Methylglyoxal administration induces diabetes-like microvascular changes and perturbs the healing process of cutaneous wounds

2005 ◽  
Vol 109 (1) ◽  
pp. 83-95 ◽  
Author(s):  
Jorge BERLANGA ◽  
Danay CIBRIAN ◽  
Isabel GUILLÉN ◽  
Freya FREYRE ◽  
José S. ALBA ◽  
...  
Keyword(s):  
Wound Healing ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Prolonged Exposure ◽  
Healing Process ◽  
Vascular Complications ◽  
Tissue Growth ◽  
Protein Glycation ◽  
Impaired Wound Healing

Increased formation of MG (methylglyoxal) and related protein glycation in diabetes has been linked to the development of diabetic vascular complications. Diabetes is also associated with impaired wound healing. In the present study, we investigated if prolonged exposure of rats to MG (50–75 mg/kg of body weight) induced impairment of wound healing and diabetes-like vascular damage. MG treatment arrested growth, increased serum creatinine, induced hypercholesterolaemia (all P<0.05) and impaired vasodilation (P<0.01) compared with saline controls. Degenerative changes in cutaneous microvessels with loss of endothelial cells, basement membrane thickening and luminal occlusion were also detected. Acute granulation appeared immature (P<0.01) and was associated with an impaired infiltration of regenerative cells with reduced proliferative rates (P<0.01). Immunohistochemical staining indicated the presence of AGEs (advanced glycation end-products) in vascular structures, cutaneous tissue and peripheral nerve fibres. Expression of RAGE (receptor for AGEs) appeared to be increased in the cutaneous vasculature. There were also pro-inflammatory and profibrotic responses, including increased IL-1β (interleukin-1β) expression in intact epidermis, TNF-α (tumour necrosis factor-α) in regions of angiogenesis, CTGF (connective tissue growth factor) in medial layers of arteries, and TGF-β (transforming growth factor-β) in glomerular tufts, tubular epithelial cells and interstitial endothelial cells. We conclude that exposure to increased MG in vivo is associated with the onset of microvascular damage and other diabetes-like complications within a normoglycaemic context.

scholarly journals Regulation of the expression of stromelysin-2 by growth factors in keratinocytes: implications for normal and impaired wound healing

1996 ◽  
Vol 320 (2) ◽  
pp. 659-664 ◽  
Author(s):  
Marianne MADLENER ◽  
Cornelia MAUCH ◽  
Walter CONCA ◽  
Maria BRAUCHLE ◽  
William C. PARKS ◽  
...  
Keyword(s):  
Wound Healing ◽  
Growth Factors ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Keratinocyte Growth Factor ◽  
Healing Process ◽  
Branching Morphogenesis ◽  
Transforming Growth Factor Β1 ◽  
Impaired Wound Healing ◽  
Factor Α

Keratinocyte growth factor (KGF) has been implicated in wound re-epithelialization and branching morphogenesis of several organs. To determine whether KGF induces these effects via induction of matrix metalloproteinase expression we have analysed the effect of KGF on the expression of stromelysin-2 in cultured HaCaT keratinocytes. Here we show a strong induction of stromelysin-2 mRNA within 5–8 h of stimulation of these cells with KGF. The degree of induction was similar to that achieved by treatment with epidermal growth factor or tumour necrosis factor α, whereas the stimulatory effect of transforming growth factor β1 was even stronger. To determine whether the induction of stromelysin-2 expression by growth factors and cytokines might be important for wound healing, we analysed the expression of this gene during the healing process of full-thickness excisional wounds in mice. Whereas stromelysin-2 mRNA could hardly be detected in unwounded skin, a biphasic induction was seen after injury and highest levels were found at days 1 and 5 after wounding. Hybridization in situ revealed the presence of stromelysin-2 mRNA in basal keratinocytes at the wound edge but not in the underlying mesenchymal tissue. During impaired wound healing as seen in glucocorticoid-treated mice, stromelysin-2 expression was significantly increased compared with untreated control mice. Taken together, these results suggest that correct regulation of this broad-spectrum metalloproteinase might be important for normal repair.

