Selenium-dependent Glutathione Peroxidase Research Articles

PRDX6 dictates ferroptosis sensitivity by directing cellular selenium utilization.

Selenium-dependent glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, preventing unrestrained (phospho)lipid peroxidation by reducing phospholipid hydroperoxides (PLOOH). However, the contribution of other phospholipid peroxidases in ferroptosis protection remains unclear. We show that cells lacking GPX4 still exhibit substantial PLOOH-reducing capacity, suggesting a contribution of alternative PLOOH peroxidases. By scrutinizing potential candidates, we found that although overexpression of peroxiredoxin 6 (PRDX6), a thiol-specific antioxidant enzyme with reported PLOOH-reducing activity, failed to prevent ferroptosis, its genetic loss sensitizes cancer cells to ferroptosis. Mechanistically, we uncover that PRDX6, beyond its known peroxidase activity, acts as a selenium-acceptor protein, facilitating intracellular selenium utilization and efficient selenium incorporation into selenoproteins, including GPX4. Its physiological significance was demonstrated by reduced GPX4 expression in Prdx6-deficient mouse brains and increased sensitivity to ferroptosis in PRDX6-deficient tumor xenografts in mice. Our study highlights PRDX6 as a critical player in directing cellular selenium utilization and dictating ferroptosis sensitivity.

Evaluation of the Use of Cell Lines in Studies of Selenium-Dependent Glutathione Peroxidase 2 (GPX2) Involvement in Colorectal Cancer.

Hydroperoxides (ROOHs) are known as damaging agents capable of mediating mutation, while a role as signaling agents through oxidation of protein sulfhydryls that can alter cancer-related pathways has gained traction. Glutathione peroxidase 2 (GPX2) is an antioxidant enzyme that reduces ROOHs at the expense of glutathione (GSH). GPX2 is noted for a tendency of large increases or decreases in expression levels during tumorigenesis that leads to investigators focusing on its role in cancer. However, GPX2 is only one component of multiple enzyme families that metabolize ROOH, and GPX2 levels are often very low in the context of these other ROOH-reducing activities. Colorectal cancer (CRC) was selected as a case study for examining GPX2 function, as colorectal tissues and cancers are sites where GPX2 is highly expressed. A case can be made for a significant impact of changes in expression levels. There is also a link between GPX2 and NADPH oxidase 1 (NOX1) from earlier studies that is seldom addressed and is discussed, presenting data on a unique association in colon and CRC. Tumor-derived cell lines are quite commonly used for pre-clinical studies involving the role of GPX2 in CRC. Generally, selection for this type of work is limited to identifying cell lines based on high and low GPX2 expression with the standard research scheme of overexpression in low-expressing lines and suppression in high-expressing lines to identify impacted pathways. This overlooks CRC subtypes among cell lines involving a wide range of gene expression profiles and a variety of driver mutation differences, along with a large difference in GPX2 expression levels. A trend for low and high GPX2 expressing cell lines to segregate into different CRC subclasses, indicated in this report, suggests that choices based solely on GPX2 levels may provide misleading and conflicting results by disregarding other properties of cell lines and failing to factor in differences in potential protein targets of ROOHs. CRC and cell line classification schemes are presented here that were intended to assist workers in performing pre-clinical studies but are largely unnoted in studies on GPX2 and CRC. Studies are often initiated on the premise that the transition from normal to CRC is associated with upregulation of GPX2. This is probably correct. However, the source normal cells for CRC could be almost any colon cell type, some with very high GPX2 levels. These factors are addressed in this study.

A short-term exposure to saxitoxin triggers a multitude of deleterious effects in Daphnia magna at levels deemed safe for human health

Harmful algal blooms and the toxins produced during these events are a human and environmental health concern worldwide. Saxitoxin and its derivatives are potent natural aquatic neurotoxins produced by certain freshwater cyanobacteria and marine algae species during these bloom events. Saxitoxins effects on human health are well studied, however its effects on aquatic biota are still largely unexplored. This work aims at evaluating the effects of a pulse acute exposure (24 h) of the model cladoceran Daphnia magna to 30 μg saxitoxin L−1, which corresponds to the safety guideline established by the World Health Organization (WHO) for these toxins in recreational freshwaters. Saxitoxin effects were assessed through a comprehensive array of biochemical (antioxidant enzymes activity and lipid peroxidation), genotoxicity (alkaline comet assay), neurotoxicity (total cholinesterases activity), behavioral (swimming patterns), physiological (feeding rate and heart rate), and epigenetic (total 5-mC DNA methylation) biomarkers. Exposure resulted in decreased feeding rate, heart rate, total cholinesterases activity and catalase activity. Contrarily, other antioxidant enzymes, namely glutathione-S-transferases and selenium-dependent Glutathione peroxidase had their activity increased, together with lipid peroxidation levels. The enhancement of the antioxidant enzymes was not sufficient to prevent oxidative damage, as underpinned by lipid peroxidation enhancement. Accordingly, average DNA damage level was significantly increased in STX-exposed daphnids. Total DNA 5-mC level was significantly decreased in exposed organisms. Results showed that even a short-term exposure to saxitoxin causes significant effects on critical molecular and cellular pathways and modulates swimming patterns in D. magna individuals. This study highlights sub-lethal effects caused by saxitoxin in D. magna, suggesting that these toxins may represent a marked challenge to their thriving even at a concentration deemed safe for humans by the WHO.

