Iron-sulfur protein odyssey: exploring their cluster functional versatility and challenging identification.

Iron-sulfur (Fe-S) clusters are an essential and ubiquitous class of protein-bound prosthetic centers that are involved in a broad range of biological processes (e.g. respiration, photosynthesis, DNA replication and repair and gene regulation) performing a wide range of functions including electron transfer, enzyme catalysis, and sensing. In a general manner, Fe-S clusters can gain or lose electrons through redox reactions, and are highly sensitive to oxidation, notably by small molecules such as oxygen and nitric oxide. The [2Fe-2S] and [4Fe-4S] clusters, the most common Fe-S cofactors, are typically coordinated by four amino acid side chains from the protein, usually cysteine thiolates, but other residues (e.g. histidine, aspartic acid) can be found. While diversity in cluster coordination ensures the functional variety of the Fe-S clusters, the lack of conserved motifs makes new Fe-S protein identification challenging especially when the Fe-S cluster is also shared between two proteins as observed in several dimeric transcriptional regulators and in the mitoribosome. Thanks to the recent development of in cellulo, in vitro and in silico approaches, new Fe-S proteins are still regularly identified, highlighting the functional diversity of this class of proteins. In this review, we will present three main functions of the Fe-S clusters and explain the difficulties encountered to identify Fe-S proteins and methods that have been employed to overcome these issues.

Safety assessment of the substance 'phosphorous acid, triphenyl ester, polymer with 1,4-cyclohexanedimethanol and polypropylene glycol, C10-16 alkyl esters', for use in food contact materials.

The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) assessed the safety of the substance 'phosphorous acid, triphenyl ester, polymer with 1,4-cyclohexanedimethanol and polypropylene glycol, C10-16 alkyl esters', when used as an additive in all types of polyolefins. The substance is a polymer containing ≤ 13% w/w of a low molecular weight fraction (LMWF, < 1000 Da). A polyethylene sample with 0.15% w/w of the substance was used in a comprehensive set of migration tests with food simulants. The specific migration was up to 0.014 and 0.023 mg/kg in 4% acetic acid and 10% ethanol, respectively. Migration into olive oil was estimated by the Panel to be up to 5.3 mg/kg under worst-case conditions of use. The migrating LMWF species were comprehensively identified. Those without phosphorous were either without alerts for genotoxicity or listed in Regulation (EU) 10/2011 with worst-case migrations well below their respective specific migration limits. Toxicological studies were performed using phosphite and phosphate versions of the substance enriched in its LMWF. The substance does not raise a concern for genotoxicity. From a repeated dose 90-day oral toxicity study in rats with a 50:50 phosphite:phosphate blend, the Panel identified a NOAEL of 250 mg/kg bw per day for each component of the blend. No delayed neurotoxicity in hens was observed. The CEP Panel concluded that the substance does not raise a safety concern for the consumer if its LMWF is not higher than 13% w/w, if it is used at up to 0.15% w/w in polyolefin materials and articles intended for contact with all food types, except for infant formula and human milk, for long-term storage at room temperature and below, after hot-fill and/or heating up to 100°C for up to 2 h, and if its migration does not exceed 5 mg/kg food.

Regulations of mitoNEET by the key redox homeostasis molecule glutathione.

Human mitoNEET (mNT) and CISD2 are two NEET proteins characterized by an atypical [2Fe-2S] cluster coordination involving three cysteines and one histidine. They act as redox switches with an active state linked to the oxidation of their cluster. In the present study, we show that reduced glutathione but also free thiol-containing molecules such as ß-mercaptoethanol can induce a loss of the mNT cluster under aerobic conditions, while CISD2 cluster appears more resistant. This disassembly occurs through a radical-based mechanism as previously observed with the bacterial SoxR. Interestingly, adding cysteine prevents glutathione-induced cluster loss. At low pH, glutathione can bind mNT in the vicinity of the cluster. These results suggest a potential new regulation mechanism of mNT activity by glutathione, an essential actor of the intracellular redox state.

