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Special Issue "Antioxidant and Cytoprotective Activity"

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A special issue of Antioxidants (ISSN 2076-3921).

Deadline for manuscript submissions: closed (20 April 2020) | Viewed by 74202

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Special Issue Editor

Dr. Kateřina Valentová

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Institute of Microbiology, Academy of Sciences of the Czech Republic, Laboratory of Biotransformation, Vídeňská 1083, CZ 142 20 Praha 4, Czech Republic
Interests: polyphenols; flavonolignans; Silybum marianum; flavonols; quercetin; rutin; isoquercitrin; metabolites; gut microbiota; biotransformation by enzymes and whole cells
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Special Issue Information

Dear Colleagues,

Numerous chronic diseases are associated with oxidative stress and therefore some natural and synthetic antioxidants are proposed for the prevention and treatment of such diseases. Cellular protection against oxidative and electrophile toxicities (chemoprevention) can be ensured by two types of small molecules: Redox active, short-living direct antioxidants and indirect antioxidants that could have anti- and prooxidant activity, activating the Keap1/Nrf2/ARE pathway, which results in transcriptional induction of cytoprotective proteins. The pathophysiology of oxidative stress in humans is complex: Individual protective systems cooperate in a complex functional interplay; cytoprotective proteins are involved in the synthesis and/or regeneration of direct antioxidants, which in turn are often required for the catalytic functions of cytoprotective proteins. Direct antioxidant therapy usually failing in clinical trials and recent studies mostly confirms the involvement of several cell signaling pathways in cell protection in oxidative-stress-related conditions. Further investigation into this subject will provide renewed insight into the implication of oxidative stress in chronic diseases.

This Special Issue welcomes original research papers or reviews that deal with cytoprotective activity of natural antioxidants and inducers of cytoprotective proteins from plants or microorganisms, but also (semi)synthetic molecules and especially pleiotropic agents with protective effects in, for example, carcinogenesis, cardiovascular diseases, chronic respiratory diseases, diabetes mellitus, neurodegenerative diseases, retinal damage, and others. Studies focusing on the molecular mechanism of action of cytoprotective agents are particularly welcome. Studies based on undefined mixtures, extracts, or “principles” will not be accepted for publication in this Issue.

Dr. Kateřina Valentová
Guest Editor

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Keywords

antioxidant
cytoprotection
chemoprevention
chronic diseases
cytoprotective proteins
mechanism of action

Published Papers (19 papers)

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Editorial

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Open AccessEditorial

Cytoprotective Activity of Natural and Synthetic Antioxidants

Kateřina Valentová

Antioxidants 2020, 9(8), 713; https://doi.org/10.3390/antiox9080713 - 06 Aug 2020

Cited by 8 | Viewed by 2100

Abstract

Numerous chronic diseases including cancer, cardiovascular, chronic respiratory or neurodegenerative diseases, diabetes mellitus, retinal damage, and others are associated with oxidative stress [...] Full article

(This article belongs to the Special Issue Antioxidant and Cytoprotective Activity)

Research

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Open AccessArticle

Calmangafodipir Reduces Sensory Alterations and Prevents Intraepidermal Nerve Fibers Loss in a Mouse Model of Oxaliplatin Induced Peripheral Neurotoxicity

Virginia Rodriguez-Menendez

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Antioxidants 2020, 9(7), 594; https://doi.org/10.3390/antiox9070594 - 07 Jul 2020

Cited by 18 | Viewed by 2724

Abstract

Oxaliplatin (OHP) is an antineoplastic compound able to induce peripheral neurotoxicity. Oxidative stress has been suggested to be a key factor in the development of OHP-related peripheral neurotoxicity. Mangafodipir, a contrast agent possessing mitochondrial superoxide dismutase (MnSOD)-mimetic activity, has been tested as a cytoprotector in chemotherapy-induced peripheral neurotoxicity (CIPN). Calmangafodipir (PledOx^®) has even better therapeutic activity. We investigated a BALB/c mouse model of OHP-related CIPN and the effects of the pre-treatment of calmangafodipir (2.5, 5, or 10 mg/kg intravenously) on sensory perception, and we performed a pathological study on skin biopsies to assess intraepidermal nerve fiber (IENF) density. At the end of the treatments, OHP alone or in pre-treatment with calmangafodipir 2.5 and 10 mg/kg, induced mechanical allodynia and cold thermal hyperalgesia, but calmangafodipir 5 mg/kg prevented these effects. Accordingly, OHP alone or in pre-treatment with calmangafodipir 2.5 and 10 mg/kg, induced a significant reduction in IENF density, but calmangafodipir 5 mg/kg prevented this reduction. These results confirm a protective effect of calmangafodipir against OHP-induced small fiber neuropathy. Interestingly, these results are in agreement with previous observations suggesting a U-shaped effect of calmangafodipir, with the 10 mg/kg dose less effective than the lower doses. Full article

