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Ferroptosis is a form of cell death that has recently been reported during exposure to erastin, a chemical compound identified in a screen for molecules able to kill cancer cells carrying an active Ras oncogene. In cells exposed to inducers of ferroptosis, a catastrophic alteration of the cellular redox metabolism occurs, resulting in massive lipid peroxidation in the plasma membrane and loss of cell viability. We present our recent observations suggesting that sorafenib, the only medical treatment with proven efficacy against hepatocellular carcinoma, induces ferroptosis, a new anti-oncogenic mode of action of this drug. The discovery of ferroptosis sheds light on the critical adaptations of the redox metabolism in cancer cells. It might also foster the discovery of new biomarkers and innovative approaches for the treatment of cancer., (© 2014 médecine/sciences – Inserm.)

Introduction: New mouthwash solutions containing microencapsulated natural extracts were developed to provide both antiseptic activity and in depth treatment of oral tissues, due to their antioxidant and immunoregulatory properties. The objective of this study was to quantify the antioxidant action of the GingiNat solution (LoB5 Foundation, Paris, France) in an in vitro cell model., Materials and Methods: Diluted GingNat solutions (0.12%, 0.06% and 0.012%) were put in contact with Jurkat type human lymphoid cells in basal radical state (cells at rest) and in provoked oxidative stress conditions (after an UVA+UVB irradiation). The lipid peroxidation was quantified by flow cytometry using a fluorescent probe., Results: The diluted GingNat solutions at 0.12%, 0.06%, and 0.012% showed a significant antioxidant effect with respectively 122.9%, 117.8% and 119.3% on average. The difference was statistically significant compared to controls for the three concentrations without any significant difference among them. This antioxidant effect was even more significant when cells were in oxidative stress with respectively 155.3%, 139.3%, and 132.5% on average. There was a significant difference between the tested concentrations (p<0.01)., Discussion: These first in vitro results confirmed the antioxidant properties of the GingiNat solution. These antioxidant properties are significantly higher at stronger concentrations. Further studies are required to analyze the influence of microencapsulation on these results. Clinical trials are needed to confirm these antioxidant properties., (Copyright 2010 Elsevier Masson SAS. All rights reserved.)

Transitional metals, as vanadium, are known to exert noxious effects by generating oxidative stress. Addition of antioxidants in the diet could decrease the cytotoxic effect related to the oxidative stress. The present study, carried out in Wistar rats, is a contribution to the evaluation of protective effects of green tea Camellia sinensis, which is known to be rich in antioxidant compounds (polyphenols...). Rats were divided into four groups: (C) was control, (V) was given ammonium metavanadate (AMV), (TH) was given herbal tea as drink (66 g/l) and TH + V was given tea and metavanadate. Group (TH) was given herbal tea one month before vanadium treatment. Metavanadate was daily i.p. injected (5 mg NH4VO3/kg body weight) for 10 days. (C) and (TH) groups received i.p. injections of 0.9% NaCl during the same period. Changes in lipid peroxidation levels (TBARS) in kidney, liver and testes, serum concentrations of vitamins E and A and superoxidismutase (SOD) and catalase (CAT) activities in blood cells were determined. One month pre-treatment with green tea, followed by 10 days of treatment (TH) did not change TBARS in liver and testes as compared to controls, but induced a clear decrease of TBARS in kidneys. Intraperitoneal administration of AMV to rats (V) induced a time-dependant increase of TBARS in kidney, liver and testes that was lowered in rats (V + TH) drinking tea. Vitamin E concentrations were found to be drastically decreased from day 1 to 10 in rats (V). Vitamin A concentration was decreased at day 10 only. Drinking tea lowered AMV inhibitory effects in rats (V + TH), and conversely an increase of vitamins A and E concentrations were found at day 10. SOD and catalase activities were found increased in the blood cells from day 1 to day 5 and conversely decreased at day 10. In contrast, associated to green tea, AMV did not affect SOD and catalase activities compared to controls.

