Antioxidants

17 pages, 74736 KiB

Open AccessArticle

Neuroprotective Effects of Salicin in a Gerbil Model of Transient Forebrain Ischemia by Attenuating Oxidative Stress and Activating PI3K/Akt/GSK3β Pathway

by Joon-Ha Park, Tae-Kyeong Lee, Dae-Won Kim, Hyejin Sim, Jae-Chul Lee, Jong-Dai Kim, Ji-Hyeon Ahn, Choong-Hyun Lee, Young-Myeong Kim, Moo-Ho Won and Soo-Young Choi

Antioxidants 2021, 10(4), 629; https://doi.org/10.3390/antiox10040629 - 20 Apr 2021

Cited by 12 | Viewed by 3458

Abstract

Salicin is a major natural compound of willow bark and displays diverse beneficial biological properties, such as antioxidant activity. However, little information available for the neuroprotective potential of salicin against ischemic brain injury has been reported. Thus, this study was performed to investigate [...] Read more.

Salicin is a major natural compound of willow bark and displays diverse beneficial biological properties, such as antioxidant activity. However, little information available for the neuroprotective potential of salicin against ischemic brain injury has been reported. Thus, this study was performed to investigate the neuroprotective potential of salicin against ischemia and reperfusion (IR) injury and its mechanisms in the hippocampus using a gerbil model of 5-min transient ischemia (TI) in the forebrain, in which a massive loss (death) of pyramidal neurons cells occurred in the subfield Cornu Ammonis 1 (CA1) among the hippocampal subregions (CA1-3) at 5 days after TI. To examine neuroprotection by salicin, gerbils were pretreated with salicin alone or together with LY294002, which is a phosphatidylinositol 3-kinase (PI3K) inhibitor, once daily for 3 days before TI. Treatment with 20 mg/kg of salicin significantly protected CA1 pyramidal neurons against the ischemic injury. Treatment with 20 mg/kg of salicin significantly reduced the TI-induced increase in superoxide anion generation and lipid peroxidation in the CA1 pyramidal neurons after TI. The treatment also reinstated the TI-induced decrease in superoxide dismutases (SOD1 and SOD2), catalase, and glutathione peroxidase in the CA1 pyramidal cells after TI. Moreover, salicin treatment significantly elevated the levels of phosphorylation of Akt and glycogen synthase kinase-3β (GSK3β), which is a major downstream target of PI3K, in the ischemic CA1. Notably, the neuroprotective effect of salicin was abolished by LY294002. Taken together, these findings clearly indicate that salicin protects against ischemic brain injury by attenuating oxidative stress and activating the PI3K/Akt/GSK3β pathway. Full article

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16 pages, 2574 KiB

Open AccessArticle

LC-ESI/MS-Phytochemical Profiling with Antioxidant, Antibacterial, Antifungal, Antiviral and In Silico Pharmacological Properties of Algerian Asphodelus tenuifolius (Cav.) Organic Extracts

by Ayoub Khalfaoui, Emira Noumi, Soumia Belaabed, Kaïss Aouadi, Bouslama Lamjed, Mohd Adnan, Andrea Defant, Adel Kadri, Mejdi Snoussi, Mushtaq Ahmad Khan and Ines Mancini

Antioxidants 2021, 10(4), 628; https://doi.org/10.3390/antiox10040628 - 20 Apr 2021

Cited by 18 | Viewed by 4488

Abstract

Asphodelus tenuifolius Cav. (A. tenuifolius) is a medicinal plant with a long history of traditional use to treat ailments. In this study, total phenolic and flavonoid content evaluation using LC-ESI/MS analysis and various biological activities (antioxidant, antibacterial, antifungal, antiviral and cytotoxicity) [...] Read more.

Asphodelus tenuifolius Cav. (A. tenuifolius) is a medicinal plant with a long history of traditional use to treat ailments. In this study, total phenolic and flavonoid content evaluation using LC-ESI/MS analysis and various biological activities (antioxidant, antibacterial, antifungal, antiviral and cytotoxicity) of organic extracts from the aerial parts of A. tenuifolius were analyzed. ADME tools were used to predict the potential of the identified compounds from the most potent extract as specific drugs. As shown, LC-ESI/MS results of chloroformic extract allowed the tentative identification of 12 compounds. Chloroformic extract was rich in polyphenols and flavonoids and exhibited the highest antioxidant activity given by DPPH (IC₅₀ = 25 µg/mL) as compared to the BHT standard (11.5 µg/mL) and β-carotene bleaching assays (IC₅₀ = 95.692 µg/mL). Antibacterial activity results showed that chloroformic extract has a highest activity against Gram-positive and -negative bacteria, especially against Salmonella Typhimurium DT104 (IZ = 19.3 mm, MIC = 18.75 mg/mL, MBC = 37.5 mg/mL). The MBC/MIC ratio was evaluated to interpret the activity that was bacteriostatic rather than bactericidal. Conversely, weaker antifungal activity was registered, and no antiviral activity was observed for all extracts against Herpes Simplex Virus type 2 and Coxsakievirus B-3 viruses. Cytotoxic activity on VERO cell line results revealed that butanol extract was not toxic, with CC₅₀ value of 1430 µg/mL, while chloroformic extract showed moderate cytotoxicity. Additionally, in silico studies performed proved promising pharmacokinetic and drug-likeness properties of the main compounds from the chloroformic extract. Taken together, this work highlights the potent bioactivity and acceptable drug-likeness of this plant, which supports its further preclinical development. Full article

(This article belongs to the Special Issue Antioxidant and Chemopreventive Activity of Natural Compounds)

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20 pages, 3913 KiB

Open AccessArticle

The Human 2-Cys Peroxiredoxins form Widespread, Cysteine-Dependent- and Isoform-Specific Protein-Protein Interactions

by Loes van Dam, Marc Pagès-Gallego, Paulien E. Polderman, Robert M. van Es, Boudewijn M. T. Burgering, Harmjan R. Vos and Tobias B. Dansen

Antioxidants 2021, 10(4), 627; https://doi.org/10.3390/antiox10040627 - 20 Apr 2021

Cited by 23 | Viewed by 6079

Abstract

Redox signaling is controlled by the reversible oxidation of cysteine thiols, a post-translational modification triggered by H₂O₂ acting as a second messenger. However, H₂O₂ actually reacts poorly with most cysteine thiols and it is not clear how [...] Read more.