(This article belongs to the Special Issue Antioxidant and Cytoprotective Activity)

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Open AccessArticle

AOP1, a New Live Cell Assay for the Direct and Quantitative Measure of Intracellular Antioxidant Effects

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Antioxidants 2020, 9(6), 471; https://doi.org/10.3390/antiox9060471 - 01 Jun 2020

Cited by 13 | Viewed by 3146

Abstract

Taking advantage of Light Up Cell System (LUCS) technology, which allows for fine monitoring of reactive oxygen species (ROS) production inside live cells, a new assay called Anti Oxidant Power 1 (AOP1) was developed to specifically measure ROS and/or free-radical scavenging effects inside living cells. This method is quantitative and EC₅₀s obtained from AOP1 dose-response experiments were determined in order to classify the intracellular antioxidant efficacy of 15 well known antioxidant compounds with different hydrophilic properties. Six of them (epigallocatechin gallate, quercetin, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethoxyquin, resveratrol) gave EC₅₀s in the range of 7–64 μM, four (Trolox, catechin, epicatechin, EUK134) in the range of 0.14 to 1 mM, and 5 (sulforaphane, astaxanthin, α- and γ-tocopherols, vitamin E acetate) showed only partial or no effect. Interestingly, effects with measurable EC₅₀s were observed for compounds with hydrophilic properties (LogP ≤ 5.3), while all antioxidants known to act at the plasma membrane level (LogP ≥ 10.3) had partial or no effect. Sulforaphane, a hydrophilic but strict Keap1/Nrf2 pathway enhancer, did not show any effect either. Importantly, AOP1 assay captures both antioxidant and prooxidant effects. Taken together, these results led us to the conclusion that AOP1 assay measures antioxidant effect of compounds that selectively enter the cell, and act as free radical scavengers in the cytosol and/or nucleus level. Full article

(This article belongs to the Special Issue Antioxidant and Cytoprotective Activity)

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Open AccessArticle

Multidrug Resistance Modulation Activity of Silybin Derivatives and Their Anti-Inflammatory Potential

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Antioxidants 2020, 9(5), 455; https://doi.org/10.3390/antiox9050455 - 25 May 2020

Cited by 20 | Viewed by 2876

Abstract

Silybin is considered to be the main biologically active component of silymarin. Its oxidized derivative 2,3-dehydrosilybin typically occurs in silymarin in small, but non-negligible amounts (up to 3%). Here, we investigated in detail complex biological activities of silybin and 2,3-dehydrosilybin optical isomers. Antioxidant activities of pure stereomers A and B of silybin and 2,3-dehydrosilybin, as well as their racemic mixtures, were investigated by using oxygen radical absorption capacity (ORAC) and cellular antioxidant activity (CAA) assay. All substances efficiently reduced nitric oxide production and cytokines (TNF-α, IL-6) release in a dose-dependent manner. Multidrug resistance (MDR) modulating potential was evaluated as inhibition of P-glycoprotein (P-gp) ATPase activity and regulation of ATP-binding cassette (ABC) protein expression. All the tested compounds showed strong dose-dependent inhibition of P-gp pump. Moreover, 2,3-dehydrosilybin A (30 µM) displayed the strongest sensitization of doxorubicin-resistant ovarian carcinoma. Despite these significant effects, silybin B was the only compound acting directly upon P-gp in vitro and also downregulating the expression of respective MDR genes. This compound altered the expression of P-glycoprotein (P-gp, ABCB1), multidrug resistance-associated protein 1 (MRP1, ABCC1) and breast cancer resistance protein (BCRP, ABCG2). 2,3-Dehydrosilybin AB exhibited the most effective inhibition of acetylcholinesterase activity. We can clearly postulate that silybin derivatives could serve well as modulators of a cancer drug-resistant phenotype. Full article

(This article belongs to the Special Issue Antioxidant and Cytoprotective Activity)

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Open AccessArticle

Evaluation of Viburnum opulus L. Fruit Phenolics Cytoprotective Potential on Insulinoma MIN6 Cells Relevant for Diabetes Mellitus and Obesity

Małgorzata Zakłos-Szyda

Agnieszka Kowalska-Baron

Nina Pietrzyk

Anna Drzazga

and

Anna Podsędek

Antioxidants 2020, 9(5), 433; https://doi.org/10.3390/antiox9050433 - 16 May 2020

