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Acute myeloid leukaemia (AML) is a highly heterogeneous disease, however the therapeutic approaches have hardly changed in the last decades. Metabolism rewiring and the enhanced production of reactive oxygen species (ROS) are hallmarks of cancer. A deeper understanding of these features could be instrumental for the development of specific AML-subtypes treatments. NADPH oxidases (NOX), the only cellular system specialised in ROS production, are also involved in leukemic metabolism control. NOX2 shows a variable expression in AML patients, so patients can be classified based on such difference. Here we have analysed whether NOX2 levels are important for AML metabolism control. The lack of NOX2 in AML cells slowdowns basal glycolysis and oxidative phosphorylation (OXPHOS), along with the accumulation of metabolites that feed such routes, and a sharp decrease of glutathione. In addition, we found changes in the expression of 725 genes. Among them, we have discovered a panel of 30 differentially expressed metabolic genes, whose relevance was validated in patients. This panel can segregate AML patients according to CYBB expression, and it can predict patient prognosis and survival. In summary, our data strongly support the relevance of NOX2 for AML metabolism, and highlights the potential of our discoveries in AML prognosis., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The peel of pomegranate fruit is a rich source of polyphenolic compounds with powerful antioxidant properties. We evaluated the therapeutic potential of pomegranate peel (PP) in the prevention of early pregnancy loss in a mouse model of embryonic mortality and abortion (female CBA/J x male DBA/2). CBA/J mice were divided into 3 groups: mice in control group (CONT group) were fed a standard diet, whereas mice in groups 2 and 3 were fed a standard diet supplemented with 1% PP (PP1% group) and 5% PP (PP5% group), respectively. All the mice were fed their diets for 10 days before mating and continued with the same diets for a further 14 days after mating. At day 14 of pregnancy the female mice were sacrificed and the placentas and maternal livers were harvested for measurement of the content of thiols and thiobarbituric acid reactive substances (TBARS), as biomarkers of oxidative stress, and the enzymatic activities of total superoxide dismutase (TSOD), copper/zinc SOD (SOD1), manganese SOD (SOD2), selenium glutathione peroxidase (GPX) and glutathione reductase (GR). Diet supplemented with 5% PP improved embryonic survival and reduced embryonic mortality from 28.2% (CONT) to 8.5% (PP5%). This was accompanied by increased activities of placental TSOD, SOD1 and SOD2, and thiol content. Diet supplemented with 5% PP also reduced placental oxidative stress as demonstrated by a decrease of placental TBARS content. This study highlights the potential of interventions with PP-supplemented diet before and during early pregnancy, in order to ameliorate embryonic survival and prevent early pregnancy loss.

Glioblastoma (GBM) is the most aggressive malignant glioma, with a very poor prognosis; as such, efforts to explore new treatments and GBM's etiology are a priority. We previously described human GBM cells (R2J-GS) as exhibiting the properties of cancer stem cells (growing in serum-free medium and proliferating into nude mice when orthotopically grafted). Sodium selenite (SS)-an in vitro attractive agent for cancer therapy against GBM-was evaluated in R2J-GS cells. To go further, we launched a preclinical study: SS was given orally, in an escalation-dose study (2.25 to 10.125 mg/kg/day, 5 days on, 2 days off, and 5 days on), to evaluate (1) the absorption of selenium in plasma and organs (brain, kidney, liver, and lung) and (2) the SS toxicity. A 6.75 mg/kg SS dose was chosen to perform a tumor regression assay, followed by MRI, in R2J-GS cells orthotopically implanted in nude mice, as this dose was nontoxic and increased brain selenium concentration. A group receiving TMZ (5 mg/kg) was led in parallel. Although not reaching statistical significance, the group of mice treated with SS showed a slower tumor growth vs. the control group ( p = 0.08). No difference was observed between the TMZ and control groups. We provide new insights of the mechanisms of SS and its possible use in chemotherapy.

Background: The peel of the pomegranate fruit is rich in polyphenols with antioxidant properties. We investigated the preventive effect of pomegranate peel (PP) powder against dextran sulfate sodium (DSS)-induced lipid peroxidation in the small intestine of rats. Rats were allocated to four groups: CONT group, fed a standard rodent diet; DSS group, fed a standard rodent diet and treated with DSS; as well as PP1%+DSS and PP5%+DSS groups, fed a standard rodent diet supplemented with either 1% or 5% of PP powder and treated with DSS. Rats of the four groups consumed their diets for 25 days. Lipid peroxidation was determined by measuring malondialdehyde (MDA) concentrations in plasma and MDA contents in the small intestine and liver. Glutathione/glutathione disulfide (GSH/GSSG) redox status and antioxidant enzyme activities were determined in the small intestine and liver., Results: MDA content was higher (P < 0.001) in the small intestines of the DSS group compared to the CONT group. MDA content was reduced (P < 0.001) in the small intestines of the PP1%+DSS and PP5%+DSS groups compared to the DSS group. GSH contents and GSH/GSSG ratios were higher (P < 0.001) in the small intestines of the PP5%+DSS group compared to the CONT, DSS and PP1%+DSS groups., Conclusion: The present study demonstrates that PP powder protects the small intestine against DSS-induced lipid peroxidation by enhancing the GSH/GSSG redox potential. Powder of PP is a promising agricultural by-product containing a mixture of bioactive polyphenols that can be used for the production of functional foods aimed at the prevention of oxidative stress-induced small intestine pathogenesis. © 2021 Society of Chemical Industry., (© 2021 Society of Chemical Industry.)