Transforming growth factor beta 1 dependent regulation of Tenascin-C in radiation impaired wound healing

2004 ◽  
Vol 72 (3) ◽  
pp. 297-303 ◽  
Author(s):  
Falk Wehrhan ◽  
Franz Rödel ◽  
Gerhard G. Grabenbauer ◽  
Kerstin Amann ◽  
Wolfgang Brückl ◽  
...  
Keyword(s):  
Wound Healing ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Impaired Wound Healing ◽  
Tenascin C ◽  
Growth Factor Beta

Transforming growth factor-? isoforms differently stimulate pro?2 (I) collagen gene expression during wound healing process in transgenic mice

2002 ◽  
Vol 190 (3) ◽  
pp. 375-381 ◽  
Author(s):  
Takuro Kinbara ◽  
Fumiaki Shirasaki ◽  
Shigeru Kawara ◽  
Yutaka Inagaki ◽  
Benoit de Crombrugghe ◽  
...  
Keyword(s):  
Gene Expression ◽  
Wound Healing ◽  
Growth Factor ◽  
Transgenic Mice ◽  
Transforming Growth Factor ◽  
Healing Process ◽  
Wound Healing Process ◽  
Collagen Gene ◽  
Collagen Gene Expression

scholarly journals Adipose Stem Cells from Type 2 Diabetic Mice Exhibit Therapeutic Potential in Wound Healing

2020 ◽  
Author(s):  
Yongfa Sun ◽  
Lili Song ◽  
Yong Zhang ◽  
Hongjun Wang ◽  
Xiao Dong
Keyword(s):  
Wound Healing ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Diabetic Patients ◽  
Therapeutic Effects ◽  
Skin Damage ◽  
Impaired Wound Healing ◽  
Collagen Iii

Abstract BACKGROUND: Diabetic patients suffer from impaired wound healing. Mesenchymal stem cell (MSC) therapy represents a promising approach toward improving skin wound healing through release of soluble growth factors and cytokines that stimulate new vessel formation and modulate inflammation. Whether adipose-derived MSCs (ASCs) from type 2 diabetes donors are suitable for skin damage repair remains largely unknown. METHODS: In this study, we compared the phenotype and functionality of ASCs harvested from high fat diet (HFD) and streptozotocin (STZ)-induced T2D or control mice, and assessed their abilities to promote wound healing in an excisional wound splinting mouse model with T2D. RESULTS: T2D ASCs expressed similar cellular markers as control ASCs, but secreted less hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and transforming growth factor β (TGF-β). T2D ASCs were somewhat less effective in promoting healing of the wound, as manifested by slightly reduced re-epithelialization, cutaneous appendage regeneration, and collagen III deposition in wound tissues. In vitro, T2D ASCs promoted proliferation and migration of skin fibroblasts to a comparable extent as control ASCs via suppression of inflammation and macrophage infiltration. CONCLUSIONS: From these findings, we conclude that, although ASCs from T2D mice are marginally inferior to control ASCs, they possess comparable therapeutic effects in wound healing.

scholarly journals Collagen extract obtained from Nile tilapia (Oreochromis niloticus L.) skin accelerates wound healing in rat model via up regulating VEGF, bFGF, and α-SMA genes expression

2020 ◽  
Vol 16 (1) ◽  
Author(s):  
Zizy I. Elbialy ◽  
Ayman Atiba ◽  
Aml Abdelnaby ◽  
Ibrahim I. Al-Hawary ◽  
Ahmed Elsheshtawy ◽  
...  
Keyword(s):  
Wound Healing ◽  
Growth Factor ◽  
Rat Model ◽  
Nile Tilapia ◽  
Transforming Growth Factor ◽  
Healing Process ◽  
Control Group ◽  
Cutaneous Wound Healing ◽  
Cutaneous Wound ◽  
Genes Expression