Safety assessment of the substance poly(2-hydroxypropanoic acid), n-octyl/n-decyl esters, for use in food contact materials.

The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) assessed the safety of poly(2-hydroxypropanoic acid), n-octyl/n-decyl esters (OLA8), which is intended to be used as a plasticiser into polylactic acid (PLA) in contact with non-fatty foods. OLA8 is intended to be used at up to 5% and 15% w/w with or without starch, respectively (or with other additives with similar function). The migration for 10 days at 40°C from the film without starch was 0.16 mg/kg in 10% ethanol and 0.01 mg/kg in 3% acetic acid, while from the film with the starch it was well above 0.05 mg/kg food in all simulants. Some of the testing conditions were inconsistently reported. The substance did not induce gene mutations in bacterial cells and did not induce structural chromosomal aberrations or polyploidy in mammalian cells, thus, does not raise concern for genotoxicity. Instead of providing a 90-day oral toxicity study, a hydrolysis study in ■■■■■ was submitted to read-across from the authorised starting substances, ■■■■■ and the ■■■■■. However, the data provided did not allow to perform the read-across, thus no appropriate toxicological data were provided to support migration above 0.05 mg/kg food (including for contact with 10% ethanol and use in combination with starch). The Panel concluded that OLA8 does not raise a safety concern for the consumer if it is used as an additive at up to 15% w/w in the manufacture of PLA articles that do not contain starch (and other additives with similar function), that are intended to be in contact for 10 days at 40°C with foods simulated by 3% acetic acid and from which the migration does not exceed 0.05 mg/kg food.

Redox-Based Strategies against Infections by Eukaryotic Pathogens.

Redox homeostasis is an equilibrium between reducing and oxidizing reactions within cells. It is an essential, dynamic process, which allows proper cellular reactions and regulates biological responses. Unbalanced redox homeostasis is the hallmark of many diseases, including cancer or inflammatory responses, and can eventually lead to cell death. Specifically, disrupting redox balance, essentially by increasing pro-oxidative molecules and favouring hyperoxidation, is a smart strategy to eliminate cells and has been used for cancer treatment, for example. Selectivity between cancer and normal cells thus appears crucial to avoid toxicity as much as possible. Redox-based approaches are also employed in the case of infectious diseases to tackle the pathogens specifically, with limited impacts on host cells. In this review, we focus on recent advances in redox-based strategies to fight eukaryotic pathogens, especially fungi and eukaryotic parasites. We report molecules recently described for causing or being associated with compromising redox homeostasis in pathogens and discuss therapeutic possibilities.

Safety assessment of 'waxes, paraffinic, refined, derived from petroleum-based or synthetic hydrocarbon feedstock, low viscosity' for use in food contact materials.

The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP Panel) assessed the safety of the 'waxes, paraffinic, refined, derived from petroleum-based or synthetic hydrocarbon feedstock, low viscosity' (FCM No. 93), for which the uses were requested to be extended for articles in contact with fatty foods. Migration from low-density polyethylene samples containing 1% w/w of a representative wax was tested in food simulants. In fatty food simulants, the migration of mineral oil saturated hydrocarbons (MOSH) ≤ C35 was 142 mg/kg food, exceeding the overall migration limit for plastic FCM. Mineral oil aromatic hydrocarbons (MOAH) with at least two rings are largely removed during the manufacturing process. Based on various lines of evidence, the Panel concluded that any concern for the potential presence of MOAH with two or more conjugated aromatic rings can be ruled out. Based on the genotoxicity studies and on the content of polycyclic aromatic hydrocarbons (PAHs), the substance does not raise a concern for genotoxicity. Available toxicokinetic data showed a limited accumulation of MOSH. No adverse effects were observed up to the highest tested dose of 9 g/kg body weight per day in a 90-day repeated oral toxicity study in Sprague-Dawley rats. The available results showed that FCM No. 93 is devoid of endocrine activity. The provided information on chronic toxicity and carcinogenicity was limited and inadequate to reach conclusions on these endpoints. Therefore, the CEP Panel concluded that under the intended and tested conditions of uses, the substance does not raise safety concern for the consumer if used to a level ensuring that its migration into food is no more than 5 mg/kg.