Adult genetic disorders causing brain lesions have been mostly described as white matter vanishing diseases. We present here the investigations realized in patients referred for psychiatric disorder with magnetic resonance imaging showing atypical basal ganglia lesions. Genetic explorations of this family revealed a new hereditary disease linked to glutathione metabolism., (© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Background: Islets of Langerhans transplantation is a promising therapy for type 1 diabetes mellitus, but this technique is compromised by transplantation stresses including inflammation. In other tissues, co-transplantation with mesenchymal stem cells has been shown to reduce damage by improving anti-inflammatory and anti-oxidant defences. Therefore, we probed the protection afforded by bone marrow mesenchymal stem cells to islets under pro-inflammatory cytokine stress., Methods: In order to evaluate the cytoprotective potential of mesenchymal stem cells on rat islets, co-cultures were exposed to the interleukin-1, tumour necrosis factor α and interferon γ cocktail for 24 h. Islet viability and functionality tests were performed. Reactive oxygen species and malondialdehyde were measured. Expression of stress-inducible genes acting as anti-oxidants and detoxifiers, such as superoxide dismutases 1 and 2, NAD(P)H quinone oxidoreductase 1, heme oxygenase-1 and ferritin H, was compared to non-stressed cells, and the corresponding proteins were measured. Data were analysed by a two-way ANOVA followed by a Holm-Sidak post hoc analysis., Results: Exposure of rat islets to cytokines induces a reduction in islet viability and functionality concomitant with an oxidative status shift with an increase of cytosolic ROS production. Mesenchymal stem cells did not significantly increase rat islet viability under exposure to cytokines but protected islets from the loss of insulin secretion. A drastic reduction of the antioxidant factors heme oxygenase-1 and ferritin H protein levels was observed in islets exposed to the cytokine cocktail with a prevention of this effect by the presence of mesenchymal stem cells., Conclusions: Our data evidenced that MSCs are able to preserve islet insulin secretion through a modulation of the oxidative imbalance mediated by heme and iron via heme oxygenase-1 and ferritin in a context of cytokine exposure.

Glioblastoma multiform (GBM) tumors are very heterogeneous, organized in a hierarchical pattern, including cancer stem cells (CSC), and are responsible for development, maintenance, and cancer relapse. Therefore, it is relevant to establish new GBM cell lines with CSC characteristics to develop new treatments. A new human GBM cell line, named R2J, was established from the cerebro-spinal fluid (CSF) of a patient affected by GBM with leptomeningeal metastasis. R2J cells exhibits an abnormal karyotype and form self-renewable spheres in a serum-free medium. Original tumor, R2J, cultured in monolayer (2D) and in spheres showed a persistence expression of CD44, CD56 (except in monolayer), EGFR, Ki67, Nestin, and vimentin. The R2J cell line is tumorigenic and possesses CSC properties. We tested in vitro the anticancer effects of sodium selenite (SS) compared to temozolomide TMZ. SS was absorbed by R2J cells, was cytotoxic, induced an oxidative stress, and arrested cell growth in G2M before inducing both necrosis and apoptosis via caspase-3. SS also modified dimethyl-histone-3-lysine-9 (H3K9m2) levels and decreased histone deacetylase (HDAC) activity, suggesting anti-invasiveness potential. This study highlights the value of this new GBM cell line for preclinical modeling of clinically relevant, patient specific GBM and opens a therapeutic window to test SS to target resistant and recurrent GBM., Competing Interests: The authors declare no conflict of interest