Cited by 24 | Viewed by 3187

Abstract

In this study, the influence of guelder rose (Viburnum opulus) fruit fresh juice (FJ) and a phenolic-rich fraction (PRF) isolated from juice on mice insulinoma MIN6 cells activities was investigated. Extracts were able to decrease intracellular oxidative stress at the highest non-cytotoxic concentrations. They induced glucagon-like peptide-1 (GLP-1) secretion in the presence of an elevated glucose concentration, and they inhibited in vitro activity of the dipeptidyl peptidase-4 (DPP4) enzyme. Nonetheless, inhibition of glucose-stimulated insulin secretion was detected, which was accompanied by a decrease of cellular membrane fluidity and hyperpolarization effect. In addition, the increase of free fatty acid uptake and accumulation of lipid droplets in MIN6 cells were observed. Elevated extract concentrations induced cell apoptosis through the intrinsic mitochondrial pathway with activation of initiatory caspase-9 and downstream caspases-3/7. The fluorescence-quenching studies indicated that PRF extract has binding affinity to human serum albumin, which is one of the factors determining drug bioavailability. Taken together, despite the cytoprotective activity against generated intracellular oxidative stress, V. opulus revealed potential toxic effects as well as decreased insulin secretion from MIN6 cells. These findings are relevant in understanding V. opulus limitations in developing diet supplements designed for the prevention and treatment of postprandial glucose elevation. Full article

(This article belongs to the Special Issue Antioxidant and Cytoprotective Activity)

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Anti-Inflammatory and Reactive Oxygen Species Suppression through Aspirin Pretreatment to Treat Hyperoxia-Induced Acute Lung Injury in NF-κB–Luciferase Inducible Transgenic Mice

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Antioxidants 2020, 9(5), 429; https://doi.org/10.3390/antiox9050429 - 15 May 2020

Cited by 13 | Viewed by 2522

Abstract

Acute lung injury (ALI), a common cause of morbidity and mortality in intensive care units, results from either direct intra-alveolar injury or indirect injury following systemic inflammation and oxidative stress. Adequate tissue oxygenation often requires additional supplemental oxygen. However, hyperoxia causes lung injury and pathological changes. Notably, preclinical data suggest that aspirin modulates numerous platelet-mediated processes involved in ALI development and resolution. Our previous study suggested that prehospital aspirin use reduced the risk of ALI in critically ill patients. This research uses an in vivo imaging system (IVIS) to investigate the mechanisms of aspirin’s anti-inflammatory and antioxidant effects on hyperoxia-induced ALI in nuclear factor κB (NF-κB)–luciferase transgenic mice. To define mechanisms through which NF-κB causes disease, we developed transgenic mice that express luciferase under the control of NF-κB, enabling real-time in vivo imaging of NF-κB activity in intact animals. An NF-κB-dependent bioluminescent signal was used in transgenic mice carrying the luciferase genes to monitor the anti-inflammatory effects of aspirin. These results demonstrated that pretreatment with aspirin reduced luciferase expression, indicating that aspirin reduces NF-κB activation. In addition, aspirin reduced reactive oxygen species expression, the number of macrophages, neutrophil infiltration and lung edema compared with treatment with only hyperoxia treatment. In addition, we demonstrated that pretreatment with aspirin significantly reduced the protein levels of phosphorylated protein kinase B, NF-κB and tumor necrosis factor α in NF-κB–luciferase^+/+ transgenic mice. Thus, the effects of aspirin on the anti-inflammatory response and reactive oxygen species suppressive are hypothesized to occur through the NF-κB signaling pathway. This study demonstrated that aspirin exerts a protective effect for hyperoxia-induced lung injury and thus is currently the drug conventionally used for hyperoxia-induced lung injury. Full article

(This article belongs to the Special Issue Antioxidant and Cytoprotective Activity)

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Open AccessArticle

Dual SMO/BRAF Inhibition by Flavonolignans from Silybum marianum

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Antioxidants 2020, 9(5), 384; https://doi.org/10.3390/antiox9050384 - 05 May 2020

