Peroxiredoxin 6 is required for blood vessel integrity in wounded skin

Peroxiredoxin 6 (Prdx6) is a cytoprotective enzyme with largely unknown in vivo functions. Here, we use Prdx6 knockout mice to determine its role in UV protection and wound healing. UV-mediated keratinocyte apoptosis is enhanced in Prdx6-deficient mice. Upon skin injury, we observe a severe hemorrhage in the granulation tissue of knockout animals, which correlates with the extent of oxidative stress. At the ultrastructural level endothelial cells appear highly damaged, and their rate of apoptosis is enhanced. Knock-down of Prdx6 in cultured endothelial cells also increases their susceptibility to oxidative stress, thus confirming the sensitivity of this cell type to loss of Prdx6. Wound healing studies in bone marrow chimeric mice demonstrate that Prdx6-deficient inflammatory and endothelial cells contribute to the hemorrhage phenotype. These results provide insight into the cross-talk between hematopoietic and resident cells at the wound site and the role of reactive oxygen species in this interplay.

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Arginase Activity in Eisenia andrei Coelomocytes: Function in the Earthworm Innate Response

International Journal of Molecular Sciences ◽

10.3390/ijms22073687 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3687

Author(s):

Joanna Homa ◽

Alina Klosowska ◽

Magdalena Chadzinska

Keyword(s):

Immune Response ◽

Wound Healing ◽

Arginase Activity ◽

Eisenia Andrei ◽

Heavy Metals Ions ◽

First Time ◽

Important Marker

Arginase is the manganese metalloenzyme catalyzing the conversion of l-arginine to l-ornithine and urea. In vertebrates, arginase is involved in the immune response, tissue regeneration, and wound healing and is an important marker of alternative anti-inflammatory polarization of macrophages. In invertebrates, data concerning the role of arginase in these processes are very limited. Therefore, in the present study, we focused on the changes in arginase activity in the coelomocytes of Eisenia andrei. We studied the effects of lipopolysaccharide (LPS), hydrogen peroxide (H2O2), heavy metals ions (e.g., Mn2+), parasite infection, wound healing, and short-term fasting (5 days) on arginase activity. For the first time in earthworms, we described arginase activity in the coelomocytes and found that it can be up-regulated upon in vitro stimulation with LPS and H2O2 and in the presence of Mn2+ ions. Moreover, arginase activity was also up-regulated in animals in vivo infected with nematodes or experiencing segment amputation, but not in fasting earthworms. Furthermore, we confirmed that the activity of coelomocyte arginase can be suppressed by l-norvaline. Our studies strongly suggest that similarly to the vertebrates, also in the earthworms, coelomocyte arginase is an important element of the immune response and wound healing processes.

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Hyperglycaemia up-regulates placental growth factor (PlGF) expression and secretion in endothelial cells via suppression of PI3 kinase-Akt signalling and activation of FOXO1

Scientific Reports ◽

10.1038/s41598-021-95511-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Samir Sissaoui ◽

Stuart Egginton ◽

Ling Ting ◽

Asif Ahmed ◽

Peter W. Hewett

Keyword(s):

Endothelial Cells ◽

Growth Factor ◽

Endothelial Dysfunction ◽

Akt Activation ◽

Forkhead Box ◽

Pi3k Activity ◽

Binding Sequence

AbstractPlacenta growth factor (PlGF) is a pro-inflammatory angiogenic mediator that promotes many pathologies including diabetic complications and atherosclerosis. Widespread endothelial dysfunction precedes the onset of these conditions. As very little is known of the mechanism(s) controlling PlGF expression in pathology we investigated the role of hyperglycaemia in the regulation of PlGF production in endothelial cells. Hyperglycaemia stimulated PlGF secretion in cultured primary endothelial cells, which was suppressed by IGF-1-mediated PI3K/Akt activation. Inhibition of PI3K activity resulted in significant PlGF mRNA up-regulation and protein secretion. Similarly, loss or inhibition of Akt activity significantly increased basal PlGF expression and prevented any further PlGF secretion in hyperglycaemia. Conversely, constitutive Akt activation blocked PlGF secretion irrespective of upstream PI3K activity demonstrating that Akt is a central regulator of PlGF expression. Knock-down of the Forkhead box O-1 (FOXO1) transcription factor, which is negatively regulated by Akt, suppressed both basal and hyperglycaemia-induced PlGF secretion, whilst FOXO1 gain-of-function up-regulated PlGF in vitro and in vivo. FOXO1 association to a FOXO binding sequence identified in the PlGF promoter also increased in hyperglycaemia. This study identifies the PI3K/Akt/FOXO1 signalling axis as a key regulator of PlGF expression and unifying pathway by which PlGF may contribute to common disorders characterised by endothelial dysfunction, providing a target for therapy.

