scholarly journals S-glutathionylation: relevance in diabetes and potential role as a biomarker

2013 ◽  
Vol 394 (10) ◽  
pp. 1263-1280 ◽  
Author(s):  
Francisco J. Sánchez-Gómez ◽  
Cristina Espinosa-Díez ◽  
Megha Dubey ◽  
Madhu Dikshit ◽  
Santiago Lamas
Keyword(s):  
Oxidative Stress ◽  
Vascular Complications ◽  
Redox Balance ◽  
Diabetic Patients ◽  
Sulfenic Acid ◽  
Diabetic Vascular Complications ◽  
Main Regulator ◽  
Species Production

Abstract Glutathione is considered the main regulator of redox balance in the cellular milieu due to its capacity for detoxifying deleterious molecules. The oxidative stress induced as a result of a variety of stimuli promotes protein oxidation, usually at cysteine residues, leading to changes in their activity. Mild oxidative stress, which may take place in physiological conditions, induces the reversible oxidation of cysteines to sulfenic acid form, while pathological conditions are associated with higher rates of reactive oxygen species production, inducing the irreversible oxidation of cysteines. Among these, neurodegenerative disorders, cardiovascular diseases and diabetes have been proposed to be pathogenetically linked to this state. In diabetes-associated vascular complications, lower levels of glutathione and increased oxidative stress have been reported. S-glutathionylation has been proposed as a posttranslational modification able to protect proteins from over-oxidizing environments. S-glutathionylation has been identified in proteins involved in diabetic models both in vitro and in vivo. In all of them, S-glutathionylation represents a mechanism that regulates the response to diabetic conditions, and has been described to occur in erythrocytes and neutrophils from diabetic patients. However, additional studies are necessary to discern whether this modification represents a biomarker for the early onset of diabetic vascular complications.

scholarly journals Epigenetic Changes in Endothelial Progenitors as a Possible Cellular Basis for Glycemic Memory in Diabetic Vascular Complications

2015 ◽  
Vol 2015 ◽  
pp. 1-17 ◽  
Author(s):  
Poojitha Rajasekar ◽  
Christina L. O’Neill ◽  
Lydia Eeles ◽  
Alan W. Stitt ◽  
Reinhold J. Medina
Keyword(s):  
Glycemic Control ◽  
Vascular Complications ◽  
Disease Process ◽  
Diabetic Patients ◽  
Negative Consequences ◽  
Diabetic Vascular Complications ◽  
Endothelial Progenitors ◽  
Glycemic Memory

The vascular complications of diabetes significantly impact the quality of life and mortality in diabetic patients. Extensive evidence from various human clinical trials has clearly established that a period of poor glycemic control early in the disease process carries negative consequences, such as an increase in the development and progression of vascular complications that becomes evident many years later. Importantly, intensive glycemic control established later in the disease process cannot reverse or slow down the onset or progression of diabetic vasculopathy. This has been named the glycemic memory phenomenon. Scientists have successfully modelled glycemic memory using variousin vitroandin vivosystems. This review emphasizes that oxidative stress and accumulation of advanced glycation end products are key factors driving glycemic memory in endothelial cells. Furthermore, various epigenetic marks have been proposed to closely associate with vascular glycemic memory. In addition, we comment on the importance of endothelial progenitors and their role as endogenous vasoreparative cells that are negatively impacted by the diabetic milieu and may constitute a “carrier” of glycemic memory. Considering the potential of endothelial progenitor-based cytotherapies, future studies on their glycemic memory are warranted to develop epigenetics-based therapeutics targeting diabetic vascular complications.

scholarly journals Metformin prevents methylglyoxal-induced apoptosis by suppressing oxidative stress in vitro and in vivo

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Gang Wang ◽  
Yanan Wang ◽  
Qinzhi Yang ◽  
Chunrong Xu ◽  
Youkun Zheng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Apoptosis ◽  
Vascular Complications ◽  
Tunel Staining ◽  
Ros Generation ◽  
Dependent Manner ◽  
Diabetic Vascular Complications ◽  
Induced Apoptosis

