Efflux Pump Inhibitors in Controlling Antibiotic Resistance: Outlook under a Heavy Metal Contamination Context.

Multi-drug resistance to antibiotics represents a growing challenge in treating infectious diseases. Outside the hospital, bacteria with the multi-drug resistance (MDR) phenotype have an increased prevalence in anthropized environments, thus implying that chemical stresses, such as metals, hydrocarbons, organic compounds, etc., are the source of such resistance. There is a developing hypothesis regarding the role of metal contamination in terrestrial and aquatic environments as a selective agent in the proliferation of antibiotic resistance caused by the co-selection of antibiotic and metal resistance genes carried by transmissible plasmids and/or associated with transposons. Efflux pumps are also known to be involved in either antibiotic or metal resistance. In order to deal with these situations, microorganisms use an effective strategy that includes a range of expressions based on biochemical and genetic mechanisms. The data from numerous studies suggest that heavy metal contamination could affect the dissemination of antibiotic-resistant genes. Environmental pollution caused by anthropogenic activities could lead to mutagenesis based on the synergy between antibiotic efficacy and the acquired resistance mechanism under stressors. Moreover, the acquired resistance includes plasmid-encoded specific efflux pumps. Soil microbiomes have been reported as reservoirs of resistance genes that are available for exchange with pathogenic bacteria. Importantly, metal-contaminated soil is a selective agent that proliferates antibiotic resistance through efflux pumps. Thus, the use of multi-drug efflux pump inhibitors (EPIs) originating from natural plants or synthetic compounds is a promising approach for restoring the efficacy of existing antibiotics, even though they face a lot of challenges.

Plant Secondary Metabolites on Efflux-Mediated Antibiotic Resistant Stenotrophomonas Maltophilia: Potential of Herbal-Derived Efflux Pump Inhibitors.

During the process of adapting to metal contamination, plants produce secondary metabolites that have the potential to modulate multidrug-resistant (MDR) phenotypes; this is achieved by inhibiting the activity of efflux pumps to reduce the minimum inhibitory concentrations (MICs) of antimicrobial substrates. Our study evaluated the effect of secondary metabolites of belowground parts of Pteris vittata L. and Fallopia japonica, two metal-tolerant plants from northern Vietnam, on six antibiotic-resistant Stenotrophomonas maltophilia strains possessing efflux pump resistance mechanisms that were isolated from soil and clinical samples. The chemical composition of aqueous and dichloromethane (DCM) fractions extracted from P. vittata and F. japonica was determined using UHPLC-DAD-ESI/QTOF analysis. The antibacterial and efflux pump inhibitory activities of the four fractions were evaluated for the six strains (K279a, 0366, BurA1, BurE1, PierC1, and 502) using a microdilution assay at fraction concentrations of 62.5, 125, and 250 µg/mL. The DCM fraction of F. japonica exhibited remarkable antibacterial activity against strain 0366, with a MIC of 31.25 µg/mL. Furthermore, this fraction also significantly decreased gentamicin MIC: four-fold and eight-fold reductions for BurA1 and BurE1 strains, respectively (when tested at 250 µg/mL), and two-fold and eight-fold reductions for K279a and BurE1 strains, respectively (when tested at 125 µg/mL). Pure emodin, the main component identified in the DCM fraction of F. japonica, and sennidine A&B only reduced by half the MIC of gentamicin (when tested at 30 µg/mL). Our results suggest that the DCM fraction components of F. japonica underground parts may be potential candidates for new bacterial efflux pump inhibitors (EPIs).

Ionomics and metabolomics analysis reveal the molecular mechanism of metal tolerance of Pteris vittata L. dominating in a mining site in Thai Nguyen province, Vietnam.