Background: Schizophrenia is a devastating psychiatric disorder with a broad range of behavioural and biologic manifestations. There are several clinical characteristics of the illness that have been consistently associated with poor premorbid adjustment, long duration of psychosis prior to treatment and prominent negative symptoms. The etiopathogenic mechanisms of lack of insight in patients with schizophrenia are to date unknown, although several hypotheses have been suggested. A point of convergence for the theoretical models occurs with regard to the neuronal membrane. Neuronal membrane contains a high proportion of polyunsaturated fatty acid and is the site for oxidative stress. Oxidative stress is a state when there is unbalance between the generation of reactive oxygen species and antioxidant defence capacity of the body. It is closely associated with a number of diseases including Parkinson's disease, Alzheimer-type dementia and Huntington's chorea. Accumulating evidence points to many interrelated mechanisms that increase production of reactive oxygen or decrease antioxidant protection in schizophrenic patients., Objectives: This review aims to summarize the perturbations in antioxidant protection systems during schizophrenia, their interrelationships with the characteristic clinics and therapeutics and the implications of these observations in the pathophysiology of schizophrenia are discussed., Literature Findings: In schizophrenia there is evidence for deregulation of free radical metabolism, as detected by abnormal activity of critical antioxidant enzymes (superoxide dismutase, glutathione peroxidase and catalase). Many studies conclude in the decrease in the activity of key antioxidant enzymes in schizophrenia. A few studies have examined levels of non enzymatic antioxidants such as plasma antioxidant proteins (albumin, bilirubine, uric acid) and trace elements. How showed decreased levels in schizophrenic patients. Others studies have provided evidence of oxidative membrane damage by examining levels of lipid peroxidation products. Such abnormalities have been associated with certain clinical symptoms and therapeutic features. Negative symptoms have been associated with low levels of GSH-Px. Positive symptoms have been positively correlated with SOD activity. Plasma TAS was significantly lower in drug-free and haloperidol treated patients with schizophrenia. A low erythrocyte SOD activity has been found in never-treated patients, but with haloperidol treatment, SOD activity increased., Discussion: These results demonstrate altered membrane dynamics and antioxidant enzyme activity in schizophrenia. Membrane dysfunction can be secondary to free a radical-mediated pathology, and may contribute to specific aspects of the schizophrenia symptomatology. Membrane defects can significantly alter a broad range of membrane functions and presumably modify behavior through multiple downstream biological effects. Phospholipid metabolism in the brain may be perturbed in schizophrenia, with reduced amounts of phosphatidylcholins and phosphatidylethanolamine in post-mortem brain tissue from schizophrenic patients, and large amounts of lipofuscin-like materiel in the oligodendrocytes. The existence of these products within cell membranes results in an unstable membrane structure, altered membrane fluidity and permeability and impaired signal transduction. Recent findings suggest that multiple neurotransmitter systems may be faulty. CNS cells are more vulnerable to the toxic effects of free radicals because they have a high rate of catecholamine oxidative metabolic activity. Neurotransmitters, like glutamate, can induce the same metabolic processes that increase free radical production and can lead to impaired dopamine-glutamate balance. These results question the role of this imbalance in the biochemical basis evoked in the etipathogenic mechanisms of schizophrenia, as well as the role of antioxidants in the therapeutic strategy and their implication in preventive and early intervention approaches in populations at risk for schizophrenia.