Abstract Background Collagen is the most abundant structural protein in the mammalian connective tissue and represents approximately 30% of animal protein. The current study evaluated the potential capacity of collagen extract derived from Nile tilapia skin in improving the cutaneous wound healing in rats and investigated the underlying possible mechanisms. A rat model was used, and the experimental design included a control group (CG) and the tilapia collagen treated group (TCG). Full-thickness wounds were conducted on the back of all the rats under general anesthesia, then the tilapia collagen extract was applied topically on the wound area of TCG. Wound areas of the two experimental groups were measured on days 0, 3, 6, 9, 12, and 15 post-wounding. The stages of the wound granulation tissues were detected by histopathologic examination and the expression of vascular endothelial growth factor (VEGF), and transforming growth factor (TGF-ß1) were investigated using immunohistochemistry. Moreover, relative gene expression analysis of transforming growth factor-beta (TGF-ß1), basic fibroblast growth factor (bFGF), and alpha-smooth muscle actin (α-SMA) were quantified by real-time qPCR. Results The histopathological assessment showed noticeable signs of skin healing in TCG compared to CG. Immunohistochemistry results revealed remarkable enhancement in the expression levels of VEGF and TGF-β1 in TCG. Furthermore, TCG exhibited marked upregulation in the VEGF, bFGF, and α-SMA genes expression. These findings suggested that the topical application of Nile tilapia collagen extract can promote the cutaneous wound healing process in rats, which could be attributed to its stimulating effect on recruiting and activating macrophages to produce chemotactic growth factors, fibroblast proliferation, and angiogenesis. Conclusions The collagen extract could, therefore, be a potential biomaterial for cutaneous wound healing therapeutics.

scholarly journals Chronic NOS inhibition actuates endothelial-mesenchymal transformation

2007 ◽  
Vol 292 (1) ◽  
pp. H285-H294 ◽  
Author(s):  
Edmond O’Riordan ◽  
Natalia Mendelev ◽  
Susann Patschan ◽  
Daniel Patschan ◽  
Jonathan Eskander ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Asymmetric Dimethylarginine ◽  
Transforming Growth Factor ◽  
Fluorescent Protein ◽  
Transforming Growth Factor Β ◽  
Tissue Growth ◽  
Collagen Xviii ◽  
Green Fluorescent

Chronic kidney diseases are accompanied by the accumulation of substances like asymmetric dimethylarginine, phenylacetic acid, homocysteine, and advanced glycation end products, known to either inhibit endothelial nitric oxide synthase (eNOS) or uncouple it, consequently limiting the amount of available nitric oxide (NO). Reduced bioavailability of NO induces endothelial dysfunction. An early loss of peritubular capillaries in tubulointerstitial fibrotic areas and injury to endothelial cells have been linked to progressive renal disease. Screening endothelial genes in cells treated with NOS inhibitors showed upregulation of collagen XVIII, a precursor of a potent antiangiogenic substance, endostatin. This finding was confirmed at the level of mRNA and protein expression. Tie-2 promoter-driven green fluorescent protein mice treated with nonhypertensinogenic doses of a NOS inhibitor exhibited upregulation of collagen XVIII/endostatin and rarefaction of capillary profiles. This was accompanied by the increased expression of transforming growth factor-β and connective tissue growth factor in the kidney. Occasional endothelial cells expressed both the marker of endothelial lineage (green fluorescent protein) and mesenchymal marker (α-smooth muscle actin or calponin). In vitro studies of endothelial cells treated with asymmetric dimethylarginine showed decreased expression of eNOS and Flk-1 and enhanced expression of calponin and fibronectin, additional markers of smooth muscle and mesenchymal cells. These cells overexpressed transforming growth factor-β and connective tissue growth factor, as well as endostatin. In conclusion, data presented here 1) ascribe to NO deficiency in endothelial cells the function of a profibrotic stimulus associated with the expression of an antiangiogenic fragment of collagen XVIII (endostatin) and 2) provide evidence of endothelial-mesenchymal transdifferentiation in the course of inhibition of NOS by a pathophysiologically important antagonist, asymmetric dimethylarginine. Both mechanisms may account for microvascular rarefaction.

scholarly journals WOUND-HEALING PROPERTIES OF TRANSFORMING GROWTH FACTOR β (TGF-β) INDUCIBLE EARLY GENE 1 (TIEG1) KNOCKOUT MICE

2008 ◽  
Vol 11 (02) ◽  
pp. 63-69 ◽  
Author(s):  
Manabu Taguchi ◽  
Steven L. Moran ◽  
Mark E. Zobitz ◽  
Chunfeng Zhao ◽  
Malayannan Subramaniam ◽  
...  
Keyword(s):  
Wound Healing ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Knockout Mice ◽  
Transforming Growth Factor ◽  
Breaking Strength ◽  
Healing Process ◽  
Early Gene ◽  
Cutaneous Wound Healing ◽  
Cutaneous Wound

