Glutathione “Redox Homeostasis” and Its Relation to Cardiovascular Disease

Bajic, Vladan P.; Van Neste, Christophe; Obradovic, Milan; Zafirovic, Sonja; Radak, Djordje; Bajic, Vladimir B.; Essack, Magbubah; Isenovic, Esma R.

doi:https://doi.org/10.1155/2019/5028181

Oxidative Medicine and Cellular Longevity

On this page

Abstract Introduction Abbreviations Disclosure Conflicts of Interest Acknowledgments References Copyright Related Articles

Special Issue

Chemistry, Biology, and Pharmacology of Modulators of Oxidative Stress

View this Special Issue

Review Article | Open Access

Volume 2019 | Article ID 5028181 | https://doi.org/10.1155/2019/5028181

Glutathione “Redox Homeostasis” and Its Relation to Cardiovascular Disease

Vladan P. Bajic,¹Christophe Van Neste,²Milan Obradovic,¹Sonja Zafirovic,¹Djordje Radak,³Vladimir B. Bajic,²Magbubah Essack,²and Esma R. Isenovic¹

Academic Editor: Luciano Saso

Received25 Jan 2019

Revised20 Mar 2019

Accepted01 Apr 2019

Published09 May 2019

Abstract

More people die from cardiovascular diseases (CVD) than from any other cause. Cardiovascular complications are thought to arise from enhanced levels of free radicals causing impaired “redox homeostasis,” which represents the interplay between oxidative stress (OS) and reductive stress (RS). In this review, we compile several experimental research findings that show sustained shifts towards OS will alter the homeostatic redox mechanism to cause cardiovascular complications, as well as findings that show a prolonged antioxidant state or RS can similarly lead to such cardiovascular complications. This experimental evidence is specifically focused on the role of glutathione, the most abundant antioxidant in the heart, in a redox homeostatic mechanism that has been shifted towards OS or RS. This may lead to impairment of cellular signaling mechanisms and elevated pools of proteotoxicity associated with cardiac dysfunction.

1. Introduction

Glutathione (GSH) and its reduced form are the most prevalent thiol-containing peptides in eukaryotic cells [1, 2]. Although GSH was described as a prominent reducing factor and the main antioxidant within the cells, subsequent investigations show that GSH exerts many other cellular functions [2, 3]. Indeed, GSH exerts multiple physiological functions including the proliferation, cell cycle regulation, apoptosis, catabolism of xenobiotics, glutathionylation of proteins, and the production of some steroids, lipid compound, and deoxyribonucleotides and represents an important source of cysteine [2–5]. Taking into account all these features of GSH, it is not surprising that GSH plays an important etiological role in the development of numerous diseases, such as cardiometabolic and cardiovascular diseases (CVD) [6–9].

Development and progression of CVD are characterized by substantial changes in the concentration of GSH and/or its oxidation state [9–12]. Three different mechanisms have been proposed to be involved in GSH diminution: increased oxidation by intracellular oxidizing agents, increased conjugation to proteins, electrophiles, and xenobiotics, and increased extrusion across the cell membrane [9, 10, 13]. Conversely, increased concentration of GSH in cells may cause negative effects, such as multidrug resistance [9, 14]. Also, the dysregulation of GSH-dependent enzymes and GSH synthesis enzymes was observed in endothelial dysfunction [10, 12].

This review aims to highlight the role of GSH in the physiology and pathology of the cardiovascular system.

2. Glutathione Structure and Function

GSH is a peptide ubiquitously present in all cells, but the liver remains the principal source of GSH in humans [1, 2]. GSH is a tripeptide formed from glycine, glutamate, and cysteine. In the cell, GSH is synthesized and mostly distributed in the cytoplasm, while in less amount, it is also found in the organelles such as the nucleus, peroxisomes, mitochondria, and endoplasmic reticulum. GSH is transported from the cytoplasm to the organelles by specific transporters [2, 8, 15]. In many cells, the concentration of GSH is in the range of 1-10 mM, while the concentration of GSH in plasma is notably low at 0.01 mM [1]. This disproportionate level of GSH concentration within cells and circulation principally depends on its rapid catabolism in blood [8, 16]. However, it is not possible to determine the total glutathione concentration, which includes GSH, the glutathione disulfide (GSSG), and all other forms [17].

Various factors regulate GSH synthesis, such as availability of L-cysteine and ATP and the concentration of GSH [1, 2]. A large amount of GSH competitively inhibits the activity of glutamate cysteine ligase (GCL) [18, 19]. GSH is synthesized by GCL and glutathione synthetase (GS) [1, 2]. Firstly, γ-glutamylcysteine is formed from glutamate and cysteine via GCL activity and consumption of one ATP molecule. Then, glycine is added to formed dipeptide in the reaction catalyzed by GS and consumption of one more ATP molecule. Interestingly, the expression of GCL is regulated by nuclear factor erythroid 2-related factor 2 (Nrf2), which can be activated by oxidative stress (OS) [16, 20]. Thus, OS leads to increased GSH production through stimulation of GCL activity [16, 20]. One of the characteristic structural features of the GSH is the γ-glutamyl bond, which makes GSH very stable and resistant to cleavage of most proteases and peptidases. γ-Glutamyl transferase (GGT) is the enzyme which catabolizes GSH (located extracellularly) by removing γ-glutamyl to obtain cysteinylglycine or cysteinylglycine conjugates, which dipeptidases further degrade [17].

GSH is the principal intracellular antioxidant, which may act directly by scavenging reactive oxygen and nitrogen species or indirectly by supporting enzymatic activity as a cofactor [3, 21]. Intracellular GSH mainly exists as a monomer in reduced form and less in the disulfide dimer or GSSG, which arises after GSH oxidation [1, 3]. GSH can be reverted from GSSG by the activity of glutathione reductase [13, 22]. The reduced and oxidized forms of GSH represent the main cellular redox buffer, and in the physiological condition, the concentration of GSH is predominant compared with GSSG [23, 24]. Thus, the ratio of GSH and GSSG is considered as a marker of OS [23, 24].

Furthermore, glutathionylation of proteins represents an important regulatory mechanism that influences the activity and kinetics of different regulatory, metabolic, and structural proteins [25, 26]. Proteins with thiol groups can respond to different stimuli, such as OS, and form disulfides [26]. S-Thiolation processes include the formation of a disulfide bond inside of one protein and between two proteins and mixed protein/nonprotein disulfides. It was observed that GSH forms part of almost 85% of mixed protein/nonprotein disulfides [9, 26, 27]. We today view the process of S-glutathionylation as a critical signaling system in CVD [28]. S-Glutathionylation is involved in oxidative phosphorylation, myocyte contraction protein synthesis, and insulin response [29]. Perturbations in protein glutathionylation contribute to myocardial infarction, hypertrophy, and inflammation. Using the ischemia-perfusion technique in the rat model for myocardial infarction, it was shown that there is an increase in overall protein glutathionylation [30]. The protein found to be heavily glutathionylated was glyceraldehyde-3-phosphate dehydrogenase. The result of glutathionylation is inhibition of glycolysis and increased apoptosis [31]. Ras glutathionylation has been investigated in the progression of cardiac hypertrophy [32]. More research has been concerned with the role of protein glutathionylation in atherosclerosis [33–35]. Human macrophages exposed to oxidized cholesterol, a fundamental component of the atherosclerotic plaque, show an increase in protein glutathionylation [36] suggesting that protein glutathionylation has a role in macrophage cell death [36]. Patients with atherosclerosis obliterans or atherosclerosis of the extremities exhibit increased levels of serum proteins that have been seen to be heavily glutathionylated [37]. These findings reflect a redox imbalance produced by OS and present a path leading to atherosclerosis of the extremities.

Past research has been concentrated on OS and its relation to CVD [38], but new studies have given light to the role of reductants that may lead to the imbalance of normal, physiological production of reactive oxygen species (ROS) to a state of “reductive stress” (RS). S-Glutathionylation of proteins, in this new light, has to be included in the analysis of how to control OS and/or RS [38].

Regulating angiogenesis is a major goal in cardiovascular research. Research into S-glutathionylation on the regulation on the low molecular weight protein tyrosine phosphatase (LMW-PTP) which is a key mediator of vascular endothelial growth factor (VEGF) cell migration [39] was reported. VEGF causes reversible S-glutathionylation of the LMW-PTP protein. Research showed that a balanced redox state is needed for VEGF to process reversible S-glutathionylation of the LMW-PTP protein and hence cell migration. On the other hand, it was shown that a shift towards “RS” or “OS” can inhibit VEGF angiogenic response [39].

There is growing evidence that glutathionyl hemoglobin may be of use as a biomarker of OS in circulation [40, 41]. GSH also functions in the detoxification of xenobiotics, which are eventually converted to the mercapturic acids and excreted through urine or feces [42].

GSH can also achieve a prooxidant effect but to a lesser extent than antioxidant effect [21]. During the GSH catabolism, removal of the γ-glutamate residue from the cysteine residue caused a prooxidant effect and may induce lipid peroxidation of the plasma membrane on the exposed, outer side [43, 44]. This may cause initiation of a signaling process inside the cell and increased production of reactive species and further cause DNA damages and lipid peroxidation [43, 45]. Moreover, the prooxidant effect of GSH can enhance the reduction of iron and oxidation of low-density lipoproteins (LDL) involved in vascular injury and atherogenesis development [21].

