Pro-oxidant Activity Research Articles

P38-MAPK and JAK/STAT Pathway Inhibition Reduces Indoxyl Sulfate-Induced Impairment of Human Endothelial Cells

Indoxyl sulfate (IS) accumulates in chronic kidney disease (CKD) patients and cannot be cleared by dialysis. It is detrimental to cardiorenal function via pro-oxidant and pro-inflammatory actions, but the effect of IS on the vasculature is largely unknown. This study determined the effect of IS in human aortic endothelial cells (HAECs). p38-MAPK and JAK-STAT pathways appear to play an important pathological role in IS-induced vasculopathy, thus the pathways were inhibited with novel drug VCP-979 and JAK Inhibitor I (JI), respectively, to reverse IS-induced impairment of HAECs.

Antioxidant Status of Rat Liver Mitochondria under Conditions of Moderate Hypothermia of Different Duration.

For evaluation of the contribution of the antioxidant system of mitochondria into the dynamics of changes in the prooxidant status, the content and activity of some of its components were studied under conditions of moderate hypothermia of varying duration. It was found that short-term hypothermia significantly increased superoxide dismutase activity and decreased the levels of low-molecular-weight antioxidants. Increasing the duration of hypothermia to 1 h led to suppression of activities of superoxide dismutase, glutathione reductase, and glutathione peroxidase and a decrease in glutathione content. Further prolongation of hypothermia (to 3 h) was associated with a significant increase in superoxide dismutase and glutathione peroxidase activities and normalization of the rate of glutathione reductase catalysis; the concentration of glutathione increased significantly.

Baicalein Preconditioning Cardioprotection Involves Pro-Oxidant Signaling and Activation of Pyruvate Dehydrogenase.

Preconditioning has a powerful protective potential against myocardial ischemia-reperfusion injury (I/R). Our prior work demonstrated that baicalein, a flavonoid derived from the root of Scatellaria baicalensis Georgi (also known as Huangqin), confers this preconditioning protection. This study further explored the mechanisms of baicalein preconditioning (BC-PC) in mouse cardiomyocytes. Cells were treated with baicalein (10 μM) for a brief period of time (10 min) prior to simulated ischemia 90 min/reperfusion for 180 min. Baicalein triggered an induction of a small amount of mitochondrial reactive oxygen species (ROS) prior to the initiation of ischemia, assessed by 6-carboxy-2', 7'-dichlorodihydrofluorescein diacetate (6-carboxy-H2DCFDA). It also significantly increased cell viability measured by propidium iodide (PI) and lactate dehydrogenase and preserved mitochondrial membrane potential assessed by TMRM fluorescence intensity. Myxothiazol, a mitochondrial electron transport chain complex III inhibitor, partially blocked ROS generation induced by BC-PC and reduced cell viability. BC-PC increased phosphorylation of Akt (Thr308 and Ser473) and eNOS Ser1177, and nitric oxide (NO) production measured using 4,5-diaminofluorescein diacetate (DAF-2 DA, 1 μM). Akt inhibitor API-2 abolished Akt phosphorylation and reduced DAF-2 production and cell viability. In addition, BC-PC decreased phosphorylation of pyruvate dehydrogenase (PDH) reflecting upregulated PDH activity, and increased ATP production at 30 min during reperfusion. Taken together, baicalein preconditioning-induced cardioprotection involves pro-oxidant generation, activates survival signaling Akt/eNOS/NO, and improves metabolic recovery after I/R injury. Our work provides new perspectives on the effect of baicalein on cardiac preconditioning against I/R injury.

Insights into antiradical mechanism and pro-oxidant enzyme inhibitor activity of walterolactone A/B 6-O-gallate-β-d-pyranoglucoside originating from Euonymus laxiflorus Champ. using in silico study.