Treatment of rape seedlings with increasing CdCl2 concentrations in the culture medium resulted in a cadmium accumulation within plant tissues, which increased with external metal dose; such accumulation was more important in roots than in leaves. Biomass production was severely inhibited, even at low cadmium concentration. In leaves, quantities of chloroplastic lipids, monogalactosyldiacylglycerol (MGDG), digalactosyldiacylglycerol (DGDG), sulfolipids (SL) and phosphatidylglycerol (PG) decreased sharply under metallic treatment. However, contents of extrachloroplastic lipids, mainly phosphatidylcholine (PC) and phosphatidylethanolamine (PE) increased significantly. In contrast to leaves, contents of root phospholipids decreased. Likewise, levels of tri-unsaturated fatty acids: linolenic (C18:3) and hexadecatrienoïc (C16:3) dropped in leaves of treated seedlings as compared to those of controls, suggesting that heavy metals induced an alteration in the fatty acid desaturation process or a stimulation of their peroxidation. Also, trans palmitoleic acid (C16:1-trans) level in PG decreased considerably. In roots, there was a slight decrease in C18:3 level, with a concomitant increase in the C18:2 percentage. Radioactive labelling of leaf lipids with (1-14C) acetate allowed to show that fatty acid biosynthesis was noticeably altered at the highest cadmium dose used (50 microM). Biosynthesis of tri-unsaturated fatty acids was also inhibited which may explain the decline in non-labelled lipid contents. Results showed that metallic ion seems to affect selectively chloroplastic membranes due to an inhibition of polyunsaturated fatty acid biosynthesis. Moreover, a lipid peroxidation occurred in our case because of the spectacular increase of malondialdehyde (MDA) content observed in cadmium treated leaves.

The paracetamol and cyclophosphamid are metabolized in the liver by the cytochrome P450. The formed reactive intermediates are responsible of a hepatocyte depletion of the glutathion and a lipoperoxydation. the vinblastine is also a chemotherapeutic agent hepatotoxic and hematotoxic. Otherwise, flavonoïds are polyphenols substances of plant origin having some biological and anti-oxydative properties. However no information is available on their effects on glutathion and glutathion-s-transferases. In our research, we valued the effect of oral administration of flavonoids (diosmine and quercetine) under shape of propolis extract to 60 mg/kg daily during 14 days, on hematological and hepatic toxicity of a single dose of cyclophosphamide 80 mg/kg by intravenous way, vinblastine 2 mg/kg by intravenous way and the hepatic toxicity of the paracetamol managed by oral way to 200 mg/kg corresponding to 2/3 the DL50 at the rat female albinos wistar. We did a blood numeration, an assessment of serum activities of transaminases and alkali phosphatases as well as quantification of the glutathion and the malondialdehyde (MDA) in liver homogenats of rats treated. Analyses are done at regular intervals; 1, 3, 7 and 14 days after the administration of drugs. In the group of rats treated by the cyclophosphamid paracetamol alone we observed since the 1st day, an increase of lipid peroxide (MDA) of 120% and a downfall of hepatic glutathion including the group receiving the vinblastine (until 210% of reduction). In the same way a severe leucopenia and a thrombopenia (70% of reduction) are observed between the 3rd and the 14th day at rats treated by the chemotherapeutic agents alone (cyclophosphamide and vinblastine). The combination of flavonoids with drugs have clearly reduced the effect of drugs toxicity. Indeed, the aplasic observed with the vinblastine, as well as the leucopenia and thrombopenia of the cyclophosphamide are corrected entirely. In the same way, we noted a restoration of rates of peroxide and glutathion. Flavonoïds seem to act by activation of the turn over of the glutathion and enzymes stimulating particularly glutathion-s-transferases permitting the captation of the reactive metabolites of the studied drugs.

Oxidation of low-density lipoproteins constitutes the first step of a very complex process leading to atherosclerosis. Vitamin E, and principally a-tocopherol, is considered as the principal inhibitor of lipid peroxidation. Some studies showed the beneficial role of vitamin E in the prevention and reduction of atherosclerosis and its associated pathologies. However, other in vitro studies advance a prooxidant role of vitamin E. The results of the epidemiologic studies are difficult to generalize without taking account of the clinical randomized tests. In this work, we reviewed the principal studies devoted to the role of vitamin E and discussed the assumption of a prooxidant effect of this molecule.