Cited by 14 | Viewed by 2966

Abstract

Silymarin is the standardized extract from the fruits of Silybum marianum (L.) Gaertn., a well-known hepatoprotectant and antioxidant. Recently, bioactive compounds of silymarin, i.e., silybins and their 2,3-dehydro derivatives, have been shown to exert anticancer activities, yet with unclear mechanisms. This study combines in silico and in vitro methods to reveal the potential interactions of optically pure silybins and dehydrosilybins with novel protein targets. The shape and chemical similarity with approved drugs were evaluated in silico, and the potential for interaction with the Hedgehog pathway receptor Smoothened (SMO) and BRAF kinase was confirmed by molecular docking. In vitro studies on SMO and BRAF V600E kinase activity and in BRAF V600E A-375 human melanoma cell lines were further performed to examine their effects on these proteins and cancer cell lines and to corroborate computational predictions. Our in silico results direct to new potential targets of silymarin constituents as dual inhibitors of BRAF and SMO, two major targets in anticancer therapy. The experimental studies confirm that BRAF kinase and SMO may be involved in mechanisms of anticancer activities, demonstrating dose-dependent profiles, with dehydrosilybins showing stronger effects than silybins. The results of this work outline the dual SMO/BRAF effect of flavonolignans from Silybum marianum with potential clinical significance. Our approach can be applied to other natural products to reveal their potential targets and mechanism of action. Full article

(This article belongs to the Special Issue Antioxidant and Cytoprotective Activity)

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Open AccessArticle

Antioxidant Properties of Embelin in Cell Culture. Electrochemistry and Theoretical Mechanism of Scavenging. Potential Scavenging of Superoxide Radical through the Cell Membrane

Francesco Caruso

Miriam Rossi

Sarjit Kaur

Emmanuel Garcia-Villar

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Antioxidants 2020, 9(5), 382; https://doi.org/10.3390/antiox9050382 - 05 May 2020

Cited by 27 | Viewed by 3080

Abstract

Embelin, a plant natural product found in Lysimachia punctata (Primulaceae), and Embelia ribes Burm (Myrsinaceae) fruit, possesses interesting biological and pharmacological properties. It is a unique chemical species as it includes both quinone and hydroquinone functional groups plus a long hydrophobic tail. By using hydrodynamic voltammetry, which generates the superoxide radical in situ, we show an unusual scavenging capability by embelin. Embelin as a scavenger of superoxide is stronger than the common food additive antioxidant 2,6-bis(1,1-dimethylethyl)-4-20 methylphenol, (butylated hydroxytoluene, BHT). In fact, embelin is even able to completely abolish the superoxide radical in the voltaic cell. Computational results indicate that two different types of embelin scavenging actions may be involved, initially through π–π interaction and followed by proton capture in the cell. A related mechanism describes embelin’s ability to circumvent superoxide leaking by transforming the anion radical into molecular oxygen. In order to confirm its antioxidant properties, its biological activity was tested in a study carried out in THP-1 human leukemic monocytes and BV-2 mice microglia. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, proliferation curves and antioxidant activity by the use of a fluorescent probe showed good antioxidant properties at 24 h. This suggests that embelin’s long alkyl C10 tail may be useful for cell membrane insertion which stimulates the antioxidant defense system, and cytoprotection in microglia. In conclusion, embelin could be an interesting pharmacological tool able to decrease the damage associated with metabolic and neurodegenerative diseases. Full article

(This article belongs to the Special Issue Antioxidant and Cytoprotective Activity)

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Open AccessArticle

Phytochemical Profile and Biological Activities of Tendrils and Leaves Extracts from a Variety of Vitis vinifera L.

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Antioxidants 2020, 9(5), 373; https://doi.org/10.3390/antiox9050373 - 30 Apr 2020

Cited by 22 | Viewed by 3596

Abstract

Winery industry by-products have a great reuse potential in the pharmaceutical and cosmetic fields due to their bioactive compounds. This study investigates the phytochemical profile and the bioactivity of Vitis vinifera variety Fetească neagră tendrils extract (TE) and leaves extract (LE), intended to be used in oral hygiene products recommended in periodontal disease. The evaluation of the phenolic content was performed by colorimetric analysis. Liquid chromatography coupled with mass spectrometry was used to determine the chemical profile of the two extracts obtained from V. vinifera. Moreover, the antioxidant activity of the extracts was determined by spectrophotometric methods, as well as on human gingival fibroblasts (HGF) cell line. The cytocompatibility and cytoprotective effect against nicotine-induced cytotoxicity were tested, as well as the anti-inflammatory and antimicrobial effects. The TE showed higher total polyphenolic content, rich in rutin, compared to the leaves extract that displayed important amounts of isoquercitrin. The antioxidant effect was confirmed by both non-cellular and cellular tests. The cytocompatibility of the extracts was confirmed at a wide range of concentrations. The cytoprotective effect was demonstrated in HGF exposed to cytotoxic doses of nicotine; 300 µg/mL of both tested extracts decreased nicotine toxicity by approximately 20%. When challenged with E. coli polysaccharides, in HGF cells co-exposed to TE and LE, a reduction in the release of proinflammatory cytokines (IL-8, IL-6 and IL-1β) was observed. The extracts were both able to reduce the levels of reactive oxygen species and inflammatory cytokines, and had notable antimicrobial effects on pathogenic bacteria associated with periodontitis. Full article