Glioblastoma (GBM) is the most common type of primary tumor of the central nervous system with a poor prognosis, needing the development of new therapeutic drugs. Few studies focused on sodium selenite (SS) effects in cancer cells cultured as multicellular tumor spheroids (MCTS or 3D) closer to in vivo tumor. We investigated SS anticancer effects in three human GBM cell lines cultured in 3D: LN229, U87 (O(6)-methyguanine-DNA-methyltransferase (MGMT) negative) and T98G (MGMT positive). SS absorption was evaluated and the cytotoxicity of SS and temozolomide (TMZ), the standard drug used against GBM, were compared. SS impacts on proliferation, cell death, and invasiveness were evaluated as well as epigenetic modifications by focusing on histone deacetylase (HDAC) activity and dimethyl-histone-3-lysine-9 methylation (H3K9m2), after 24h to 72h SS exposition. SS was absorbed by spheroids and was more cytotoxic than TMZ (i.e., for LN229, the IC50 was 38 fold-more elevated for TMZ than SS, at 72h). SS induced a cell cycle arrest in the S phase and apoptosis via caspase-3. SS decreased carbonic anhydrase-9 (CA9) expression, invasion on a Matrigel matrix and modulated E- and N-Cadherin transcript expressions. SS decreased HDAC activity and modulated H3K9m2 levels. 3D model provides a relevant strategy to screen new drugs and SS is a promising drug against GBM that should now be tested in GBM animal models., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Anemia is a frequent cytopenia in myelodysplastic syndromes (MDS) and most patients require red blood cell transfusion resulting in iron overload (IO). Deferasirox (DFX) has become the standard treatment of IO in MDS and it displays positive effects on erythropoiesis. In low risk MDS samples, mechanisms improving erythropoiesis after DFX treatment remain unclear. Herein, we addressed this question by using liquid cultures with iron overload of erythroid precursors treated with low dose of DFX (3μM), which corresponds to DFX 5 mg/kg/day, an unusual dose used for iron chelation. We highlight a decreased apoptosis rate and an increased proportion of cycling cells, both leading to higher proliferation rates. The iron chelation properties of low dose DFX failed to activate the Iron Regulatory Proteins and to support iron depletion, but low dose DFX dampers intracellular reactive oxygen species. Furthermore low concentrations of DFX activate the NF-κB pathway in erythroid precursors triggering anti-apoptotic and anti-inflammatory signals. Establishing stable gene silencing of the Thioredoxin (TRX) 1 genes, a NF-κB modulator, showed that fine-tuning of reactive oxygen species (ROS) levels regulates NF-κB. These results justify a clinical trial proposing low dose DFX in MDS patients refractory to erythropoiesis stimulating agents., Competing Interests: CONFLICTS OF INTEREST Sophie Park: research funding by Novartis. The remaining authors declare no conflicts of interest.

There has been a growing interest in the role played by antioxidant enzymes in the regulation of endometrial function in mammals. However, little is known about enzymatic antioxidative pathways involved in conditioning the cyclic and early pregnant endometrium for conceptus attachment and implantation in domestic ruminants. We aimed to investigate changes in activities of superoxide dismutase 1 and 2 (SOD1, SOD2), glutathione peroxidase (GPX), glutathione reductase (GR) and catalase (CAT) in sheep caruncles (CAR) and intercaruncles (ICAR) endometrial tissues of cyclic and early pregnant ewes. Irrespective of day of cycle or pregnancy, CAR demonstrated higher activities of SOD1 and SOD2 than in ICAR. On day 12 of the estrous cycle, ICAR demonstrated higher activity of GPX and GR than in CAR tissues. On days 12 and 16 the estrous cycle, ICAR demonstrated higher activity of CAT than in CAR. CAR demonstrated higher activity of GPX on day 18 than on days 4, 8, 12 and 16 of the estrous cycle. CAR demonstrated higher activity of CAT on day 18 than on days 4, 8, 12 and 16 of the estrous cycle. ICAR demonstrated higher activity of CAT on day 18 than on days 4, 8, and 16 of the estrous cycle. The activity of CAT in ICAR increased from days 4 and 8 to day 12 of the estrous cycle. The activity of SOD2 in CAR increased from day 16 to day 18 of pregnancy. On day 12 of pregnancy, CAR demonstrated higher activity of GPX than in ICAR. On day 16 of pregnancy, ICAR demonstrated higher activity of GPX than in CAR. The activity of GPX in ICAR increased from day 12 to day 16 of pregnancy. The activity of GPX in CAR increased from day 16 to day 18 of pregnancy. The activity of GR in CAR and ICAR increased from days 12 and 16 to day 18 of pregnancy. On days 16 and 18 of pregnancy, ICAR demonstrated higher activity of CAT than in CAR. The activity of CAT in CAR decreased from day 12 to days 16 and 18 of pregnancy. The activity of CAT in ICAR decreased from day 12 to day 16 of pregnancy and then increased from day 16 to day 18 of pregnancy. In conclusion, different antioxidant mechanisms operate within CAR and ICAR endometrium throughout the estrous cycle and during early pregnancy. This might be related to the different but important roles of CAR and ICAR endometrial tissues for the establishment of pregnancy., (Copyright © 2017. Published by Elsevier Inc.)