Novel Insights into Redox-Based Mechanisms for Auranofin-Induced Rapid Cancer Cell Death.

Auranofin (Ridaura®, AUF) is a gold complex originally approved as an antirheumatic agent that has emerged as a potential candidate for multiple repurposed therapies. The best-studied anticancer mechanism of AUF is the inhibition of thioredoxin reductase (TrxR). However, a number of reports indicate a more complex and multifaceted mode of action for AUF that could be cancer cell type- and dose-dependent. In this study, we observed that AUF displayed variable cytotoxicity in five triple-negative breast cancer cell lines. Using representative MDA-MB-231 cells treated with moderate and cytotoxic doses of AUF, we evidenced that an AUF-mediated TrxR inhibition alone may not be sufficient to induce cell death. Cytotoxic doses of AUF elicited rapid and drastic intracellular oxidative stress affecting the mitochondria, cytoplasm and nucleus. A "redoxome" proteomics investigation revealed that a short treatment with a cytotoxic dose AUF altered the redox state of a number of cysteines-containing proteins, pointing out that the cell proliferation/cell division/cell cycle and cell-cell adhesion/cytoskeleton structure were the mostly affected pathways. Experimentally, AUF treatment triggered a dose-dependent S-phase arrest and a rapid disintegration of the actin cytoskeleton structure. Our study shows a new spectrum of AUF-induced early effects and should provide novel insights into the complex redox-based mechanisms of this promising anticancer molecule.

Safety assessment of the process Loop Polymers, used to recycle polyethylene and polypropylene printed offcuts and scrap for use as food contact materials.

The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) assessed the safety of the recycling process Loop Polymers (EU register number RECYC252). The input consists of polyethylene (PE) and polypropylene (PP) offcuts and scrap from the production of food contact packaging that has not been in contact with food, but carry coatings, ink systems and adhesives. Decontaminated material is intended to be used to produce new articles for their original application. The Panel considered critical the management system put in place to provide full traceability from input to the final product, the material review before processing, as well as the removal of coatings, ink systems and adhesives during recycling. The CEP Panel considered that the applicant did not demonstrate that coatings, ink systems and adhesives were adequately removed during the process. Consequently, it concluded that the applicant has not demonstrated that the recycling process is able to reduce the contamination of the PE or PP recyclate to a concentration that does not pose a risk to human health.

Safety assessment of the process LOGIFRUIT, used to recycle high-density polyethylene and polypropylene crates for use as food contact materials.

The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) assessed the safety of the recycling process LOGIFRUIT (EU register number RECYC260). The input consists of pre-washed high-density polyethylene (HDPE) or polypropylene (PP) crates from closed and controlled food distribution loops. The process separates crates by material type. Crates are ground to flakes, possibly extruded to pellets and used by companies approved to be in the loop to manufacture new crates. The Panel considered that the quality management system (QAS) put in place to ensure compliance of the origin of the input with Commission Regulation (EC) No 282/2008 and to provide full traceability is critical. The Panel concluded that, when run under the conditions described, the input of the process LOGIFRUIT exclusively originates from product loops which are in closed and controlled chains. The process is designed to ensure that only crates intended for food contact are used and that contamination other than by food can be ruled out. Therefore, the recycling process LOGIFRUIT to produce HDPE and PP crates to be used in contact with fruits and vegetables, and packed meat and fish, dairy, bakery and pastry products is not of safety concern.

Safety evaluation of the food enzyme chymosin from the genetically modified Kluyveromyces lactis strain CIN.