C60 Fullerene Reduces the Level of Liver Damage in Chronic Alcohol Intoxication of Rats.

The liver is the main organ responsible for the metabolism of ethanol, which suffers significantly as a result of tissue damage due to oxidative stress. It is known that C60 fullerenes are able to efficiently capture and inactivate reactive oxygen species in in vivo and in vitro systems. Therefore, the purpose of this study is to determine whether water-soluble C60 fullerene reduces the level of pathological process development in the liver of rats induced by chronic alcohol intoxication for 3, 6, and 9 months, depending on the daily dose (oral administration; 0.5, 1, and 2 mg/kg) of C60 fullerene throughout the experiment. In this context, the morphology of the C60 fullerene nanoparticles in aqueous solution was studied using atomic force microscopy. Such biochemical parameters of experimental animal blood as ALT (alanine aminotransferase), AST (aspartate aminotransferase), GGT (gamma-glutamyl transferase) and ALP (alkaline phosphatase) enzyme activities, CDT (carbohydrate-deficient transferrin) level, values of pro-antioxidant balance indicators (concentrations of H2O2 (hydrogen peroxide) and GSH (reduced glutathione), activities of CAT (catalase), SOD (superoxide dismutase) and GPx (selenium-dependent glutathione peroxidase)), and pathohistological and morphometric features of liver damage were analyzed. The most significant positive change in the studied biochemical parameters (up to 29 ± 2% relative to the control), as markers of liver damage, was recorded at the combined administration of alcohol (40% ethanol in drinking water) and water-soluble C60 fullerenes in the optimal dose of 1 mg/kg, which was confirmed by small histopathological changes in the liver of rats. The obtained results prove the prospective use of C60 fullerenes as powerful antioxidants for the mitigation of pathological conditions of the liver arising under prolonged alcohol intoxication.

Abstract 5220: Reduced expression of Glutathione peroxidase 2 (GPX2) is an independent predictor of poor prognosis in muscle-invasive urothelial carcinoma of the bladder

Abstract Background: The Glutathione peroxidase 2 (GPX2) is a selenium-dependent glutathione peroxidase with a pivotal role in removing potentially harming reactive oxygen species (ROS) from cells by catalyzing the reduction process of hydrogen peroxide to water. GPX2 is strongly expressed in normal urothelium but can be reduced in urothelial cancer. The aim of the study was to evaluate the potential clinical significance of GPX2 expression in urothelial bladder cancer. Design: GPX2 was analyzed by immunohistochemistry (IHC) in more than 2,500 urothelial bladder carcinomas in a tissue microarray format. Follow-up data were available for more than 600 patients with muscle-invasive disease. Results: GPX2 staining occurred in 67.5% of urothelial carcinomas including 11.4% with weak, 11.9% with moderate, and 44.2% with strong staining. While GPX2 staining was always strong in normal urothelium, it decreased markedly during grade and stage progression. Within pTa tumors, GPX2 positivity continuously decreased from pTaG2 low grade (99.4% positive) to pTa G2 high grade (97.2% positive) and to pTa G3 (90.5%; p=0.0013) while there was a marked further drop of GPX2 positivity from pTaG3 to muscle-invasive cancers (56.6%; p<0.0001 for pT2-4 vs. pTa G3). Within pT2-4 carcinomas, low or absent GPX2 staining was significantly linked to poor overall survival (p=0.0140), V1 (p<0.0001), L1 (p=0.0014), and high grade (p=0.0091), but statistically unrelated to pT and pN. In a multivariate analysis, the prognostic impact of reduced GPX2 expression (p=0.0081) was independent of pT (p<0.0001) and pN (p<0.0001) in pT2-4 tumors. GPX2 expression loss was inversely related to the expression of the luminal subtype markers GATA3 (p<0.0001), uroplakin 1b (p<0.0001) and cytokeratin 20 (p<0.0001) in pT2-4 carcinomas. Conclusion: GPX2 expression loss is a common event during bladder cancer progression which is strongly associated with poor prognosis in patients with pT2-4 urothelial carcinomas. GPX2 expression measurement - optimally together with other markers - could be useful for clinical risk assessment of bladder cancer patients. Citation Format: Henning Plage, Sebastian Hofbauer, Kira Furlano, Sarah Weinberger, Antonia Franz, Annika Fendler, Joachim Weischenfeldt, Florian Roßner, Simon Schallenberg, Sefer Elezkurtaj, Martina Kluth, Andreas H. Marx, Henrik Samtleben, Margit Fisch, Marcin Slojewski, Krystian Kaczmarek, Thorsten Ecke, Stefan Koch, Nico Adamini, Ronald Simon, Guido Sauter, Henrik Zecha, Tobias Klatte, Sarah Minner, David Horst, Thorsten Schlomm, Michael Rink, Maximilian Lennartz. Reduced expression of Glutathione peroxidase 2 (GPX2) is an independent predictor of poor prognosis in muscle-invasive urothelial carcinoma of the bladder [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5220.