Redox signaling is controlled by the reversible oxidation of cysteine thiols, a post-translational modification triggered by H₂O₂ acting as a second messenger. However, H₂O₂ actually reacts poorly with most cysteine thiols and it is not clear how H₂O₂ discriminates between cysteines to trigger appropriate signaling cascades in the presence of dedicated H₂O₂ scavengers like peroxiredoxins (PRDXs). It was recently suggested that peroxiredoxins act as peroxidases and facilitate H₂O₂-dependent oxidation of redox-regulated proteins via disulfide exchange reactions. It is unknown how the peroxiredoxin-based relay model achieves the selective substrate targeting required for adequate cellular signaling. Using a systematic mass-spectrometry-based approach to identify cysteine-dependent interactors of the five human 2-Cys peroxiredoxins, we show that all five human 2-Cys peroxiredoxins can form disulfide-dependent heterodimers with a large set of proteins. Each isoform displays a preference for a subset of disulfide-dependent binding partners, and we explore isoform-specific properties that might underlie this preference. We provide evidence that peroxiredoxin-based redox relays can proceed via two distinct molecular mechanisms. Altogether, our results support the theory that peroxiredoxins could play a role in providing not only reactivity but also selectivity in the transduction of peroxide signals to generate complex cellular signaling responses. Full article

(This article belongs to the Special Issue Thiol-Based Redox Regulation of Cellular and Organismal Function)

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19 pages, 2790 KiB

Open AccessArticle

Untargeted Metabolomics of Korean Fermented Brown Rice Using UHPLC Q-TOF MS/MS Reveal an Abundance of Potential Dietary Antioxidative and Stress-Reducing Compounds

by Akanksha Tyagi, Su-Jung Yeon, Eric Banan-Mwine Daliri, Xiuqin Chen, Ramachandran Chelliah and Deog-Hwan Oh

Antioxidants 2021, 10(4), 626; https://doi.org/10.3390/antiox10040626 - 19 Apr 2021

Cited by 24 | Viewed by 4240

Abstract

Free radical-induced oxidative stress is the root cause of many diseases, such as diabetes, stress and cardiovascular diseases. The objective of this research was to screen GABA levels, antioxidant activities and bioactive compounds in brown rice. In this study, we first fermented brown [...] Read more.

Free radical-induced oxidative stress is the root cause of many diseases, such as diabetes, stress and cardiovascular diseases. The objective of this research was to screen GABA levels, antioxidant activities and bioactive compounds in brown rice. In this study, we first fermented brown rice with different lactic acid bacteria (LABs), and the best LAB was selected based on the levels of GABA in the fermentate. Lactobacillus reuterii generated the highest levels of GABA after fermentation. To ascertain whether germination can improve the GABA levels of brown rice, we compared the levels of GABA in raw brown rice (Raw), germinated brown rice (Germ), fermented brown rice (Ferm) and fermented-germinated brown rice (G+F) to identify the best approach. Then, antioxidant activities were investigated for Raw BR, Germ BR, Ferm BR and G+F BR. Antioxidant activity was calculated using a 2,2-diphenyl-1-picryl hydrazile radical assay, 2,2-azino-bis-(3-ethylene benzothiozoline-6-sulfonic acid) radical assay and ferric-reducing antioxidant power. In Ferm BR, DPPH (114.40 ± 0.66), ABTS (130.52 ± 0.97) and FRAP (111.16 ± 1.83) mg Trolox equivalent 100 g, dry weight (DW), were observed as the highest among all samples. Total phenolic content (97.13 ± 0.59) and total flavonoids contents (79.62 ± 1.33) mg GAE/100 g and catechin equivalent/100 g, DW, were also found to be highest in fermented BR. Furthermore, an untargeted metabolomics approach using ultra-high-performance liquid tandem chromatography quadrupole time of flight mass spectrometry revealed the abundance of bioactive compounds in fermented BR, such as GABA, tryptophan, coumaric acid, L-ascorbic acid, linoleic acid, β-carotenol, eugenol, 6-gingerol, etc., as well as bioactive peptides which could contribute to the health-promoting properties of L. reuterii fermented brown rice. Full article

(This article belongs to the Special Issue The Potential of Dietary Antioxidants)

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19 pages, 6321 KiB

Open AccessArticle

Noise-Induced Vascular Dysfunction, Oxidative Stress, and Inflammation Are Improved by Pharmacological Modulation of the NRF2/HO-1 Axis

by Maria Teresa Bayo Jimenez, Katie Frenis, Swenja Kröller-Schön, Marin Kuntic, Paul Stamm, Miroslava Kvandová, Matthias Oelze, Huige Li, Sebastian Steven, Thomas Münzel and Andreas Daiber

Antioxidants 2021, 10(4), 625; https://doi.org/10.3390/antiox10040625 - 19 Apr 2021

Cited by 24 | Viewed by 4006

Abstract

Vascular oxidative stress, inflammation, and subsequent endothelial dysfunction are consequences of traditional cardiovascular risk factors, all of which contribute to cardiovascular disease. Environmental stressors, such as traffic noise and air pollution, may also facilitate the development and progression of cardiovascular and metabolic diseases. [...] Read more.