The ability of a new compound, Wal, (walterolactone A/B 6-O-gallate-β-d-pyranoglucoside) originating from Euonymus laxiflorus Champ. as a hydroperoxyl radical scavenger and pro-oxidant enzyme inhibitor was studied in silico. Different mechanisms, reaction locations, and chemical species of Wal in aqueous solution were taken into consideration. Formal hydrogen transfer from the OH group has been discovered as the chemical process that contributes most to the antioxidant properties of Wal in nonpolar and aqueous solutions. The overall rate coefficients for polar and non-polar environments are expected to have values of 7.85 × 106 M-1 s-1 and 4.84 × 105 M-1 s-1, respectively. According to the results of the investigation, Wal has greater scavenging activity against the HOO˙ radical than the reference antioxidant Trolox at physiological pH (7.4). In addition, docking results indicate that Wal's antioxidant properties involve the inhibition of the activity of enzyme families (CP450, MP, NO, and XO) that are responsible for ROS production.

<i>Hypericum alpestre</i> extract affects the activity of the key antioxidant enzymes in microglial BV-2 cellular models

<abstract> <p>In the presented work, we aimed to investigate the antioxidant and possible neuroprotective capacity of extract of the aerial parts of <italic>Hypericum alpestre</italic>, found in high altitude Armenian landscape. The neuroprotective activity was evaluated using BV-2 wild type (WT) cells and acyl-CoA oxidase 1 (ACOX1) deficient (<italic>Acox1<sup>-/-</sup></italic>) microglial cell lines. In the chemical-based tests, <italic>H. alpestre</italic> extract showed high antioxidant activity, which was maintained even after heat treatment at 121 °C for 30 min. MTT test showed that the sub-cytotoxic concentration of investigated extracts for both microglial cell lines was 40 µg/mL. There were no significant changes in catalase activity during all period of treatment in both cell lines, meanwhile, SOD activity increased (up to 30%) in WT cells during the 48 h treatment. Increase of SOD activity (up to 50%) in Acox<sup>-/-</sup> cells was observed under the 24 h treatment. Significant modulation in activity of palmitoyl-CoA oxidase 1 was noticed only during the 48 h treatment of WT microglial cells. These results evidenced the pro-oxidant activity of the investigated extract. This finding can serve as a basis for further evaluation of plant extracts influence on cancer cell lines.</p> </abstract>

Nanoencapsulated Myricetin to Improve Antioxidant Activity and Bioavailability: A Study on Zebrafish Embryos

Flavonoids are natural polyphenolic compounds that mainly possess antioxidant properties due to more hydroxyl groups in their structure and play an important role in combatting many diseases. Myricetin is a flavonoid found in grapes, green tea, fruits, and vegetables and is not only an antioxidant but also is a pro-oxidant. Myricetin is sparingly soluble in water and restricts its properties due to low bioavailability. The present study reports the liposomal nanoformulations of myricetin to improve its bioavailability with reduced pro-oxidant activity. The nanoformulated myricetin was characterized using different photophysical tools, such as dynamic light scattering (DLS), zeta potential, and scanning electron microscopy (SEM). The effect of nanoencapsulated myricetin on the developing zebrafish embryo was studied in terms of microscopic observations, cumulative hatchability, and antioxidant activities, such as catalase, glutathione peroxidase, and superoxide dismutase, after treating the zebrafish embryo with standard oxidant hydrogen peroxide. The results obtained from the cumulative hatchability, developmental studies, and antioxidant assays indicated that the liposomal nanoformulation of myricetin had enhanced antioxidant activity, leading to defense against oxidative stress. The formulation was highly biocompatible, as evidenced by the cumulative hatching studies as well as microscopic observations. The positive effects of liposomal nanoformulation on zebrafish embryos can open an avenue for other researchers to carry out further related research and to check its activities in clinical studies and developmental studies.

Factors impacting the antioxidant/prooxidant activity of tea polyphenols on lipids and proteins in oil-in-water emulsions

Tea polyphenols (TP) may inhibit or promote the oxidation of proteins and lipids in foods, depending on system conditions. In this study, we examined the effects of TP concentration (0, 100, and 400 mg/L), solution pH (3 and 7), and the addition of ethylenediaminetetraacetic acid (0 or 20 μmol/L EDTA) on the antioxidant/prooxidant activities of TP in walnut oil-in-water (O/W) emulsions under accelerated storage conditions (50 °C for 0, 48, 96 h). At pH 3, a lower concentration of TP (100 mg/L) exhibited stronger antioxidant activity for lipids and proteins than the higher concentration (400 mg/L). At pH 7, the lower concentration of polyphenols was still more effective, while the higher concentration resulted in prooxidant activity toward the proteins. In the absence of TP, the incorporation of EDTA into the emulsions (pH 7) inhibited lipid and protein oxidation, which was attributed to its ability to chelate and inactivate the prooxidant transition metals. Interestingly, the antioxidant activity of EDTA decreased in the presence of TP. Therefore, these results suggested that TP could be used to retard protein and lipid oxidation in emulsion-based foods, but their levels should be optimized due to their complex prooxidant and antioxidant mechanisms, depending on system composition and environmental conditions.