3. Glutathione and Reductive Stress

Albert Wendel coined reductive stress, to describe NADH facilitating a reduction of chelated ferric iron when excessive concentrations of NADH are present [46]. It is now known that RS is the counterpart of OS that is characterized by excessive levels of reducing bioequivalents [47]. The endogenous intracellular antioxidant, GSH, was shown to be involved in several RS-related mechanisms.

Salvemini et al. [48] showed that the HeLa cells when transfected with the human glucose-6-phosphate dehydrogenase (G6PD) gene, responsible for the generation of NADPH, exhibited increased levels of GSH and decreased ROS production. Moreover, these clones displayed significant resistance to oxidant-mediated cell killing and resistance to NF-kappaB activation [48]. Thus, these clones represent a reduced state to a certain extent.

Heat shock proteins (HSPs) were also shown to exhibit protection against several stress stimuli in mammalian cells. In line with this fact, Preville et al. [49] demonstrated that human heat shock protein 27 (Hsp27)—and murine (L929 fibroblast) heat shock protein 25 (Hsp25)—mediates protection against H₂O₂-induced OS by increasing levels of reduced GSH in a G6PD-dependent manner. Also, Baek et al. [50] demonstrated that the overexpression of Hsp25 enhances radiation survival in L929 cells by reducing apoptosis. However, these clones also showed increased concentrations of GSH, not as a consequence of glutathione synthesis but rather a consequence of GSSG being reduced faster to GSH. Thus, the GSH/GSSG ratio was significantly less in the controls when compared with the clones. These reports provide the first evidence that HSPs help facilitate the glutathione-redox cycle by increasing GSH levels thereby promoting a reduced state [50].

McMahon et al. [51] demonstrated that Kelch-like ECH-associated protein 1 (Keap1)-dependent proteasomal degradation of regulatory protein Nrf2 contributes to the decreased expression of several antioxidant enzymes. It has been shown in a study by Zhang et al. [52] that cardiac-related adaptation to chronic stress is facilitated by NADPH oxidase-4 (NOX4). Brewer et al. [53] showed the connection between these studies by demonstrating that NOX4 activated Nrf2 which facilitates the expression of antioxidant-related genes, which resulted in increased concentrations of GSH and consequently an increased GSH/GSSG ratio.

Rajasekaran et al. later demonstrated that increased levels of GSH, NADPH, and antioxidative pathway enzymes associated with RS, and decreased OS biomarkers could be linked to protein aggregation cardiomyopathy and cardiac hypertrophy [54]. Activation of reactive persulfides and polysulfides that have better scavenging activity than GSH can also cause “RS-related redox collapse,” but this is not well studied [55]. Nonetheless, these shifts towards reduction that induced the “RS-related redox collapse” have been linked to several complications including lipid damage [56], cytotoxicity [57], mitochondrial dysfunction [57], triacylglycerol deposition [58], and cardiac ischemic injury [59].

The role of OS in the cardiovascular system (CVS) has been well demonstrated in numerous animal and human studies discussed below. However, more recent work focuses on the role of RS in CVS, as a consequence of antioxidant-based treatments often being ineffective.

In line with this thought pattern, Zhang et al. [60] explored whether overexpression of Hsp27 induces RS that results in cardiomyopathy using low to high expression levels of Hsp27 in transgenic mice. High Hsp27-expressing transgenic mice developed cardiomyopathy. Moreover, an increased GSH/GSSG ratio increased levels of glutathione peroxidase 1 (GPx-1), and decreased levels of ROS indicated that the myopathic hearts were under RS. Zhang et al. [60] then confirmed the role of RS in cardiomyopathy by demonstrating that the development of cardiomyopathy is significantly attenuated through the inhibition of GPx-1.

The link of the NADPH oxidase (NOX) protein family has been suggested for several pathologies because it produces ROS, whose excessive production leads to OS. Thus, Yu et al. [59] explored the role of NOX4 in cardiac ischemic injury using mice with cardiac-specific overexpression (CSO) of NOX4 or dominant negative NOX4. CSO of NOX4 led to OS, while the dominant negative NOX4 exhibited an increased GSH/GSSG ratio and decreased NAD(P)(+)/NAD(P)H reflective of RS. Moreover, increasing ROS production during ischemia did not recover heart function, whereas limiting levels of reducing equivalent protected the dominant negative NOX4 hearts from ischemic injury.

Here, a question arises as to whether the RS counterpart OS could alleviate such complications, in the context of redox homeostasis distorted towards the RS side. In this regard, Schulz et al. [61] demonstrated that the glucose restriction induces catalase activity and ROS formation and increases OS resistance and survival rates in Caenorhabditis elegans. In 2011, Ristow and Schmeisser [62] published a review focused on several such longevity-promoting interventions that are thought to converge by causing activation of mitochondrial oxygen consumption which increases ROS formation.

4. Glutathione Synthesis or Recuperation Deregulation

Generally, total cellular GSH content and the GSH/GSSG ratio are controlled by a GSH-negative feedback loop, as the cells undergo fluctuating OS levels. However, the general regulation of glutathione synthesis or recuperation will determine the average around which total GSH and GSH/GSSG ratio shift. This, among others, will depend on microRNAs, long noncoding RNAs (lncRNA), and mutations affecting the core synthesis or recuperation genes and their transcription (co)-factors. In light of this review, any of these factors that increase the average GSH content is of interest. As most research is focused on the detrimental effects of synthesis deficiency, there is not a lot of explicit emphasis on changes that increase the GSH content.

The miRNA miR-96-5p was shown to be upregulated in hypertrophic cardiomyopathy disease patients compared to the normal control group [63]. Kinoshita et al. [64] demonstrated that miR-96-5p increases the levels of GSH and excitatory amino acid carrier 1 (EAAC1, official name SLC1A1), the latter being a glutamate and cysteine transporter expressed on mature CNS neurons, contributing in this way to glutathione synthesis. Their results also showed the correlation of the diurnal miR-96-5p rhythm on the levels of neuronal GSH. Consequentially, the average level of miR-96-5p could be a factor determining the average level of GSH [65]. Moreover, to identify the miRNA signature for myocardial RS, Quiles et al. used the Nrf2 expression to generate mouse models exhibiting myocardial RS. These models exhibited increased GSH levels. It was demonstrated that miR-1983, miR-582-5p, miR-208b-3p, miR-1927, miR-361-5p, miR-671-5p, miR-491-5p, miR-34c-3p, and miR-96-5p were significantly upregulated. The miRNA expression profile seems to be conserved, as sulforaphane-induced RS in HL-1 cardiomyocytes exhibited increased levels of miR-208b-3p, miR-1927, miR-671-5p, and miR-96-5p as well [66].

Glutamate cysteine ligase (GCL) required for GSH biosynthesis is a heterodimer made up of glutamate-cysteine ligase modifier subunit (GCLM) and glutamate-cysteine ligase catalytic subunit (GCLC) [67]. In ovarian cancer cell lines that have high expression of GCLC, the expression of GCLC is predicted to be positively regulated by hsa-miR-133a and negatively by hsa-miR-140-3p. In this cellular context, GCLC is shown to exert antiapoptotic effects [68–70]. However, GCLC is also known to be tightly regulated with the negative feedback loop through the Nrf2-Keap1 interplay. There is evidence that Nrf2 expression is directly regulated by miR153, miR27a, miR142-5p, and miR144 independently from the Keap1 interaction [71, 72]. Keap1 mRNA can be targeted by miR-200a, lowering its expression and releasing more Nrf2 into the nucleus, whereas Nrf2 nuclear export is regulated by sirtuin1 (Sirt1) which is targeted by miR-34a [73]. GCLC is also regulated by LINC00942; this lncRNA can be targeted with antisense oligonucleotides to reduce expression of GCLC. It seems to be involved purely with the transcription of GCLC, and LINC00942 is itself transcriptionally regulated by Nrf2 [74]. Clinically relevant variants have been reported for GCLC that affect its binding with GCLM. GCLC protein of Cys248Ala, Cys249Ala, and Pro158Leu variants shows similar binding strength with GCLM as did wild-type GCLC, but they have a large decrease in catalytic activity. Higher quantities of GCLM can sometimes counterbalance the impact of these less efficiently binding variants [75, 76]. For GCLM, an upstream variant C588T has been reported. Using a luciferase reporter gene assay, the variant was shown to have lower promoter activity in response to oxidants and consequently lower GSH levels [77]. GCLC also has a relatively close intergenic LNC RP11-345L23.1 (LINC01564) at 11 kb that could be relevant for its expression [74].

Expression of circulating miR-92a, let-7c, miR-145, and miR-155 was also shown to be significantly reduced in coronary artery disease patients in comparison to the control group [78]. Overexpression of miR-145 decreases the expression of the prostate-specific androgen-regulated lncRNA, Pcgem1 [79]. Pcgem1 regulates expression of glutaminase, type I gamma-glutamyltransferase, and glutathione reductase (GSR), all involved in the metabolism of glutamine, a precursor of glutathione [80]. The overall effect of decreased Pcgem1 is the decreased production of glutathione.

The combined result of microRNAs, mutations of key proteins, and to a lesser extent, lncRNA regulation will set a tissue-specific average level of GSH (Figure 1). When this is low, it can lead to the diseases caused by OS; on the other hand, a high average GSH level will cause a continued state of RS with possible implications for cardiovascular disease.

Figure 1

Overview of key components involved in CV-related reductive stress. Metabolites are shown in blue ovals, proteins in green rounded rectangles, and RNAs (microRNA or lncRNA) in octagonals. If the latter have a positive impact on GSH content, they are colored peach; if negative, they are orange. GSH: glutathione; GCL: glutamate cysteine ligase; GSSG: glutathione disulfide; GS: glutathione synthetase; Keap1: Kelch-like ECH-associated protein 1; Nrf2: nuclear factor erythroid 2-related factor 2; ROS: reactive oxygen species; GSR: glutathione reductase.