(This article belongs to the Special Issue Antioxidant and Cytoprotective Activity)

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Cytoprotective Effects of Delphinidin for Human Chondrocytes against Oxidative Stress through Activation of Autophagy

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Antioxidants 2020, 9(1), 83; https://doi.org/10.3390/antiox9010083 - 19 Jan 2020

Cited by 30 | Viewed by 4074

Abstract

Antioxidant enzymes are decreased in osteoarthritis (OA) patients, implying the role of oxidative stress in osteoarthritis pathogenesis. The aim of this study was to evaluate the cytoprotective effects of delphinidin, a potent antioxidant, in human chondrocytes and the underlying mechanisms. The cytoprotective mechanism induced by delphinidin against oxidative stress (H₂O₂) in human chondrocytes was investigated. Cell viability and death were evaluated using proapoptotic and antiapoptotic markers such as cleaved caspase-3 (c-caspase-3), cleaved poly(ADP-ribose) polymerase N-acetylcysteine (c-PARP), Bcl-X_L, and transcription factors associated with redox and inflammation regulation, including nuclear factor kappa B (NF-κB) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Induction of autophagy was assessed by formation of LC3-II and autophagosome-(LC3 punctate, monodansylcadaverine (MDC) and acridine orange staining) in the presence or absence of an autophagy inhibitor. Treatment with delphinidin itself at concentration below 50 µM for 24 h did not affect viability of chondrocytes. Delphinidin inhibited reactive oxygen species (ROS)-induced apoptosis by significantly decreasing apoptosis markers such as c-caspase-3 and c-PARP while increasing antiapoptotic marker Bcl-X_L and antioxidant response NF-κB and Nrf2 pathways. Delphinidin also activated cytoprotective autophagy to protect chondrocytes during oxidative stresses. Activation of autophagy with autophagy inducer rapamycin also inhibited ROS-induced cell death and decreased proapoptotic proteins but increased antiapoptotic protein Bcl-X_L, NF-κB, and Nrf2. Delphinidin can protect chondrocytes against H₂O₂-induced apoptosis via activation of Nrf2 and NF-κB and protective autophagy. Thus, it can inhibit OA with protection of chondrocytes. Delphinidin can protect chondrocytes against H₂O₂-induced ROS with maintenance of homeostasis and redox. These results suggest that delphinidin could be used to protect chondrocytes against age-related oxidative stress and other oxidative stresses in the treatment of OA. Thus, delphinidin may play a critical role in preventing the development and progression of OA. Full article

(This article belongs to the Special Issue Antioxidant and Cytoprotective Activity)

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Open AccessArticle

Feijoa Fruit Peel: Micro-morphological Features, Evaluation of Phytochemical Profile, and Biological Properties of Its Essential Oil

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Antioxidants 2019, 8(8), 320; https://doi.org/10.3390/antiox8080320 - 19 Aug 2019

Cited by 10 | Viewed by 4631

Abstract

Acca sellowiana (O. Berg) Burret (Feijoa) is an evergreen shrub, belonging to the Mirtaceae family. The aim of this study was to investigate the micromorphological features of the feijoa fruit peel and to evaluate the phytochemical profile, as well as the antioxidant, cytoprotective, and antimicrobial properties of its essential oil (EO), by several in vitro cell-free and cell-based assays. The micromorphological analysis showed several schizogenic secretory cavities, immediately below the epidermal layer. Forty compounds were identified and quantified by GC-FID and GC-MS analyses. Sesquiterpenes were the most abundant ones (76.89%), followed by monoterpene hydrocarbons (3.26%), and oxygenated monoterpenes (0.34%). The main compounds were γ-Selinene (17.39%), α-Cariophyllene (16.74%), β-Cariophyllene (10.37%), and Germacene D (5.32%). The EO showed a strong and dose-dependent antioxidant, and free-radical scavenging activity. Furthermore, it showed cytoprotective activity on the lymphocytes, that have been pre-treated with 100 μM tert-butyl-hydroperoxide (t-BOOH), as well as a decrease in intracellular reactive oxygen species (ROS), induced by t-BOOH on erythrocytes. A preliminary antimicrobial screening against GRAM+ and GRAM− bacteria, as well as on fungi highlighted that EO showed the best activity against S. aureus and C. albicans (MIC 2.7 mg/mL). In light of these results, feijoa fruit EO could find various applications, especially in the food, nutraceutical, and pharmaceutical fields. Full article