Using Information from Public Databases to Critically Evaluate Studies Linking the Antioxidant Enzyme Selenium-Dependent Glutathione Peroxidase 2 (GPX2) to Cancer

Recent research on selenium-dependent glutathione peroxidase 2 (GPX2) tends to focus on possible roles in tumorigenesis. This is based on the idea that normally generated hydroperoxide species can damage DNA to produce mutations and react with protein sulfhydryl groups to perturb normal regulation of cancer-related pathways. GPX2 is one of many peroxidases available to control hydroperoxide levels. Altered GPX2 expression levels from normal to cancer or with cancer stages seems to be the main feature in bringing it to the attention of investigators. In this commentary, we examine this premise as a basis for cancer studies, largely by trying to place GPX2 within the larger context of antioxidant enzyme gene expression. We make use of public databases and illustrate their possible role in approaching this issue. Since use of such databases is new to us, we looked to sources in the literature to evaluate expression level data, finding general agreement with some discrepancies over the range of expression and relative expression levels among some samples. Using the database information, we critically evaluate methods used to study GPX2 in the current literature for a variety of cancers. Second, groups are now trying to compare enzymatic properties of GPX1 and GPX2 using proteins from bacterial cultures. We weigh in on these recent findings and discuss the impact on the relative GPX2 and GPX1 functions.

Effects of dietary Radix bupleuri root extract on the growth, muscle composition, histology, immune responses and microcystin-LR stress resistance of juvenile red claw crayfish (Cherax quadricarinatus)

The current study was conducted to determine the effects of dietary Radix bupleuri root extract (RBE) on the growth performance, muscle composition, immune responses, and microcystin-LR (MC-LR) stress resistance of juvenile red claw crayfish (Cherax quadricarinatus). Crayfish (0.28 ± 0.02 g) were fed experimental diets containing graded RBE levels as 0 (Diet 1), 0.2 (Diet 2), 0.4 (Diet 3), 0.6 (Diet 4), 0.8 (Diet 5) and 1.6 (Diet 6) g/kg RBE for 8 weeks. The results showed that specific growth rate (SGR) and weight gain rate (WGR) were significantly increased in the Diet 4 and Diet 5 groups. The content of muscle crude protein was significantly increased in the Diet 4 and Diet 5 groups, and the crude lipid content was significantly decreased in the Diet 5 group. Dietary RBE did not alter the structure of the hepatopancreas. Total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) activities in hepatopancreas and plasma were significantly increased in Diet 4 and Diet 5 groups compared to the control group, while the malondialdehyde (MDA) content in hepatopancreas and plasma was significantly decreased in the Diet 5 group. Plasma alkaline phosphatase (AKP) activity was significantly higher in the Diet 3, Diet 4, Diet 5 and Diet 6 groups. Hepatopancreas and plasma PO activities were significantly increased in Diet 4 and Diet 5 groups. The mRNA levels of extracellular copper/zinc superoxide dismutase (ecCu, Zn-SOD), hemocyanin, C-type lysozyme (C-LZM), GPx, and selenium-dependent glutathione peroxidase (Se-GPx) were significantly up-regulated in the hepatopancreas of crayfish fed Diet 5 than those of the control group. After MC-LR challenge, the survival rates of crayfish in the Diet 4 and Diet 5 groups were significantly higher than the control group. The findings suggest that 0.6–0.8 g/kg of RBE can improve growth and muscle composition and enhance immunity and microcystin-LR resistance.