The food enzyme chymosin (EC 3.4.23.4) is produced with the genetically modified Kluyveromyces lactis strain CIN by DSM Food Specialties B.V. The genetic modifications do not give rise to safety concerns. The food enzyme is free from viable cells of the production organism and its recombinant DNA. It is intended to be used in milk processing for cheese production and for the production of fermented milk products. Dietary exposure was estimated to be up to 0.73 mg total organic solids (TOS)/kg body weight (bw) per day in European populations. Genotoxicity tests did not raise a safety concern. The systemic toxicity was assessed by means of a repeated dose 90-day oral toxicity study in rats. The Panel identified a no observed adverse effect level of 1,000 mg TOS/kg bw per day, the highest dose tested, which when compared with the estimated dietary exposure, results in a margin of exposure of at least 1,300. Similarity of the amino acid sequence of the food enzyme to those of known allergens was searched for and four matches were found. The Panel considered that under the intended conditions of use the risk of allergic sensitisation and elicitation reactions by dietary exposure, although unlikely, cannot be excluded, particularly for individuals sensitised to cedar pollen allergens. Based on the data provided, the Panel concluded that this food enzyme does not give rise to safety concerns under the intended conditions of use.

Safety assessment of the process Cajas y Palets en una Economia Circular (CAPEC), used to recycle high-density polyethylene and polypropylene crates for use as food contact materials.

The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) assessed the safety of the recycling process Cajas y Palets en una Economia Circular (CAPEC) (EU register number RECYC242). The input consists of crates made of high-density polyethylene (HDPE) or polypropylene (PP) originating from closed and controlled product loops for the packaging of whole fruits and vegetables. Flakes or pellets are produced that will be used by manufacturers of new crates for food contact. The Panel considered that the management system put in place to ensure compliance of the origin of the input with Commission Regulation (EC) No 282/2008 and to provide full traceability from input to final product is the critical process step. It concluded that the input of the process CAPEC originates from product loops which are in closed and controlled chains designed to ensure that only materials and articles that have been intended for food contact are used and that contamination can be ruled out when run under the conditions described by the applicant. The recycling process CAPEC is therefore suitable to produce recycled HDPE and PP crates intended to be used in contact with fruits and vegetables.

Identification and prioritisation for risk assessment of phthalates, structurally similar substances and replacement substances potentially used as plasticisers in materials and articles intended to come into contact with food.

The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids was requested by the European Commission to re-evaluate the risks to public health related to the presence of plasticisers such as phthalates, structurally similar substances and replacement substances, as a consequence of migration from food contact materials (FCMs). As the first part of the two-part mandate, EFSA was tasked with identifying and prioritising those plasticisers used in FCMs that may warrant further data collection and eventual risk assessment. Close collaboration with the European Chemicals Agency (ECHA) was requested in the mandate. Substances potentially used as plasticisers were identified using Annex II of the mandate, ECHA's PLASI inventory, the Plastics Regulation and the Regenerated Cellulose Film Directive, the ECHA database, the ECHA grouping approach, and consultation with the Member States. Only substances authorised for FCMs at EU or at national level were prioritised. Five substances classified either as carcinogenic, mutagenic, toxic to reproduction Cat. 1 (under CLP) or as endocrine disruptors, persistent, bioaccumulative and toxic, very persistent/very bioaccumulative (under REACH) were placed into an 'exclusion group'. Prioritisation was based on the date of the most recent risk assessment in the context of FCM, with substances assessed before 2001 being placed in the high-priority group, substances assessed between 2001 and 2011 in the medium-priority group and substances assessed after 2011 in the low-priority group. For the EU stream, the 76 substances were split into 59 high-, 14 medium- and 3 low-priority substances. For the nationally authorised stream, the split of the 72 substances is 66, 3 and 3, respectively. The outcome of follow-up calls for data in support of the exposure assessment will be used for a final ranking.

Safety assessment of bleached cellulose pulp for use in plastic food contact materials.