Vascular oxidative stress, inflammation, and subsequent endothelial dysfunction are consequences of traditional cardiovascular risk factors, all of which contribute to cardiovascular disease. Environmental stressors, such as traffic noise and air pollution, may also facilitate the development and progression of cardiovascular and metabolic diseases. In our previous studies, we investigated the influence of aircraft noise exposure on molecular mechanisms, identifying oxidative stress and inflammation as central players in mediating vascular function. The present study investigates the role of heme oxygenase-1 (HO-1) as an antioxidant response preventing vascular consequences following exposure to aircraft noise. C57BL/6J mice were treated with the HO-1 inducer hemin (25 mg/kg i.p.) or the NRF2 activator dimethyl fumarate (DMF, 20 mg/kg p.o.). During therapy, the animals were exposed to noise at a maximum sound pressure level of 85 dB(A) and a mean sound pressure level of 72 dB(A). Our data showed a marked protective effect of both treatments on animals exposed to noise for 4 days by normalization of arterial hypertension and vascular dysfunction in the noise-exposed groups. We observed a partial normalization of noise-triggered oxidative stress and inflammation by hemin and DMF therapy, which was associated with HO-1 induction. The present study identifies possible new targets for the mitigation of the adverse health effects caused by environmental noise exposure. Since natural dietary constituents can achieve HO-1 and NRF2 induction, these pathways represent promising targets for preventive measures. Full article

(This article belongs to the Special Issue Transcription Factor Nrf2)

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28 pages, 14934 KiB

Open AccessFeature PaperArticle

Natural Chain-Breaking Antioxidants and Their Synthetic Analogs as Modulators of Oxidative Stress

by Vessela D. Kancheva, Maria Antonietta Dettori, Davide Fabbri, Petko Alov, Silvia E. Angelova, Adriana K. Slavova-Kazakova, Paola Carta, Valerii A. Menshov, Olga I. Yablonskaya, Aleksei V. Trofimov, Ivanka Tsakovska and Luciano Saso

Antioxidants 2021, 10(4), 624; https://doi.org/10.3390/antiox10040624 - 19 Apr 2021

Cited by 14 | Viewed by 4234

Abstract

Oxidative stress is associated with the increased production of reactive oxygen species or with a significant decrease in the effectiveness of antioxidant enzymes and nonenzymatic defense. The penetration of oxygen and free radicals in the hydrophobic interior of biological membranes initiates radical disintegration [...] Read more.

Oxidative stress is associated with the increased production of reactive oxygen species or with a significant decrease in the effectiveness of antioxidant enzymes and nonenzymatic defense. The penetration of oxygen and free radicals in the hydrophobic interior of biological membranes initiates radical disintegration of the hydrocarbon “tails” of the lipids. This process is known as “lipid peroxidation”, and the accumulation of the oxidation products as peroxides and the aldehydes and acids derived from them are often used as a measure of oxidative stress levels. In total, 40 phenolic antioxidants were selected for a comparative study and analysis of their chain-breaking antioxidant activity, and thus as modulators of oxidative stress. This included natural and natural-like ortho-methoxy and ortho-hydroxy phenols, nine of them newly synthesized. Applied experimental and theoretical methods (bulk lipid autoxidation, chemiluminescence, in silico methods such as density functional theory (DFT) and quantitative structure–activity relationship ((Q)SAR) modeling) were used to clarify their structure–activity relationship. Kinetics of non-inhibited and inhibited lipid oxidation in close connection with inhibitor transformation under oxidative stress is considered. Special attention has been paid to chemical reactions resulting in the initiation of free radicals, a key stage of oxidative stress. Effects of substituents in the side chains and in the phenolic ring of hydroxylated phenols and biphenols, and the concentration were discussed. Full article

(This article belongs to the Special Issue Modulators of Oxidative Stress: Chemical and Pharmacological Aspects 2021)

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13 pages, 4433 KiB

Open AccessArticle

Glycerol Improves Intracerebral Hemorrhagic Brain Injury and Associated Kidney Dysfunction in Rats

by Cheng-Yi Chang, Ping-Ho Pan, Jian-Ri Li, Yen-Chuan Ou, Su-Lan Liao, Wen-Ying Chen, Yu-Hsiang Kuan and Chun-Jung Chen

Antioxidants 2021, 10(4), 623; https://doi.org/10.3390/antiox10040623 - 19 Apr 2021

Cited by 6 | Viewed by 4542

Abstract

In stroke patients, the development of acute kidney injury (AKI) is closely linked with worse outcomes and increased mortality. In this study, the interplay between post-stroke and AKI and treatment options was investigated in a rodent model of hemorrhagic stroke. Intrastriatal collagenase injection [...] Read more.

In stroke patients, the development of acute kidney injury (AKI) is closely linked with worse outcomes and increased mortality. In this study, the interplay between post-stroke and AKI and treatment options was investigated in a rodent model of hemorrhagic stroke. Intrastriatal collagenase injection for 24 h caused neurological deficits, hematoma formation, brain edema, apoptosis, blood–brain barrier disruption, oxidative stress, and neuroinflammation in Sprague Dawley rats. Elevation of serum blood urea nitrogen, serum creatinine, urine cytokine-induced neutrophil chemoattractant-1, and urine Malondialdehyde, as well as moderate histological abnormality in the kidney near the glomerulus, indicated evidence of kidney dysfunction. The accumulation of podocalyxin DNA in urine further suggested a detachment of podocytes and structural deterioration of the glomerulus. Circulating levels of stress hormones, such as epinephrine, norepinephrine, corticosterone, and angiotensin II were elevated in rats with intracerebral hemorrhage. Osmotic agent glycerol held promising effects in alleviating post-stroke brain injury and kidney dysfunction. Although the detailed protective mechanisms of glycerol have yet to be determined, the intrastriatal collagenase injection hemorrhagic stroke model in rats allowed us to demonstrate the functional and structural integrity of glomerulus are targets that are vulnerable to post-stroke injury and stress hormones could be surrogates of remote communications. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation as Targets for Novel Preventive and Therapeutic Approaches in Non Communicable Diseases II)

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19 pages, 2296 KiB

Open AccessReview

Contribution of Adipose Tissue Oxidative Stress to Obesity-Associated Diabetes Risk and Ethnic Differences: Focus on Women of African Ancestry

by Pamela A. Nono Nankam, Télesphore B. Nguelefack, Julia H. Goedecke and Matthias Blüher

Antioxidants 2021, 10(4), 622; https://doi.org/10.3390/antiox10040622 - 19 Apr 2021

Cited by 25 | Viewed by 5797

Abstract

Adipose tissue (AT) storage capacity is central in the maintenance of whole-body homeostasis, especially in obesity states. However, sustained nutrients overflow may dysregulate this function resulting in adipocytes hypertrophy, AT hypoxia, inflammation and oxidative stress. Systemic inflammation may also contribute to the disruption [...] Read more.