5. Glutathione in CVS

5.1. Evidence from Animal Studies

OS leads to a number of diseases, from neurodegenerative disease [81] to CVD and diabetes type II [82]. Using the model of atherosclerosis in mice or the apolipoprotein E-deficient mice, Rosenblat et al. [83] reported that liposomal coated GSH in a dose of 50 mg/kg/day for two months showed significant reduction in serum susceptibility of 2,2-azobis(2-amidinopropane) dihydrochloride (AAPH) oxidation, in a correlation with an increased level of GSH content in peritoneal macrophages, reduction in lipid peroxides [83], and also a decrease of the extent of oxidized LDL. Another study by Lin et al. showed that N-acetyl cysteine (NAC) could increase GSH levels, and consequently, GSH can reduce significantly cholesterol levels in the liver and plasma in mice that are on a high saturated fat diet [84]. One explanation is that GSH increases the expression of cholesterol 7 alpha-hydroxylase, thus resulting in the increased biosynthesis of bile acids from cholesterol [84, 85]. Moreover, depressed GSH synthesis will lead to and/or precede OS and atherogenesis [86]. These results present a novel pathway of how glutathione in this form has antioxidative and antiatherogenic properties and may lead to remission of atherosclerosis [83, 87].

In the hyperglycemic state [88], the production of nitric oxide (NO) and a reduction of antioxidant effects are increased. Using alloxan-induced hyperglycemia into rabbits, the authors investigated the level of nitrotyrosine (as a stable product of nitrosative stress) as a marker for NO-dependent damages. Also, in the same study, the level of GSH was measured. Hyperglycemic rats show that tissues differ (heart vs. brain, liver) in neutralizing nitrosative stress, and this process is placed by different adaptive responses of their GSH redox cycle [88].

In a previous study [89] using the same experimental model, the authors analyzed the effect of pioglitazone, an antidiabetic drug, on the heart. GSH, GSR, GPx, lipid peroxidation products, ascorbic acid, and other parameters were measured. The result from this study shows that pioglitazone increased the GSH system parameters, thus reducing OS, and the authors proposed that similar action improves atherosclerotic problems in diabetic patients.

In the process of atherogenesis, GSH capacity to be synthesized in cells, but especially in macrophages, has an inverse relationship to the initiation and progression of atherosclerosis in ApoE^−/− mice [90]. Results from animal models (hyperlipidemic mice) show that a crucial event for the progression of early vascular lesions (atherosclerotic plaque) is GSH plasma concentrations [83, 90]. These results are supported by the results showing that bone marrow transplants are capable of synthesizing 3x more GSH than normal and show the reduced progression of lesions up to 35% [90]. Reduction in Lp(a), apoB, LDL-c, and total plasma cholesterol has been reported in transhumanized mice with proatherogenic lipid metabolism after administration of ribose cysteine that increases the level of GSH and GPx activity [91].

Glutathione peroxidase 1 is implicated in DM-associated atherogenesis [92]. GPx catalyzes the reaction between glutathione and hydrogen peroxide and is the most abundant (type 1) in all mammalian tissues. In a diabetic apolipoprotein E-deficient mouse model [92], decreased levels or lack of GPx-1 accelerates diabetes-associated atherosclerosis. Other animal studies [93, 94] showed that GPx-1 when reduced increases the level of the cell LDL oxidation process. These results show that GPx-1 which is present in the mitochondria and the cytosol is a critical enzyme in the protection of vessels from OS and atherogenesis.

Altered silencing of protein activity by noncoding RNA fragments (miRNA) has been proposed to be a mechanism that may impact CVD [95]. New research [96] shows that microRNAs are possible regulators of expression of GPx in obesity-related pathologies. miRNA 494 was found in an in vivo model to regulate plaque size and the stability of the lesions and decrease the occurrence of rupture [97]. miRNA 27a and miRNA 223 contribute to cholesterol homeostasis [98, 99]. Also, Milenkovic et al. [100] reported that plant polyphenols could modulate the expression miRNAs in ApoE-deficient mice.

Special attention should be made on exogenous miRNA as it can be absorbed by our diet and by the gastrointestinal tract and reaching plasma levels in stable microvesicles [101] and consequently modulate and influence a number of antioxidant proteins, including GSH [102].

Results from in vivo studies show that pharmacological interventions modestly protect against the development of early fat streak in the aortic sinus [87]. These results coincide with human intervention studies that show that antioxidant supplementation does not coincide with any progress in the attenuation of CVD in mice and humans [103, 104]. Furthermore, interventions on the GSH system by increasing its endogenous levels show a promising strategy to enhance its antiatherogenic effects [105–108]. Changes in the GSH content in macrophages also affect NFκB and other proinflammatory cytokines that are responsible for the stimulation adhesion molecules in endothelial cells and recruitment of monocytes or macrophages in arterial lesions [109, 110]. These effects are strengthened by the notion that increasing and decreasing levels of antioxidants of the GSH system in macrophages are sufficient to impact the already established atherosclerotic process [108].

5.2. Evidence from Human Studies

There are numerous results from both animal (Table 1) and human (Table 2) studies showing beneficial effects of GSH on CVS [111, 112]. Depletion of GSH increases predisposition to OS and leads to the occurrence of many diseases, including CVD. Several studies reported that patients with heart disease and diabetes have a lower level of plasma GSH [113, 114].

One of the first retrospective population-based case-control studies that evaluated the level of GSH in patients with CVD was conducted in the mid-90s in Japan. In the Hisayama study, Shimizu et al. [113] examined the level of total GSH in plasma and red blood cells of 134 patients with stroke and myocardial infarction. Results show that the increased level of GSH leads to decreased values of systolic and diastolic pressures and that the increased level of GSH is also followed by a decreased incidence of diabetes. Furthermore, the same authors reported that patients with CVD have a lower level of GSH compared with control subjects with no previous history of CVD [113]. Similar results were obtained in another study, where decreased levels of GSH and enzymes involved in GSH synthesis were measured in patients with type 2 diabetes mellitus (T2DM). In contrary, the level of GSSG and transforming growth factor beta (TGF-β) was significantly higher in diabetic patients compared with healthy controls. In this study, the authors demonstrated that the increased level of proinflammatory cytokines (e.g., TGF-β) decreases expression of enzymes involved in GSH synthesis, such as GS and GCL, and thus affect GSH decrease faster than it could be synthesized [115].

Chaves et al. [116] in order to assess the role of OS in hypertension measured the levels of GSH and GSSG in mononuclear cells of 38 control subjects and 35 patients with nontreated hypertension. Parameters of OS were measured in both groups, at the beginning of a study and three months after the administration of different antihypertensive therapies to individuals with hypertension. Results show that the level of GSH was decreased in hypertensive patients while the level of GSSG was increased compared with control subjects. On the other hand, three months of antihypertensive therapy decreased the level of OS and GSSG and increased the level of GSH in hypertensive patients [116]. Similar results were obtained in an observational study by Redon et al. [117] where the level of GSH was decreased while the level of GSSG was increased in mononuclear cells of 66 hypertensive patients compared with 16 control subjects without hypertension. Authors pointed out the importance of OS in the onset of hypertension and further development of the CVD [116, 117]. Also, Robaczewska et al. [118] suggested that the level of GSH and enzymes involved in the synthesis of GSH is disturbed in old people with diagnosed hypertension. Rybka et al. [119] went a step further and investigated the effect of different types of antihypertensive drugs on the level of GSH and enzymes involved in the synthesis of GSH in old people. The study was conducted on 18 patients diagnosed as hypertensive who were on antihypertensive therapy and 15 healthy controls. Measurement of the level of GSH, the activity of GSH, and other values of all antioxidant enzymes was higher in hypertensive patients on antihypertensive therapy compared with healthy subjects, and this hint that antihypertensive therapy has positive effects on the antioxidant system in elderly people [119].

Damy et al. [120] evaluated results of the level of GSH in 76 patients who had some form of cardiac surgery (heart transplantation, coronary artery bypass grafting, ventricular assist device implantation, and aortic valve replacement). In this study, the level of GSH was measured during surgery in right atrial appendages and blood. The authors noticed that the lower level of GSH was in patients with coronary artery disease and that this decrease in the GSH level was consistent with the severity of left ventricular dysfunction [120]. Additionally, in comparison with healthy controls, the level of GSH was 21% and 40% decreased in patients with asymptomatic and symptomatic CVD, respectively. From these results, the authors concluded that decreases in the level of GSH are closely linked to cardiac abnormalities in patients with CVD. Furthermore, since these results show that the level of GSH was also decreased in patients with still undetected CVD, authors suggested that a blood test for measuring the level of GSH should be used as a new biomarker for detection of asymptomatic patients with CVD [120].

During cardiac procedures, increased OS could lead to myocardial infarction (MI). Glutathione S-transferase (GST) polymorphism is identified as one of the factors that could lead to an increased incidence of MI during cardiac surgery. To investigate the association between GST polymorphism and MI, Kovacs et al. [121] conducted a study on 758 patients that had cardiac surgery. After measuring levels of troponin 1 (T1) and myocardial-based creatine kinase (CKMB), two groups of patients were formed. The control group consisted of 78 patients, with no signs of MI and with double values of T1 and CKMB after surgery, while the second group consisted of 54 patients, with signs of MI after cardiac surgery and with five times higher values of T1 and CKMB. Both groups of patients underwent genetic testing for the presence of GST polymorphism (GST P1, alleles A, B, and C). Results show that the presence of BB allele was higher in the control group of the patient without MI. On the other hand, allele AC was detected in a group of patients with MI. Authors suggested that the presence of allele B may have a protective role in the development of MI, while the presence of alleles A and C was associated with increased risk for MI [121].

