Preclinical Evaluation of Sodium Selenite in Mice: Toxicological and Tumor Regression Studies after Striatum Implantation of Human Glioblastoma Stem Cells.

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.

Pomegranate peel attenuates dextran sulfate sodium-induced lipid peroxidation in rat small intestine by enhancing the glutathione/glutathione disulfide redox potential.

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.

Assessment of oxidative stress after out-of-hospital cardiac arrest.

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.

Pomegranate peel extract decreases small intestine lipid peroxidation by enhancing activities of major antioxidant enzymes.

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.

NOX2 control over energy metabolism plays a role in acute myeloid leukaemia prognosis and survival.

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.

Roles of antioxidant enzymes in corpus luteum rescue from reactive oxygen species-induced oxidative stress.

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.

Enhanced susceptibility of T lymphocytes to oxidative stress in the absence of the cellular prion protein.

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.

Diet Supplementation with Pomegranate Peel Improves Embryonic Survival in a Mouse Model of Early Pregnancy Loss.

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.

Effects of static magnetic field and cadmium on oxidative stress and DNA damage in rat cortex brain and hippocampus.

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.

Effect of selenium pre-treatment on plasma antioxidant vitamins A (retinol) and E (α-tocopherol) in static magnetic field-exposed rats.

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.

Antioxidant adaptive responses of extraembryonic tissues from cloned and non-cloned bovine conceptuses to oxidative stress during early pregnancy.

Placental oxidative stress has been suggested as a key factor in early pregnancy failure. Abnormal placental development limits success in pregnancies obtained by somatic cell nuclear transfer (SCNT). Malondialdehyde (MDA) content, an index of oxidative stress, and superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) activities were determined in bovine extraembryonic tissues of SCNT or artificial insemination (AI) conceptuses. Chorionic tissues of SCNT and AI conceptuses show no difference in MDA content at day 32 of pregnancy. MDA content in chorionic tissues of SCNT and AI conceptuses decreased from day 32 to 62 of pregnancy. MDA content was lower in chorionic tissues of SCNT conceptuses than that in chorionic tissues of AI conceptuses at day 62 of pregnancy. SOD1, SOD2 and GPX activities in chorionic tissues of SCNT conceptuses were not different from those in chorionic tissues of AI conceptuses at both gestational ages. CAT activity in chorionic tissues of SCNT conceptuses was lower at day 32, and it was higher at day 62 of pregnancy than that in chorionic tissues of AI conceptuses. CAT and GPX activities increased in chorionic tissues of SCNT conceptuses with gestational age. SOD1 activity decreased while that of SOD2 and GPX increased in chorionic tissues of AI conceptuses with gestational age. At day 62 of pregnancy, MDA content and enzyme activities in cotyledonary tissues were not different between AI and SCNT conceptuses. Different antioxidant mechanisms may operate within the chorion of AI and SCNT conceptuses. Further experiments are required to elucidate this point.

The role of oxidative stress in amyotrophic lateral sclerosis and Parkinson's disease.

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.

Effect of static magnetic field and/or cadmium in the antioxidant enzymes activity in rat heart and skeletal muscle.

Currently, environmental and industrial pollution along with increase and causes multiple stress conditions, the combined exposure to magnetic field and other toxic agents is recognised as an important research area, with a view to better protecting human health against their probable unfavourable effects. In the present study, we investigated the effect of co-exposure to static magnetic field (SMF) and cadmium (Cd) on the antioxidant enzymes activity and the malondialdehyde (MDA) concentration in rat skeletal and cardiac muscles. The exposure of rats to SMF (128 mT, 1 h/day during 30 consecutive days) decreased the activities of glutathione peroxidase (GPx) and the superoxide dismutase (CuZn-SOD) in heart muscle. Sub-chronic exposure to SMF increased the MDA concentration in rat cardiac muscle. Cd treatment (CdCl2, 40 mg/l, per os) during 4 weeks decreased the activities of catalase (CAT) in skeletal muscle and the CuZn-SOD in the heart. Moreover, Cd administration increased MDA concentration in the both structures. The combined effect of SMF (128 mT, 1 h/day during 30 consecutive days) and Cd (40 mg/l, per os) disrupt the antioxidant enzymes activity in rat skeletal and cardiac muscles. Moreover, we noted a huge increase in MDA concentration in the heart and skeletal muscle compared to control group. Thus it is possible that the SMF- and/or Cd-induced depletion of antioxidant enzymes activity in muscle tissues might, like the enhanced lipid peroxidation, importantly contribute to oxidative damage. The combined effect of SMF and Cd altered significantly the antioxidant enzymatic capacity and induced lipid peroxidation in both skeletal and cardiac muscle.

Familial deep cavitating state with a glutathione metabolism defect.

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.