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MiR-22-3p Suppresses Vascular Remodeling and Oxidative Stress by Targeting CHD9 during the Development of Hypertension

Journal of Vascular Research ◽

10.1159/000514311 ◽

2021 ◽

pp. 1-11

Author(s):

Hanqing Chen ◽

Xiru Xu ◽

Zhengqing Liu ◽

Yong Wu

Keyword(s):

Oxidative Stress ◽

Vascular Remodeling ◽

Underlying Mechanism ◽

Inhibitory Effect ◽

Spontaneously Hypertensive ◽

Aortic Smooth Muscle ◽

Phenotype Switch ◽

And Oxidative Stress

Hypertension is considered a risk factor for a series of systematic diseases. Known factors including genetic predisposition, age, and diet habits are strongly associated with the initiation of hypertension. The current study aimed to investigate the role of miR-22-3p in hypertension. In this study, we discovered that the miR-22-3p level was significantly decreased in the thoracic aortic vascular tissues and aortic smooth muscle cells (ASMCs) of spontaneously hypertensive rats. Functionally, the overexpression of miR-22-3p facilitated the switch of ASMCs from the synthetic to contractile phenotype. To investigate the underlying mechanism, we predicted 11 potential target mRNAs for miR-22-3p. After screening, chromodomain helicase DNA-binding 9 (CHD9) was validated to bind with miR-22-3p. Rescue assays showed that the co-overexpression of miR-22-3p and CHD9 reversed the inhibitory effect of miR-22-3p mimics on cell proliferation, migration, and oxidative stress in ASMCs. Finally, miR-22-3p suppressed vascular remodeling and oxidative stress in vivo. Overall, miR-22-3p regulated ASMC phenotype switch by targeting CHD9. This new discovery provides a potential insight into hypertension treatment.

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Role of Leukocytes and Endothelial Cells in the Development of Angiogenesis in Inflammation and Wound Healing

Archives of Pathology & Laboratory Medicine ◽

10.5858/2001-125-0067-rolaec ◽

2001 ◽

Vol 125 (1) ◽

pp. 67-71 ◽

Cited By ~ 2

Author(s):

Mark W. Lingen

Keyword(s):

Wound Healing ◽

Endothelial Cells ◽

Blood Vessels ◽

Peripheral Blood ◽

Inflammatory Process ◽

Signs And Symptoms ◽

Critical Component ◽

Complex Environment ◽

Seminal Article

Abstract The basic signs and symptoms of inflammation and wound healing have been appreciated for thousands of years. However, the specific cells involved and their roles in this complex environment are still being elucidated today. In 1926, the origin of the phagocytic mononuclear ameboid wandering cell (macrophage) had not been determined. One popular theory was that the cells were differentiated from the endothelial cells of the nearby blood vessels, whereas others believed that the cells came from the peripheral blood or resting wandering cells. The purpose of this article is to review the seminal article published by Lang regarding this topic nearly 75 years ago. In addition, this article will review what is now known with regard to the role of the macrophage and endothelial cells in the development of angiogenesis, which is arguably the most critical component of successful inflammatory process or wound healing.

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Effects of Nrf2 Deficiency on Bone Microarchitecture in an Experimental Model of Osteoporosis

Oxidative Medicine and Cellular Longevity ◽

10.1155/2014/726590 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 36

Author(s):

Lidia Ibáñez ◽

María Luisa Ferrándiz ◽

Rita Brines ◽

David Guede ◽

Antonio Cuadrado ◽

...

Keyword(s):

Oxidative Stress ◽

Bone Marrow ◽

Bone Metabolism ◽

Bone Microarchitecture ◽

Related Factor ◽

Mineral Density ◽

Trabecular Bone Mineral Density ◽

Bone Marrow Derived Cells

Objective. Redox imbalance contributes to bone fragility. We have evaluated the in vivo role of nuclear factor erythroid derived 2-related factor-2 (Nrf2), an important regulator of cellular responses to oxidative stress, in bone metabolism using a model of postmenopausal osteoporosis.Methods. Ovariectomy was performed in both wild-type and mice deficient in Nrf2 (Nrf2−/−). Bone microarchitecture was analyzed byμCT. Serum markers of bone metabolism were also measured. Reactive oxygen species production was determined using dihydrorhodamine 123.Results. Sham-operated or ovariectomized Nrf2−/−mice exhibit a loss in trabecular bone mineral density in femur, accompanied by a reduction in cortical area in vertebrae. Nrf2 deficiency tended to increase osteoblastic markers and significantly enhanced osteoclastic markers in sham-operated animals indicating an increased bone turnover with a main effect on bone resorption. We have also shown an increased production of oxidative stress in bone marrow-derived cells from sham-operated or ovariectomized Nrf2−/−mice and a higher responsiveness of bone marrow-derived cells to osteoclastogenic stimuli in vitro.Conclusion. We have demonstrated in vivo a key role of Nrf2 in the maintenance of bone microarchitecture.