Adipose tissue (AT) storage capacity is central in the maintenance of whole-body homeostasis, especially in obesity states. However, sustained nutrients overflow may dysregulate this function resulting in adipocytes hypertrophy, AT hypoxia, inflammation and oxidative stress. Systemic inflammation may also contribute to the disruption of AT redox equilibrium. AT and systemic oxidative stress have been involved in the development of obesity-associated insulin resistance (IR) and type 2 diabetes (T2D) through several mechanisms. Interestingly, fat accumulation, body fat distribution and the degree of how adiposity translates into cardio-metabolic diseases differ between ethnicities. Populations of African ancestry have a higher prevalence of obesity and higher T2D risk than populations of European ancestry, mainly driven by higher rates among African women. Considering the reported ethnic-specific differences in AT distribution and function and higher levels of systemic oxidative stress markers, oxidative stress is a potential contributor to the higher susceptibility for metabolic diseases in African women. This review summarizes existing evidence supporting this hypothesis while acknowledging a lack of data on AT oxidative stress in relation to IR in Africans, and the potential influence of other ethnicity-related modulators (e.g., genetic-environment interplay, socioeconomic factors) for consideration in future studies with different ethnicities. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in Health and Diseases)

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16 pages, 1222 KiB

Open AccessArticle

Neurochemical and Cognitive Beneficial Effects of Moderate Physical Activity and Catechin in Aged Rats

by Margarita R. Ramis, Fiorella Sarubbo, David Moranta, Silvia Tejada, Jerònia Lladó, Antoni Miralles and Susana Esteban

Antioxidants 2021, 10(4), 621; https://doi.org/10.3390/antiox10040621 - 19 Apr 2021

Cited by 7 | Viewed by 2978

Abstract

A healthy aging process is a requirement for good life quality. A relationship between physical activity, the consumption of antioxidants and brain health has been stablished via the activation of pathways that reduce the harmful effects of oxidative stress, by inducing enzymes such [...] Read more.

A healthy aging process is a requirement for good life quality. A relationship between physical activity, the consumption of antioxidants and brain health has been stablished via the activation of pathways that reduce the harmful effects of oxidative stress, by inducing enzymes such as SIRT1, which is a protector of brain function. We analyzed the cognitive and neurochemical effects of applying physical exercise in elderly rats, alone or in combination with the antioxidant catechin. Several tests of spatial and episodic memory and motor coordination were evaluated. In addition, brain monoaminergic neurotransmitters and SIRT1 protein levels were assessed in the brains of the same rats. The results show that physical activity by itself improved age-related memory and learning deficits, correlating with the restoration of brain monoaminergic neurotransmitters and SIRT1 protein levels in the hippocampus. The administration of the antioxidant catechin along with the exercise program enhanced further the monoaminergic pathways, but not the other parameters studied. These results agree with previous reports revealing a neuroprotective effect of physical activity, probably based on its ability to improve the redox status of the brain, demonstrating that exercise at an advanced age, combined with the consumption of antioxidants, could produce favorable effects in terms of brain health. Full article

(This article belongs to the Special Issue Role of Natural Antioxidants in Free Radical Biology and Human Health)

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11 pages, 1153 KiB

Open AccessFeature PaperReview

Antioxidant Effects of Schisandra chinensis Fruits and Their Active Constituents

by Dalia M. Kopustinskiene and Jurga Bernatoniene

Antioxidants 2021, 10(4), 620; https://doi.org/10.3390/antiox10040620 - 18 Apr 2021

Cited by 69 | Viewed by 8645

Abstract

Schisandra chinensis Turcz. (Baill.) fruits, their extracts, and bioactive compounds are used in alternative medicine as adaptogens and ergogens protecting against numerous neurological, cardiovascular, gastrointestinal, liver, and skin disorders. S. chinensis fruit extracts and their active compounds are potent antioxidants and mitoprotectors exerting [...] Read more.

Schisandra chinensis Turcz. (Baill.) fruits, their extracts, and bioactive compounds are used in alternative medicine as adaptogens and ergogens protecting against numerous neurological, cardiovascular, gastrointestinal, liver, and skin disorders. S. chinensis fruit extracts and their active compounds are potent antioxidants and mitoprotectors exerting anti-inflammatory, antiviral, anticancer, and anti-aging effects. S. chinensis polyphenolic compounds—flavonoids, phenolic acids and the major constituents dibenzocyclooctadiene lignans are responsible for the S. chinensis antioxidant activities. This review will focus on the direct and indirect antioxidant effects of S. chinensis fruit extract and its bioactive compounds in the cells during normal and pathological conditions. Full article

(This article belongs to the Special Issue Antioxidant Activity of “Polyphenolic Food” and Human Health)

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15 pages, 6665 KiB

Open AccessArticle

Estrogen Decreases Cytoskeletal Organization by Forming an ERα/SHP2/c-Src Complex in Osteoclasts to Protect against Ovariectomy-Induced Bone Loss in Mice

by Hyun-Jung Park, Malihatosadat Gholam-Zadeh, Sun-Young Yoon, Jae-Hee Suh and Hye-Seon Choi

Antioxidants 2021, 10(4), 619; https://doi.org/10.3390/antiox10040619 - 17 Apr 2021

Cited by 9 | Viewed by 3149

Abstract

Loss of ovarian function is closely related to estrogen (E₂) deficiency, which is responsible for increased osteoclast (OC) differentiation and activity. We aimed to investigate the action mechanism of E₂ to decrease bone resorption in OCs to protect from ovariectomy [...] Read more.