AbstractMethylglyoxal (MGO) is an active metabolite of glucose and plays a prominent role in the pathogenesis of diabetic vascular complications, including endothelial cell apoptosis induced by oxidative stress. Metformin (MET), a widely prescribed antidiabetic agent, appears to reduce excessive reactive oxygen species (ROS) generation and limit cell apoptosis. However, the molecular mechanisms underlying this process are still not fully elucidated. We reported here that MET prevents MGO-induced apoptosis by suppressing oxidative stress in vitro and in vivo. Protein expression and protein phosphorylation were investigated using western blotting, ELISA, and immunohistochemical staining, respectively. Cell viability and apoptosis were assessed by the MTT assay, TUNEL staining, and Annexin V-FITC and propidium iodide double staining. ROS generation and mitochondrial membrane potential (MMP) were measured with fluorescent probes. Our results revealed that MET prevented MGO-induced HUVEC apoptosis, inhibited apoptosis-associated biochemical changes such as loss of MMP, the elevation of the Bax/Bcl-2 ratio, and activation of cleaved caspase-3, and attenuated MGO-induced mitochondrial morphological alterations in a dose-dependent manner. MET pretreatment also significantly suppressed MGO-stimulated ROS production, increased signaling through the ROS-mediated PI3K/Akt and Nrf2/HO-1 pathways, and markedly elevated the levels of its downstream antioxidants. Finally, similar results were obtained in vivo, and we demonstrated that MET prevented MGO-induced oxidative damage, apoptosis, and inflammation. As expected, MET reversed MGO-induced downregulation of Nrf2 and p-Akt. In addition, a PI3K inhibitor (LY-294002) and a Nrf2 inhibitor (ML385) observably attenuated the protective effects of MET on MGO-induced apoptosis and ROS generation by inhibiting the Nrf2/HO-1 pathways, while a ROS scavenger (NAC) and a permeability transition pores inhibitor (CsA) completely reversed these effects. Collectively, these findings broaden our understanding of the mechanism by which MET regulates apoptosis induced by MGO under oxidative stress conditions, with important implications regarding the potential application of MET for the treatment of diabetic vascular complications.

Susceptibility of Glutathione--S-Transferase Polymorphism to CVD Development in Type 2 Diabetes Mellitus - A Review

2021 ◽  
Vol 21 ◽  
Author(s):  
Santhi Priya Sobha ◽  
Kumar Ebenezar
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Metabolic Disorder ◽  
Vascular Complications ◽  
Clinical Importance ◽  
Diabetic Patients ◽  
Diabetic Vascular Complications ◽  
Metabolic Conditions ◽  
Gst Polymorphism ◽  
Gene Status

Background: Metabolic disorder affects normal homeostasis and can lead to the development of diseases. Diabetes mellitus is the most common metabolic disorder, and a cluster of metabolic conditions can lead to cardiovascular disease (CVD) development. Diabetes mellitus and CVD are closely related, with oxidative stress, playing a major role in the pathophysiology. Glutathione-S-Transferases (GST) potentially play an important role by reducing oxidative stress and is found to be the underlying pathophysiology in the development of diabetes, cardiovascular diseases (CVD), etc. Objectives: In this review, the role of GST genetic variant in the development of diabetes mellitus, CVD and diabetic vascular complications has been focused. Results: Based on the literature, it is evident that the GST can act as an important biochemical tool providing significant evidence regarding oxidative stress predominant in the development of diseases. Analysis of GST gene status, particularly detection of GSTM1 and GSTT1 null mutations and GSTP1 polymorphism, have clinical importance. Conclusion: The analysis of GST polymorphism may help identify the people at risk and provide proper medical management. Genotyping of GST gene would be a helpful biomarker for early diagnosis of CVD development in DM and also in CVD cases. More studies focusing on the association of GST polymorphism with CVD development in diabetic patients will help us determine the pathophysiology better.

scholarly journals Cystine/glutamate antiporter xCT (SLC7A11) facilitates oncogenic RAS transformation by preserving intracellular redox balance

2019 ◽  
Vol 116 (19) ◽  
pp. 9433-9442 ◽  
Author(s):  
Jonathan K. M. Lim ◽  
Alberto Delaidelli ◽  
Sean W. Minaker ◽  
Hai-Feng Zhang ◽  
Milena Colovic ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Redox Balance ◽  
Gene Encoding ◽  
Oncogenic Ras ◽  
Opposing Effects ◽  
Whole Transcriptome ◽  
Intracellular Redox