The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids assessed the safety of the substance bleached cellulose pulp, consisting of cellulose fibres (70-92%) and hemicellulose (8-30%) obtained from pine and spruce wood. The substance is intended to be used ■■■■■ in polyethylene and polypropylene food contact materials. The final articles are intended to be used for all food types and for long-term storage at room temperature, with or without a short time at higher temperature, including hot-fill. Low-density polyethylene samples containing ■■■■■ of the substance were subjected to a broad set of migration tests with food simulants and extraction tests with dichloromethane. The limits of detection ranged from ■■■■■ (when specified). The Panel noted that they do not ensure the detection of genotoxic substances at a concentration leading to a human exposure above the Threshold of Toxicological Concern. Moreover, not all possibly migrating substances were identified or amenable to the analytical methods applied. No toxicological data were provided for the substance itself, as its migration into food is not expected. The safety of the potentially migrating substances of low molecular mass detected was addressed individually and was considered adequate. However, the Panel considered this approach insufficient owing to a substantial fraction of unidentified components. The Panel concluded that the information provided by the applicant does not allow the safety assessment of the substances below 1,000 Da from bleached cellulose pulp from pine and spruce wood used in plastic food contact materials potentially migrating into food. Therefore, the Panel could not conclude on the safety of the use of bleached cellulose pulp from pine and spruce wood as a plastic additive.

Safety assessment of the process Srichakra Polyplast, based on the Starlinger iV+ technology, used to recycle post-consumer PET into food contact materials.

The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) assessed the safety of the recycling process Srichakra Polyplast (EU register number RECYC229), which uses the Starlinger iV+ technology. The input is hot caustic washed and dried poly(ethylene terephthalate) (PET) flakes mainly originating from collected post-consumer PET containers, with no more than 5% PET from non-food consumer applications. The flakes are dried and crystallised in a first reactor, then extruded into pellets. These pellets are crystallised, preheated and treated in a solid-state polycondensation (SSP) reactor. Having examined the challenge test provided, the Panel concluded that the drying and crystallisation (step 2), extrusion and crystallisation (step 3) and SSP (step 4) are critical in determining the decontamination efficiency of the process. The operating parameters to control the performance of these critical steps are temperature, air flow and residence time for the drying and crystallisation step, and temperature, pressure and residence time for the extrusion and crystallisation step as well as the SSP step. It was demonstrated that this recycling process is able to ensure that the level of migration of potential unknown contaminants into food is below the conservatively modelled migration of 0.1 µg/kg food. Therefore, the Panel concluded that the recycled PET obtained from this process is not of safety concern when used at up to 100% for the manufacture of materials and articles for contact with all types of foodstuffs for long-term storage at room temperature, with or without hotfill. The final articles made of this recycled PET are not intended to be used in microwave and conventional ovens and such uses are not covered by this evaluation.

Safety assessment of the process deSter, used to recycle plastic catering tableware for use as food contact materials.

The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) assessed the safety of the recycling process deSter (EU register number RECYC196). The input consists of catering tableware food contact articles from airline on-board services, made of polypropylene (PP), polyethylene terephthalate (PET), styrene acrylonitrile resin (SAN) or acrylonitrile butadiene styrene (ABS). The recyclate produced by deSter will be used to manufacture articles for the same on-board services. The Panel considered that the management system put in place to ensure compliance of the origin of the input with Commission Regulation (EC) No 282/2008 and to provide full traceability from input to final product is the critical process step. The process deSter uses only materials and articles intended for food contact and ensures that any contamination can be ruled out, since the input originates from this product loop managed in a closed and controlled chain. Therefore, the Panel concluded that the recycled materials obtained from this process and used within this loop are not of safety concern, when used at up to 100% for the manufacture of plastic tableware for contact with all types of foodstuffs under the conditions of use of the articles before recycling.