Glutathione peroxidase has an important role in OS. Decreased activity of GPx-1 increases risks for stroke and coronary heart disease [122, 123]. The level of erythrocyte GPx-1, in a study of 83 patients who died from some form of CVD or had a myocardial infarction and 553 control subjects without any CVD, was lower in patients with CVD compared with control subjects [123]. These results show that GPx-1 is inversely associated with CVD and also that GPx-1 is important for maintenance of a normal level of GSH. Authors predicted that measuring the level of erythrocyte GPx-1 could be used as prognostic value and that increasing the level of GPx-1 could have a beneficial effect on CVS [123].

Investigation of connection between GPx-1 polymorphism and development of atherosclerosis in 184 Japanese patients with the T2DM show that GPx-1 is the most important enzyme, with the protective role in the development of endothelial dysfunction and atherosclerosis in diabetes. In this study, patients were divided into two groups, depending on the presence of GPx-1 genotype (Pro/Pro: ; Pro/Leu: ), and intima-media thickness (IMT) of carotid arteries was measured. Results show higher values of IMT in the Pro/Leu group compared with values of IMT measured in the Pro/Pro group of subjects. Since increased IMT values are positively related with the onset of atherosclerosis, authors concluded that incidence of CVD was higher in a group of patients with GPx-1 Pro/Leu genotype, which is also consistent with obtained values of IMT measurement [94].

Gene expression for biosynthesis of glutamate-ammonia ligase depends on single nucleotide polymorphism (SNP) rs10911021. SNP rs10911021 is also associated with coronary heart disease (CHD) in diabetic patients. In a study with 425 patients with CHD, where 275 of them were diabetic, a direct association between SNP rs10911021 and diabetes was found among CHD patients. The level of GSH was lower, while the GSSG level was higher in patients compared with controls. These results suggest that the presence of SNP rs10911021 may affect the risk for an increase of CHD in diabetes by promoting OS [124].

De Mattia et al. [125] in a randomized, double-blind cross-over study with 15 diabetic patients tested the hypothesis that the level of vascular cell adhesion protein 1 (VCAM-1), which is increased in atherosclerosis, could be decreased by administration of antioxidant agents. Patients received oral NAC in a dose of 1200 mg per day or placebo for one month, and the results show that administration of NAC increased levels of GSH as well as the ratio GSH : GSSG, while reduced levels of VCAM-1 and GSSG. The decrease of endothelial adhesion molecules after NAC treatment could prevent vascular damage in patients with diabetes [125].

In an open-label pilot study, Szkudlinska et al. [126] tested their hypothesis that oral administration of NAC decreases markers of OS, increases levels of GSH, and thus improves β-cell function in patients with diabetes. For 30 days, 13 subjects with T2DM were on NAC treatment. During the first two weeks, subjects were treated with oral NAC in a dose 600 mg, twice a day, and for the last two weeks twice a day with a double dose of oral NAC (1200 mg). Markers of OS, GSH, and GSH/GSSG were measured after two and four weeks of NAC supplementation. At the end of study, authors concluded that oral administration of NAC had no effect in patients with T2DM and that levels of GSH and GSH/GSSG remain unchanged [126].

Most of the studies where attention was on the effects of oral administration of GSH show that the level of GSH remains the same in cells, especially in red blood cells [127]. Effect of oral GSH on markers of OS (GSH, GSSG, and GSH : GSSG) was tested in 40 healthy adults. After four weeks of oral administration of GSH (500 mg twice a day), no change in markers of OS was observed [128]. In contrary, in a 6-month placebo-controlled, randomized, double-blinded trial effects of different doses (low dose of GSH (250 mg/day) or high dose of GSH (1000 mg/day)) of oral administration of GSH on the level of GSH in lymphocytes, erythrocytes, and plasma show that the level of GSH was increased in lymphocytes, erythrocytes, and plasma in the high-dose group of patients, while in the low-dose group of patients, increases were detected in erythrocyte counts only. Furthermore, results from the same study show that the increased level of GSH was only observed during administration of oral GSH supplementation, and after one month without treatment, the level of GSH returned to normal [111].

Oral administration of GSH may not be the best solution since it was shown that intestinal and hepatic GGT have the ability to metabolize GSH and thus decrease the level of administered GSH [129]. To evaluate the level of GSH in blood, Buonocore et al. [130] analyzed effects of pure GSH in the form of an orobuccal tablet with a fast-slow release on 15 healthy volunteers and concluded that the increased level of GSH in blood is probably a result of GSH absorption through mouth mucosa. In a randomized crossover study performed by Schmitt et al. [129], authors compared the level of GSH and other markers of OS in the blood of 20 subjects with metabolic syndrome after administration of different forms of GSH (oral and sublingual) and NAC. For three weeks, randomly selected subjects received oral or sublingual GSH in a 450 mg dose or a NAC in a 200 mg dose. The experiment was repeated two more times, with two weeks without treatment before the next administration of GSH or NAC. Results show that administration of sublingual GSH compared to oral GSH leads to an increase in the level of GSH and the GSH/GSSG ratio. Also, increased levels of GSH and GSH/GSSG were detected comparing the effects of sublingual GSH with NAC. Since overproduction of ROS is involved in the development of metabolic syndrome, authors concluded that administration of the sublingual form of GSH could be a possible treatment for decreasing OS and preventing the occurrence of metabolic syndrome [129]. Another study on human subjects investigated the effect of intracoronary infusion of GSH to patients admitted to the hospital for chest pain and which were planned for cardiac catheterization. All 26 patients were injected with acetylcholine (Ach) (50 mg/min) into the left coronary artery. After 15 minutes, 14 patients received in the same manner GSH (50 mg/min for 6 min), while the remaining 12 patients were treated with the same dose of saline. Authors noticed that a combination of Ach and GSH has vasodilatory effects on coronary arteries and increases blood flow but does not affect blood pressure. On the other hand, no effect was noticed in patients that received a combination of Ach and saline. Authors concluded that GSH has positive effects on CVS, increases dilatation of human arteries, and suggest that these positive effects could be mediated via activation of NO synthase or guanylate cyclase [112].

6. Concluding Remarks

Glutathione plays an important etiological role in the development of numerous diseases, such as cardiometabolic disease and CVD [6–9]. To avoid negative health consequences, the redox homeostasis has to be preserved, with glutathione as one of the key etiological factors in these processes. Despite many available literature data, the role of glutathione, in both normal and pathological conditions, such as CVD, still remains unclear. The literature data discussed in this review that are related to the effects of glutathione, the most abundant antioxidant in the heart, in CVS, suggests that glutathione has an important role in cell redox homeostatic mechanisms that have been shifted towards OS or RS. Further studies should focus on the understanding of the molecular mechanisms underlying the effects of glutathione in physiological conditions as well as in pathological conditions.

Abbreviations

Ach:	Acetylcholine
CVS:	Cardiovascular system
CVD:	Cardiovascular disease
CHD:	Coronary heart disease
CSO:	Cardiac-specific overexpression
CKMB:	Creatine kinase myocardial-based
GSH:	Glutathione
GCL:	Glutamate cysteine ligase
GSSG:	Glutathione disulfide
GS:	Glutathione synthetase
GST:	Glutathione S-transferase
GPx:	Glutathione peroxidase
GSR:	Glutathione reductase
GGT:	Gamma-glutamyl transferase
GCLM:	Glutamate-cysteine ligase modifier subunit
GCLC:	Glutamate-cysteine ligase catalytic subunit
G6PD:	Glucose-6-phosphate dehydrogenase
Hsp27:	Heat shock protein 27
IMT:	Intima-media thickness
Keap1:	Kelch-like ECH-associated protein 1
LMW-PTP:	Low molecular weight protein tyrosine phosphatase
LDL:	Low-density lipoproteins
lncRNA:	Long noncoding RNA
MI:	Myocardial infarction
NAC:	N-Acetyl cysteine
Nrf2:	Nuclear factor erythroid 2-related factor 2
NOX4:	NADPH oxidase-4
OS:	Oxidative stress
ROS:	Reactive oxygen species
RS:	Reductive stress
T2DM:	Type 2 diabetes mellitus
TGF-β:	Transforming growth factor beta
T1:	Troponin 1
VCAM-1:	Vascular cell adhesion protein 1
VEGF:	Vascular endothelial growth factor.

Disclosure

This work is part of the collaboration between the Laboratory of Radiobiology and Molecular Genetics, Institute of Nuclear Sciences Vinca, University of Belgrade, Belgrade, Serbia, and King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Thuwal, Saudi Arabia.

Conflicts of Interest

The authors have no conflicts of interest.

Acknowledgments

This work has been supported by grants from the Ministry of Education, Science and Technological Development, Republic of Serbia (No. 173033 (ERI), No. 173034 (BSP), and No. 41002 (DjR)). VBB has been supported by the King Abdullah University of Science and Technology (KAUST) Base Research Fund (BAS/1/1606-01-01) and ME by KAUST Office of Sponsored Research (OSR) Awards (No. FCC/1/1976-24-01).