Loss of ovarian function is closely related to estrogen (E₂) deficiency, which is responsible for increased osteoclast (OC) differentiation and activity. We aimed to investigate the action mechanism of E₂ to decrease bone resorption in OCs to protect from ovariectomy (OVX)-induced bone loss in mice. In vivo, tartrate-resistant acid phosphatase (TRAP) staining in femur and serum carboxy-terminal collagen crosslinks-1 (CTX-1) were analyzed upon E₂ injection after OVX in mice. In vitro, OCs were analyzed by TRAP staining, actin ring formation, carboxymethylation, determination of reactive oxygen species (ROS) level, and immunoprecipitation coupled with Western blot. In vivo and in vitro, E₂ decreased OC size more dramatically than OC number and Methyl-piperidino-pyrazole hydrate dihydrochloride (MPPD), an estrogen receptor alpha (ERα) antagonist, augmented the OC size. ERα was found in plasma membranes and E₂/ERα signaling affected receptor activator of nuclear factor κB ligand (RANKL)-induced actin ring formation by rapidly decreasing a proto-oncogene tyrosine-protein kinase, cellular sarcoma (c-Src) (Y416) phosphorylation in OCs. E₂ exposure decreased physical interactions between NADPH oxidase 1 (NOX1) and the oxidized form of c-Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), leading to higher levels of reduced SHP2. ERα formed a complex with the reduced form of SHP2 and c-Src to decrease c-Src activation upon E₂ exposure, which blocked a signal for actin ring formation by decreased Vav guanine nucleotide exchange factor 3 (Vav3) (p–Y) and Ras-related C3 botulinum toxin substrate 1 (Rac1) (GTP) activation in OCs. E₂/ERα signals consistently inhibited bone resorption in vitro. In conclusion, our study suggests that E₂-binding to ERα forms a complex with SHP2/c-Src to attenuate c-Src activation that was induced upon RANKL stimulation in a non-genomic manner, resulting in an impaired actin ring formation and reducing bone resorption. Full article

(This article belongs to the Special Issue Oxidative Stress in Osteoclasts)

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20 pages, 3361 KiB

Open AccessArticle

Differential and Overlapping Effects of Melatonin and Its Metabolites on Keratinocyte Function: Bioinformatics and Metabolic Analyses

by Joanna Stefan, Tae-Kang Kim, Fiona Schedel, Zorica Janjetovic, David K. Crossman, Kerstin Steinbrink, Radomir M. Slominski, Jaroslaw Zmijewski, Meri K. Tulic, Russel J. Reiter, Konrad Kleszczyński and Andrzej T. Slominski

Antioxidants 2021, 10(4), 618; https://doi.org/10.3390/antiox10040618 - 17 Apr 2021

Cited by 7 | Viewed by 3546

Abstract

We investigated the effects of melatonin and its selected metabolites, i.e., N¹-Acetyl-N²-formyl-5-methoxykynurenamine (AFMK) and 6-hydroxymelatonin (6(OH)Mel), on cultured human epidermal keratinocytes (HEKs) to assess their homeostatic activities with potential therapeutic implications. RNAseq analysis revealed a significant number [...] Read more.

We investigated the effects of melatonin and its selected metabolites, i.e., N¹-Acetyl-N²-formyl-5-methoxykynurenamine (AFMK) and 6-hydroxymelatonin (6(OH)Mel), on cultured human epidermal keratinocytes (HEKs) to assess their homeostatic activities with potential therapeutic implications. RNAseq analysis revealed a significant number of genes with distinct and overlapping patterns, resulting in common regulation of top diseases and disorders. Gene Set Enrichment Analysis (GSEA), Reactome FIViZ, and Ingenuity Pathway Analysis (IPA) showed overrepresentation of the p53-dependent G1 DNA damage response gene set, activation of p53 signaling, and NRF2-mediated antioxidative pathways. Additionally, GSEA exhibited an overrepresentation of circadian clock and antiaging signaling gene sets by melatonin derivatives and upregulation of extension of telomere signaling in HEKs, which was subsequently confirmed by increased telomerase activity in keratinocytes, indicating possible antiaging properties of metabolites of melatonin. Furthermore, Gene Ontology (GO) showed the activation of a keratinocyte differentiation program by melatonin, and GSEA indicated antitumor and antilipidemic potential of melatonin and its metabolites. IPA also indicated the role of Protein Kinase R (PKR) in interferon induction and antiviral response. In addition, the test compounds decreased lactate dehydrogenase A (LDHA) and lactate dehydrogenase C (LDHC) gene expression. These results were validated by qPCR and by Seahorse metabolic assay with significantly decreased glycolysis and lactate production under influence of AFMK or 6(OH)Mel in cells with a low oxygen consumption rate. In summary, melatonin and its metabolites affect keratinocytes’ functions via signaling pathways that overlap for each tested molecule with some distinctions. Full article

(This article belongs to the Special Issue Melatonin and Vitamin D in Diseases and Health)

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2 pages, 188 KiB

Open AccessEditorial

Oxidative Stress and Rare Diseases: From Molecular Crossroads to Therapeutic Avenues

by Carlos Romá-Mateo and José Luis García-Giménez

Antioxidants 2021, 10(4), 617; https://doi.org/10.3390/antiox10040617 - 16 Apr 2021

Cited by 4 | Viewed by 1961

Abstract

Writing an editorial about rare diseases can become a messy subject from the biological perspective [...] Full article

(This article belongs to the Special Issue Oxidative Stress and Rare Diseases)

16 pages, 27372 KiB

Open AccessArticle

Curcumin-Loaded Hydrophobic Surface-Modified Hydroxyapatite as an Antioxidant for Sarcopenia Prevention

by Ya-Jyun Liang, I-Hsuan Yang, Yi-Wen Lin, Jhih-Ni Lin, Chang-Chin Wu, Chih-Yung Chiang, Kun-Hung Lai and Feng-Huei Lin

Antioxidants 2021, 10(4), 616; https://doi.org/10.3390/antiox10040616 - 16 Apr 2021

Cited by 16 | Viewed by 4169

Abstract

Oxidative stress and later-induced chronic inflammation have been reported to play an important role on the progression of sarcopenia. Current treatments for sarcopenia are mainly administered to patients whom sarcopenia already developed. However, there has been no promising results shown in therapy. Therefore, [...] Read more.