Cisplatin Chemotherapy and Cochlear Damage: Otoprotective and Chemosensitization Properties of Polyphenols.

Significance: Cisplatin is an important component of treatment regimens for different cancers. Notwithstanding that therapeutic success often results from partial efficacy or stabilizing the disease, chemotherapy failure is driven by resistance to drug treatment and occurrence of side effects, such as progressive irreversible ototoxicity. Cisplatin's side effects, including ototoxicity, are often dose limiting. Recent Advances: Cisplatin ototoxicity results from several mechanisms, including redox imbalance caused by reactive oxygen species production and lipid peroxidation, activation of inflammation, and p53 and its downstream pathways that culminate in apoptosis. Considerable efforts in research have targeted development of molecular interventions that can be concurrently administered with cisplatin or other chemotherapies to reduce side effect toxicities while preserving or enhancing the antineoplastic effects. Evidence from studies has indicated some polyphenols, such as curcumin, can help to regulate redox signaling and inflammatory effects. Furthermore, polyphenols can exert opposing effects in different types of tissues, that is, normal cells undergoing stressful conditions versus cancer cells. Critical Issues: This review article summarizes evidence of curcumin antioxidant effect against cisplatin-induced ototoxicity that is converted to a pro-oxidant activity in cisplatin-treated cancer cells, thus providing an ideal chemosensitivity combined with otoprotection. Polyphenols can modulate the adaptive responses to stress in the cisplatin-exposed cochlea. These adaptive effects can result from the interaction/cross talk between the cell's defenses, inflammatory molecules, and the key signaling molecules of signal transducers and activators of transcription 3 (STAT-3), nuclear factor κ-B (NF-κB), p53, and nuclear factor erythroid 2-related factor 2 (Nrf-2). Future Directions: We provide molecular evidence for alternative strategies for chemotherapy with cisplatin addressing the otoprotection and chemosensitization properties of polyphenols. Antioxid. Redox Signal. 36, 1229-1245.

Physical and oxidative stability of n‐3 delivery emulsions added seaweed‐based polysaccharide extracts from Nordic brown algae Saccharina latissima

AbstractEnriching foods with long‐chain n‐3 polyunsaturated fatty acids requires a delivery emulsion system, which is both thermodynamically and oxidatively stable. The antioxidant and stabilizing properties of three types of polysaccharide extracts from brown algae Saccharina latissima with a mixed composition of polysaccharides (SA: 98% sodium alginate, SF: 90% alginate and 9% fucoidan, SL: 14.5% fucoidan, 9.5% laminarin, and co‐extracted nonpolysaccharides) were evaluated. SA, SF, SL, and REF (added commercial sodium alginate) showed in vitro ferrous ion chelating ability in the order: SA (99%) > SL (78%) > REF (31%) > SF (16%). The difference in antioxidant activity between SA, REF, and SF appeared related to structural differences of alginate (M/G ratio). A storage trial was conducted using 70% (w/w) fish oil‐in‐water delivery emulsions added sodium caseinate (NaCas) (0.23 wt%) as emulsifier in combination with SA, SF, SL, or commercial NaAlg (REF) in different concentrations (C1 = 0.1, C2 = 0.2, C3 = 0.3, and C4 = 0.4 wt%). A control with only NaCas was included (CON). The physical (e.g., creaming and droplet‐size distribution) and oxidative (peroxide value and volatiles) stability of the emulsions, were evaluated (12 days, dark at 20˚C). Acceptable physical stability (creaming index) was found for REF (all concentrations), SF = 0.2 wt% (C2), SL and SA = 0.3 wt% (C3) and 0.4 wt% (C4). In general, the oxidative stability decreased by adding REF, SA, and SF (except for REF at C1), as prooxidant activity was observed. However, SA showed antioxidant activity against the formation of 2‐ethylfuran. SL showed antioxidant activity in decreasing the formation of volatile compounds in emulsions when added in concentrations above 0.2 wt%.