This study aims to find the interaction between ionome and metabolome profiles of Pteris vittata L., an arsenic hyperaccumulator plant, to reveal its metal tolerance mechanism. Therefore, at the Pb-Zn mining sites located in Thai Nguyen province, Vietnam, where these species dominate, soil and plant samples were collected. Their multi-element compositions were analyzed using inductively coupled plasma mass spectrometry (ICP-MS) and thus referred to as the "ionomics" approach. In parallel, the widely targeted metabolomics profiles of these plant samples were performed using liquid chromatography-tandem mass spectrometry (UPLC-QqQ-MS). Nineteen elements, including both metals and nonmetals, were detected and quantified in both tissues of thirty-five plant individuals. A comparison of these elements' levels in two tissues showed that above-ground parts accumulated more As and inorganic P, whereas Zn, Pb, and Sb were raised mostly in the under-ground samples. The partial least squares regression (PLSR) model predicting the level of each element by the whole metabolome indicated that the enhancement of flavonoids content plays an essential contribution in adaptation with the higher levels of Pb, Ag, and Ni accumulated in the aerial part, and Mn, Pb in subterranean part. Moreover, the models also highlighted the effect of Mn and Pb on the metabolic induction of adenosine derivatives in subterranean parts. At the same time, the model presented the most contribution of As to the metabolisms of the amino acids of this tissue. On those accounts, the developed integration approach linking the ionomics and metabolomics data of P. vittata improved the understanding of the molecular mechanism of hyperaccumulation characteristics and provided markers that could be targeted in future investigations.

Alkyl-Quinolones derivatives as potential biomarkers for Pseudomonas aeruginosa infection chronicity in Cystic Fibrosis.

In Cystic Fibrosis (CF), a rapid and standardized definition of chronic infection would allow a better management of Pseudomonas aeruginosa (Pa) infections, as well as a quick grouping of patients during clinical trials allowing better comparisons between studies. With this purpose, we compared the metabolic profiles of 44 in vitro cultures of Pa strains isolated from CF patients at different stages of infection in order to identify metabolites differentially synthetized according to these clinical stages. Compounds produced and secreted by each strain in the supernatant of a liquid culture were analysed by metabolomic approaches (UHPLC-DAD-ESI/QTOF, UV and UPLC-Orbitrap, MS). Multivariate analyses showed that first colonization strains could be differentiated from chronic colonization ones, by producing notably more Alkyl-Quinolones (AQs) derivatives. Especially, five AQs were discriminant: HQC5, HQNOC7, HQNOC7:1, db-PQS C9 and HQNOC9:1. However, the production of HHQ was equivalent between strain types. The HHQ/HQNOC9:1 ratio was then found to be significantly different between chronic and primo-colonising strains by using both UV (p = 0.003) and HRMS data (p = 1.5 × 10-5). Our study suggests that some AQ derivatives can be used as biomarkers for an improved management of CF patients as well as a better definition of the clinical stages of Pa infection.

Development of a Pteris vittata L. compound database by widely targeted metabolomics profiling.

The objective of this work was the development of a detailed, extensive and reliable database of the metabolomes of P. vittata. Using an ultra-performance liquid chromatography-triple quadrupole tandem mass spectrometry system (UPLC-QqQ-MS/MS) and based on the knowledge of retention time and mass spectral characteristics of an in-house collection of authentic standards, we screened for the presence of a large collection of natural compounds. The database represents 359 authenticated metabolites, comprising 220 primary and 139 secondary metabolites (70 flavonoids, 16 phenylpropanoic acid derivatives, five coumarins, two stilbenoids, 14 benzoic acids, nine phenols, 20 alkaloids and three terpenoids). Comparison of the accumulation of these compounds in two tissues showed that the aerial parts were enriched in flavonols, whereas the subterranean parts were enriched in anthocyanins. The comprehensive database developed here will be beneficial in improving the understanding of the chemical basis of plant therapeutic profile using multivariate analysis, with a particular example of antioxidant activity.

Chemical Composition, Antioxidant, Genotoxique and Antigenotoxic Potentials of Phlomis Bovei De Noé Aerial Parts.

In the present work, chemical investigation of the aerial parts of Phlomis bovei de Noé an endemic species from Algeria, led to the isolation and identification of seven known compounds including five flavones glycosides: Chrysoeriol 7-O-(3''-(E et Z)-p-coumaroyl)-ß-glucoside (1), terniflorin (apigenin-7-O-(6''-E-p-coumaroyl)glucoside) (3), apigenin-7-O-(6''-(5'''-methoxy-coumaryl) glucoside (4), apigenin 7-O-(3″-p-coumaryl)glucoside (5), hispidulin-7-O-glucuronide (6) and two cinnamic acid derivatives: p-coumaric acid methyl ester (E et Z) (2), chlorogenic acid (7). Compound 4 is described for the first time in the species bovei de Noé, the genus Phlomis and the Lamiaceae family. Structures elucidation was performed by comprehensive 1D and 2D NMR analyses, mass spectrometry and by comparison with literature data. Some pure compounds and extracts have been evaluated for their antioxidant activities through different methods: DPPH and ABTS assays as well as CUPRAC assay. Genotoxic and antigenotoxic activities of pure compounds were also evaluated in-vitro on Escherichia coli PQ37 cells by the SOS Chromotest.