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

Swedish Journal of BioScience Research ◽

10.51136/sjbsr.2020.1.15 ◽

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.

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Oxidative stress promotes liver cancer metastasis via a PKA-activated RNF25/ECAD/YAP circuit

10.21203/rs.3.rs-1197819/v1 ◽

2022 ◽

Author(s):

Zhao Huang ◽

Li Zhou ◽

Jiufei Duan ◽

Siyuan Qin ◽

Yu Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Cancer Metastasis ◽

Anoikis Resistance ◽

Antioxidant Genes ◽

Redox Sensor ◽

Stress Signals ◽

Hcc Cells

Abstract Loss of E-cadherin (ECAD), often caused by epigenetic inactivation, is closely associated with tumor metastasis. However, how ECAD is regulated in response to oxidative stress during tumorigenesis is largely unknown. Here we identify RNF25 as a new E3 ligase of ECAD, whose activation by oxidative stress leads to ECAD protein degradation in hepatocellular carcinoma (HCC). Loss of ECAD activates YAP, which in turn promotes the transcription of RNF25, thus forming a positive feedback loop to sustain the ECAD downregulation. YAP activation mitigates oxidative stress in detached HCC cells by upregulating antioxidant genes, protecting detached HCC cells from ferroptosis, resulting in anoikis resistance. Mechanistically, we found that protein kinase A (PKA) senses oxidative stress by redox modification in its β catalytic subunit (PRKACB) at Cys200 and Cys344, which increases its kinase activity towards RNF25 phosphorylation at Ser450, facilitating RNF25-mediated degradation of ECAD. Moreover, RNF25 expression is associated with HCC metastasis and depletion of RNF25 is sufficient to diminish HCC invasion and metastasis in vitro and in vivo. Together, these results identify a dual role of RNF25 as a critical regulator of ECAD protein turnover, promoting both anoikis resistance and metastasis, and PKA is a necessary redox sensor to enable this process. Our study provides mechanistic insight into how tumor cells sense oxidative stress signals to spread while escaping cell death.

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Cytoprotection of human endothelial cells from oxidative stress by polyphenols: the role of gene expression versus direct antioxidant effect

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.760.3 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Xinyu Wang ◽

James Bynum ◽

Salomon Stavchansky ◽

Michael Dubick ◽

Robert Hackman ◽

...

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Endothelial Cells ◽

Antioxidant Effect ◽

Human Endothelial Cells

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Metformin-stimulated AMPK-α1 promotes microvascular repair in acute lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00173.2013 ◽

2013 ◽

Vol 305 (11) ◽

pp. L844-L855 ◽

Cited By ~ 47

Author(s):

Ming-Yuan Jian ◽

Mikhail F. Alexeyev ◽

Paul E. Wolkowicz ◽

Jaroslaw W. Zmijewski ◽

Judy R. Creighton

Keyword(s):

Endothelial Cells ◽

Acute Lung Injury ◽

Lung Injury ◽

Ex Vivo ◽

Endothelial Permeability ◽

Beneficial Effects ◽

Isolated Lung

Acute lung injury secondary to sepsis is a leading cause of mortality in sepsis-related death. Present therapies are not effective in reversing endothelial cell dysfunction, which plays a key role in increased vascular permeability and compromised lung function. AMP-activated protein kinase (AMPK) is a molecular sensor important for detection and mediation of cellular adaptations to vascular disruptive stimuli. In this study, we sought to determine the role of AMPK in resolving increased endothelial permeability in the sepsis-injured lung. AMPK function was determined in vivo using a rat model of endotoxin-induced lung injury, ex vivo using the isolated lung, and in vitro using cultured rat pulmonary microvascular endothelial cells (PMVECs). AMPK stimulation using N1-(α-d-ribofuranosyl)-5-aminoimidizole-4-carboxamide or metformin decreased the LPS-induced increase in permeability, as determined by filtration coefficient ( Kf) measurements, and resolved edema as indicated by decreased wet-to-dry ratios. The role of AMPK in the endothelial response to LPS was determined by shRNA designed to decrease expression of the AMPK-α1 isoform in capillary endothelial cells. Permeability, wounding, and barrier resistance assays using PMVECs identified AMPK-α1 as the molecule responsible for the beneficial effects of AMPK in the lung. Our findings provide novel evidence for AMPK-α1 as a vascular repair mechanism important in the pulmonary response to sepsis and identify a role for metformin treatment in the management of capillary injury.

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