Determination of Prooxidant Activities of Several Fruit Juices and Herbs

Under oxidative stress conditions, which are defined as the deterioration of antioxidant and prooxidant balance in the organism in favor of prooxidants, ROS species that trigger the formation of various diseases occur. The fact that these harmful species cause oxidative damage to biological macromolecules is expressed as prooxidant activity. In this study, Cu(II)‒catalyzed prooxidant activities of pomegranate, apricot, peach, and pear juices and extracts of mint, white tea, and rosehip were measured by using gold nanoclusters synthesized via chicken egg white proteins. Fluorometric and spectrophotometric gold nanocluster biosensors and carbonyl assay were used. The fruit juices were used directly by diluting with pure water. Herbal plant samples were extracted in an ultrasonic water bath, filtered through microfilters, and stored in the refrigerator. Total prooxidant activities of fruit juices and herbal plants were calculated in terms of mM epicatechin equivalent, and the results obtained by applying all methods were compared with each other. It has been found that the applied methods can be used to accurately determine the total prooxidant activity of many food products.

Antioxidant and prooxidant activities of tea polyphenols in oil-in-water emulsions depend on the level used and the location of proteins

We studied the impacts of protein location (interface or aqueous phase) on the antioxidant and prooxidant activities of tea polyphenols (TP) in model oil-in-water emulsions (pH 7) at a low (0.01% w/v) or high (0.04 % w/v) concentration. TP at 0.01% reduced the levels of both lipid and protein oxidation markers in emulsions, independent of the protein location. However, TP were more potent when proteins were located at the interface. At 0.04%, TP were only weakly antioxidant towards lipids but were prooxidant towards proteins in emulsions with proteins at the interface, whereas they were still somewhat antioxidant for aqueous phase proteins. These results indicate that TP may act as either antioxidants or prooxidants depending on their concentration and also on the location of the proteins in emulsions. The level of TP should be optimized for emulsion-based foods or beverages to achieve optimum antioxidant activity.

An In Vitro and In Silico Study of the Enhanced Antiproliferative and Pro-Oxidant Potential of Olea europaea L. cv. Arbosana Leaf Extract via Elastic Nanovesicles (Spanlastics).

The olive tree is a venerable Mediterranean plant and often used in traditional medicine. The main aim of the present study was to evaluate the effect of Olea europaea L. cv. Arbosana leaf extract (OLE) and its encapsulation within a spanlastic dosage form on the improvement of its pro-oxidant and antiproliferative activity against HepG-2, MCF-7, and Caco-2 human cancer cell lines. The LC-HRESIMS-assisted metabolomic profile of OLE putatively annotated 20 major metabolites and showed considerable in vitro antiproliferative activity against HepG-2, MCF-7, and Caco-2 cell lines with IC50 values of 9.2 ± 0.8, 7.1 ± 0.9, and 6.5 ± 0.7 µg/mL, respectively. The encapsulation of OLE within a (spanlastic) nanocarrier system, using a spraying method and Span 40 and Tween 80 (4:1 molar ratio), was successfully carried out (size 41 ± 2.4 nm, zeta potential 13.6 ± 2.5, and EE 61.43 ± 2.03%). OLE showed enhanced thermal stability, and an improved in vitro antiproliferative effect against HepG-2, MCF-7, and Caco-2 (IC50 3.6 ± 0.2, 2.3 ± 0.1, and 1.8 ± 0.1 µg/mL, respectively) in comparison to the unprocessed extract. Both preparations were found to exhibit pro-oxidant potential inside the cancer cells, through the potential inhibitory activity of OLE against glutathione reductase and superoxide dismutase (IC50 1.18 ± 0.12 and 2.33 ± 0.19 µg/mL, respectively). These inhibitory activities were proposed via a comprehensive in silico study to be linked to the presence of certain compounds in OLE. Consequently, we assume that formulating such a herbal extract within a suitable nanocarrier would be a promising improvement of its therapeutic potential.