N,N'-disubstituted cinnamamide derivatives potentiate ciprofloxacin activity against overexpressing NorA efflux pump Staphylococcus aureus 1199B strains.

A multi-step procedure has been described which afforded satisfactory yields of N,N'-disubstituted cinnamamides derived from N-Boc-protected amino acids (Boc-Gly, Boc-Val, Boc-Phe). The key step of this synthesis was a regioselective RedAl reduction of an amide function in presence of a carbamate group. Next, these cinnamamides were evaluated in co-admnistration with ciprofloxacin as efflux pump inhibitors against two S. aureus strains, NorA overexpressing SA1199B and wild type SA1199. In parallel, their intrinsic toxicity was appreciated on human lung fibroblast MRC5 cells. Therefore, the cinnamamide combining both carbamate and indol-3-yl groups, was found to be the most active and one of the less toxic EPI and constituted a promising hit.

Impact of metal stress on the production of secondary metabolites in Pteris vittata L. and associated rhizosphere bacterial communities.

Plants adapt to metal stress by modifying their metabolism including the production of secondary metabolites in plant tissues. Such changes may impact the diversity and functions of plant associated microbial communities. Our study aimed to evaluate the influence of metals on the secondary metabolism of plants and the indirect impact on rhizosphere bacterial communities. We then compared the secondary metabolites of the hyperaccumulator Pteris vittata L. collected from a contaminated mining site to a non-contaminated site in Vietnam and identified the discriminant metabolites. Our data showed a significant increase in chlorogenic acid derivatives and A-type procyanidin in plant roots at the contaminated site. We hypothesized that the intensive production of these compounds could be part of the antioxidant defense mechanism in response to metals. In parallel, the structure and diversity of bulk soil and rhizosphere communities was studied using high-throughput sequencing. The results showed strong differences in bacterial composition, characterized by the dominance of Proteobacteria and Nitrospira in the contaminated bulk soil, and the enrichment of some potential human pathogens, i.e., Acinetobacter, Mycobacterium, and Cupriavidus in P. vittata's rhizosphere at the mining site. Overall, metal pollution modified the production of P. vittata secondary metabolites and altered the diversity and structure of bacterial communities. Further investigations are needed to understand whether the plant recruits specific bacteria to adapt to metal stress.

Antioxidant, Antimutagenic, Tanning and Calpain Induction Activities of Methanolic Extract of Tunisian Plant (Moricandia Arvensis).

In this study, we investigate the potential of Moricandia arvensis methanol leaf extract (MeOHL) on calpain activity, melanin biosynthesis and DNA mutagenicity. Cytotoxic effect and measurement of reactive oxygen species (ROS) induced by lucigenin in colorectal cells (BE) were also determined. In addition, the chemical analysis of the extract was also studied and the chemical profile illustrates its content in para-hydroxybenzoic acid (p-HBA), a glycosylated kampferol (GK), a glycosylated kampferol with Rhamnose (GKR) and 19 amino acids (AAs). Our results showed that MeOHL extract enhanced a significant cytotoxic (max of IP = 89.23%) and antioxidant (max of IP=100%) activities. Furthermore, the tested extract stimulated calpain activity and significantly increased the production of intra (46 µg/mL cells) and extracellular melanin content (12.5µg/mL). Using Ames assay, the extract exhibits a significant inhibition of mutagenicity induced by methy-methane-sulfonate (MMS) (76.32%) as well as 2-aminoanthracene (2-AA) (91%) in the Salmonella thyphimurium TA104 assay system.

In vitro and in vivo anti-melanoma effects of Daphne gnidium aqueous extract via activation of the immune system.