References

A. Meister and M. E. Anderson, “Glutathione,” Annual Review of Biochemistry, vol. 52, no. 1, pp. 711–760, 1983.
View at: Publisher Site | Google Scholar
H. Jefferies, J. Coster, A. Khalil, J. Bot, R. D. McCauley, and J. C. Hall, “Glutathione,” ANZ Journal of Surgery, vol. 73, no. 7, pp. 517–522, 2003.
View at: Publisher Site | Google Scholar
H. Sies, “Glutathione and its role in cellular functions,” Free Radical Biology & Medicine, vol. 27, no. 9-10, pp. 916–921, 1999.
View at: Publisher Site | Google Scholar
J. P. Shaw and I. N. Chou, “Elevation of intracellular glutathione content associated with mitogenic stimulation of quiescent fibroblasts,” Journal of Cellular Physiology, vol. 129, no. 2, pp. 193–198, 1986.
View at: Publisher Site | Google Scholar
C. L. Hammond, T. K. Lee, and N. Ballatori, “Novel roles for glutathione in gene expression, cell death, and membrane transport of organic solutes,” Journal of Hepatology, vol. 34, no. 6, pp. 946–954, 2001.
View at: Publisher Site | Google Scholar
M. Reid and F. Jahoor, “Glutathione in disease,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 4, no. 1, pp. 65–71, 2001.
View at: Publisher Site | Google Scholar
T. P. Dalton, Y. Chen, S. N. Schneider, D. W. Nebert, and H. G. Shertzer, “Genetically altered mice to evaluate glutathione homeostasis in health and disease,” Free Radical Biology and Medicine, vol. 37, no. 10, pp. 1511–1526, 2004.
View at: Publisher Site | Google Scholar
G. Wu, Y. Z. Fang, S. Yang, J. R. Lupton, and N. D. Turner, “Glutathione metabolism and its implications for health,” The Journal of Nutrition, vol. 134, no. 3, pp. 489–492, 2004.
View at: Publisher Site | Google Scholar
R. Franco, O. J. Schoneveld, A. Pappa, and M. I. Panayiotidis, “The central role of glutathione in the pathophysiology of human diseases,” Archives of Physiology and Biochemistry, vol. 113, no. 4-5, pp. 234–258, 2007.
View at: Publisher Site | Google Scholar
C. Espinosa-Díez, V. Miguel, S. Vallejo et al., “Role of glutathione biosynthesis in endothelial dysfunction and fibrosis,” Redox Biology, vol. 14, pp. 88–99, 2018.
View at: Publisher Site | Google Scholar
B. J. Mills, M. M. Weiss, C. A. Lang, M. C. Liu, and C. Ziegler, “Blood glutathione and cysteine changes in cardiovascular disease,” Journal of Laboratory and Clinical Medicine, vol. 135, no. 5, pp. 396–401, 2000.
View at: Publisher Site | Google Scholar
C. A. Chen, T. Y. Wang, S. Varadharaj et al., “S-Glutathionylation uncouples eNOS and regulates its cellular and vascular function,” Nature, vol. 468, no. 7327, pp. 1115–1118, 2010.
View at: Publisher Site | Google Scholar
M. Deponte, “The incomplete glutathione puzzle: just guessing at numbers and figures?” Antioxidants & Redox Signaling, vol. 27, no. 15, pp. 1130–1161, 2017.
View at: Publisher Site | Google Scholar
M. H. Hanigan, “Gamma-glutamyl transpeptidase: redox regulation and drug resistance,” Advances in Cancer Research, vol. 122, pp. 103–141, 2014.
View at: Publisher Site | Google Scholar
J. Martensson, J. C. Lai, and A. Meister, “High-affinity transport of glutathione is part of a multicomponent system essential for mitochondrial function,” Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 18, pp. 7185–7189, 1990.
View at: Publisher Site | Google Scholar
G. Lian, J. R. Gnanaprakasam, T. Wang et al., “Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation,” elife, vol. 7, 2018.
View at: Publisher Site | Google Scholar
M. Deponte, “Glutathione catalysis and the reaction mechanisms of glutathione-dependent enzymes,” Biochimica et Biophysica Acta (BBA) - General Subjects, vol. 1830, no. 5, pp. 3217–3266, 2013.
View at: Publisher Site | Google Scholar
D. A. Dickinson and H. J. Forman, “Cellular glutathione and thiols metabolism,” Biochemical Pharmacology, vol. 64, no. 5-6, pp. 1019–1026, 2002.
View at: Publisher Site | Google Scholar
S. K. Bhardwaj, M. L. Sharma, G. Gulati et al., “Effect of starvation and insulin-induced hypoglycemia on oxidative stress scavenger system and electron transport chain complexes from rat brain, liver, and kidney,” Molecular and Chemical Neuropathology, vol. 34, no. 2-3, pp. 157–168, 1998.
View at: Publisher Site | Google Scholar
C. M. Krejsa, C. C. Franklin, C. C. White, J. A. Ledbetter, G. L. Schieven, and T. J. Kavanagh, “Rapid activation of glutamate cysteine ligase following oxidative stress,” Journal of Biological Chemistry, vol. 285, no. 21, pp. 16116–16124, 2010.
View at: Publisher Site | Google Scholar
C. Gaucher, A. Boudier, J. Bonetti, I. Clarot, P. Leroy, and M. Parent, “Glutathione: antioxidant properties dedicated to nanotechnologies,” Antioxidants, vol. 7, no. 5, p. 62, 2018.
View at: Publisher Site | Google Scholar
M. S. Yang, H. W. Chan, and L. C. Yu, “Glutathione peroxidase and glutathione reductase activities are partially responsible for determining the susceptibility of cells to oxidative stress,” Toxicology, vol. 226, no. 2-3, pp. 126–130, 2006.
View at: Publisher Site | Google Scholar
F. Q. Schafer and G. R. Buettner, “Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple,” Free Radical Biology & Medicine, vol. 30, no. 11, pp. 1191–1212, 2001.
View at: Publisher Site | Google Scholar
I. Rebrin and R. S. Sohal, “Comparison of thiol redox state of mitochondria and homogenates of various tissues between two strains of mice with different longevities,” Experimental Gerontology, vol. 39, no. 10, pp. 1513–1519, 2004.
View at: Publisher Site | Google Scholar
A. J. Cooper, J. T. Pinto, and P. S. Callery, “Reversible and irreversible protein glutathionylation: biological and clinical aspects,” Expert Opinion on Drug Metabolism & Toxicology, vol. 7, no. 7, pp. 891–910, 2011.
View at: Publisher Site | Google Scholar
I. Dalle-Donne, R. Rossi, D. Giustarini, R. Colombo, and A. Milzani, “S-Glutathionylation in protein redox regulation,” Free Radical Biology & Medicine, vol. 43, no. 6, pp. 883–898, 2007.
View at: Publisher Site | Google Scholar
P. T. Kang, C. L. Chen, and Y. R. Chen, “Increased mitochondrial prooxidant activity mediates up-regulation of complex I S-glutathionylation via protein thiyl radical in the murine heart of eNOS^−/−,” Free Radical Biology & Medicine, vol. 79, pp. 56–68, 2015.
View at: Publisher Site | Google Scholar
A. Pastore and F. Piemonte, “Protein glutathionylation in cardiovascular diseases,” International Journal of Molecular Sciences, vol. 14, no. 10, pp. 20845–20876, 2013.
View at: Publisher Site | Google Scholar
D. N. P. Munkanatta Godage, G. C. VanHecke, K. T. G. Samarasinghe et al., “SMYD2 glutathionylation contributes to degradation of sarcomeric proteins,” Nature Communications, vol. 9, no. 1, p. 4341, 2018.
View at: Publisher Site | Google Scholar
P. Eaton, N. Wright, D. J. Hearse, and M. J. Shattock, “Glyceraldehyde phosphate dehydrogenase oxidation during cardiac ischemia and reperfusion,” Journal of Molecular and Cellular Cardiology, vol. 34, no. 11, pp. 1549–1560, 2002.
View at: Publisher Site | Google Scholar
F. C. Chen and O. Ogut, “Decline of contractility during ischemia-reperfusion injury: actin glutathionylation and its effect on allosteric interaction with tropomyosin,” American Journal of Physiology-Cell Physiology, vol. 290, no. 3, pp. C719–C727, 2006.
View at: Publisher Site | Google Scholar
D. R. Pimentel, T. Adachi, Y. Ido et al., “Strain-stimulated hypertrophy in cardiac myocytes is mediated by reactive oxygen species-dependent Ras S-glutathiolation,” Journal of Molecular and Cellular Cardiology, vol. 41, no. 4, pp. 613–622, 2006.
View at: Publisher Site | Google Scholar
C. Pantano, N. L. Reynaert, A. V. D. Vliet, and Y. M. W. Janssen–Heininger, “Redox-sensitive kinases of the nuclear factor-κB signaling pathway,” Antioxidants & Redox Signaling, vol. 8, no. 9-10, pp. 1791–1806, 2006.
View at: Publisher Site | Google Scholar
Y. Wang, M. Qiao, J. J. Mieyal, L. M. Asmis, and R. Asmis, “Molecular mechanism of glutathione-mediated protection from oxidized low-density lipoprotein-induced cell injury in human macrophages: role of glutathione reductase and glutaredoxin,” Free Radical Biology & Medicine, vol. 41, no. 5, pp. 775–785, 2006.
View at: Publisher Site | Google Scholar
M. Okuda, N. Inoue, H. Azumi et al., “Expression of glutaredoxin in human coronary arteries: its potential role in antioxidant protection against atherosclerosis,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 21, no. 9, pp. 1483–1487, 2001.