The RAS family of proto-oncogenes are among the most commonly mutated genes in human cancers and predict poor clinical outcome. Several mechanisms underlying oncogenic RAS transformation are well documented, including constitutive signaling through the RAF-MEK-ERK proproliferative pathway as well as the PI3K-AKT prosurvival pathway. Notably, control of redox balance has also been proposed to contribute to RAS transformation. However, how homeostasis between reactive oxygen species (ROS) and antioxidants, which have opposing effects in the cell, ultimately influence RAS-mediated transformation and tumor progression is still a matter of debate and the mechanisms involved have not been fully elucidated. Here, we show that oncogenic KRAS protects fibroblasts from oxidative stress by enhancing intracellular GSH levels. Using a whole transcriptome approach, we discovered that this is attributable to transcriptional up-regulation of xCT, the gene encoding the cystine/glutamate antiporter. This is in line with the function of xCT, which mediates the uptake of cystine, a precursor for GSH biosynthesis. Moreover, our results reveal that the ETS-1 transcription factor downstream of the RAS-RAF-MEK-ERK signaling cascade directly transactivates the xCT promoter in synergy with the ATF4 endoplasmic reticulum stress-associated transcription factor. Strikingly, xCT was found to be essential for oncogenic KRAS-mediated transformation in vitro and in vivo by mitigating oxidative stress, as knockdown of xCT strongly impaired growth of tumor xenografts established from KRAS-transformed cells. Overall, this study uncovers a mechanism by which oncogenic RAS preserves intracellular redox balance and identifies an unexpected role for xCT in supporting RAS-induced transformation and tumorigenicity.

Oxidative stress in primary culture hepatocytes isolated from partially hepatectomized rats

2007 ◽  
Vol 85 (10) ◽  
pp. 1047-1051 ◽  
Author(s):  
Daniel Francés ◽  
M. Teresa Ronco ◽  
Elena Ochoa ◽  
M. Luján Alvarez ◽  
Ariel Quiroga ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Primary Culture ◽  
Cell Injury ◽  
Cultured Cells ◽  
Male Wistar Rats ◽  
Metabolic Activities ◽  
Stress Oxidative ◽  
Species Production

The aim of this study was to evaluate the influence of partial hepatectomy prior to cell isolation on hepatocytes in vitro. We characterized the possible changes of various stress oxidative parameters within the first 24 h after seeding. Male Wistar rats served as donors. Hepatocytes were isolated by collagenase digestion from either liver of simulated surgery (SH) or from liver 1 h after 70% hepatectomy (PH), and the changes in stress parameters were analyzed after 1, 3, 18, and 24 h in culture. At 24 h, only hepatocytes from PH maintained significantly increased reactive oxygen species production, oxidized glutathione percentage, and Cu/Zn superoxide dismutase and catalase activities. Our results show that hepatocytes suffer significant cell injury as a result of the isolation procedure, but primary cultured cells from SH metabolically recover from this stress after 18 h. After this time, primary culture hepatocytes primed by PH maintain their in vivo-like metabolic activities (increase in both oxidative stress and antioxidant status).

Antioxidant Activity In vivo and Ex Vivo of Tautomeric Pair of Polyprenylated Benzophenone - Garcinielliptone FC (Platonia insignis Mart Seeds)

2020 ◽  
Vol 16 (3) ◽  
pp. 284-293
Author(s):  
George Laylson da Silva Oliveira ◽  
Maria das Dores Alves de Oliveira ◽  
Maria da Conceição Oliveira Prado ◽  
Alexandre de Barros Falcão Ferraz ◽  
José Carlos Correia Lima da Silva ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Antioxidant Activity ◽  
Oxidative Damage ◽  
Ex Vivo ◽  
Redox Balance ◽  
Oxidative Stress Biomarkers ◽  
Iron Citrate

Background: Garcinielliptone FC corresponds to a polyprenylated acylphloroglucinol having a benzophenonic core (diphenylmethanone) substituted with isoprenyl(s) group(s) (3-methyl-2-butenyl) and 2-isopropenyl-hex-5-enyl. Objective: The present work evaluated the antioxidant activity of garcinielliptone FC (GFC) in vitro against non-biological radicals [2,2-diphenyl-1-picrylhydrazyl (DPPH•) and 2,2'-azinobis-3- ethylbenzothiazoline-6-sulfonic acid (ABTS•+)] and ex vivo against oxidative damage induced by AAPH (2,2'-azobis-2-methylpropionamidine dihydrochloride) and iron/citrate ion in erythrocytes and mitochondria, respectively. Methods: In addition to the protective effect, the main biochemical indexes of oxidative stress, such as lipid peroxidation through the formation of Thiobarbituric Acid Reactive Substances (TBARS), Superoxide Dismutase (SOD), Catalase (CAT) activity and reduced glutathione (GSH) levels. Results: According to the results obtained in erythrocytes, the antioxidant results at concentrations of 0.1, 0.3, 0.7, 1.5 and 3.0 mM were 26.34 ± 0.68, 43.39 ± 2.17, 62.27 ± 2.17, 86.69 ± 0.47 and 92.89 ± 0.45%, respectively, where GFC reduced the rate of oxidative hemolysis when compared to AAPH (p<0.05). The antioxidant activity observed in erythrocytes was also seen in mitochondria in which GFC reduced mitochondrial swelling by increasing the absorbance when compared to iron/citrate ion complex (p<0.05). In both biological models, GFC had an antioxidant effect on erythrocyte and mitochondrial redox balance when analyzing oxidative stress biomarkers, such as reduction of lipid peroxidation and inhibition of depletion in the activity of SOD, CAT and GSH levels. Conclusion: In conclusion, GFC had in vitro and ex vivo antioxidant activity against oxidative damage induced in erythrocytes and mitochondria acting on the erythrocytic and mitochondrial redox balance.