Oxidative stress and later-induced chronic inflammation have been reported to play an important role on the progression of sarcopenia. Current treatments for sarcopenia are mainly administered to patients whom sarcopenia already developed. However, there has been no promising results shown in therapy. Therefore, the development of therapeutic and preventive strategies against sarcopenia would be necessary. Curcumin is a traditional medicine that possesses anti-inflammatory and antioxidative properties. In the present study, hydroxyapatite was subjected to hydrophobic surface modifications for curcumin loading (Cur-SHAP). It was, subsequently, utilized for delivery to the patient’s body via intramuscular injection in order to achieve constant release for more than 2 weeks, preventing the progression of the sarcopenia or even leading to recovery from the early stage of the illness. According to the results of WST-1, LIVE/DEAD, DCFDA, and gene expression assays, Cur-SHAP exhibited good biocompatibility and showed great antioxidant/anti-inflammatory effects through the endocytic pathway. The results of the animal studies showed that the muscle endurance, grip strength, and fat/lean mass ratio were all improved in Cur-SHAP-treated rats from LPS-induced sarcopenia. In summary, we successfully synthesized hydrophobic surface modification hydroxyapatite for curcumin loading (Cur-SHAP) and drug delivery via the IM route. The LPS-induced sarcopenia rats were able to recover from disease after the Cur-SHAP treatment. Full article

(This article belongs to the Special Issue Antioxidants and Biomaterials in Health and Nutrition)

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14 pages, 3777 KiB

Open AccessArticle

Melatonin Protects against the Side-Effects of 5-Fluorouracil on Hippocampal Neurogenesis and Ameliorates Antioxidant Activity in an Adult Rat Hippocampus and Prefrontal Cortex

by Kornrawee Suwannakot, Nataya Sritawan, Ram Prajit, Anusara Aranarochana, Apiwat Sirichoat, Wanassanun Pannangrong, Peter Wigmore and Jariya Umka Welbat

Antioxidants 2021, 10(4), 615; https://doi.org/10.3390/antiox10040615 - 16 Apr 2021

Cited by 26 | Viewed by 3459

Abstract

Melatonin is an endogenous hormone that exhibits antioxidant functions and neuroprotective effects. The hippocampus and the prefrontal cortex (PFC) play an important role linked to working memory. 5-fluorouracil (5-FU) can induce oxidative stress and reduce neurogenesis in the subgranular zone (SGZ) of the [...] Read more.

Melatonin is an endogenous hormone that exhibits antioxidant functions and neuroprotective effects. The hippocampus and the prefrontal cortex (PFC) play an important role linked to working memory. 5-fluorouracil (5-FU) can induce oxidative stress and reduce neurogenesis in the subgranular zone (SGZ) of the dentate gyrus in a rat hippocampus and these alterations are related to working memory deficits. This study aimed to determine the effect of melatonin on 5-FU-induced oxidative stress that interferes with the antioxidant enzymes and protein expression levels in a rat hippocampus and PFC. A total of 68 male Sprague Dawley rats were divided into four groups: vehicle, 5-FU, melatonin and melatonin+5-FU groups. Rats were administered 5-FU (25 mg/kg, i.v.) on days 9, 12, 15, 18 and 21 and received melatonin (8 mg/kg, i.p.) at 19:00 from day 1 to day 21 of the experiment. Lipid peroxidation was assessed by measuring malondialdehyde (MDA) levels. Antioxidant enzyme levels including glutathione peroxidase (GPX), catalase (CAT) and superoxide dismutase (SOD) were determined. p21 immunofluorescence staining and Western blotting were used to detect the cell cycle arrest and protein expression of the nuclear factor erythroid 2-related factor 2 (Nrf2), doublecortin (DCX) and brain derived neurotrophic factor (BDNF), respectively. The results showed that melatonin reduced the number of p21-positive cells in the SGZ of the dentate gyrus and increased Nrf2, DCX and BDNF protein expression in rats treated with 5-FU. Moreover, melatonin restored antioxidant enzyme levels and reduced oxidative stress in the hippocampus and PFC caused by 5-FU. These findings reveal a mechanism of the neuroprotective properties of melatonin against 5-FU in a rat hippocampus and PFC. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Disease)

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14 pages, 2205 KiB

Open AccessArticle

Catalase Modulates the Radio-Sensitization of Pancreatic Cancer Cells by Pharmacological Ascorbate

by Juan Du, Rory S. Carroll, Garett J. Steers, Brett A. Wagner, Brianne R. O’Leary, Chris S. Jensen, Garry R. Buettner and Joseph J. Cullen

Antioxidants 2021, 10(4), 614; https://doi.org/10.3390/antiox10040614 - 16 Apr 2021

Cited by 6 | Viewed by 3024

Abstract

Pancreatic cancer cells (PDACs) are more susceptible to an oxidative insult than normal cells, resulting in greater cytotoxicity upon exposure to agents that increase pro-oxidant levels. Pharmacological ascorbate (P-AscH⁻), i.e., large amounts given intravenously (IV), generates significant fluxes of hydrogen peroxide [...] Read more.

Pancreatic cancer cells (PDACs) are more susceptible to an oxidative insult than normal cells, resulting in greater cytotoxicity upon exposure to agents that increase pro-oxidant levels. Pharmacological ascorbate (P-AscH⁻), i.e., large amounts given intravenously (IV), generates significant fluxes of hydrogen peroxide (H₂O₂), resulting in the killing of PDACs but not normal cells. Recent studies have demonstrated that P-AscH⁻ radio-sensitizes PDAC but is a radioprotector to normal cells and tissues. Several mechanisms have been hypothesized to explain the dual roles of P-AscH⁻ in radiation-induced toxicity including the activation of nuclear factor-erythroid 2-related factor 2 (Nrf2), RelB, as well as changes in bioenergetic profiles. We have found that P-AscH⁻ in conjunction with radiation increases Nrf2 in both cancer cells and normal cells. Although P-AscH⁻ with radiation decreases RelB in cancer cells vs. normal cells, the knockout of RelB does not radio-sensitize PDACs. Cellular bioenergetic profiles demonstrate that P-AscH⁻ with radiation increases the ATP demand/production rate (glycolytic and oxidative phosphorylation) in both PDACs and normal cells. Knocking out catalase results in P-AscH⁻ radio-sensitization in PDACs. In a phase I trial where P-AscH⁻ was included as an adjuvant to the standard of care, short-term survivors had higher catalase levels in tumor tissue, compared to long-term survivors. These data suggest that P-AscH⁻ radio-sensitizes PDACs through increased peroxide flux. Catalase levels could be a possible indicator for how tumors will respond to P-AscH⁻. Full article

(This article belongs to the Special Issue Hydrogen Peroxide in Redox Signaling)

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13 pages, 2447 KiB

Open AccessArticle

Preventive Effects against Retinal Degeneration by Centella asiatica Extract (CA-HE50) and Asiaticoside through Apoptosis Suppression by the Nrf2/HO-1 Signaling Pathway

by Dae-Won Park, Yeong-Geun Lee, Yong-Joon Jeong, Hyelin Jeon and Se-Chan Kang

Antioxidants 2021, 10(4), 613; https://doi.org/10.3390/antiox10040613 - 16 Apr 2021

Cited by 15 | Viewed by 3551

Abstract

Age-related macular degeneration (AMD) is caused by the chronic and gradual oxidative degeneration of the retina. Unfortunately, the general purpose of current treatments is to slow AMD progression, as the retina cannot be restored to its pre-AMD condition. We aimed to identify natural [...] Read more.

