes. However, the underlying mechanism of how DM affects fibroblasts remains elusive. To understand the effects of DM on fibroblasts, the current study mimicked DM by high-glucose (HG) supplementation in the culture medium of human foreskin primary fibroblast cells, and the analysis of transcriptomic changes was conducted. RNA sequencing-based transcriptome analysis identified that, upon HG stress, 463 genes were upregulated and 351 genes downregulated (>1.5-fold changes; P<0.05). These altered genes were distributed into 20 different pathways. In addition, gene ontology (GO) analysis indicated that 31 GO terms were enriched. Among the pathways identified, nuclear factor κB (NF-κB) pathway genes were highly expressed, and the addition of Bay11-7082, a typical NF-κB signaling inhibitor, blocked the previously observed alterations in plasminogen activator inhibitor 1 (PAI1), an inflammation marker and frizzled class receptor 8 (FZD8), a Wnt signaling gene, expression that resulted from HG stress. Furthermore, an inhibitor of Wnt signaling diminished the role of Bay11-7082 in the regulation of PAI1 expression under HG conditions, suggesting that Wnt signaling may function downstream of the NF-κB pathway to protect fibroblast cells from HG stress. To the best of our knowledge, the current study is the first analysis of transcriptomic responses under HG stress in human fibroblasts. The data provided here may aid the understanding of the molecular mechanisms by which fibroblast cells are damaged in the skin of patients with DM.

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Section: Hg Induces Apoptosis and Inflammatory Responses In Fibro-mentioning

confidence: 99%

Transcriptomic study of high-glucose effects on human skin fibroblast cells

Pang

Wang

Zheng

et al. 2016

Molecular Medicine Reports

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“…34 The high glucose level was greatly associated with decreased migration, proliferation, and increased apoptosis of fibroblasts. 13,16,35,36 The blood vessels of the diabetic group had been changed in their histological appearances and expressed with thickening in their wall, constriction of the lumen, and infiltration of the wall with chronic inflammatory cells. These changes may be due to many factors, one of these factors is the action of excessive TNF alpha production, which causes clotting of the blood over the internal wall of the vessel through inactivation of the heparin like material presented in the endothelial cells that enclose the wall of the vessel, atheroma like structure laying down, and destruction of the smooth muscle fibers of the vessel.…”

Section: Discussionmentioning

confidence: 99%

The effect of Tumor Necrosis Factor alpha inhibitor on wound healing of oral mucosa in induced diabetic rats

Maroof

Fareed

2016

ZJMS

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A large number of growth factors are important in stimulating and orginizing cellular events that occur during normal wound healing. 6 Among them, cytokines and chemokines are especially noted because of their roles in promoting inflammation, budding new blood vessels, leukocyte migration, and reepithelialization. Proinflammatory cytokines that are Background and objective: Impaired wound healing is a major complication of diabetes mellitus. This study was carried out to determine the healing process of oral mucosa in diabetic rats and the role of systemic tumor necrosis factor alpha inhibitor (infliximab). Methods: Thirty eight male rats were divided into two groups, the normoglycemic group (11 rats), and diabetic group (27 rats) that were rendered diabetic by alloxan injection. Two months later, wound was created in the lateral side of the tongue for both groups. The diabetic group was then subdivided into two subgroups, 14 rats received 5mg/kg infliximab subcutaneous injection at the day of wound creation while the other 13 rats received saline injection. After 7 days, biopsies of the tongue were collected and subjected to histological and histochemical procedure. Results: Histological examinations showed delayed healing in the diabetic group with persistence of epithelial discontinuity, large amount of granulation tissue and destruction of the underlying muscle fibers. In the subgroup injected with infliximab, reepitheliazation of the wound was demonstrated with well arranged underlying collagen fibers. Using PAS stain, diabetic group revealed a dramatically high amount of PAS positive precipitants in the lamina properia, especially in the wall of the blood vessels, while with infliximab injection, the PAS+ve precipitants were more prominent than normoglycemic group but less than diabetic group without infliximab. Conclusion: These findings suggest that infliximab accelerated mucosal wound healing in the diabetic rats with the formation of well organized connective tissue.

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“…Most of these attributes are reproduced under acute exposures to high glucose concentrations so that migration speed is reduced by ~40 % associated to a decrease in cell directionality and to non-productive protrusive events, such as loss of cell polarization, consistent with the increased activity of Rac1 and the projection of multiple lamellipodia. This experiment concluded that the generation of reactive oxygen species (ROS) may lie behind these abnormalities as they were partially or completely rescued by treatment with N-Acetyl-Cysteine (NAC) [86].…”

Section: The Diabetic Wound Fibroblastmentioning

confidence: 99%

Type 2 Diabetes Mellitus (T2DM): Biological Overview from Pathways to Organelles and its Translation toward a Torpid Wound Healing Process

Guillen-Nieto¹,

Herrera-Martínez²

2013

J Diabetes Metab

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T2DM is a heterogeneous group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Hyperglycemia may simply represent the tip of a broad series of molecular events from mitochondrial damages, to epigenetic and metabolic pathways deregulations. At the same time, hyperglycemia appears as the most proximal trigger for the onset and perpetual progression of multi-organ complications even under normoglycemic conditions. Thus, the initial hyperglycemic hit translates into a permanently harmful cellular imprinting as has been demonstrated in diabetic donors' cells after several passages and cultured in ideal conditions. The wound healing failure along with the inability of the innate immunity to control peripheral infections is the hybrid that determines that 85% of all non-traumatic lower extremity amputations are practiced in diabetic subjects. Diabetic wounds exhibit a complex networking of inflammatory cytokines, local proteases, cytotoxic reactive oxygen and nitrogen species and a polymicrobial biofilm that impose a stagnant phenotype. All these ingredients negatively impact on fibroblasts, endothelial cells and keratinocytes while paradoxically perpetuate the immuno-inflammatory infiltrate. Although the molecular fundamentals toward chronification have not been elucidated, it seems that different gene simultaneously converge to impose the wound cells a pro-senescent, pro-catabolic and pro-apoptotic phenotype given the lack of a "physiological tuning" of tyrosine kinase-dependent receptors due to their limited activation by insulin and local growth factors. Although recombinant growth factors and smart devices have been introduced during the last years the figures of amputations are still discouraging. Faults have been committed while selecting the appropriate growth factor and because of the "chronic" instinct to treat the chronic wounds topically, where bioavailability of the active principle is compromised by wound and bacterial biofilm proteases. The periodic intralesional infiltration of epidermal growth factor has proved to overcome this hurdle. Granulation tissue growth stimulation and wound healing capacity has been restored in diabetic patients by this procedure in several clinical trials and common clinical practice studies.

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High Glucose-Mediated Oxidative Stress Impairs Cell Migration

Cited by 138 publications

References 45 publications

Transcriptomic study of high-glucose effects on human skin fibroblast cells

Transcriptomic study of high-glucose effects on human skin fibroblast cells

The effect of Tumor Necrosis Factor alpha inhibitor on wound healing of oral mucosa in induced diabetic rats

Type 2 Diabetes Mellitus (T2DM): Biological Overview from Pathways to Organelles and its Translation toward a Torpid Wound Healing Process

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