Transforming growth factor beta (TGF-β) has a broad effect on wound healing, but many questions remain about the regulation of TGF-β during the healing process. TGF-β inducible early gene 1 (TIEG1) is a primary response gene for TGF-β that controls the activities of the TGF-β/Smad pathway, the primary TGF-β signaling pathway. The purpose of this study was to investigate the role of TIEG1 in cutaneous wound healing using TIEG1 knockout mice. The wound healing in TIEG1 knockout mice and wild-type controls was evaluated by wound breaking strength, Western blot, and histology at postoperative days 3, 7, and 14. Although re-epithelialization of both groups was similarly complete at day 7, the TIEG1 knockout mice had a significantly lower wound breaking strength than the controls at postoperative day 14. These results suggest that TIEG1 expression may be an important factor involved in the initiation and support of normal cutaneous wound healing.

scholarly journals Keratinocyte Function in Normal and Diabetic Wounds and Modulation by FOXO1

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Yulan Wang ◽  
Dana T. Graves
Keyword(s):  
Growth Factor ◽  
Connective Tissue ◽  
Transforming Growth Factor ◽  
Negative Impact ◽  
Healing Process ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Tissue Growth ◽  
Complex Interactions ◽  
Multiple Cell

Diabetes has a significant and negative impact on wound healing, which involves complex interactions between multiple cell types. Keratinocytes play a crucial role in the healing process by rapidly covering dermal and mucosal wound surfaces to reestablish an epithelial barrier with the outside environment. Keratinocytes produce multiple factors to promote reepithelialization and produce factors that enhance connective tissue repair through the elaboration of mediators that stimulate angiogenesis and production of connective tissue matrix. Among the factors that keratinocytes produce to aid healing are transforming growth factor-β (TGF-β), vascular endothelial growth factor-A (VEGF-A), connective tissue growth factor (CTGF), and antioxidants. In a diabetic environment, this program is disrupted, and keratinocytes fail to produce growth factors and instead switch to a program that is detrimental to healing. Changes in keratinocyte behavior have been linked to high glucose and advanced glycation end products that alter the activities of the transcription factor, FOXO1. This review examines reepithelialization and factors produced by keratinocytes that upregulate connective tissue healing and angiogenesis and how they are altered by diabetes.

Myostatin-null mice exhibit delayed skin wound healing through the blockade of transforming growth factor-β signaling by decorin

2012 ◽  
Vol 302 (8) ◽  
pp. C1213-C1225 ◽  
Author(s):  
Chen Zhang ◽  
Chek Kun Tan ◽  
Craig McFarlane ◽  
Mridula Sharma ◽  
Nguan Soon Tan ◽  
...  
Keyword(s):  
Wound Healing ◽  
Growth Factor ◽  
Wound Repair ◽  
Transforming Growth Factor ◽  
Healing Process ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Skin Wound ◽  
Wound Healing Process ◽  
Skin Wound Healing

Myostatin (Mstn) is a secreted growth and differentiation factor that belongs to the transforming growth factor-β (TGF-β) superfamily. Mstn has been well characterized as a regulator of myogenesis and has been shown to play a critical role in postnatal muscle regeneration. Herein, we report for the first time that Mstn is expressed in both epidermis and dermis of murine and human skin and that Mstn-null mice exhibited delayed skin wound healing attributable to a combination of effects resulting from delayed epidermal reepithelialization and dermal contraction. In epidermis, reduced keratinocyte migration and protracted keratinocyte proliferation were observed, which subsequently led to delayed recovery of epidermal thickness and slower reepithelialization. Furthermore, primary keratinocytes derived from Mstn-null mice displayed reduced migration capacity and increased proliferation rate as assessed through in vitro migration and adhesion assays, as well as bromodeoxyuridine incorporation and Western blot analysis. Moreover, in dermis, both fibroblast-to-myofibroblast transformation and collagen deposition were concomitantly reduced, resulting in a delayed dermal wound contraction. These decreases are due to the inhibition of TGF-β signaling. In agreement, the expression of decorin, a naturally occurring TGF-β suppressor, was elevated in Mstn-null mice; moreover, topical treatment with TGF-β1 protein rescued the impaired skin wound healing observed in Mstn-null mice. These observations highlight the interplay between TGF-β and Mstn signaling pathways, specifically through Mstn regulation of decorin levels during the skin wound healing process. Thus we propose that Mstn agonists might be beneficial for skin wound repair.

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