Introduction: Pathophysiology of cardiac arrest corresponds to a whole body ischemia-reperfusion. This phenomenon is usually associated with an oxidative stress in various settings, but few data are available on cardiac arrest in human. The aim of the present study was to evaluate different oxidative stress markers in out-of-hospital cardiac arrest (OHCA) patients treated with therapeutic hypothermia., Materials and Methods: We conducted a prospective study assessing oxidative stress markers (thiobarbituric acid reactive species, carbonyls, thiols, glutathione, and glutathione peroxidase) in OHCA patients treated with therapeutic hypothermia. Measurements were performed during the 4 days after admission and compared between good and poor outcome patients according to Cerebral Performance Category., Results: Thirty-four patients were included, 10 good and 24 poor outcomes at 6 months. Thiobarbituric acid reactive species were higher in the poor outcome group on admission and when therapeutic hypothermia was reached. The other markers were not different between groups. No markers seemed modified by the use of therapeutic hypothermia in each group., Conclusions: After OHCA, good outcome patients exhibit lower oxidative stress markers than poor outcome patients. Thiobarbituric acid reactive species appears to be an early prognostic parameter. Oxidative stress markers seem not mitigated by therapeutic hypothermia., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Pomegranate peel extract (PPE) contains several compounds with antioxidative properties. PPE added to foods may interact with endogenous antioxidants and promote health. However, little is known about the biochemical mechanisms by which PPE exerts their actions on tissues of biological systems in vivo. The purpose of this study was to determine the effects of PPE on activities of antioxidant enzymes. Mice were used to investigate the effects of PPE on plasma levels of malondialdehyde (MDA), tissue MDA content and activities of superoxide dismutase 1 (SOD1), SOD2 and glutathione peroxidase (GPX) in the small intestine, liver and skeletal muscle - different tissues involved in the digestion, absorption and metabolism of dietary nutrients. Control mice were fed a standard diet, whereas treated mice were fed for 40 days with the standard diet containing 5% or 10% PPE., Results: Mice fed the 10% PPE diet exhibited lower plasma MDA concentrations, reduced content of MDA in the small intestine and liver and higher levels of SOD1 and GPX activities in the small intestine compared to mice fed the control diet., Conclusions: These findings demonstrate that intake of PPE in diet attenuates small intestine lipid peroxidation and strengthens the first line of small intestine antioxidant defense by enhancing enzymatic antioxidative pathways. PPE is worthy of further study as a therapeutic approach to prevent peroxidative stress-induced gut pathogenesis. © 2015 Society of Chemical Industry., (© 2015 Society of Chemical Industry.)

The sex-specific divergence of antioxidant pathways in fetal organs of opposite-sex twin is unknown and remains urgently in need of investigation. Such study faces many challenges, mainly the ethical impossibility of obtaining human fetal organs. Opposite-sex sheep twins represent a unique model for studying a sex dimorphism for antioxidant systems. The activity of total superoxide dismutase (SOD), SOD1, SOD2, glutathione peroxidase (GPX), glutathione reductase (GR) and catalase (CAT), the content of total glutathione, reduced glutathione (GSH), and oxidized glutathione (GSSG) were measured in brain, lung, liver, kidney, and skeletal muscles of female and male fetuses collected from sheep twin pregnancies at day 65 of gestation. Lipid peroxidation was assessed by measuring melondialdehyde (MDA) tissue content. Male brain has greater total SOD and SOD1 activities than female brain. Female liver has greater SOD2 activity than male liver. Male liver has greater GR activity than female liver. Male liver has higher total GSH and GSSG content than female liver. Male skeletal muscles have higher total GSH, GSH, and GSSG content than female skeletal muscles. Female brain and liver have higher MDA content than male brain and liver. This is the first report of a sex dimorphism for fetal organ antioxidative pathways. Brain, liver, and skeletal muscles of male and female fetuses display distinct antioxidant pathways. Such sexually dimorphic responses to early life oxidative stress might be involved in the sex-related difference in fetal development that may have a long-term effect on offspring. Our study urges researchers to take into consideration the importance of sex as a biologic variable in their investigations.

Glutathione (GSH) is critical to fight against oxidative stress. Its very low bioavailability limits the interest of a supplementation. The purpose of this study was to compare the bioavailability, the effect on oxidative stress markers and the safety of a new sublingual form of GSH with two commonly used dietary supplements, N-acetylcysteine (NAC) and oral GSH. The study was a three-week randomized crossover trial. 20 Volunteers with metabolic syndrome were enrolled. GSH levels and several oxidative stress markers were determined at different times during each 21-days period. Compared to oral GSH group, an increase of total and reduced GSH levels in plasma and a higher GSH/GSSG ratio (p=0.003) was observed in sublingual GSH group. After 3 weeks of administration, there was a significant increase of vitamin E level in plasma only in sublingual GSH group (0.83 µmol/g; p=0.04). Our results demonstrate the superiority of a new sublingual form of GSH over the oral GSH form and NAC in terms of GSH supplementation., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