(This article belongs to the Special Issue Antioxidant and Cytoprotective Activity)

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Open AccessArticle

Complex Evaluation of Antioxidant Capacity of Milk Thistle Dietary Supplements

Jitka Viktorova

Milena Stranska-Zachariasova

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Antioxidants 2019, 8(8), 317; https://doi.org/10.3390/antiox8080317 - 18 Aug 2019

Cited by 24 | Viewed by 4263

Abstract

Numerous in vitro assays are used to characterize the antioxidant properties of natural-based matrices. However, many of them generate contradictory and non-compliant results. In our study, we focused on the characterization of traditionally used biochemical (2,2′-azino-bis-(3-ethylbenzothiazoline-6 sulfonic acid) (ABTS), Oxygen Radical Absorption Capacity (ORAC), and 2,2-diphenyl-1-picrylhydrazyl (DPPH)) and cellular (CAA) antioxidant tests on a broad set of milk thistle dietary supplements containing silymarin. In addition to 26 commercially available preparations, also the natural silymarin extract available from Sigma Aldrich, St. Louis, MI, USA, and a model mixture of pure flavonoid/flavonolignans mimicking the silymarin composition were investigated as control samples. Significant differences in the antioxidant capacity of the supplements were observed. Unlike the DPPH, the results of the ABTS and ORAC methods correlated with the silymarin components determined by U-HPLC-HRMS/MS. The responses in CAA were considerably lower than in other assays. Silymarin exhibited a significantly higher antioxidant capacity than the artificially prepared flavonoid/flavonolignans mixture in all tests, indicating possible presence of other antioxidants of natural origin. The follow-up U-HPLC-HRMS/MS screening revealed the presence of tens of non-silymarin compounds with reported antioxidant activity (not only in the silymarin extract, but also in the milk thistle preparations). The sum of the total phenolics and the sum of the simple phenolics correlated with CAA results more than silymarin. Full article

(This article belongs to the Special Issue Antioxidant and Cytoprotective Activity)

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Open AccessArticle

Antioxidant, Anti-Inflammatory, and Multidrug Resistance Modulation Activity of Silychristin Derivatives

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Antioxidants 2019, 8(8), 303; https://doi.org/10.3390/antiox8080303 - 14 Aug 2019

Cited by 21 | Viewed by 4166

Abstract

Silychristin A is the second most abundant compound of silymarin. Silymarin complex was previously described as an antioxidant with multidrug resistance modulation activity. Here, the results of a classical biochemical antioxidant assay (ORAC) were compared with a cellular assay evaluating the antioxidant capacity of pure silychristin A and its derivatives (anhydrosilychristin, isosilychristin and 2,3-dehydrosilychristin A). All the tested compounds acted as antioxidants within the cells, but 2,3-dehydro- and anhydro derivatives were almost twice as potent as the other tested compounds. Similar results were obtained in LPS-stimulated macrophages, where 2,3-dehydro- and anhydrosilychristin inhibited NO production nearly twice as efficiently as silychristin A. The inhibition of P-glycoprotein (P-gp) was determined in vitro, and the respective sensitization of doxorubicin-resistant ovarian carcinoma overproducing P-gp was detected. Despite the fact that the inhibition of P-gp was demonstrated in a concentration-dependent manner for each tested compound, the sensitization of the resistant cell line was observed predominantly for silychristin A and 2,3-dehydrosilychristin A. However, anhydrosilychristin and isosilychristin affected the expression of both the P-gp (ABCB1) and ABCG2 genes. This is the first report showing that silychristin A and its 2,3-dehydro-derivative modulate multidrug resistance by the direct inhibition of P-gp, in contrast to anhydrosilychristin and isosilychristin modulating multidrug resistance by downregulating the expression of the dominant transmembrane efflux pumps. Full article

(This article belongs to the Special Issue Antioxidant and Cytoprotective Activity)

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Viburnum opulus Fruit Phenolic Compounds as Cytoprotective Agents Able to Decrease Free Fatty Acids and Glucose Uptake by Caco-2 Cells

Małgorzata Zakłos-Szyda

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Antioxidants 2019, 8(8), 262; https://doi.org/10.3390/antiox8080262 - 01 Aug 2019