View at: Publisher Site | Google Scholar
Y. R. Chen, C. L. Chen, D. R. Pfeiffer, and J. L. Zweier, “Mitochondrial complex II in the post-ischemic heart: oxidative injury and the role of protein S-glutathionylation,” Journal of Biological Chemistry, vol. 282, no. 45, pp. 32640–32654, 2007.
View at: Publisher Site | Google Scholar
K. Nonaka, N. Kume, Y. Urata et al., “Serum levels of S-glutathionylated proteins as a risk-marker for arteriosclerosis obliterans,” Circulation Journal, vol. 71, no. 1, pp. 100–105, 2007.
View at: Publisher Site | Google Scholar
M. Narasimhan and N. S. Rajasekaran, “Reductive potential — a savior turns stressor in protein aggregation cardiomyopathy,” Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, vol. 1852, no. 1, pp. 53–60, 2015.
View at: Publisher Site | Google Scholar
M. A. Abdelsaid and A. B. El-Remessy, “S-Glutathionylation of LMW-PTP regulates VEGF-mediated FAK activation and endothelial cell migration,” Journal of Cell Science, vol. 125, no. 20, pp. 4751–4760, 2012, Pt 20.
View at: Publisher Site | Google Scholar
S. E. Bursell and G. L. King, “The potential use of glutathionyl hemoglobin as a clinical marker of oxidative stress,” Clinical Chemistry, vol. 46, no. 2, pp. 145-146, 2000.
View at: Google Scholar
T. Niwa, C. Naito, A. H. Mawjood, and K. Imai, “Increased glutathionyl hemoglobin in diabetes mellitus and hyperlipidemia demonstrated by liquid chromatography/electrospray ionization-mass spectrometry,” Clinical Chemistry, vol. 46, no. 1, pp. 82–88, 2000.
View at: Google Scholar
A. Pastore, G. Federici, E. Bertini, and F. Piemonte, “Analysis of glutathione: implication in redox and detoxification,” Clinica Chimica Acta, vol. 333, no. 1, pp. 19–39, 2003.
View at: Publisher Site | Google Scholar
A. Paolicchi, S. Dominici, L. Pieri, E. Maellaro, and A. Pompella, “Glutathione catabolism as a signaling mechanism,” Biochemical Pharmacology, vol. 64, no. 5-6, pp. 1027–1035, 2002.
View at: Publisher Site | Google Scholar
S. Dominici, A. Paolicchi, A. Corti, E. Maellaro, and A. Pompella, “Prooxidant Reactions Promoted by Soluble and Cell‐Bound γ‐Glutamyltransferase Activity,” Methods in Enzymology, vol. 401, pp. 484–501, 2005.
View at: Publisher Site | Google Scholar
A. Corti, T. L. Duarte, C. Giommarelli et al., “Membrane gamma-glutamyl transferase activity promotes iron-dependent oxidative DNA damage in melanoma cells,” Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, vol. 669, no. 1-2, pp. 112–121, 2009.
View at: Publisher Site | Google Scholar
A. Wendel, “Measurement of in vivo lipid peroxidation and toxicological significance,” Free Radical Biology & Medicine, vol. 3, no. 5, pp. 355–358, 1987.
View at: Publisher Site | Google Scholar
I. Perez-Torres, V. Guarner-Lans, and M. E. Rubio-Ruiz, “Reductive stress in inflammation-associated diseases and the pro-oxidant effect of antioxidant agents,” International Journal of Molecular Sciences, vol. 18, no. 10, p. 2098, 2017.
View at: Publisher Site | Google Scholar
F. Salvemini, A. Franzé, A. Iervolino, S. Filosa, S. Salzano, and M. V. Ursini, “Enhanced glutathione levels and oxidoresistance mediated by increased glucose-6-phosphate dehydrogenase expression,” Journal of Biological Chemistry, vol. 274, no. 5, pp. 2750–2757, 1999.
View at: Publisher Site | Google Scholar
X. Préville, F. Salvemini, S. Giraud et al., “Mammalian small stress proteins protect against oxidative stress through their ability to increase glucose-6-phosphate dehydrogenase activity and by maintaining optimal cellular detoxifying machinery,” Experimental Cell Research, vol. 247, no. 1, pp. 61–78, 1999.
View at: Publisher Site | Google Scholar
S. H. Baek, J. N. Min, E. M. Park et al., “Role of small heat shock protein HSP25 in radioresistance and glutathione-redox cycle,” Journal of Cellular Physiology, vol. 183, no. 1, pp. 100–107, 2000.
View at: Publisher Site | Google Scholar
M. McMahon, K. Itoh, M. Yamamoto, and J. D. Hayes, “Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression,” Journal of Biological Chemistry, vol. 278, no. 24, pp. 21592–21600, 2003.
View at: Publisher Site | Google Scholar
M. Zhang, A. C. Brewer, K. Schroder et al., “NADPH oxidase-4 mediates protection against chronic load-induced stress in mouse hearts by enhancing angiogenesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 42, pp. 18121–18126, 2010.
View at: Publisher Site | Google Scholar
A. C. Brewer, T. V. A. Murray, M. Arno et al., “Nox4 regulates Nrf2 and glutathione redox in cardiomyocytes in vivo,” Free Radical Biology & Medicine, vol. 51, no. 1, pp. 205–215, 2011.
View at: Publisher Site | Google Scholar
N. S. Rajasekaran, P. Connell, E. S. Christians et al., “Human αB-crystallin mutation causes oxido-reductive stress and protein aggregation cardiomyopathy in mice,” Cell, vol. 130, no. 3, pp. 427–439, 2007.
View at: Publisher Site | Google Scholar
T. Ida, T. Sawa, H. Ihara et al., “Reactive cysteine persulfides and S-polythiolation regulate oxidative stress and redox signaling,” Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 21, pp. 7606–7611, 2014.
View at: Publisher Site | Google Scholar
A. Torreggiani, C. Chatgilialoglu, C. Ferreri, M. Melchiorre, S. Atrian, and M.'. Capdevila, “Non-enzymatic modifications in metallothioneins connected to lipid membrane damages: structural and biomimetic studies under reductive radical stress,” Journal of Proteomics, vol. 92, pp. 204–215, 2013.
View at: Publisher Site | Google Scholar
H. Zhang, N. S. Rajasekaran, A. Orosz, X. Xiao, M. Rechsteiner, and I. J. Benjamin, “Selective degradation of aggregate-prone CryAB mutants by HSPB1 is mediated by ubiquitin–proteasome pathways,” Journal of Molecular and Cellular Cardiology, vol. 49, no. 6, pp. 918–930, 2010.
View at: Publisher Site | Google Scholar
Q. He, M. Wang, C. Petucci, S. J. Gardell, and X. Han, “Rotenone induces reductive stress and triacylglycerol deposition in C2C12 cells,” The International Journal of Biochemistry & Cell Biology, vol. 45, no. 12, pp. 2749–2755, 2013.
View at: Publisher Site | Google Scholar
Q. Yu, C. F. Lee, W. Wang et al., “Elimination of NADPH oxidase activity promotes reductive stress and sensitizes the heart to ischemic injury,” Journal of the American Heart Association, vol. 3, no. 1, article e000555, 2014.
View at: Publisher Site | Google Scholar
X. Zhang, X. Min, C. Li et al., “Involvement of reductive stress in the cardiomyopathy in transgenic mice with cardiac-specific overexpression of heat shock protein 27,” Hypertension, vol. 55, no. 6, pp. 1412–1417, 2010.
View at: Publisher Site | Google Scholar
T. J. Schulz, K. Zarse, A. Voigt, N. Urban, M. Birringer, and M. Ristow, “Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress,” Cell Metabolism, vol. 6, no. 4, pp. 280–293, 2007.
View at: Publisher Site | Google Scholar
M. Ristow and S. Schmeisser, “Extending life span by increasing oxidative stress,” Free Radical Biology & Medicine, vol. 51, no. 2, pp. 327–336, 2011.
View at: Publisher Site | Google Scholar
L. Fang, A. H. Ellims, X. L. Moore et al., “Circulating microRNAs as biomarkers for diffuse myocardial fibrosis in patients with hypertrophic cardiomyopathy,” Journal of Translational Medicine, vol. 13, no. 1, p. 314, 2015.
View at: Publisher Site | Google Scholar
C. Kinoshita, K. Aoyama, N. Matsumura, K. Kikuchi-Utsumi, M. Watabe, and T. Nakaki, “Rhythmic oscillations of the microRNA miR-96-5p play a neuroprotective role by indirectly regulating glutathione levels,” Nature Communications, vol. 5, no. 1, p. 3823, 2014.
View at: Publisher Site | Google Scholar
K. Aoyama, N. Matsumura, M. Watabe, and T. Nakaki, “Oxidative stress on EAAC1 is involved in MPTP-induced glutathione depletion and motor dysfunction,” European Journal of Neuroscience, vol. 27, no. 1, pp. 20–30, 2008.
View at: Publisher Site | Google Scholar
J. M. Quiles, M. Narasimhan, G. Shanmugam, T. Mosbruger, and N. S. Rajasekaran, “A novel microRNA signature in myocardial reductive stress,” Free Radical Biology & Medicine, vol. 100, article S149, 2016.
View at: Publisher Site | Google Scholar
A. Meister, “[3] Glutathione biosynthesis and its inhibition,” Methods in Enzymology, vol. 252, pp. 26–30, 1995.
View at: Publisher Site | Google Scholar