Previous studies have demonstrated that ascorbic acid associated with ferrous ions induced deleterious effects on several targets or functions of striatal dopaminergic nerve endings, which were prevented by the Ginkgo biloba extract EGb 761. The present study attempted to assess whether a peroxidation of polyunsaturated fatty acids of their membranes could be associated with (or even responsible for) these alterations. Synaptosomes were prepared from mice striata. Their 1 h incubation with ascorbic acid (0.1 mM) resulted in a marked increase (+300%) of thiobarbituric acid reactive substances, that roughly are considered to correspond to the malondialydehyde level. Under these conditions the level of polyunsaturated fatty acids, measured by gas chromatography, decreased by -23% whereas the level of saturated fatty acids was not modified. Both the increase in thiobarbituric acid reactive substances and the decrease in polyunsaturated fatty acids were prevented by EGb 761 (10 micro g/ml). Similarly, the increase of TBARS was prevented by the vitamin E analogue trolox C (0.1mM) as well as by the ferrous ions chelating agent desferrioxamine (0.1mM). These data suggest that the polyunsaturated fatty acids peroxidation could be the origin of previously reported synaptosomal alterations induced by ascorbic acid/Fe(2 +).

Moderate and regularly alcohol consumption reduces death rate from coronary heart disease and thrombotic stroke. This beneficial correlation observed with several alcoholic beverages seems to be mainly due to an ethanol effect. However the particular role of microconstituants contained in red wine must be considered. The mechanism of the putative protective effect of alcohol intake is mediated through the elevation of HDL cholesterol and through the aintioxydative effect of polyphenolic compounds. In addition, alcohol acts favourably on platelets agregation, fibrinolysis and several other coagulation parameters. Despite these explanations are yet speculative and there is no causal relation between alcohol and reduced coronary death, epidemiological data are consistent with the belief that daily consumption of one or two glasses of an alcoholic beverage has salutary effect on health.

Numerous studies suggest that lipid peroxidation is involved in the atherosclerosis and hemolytic disease processes. Nicanartine improves in vitro resistance of LDL (low density lipoproteins) to oxidation in the conjugated dienes model. Polarographic assays show that hemin-bound drugs inhibit erythrocyte membrane peroxidation. A method to measure the antioxidant capacity of plasma is proposed and tested in sickle cell disease. These in vitro results suggest drugs and drugs combination which could be efficient to inhibit lipid peroxidation in vivo.

A novel family of prostaglandin F2 isomers, called F2-isoprostanes, produced in large quantities in vivo by a free radical peroxidation of arachidonic acid, has recently been described. The quantification of the two major isoforms (isoprostaglandin F2alpha type-III and VI) in biological fluids and tissues as markers of lipid peroxidation appears to be an important advance in our ability to explore the role of free radicals in the pathogenesis of human disease. In addition, F2-isoporstanes quantification seems promising as intermediate endpoints for clinical studies of antioxidant therapies.

While mitochondria are key factors in energy production in cells they are also key factors in their life cycle because under certain circumstances they can provoke cellular apoptosis. Some 45 per cent of myocardial volume is taken up by mitochondria. Furthermore, mitochondria are key to many aspects of neuronal activity and can trigger neurodegenerative processes. Lipid oxidation is responsible for the production of much ATP resynthesis in the heart but this process is less oxygen efficient than glucose oxidation. During ischaemia, lipid oxidation is suddenly blocked, but markedly increased during reperfusion, causing accumulation of potentially toxic metabolites (acylcarnitines, acyl-CoA, lysophospholipids). These metabolites can change calcium handling, inducing arrhythmias. Trimetazidine, and another product in development, ranolazine, by inhibiting lipid oxidation favours glucose oxidation and inhibits the production of deleterious lipid metabolites. Thus this class of drugs can have beneficial effects on myocardial metabolism without direct haemodynamic effects.