Cited by 41 | Viewed by 5012

Abstract

In recent years, there has been increasing interest in studying food-originated phytocompounds with beneficial influences for humans. Amongst the most active natural substances are polyphenols, for which high content has been identified in the Viburnum opulus berry, and which are unused in Western Europe. Due to its strong antioxidant activity we explored the potential of V. opulus as a preventive agent against diet-related chronic diseases, such as obesity and type 2 diabetes. Among the causes of these ailments is oxidative stress, as well as impaired glucose and free fatty acids (FFA) uptake. Thus, the purpose of this study was to determine biological activity of V. opulus phenolic extracts as cytoprotective agents able to decrease induced oxidative stress, lower lipid accumulation and attenuate glucose and FFA uptake by Caco-2 cells via GLUT2 and CD36/FAT transporters. To determine the source of the most biologically active phenolic compounds, we obtained four phenolic compounds extracts as crude juice, phenolics isolated from juice and two preparations of phenolics obtained with different extraction agents from fruit pomace. Among the studied extracts, the phenolic rich fraction obtained from fruit juice revealed the strongest activity to decrease uptake of glucose, FFA and accumulation of lipid droplets in Caco-2 cells without affecting their viability (IC₀ 50 μg/mL). Observed uptake attenuation was followed by decrease of the CD36/FAT gene expression, without influence on the GLUT2 and PPARα levels. We suspect that V. opulus phenolics were able to modulate the cellular membrane dynamic, although that hypothesis requires further, more detailed studies. Extracts revealed strong chemo-preventive activity against oxidative stress induced chemically by tert-butylhydroperoxide (t-BOOH), as well as against DNA damage through the induction of DNA repair after cell exposition to methylnitronitrosoguanidine (MNNG) and H₂O₂. Our findings suggest Viburnum opulus fruit as a dietary source of phytocompounds, which could be considered as a tailored design food supplement components for the prevention and treatment of postprandial elevation of glucose and fatty acids through delaying the rate of glucose and fatty acid absorption by intestinal cells. Full article

(This article belongs to the Special Issue Antioxidant and Cytoprotective Activity)

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Quantification of Berberine in Berberis vulgaris L. Root Extract and Its Curative and Prophylactic Role in Cisplatin-Induced In Vivo Toxicity and In Vitro Cytotoxicity

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Antioxidants 2019, 8(6), 185; https://doi.org/10.3390/antiox8060185 - 19 Jun 2019

Cited by 23 | Viewed by 4951

Abstract

Cisplatin is amongst the most potent chemotherapeutic drugs with applications in more than 50% of cancer treatments, but dose-dependent side effects limit its usefulness. Berberis vulgaris L. (B. vulgaris) has a proven role in several therapeutic applications in the traditional medicinal system. High-performance liquid chromatography was used to quantify berberine, a potent alkaloid in the methanolic root extract of B. vulgaris (BvRE). Berberine chloride in BvRE was found to be 10.29% w/w. To assess the prophylactic and curative protective effects of BvRE on cisplatin-induced nephrotoxicity, hepatotoxicity, and hyperlipidemia, in vivo toxicity trials were carried out on 25 healthy male albino Wistar rats (130–180 g). Both prophylactic and curative trials included a single dose of cisplatin (4 mg/kg, i.p.) and nine doses of BvRE (500 mg/kg/day, orally). An array of marked toxicity effects appeared in response to cisplatin dosage evident by morphological condition, biochemical analysis of serum (urea, creatinine, total protein, alanine transaminase, aspartate transaminase, total cholesterol, and triglyceride), and organ tissue homogenates (malondialdehyde and catalase). Statistically-significant (p < 0.05) variations were observed in various parameters. Moreover, histological studies of liver and kidney tissues revealed that the protective effect of BvRE effectively minimized and reversed nephrotoxic, hepatotoxic, and hyperlipidemic effects caused by cisplatin in both prophylactic and curative groups with relatively promising ameliorative effects in the prophylactic regimen. The in vitro cell viability effect of cisplatin, BvRE, and their combination was determined on HeLa cells using the tetrazolium (MTT) assay. MTT clearly corroborated that HeLa cells appeared to be less sensitive to cisplatin and berberine individually, while the combination of both at the same concentrations resulted in growth inhibition of HeLa cells in a remarkable synergistic way. The present study validated the use of BvRE as a protective agent in combination therapy with cisplatin. Full article

(This article belongs to the Special Issue Antioxidant and Cytoprotective Activity)

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Open AccessReview

Potential Cytoprotective Activity of Ozone Therapy in SARS-CoV-2/COVID-19

Gregorio Martínez-Sánchez

Adriana Schwartz

and

Vincenzo Di Donna

Antioxidants 2020, 9(5), 389; https://doi.org/10.3390/antiox9050389 - 06 May 2020