Transfer of mouse blastocysts exposed to ambient oxygen levels can lead to impaired lung development and redox balance

2019 ◽  
Vol 25 (11) ◽  
pp. 745-754
Author(s):  
Nedim Karagenç ◽  
Göksel Doğan ◽  
Kerem Esmen ◽  
Bengi Çınar Kul ◽  
Hasan Yeşilkaya ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Lung Development ◽  
Atmospheric Oxygen ◽  
Redox Balance ◽  
Perinatal Period ◽  
Altered Expression ◽  
Short Period

Abstract In vitro culture under atmospheric oxygen puts embryos under oxidative stress and impairs preimplantation development. However, to what extent this process alters the redox balance in the perinatal period remains largely unknown. The aim of the present study was to examine if the redox balance is altered in the lung tissue of fetuses generated through transfer of mouse embryos exposed to atmospheric oxygen at different stages of development and to determine if this has any effect on lung morphogenesis and gene expression. Two experimental groups (EGs) were generated by transferring in vitro- and in vivo-derived blastocysts to pseudo-pregnant females. In vivo-developed fetuses served as control. Enzymatic/nonenzymatic antioxidants, malondialdehyde (MDA) levels, total antioxidant capacity, stage of lung development and gene expression were evaluated on day 18 of pregnancy. Weight of fetuses was significantly less in both experimental cohorts (ANOVA, P < 0.001 versus control), associated with delayed lung development, higher amounts of MDA (ANOVA, P < 0.001 versus control) and altered expression of several genes in oxidative stress/damage pathways. Evidence gathered in the present study indicates that pre-implantation stress caused by culture under atmospheric oxygen, even for a short period of time, leads to fetal growth restriction, impaired lung development and redox balance along with dysregulation of several genes in oxidative stress response. Absence of an EG in which in vitro embryo culture was performed at 5% oxygen and the use of genetically heterogeneous F2 fetuses are the limitations of the study. In any case, the long-term impact of such dramatic changes in the developmental programming of resulting fetuses warrants further investigations.

scholarly journals Parkinson Disease-Linked Parkin Mediates Redox Reactions That Lower Oxidative Stress In Mammalian Brain

2020 ◽  
Author(s):  
Daniel N. El Kodsi ◽  
Jacqueline M. Tokarew ◽  
Rajib Sengupta ◽  
Nathalie A. Lengacher ◽  
Andy C. Ng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reductase Activity ◽  
Redox Homeostasis ◽  
Redox Balance ◽  
Oxidative Modification ◽  
Reduced Form ◽  
Mammalian Brain ◽  
Anti Oxidant

SUMMARYWe recently hypothesized that parkin plays a role in redox homeostasis and provided evidence that it directly reduces hydrogen peroxide (H2O2) in vitro. Here, we examined this anti-oxidant activity in vivo. Informed by findings in human brain, we demonstrate that elevated oxidative stress promotes parkin insolubility in mice. In normal mouse brain parkin was partially oxidized, e.g., at cysteines 195 and 252, which was augmented by oxidative stress. Although under basal conditions H2O2 levels were unchanged in adult prkn-/- brain, a parkin-dependent reduction of cytosolic H2O2 was observed when mitochondria were impaired, either due to neurotoxicant exposure (MPTP) or Sod2 haploinsufficiency. In accordance, markers of oxidative stress, e.g., protein carbonylation and nitrotyrosination, were elevated in the cytosol but not in mitochondria from prkn-/- mice. Nevertheless, this rise in oxidative stress led to changes in mitochondrial enzyme activities and the metabolism of glutathione in cells and mammalian brain. In parkin’s absence reduced glutathione concentrations were increased including in human cortex. This compensation was not due to new glutathione synthesis but attributed to elevated oxidized glutathione (GSSG)-reductase activity. Moreover, we discovered that parkin also recycled GSSG to its reduced form. With this reaction, parkin became S-glutathionylated, e.g., at cysteines 59 and human-specific 95. This oxidative modification was reversed by glutaredoxin. Our results demonstrate that cytosolic parkin mediates anti-oxidant reactions including H2O2 reduction and glutathione regeneration. These reducing activities lead to a range of oxidative modifications in parkin itself. In parkin-deficient brain oxidative stress rises despite changes to maintain redox balance.