Silibinin (SDH) is a flavonoid with ascertained hepatoprotective effects, which have been partially attributed to its antioxidant properties. Oxidation of blood constituents could have a role in atherogenesis and interfere with the rheologic properties of the blood. In this study we investigated, whether SDH could protect some blood constituents against oxidative modification. In human plasma we measured TBARS and fluorescence generation as indicators of copper or azobis amidinopropane hydrochloride (AAPH) at 760 mm Hg PO2-induced lipid peroxidation. SDH at 50 microM inhibited copper-induced TBARS formation by 25% and fluorescence by 47%. SDH also inhibited AAPH-induced lipid peroxidation, but at 175 microM concentration only. Oxidative modification of albumine was evaluated by fluorescence generation. SDH at 50 microM inhibited copper/hydrogen peroxide fluorescence generation by 54% and at 2.5 microM it inhibited EDTA-Fe (II)/hydrogen peroxide fluorescence generation by 31%. The protection of albumin by SDH was confirmed by SDS-PAGE electrophoresis. Copper-induced red-cell lipid peroxidation was evaluated by TBARS formation. SDH at 250 microM inhibited copper-induced lipid peroxidation and hemolysis by 45% and 94%, respectively. SDH also inhibited hemolysis in red-cell suspensions exposed to hydrogen peroxide, but not lipid peroxidation. Our results show that SDH may protect blood constituents from oxidative damage.

The aim of this study is to appreciate hepatoprotective properties of lyophilized aqueous extract of Tinospora bakis roots. We used hepatocytes isolated from rats and intoxicated by CCl4. Before and after intoxication cells were treated with different concentrations of Tinospora bakis extract. (1 mg to 4 mg/ml). Protection of cells was evaluated by the decrease of intracellular enzymes release (LDH and ASAT). The impact of time on the cytoprotection was also studied. From each rat we isolated 185.4 millions +/- 71.5 hepatocytes. The percent of ASAT and LDH release was significatively decreased when we compared treated and no treated hepatocytes suggesting cells protection. This cytoprotection is dose independent but is more effective for long course treatment. These results show the direct protection of isolated hepatocytes by Tinospora bakis extract.

Oxidizing activity study of inorganic compounds is based on a mechanistic approach. This approach implies research of the capacity of these materials, after interaction with molecular oxygen, to generate activated oxygen species (AOS) in aqueous medium. These electrophilic species are able to participate in oxidative stress processes and some AOS differ in their oxidizing power; highly oxidizing species (A*) and entities (P*) less oxidizing than A*. These AOS are capable of initiating linolenic acid peroxidation leading to formation of different degradation products such MDA, monoaldehydes, conjugated dienes and trienes, hydroperoxydes, and ethane. The detection of these products allows to reveal the presence of AOS. Our data show that the global assessment of lipid peroxidation should be established from the whole of formed peroxidation products and not from one type of degradation products.

Diosmin (DI) 3'5,7-trihydroxy-4'-methoxy flavone rutinoside is a member of the flavonoid family, some of whom have antioxidant or free radical scavenger properties. Paw oedema induced by doxorubicin in rats is reduced by DI as observed by SAUVAIRE et al (1989). This suggests a free radical scavenger activity for DI. In this work we demonstrate that such activity is able to protect isolated human LDL from oxidation in vitro. The study of the electrophoretic mobility of oxidized LDL and of total-MDA values as lipoperoxidation-marker indicates an oxidation inhibiting effect higher than 70% for 0.16 mM DI in LDL mixtures containing 50 mM Cu2+ or 4.3 mU/ml xanthine-oxidase and incubated during 20 and 6 hours respectively. Owing to the high level of the oxidizing conditions and the vitamin E (48 mM), vitamin A (1.4 mM) and beta-carotene (2.4 mM) content of the LDL mixtures, it is concluded that DI is clearly able to complement the antioxidant effect of isoprenoids which are naturally present in LDL mixtures.

Lipoperoxidation has an important role in the normal processes of the cell-life. The induction is produced by oxygen-derived free radicals which attack the membrane phospholipids. Such an attack is modulated by an enzymatic protection system (superoxide dismutase, catalase, glutathione peroxidase, glutathione transferase) and by a non-enzymatic one (vitamin C, vitamin E...). In various pathologic conditions, a dispoise takes place between radical attack and antiradical protection. The place taken by lipoperoxidation in the ageing process seems to be fundamental. We report here the results of a study carried out in aged and sick patients who were given an antioxidant medicamentous combination made from Vitamin C, Vitamin E and Rutin. Our results evidence that such a synergistic combination does modify both enzymatic protection system and lipoperoxidation, this latter showing a decrease under treatment.