Age-related macular degeneration (AMD) is caused by the chronic and gradual oxidative degeneration of the retina. Unfortunately, the general purpose of current treatments is to slow AMD progression, as the retina cannot be restored to its pre-AMD condition. We aimed to identify natural products that can be potential treatments that prevent AMD and can delay the development of late-AMD and selected Centella asiatica extract (CA-HE50), which shows excellent efficacy in cytoprotection. In animal experiments using N-methyl-N-nitrosourea (MNU), CA-HE50 dramatically increased the thickness of photoreceptors and the outer nuclear layer (ONL) and the number of nuclei in the ONL (p < 0.05). Using retinal epithelial ARPE-19 cells showed that CA-HE50 inhibited apoptosis through inhibition of the intrinsic apoptosis signaling pathway and cell cycle regulation (p < 0.05). The anti-apoptotic efficacy was confirmed to be due to activation of the Nrf2/HO-1 antioxidation pathway (p < 0.05). These results were also observed with asiaticoside, a functional substance of CA-HE50. In addition, the accumulation of oxidized-N-retinylidene-N-retinylethanolamine (A2E), which induces AMD, was inhibited by CA-HE50, resulting in increased ARPE-19 cell viability (p < 0.05). This study demonstrates that CA-HE50 is worth further research and human application tests, to develop it as a raw material for treatment or dietary supplement for the prevention of AMD. Full article

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3 pages, 185 KiB

Open AccessEditorial

Antioxidants of Natural Products

by Mee Ree Kim

Antioxidants 2021, 10(4), 612; https://doi.org/10.3390/antiox10040612 - 16 Apr 2021

Cited by 11 | Viewed by 3041

Abstract

Antioxidant ingredients are known to contribute to the beneficial effects of natural products in health promotion as well as disease prevention by reducing oxidative stress, caused by reactive oxygen or nitrogen species, in biological systems [...] Full article

(This article belongs to the Special Issue Antioxidants of Natural Product)

19 pages, 6100 KiB

Open AccessEditor’s ChoiceArticle

Nitric Oxide Regulates Plant Growth, Physiology, Antioxidant Defense, and Ion Homeostasis to Confer Salt Tolerance in the Mangrove Species, Kandelia obovata

by Mirza Hasanuzzaman, Masashi Inafuku, Kamrun Nahar, Masayuki Fujita and Hirosuke Oku

Antioxidants 2021, 10(4), 611; https://doi.org/10.3390/antiox10040611 - 16 Apr 2021

Cited by 53 | Viewed by 4097

Abstract

Facultative halophyte Kandelia obovata plants were exposed to mild (1.5% NaCl) and severe (3% NaCl) salt stress with or without sodium nitroprusside (SNP; 100 µM; a NO donor), hemoglobin (Hb, 100 µM; a NO scavenger), or Nω-nitro-L-arginine methyl ester (L-NAME, 100 µM; a [...] Read more.

Facultative halophyte Kandelia obovata plants were exposed to mild (1.5% NaCl) and severe (3% NaCl) salt stress with or without sodium nitroprusside (SNP; 100 µM; a NO donor), hemoglobin (Hb, 100 µM; a NO scavenger), or Nω-nitro-L-arginine methyl ester (L-NAME, 100 µM; a NO synthase inhibitor). The plants were significantly affected by severe salt stress. They showed decreases in seedling growth, stomatal conductance, intercellular CO₂ concentration, SPAD value, photosynthetic rate, transpiration rate, water use efficiency, and disrupted antioxidant defense systems, overproduction of reactive oxygen species, and visible oxidative damage. Salt stress also induced ion toxicity and disrupted nutrient homeostasis, as indicated by elevated leaf and root Na⁺ contents, decreased K⁺ contents, lower K⁺/Na⁺ ratios, and decreased Ca contents while increasing osmolyte (proline) levels. Treatment of salt-stressed plants with SNP increased endogenous NO levels, reduced ion toxicity, and improved nutrient homeostasis while further increasing Pro levels to maintain osmotic balance. SNP treatment also improved gas exchange parameters and enhanced antioxidant enzymes’ activities (catalase, ascorbate peroxidase, monodehydroascorbate reductase, and dehydroascorbate reductase). Treatment with Hb and l-NAME reversed these beneficial SNP effects and exacerbated salt damage, confirming that SNP promoted stress recovery and improved plant growth under salt stress. Full article

(This article belongs to the Special Issue Approaches in Enhancing Antioxidant Defense in Plants)

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12 pages, 6905 KiB

Open AccessArticle

Amino Acid Signature of Oxidative Stress in Patients with Type 2 Diabetes: Targeted Exploratory Metabolomic Research

by Cornelia G. Bala, Adriana Rusu, Dana Ciobanu, Camelia Bucsa and Gabriela Roman

Antioxidants 2021, 10(4), 610; https://doi.org/10.3390/antiox10040610 - 15 Apr 2021

Cited by 29 | Viewed by 3704

Abstract

Oxidative stress plays a key role in the development of chronic diabetes-related complications. Previous metabolomic studies showed a positive association of diabetes and insulin resistance with branched-chain amino acids (AAs) and aromatic AAs. The purpose of this research is to identify distinct metabolic [...] Read more.