Conceptus-derived paracrine signals play crucial roles in the preparation of a uterine environment capable of supporting implantation and development of the conceptus. However, little is known about the regulation of endometrial tryptophanyl tRNA synthetase (WARS) and manganese superoxide dismutase (SOD2) protein expression by the implanting and post-implanting conceptus. We hypothesized that the conceptus-derived signals favourably influences uterine environment for implantation through regulation of WARS and SOD2 expression in ovine caruncular endometrium. To test this hypothesis, WARS and SOD2 protein and mRNA expression was determined in caruncular endometrial tissues of unilaterally pregnant ewes at implantation (day 16) and post-implantation (day 20) periods. WARS protein expression increased in caruncular tissues of the gravid uterine horns compared with the non-gravid uterine horns on days 16 and 20 of pregnancy. There were no changes in SOD2 protein expression between the gravid and non-gravid uterine horns, irrespective of the day of pregnancy. On day 16 of pregnancy, there were no differences in WARS and SOD2 mRNA expression between the gravid and non-gravid uterine horns but expression of both genes was higher in the gravid uterine horns when compared with the non-gravid uterine horns on day 20 of pregnancy. In conclusion, the use of the unilaterally pregnant ewe model provides for the first time firm evidence that the early implantation and post-implanting conceptus-derived signals up-regulate WARS protein expression within the caruncular endometrium. Further studies are necessary to identify these signalling molecules and to understand mechanisms whereby they exert paracrine action within the endometrium., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Oxidative stress is associated with decreased female fertility and adversely affects prenatal development. Mammalian cells have developed a network of enzymatic and non-enzymatic antioxidant defence systems to prevent oxidative stress. Little attention has been paid to the antioxidative pathways in placentas of normal and disturbed pregnancies, leaving a gap in our knowledge about the role of antioxidants in the control of foeto-placental development. The challenges in studying early human pregnancy can partly be overcome by designing animal models of abnormal pregnancy. We aimed to determine whether the antioxidant status of placentas from the CBA/J × DBA/2 abortion-prone pregnant mice differed from that of normal pregnant mice. The foetal/placental weight ratio was lower in abortion-prone matings compared with that in non-abortion-prone matings. The increased placental malondialdehyde (MDA) content, the end products of lipid peroxidation, with concomitants alterations in placental antioxidants, namely copper-zinc containing superoxide dismutase (SOD1), manganese containing (SOD2), glutathione peroxidases (GPX), glutathione reductase (GR) and catalase (CAT) activities may be involved in placental and foetal growth restriction. We show that placental oxidative stress is linked with poor prenatal development and pregnancy losses in CBA/J × DBA/2 mice matings. This animal model may be useful in the evaluation of nutritional antioxidant therapies for oxidative stress and associated prenatal developmental disorders.

Selenium (Se) is an essential trace element with a narrow safety zone and unclear effects on skin photoageing. The aim of this work was to investigate the photoageing properties of sodium selenite or selenomethionine (SeMet) after a long term (6 days) Se supplementation in normal human skin fibroblasts (NHSF) subjected to ultraviolet-A (UVA) irradiation inducing 30% cell death. The uptake, toxicity and antioxidant effects of sodium selenite and SeMet were compared to better understand their photoageing properties. SeMet uptake was better than sodium selenite and their uptake by fibroblasts was not via an actively transport process. Sodium selenite induced a higher toxicity than SeMet. At 5 μM, sodium selenite inhibited cell proliferation associated with a blockage in the G2 phase and induced DNA fragmentation leading to caspase-3-dependent apoptosis cell death. At low doses (<1 μM), SeMet and sodium selenite induced glutathione peroxidase-1 (GPX1) activity and selenoproteinW1 (SEPW1) transcript expression but metalloproteinase (MMP)-1 was only induced by sodium selenite. SeMet and sodium selenite did not protect NHSFs from UVA-induced cell death. However, SeMet decreased malondialdehyde (MDA) and protected NHSFs from UVA-induced MMP1 and MMP3. We then observed a large difference in terms of photoprotection according to selenium forms. SeMet may be a potential agent for the prevention and treatment of skin photoageing.

The expression and regulation of endometrial proteins are crucial for conceptus implantation and development. However, little is known about site-specific proteome profiles of the mammalian endometrium during the peri-implantation period. We utilised a two-dimensional gel electrophoresis/mass spectrometry-based proteomics approach to compare and identify differentially expressed proteins in sheep endometrium. Caruncular and intercaruncular endometrium were collected on days 12 (C12) and 16 (C16) of the oestrous cycle and at three stages of pregnancy corresponding to conceptus pre-attachment (P12), implantation (P16) and post-implantation (P20). Abundance and localisation changes in differentially expressed proteins were determined by western blot and immunohistochemistry. In caruncular endometrium, 45 protein spots (5% of total spots) altered between day 12 of pregnancy (P12) and P16 while 85 protein spots (10% of total spots) were differentially expressed between P16 and C16. In intercaruncular endometrium, 31 protein spots (2% of total spots) were different between P12 and P16 while 44 protein spots (4% of total spots) showed differential expression between C12 and C16. The pattern of protein changes between caruncle and intercaruncle sites was markedly different. Among the protein spots with implantation-related changes in volume, 11 proteins in the caruncular endometrium and six proteins in the intercaruncular endometrium, with different functions such as protein synthesis and degradation, antioxidant defence, cell structural integrity, adhesion and signal transduction, were identified. Our findings highlight the different but important roles of the caruncular and intercaruncular proteins during early pregnancy.