Human mesenchymal stem cells improve rat islet functionality under cytokine stress with combined upregulation of heme oxygenase-1 and ferritin.

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.

Regulation of key antioxidant enzymatic systems in the sheep endometrium by ovarian steroids.

Reactive oxygen species (ROS) and their control by antioxidant enzymes are involved in the physiology of the female reproductive system. Thus, it is important to understand the regulation of key antioxidant enzymatic pathways. The roles of estrogen and progesterone in regulating the physiological functions of the endometrium have become central dogma. We examined the effects of ovarian steroids on superoxide dismutases (SOD1 and SOD2), catalase (CAT), glutathione peroxidase (GPX), and glutathione reductase (GSR) activities in the aglandular caruncular and glandular inter-caruncular endometrial tissues of ovariectomized (OVX) ewes and in OVX ewes treated with estradiol (E2), progesterone (P4), or both hormones according to schedules designed to produce physiological changes of these hormones during the estrous cycle. The activities SOD2, CAT, GPX and GSR in both endometrial tissues were unaffected by P4 treatment. The activity of SOD1 in the aglandular tissue was unaffected by P4 treatment, however this treatment decreased SOD1 activity in the glandular tissue (P < 0.01). Treatment with E2, either alone or in combination with P4, decreased SOD1 (P < 0.01), CAT (P < 0.01) and GPX (P < 0.05) activities in both endometrial tissues. The activity of GSR decreased only in the glandular tissue (P < 0.05) after E2 treatment, either alone or in combination with P4. No change in SOD2 activity was detected in both endometrial tissues after administration of E2, P4 or both hormones. This study provides the first firm evidence for the role of ovarian steroid hormones in the regulation of the activities of key antioxidant enzyme in the endometrium of female mammals.

Cadmium-induced oxidative stress and DNA damage in kidney of pregnant female rats.

In the present study, we have investigated the influence of sub-acute treatment with cadmium (Cd) on some parameters indicative of oxidative stress and DNA damage in tissues of pregnant female rats. Pregnant female rats (n=6) were injected subcutaneously, daily with a dose of cadmium chloride of 3 mg/kg body weight (b.w.) from day 6 to day 19 of pregnancy, and they were allowed to deliver normally. MDA level and GPx, CAT and SOD activities were used as markers of oxidative stress in liver and kidney. The 8-oxo-dG level was measured by the HPLC-EC system. Cd treatment increased MDA (+116%, p<0.01) in kidney. Moreover, Cd treatment also decreased CuZn-SOD (-11%, p<0.05) and GSH level (-52%, p<0.05) in kidney. Treated rats displayed an increase of the liver metallothionein (MT) level. Induction of MT in liver was probably implicated in the detoxification of Cd. The high level of Cd (3 mg/kg) used in the present study is partially neutralized by MT in liver, whereas the free fraction could be implicated in the oxidative stress and DNA oxidation observed in kidney. Cd treatment failed to alter 8-oxodGuo, indicating the absence of DNA oxidation in liver; by contrast, the same treatment increased the 8-oxodGuo level (+51%, p<0.05) in the kidney of pregnant female rats, indicating an oxidative stress associated with DNA damage only in kidney.

Oxidative stress and DNA damage induced by cadmium in the human keratinocyte HaCaT cell line: role of glutathione in the resistance to cadmium.

Cadmium affects the cellular homeostasis and generates damage via complex mechanisms involving interactions with other metals and oxidative stress induction. In this work we used a human keratinocyte cell line (HaCaT) as a model to study the oxidative damage induced by cadmium to cellular macromolecules, its effect on the antioxidant systems and the role of glutathione in cell protection toward cadmium toxicity. The cells were incubated for 24 and 48 h with cadmium (3, 15, 50 and 100 microM). High doses of cadmium were required to induce a cytotoxicity: 100 microM lead to 30% mortality after 24h and 50% after 48 h. The oxidation of lipids and proteins and the DNA damage, respectively, assessed by thiobarbituric acid reactants determination, thiol group measurement and comet assay, were observed for 50-100 microM cadmium. The cytotoxic effects were strongly correlated to the cellular cadmium content. The glutathione peroxidase and the catalase activities were decreased, while the glutathione reductase activity and the glutathione concentration were increased after cadmium treatment. The superoxide dismutases activities were unchanged. A depletion in glutathione prior to cadmium exposure increased the cytotoxic effects and provoked DNA damage. Our results suggested that the hydroxyl radical could be the major compound involved in the oxidative stress generated by cadmium and that glutathione could play a major role in the protection of HaCaT cells from cytotoxicity but mostly from DNA damage induced by cadmium.

A New Patient-Derived Metastatic Glioblastoma Cell Line: Characterisation and Response to Sodium Selenite Anticancer Agent.

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.