Dapagliflozin Restores Diabetes-Associated Decline in Vasculogenic Capacity of Endothelial Progenitor Cells via Activating AMPK-Mediated Inhibition of Inflammation and Oxidative Stress

2021 ◽  
Author(s):  
Lifang Luo ◽  
Bing Dong ◽  
Jianning Zhang ◽  
Yumin Qiu ◽  
Xiaolin Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Vascular Complications ◽  
Diabetic Patients ◽  
Vascular Protection ◽  
Endothelial Progenitor ◽  
Ampk Signaling ◽  
And Oxidative Stress

Abstract Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) provides added vascular protection beyond glucose lowering to patients with type 2 diabetes mellitus (T2DM). Endothelial progenitor cells (EPCs) are an important endogenous repair mechanism for diabetic vascular complications. Yet, whether SGLT2i protect vascular in diabetic patients by improving the function of EPCs remain to be elucidated. Methods: Sixty-three T2DM patients and 60 healthy participants were enrolled, and 15 of T2DM group taken dapagliflozin for 3 months. Retinal capillary density (RCD) and vasculogenic capacity of EPCs in vitro and in vivo were assessed among different groups. Genes related to inflammation/oxidative stress, and the AMPK signaling of EPCs in T2DM were determined before and after dapagliflozin treatment. Results: T2DM demonstrated a declined RCD and impaired vasculogenic capacity of EPCs. There is a linear correlation between RCD and the number of circulating EPCs. The expression of inflammation correlative genes was increased; however, anti-oxidative stress related genes expression was decreased in EPCs form T2DM, which were accompanied with reduced phosphorylation level of AMPK. Dapagliflozin treatment activated AMPK signaling, decreased the level of inflammation and oxidative stress, and rescued vasculogenic capacity of EPCs from T2DM. Furthermore, AMPK inhibitor pretreatment diminished the enhancement vasculogenic capacity of diabetic EPCs from dapagliflozin treatment.Conclusions: This study demonstrates for the first time that dapagliflozin restores vasculogenic capacity of EPCs via activating AMPK-mediated inhibition of inflammation and oxidative stress in T2DM.

scholarly journals Neither Excessive Nitric Oxide Accumulation nor Acute Hyperglycemia Affects the N-Acetylaspartate Network in Wistar Rat Brain Cells

2020 ◽  
Vol 21 (22) ◽  
pp. 8541
Author(s):  
Marlena Zyśk ◽  
Piotr Pikul ◽  
Robert Kowalski ◽  
Krzysztof Lewandowski ◽  
Monika Sakowicz-Burkiewicz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Wistar Rat ◽  
Diabetic Patients ◽  
Mrna Levels ◽  
Male Adult ◽  
The Impact

The N-acetylaspartate network begins in neurons with N-acetylaspartate production catalyzed by aspartate N-acetyltransferase from acetyl-CoA and aspartate. Clinical studies reported a significant depletion in N-acetylaspartate brain level in type 1 diabetic patients. The main goal of this study was to establish the impact of either hyperglycemia or oxidative stress on the N-acetylaspartate network. For the in vitro part of the study, embryonic rat primary neurons were treated by using a nitric oxide generator for 24 h followed by 6 days of post-treatment culture, while the neural stem cells were cultured in media with 25–75 mM glucose. For the in vivo part, male adult Wistar rats were injected with streptozotocin (65 mg/kg body weight, ip) to induce hyperglycemia (diabetes model) and euthanized 2 or 8 weeks later. Finally, the biochemical profile, NAT8L protein/Nat8l mRNA levels and enzymatic activity were analyzed. Ongoing oxidative stress processes significantly affected energy metabolism and cholinergic neurotransmission. However, the applied factors did not affect the N-acetylaspartate network. This study shows that reduced N-acetylaspartate level in type 1 diabetes is not related to oxidative stress and that does not trigger N-acetylaspartate network fragility. To reveal why N-acetylaspartate is reduced in this pathology, other processes should be considered.

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