Chalcones are naturally occurring compounds with diverse pharmacological activities. Chalcones derive from the common structure: 1,3-diphenylpropenone. The present study aims to better understand the mechanistic pathways triggering chalcones anticancer effects and providing evidences that minor structural difference could lead to important difference in mechanistic effect. We selected two recently investigated chalcones (A and B) and investigated them on glioblastoma cell lines. It was found that chalcone A induced an apoptotic process (type I PCD), via the activation of caspase-3, -8 and -9. Chalcone A also increased CDK1/cyclin B ratios and decreased the mitochondrial transmembrane potential (ΔΨm). Chalcone B induced an autophagic cell death process (type II PCD), ROS-related but independent of both caspases and protein synthesis. Both chalcones increased Bax/Bcl2 ratios and decreased Ki67 and CD71 antigen expressions. The present investigation reveals that despite the close structure of chalcones A and B, significant differences in mechanism of effect were found., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The beneficial effect of selenium (Se) on cancer is known to depend on the chemical form, the dose and the duration of the supplementation. The aim of this work was to explore long term antagonist (antioxidant versus toxic) effects of an inorganic (sodium selenite, Na2SeO3) and an organic (seleno-L-methionine, SeMet) forms in human immortalized keratinocytes HaCaT cells. HaCaT cells were supplemented with Na2SeO3 or SeMet at micromolar concentrations for 144 h, followed or not by UVA radiation. Se absorption, effects of UVA radiation, cell morphology, antioxidant profile, cell cycle processing, DNA fragmentation, cell death triggered and caspase-3 activity were determined. At non-toxic doses (10 μM SeMet and 1 μM Na2SeO3), SeMet was better absorbed than Na2SeO3. The protection of HaCaT from UVA-induced cell death was observed only with SeMet despite both forms increased glutathione peroxidase-1 (GPX1) activities and selenoprotein-1 (SEPW1) transcript expression. After UVA irradiation, malondialdehyde (MDA) and SH groups were not modulated whatever Se chemical form. At toxic doses (100 μM SeMet and 5 μM Na2SeO3), Na2SeO3 and SeMet inhibited cell proliferation associated with S-G2 blockage and DNA fragmentation leading to apoptosis caspase-3 dependant. SeMet only led to hydrogen peroxide production and to a decrease in mitochondrial transmembrane potential. Our study of the effects of selenium on HaCaT cells reaffirm the necessity to take into account the chemical form in experimental and intervention studies.

Progesterone produced by the corpus luteum (CL) regulates the synthesis of various endometrial proteins required for embryonic implantation and development. Compromised CL progesterone production is a potential risk factor for prenatal development. Reactive oxygen species (ROS) play diverse roles in mammalian reproductive biology. ROS-induced oxidative damage and subsequent adverse developmental outcomes constitute important issues in reproductive medicine. The CL is considered to be highly exposed to locally produced ROS due to its high blood vasculature and steroidogenic activity. ROS-induced apoptotic cell death is involved in the mechanisms of CL regression that occurs at the end of the non-fertile cycle. Luteal ROS production and propagation depend upon several regulating factors, including luteal antioxidants, steroid hormones and cytokines, and their crosstalk. However, it is unknown which of these factors have the greatest contribution to the maintenance of CL integrity and function during the oestrous/menstrual cycle. There is evidence to suggest that antioxidants play important roles in CL rescue from luteolysis when pregnancy ensues. As luteal phase defect impacts fertility by preventing implantation and early conceptus development in livestock and humans, this review attempts to address the importance of ROS-scavenging antioxidant enzymes in the control of mammalian CL function and integrity. The corpus luteum (CL) is a transient endocrine organ that develops after ovulation from the ovulated follicle during each reproductive cycle. The main function of the CL is the production and secretion of progesterone which is necessary for embryonic implantation and development. Compromised CL progesterone production is a potential risk factor for prenatal development and pregnancy outcomes. Reactive oxygen species (ROS), which are natural by-products of cellular respiration and metabolism, play diverse roles in mammalian reproductive biology. ROS-induced oxidative damage and subsequent development of adverse pregnancy outcomes constitute important issues in reproductive medicine. Before the end of the first trimester, a high rate of human and animal conceptions end in spontaneous abortion and most of these losses occur at the time of implantation in association with ROS-induced oxidative damage. Every cell in the body is normally able to defend itself against the oxidative damage caused by the ROS. The cellular antioxidant enzymes constitute the first line of defence against the toxic effects of ROS. The CL is considered to be highly exposed to locally produced ROS due to its high blood vasculature and metabolic activity. There is now evidence to suggest that cellular antioxidants play important roles in CL rescue from regression when pregnancy ensues. As defective CL function impacts fertility by preventing implantation and early conceptus development in livestock and humans, this review attempts to address the importance of antioxidant enzymes in the control of mammalian CL function and integrity., (Copyright © 2012 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Conceptus (embryo and associated extraembryonic membranes) implantation and development require a reciprocal biochemical and physical interactions between the extraembryonic membranes and the endometrium. However, the enzymatic antioxidative pathways controlling reactive oxygen species production at the endometrial-extraembryonic membrane interface early in pregnancy are not known. We aimed therefore to determine the content of malondialdehyde, as biomarkers of lipid peroxidation, and the activities of the major antioxidant enzymes, copper-zinc containing and manganese containing superoxide dismutases, catalase and glutathione peroxidase, in sheep extraembryonic membranes, caruncular and intercaruncular endometrium zones sampled at specific stages of pregnancy corresponding to the conceptus implantation (day 16) and the early post-implantation period (day 21). Malondialdehyde content in caruncular, intercaruncular and extraembryonic tissues was not different between stages of the pregnancy. Extraembryonic membranes demonstrated increased manganese containing superoxide dismutase and glutathione peroxidase activities, whereas catalase activity in these tissues decreased from day 16 to day 21. Caruncular tissues demonstrated increased manganese containing superoxide dismutase activity from day 16 to day 21. Intercaruncular tissues demonstrated increased copper-zinc containing superoxide dismutase, manganese containing superoxide dismutase and catalase activities from day 16 to day 21. The ovine extraembryonic membranes exhibit dynamic changes in enzymatic antioxidative pathways different from those of endometrial tissues during the transition from implantation to post-implantation period. This biochemical data provides novel insights into the developmental changes in antioxidative pathways of extraembryonic membranes and endometrium during early conceptus development., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Obstructive sleep apnea (OSA) and metabolic syndrome (MetS) are associated with increased cardiovascular morbidity and mortality. Increased homocysteine is suggested as an independent risk factor for atherosclerosis and cardiovascular disease but remains disputed in OSA. We assessed polysomnography, carotid intima-media thickness (CIMT) and biology in 35 MetS patients, according to the presence (OSA+MetS; n=26) or the absence of OSA (MetS; n=9). In OSA+MetS patients, homocysteine levels were increased compared to MetS subjects (12.8 ± 3.8 vs. 9.5 ± 2.5 μmol/L; P=0.026). In the whole population, homocysteine correlated with apnea-hypopnea index (AHI) (r=0.522; P=0.001) and CIMT (r=0.376; P=0.026). Homocysteine was negatively correlated with plasma thiols (r=-0.406; P=0.017) and positively with urinary 15-F2t-isoprostanes (r=0.347; P=0.044). Multivariate regression analysis revealed that AHI (β=0.559; P<0.001) and urinary 15-F2t-isoprostane (β=0.310; P=0.018) were independently associated with homocysteine level. We conclude that homocysteine level was higher in MetS when associated with OSA and proportional to OSA severity. In this context, vascular remodeling appeared more severe and mediated by oxidative stress., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The protection of the developing organism from oxidative damage is ensured by antioxidant defense systems to cope with reactive oxygen species (ROS), which in turn can be influenced by dietary polyunsaturated fatty acids (PUFAs). PUFAs in membrane phospholipids are substrates for ROS-induced peroxidation reactions. We investigated the effects of dietary supplementation with omega-3 PUFAs on lipid peroxidation and antioxidant enzyme activities in rat cerebrum, liver and uterus. Pups born from dams fed a diet low in omega-3 PUFAs were fed at weaning a diet supplying low α-linolenic acid (ALA), adequate ALA or enriched with eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA). Malondialdehyde (MDA), a biomarker of lipid peroxidation, and the activities of superoxide dismutase 1 (SOD1), SOD2, catalase (CAT) and glutathione peroxidase (GPX) were determined in the three target organs. Compared to low ALA feeding, supplementation with adequate ALA or with EPA+DHA did not affect the cerebrum MDA content but increased MDA content in liver. Uterine MDA was increased by the EPA+DHA diet. Supplementation with adequate ALA or EPA+DHA increased SOD2 activity in the liver and uterus, while only the DHA diet increased SOD2 activity in the cerebrum. SOD1, CAT and GPX activities were not altered by ALA or EPA+DHA supplementation. Our data suggest that increased SOD2 activity in organs of the growing female rats is a critical determinant in the tolerance to oxidative stress induced by feeding a diet supplemented with omega-3 PUFAs. This is may be a specific cellular antioxidant response to ROS production within the mitochondria., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