Abstract P1060: Correlation Of Plasma Glutathione Peroxidase 4 Concentration With Coronary Heart Disease And The Severity Of Coronary Artery Stenosis

Introduction: Selenium-dependent glutathione peroxidase (GPX4) is an antioxidative, monomeric enzyme that can protect cells from membrane lipid oxidation-linked damage. Given the potential influence of GPX4 concentration on cardiovascular risk, we investigated how GPX4 levels change in patients with coronary heart disease (CHD), and whether GPX4 concentration correlates with the severity of coronary artery stenosis (CAS). Methods: Patients admitted at our institution between August 2022 and January 2023 for suspected CHD and completed coronary angiography were included. Patients were stratified according to their coronary angiography results: CHD group (positive) and control group (negative). The severity of CAS in patients with CHD was evaluated by dividing patients into low (<43 points) or high (≥43 points) Gensini score groups. Plasma GPX4 concentration was measured by enzyme-linked immunosorbent assay (ELISA). Results: Eighty-one patients were included based on our eligibility criteria, 41 patients in the CHD group and 40 patients in the control group. Patients with CHD were more commonly male and hypertensive, and presented with significantly greater levels of triglycerides and LDL-cholesterol at baseline. ELISA analysis indicates that patients with CHD have significantly lower plasma GPX4 concentrations as compared to patients in the control group. Furthermore, Spearman’s correlation analysis shows an inverse association between plasma GPX4 concentration and Gensini score in patients with CHD. Conclusion: Our results suggest that plasma GPX4 concentration was significantly lower in patients with CHD and is negatively correlated with the severity of CAS.

Cloning and mRNA expression of selenium-dependent glutathione peroxidase from the oyster Magallana hongkongensis in response to cadmium exposure and aerial exposure at different temperatures

Cloning and mRNA expression of selenium-dependent glutathione peroxidase from the oyster Magallana hongkongensis in response to cadmium exposure and aerial exposure at different temperatures

PTFS12-02-23 Transcriptional Regulation of Elongase 3 by Selenium-Dependent Glutathione Peroxidase 1 in Mice Tissues

PTFS12-02-23 Transcriptional Regulation of Elongase 3 by Selenium-Dependent Glutathione Peroxidase 1 in Mice Tissues

Comparative Effects of Inorganic and Organic Dietary Sources of Selenium on Selenium Levels and Selenium-Dependent Glutathione Peroxidase Activity in Blood of Young Turkeys

The effect of various dietary sources of Se on Se-dependent glutathione peroxidase (SeGSH-Px) activity in plasma and whole blood was studied in turkeys. Dayold poults were fed low Se diets (supplemented with vitamin E) for 15 to 24 days before being fed experimental diets for 7 to 10 days. Menhaden fish meal (0.1 ppm Se) increased plasma SeGSH-Px activity by 45% of the response to 0.1 ppm Se as Na2SeO3. Poults supplemented with 0, 0.1, 0.2, or 0.4 ppm Se as Na2SeO3, had similar increases in plasma and whole blood Se levels; however, SeGSH-Px activity of plasma (r = 0.96) was better correlated with dietary Se than that of whole blood (r = 0.64). The supplement of 0.4 ppm Se increased the activity of SeGSH-Px almost 20 times in plasma but only 1.6 times in whole blood. The effectiveness of several compounds providing 0.2 ppm Se for increasing plasma SeGSH-Px activity was: Na2SeO4 > Se-dl-cystine > Se-dl-methionine and Se-dl-ethionine. The effect of Na2SeO3 was not significantly different from that of Se-dl-cystine, Se-dl-methionine or Se-dl-ethionine. The ratio of SeGSH-Px activity:Se concentration, indicating the amount of Se associated with enzyme activity, was highest in plasma of poults fed Na2SeO4 andSe-dl-cystine. The data demonstrate differences in the availability of various Se sources for SeGSH-Px activity in poults.selenium glutathione peroxidase turkeys fish meal

Classical Selenium-Dependent Glutathione Peroxidase Expression Is Decreased Secondary to Iron Deficiency in Rats