Insights into the Relation between Oxidative Stress and Malaria: A Mechanistic and Therapeutic Approach

The mortality rate due to malaria has increased tremendously in the last decade. Even though the causative agent of this disease is known, the preventive measures are not potent enough to control the spread of this disease. Malarial infection involves a strong interrelationship between oxidative stress and pathogenesis. This review addresses the various oxidative stress-related mechanisms associated with vector defense, host immunity, plasmodial pathogenesis, and corresponding therapeutic strategies. The mechanisms involving host and vector defense show both similarity and contradiction to the processes involving plasmodial pathogenesis under different circumstances. Therefore, corresponding ameliorative peculiarities are observed in the therapeutic mechanisms adopted by the anti-malarial drugs. The malarial parasite augments oxidative stress to weaken the host and exerts antioxidant effects against host defense mechanisms. However, the anti-malarial drugs induce oxidative insult to reduce parasitic load and exert antioxidant effects against parasite infection-induced oxidative stress in host. Thus, the anti-malarial drugs exhibit antioxidant activity in hosts and/or pro-oxidant activity in parasites.

Predicted Shelf-Life, Thermodynamic Study and Antioxidant Capacity of Breadsticks Fortified with Grape Pomace Powders

Grape pomace (GP), is the main winemaking by-product and could represent a valuable functional food ingredient being a source of bioactive compounds, like polyphenols. Polyphenols prevent many non-communicable diseases and could contrast the oxidation reaction in foods. However, the high content in polyunsaturated fatty acid, the described pro-oxidant potential action of some polyphenols and the complex interactions with other components of matrices during food processing must be considered. Indeed, all these factors could promote oxidative reactions and require focused and specific assay. The aims of this study were to evaluate the effects of GP powder (GPP) addition (at 0%, 5% and 10% concentrations) in breadsticks formulations both on the antioxidant activity at room temperature during storage and on the shelf-life by the OXITEST predictive approach. GPP fortification increased the total polyphenols content and the antioxidant activities of breadsticks. FRAP reduced during the first two days of storage at room temperature, TPC increased during the 75 days, while ABTS showed a slight progressive decrease. However, GP negatively influenced OXITEST estimated shelf-life of breadsticks, incrementing the oxidation rate. In conclusion, even if GP fortification of breadsticks could improve the nutritional value of the products, the increased commercial perishability represents a drawback that must be considered.

Pro-oxidant drug-loaded porphyrinic zirconium metal-organic-frameworks for cancer-specific sonodynamic therapy

Sonodynamic therapy, which utilizes ultrasound (US) to produce cytotoxic reactive oxygen species (ROS), can overcome the critical drawbacks of photodynamic therapy, such as limited tissue penetration depth. However, the development of sonosensitizers having superior sonodynamic effects and desirable biocompatibility remains a major challenge. In this study, nanoscale zirconium-based porphyrinic metal organic frameworks (MOFs) (PCN-222) were developed as safe and effective nanosonosensitizers. Polyethylene glycol (PEG)-coated PCN-222 (PEG-PCN) was loaded with a pro-oxidant drug, piperlongumine (PL), to enable tumor-specific chemo-photodynamic combination therapy. Both PEG-PCN and PL-incorporated PEG-PCN (PL-PEG-PCN) showed high colloidal stability in biological media. In addition, nanoscale PL-PEG-PCN was efficiently internalized by breast cancer cells, leading to substantially increased ROS generation under US exposure. The effective intracellular delivery of PL by PEG-PCN further elevated the level of intracellular ROS in breast cancer cells owing to the pro-oxidative activity of PL. Therefore, PL-PEG-PCN revealed significantly higher sonotoxicity than free PL and PEG-PCN. Owing to the cancer-specific apoptosis triggered by PL, PL-PEG-PCN showed cancer-selective cell death in breast cancer cells compared with normal fibroblast cells. This study demonstrates that pro-oxidant drug-loaded porphyrinic MOFs are biocompatible and effective sonosensitizers for cancer-targeted chemo-sonodynamic combination therapy.