In the present study, we evaluate the effect of the co-exposure to static magnetic field (SMF) and selenium (Se) on the antioxidant vitamins A and E levels and some other parameters of oxidative stress in rat. Sub-acute exposure of male adult rats to a uniform SMF (128 mT, 1 h/day during 5 consecutive days) increased plasma activity of glutathione peroxidase (+35%) but decreased α-tocopherol (-67%) and retinol levels (-41%). SMF exposure failed to alter the plasmatic thiobarbituric acid-reactive species (TBARs), total thiol groups and selenium concentrations. Sub-chronic administration of Se (Na(2)SeO(3), 0.2 mg/L, for 30 consecutive days, per os) ameliorated the antioxidant capacities in SMF-treated rats. Our investigation demonstrated that sub-acute exposure to SMF induced oxidative stress, which may be prevented by a pretreatment with selenium.

The present study was undertaken to determine the effect of co-exposure to static magnetic field (SMF) and cadmium (Cd) on the antioxidant enzymes activity and DNA integrity in rat brain. Sub-chronic exposure to CdCl (CdCl(2), 40 mg/L, per os) for 30 days resulted in a significant reduction in antioxidant enzyme activity such as the glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD) in frontal cortex and hippocampus. Total GSH were decreased in the frontal cortex of the Cd-exposed group. Cd exposure induced an increase in malondialdehyde (MDA) concentration in the frontal cortex and hippocampus. Moreover, the same exposure increased 8-oxo-7,8-dihydro-2-desoxyguanosine (8-oxodGuo) level in rat brain. Interestingly, the combined effect of SMF (128 mT, 1 hour/day for 30 consecutive days) and CdCl (40 mg/L, per os) decreased the SOD activity and glutathione level in frontal cortex as compared with the Cd group. Moreover, the association between SMF and Cd increased MDA concentration in frontal cortex as compared with Cd-exposed rats. DNA analysis revealed that SMF exposure failed to alter 8-oxodGuo concentration in Cd-exposed rats. Our data showed that Cd exposure altered the antioxidant enzymes activity and induced oxidative DNA lesions in rat brain. The combined effect of SMF and Cd increased oxidative damage in rat brain as compared with Cd-exposed rats.