While there are reports that classical selenium-dependent glutathione peroxidase (Se-GPX1) activity is decreased during iron deficiency, the relationship between tissue iron status and Se-GPX1 activity remains speculative. This study was undertaken to investigate the mechanism for the decrease in Se-GPX1 activity during iron deficiency. Male weanling Sprague-Dawley rats were given free access to either an iron-deficient or an iron-adequate diet for eight weeks, after which blood, livers, kidneys, hearts, brains and testes were surgically excised. During iron deficiency, Se-GPX1 mRNA levels in liver tissue were decreased by approximately 55%. Similarly, the concentration of immunoreactive Se-GPX1 protein and total selenium-dependent glutathione peroxidase (Se-GPX) activity were decreased by 55% and 60%, respectively. In kidney, heart and brain total Se-GPX activities were depressed as much as 33%. Selenium concentration in liver was reduced by 42%, whereas the decrease in Se concentrations in kidney, heart, and brain ranged from 17 to 25%. Concentrations of plasma Se also were reduced by 18%, but testes showed little change in either Se-GPX activity or Se concentration during iron deficiency. Results suggest that the synthesis of Se-GPX1 protein is decreased during iron deficiency possibly due to pretranslational regulation.

Effects of Dietary Eucommia ulmoides Leaf Extract on Growth, Muscle Composition, Hepatopancreas Histology, Immune Responses and Microcystin-LR Resistance of Juvenile Red Claw Crayfish (Cherax quadricarinatus)

The objective of the present study was to investigate the effects of different doses of dietary Eucommia ulmoides leaf extract (ELE) on juvenile red claw crayfish (Cherax quadricarinatus). A total number of 720 red claw crayfish (initial body weight of 0.24 ± 0.01 g) were randomly assigned to six groups and fed diets containing 0 (Diet 1), 0.5 (Diet 2), 1 (Diet 3), 2 (Diet 4), 4 (Diet 5) and 10 (Diet 6) g dry weight (dw) ELE kg (dw)−1 diets for eight weeks and challenged with microcystin-LR stress. The results indicated that dietary supplementation with 1–2 g dw ELE kg (dw)−1 diet could significantly improve the weight gain rate (WGR) and specific growth rate (SGR) of crayfish. Muscle crude protein contents of crayfish fed Diet 2, Diet 3, and Diet 4 were significantly higher than those of the control group. Compared with the control group, dietary ELE could increase total antioxidant capacity (T-AOC), superoxide dismutase (SOD), glutathione peroxidase (GPx), acid phosphatase (ACP), alkaline phosphatase (AKP), and phenoloxidase (PO) activities and decrease malondialdehyde (MDA) level of crayfish. Dietary ELE significantly increased the relative expression levels of SOD, thioredoxin 1 (TRX1), GPx, selenium-dependent glutathione peroxidase (Se-GPx), cytochrome P450 (CYP450), anti-lipopolysaccharide factor (ALF) and C-type lysozyme (C-LZM) mRNA of crayfish compared with the control group during the feeding experiment. When subjected to MC-LR stress for 48 h, the mRNA expression levels of SOD, GPx, Se-GPx, glutathione-s-transferase 1 (GST1), ALF, hemocyanin (HEM), and C-LZM in the hepatopancreas could be improved to varying degrees compared with the Diet 1. Supplementation of 1–2 g dw ELE kg (dw)−1 diet could improve the survival rate (SR) of crayfish under MC-LR stress. These results indicated that dietary ELE (1–2 g dw ELE kg (dw)−1 diet) could improve the growth performance, muscle protein, and non-specific immune response and increase the SR of crayfish under MC-LR stress by regulating the mRNA expression levels of the immune- and antioxidant-related genes.

Ecotoxicity of Copper(I) Chloride in Grooved Carpet Shell (Ruditapes decussatus).

Copper (Cu) is a ubiquitous trace element in the aquatic environment, and is usually found at low levels. Copper environmental concentrations can be altered as a result anthropogenic activities. Shellfish are useful bioindicators to ensure adequate environmental monitoring. Thus, the aim of the present study was as follows: (a) determine the LC50 of copper(I) chloride in grooved carpet shell (Ruditapes decussatus) collected in the Santa Gilla lagoon (Sardinia, Italy), and (b) analyze the antioxidant biomarkers in digestive gland and gills of same specimens exposed to different concentrations of the above-mentioned metal (0.045, 0.45, and 0.90 mg/L) for 96 h. A withdrawal period of 96 h was considered for the treated clam, carrying out the same biochemical analyses, superoxide dismutase (SOD), catalase (CAT), selenium-dependent glutathione peroxidase (Se-GPx), glutathione S-transferases (GSTs), and total glutathione (GSH+2GSSG) in the two tissues. Different time and dose responses of the antioxidant biomarkers were recorded in the digestive glands and gills. Oxidative stress biomarkers highlighted the ability of Cu to induce oxidative stress in R. decussatus. Clam, following the withdrawal period of 96 h, has not been able to achieve the control levels of all biochemical markers in the digestive gland and gills. R. decussatus can be a suitable model to assess the ecotoxicity of copper in aquatic ecosystems. These findings may advance knowledge on the role and the effects of copper on oxidative stress biomarkers in grooved carpet shell. The metal ecotoxicity response can be useful to perform accurate biomarker-based monitoring programs using this bivalve species.