Fe-S coordination defects in the replicative DNA polymerase delta cause deleterious DNA replication in vivo and subsequent DNA damage in the yeast Saccharomyces cerevisiae.

B-type eukaryotic polymerases contain a [4Fe-4S] cluster in their C-terminus domain, whose role is not fully understood yet. Among them, DNA polymerase delta (Polδ) plays an essential role in chromosomal DNA replication, mostly during lagging strand synthesis. Previous in vitro work suggested that the Fe-S cluster in Polδ is required for efficient binding of the Pol31 subunit, ensuring stability of the Polδ complex. Here, we analyzed the in vivo consequences resulting from an impaired coordination of the Fe-S cluster in Polδ. We show that a single substitution of the very last cysteine coordinating the cluster by a serine is responsible for the generation of massive DNA damage during S phase, leading to checkpoint activation, requirement of homologous recombination for repair, and ultimately to cell death when the repair capacities of the cells are overwhelmed. These data indicate that impaired Fe-S cluster coordination in Polδ is responsible for aberrant replication. More generally, Fe-S in Polδ may be compromised by various stress including anti-cancer drugs. Possible in vivo Polδ Fe-S cluster oxidation and collapse may thus occur, and we speculate this could contribute to induced genomic instability and cell death, comparable to that observed in pol3-13 cells.

Assessment of the impact of the IARC Monograph Vol. 121 on the safety of the substance styrene (FCM No 193) for its use in plastic food contact materials.

The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) was requested by the European Commission to re-evaluate the safety of styrene (FCM No 193) for use in plastic food contact materials (FCM) following the classification by the International Agency for Research on Cancer (IARC) as 'probably carcinogenic to humans'. The IARC Monograph pertains to hazard identification, based on studies on high-dose occupational exposures by inhalation and animal studies, also mainly by inhalation. The Panel considered that the IARC conclusions cannot be directly applied to the evaluation of risks for consumers from the oral exposure to styrene, but also concluded that, based on the data provided in the IARC Monograph and by the industry, a concern for genotoxicity associated with oral exposure to styrene cannot be excluded. The migration of styrene into foods packed in styrenic plastics is below 10 µg/kg for the majority of the foods, but up to 230 µg/kg was reported. Migration tends to be high for contact with fatty foods, and/or with high surface to volume ratios of the FCM. Dietary exposure of the consumers to styrene migrating from styrenic plastics was estimated in the order of 0.1 µg/kg body weight (bw) per day. It is in the same range as exposure from styrene present in foods as such. The dietary exposure (food component plus migration from styrenic plastics) is similar or lower than that by inhalation in the general population. Taking the human exposure data into account, the Panel concluded that a systematic review of genotoxicity and mechanistic data, comparative toxicokinetics and analysis of species differences is required for assessing the safety of styrene for its use in FCM.

Review and priority setting for substances that are listed without a specific migration limit in Table 1 of Annex 1 of Regulation 10/2011 on plastic materials and articles intended to come into contact with food.

The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) was requested by the European Commission to review the substances for which a Specific Migration Limit (SML) is not assigned in Regulation (EU) No 10/2011. These substances had been covered by the Generic SML of 60 mg/kg food, but with Regulation (EU) 2016/1416 it was removed, necessitating their re-examination. EFSA was requested to identify those substances requiring an SML to ensure the authorisation is sufficiently protective to health, grouping them in high, medium and low priority to serve as the basis for future re-evaluations of individual substances. The CEP Panel established a stepwise procedure. This took into account existing hazard assessments for each substance on carcinogenicity/mutagenicity/reprotoxicity (CMR), bioaccumulation and endocrine disruptor (ED) properties along with the use of in silico generated predictions on genotoxicity. Molecular weights and boiling points were considered with regard to their effect on potential consumer exposure. This prioritisation procedure was applied to a total of 451 substances, from which 78 substances were eliminated at the outset, as they had previously been evaluated by EFSA as food contact substances. For 89 substances, the Panel concluded that a migration limit should not be needed. These are in the lists 0 and 1 of the Scientific Committee for Food (SCF), defined as substances for which an Acceptable Daily Intake (ADI) does not need to be established, along with substances that are controlled by existing restrictions and/or generic limits. Of the remaining 284 substances, 179 were placed into the low priority group, 102 were placed into the medium priority group and 3 were placed into the high priority group, i.e. salicylic acid (FCM No 121), styrene (FCM No 193) and lauric acid, vinyl ester (FCM No 436).