The purpose of this study was to assess the antitumor and immunomodulatory effects of the aqueous extract from Daphne gnidium in mice-bearing melanoma tumor. Balb/C mice were subcutaneously implanted with B16-F10 cells and treated intraperitoneally with the aqueous extract at 200 mg/Kg b.w for 21 days. After euthanization on day 22, the tumors were weighed; lymphocyte proliferation, cytotoxic T lymphocyte (CTL), and natural killer (NK) cell activities were evaluated using the MTT assay. Macrophage phagocytosis was studied by measuring the lysosomal activity. In addition to its potential to inhibit the growth of the transplantable tumor, the aqueous extract remarkably induced splenocyte proliferation and both NK and CTL activities in tumor-bearing mice. The aqueous extract was also seen to have promoted lysosomal activity of host macrophages.

Medicinal Plants from the Ouaddaï Province (Chad): An Ethnobotanical Survey of Plants Used in Traditional Medicine.

BACKGROUND/OBJECTIVE: Plants are the basis of all health care systems. This study sought to inventory the most used medicinal plants in the local therapeutic patrimony of the Ouaddaï (East Chad) through an ethnobotanical investigation. METHODS: The inventory described the plant parts used, their mode of preparation, and their therapeutic uses. RESULTS: Thirty-eight plants species are used for different purposes and diseases. The most used species belongs to the Mimosaceae (eight species), Caesalpiniaceae (four species), and Combretaceae (four species) families. The traditional medicinal uses, as well as the preparations, of these plants are diverse. The used parts are leaves (36.4%), peels (23.7%), fruits (18.2%), roots (10.9%), stems (5.5%), and other (5.3%). These plants are used to treat 16 different illnesses, notably amoebiasis (26.8%), respiratory infections (14.3%), fever (12.5%), kidney stones (7.1%), snake bites (7.1%), tooth decay (5.4%), and leprosy (5.4%). CONCLUSION: The results obtained from this survey constitute the starting point of an inventory of local medicinal plants to be completed by phytochemical, pharmacologic, and toxicologic studies to allow good exploitation of the local medicinal flora.

Phytochemical and biological activities of Bituminaria bituminosa L. (Fabaceae).

OBJECTIVE: To investigate the phytochemical composition, the antioxidant and antibacterial activities of Bituminaria bituminosa L. (Fabaceae) (B. bituminosa). METHODS: The aerial parts of B. bituminosa yielded two compounds. The structures of these compounds were determinated using UV, (1)H-NMR and (13)C-NMR experiments and comparison of their spectroscopic properties with literature data. The antibacterial activity of the extracts (CH2Cl2, ethyl acetate and n-BuOH) was determinated using disk diffusion method against standard and clinical strains. Antioxidant potential of n-BuOH extract was evaluated through two methods: DPPH and cupric ion reducing antioxidant capacity assay. RESULTS: The n-BuOH extract from B. bituminosa yielded the isolation of isoflavone and flavone. The extracts CH2Cl2, ethyl acetate and n-BuOH demonstrated significant antibacterial activities. CH2Cl2 extract showed the maximum antibacterial activity with high concentration of 2 mg/mL against Staphylococcus aureus ATCC 29213, Klebsiella pneumonia and Escherichia coli ATCC 25922 (20.45 mm, 16.41 mm and 15.74 mm inhibition zone, respectively). The value IC50 was 0.26 µg/mL for n-BuOH extract using DPPH method. Whereas the E% value was 0.10 L/mg every centimeter for cupric ion reducing antioxidant capacity assay. CONCLUSIONS: The phytochemical study of B. bituminosa revealed the presence of isoflavone (daidzin) and flavone (isoorientin) and identified for the first time in this specie. The antibacterial activity of the plant B. bituminosa is certainly related to its chemical content. The n-BuOH extract showed a significant antioxidant activity.

In vitro antileukaemic activity of extracts from Daphne gnidium leaves against sensitive and multidrug resistant K562/R7 cells.