Cited by 59 | Viewed by 12775

Abstract

(1) Background: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) in China at the end of 2019 has caused a large global outbreak. Systemic ozone therapy (OT) could be potentially useful in the clinical management of several complications secondary to SARS-CoV-2. The rationale and mechanism of action has already been proven clinically in other viral infections and has been shown in research studies to be highly effective at decreasing organ damage mediated by inflammation and oxidative stress. This review summarizes the OT studies that illustrate the possible cytoprotective mechanism of action of ozone and its physiological by-products in target organs affected by SARS-CoV-2. (2) Methods: This review encompasses a total of 74 peer-reviewed original articles. It is mainly focused on ozone as a modulator of the NF-κB/Nrf2 pathways and IL-6/IL-1β expression. (3) Results: In experimental models and the few existent clinical studies, homeostasis of the free radical and antioxidant balance by OT was associated with a modulation of NF-κB/Nrf2 balance and IL-6 and IL-1β expression. These molecular mechanisms support the cytoprotective effects of OT against tissue damage present in many inflammatory diseases, including viral infections. (4) Conclusions: The potential cytoprotective role of OT in the management of organ damage induced by COVID-19 merits further research. Controlled clinical trials are needed. Full article

(This article belongs to the Special Issue Antioxidant and Cytoprotective Activity)

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Open AccessReview

A Bibliometric Review of the Keap1/Nrf2 Pathway and its Related Antioxidant Compounds

Ana Paunkov

Dionysios V. Chartoumpekis

Panos G. Ziros

and

Gerasimos P. Sykiotis

Antioxidants 2019, 8(9), 353; https://doi.org/10.3390/antiox8090353 - 01 Sep 2019

Cited by 60 | Viewed by 4851

Abstract

Nrf2 is a master transcriptional regulator of antioxidant and cytoprotective pathways. Currently in its third decade, research on Nrf2 has expanded to encompass not only basic but also clinical studies. In the present bibliometric review, we employed the VOSviewer tool to describe the existing Nrf2 literature landscape. As of July 2019, 11,931 papers on Nrf2 were listed in the “Web of Science” database, with more than 1000 new papers published each year. As expected, terms related to oxidative stress and antioxidant molecules occur very often in the Nrf2 literature throughout the years. Interestingly, there is also a gradual increase in the occurrence of terms related to diseases or to natural compounds, the most prominent being sulforaphane, curcumin, and resveratrol that modulate the Nrf2 pathway. Going beyond molecular biology/biochemistry and related fields, Nrf2 research has begun to spread into more clinical areas like endocrinology/metabolism, cardiology, and nephrology, likely reflecting an increased interest in clinical applications of Nrf2 pathway activators. China has become the most prolific producer of Nrf2 papers the last five years followed by the USA and Japan, a reverse pattern compared to the past. In conclusion, Nrf2 is the subject of a globally active research field that keeps growing and extends from bench to bedside. Full article

(This article belongs to the Special Issue Antioxidant and Cytoprotective Activity)

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Open AccessReply

Reply to a Comment Paper on the Published Paper by Canta, A. et al: “Calmangafodipir Reduces Sensory Alterations and Prevents Intraepidermal Nerve Fibers Loss in a Mouse Model of Oxaliplatin Induced Peripheral Neurotoxicity”—Antioxidants 2020, 9, 594

Virginia Rodriguez-Menendez

and

Antioxidants 2020, 9(9), 807; https://doi.org/10.3390/antiox9090807 - 01 Sep 2020

Cited by 1 | Viewed by 1115

Abstract

The comments sent by Stehr, Lundstom and Karlsson with reference to our article “Calmangafodipir reduces sensory alterations and prevents intraepidermal nerve fiber loss in a mouse model of oxaliplatin-induced peripheral neurotoxicity“ are very interesting, since they suggest possible mechanisms of action of the [...] Read more.

(This article belongs to the Special Issue Antioxidant and Cytoprotective Activity)

Open AccessComment

Comment on “Calmangafodipir Reduces Sensory Alterations and Prevents Intraepidermal Nerve Fibers Loss in a Mouse Model of Oxaliplatin Induced Peripheral Neurotoxicity” Antioxidants 2020, 9, 594

Jan Eric Stehr

Ingemar Lundström

and

Jan Olof G. Karlsson

Antioxidants 2020, 9(9), 802; https://doi.org/10.3390/antiox9090802 - 28 Aug 2020

Viewed by 1286

Abstract

We have with enthusiasm read the article “Calmangafodipir Reduces Sensory Alterations and Prevents Intraepidermal Nerve Fibers Loss in a Mouse Model of Oxaliplatin Induced Peripheral Neurotoxicity” written by Annalisa Canta, Guido Cavaletti and co-workers and published in Antioxidants [...] Full article

(This article belongs to the Special Issue Antioxidant and Cytoprotective Activity)

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