Biochemical and molecular assessment of selenium forms for the alleviation of oxidative stress in senescent human fibroblasts.

Selenium enhances the cellular antioxidant capacity and alleviates oxidative stress. We investigated the transcriptional and enzymatic activities of selenium-dependent glutathione peroxidase 1 and thioredoxin reductase 1 (TrxR1), and levels of glutathione, hydrogen peroxide, lipid peroxides, and protein carbonyls in primary passage 5 (P5) and senescent passage 25 (P25) and 30 (P30) fibroblasts. Cells were incubated in either standard Dulbecco growth medium (CM1) containing normal plasma selenium levels (0.8 μmol/l), or in CM2, CM3, and CM4 containing 3 μmol/l (5 μmol/l for TrxR1) sodium selenite, L-hydroxyselenomethionine, or Se-methylselenocysteine, respectively. Gene transcripts and activities of both investigated enzymes as well as the levels of reduced glutathione were significantly increased in CM2-, CM3-, and CM4-incubated senescent P25 and P35 cells compared against those incubated in CM1. In congruence, although all oxidative stress parameters including oxidized glutathione were significantly lower in CM2-, CM3-, and CM4-incubated senescent cells compared against those incubated in CM1, such reductions were of significantly higher magnitude in CM3 and CM4 cells compared against those in CM2. In conclusion, organic L-hydroxyselenomethionine and Se-methylselenocysteine are equally more potent at alleviating oxidative stress in senescent cells than inorganic sodium selenite, and thus could be beneficial for use in elderly subjects and those with oxidative stress-associated disease.

The Correlation between Selenium-Dependent Glutathione Peroxidase Activity and Oxidant/Antioxidant Balance in Sera of Diabetic Patients with Nephropathy.

Oxidative stress is an imbalance between free radical's production and the body's ability to counteract or detoxify their harmful effects through neutralization by antioxidants, oxidative stress is thought to be involved in the pathogenesis of diabetic nephropathy. One of the key enzymatic antioxidants is glutathione peroxidase (GPx), which plays an important protective function in diabetes complications, by reducing the rising state of oxidative stress and removing toxicity from peroxides and converting them into a non-toxic substance. The objective of this research was to evaluate the rule of glutathione peroxidase in regulate oxidants/antioxidants levels diabetic patients with nephropathy. In a case-control study, we assessed serum GPx activity (Se-Dependent, non-selenium dependent and total GPx), total oxidant, lipid peroxidation, total antioxidant, and catalase in healthy control subjects (group 1), in diabetic patients without diabetic nephropathy (group 2) and diabetic patients with nephropathy (group 3). GPx activity was significantly lower in T2D patients with and without nephropathy compared to healthy subject's control. Total oxidants and lipids peroxidation have a negative correlation with the GPx and other antioxidants. Decreased GPx activity indicate a relationship between GPx activity and diabetic nephropathy.

GPx-1-encoded adenoviral vector attenuates dopaminergic impairments induced by methamphetamine in GPx-1 knockout mice through modulation of NF-κB transcription factor

We suggested that selenium-dependent glutathione peroxidase (GPx) plays a protective role against methamphetamine (MA)-induced dopaminergic toxicity. We focused on GPx-1, a major selenium-dependent enzyme and constructed a GPx-1 gene-encoded adenoviral vector (Ad-GPx-1) to delineate the role of GPx-1 in MA-induced dopaminergic neurotoxicity. Exposure to Ad-GPx-1 significantly induced GPx activity and GPx-1 protein levels in GPx-1-knockout (GPx-1-KO) mice. MA-induced dopaminergic impairments [i.e., hyperthermia; increased nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) DNA-binding activity; and decreased dopamine levels, TH activity, and behavioral activity] were more pronounced in GPx-1-KO mice than in WT mice. In contrast, exposure to Ad-GPx-1 significantly attenuated MA-induced dopaminergic loss in GPx-1-KO mice. The protective effect exerted by Ad-GPx-1 was comparable to that exerted by pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor against MA insult. Consistently, GPx-1 overexpression significantly attenuated MA dopaminergic toxicity in mice. PDTC did not significantly impact the protective effect of GPx-1 overexpression, suggesting that interaction between NF-κB and GPx-1 is critical for dopaminergic protection. Thus, NF-κB is a potential therapeutic target for GPx-1-mediated dopaminergic protective activity. This study for the first time demonstrated that Ad-GPx-1 rescued dopaminergic toxicity in vivo following MA insult. Furthermore, GPx-1-associated therapeutic interventions may be important against dopaminergic toxicity.