The antiproliferative potential of extracts of Daphne gnidium L. (Thymelaeaceae) on K562 cells was assessed, and the capacity of these extracts to disturb the cell cycle of K562 cells and to inhibit human P-glycoprotein was evaluated. The antiproliferative activity was evaluated using the MTT assay. The cell cycle analysis and the inhibition of P-glycoprotein were tested by flow cytometry. All the tested extracts exhibited significant anti-proliferative effects. Ethyl acetate extract has the strongest cytotoxic effect with an IC50 of 18.5 µg/ml. Furthermore, cell cycle analysis revealed that cells treated with chloroform, butanol and aqueous extracts were arrested predominantly in G2-M phase. Butanol extract was the most active extract. Percentage of cells arrested in G2-M was 34 %, 36.67 % and 42.63 % respectively, after treatment with 25, 75 and 100 µg/ml of the extract, versus 19 % in the cells treated with the vehicle solvent. In addition, chloroform extract had the ability to inhibit human P-glycoprotein-mediated daunorubicin in K562/R7 leukaemic cells in a dose-dependent manner compared to the positive control, cyclosporin A. These findings demonstrate that extracts from D. gnidium leaves have antileukaemic activity by perturbing the cell cycle of K562 and inhibiting human P-glycoprotein in K562/R7 cell line.

Antioxidant and antigenotoxic properties of compounds isolated from Marrubium deserti de Noé.

In our continual course toward the valorization of traditionally used endemic flora through the analysis of its chemobiodiversity, the phytochemical analysis of aerial parts of Marrubium deserti de Noé was undertaken. Dichloromethane and methanol extracts led to the isolation of terpenoid derivatives among which two were new labdane diterpenes named marrulibacetal A and desertine, respectively. Six of them were known compounds (a mixture of the isomers cyllenin A and 15-epi-cyllenin A, marrubiin, marrulactone, marrulibacetal and ß-stigmasterol) and seven known phenolic compounds were also isolated: apigenin and several 7-O-substituted derivatives (apigenin-7-O-ß-neohesperidoside, apigenin-7-O-glucoside, terniflorin and apigenin-7-O-glucuronide) together with two phenylethanoid glucosides (acteoside and forsythoside B). The structures and relative configurations of the new compounds were elucidated by MS and a series of 1D and 2D NMR analyses. Some pure compounds have been evaluated for their antioxidant activities through different methods: DPPH and ABTS assays as well as CUPRAC assay. Genotoxic and antigenotoxic activities of extracts and pure compounds were also evaluated in vitro on Escherichia coli PQ37 cells by the SOS Chromotest. Some of the isolated compounds like phenylethanoid derivatives showed stronger antioxidant capacity than trolox and were also able to significantly inhibit ß-galactosidase induction caused by the mutagen agent nitrofurantoin.

Evaluation of antioxidant and antigenotoxic activity of two flavonoids from Rhamnus alaternus L. (Rhamnaceae): kaempferol 3-O-ß-isorhamninoside and rhamnocitrin 3-O-ß-isorhamninoside.

The antioxidant activity of kaempferol 3-O-ß-isorhamninoside (K3O-ir) and rhamnocitrin 3-O-ß-isorhamninoside (R3O-ir), isolated from the leaves of Rhamnus alaternus L., was determined by the ability of each compound to inhibit NBT photoreduction and to scavenge the free radical ABTS(+)(.). Genotoxic and antigenotoxic activities were assessed using the SOS chromotest. At a concentration of 150 µg/assay the two compounds showed the most potent inhibitory activity against superoxide anion by respectively 80.4% and 85.6%. K3O-ir was a very potent radical scavenger with an IC(50) value of 18.75 µg/ml. Moreover, these two compounds exhibit an inhibitory activity against genotoxicity induced by nitrofurantoine and aflatoxine B1 using the SOS chromotest bacterial assay system in the presence of Escherichia coli PQ37 strain. In this study, we have also evaluated correlation between antigenotoxic and antioxidant effects of K3O-ir and R3O-ir. The highest correlation was showed with R3O-ir (r=0.999).

Assessment of isorhamnetin 3-O-neohesperidoside from Acacia salicina: protective effects toward oxidation damage and genotoxicity induced by aflatoxin B1 and nifuroxazide.

Antioxidant activity of isorhamnetin 3-O-neohesperidoside, isolated from the leaves of Acacia salicina, was determined by the ability of this compound to inhibit xanthine oxidase activity and to scavenge the free radical 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) (ABTS(.-)) diammonium salt. Antigenotoxic activity was assessed using the SOS chromotest assay. This compound has the ability to scavenge the ABTS(.+) radical by a hydrogen donating mechanism. We also envisaged the study of the antioxidant effect of this compound by the enzymatic xanthine/xanthine oxidase (X/XOD) assay. Results indicated that isorhamnetin 3-O-neohesperidoside was a potent inhibitor of xanthine oxidase and superoxide anion scavengers. Moreover, this compound induced an inhibitory activity against nifuroxazide and aflatoxine B1 (AFB1) induced genotoxicity. Taken together, these observations provide evidence that isorhamnetin 3-O-neohesperidoside isolated from the leaves of A. salicina is able to protect cells against the consequences of oxidative stress.