Targeting inflammation and redox aberrations by perindopril attenuates methotrexate-induced intestinal injury in rats: Role of TLR4/NF-κB and c-Fos/c-Jun pro-inflammatory pathways and PPAR-γ/SIRT1 cytoprotective signals

AimsThe use of methotrexate (MTX), a classical immunosuppressant and anti-cancer agent, is associated with multiple organ toxicities, including the intestinal injury. Components of the renin-angiotensin system are expressed in the intestinal epithelium and mucosal immune cells where they provoke pro-inflammatory and pro-oxidant action. The present study was conducted to investigate the potential ability of perindopril (PER), an angiotensin-converting enzyme inhibitor (ACEI), to attenuate MTX-induced intestinal injury with emphasis on the role of the pro-inflammatory TLR4/NF-κB and c-Fos/c-Jun pathways alongside PPAR-γ and SIRT1 cytoprotective signals. Materials and methodsThe intestinal injury was induced by a single-dose injection of 20 mg/kg of MTX i.p at the end of the 5th day. PER was administrated once daily in a dose of 1 mg/kg, i.p, for five days before MTX and five days later. ResultsHerein, perindopril attenuated the intestinal injury as seen by lowering the histopathological aberrations and preserving the goblet cells in villi/crypts. These beneficial actions were associated with downregulating the expression of the pro-inflammatory angiotensin II, TNF-α, IL-1β, and IL-6 cytokines, alongside upregulating the anti-inflammatory angiotensin (1–7) and IL-10. At the molecular level, perindopril downregulated the TLR4/NF-κB and c-Fos/c-Jun pathways in inflamed intestine of rats. Moreover, it attenuated the pro-oxidant events by lowering intestinal MDA and boosting GSH, SOD, and GST antioxidants together with PPAR-γ and SIRT1 cytoprotective signals. The aforementioned findings were also highlighted using molecular docking and network pharmacology analysis. ConclusionsPerindopril demonstrated notable mitigation of MTX-induced intestinal injury through suppression of TLR4/NF-κB and c-Fos/c-Jun pathways alongside the augmentation of PPAR-γ/SIRT1 cytoprotective signals.

Polyphosphates as an effective vehicle for delivery of bioavailable nanoparticulate iron(III)

Polyphosphates are widely used food additives with the potential to increase iron bioavailability but chemical nature of their soluble complexes with iron remains largely unknown. Here, pyrophosphate, tripolyphosphate, hexametaphosphate and ∼25-chain-length polyphosphate solubilized 896, 896, 1120 and 1344 mg Fe(III) per g, respectively, at neutral pH by mediating the formation of highly-negatively-charged ferric hydroxide-polyphosphate nanoparticles (PolyP-FeONPs). PolyP-FeONPs displayed fading yellow color with increasing initial dissolved P/Fe ratio ((P/Fe)init) and decreasing polyphosphate length due to rising proportion of Fe(III)-phosphate bonds, and specifically, pyrophosphate resulted colorless PolyP-FeONPs at (P/Fe)init ≥ 4. PolyP-FeONPs had weak pro-oxidant activity in glyceryl trilinoleate emulsion and good colloidal stability under spray/freeze-drying and gastrointestinal conditions. Serum iron kinetics in rats revealed sustained iron release and ∼170% iron bioavailability of oral PolyP-FeONPs relative to FeSO4. Calcein-fluorescence-quenching assay in polarized Caco-2 cells unveiled divalent-metal-transporter-1-independent and macropinocytosis-dependent iron uptake from PolyP-FeONPs. This study helps develop food-compatible, highly-bioavailable and sustained-release iron preparations.

Oxidative Transformations of 3,4-Dihydroxyphenylacetaldehyde Generate Potential Reactive Intermediates as Causative Agents for Its Neurotoxicity.