Antioxidant balance in plasma of patients on home parenteral nutrition: A pilot study comparing three different lipid emulsions

Parenteral nutrition (PN) can supply all essential nutrients to a patient with gastrointestinal insufficiency. However, the sensitivity to lipid peroxidation might increase in those receiving PN, especially home parenteral nutrition (HPN). This study aimed to investigate whether PN affects the antioxidant balance of plasma of HPN patients without comorbidities and whether this balance is influenced by comorbidities and according to the type of lipid emulsion included in the PN. Adult patients on HPN (n=86) received one of three types of lipid emulsion (based on 1) soyabean oil, 2) olive and soyabean oil or 3) soyabean, coconut, olive and fish oil) in all-in-one mixtures; in addition healthy controls (n=66) were studied as comparators. HPN patients were classified to the following subgroups: 1) patients without (n=58) or with (n=28) comorbidities 2) patients on Intralipid (GINTRA, n=53), ClinOleic (GCLIN, n=17) or SMOFlipid (GSMOFn=16). The activities of total glutathione peroxidase (GSH-Px), selenium dependent glutathione peroxidase (Se-GSHPx) and glutathione S-transferase (GST) in plasma were determined spectrophotometrically. The antioxidant potential of plasma was determined using oxygen radical absorbance capacity (ORAC). The lipid peroxidation marker malondialdehyde (MDA) was analyzed with high performance liquid chromatography. MDA concentration was the highest in GINTRA and the lowest in GSMOF (p<0.05). GSMOF also had the highest activity of GSH-Px. No differences in Se-GSHPx, GST and ORAC were observed among GINTRA, GCLIN and GSMOF. Comparing with healthy controls, significantly lower GST (p=0.0293) and ORAC (p<0.0001) were observed in the HPN patients. Among all measured parameters only the concentration of MDA was significantly higher in patients with comorbidities compared to those without them. Comorbidities did not influence MDA level in GINTRA and GSMOF being still the lowest in GSMOF (p=0.0033). In contrast, significantly higher MDA level was observed for GCLIN in those with vs. without comorbidities (p=0.0262). Patients on HPN have lower antioxidant defenses than healthy controls. The type of lipid emulsion used in HPN affects lipid peroxidation (even after taking into account comorbidities which often involve oxidative stress) being the highest in GINTRA and the lowest in GSMOF. Thus, to minimize the risk of oxidative stress, SMOFlipid can be considered in patients in HPN especially for those with comorbidities. ClinOleic can be considered in HPN patients without comorbidities. The observation should be confirmed in larger studies.