A. K. Godwin, A. Meister, P. J. O'Dwyer, C. S. Huang, T. C. Hamilton, and M. E. Anderson, “High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 7, pp. 3070–3074, 1992.
View at: Publisher Site | Google Scholar
D. Botta, C. C. Franklin, C. C. White et al., “Glutamate-cysteine ligase attenuates TNF-induced mitochondrial injury and apoptosis,” Free Radical Biology & Medicine, vol. 37, no. 5, pp. 632–642, 2004.
View at: Publisher Site | Google Scholar
G. D. Miles, M. Seiler, L. Rodriguez, G. Rajagopal, and G. Bhanot, “Identifying microRNA/mRNA dysregulations in ovarian cancer,” BMC Research Notes, vol. 5, no. 1, p. 164, 2012.
View at: Publisher Site | Google Scholar
M. Narasimhan, D. Patel, D. Vedpathak, M. Rathinam, G. Henderson, and L. Mahimainathan, “Identification of novel microRNAs in post-transcriptional control of Nrf2 expression and redox homeostasis in neuronal, SH-SY5Y cells,” PLoS One, vol. 7, no. 12, article e51111, 2012.
View at: Publisher Site | Google Scholar
H. Y. Xing, Y. Q. Cai, X. F. Wang et al., “The cytoprotective effect of hyperoside against oxidative stress is mediated by the Nrf2-ARE signaling pathway through GSK-3β inactivation,” PLoS One, vol. 10, no. 12, article e0145183, 2015.
View at: Publisher Site | Google Scholar
K. Richter, A. Konzack, T. Pihlajaniemi, R. Heljasvaara, and T. Kietzmann, “Redox-fibrosis: impact of TGFβ1 on ROS generators, mediators and functional consequences,” Redox Biology, vol. 6, pp. 344–352, 2015.
View at: Publisher Site | Google Scholar
C. Bode, B. Buchwald, and H. Goebell, “Suppression of ethanol degradation caused by protein deficiency in man,” Deutsche Medizinische Wochenschrift, vol. 96, no. 40, pp. 1576-1577, 1971.
View at: Google Scholar
Y. Yang, Y. Chen, E. Johansson et al., “Interaction between the catalytic and modifier subunits of glutamate-cysteine ligase,” Biochemical Pharmacology, vol. 74, no. 2, pp. 372–381, 2007.
View at: Publisher Site | Google Scholar
M. N. Willis, Y. Liu, E. I. Biterova et al., “Enzymatic defects underlying hereditary glutamate cysteine ligase deficiency are mitigated by association of the catalytic and regulatory subunits,” Biochemistry, vol. 50, no. 29, pp. 6508–6517, 2011.
View at: Publisher Site | Google Scholar
S. Nakamura, K. Kugiyama, S. Sugiyama et al., “Polymorphism in the 5-flanking region of human glutamate-cysteine ligase modifier subunit gene is associated with myocardial infarction,” Circulation, vol. 105, no. 25, pp. 2968–2973, 2002.
View at: Publisher Site | Google Scholar
J. Faccini, J. B. Ruidavets, P. Cordelier et al., “Circulating miR-155, miR-145 and let-7c as diagnostic biomarkers of the coronary artery disease,” Scientific Reports, vol. 7, no. 1, article 42916, 2017.
View at: Publisher Site | Google Scholar
J. H. He, J. Z. Zhang, Z. P. Han, L. Wang, Y. B. Lv, and Y. G. Li, “Reciprocal regulation of PCGEM1 and miR-145 promote proliferation of LNCaP prostate cancer cells,” Journal of Experimental & Clinical Cancer Research, vol. 33, no. 1, p. 72, 2014.
View at: Publisher Site | Google Scholar
F. O. Beltran-Anaya, A. Cedro-Tanda, A. Hidalgo-Miranda, and S. L. Romero-Cordoba, “Insights into the regulatory role of non-coding RNAs in cancer metabolism,” Frontiers in Physiology, vol. 7, p. 342, 2016.
View at: Publisher Site | Google Scholar
G. Perry, R. J. Castellani, K. Hirai, and M. A. Smith, “Reactive oxygen species mediate cellular damage in Alzheimer disease,” Journal of Alzheimer's Disease, vol. 1, no. 1, pp. 45–55, 1998.
View at: Publisher Site | Google Scholar
E. Wright Jr., J. L. Scism-Bacon, and L. C. Glass, “Oxidative stress in type 2 diabetes: the role of fasting and postprandial glycaemia,” International Journal of Clinical Practice, vol. 60, no. 3, pp. 308–314, 2006.
View at: Publisher Site | Google Scholar
M. Rosenblat, N. Volkova, R. Coleman, and M. Aviram, “Anti-oxidant and anti-atherogenic properties of liposomal glutathione: studies in vitro, and in the atherosclerotic apolipoprotein E-deficient mice,” Atherosclerosis, vol. 195, no. 2, pp. e61–e68, 2007.
View at: Publisher Site | Google Scholar
C. C. Lin, M. C. Yin, C. C. Hsu, and M. P. Lin, “Effect of five cysteine-containing compounds on three lipogenic enzymes in Balb/cA mice consuming a high saturated fat diet,” Lipids, vol. 39, no. 9, pp. 843–848, 2004.
View at: Publisher Site | Google Scholar
A. S. Hassan, D. Bunick, S. H. St Denis, and L. A. Lund, “Glutathione and bile acid synthesis. II. Effect of hepatic glutathione content on the activity and mRNA levels of cholesterol 7α-hydroxylase in the rat,” Biochemical Pharmacology, vol. 46, no. 3, pp. 555-556, 1993.
View at: Publisher Site | Google Scholar
S. K. Biswas, D. E. Newby, I. Rahman, and I. L. Megson, “Depressed glutathione synthesis precedes oxidative stress and atherogenesis in Apo-E^−/− mice,” Biochemical and Biophysical Research Communications, vol. 338, no. 3, pp. 1368–1373, 2005.
View at: Publisher Site | Google Scholar
M. Rosenblat, R. Coleman, and M. Aviram, “Increased macrophage glutathione content reduces cell-mediated oxidation of LDL and atherosclerosis in apolipoprotein E-deficient mice,” Atherosclerosis, vol. 163, no. 1, pp. 17–28, 2002.
View at: Publisher Site | Google Scholar
A. Gumieniczek and M. Wilk, “Nitrosative stress and glutathione redox system in four different tissues of alloxan-induced hyperglycemic animals,” Toxicology Mechanisms and Methods, vol. 19, no. 4, pp. 302–307, 2009.
View at: Publisher Site | Google Scholar
A. Gumieniczek, “Modification of oxidative stress by pioglitazone in the heart of alloxan-induced diabetic rabbits,” Journal of Biomedical Science, vol. 12, no. 3, pp. 531–537, 2005.
View at: Publisher Site | Google Scholar
A. Callegari, Y. Liu, C. C. White et al., “Gain and loss of function for glutathione synthesis: impact on advanced atherosclerosis in apolipoprotein E–deficient mice,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 31, no. 11, pp. 2473–2482, 2011.
View at: Publisher Site | Google Scholar
T. Kader, C. M. Porteous, M. J. A. Williams, S. P. Gieseg, and S. P. A. McCormick, “Ribose-cysteine increases glutathione-based antioxidant status and reduces LDL in human lipoprotein(a) mice,” Atherosclerosis, vol. 237, no. 2, pp. 725–733, 2014.
View at: Publisher Site | Google Scholar
P. Lewis, N. Stefanovic, J. Pete et al., “Lack of the antioxidant enzyme glutathione peroxidase-1 accelerates atherosclerosis in diabetic apolipoprotein E–deficient mice,” Circulation, vol. 115, no. 16, pp. 2178–2187, 2007.
View at: Publisher Site | Google Scholar
Z. Guo, H. van Remmen, H. Yang et al., “Changes in expression of antioxidant enzymes affect cell-mediated LDL oxidation and oxidized LDL–induced apoptosis in mouse aortic cells,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 21, no. 7, pp. 1131–1138, 2001.
View at: Publisher Site | Google Scholar
T. Hamanishi, H. Furuta, H. Kato et al., “Functional variants in the glutathione peroxidase-1 (GPx-1) gene are associated with increased intima-media thickness of carotid arteries and risk of macrovascular diseases in Japanese type 2 diabetic patients,” Diabetes, vol. 53, no. 9, pp. 2455–2460, 2004.
View at: Publisher Site | Google Scholar
L. Goedeke, N. Rotllan, A. Canfrán-Duque et al., “MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels,” Nature Medicine, vol. 21, no. 11, pp. 1280–1289, 2015.
View at: Publisher Site | Google Scholar
P. Matoušková, B. Hanousková, and L. Skálová, “MicroRNAs as potential regulators of glutathione peroxidases expression and their role in obesity and related pathologies,” International Journal of Molecular Sciences, vol. 19, no. 4, p. 1199, 2018.
View at: Publisher Site | Google Scholar
A. Wezel, S. M. J. Welten, W. Razawy et al., “Inhibition of microRNA-494 reduces carotid artery atherosclerotic lesion development and increases plaque stability,” Annals of Surgery, vol. 262, no. 5, pp. 841–848, 2015.
View at: Publisher Site | Google Scholar
K. C. Vickers, S. R. Landstreet, M. G. Levin et al., “MicroRNA-223 coordinates cholesterol homeostasis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 40, pp. 14518–14523, 2014.
View at: Publisher Site | Google Scholar
M. L. Alvarez, M. Khosroheidari, E. Eddy, and S. C. Done, “MicroRNA-27a decreases the level and efficiency of the LDL receptor and contributes to the dysregulation of cholesterol homeostasis,” Atherosclerosis, vol. 242, no. 2, pp. 595–604, 2015.