Breast cancer resistance protein (BCRP/ABCG2): new inhibitors and QSAR studies by a 3D linear solvation energy approach.

A series of compounds derived from naturally occurring flavonoids and synthetic analogs have been evaluated on cell lines overexpressing the wild-type breast cancer resistance protein (BCRP/ABCG2) half-transporter. Human ABCG2-transfected cells were used for screening their inhibitory activity. Five new natural compounds obtained from Morus mesozygia Stapf and one synthetic chromone, comprising a flavonoidic scaffold, were also evaluated. Based on the results obtained with a total of 34 compounds, a 3D linear solvation energy QSAR was investigated by VolSurf descriptors of molecular-interaction fields (MIFs) related to hydrophobic-interaction forces, polarisability and hydrogen-bonding capacity. Accuracy of the constructed 3D-QSAR model was attested by a correlation coefficient r(2) of 0.77. Shape parameters and hydrophobicity were revealed to be major physicochemical parameters responsible for the inhibition activity of flavonoid derivatives and synthetic analogs towards ABCG2, whereas hydrogen-bond donor capacity appeared highly unfavorable.

Cytotoxic and antiplasmodial xanthones from Pentadesma butyracea.

Four new xanthones, butyraxanthones A-D (1-4), were isolated from the stem bark of Pentadesma butyracea, together with six known xanthones (5-10) and a triterpenoid (lupeol). The structures of 1-4 were established by spectroscopic methods. Compounds 1-10 were tested in vitro for antiplasmodial activity against a Plasmodium falciparum chloroquine-resistant strain and for cytotoxicity against a human breast cancer cell line (MCF-7). Nearly all of these xanthones exhibited good antiplasmodial activity, and some of them also demonstrated potent cytotoxicity.

Selective modulation of P-glycoprotein activity by steroidal saponines from Paris polyphylla.

Bio-guided fractionation of the roots of Paris polyphylla (Trilliaceae), based on inhibition of P-glycoprotein-mediated daunorubicin efflux in K562/R7 cell line, led to isolation and identification of the three saponins 3-O-Rha(1-->2)[Ara(1-->4)]Glc-pennogenine, gracillin and polyphyllin D, and the two ecdysteroids 20-hydroxyecdysone and pinnatasterone. These compounds were tested for multidrug reversion on P-glycoprotein (ABCB1) with both drug-selected and transfected cell lines, and also on Breast Cancer Resistance Protein (BCRP/ABCG2). By contrast to a weak efficiency on BCRP, the three saponins displayed significant effects as inhibitors of P-glycoprotein-mediated drug efflux.

Antimutagenic, antigenotoxic and antioxidant activities of Acacia salicina extracts (ASE) and modulation of cell gene expression by H2O2 and ASE treatment.

The total oligomers flavonoids (TOF), chloroform, petroleum ether and aqueous extracts from Acacia salicina, were investigated for the antioxidative, cytotoxic, antimutagenic and antigenotoxic activities. The viability of K562 cells were affected by all extracts after 48 h exposure. Our results showed that A. salicina extracts have antigenotoxic and/or antimutagenic activities. TOF and chloroform extracts exhibit antioxidant properties, expressed by the capacity of these extracts to inhibit xanthine oxidase activity. To further explore the mechanism of action of A. salicina extracts, we characterized expression profiles of genes involved in antioxidant protection and DNA repair in the human lymphoblastic cell line K562 exposed to H2O2. Transcription of several genes related to the thioredoxin antioxidant system and to the DNA base-excision repair pathway was up-regulated after incubation with chloroform, TOF and petroleum ether extracts. Moreover genes involved in the nucleotide-excision repair pathway and genes coding for catalase and Mn-superoxide-dismutase, two important antioxidant enzymes, were induced after incubation with the chloroform extract. Taken together, these observations provide evidence that the chloroform and TOF extracts of A. salicina leaves contain bioactive compounds that are able to protect cells against the consequences of an oxidative stress.