The cellular prion glycoprotein (PrP(C)) is ubiquitously expressed but its physiologic functions remain enigmatic, particularly in the immune system. Here, we demonstrate in vitro and in vivo that PrP(C) is involved in T lymphocytes response to oxidative stress. By monitoring the intracellular level of reduced glutathione, we show that PrP(-/-) thymocytes display a higher susceptibility to H(2)O(2) exposure than PrP(+/+) cells. Furthermore, we find that in mice fed with a restricted diet, a regimen known to increase the intracellular level of ROS, PrP(-/-) thymocytes are more sensitive to oxidative stress. PrP(C) function appears to be specific for oxidative stress, since no significant differences are observed between PrP(-/-) and PrP(+/+) mice exposed to other kinds of stress. We also show a marked evolution of the redox status of T cells throughout differentiation in the thymus. Taken together, our results clearly ascribe to PrP(C) a protective function in thymocytes against oxidative stress.

The aim of this study was to investigate the effect of selenium supplementation on the antioxidant enzymatic system (such as GPx, GR and SOD), GSH and selenium level in liver, kidney, muscle and brain of static magnetic field (SMF) exposed rats. Male adult rats were divided into control rats (n=6), SMF-exposed rats (128 mT; 1h/day for 5 days), selenium-treated rats (Na(2)SeO(3), 0.2mg/l, in drinking water for 4 weeks) and co-exposed rats (selenium for 4 weeks and SMF during the last 5 consecutive days). Sub-acute exposure to SMF induces a decrease of selenium levels in kidney, muscle and brain. Our results also revealed a decrease of GPx activities in kidney and muscle. By contrast, SMF exposure increased total GSH levels and total SOD activities in liver, while glutathione reductase activity is unaffected. Selenium supplementation in SMF-exposed rats restored selenium levels in kidney, muscle and brain and elevated the activities of GPx in kidney and muscle to those of control group. In the liver, selenium supplementation failed to bring down the elevated levels of total GSH and SOD activity. Our investigations suggested that sub-acute exposure to SMF altered the antioxidant response by decreasing the level of total selenium in kidney, muscle and brain. Interestingly, selenium supplementation ameliorates antioxidant capacity in rat tissues exposed to SMF., (Copyright © 2010 Elsevier B.V. All rights reserved.)

We examined oxidative stress markers of 31 patients suffering from ALS, 24 patients suffering from PD and 30 healthy subjects were included. We determined the plasma levels of lipid peroxidation (malondialdehyde, MDA), of protein oxidative lesions (plasma glutathione, carbonyls and thiols) and the activity of antioxidant enzymes i.e. erythrocyte Cu,Zn-Superoxide dismutase (SOD), Glutathione peroxidase (GSH-Px) and catalase. MDA and thiols were significantly different in both neurodegenerative diseases versus control population. A trend for an enhancement of oxidized glutathione was noted in ALS patients. Univariate analysis showed that SOD activity was significantly decreased in ALS and GSH-Px activity was decreased in PD. After adjusting for demographic parameters and enzyme cofactors, we could emphasize a compensatory increase of SOD activity in PD. Different antioxidant systems were not involved in the same way in ALS and PD, suggesting that oxidative stress may be a cause rather than a consequence of the neuronal death.

Reactive oxygen species (ROS) are generated as by-products of aerobic respiration and metabolism. Mammalian cells have evolved a variety of enzymatic mechanisms to control ROS production, one of the central elements in signal transduction pathways involved in cell proliferation, differentiation and apoptosis. Antioxidants also ensure defenses against ROS-induced damage to lipids, proteins and DNA. ROS and antioxidants have been implicated in the regulation of reproductive processes in both animal and human, such as cyclic luteal and endometrial changes, follicular development, ovulation, fertilization, embryogenesis, embryonic implantation, and placental differentiation and growth. In contrast, imbalances between ROS production and antioxidant systems induce oxidative stress that negatively impacts reproductive processes. High levels of ROS during embryonic, fetal and placental development are a feature of pregnancy. Consequently, oxidative stress has emerged as a likely promoter of several pregnancy-related disorders, such as spontaneous abortions, embryopathies, preeclampsia, fetal growth restriction, preterm labor and low birth weight. Nutritional and environmental factors may contribute to such adverse pregnancy outcomes and increase the susceptibility of offspring to disease. This occurs, at least in part, via impairment of the antioxidant defense systems and enhancement of ROS generation which alters cellular signalling and/or damage cellular macromolecules. The links between oxidative stress, the female reproductive system and development of adverse pregnancy outcomes, constitute important issues in human and animal reproductive medicine. This review summarizes the role of ROS in female reproductive processes and the state of knowledge on the association between ROS, oxidative stress, antioxidants and pregnancy outcomes in different mammalian species., (Copyright 2010 Elsevier Ltd. All rights reserved.)