View at: Publisher Site | Google Scholar
D. Milenkovic, C. Deval, E. Gouranton et al., “Modulation of miRNA expression by dietary polyphenols in apoE deficient mice: a new mechanism of the action of polyphenols,” PLoS One, vol. 7, no. 1, article e29837, 2012.
View at: Publisher Site | Google Scholar
L. Zhang, D. Hou, X. Chen et al., “Exogenous plant MIR168a specifically targets mammalian LDLRAP1: evidence of cross-kingdom regulation by microRNA,” Cell Research, vol. 22, no. 1, pp. 107–126, 2012.
View at: Publisher Site | Google Scholar
S. R. Baier, C. Nguyen, F. Xie, J. R. Wood, and J. Zempleni, “MicroRNAs are absorbed in biologically meaningful amounts from nutritionally relevant doses of cow milk and affect gene expression in peripheral blood mononuclear cells, HEK-293 kidney cell cultures, and mouse livers,” The Journal of Nutrition, vol. 144, no. 10, pp. 1495–1500, 2014.
View at: Publisher Site | Google Scholar
M. M. Averill, B. J. Bennett, M. Rattazzi et al., “Neither antioxidants nor genistein inhibit the progression of established atherosclerotic lesions in older apoE deficient mice,” Atherosclerosis, vol. 203, no. 1, pp. 82–88, 2009.
View at: Publisher Site | Google Scholar
P. M. Kris-Etherton, A. H. Lichtenstein, B. V. Howard, D. Steinberg, and J. L. Witztum, “Antioxidant vitamin supplements and cardiovascular disease,” Circulation, vol. 110, no. 5, pp. 637–641, 2004.
View at: Publisher Site | Google Scholar
F. Bea, F. N. Hudson, H. Neff-LaFord et al., “Homocysteine stimulates antioxidant response element-mediated expression of glutamate-cysteine ligase in mouse macrophages,” Atherosclerosis, vol. 203, no. 1, pp. 105–111, 2009.
View at: Publisher Site | Google Scholar
M. M. Cortese, C. V. Suschek, W. Wetzel, K. D. Kroncke, and V. Kolb-Bachofen, “Zinc protects endothelial cells from hydrogen peroxide via Nrf2-dependent stimulation of glutathione biosynthesis,” Free Radical Biology & Medicine, vol. 44, no. 12, pp. 2002–2012, 2008.
View at: Publisher Site | Google Scholar
G. V. Z. Dedoussis, A. C. Kaliora, S. Psarras et al., “Antiatherogenic effect of Pistacia lentiscus via GSH restoration and downregulation of CD36 mRNA expression,” Atherosclerosis, vol. 174, no. 2, pp. 293–303, 2004.
View at: Publisher Site | Google Scholar
M. Rosenblat and M. Aviram, “Macrophage glutathione content and glutathione peroxidase activity are inversely related to cell-mediated oxidation of LDL: in vitro and in vivo studies,” Free Radical Biology & Medicine, vol. 24, no. 2, pp. 305–317, 1998.
View at: Publisher Site | Google Scholar
B. A. Neuschwander-Tetri, J. M. Bellezzo, R. S. Britton, B. R. Bacon, and E. S. Fox, “Thiol regulation of endotoxin-induced release of tumour necrosis factor α from isolated rat Kupffer cells,” Biochemical Journal, vol. 320, no. 3, pp. 1005–1010, 1996.
View at: Publisher Site | Google Scholar
M. Parmentier, N. Hirani, I. Rahman, K. Donaldson, W. MacNee, and F. Antonicelli, “Regulation of lipopolysaccharide-mediated interleukin-1beta release by N-acetylcysteine in THP-1 cells,” European Respiratory Journal, vol. 16, no. 5, pp. 933–939, 2000.
View at: Publisher Site | Google Scholar
J. P. Richie, S. Nichenametla, W. Neidig et al., “Randomized controlled trial of oral glutathione supplementation on body stores of glutathione,” European Journal of Nutrition, vol. 54, no. 2, pp. 251–263, 2015.
View at: Publisher Site | Google Scholar
K. Kugiyama, M. Ohgushi, T. Motoyama et al., “Intracoronary infusion of reduced glutathione improves endothelial vasomotor response to acetylcholine in human coronary circulation,” Circulation, vol. 97, no. 23, pp. 2299–2301, 1998.
View at: Publisher Site | Google Scholar
H. Shimizu, Y. Kiyohara, I. Kato et al., “Relationship between plasma glutathione levels and cardiovascular disease in a defined population: the Hisayama study,” Stroke, vol. 35, no. 9, pp. 2072–2077, 2004.
View at: Publisher Site | Google Scholar
M. Julius, C. A. Lang, L. Gleiberman, E. Harburg, W. Difranceisco, and A. Schork, “Glutathione and morbidity in a community-based sample of elderly,” Journal of Clinical Epidemiology, vol. 47, no. 9, pp. 1021–1026, 1994.
View at: Publisher Site | Google Scholar
M. Lagman, J. Ly, T. Saing et al., “Investigating the causes for decreased levels of glutathione in individuals with type II diabetes,” PLoS One, vol. 10, no. 3, article e0118436, 2015.
View at: Publisher Site | Google Scholar
F. J. Chaves, M. L. Mansego, S. Blesa et al., “Inadequate cytoplasmic antioxidant enzymes response contributes to the oxidative stress in human hypertension,” American Journal of Hypertension, vol. 20, no. 1, pp. 62–69, 2007.
View at: Publisher Site | Google Scholar
J. Redón, M. R. Oliva, C. Tormos et al., “Antioxidant activities and oxidative stress byproducts in human hypertension,” Hypertension, vol. 41, no. 5, pp. 1096–1101, 2003.
View at: Publisher Site | Google Scholar
J. Robaczewska, K. Kedziora-Kornatowska, M. Kozakiewicz et al., “Role of glutathione metabolism and glutathione-related antioxidant defense systems in hypertension,” Journal of Physiology and Pharmacology, vol. 67, no. 3, pp. 331–337, 2016.
View at: Google Scholar
J. Rybka, D. Kupczyk, K. Kędziora-Kornatowska et al., “Glutathione-related antioxidant defense system in elderly patients treated for hypertension,” Cardiovascular Toxicology, vol. 11, no. 1, pp. 1–9, 2011.
View at: Publisher Site | Google Scholar
T. Damy, M. Kirsch, L. Khouzami et al., “Glutathione deficiency in cardiac patients is related to the functional status and structural cardiac abnormalities,” PLoS One, vol. 4, no. 3, article e4871, 2009.
View at: Publisher Site | Google Scholar
V. Kovacs, B. Gasz, B. Balatonyi et al., “Polymorphisms in glutathione S-transferase are risk factors for perioperative acute myocardial infarction after cardiac surgery: a preliminary study,” Molecular and Cellular Biochemistry, vol. 389, no. 1-2, pp. 79–84, 2014.
View at: Publisher Site | Google Scholar
D. Lapenna, S. de Gioia, G. Ciofani et al., “Glutathione-related antioxidant defenses in human atherosclerotic plaques,” Circulation, vol. 97, no. 19, pp. 1930–1934, 1998.
View at: Publisher Site | Google Scholar
S. Blankenberg, H. J. Rupprecht, C. Bickel et al., “Glutathione peroxidase 1 activity and cardiovascular events in patients with coronary artery disease,” The New England Journal of Medicine, vol. 349, no. 17, pp. 1605–1613, 2003.
View at: Publisher Site | Google Scholar
S. U. Shahid, Shabana, and S. Humphries, “The SNP rs10911021 is associated with oxidative stress in coronary heart disease patients from Pakistan,” Lipids in Health and Disease, vol. 17, no. 1, p. 6, 2018.
View at: Publisher Site | Google Scholar
G. de Mattia, M. C. Bravi, O. Laurenti et al., “Reduction of oxidative stress by oral N-acetyl-L-cysteine treatment decreases plasma soluble vascular cell adhesion molecule-1 concentrations in non-obese, non-dyslipidaemic, normotensive, patients with non-insulin-dependent diabetes,” Diabetologia, vol. 41, no. 11, pp. 1392–1396, 1998.
View at: Publisher Site | Google Scholar
M. A. Szkudlinska, A. D. von Frankenberg, and K. M. Utzschneider, “The antioxidant N-acetylcysteine does not improve glucose tolerance or β-cell function in type 2 diabetes,” Journal of Diabetes and its Complications, vol. 30, no. 4, pp. 618–622, 2016.
View at: Publisher Site | Google Scholar
J. Pizzorno, “Glutathione!,” Integrative Medicine, vol. 13, no. 1, pp. 8–12, 2014.
View at: Google Scholar
J. Allen and R. D. Bradley, “Effects of oral glutathione supplementation on systemic oxidative stress biomarkers in human volunteers,” The Journal of Alternative and Complementary Medicine, vol. 17, no. 9, pp. 827–833, 2011.
View at: Publisher Site | Google Scholar
B. Schmitt, M. Vicenzi, C. Garrel, and F. M. Denis, “Effects of N-acetylcysteine, oral glutathione (GSH) and a novel sublingual form of GSH on oxidative stress markers: a comparative crossover study,” Redox Biology, vol. 6, pp. 198–205, 2015.
View at: Publisher Site | Google Scholar
D. Buonocore, M. Grosini, S. Giardina et al., “Bioavailability study of an innovative orobuccal formulation of glutathione,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 3286365, 7 pages, 2016.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2019 Vladan P. Bajic et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

8384

Downloads

2131

Citations