Clinical Research on Antioxidant-Based Modalities in 2021

Being updated biweekly till the end of the year, this Education &amp; Resources web page lists major clinical studies on antioxidant-based modalities or related entities in disease intervention and health promotion, which have been published in highly influential journals during 2021. It should be noted that this is not intended to be a complete list, but is rather to focus on rigorously designed and well conducted high-profile randomized controlled trials (RCTs) whose findings were reported in medical or bioscience journals of the highest impact. For more comprehensive information on antioxidant-based clinical trials, the reader may refer to the ClinicalTrials.gov (https://clinicaltrials.gov), the largest clinical trials database, run by the US National Library of Medicine, that holds registrations from over 368,000 trials from 219 countries. 2021 LIST IN REVERSE CHRONOLOGICAL ORDER Xu et al. Edaravone dexborneol versus edaravone alone for the treatment of acute ischemic stroke: a phase III, randomized, double-blind, comparative trial. Stroke 2021 Mar; 52(3):772-780. doi: https://dx.doi.org/10.1161/STROKEAHA.120.031197. Key finding: Edaravone dexborneol (a combination of edaravone and borneol) was superior to edaravone alone in improving the clinical outcomes of the acute ischemic stroke patients. Note: Edaravone, a synthetic free radical scavenger, was approved by the US FDA in 2017 for treating amyotrophic lateral sclerosis (ALS). Borneol is a phytochemical with diverse biological activities including antioxidative and anti-inflammatory effects. Kim et al. Reactive oxygen species scavenger in acute intracerebral hemorrhage patients: a multicenter, randomized controlled trial. Stroke 2021 Feb 25; doi: https://doi.org/10.1161/STROKEAHA.120.032266. Key finding: Giving N-acetylcysteine 2000 mg/day and selenium 1600 µg/day, intravenously, for 14 days significantly improved the clinical outcomes in the acute intracerebral hemorrhage patients. Note: N-Acetylcysteine is a precursor of glutathione (GSH). Selenium acts as an antioxidant element due, at least partly, to its essentialness for the function of various selenoproteins, including selenium-dependent glutathione peroxidases (GPx). Kalstad et al. Effects of n-3 fatty acid supplements in elderly patients after myocardial infarction: a randomized, controlled trial. Circulation 2021 Feb 9; 143(6):528-539. doi: https://dx.doi.org/10.1161/CIRCULATIONAHA.120.052209. Key finding: Null Note: n-3 Fatty acids, also known as omega-3 fatty acids, possess potent antioxidative and anti-inflammatory activities. Lynch et al. Safety and efficacy of omaveloxolone in Friedreich ataxia (MOXIe Study). Ann Neurol 2021 Feb; 89(2):212-225. doi: https://dx.doi.org/10.1002/ana.25934. Key finding: Omaveloxolone significantly improved neurological function compared to placebo and is well tolerated. Note: Omaveloxolone, a synthetic oleanane triterpenoid, is an activator of Nrf2, the chief regulator of cellular antioxidant and other cytoprotective genes. Meir et al. Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial. Gut 2021 Jan 18; gutjnl-2020-323106. doi: https://dx.doi.org/10.1136/gutjnl-2020-323106. Key finding: Green-Mediterranean diet enriched with green plants and polyphenols improved non-alcoholic fatty liver disease (NAFLD). Note: Mediterranean diet and green plants (green tea) and nuts are rich in antioxidants and anti-inflammatory compounds and possess many health benefits, especially cardiovascular protection. However, the exact contribution of antioxidant components to the health benefits of Mediterranean diet remains to be established. Rinott et al. Effects of diet-modulated autologous fecal microbiota transplantation on weight regain. Gastroenterology 2021 Jan; 160(1):158-173.e10. doi: https://dx.doi.org/10.1053/j.gastro.2020.08.041. Key finding: Polyphenol-enriched diet-modulated autologous fecal microbiota transplantation attenuated weight regain and preserved glycemic control. Note: Dietary polyphenols possess antioxidative, anti-inflammatory, and many other biological activities. Zheng et al. Plasma vitamin C and type 2 diabetes: genome-wide association study and Mendelian randomization analysis in European populations. Diabetes Care 2021 Jan; 44(1):98-106. doi: https://dx.doi.org/10.2337/dc20-1328. Key finding: Null; no evidence to support an efficacy of vitamin C supplement in type 2 diabetes prevention. Note: Vitamin C is a multitasking compound; it is an antioxidant, but also possesses many other biological functions. According to Dr Davey Smith, Mendelian randomization is a method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in observational studies (from the US CDC website: https://cdc.gov). A positive finding in a Mendelian randomization study provides strong evidence for a causal relationship. Luo et al. Diet-derived circulating antioxidants and risk of coronary heart disease: a Mendelian randomization study. J Am Coll Cardiol 2021 Jan 5; 77(1):45-54. doi: https://dx.doi.org/10.1016/j.jacc.2020.10.048. Key finding: Null Note: According to Dr Davey Smith, Mendelian randomization is a method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in observational studies (from the US CDC website: https://cdc.gov). A positive finding in a Mendelian randomization study provides strong evidence for a causal relationship.

Ferroptosis and its emerging role in tumor.

Ferroptosis is a novel form of programmed cell death characterized by iron-dependent lipid peroxidation accumulation. It is morphologically, biochemically, and genetically distinct from other known cell death, such as apoptosis, necrosis, and pyroptosis. Its regulatory mechanisms include iron metabolism, fatty acid metabolism, mitochondrial respiration, and antioxidative systems eliminating lipid peroxidation, such as glutathione synthesis, selenium-dependent glutathione peroxidase 4, and ubiquinone. The disruption of cellular redox systems causes damage to the cellular membrane leading to ferroptotic cell death. Recent studies have shown that numerous pathological diseases, like tumors, neurodegenerative disorders, and ischemia-reperfusion injury are associated with ferroptosis. As such, pharmacological regulation of ferroptosis either by activation or by suppression will provide a vast potential for treatments of relevant diseases. This review will discuss the advanced progress in ferroptosis and its regulatory mechanisms from both the antioxidative and oxidative sides. In addition, the roles of ferroptosis in various tumorigenesis, development, and therapeutic strategies will be addressed, particularly to chemotherapy and immunotherapy, as well as the discoveries from Traditional Chinese Medicine. This review will lead us to have a comprehensive understanding of the future exploration of ferroptosis and cancer therapy.