Neurogenerative diseases, such as Parkinson’s disease, are associated, not only with the selective loss of dopamine (DA), but also with the accumulation of reactive catechol-aldehyde, 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is formed as the immediate oxidation product of cytoplasmic DA by monoamine oxidase. DOPAL is well known to exhibit toxic effects on neuronal cells. Both catecholic and aldehyde groups seem to be associated with the neurotoxicity of DOPAL. However, the exact cause of toxicity caused by this compound remains unknown. Since the reactivity of DOPAL could be attributed to its immediate oxidation product, DOPAL-quinone, we examined the potential reactions of this toxic metabolite. The oxidation of DOPAL by mushroom tyrosinase at pH 5.3 produced conventional DOPAL-quinone, but oxidation at pH 7.4 produced the tautomeric quinone-methide, which gave rise to 3,4-dihydroxyphenylglycolaldehyde and 3,4-dihydroxybenzaldehyde as products through a series of reactions. When the oxidation reaction was performed in the presence of ascorbic acid, two additional products were detected, which were tentatively identified as the cyclized products, 5,6-dihydroxybenzofuran and 3,5,6-trihydroxybenzofuran. Physiological concentrations of Cu(II) ions could also cause the oxidation of DOPAL to DOPAL-quinone. DOPAL-quinone exhibited reactivity towards the cysteine residues of serum albumin. DOPAL-oligomer, the oxidation product of DOPAL, exhibited pro-oxidant activity oxidizing GSH to GSSG and producing hydrogen peroxide. These results indicate that DOPAL-quinone generates several toxic compounds that could augment the neurotoxicity of DOPAL.

Comparative Study of Antioxidant and Pro-Oxidant Properties of Homoleptic and Heteroleptic Copper Complexes with Amino Acids, Dipeptides and 1,10-Phenanthroline: The Quest for Antitumor Compounds.

In a search for new antitumoral agents, a series of homoleptic copper(II) complexes with amino acids and dipeptides, as well as heteroleptic complexes containing both dipeptides and 1,10-phenanthroline, were studied. Furthermore, a single-crystal structure containing alanyl-leucinato ([Cu3(AlaLeu)3(H2O)3(CO3)]·PF6·H2O), which is the first homotrinuclear carbonato-bridged copper(II) complex with a dipeptide moiety, is presented. To assess possible antitumor action mechanisms, we focused on the comparative analysis of pro- and antioxidant behaviors. Pro-oxidant activity, in which the reactive oxygen species (ROS) formed by the reaction of the complexes with H2O2 produce oxidative damage to 2-deoxy-d-ribose, was evaluated using the TBARS method. Additionally, the antioxidant action was quantified through the superoxide dismutase (SOD)-like activity, using a protocol based on the inhibitory effect of SOD on the reduction of nitrobluetetrazolium (NBT) by the superoxide anion generated by the xanthine/xanthine oxidase system. Our findings show that Cu–amino acid complexes are strong ROS producers and moderate SOD mimics. Conversely, Cu–dipeptide–phen complexes are good SOD mimics but poor ROS producers. The activity of Cu–dipeptide complexes was strongly dependent on the dipeptide. A DFT computational analysis revealed that complexes with high SOD-like activity tend to display a large dipole moment and condensed-to-copper charge, softness and LUMO contribution. Moreover, good ROS producers have higher global hardness and copper electrophilicity, lower copper softness and flexible and freely accessible coordination polyhedra.

Anticancer Activity of Aqueous Extracts from Asparagus officinalis L. Byproduct on Breast Cancer Cells.

Cultivation of asparagus (Asparagus officinalis L.; Asp) for food and medicinal use has taken place since the early Roman Empire. Today, Asp represents a worldwide diffuse perennial crop. Lower portions of the spears represent a food industry waste product that can be used to extract bioactive molecules. In this study, aqueous extracts derived from the non-edible portion of the plant (hard stem) were prepared and characterized for chemical content. Furthermore, the biocompatibility and bioactivity of Asp aqueous extracts were assessed in vitro on normal fibroblasts and on breast cancer cell lines. Results showed no interference with fibroblast viability, while a remarkable cytostatic concentration-dependent activity, with significant G1/S cell cycle arrest, was specifically observed in breast cancer cells without apoptosis induction. Asp extracts were also shown to significantly inhibit cell migration. Further analyses showed that Asp extracts were characterized by specific pro-oxidant activity against tumoral cells, and, importantly, that their combination with menadione resulted in a significant enhancement of oxidants production with respect to menadione alone in breast cancer cells but not in normal cells. This selectivity of action on tumoral cells, together with the easiness of their preparation, makes the aqueous Asp extracts very attractive for further investigation in breast cancer research, particularly to investigate their role as possible co-adjuvant agents of clinical drug therapies.