[D-enantiomeric peptides could be a new therapeutic approach in Alzheimer's disease]. / Les peptides D-énantiomériques pourraient représenter une nouvelle piste thérapeutique dans la maladie d'Alzheimer.

TITLE: Les peptides D-énantiomériques pourraient représenter une nouvelle piste thérapeutique dans la maladie d'Alzheimer. ABSTRACT: Pour la quatrième année, dans le cadre du module d'enseignement « Physiopathologie de la signalisation ¼ proposé par l'université Paris-sud, les étudiants du Master « Biologie Santé ¼ de l'université Paris-Saclay se sont confrontés à l'écriture scientifique. Ils ont sélectionné 15 articles scientifiques récents dans le domaine de la signalisation cellulaire présentant des résultats originaux, via des approches expérimentales variées, sur des thèmes allant des relations hôte-pathogène aux innovations thérapeutiques, en passant par la signalisation hépatique et le métabolisme. Après un travail préparatoire réalisé avec l'équipe pédagogique, les étudiants, organisés en binômes, ont ensuite rédigé, guidés par des chercheurs, une Nouvelle soulignant les résultats majeurs et l'originalité de l'article étudié. Ils ont beaucoup apprécié cette initiation à l'écriture d'articles scientifiques et, comme vous pourrez le lire, se sont investis dans ce travail avec enthousiasme ! Deux de ces Nouvelles sont publiées dans ce numéro, les autres le seront dans des prochains numéros.

Redox modifications of cysteine-containing proteins, cell cycle arrest and translation inhibition: Involvement in vitamin C-induced breast cancer cell death.

Vitamin C (VitC) possesses pro-oxidant properties at high pharmacologic concentrations which favor repurposing VitC as an anti-cancer therapeutic agent. However, redox-based anticancer properties of VitC are yet partially understood. We examined the difference between the reduced and oxidized forms of VitC, ascorbic acid (AA) and dehydroascorbic acid (DHA), in terms of cytotoxicity and redox mechanisms toward breast cancer cells. Our data showed that AA displayed higher cytotoxicity towards triple-negative breast cancer (TNBC) cell lines in vitro than DHA. AA exhibited a similar cytotoxicity on non-TNBC cells, while only a minor detrimental effect on noncancerous cells. Using MDA-MB-231, a representative TNBC cell line, we observed that AA- and DHA-induced cytotoxicity were linked to cellular redox-state alterations. Hydrogen peroxide (H2O2) accumulation in the extracellular medium and in different intracellular compartments, and to a lesser degree, intracellular glutathione oxidation, played a key role in AA-induced cytotoxicity. In contrast, DHA affected glutathione oxidation and had less cytotoxicity. A "redoxome" approach revealed that AA treatment altered the redox state of key antioxidants and a number of cysteine-containing proteins including many nucleic acid binding proteins and proteins involved in RNA and DNA metabolisms and in energetic processes. We showed that cell cycle arrest and translation inhibition were associated with AA-induced cytotoxicity. Finally, bioinformatics analysis and biological experiments identified that peroxiredoxin 1 (PRDX1) expression levels correlated with AA differential cytotoxicity in breast cancer cells, suggesting a potential predictive value of PRDX1. This study provides insight into the redox-based mechanisms of VitC anticancer activity, indicating that pharmacologic doses of VitC and VitC-based rational drug combinations could be novel therapeutic opportunities for triple-negative breast cancer.