Oxidative stress plays a key role in the development of chronic diabetes-related complications. Previous metabolomic studies showed a positive association of diabetes and insulin resistance with branched-chain amino acids (AAs) and aromatic AAs. The purpose of this research is to identify distinct metabolic changes associated with increased oxidative stress, as assessed by nitrotyrosine levels, in type 2 diabetes (T2DM). Serum samples of 80 patients with insulin-treated T2DM are analyzed by AA-targeted metabolomics using ultrahigh-performance liquid chromatography/mass spectrometry. Patients are divided into two groups based on their nitrotyrosine levels: the highest level of oxidative stress (Q4 nitrotyrosine) and lower levels (Q1–Q3 nitrotyrosine). The identification of biomarkers is performed in MetaboAnalyst version 5.0 using a t-test corrected for false discovery rate, unsupervised principal component analysis and supervised partial least-squares discriminant analysis (PLS-DA). Four AAs have significantly different levels between the groups for highest and lower oxidative stress. Cysteine, phenylalanine and tyrosine are substantially increased while citrulline is decreased (p-value <0.05 and variable importance in the projection [VIP] >1). Corresponding pathways that might be disrupted in patients with high oxidative stress are phenylalanine, tyrosine and tryptophan biosynthesis, arginine biosynthesis, phenylalanine metabolism, cysteine and methionine metabolism and tyrosine metabolism. Full article

(This article belongs to the Special Issue Role of Oxidative Stress in Diabetes and Complications: From Biomarkers to Therapeutic Targets)

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35 pages, 2601 KiB

Open AccessReview

Re-Evaluating the Oxidative Phenotype: Can Endurance Exercise Save the Western World?

by Filip Kolodziej and Ken D. O’Halloran

Antioxidants 2021, 10(4), 609; https://doi.org/10.3390/antiox10040609 - 15 Apr 2021

Cited by 12 | Viewed by 5461

Abstract

Mitochondria are popularly called the “powerhouses” of the cell. They promote energy metabolism through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation, which in contrast to cytosolic glycolysis are oxygen-dependent and significantly more substrate efficient. That is, mitochondrial metabolism provides substantially more cellular [...] Read more.

Mitochondria are popularly called the “powerhouses” of the cell. They promote energy metabolism through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation, which in contrast to cytosolic glycolysis are oxygen-dependent and significantly more substrate efficient. That is, mitochondrial metabolism provides substantially more cellular energy currency (ATP) per macronutrient metabolised. Enhancement of mitochondrial density and metabolism are associated with endurance training, which allows for the attainment of high relative VO₂ max values. However, the sedentary lifestyle and diet currently predominant in the Western world lead to mitochondrial dysfunction. Underdeveloped mitochondrial metabolism leads to nutrient-induced reducing pressure caused by energy surplus, as reduced nicotinamide adenine dinucleotide (NADH)-mediated high electron flow at rest leads to “electron leak” and a chronic generation of superoxide radicals (O₂⁻). Chronic overload of these reactive oxygen species (ROS) damages cell components such as DNA, cell membranes, and proteins. Counterintuitively, transiently generated ROS during exercise contributes to adaptive reduction-oxidation (REDOX) signalling through the process of cellular hormesis or “oxidative eustress” defined by Helmut Sies. However, the unaccustomed, chronic oxidative stress is central to the leading causes of mortality in the 21st century—metabolic syndrome and the associated cardiovascular comorbidities. The endurance exercise training that improves mitochondrial capacity and the protective antioxidant cellular system emerges as a universal intervention for mitochondrial dysfunction and resultant comorbidities. Furthermore, exercise might also be a solution to prevent ageing-related degenerative diseases, which are caused by impaired mitochondrial recycling. This review aims to break down the metabolic components of exercise and how they translate to athletic versus metabolically diseased phenotypes. We outline a reciprocal relationship between oxidative metabolism and inflammation, as well as hypoxia. We highlight the importance of oxidative stress for metabolic and antioxidant adaptation. We discuss the relevance of lactate as an indicator of critical exercise intensity, and inferring from its relationship with hypoxia, we suggest the most appropriate mode of exercise for the case of a lost oxidative identity in metabolically inflexible patients. Finally, we propose a reciprocal signalling model that establishes a healthy balance between the glycolytic/proliferative and oxidative/prolonged-ageing phenotypes. This model is malleable to adaptation with oxidative stress in exercise but is also susceptible to maladaptation associated with chronic oxidative stress in disease. Furthermore, mutations of components involved in the transcriptional regulatory mechanisms of mitochondrial metabolism may lead to the development of a cancerous phenotype, which progressively presents as one of the main causes of death, alongside the metabolic syndrome. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in Exercise Training and Sports)

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3 pages, 191 KiB

Open AccessEditorial

Role of Natural Antioxidants on Neuroprotection and Neuroinflammation

by Domenico Nuzzo

Antioxidants 2021, 10(4), 608; https://doi.org/10.3390/antiox10040608 - 15 Apr 2021

Cited by 13 | Viewed by 2369

Abstract

All cells continuously generate reactive oxygen species (ROS) through the respiratory chain during the energy metabolism process [...] Full article

(This article belongs to the Special Issue Role of Natural Antioxidants on Neuroprotection and Neuroinflammation)

25 pages, 3948 KiB

Open AccessArticle

Enhanced Recovery of Phenolic and Tocopherolic Compounds from Walnut (Juglans Regia L.) Male Flowers Based on Process Optimization of Ultrasonic Assisted-Extraction: Phytochemical Profile and Biological Activities

by Anca Pop, Ionel Fizeșan, Laurian Vlase, Marius Emil Rusu, Julien Cherfan, Mihai Babota, Ana-Maria Gheldiu, Ioan Tomuta and Daniela-Saveta Popa

Antioxidants 2021, 10(4), 607; https://doi.org/10.3390/antiox10040607 - 15 Apr 2021

Cited by 37 | Viewed by 3827

Abstract

The extraction of bioactive compounds present in walnut (Juglans regia L.) male flowers (WMFs) was performed based on an experimental design using ultrasonic-assisted extraction. Solvent nature, extraction time, and water content were selected as experimental variables, and phenolic, flavonoidic, and condensed tannins [...] Read more.

The extraction of bioactive compounds present in walnut (Juglans regia L.) male flowers (WMFs) was performed based on an experimental design using ultrasonic-assisted extraction. Solvent nature, extraction time, and water content were selected as experimental variables, and phenolic, flavonoidic, and condensed tannins contents and antioxidant properties were evaluated. Acetone was the solvent with the highest extraction performance, with the extracts obtained using this solvent displaying an increased concentration of bioactive compounds and increased antioxidant activities. For several extracts with high bioactive content, individual polyphenolic and tocopherolic compounds were evaluated by means of LC-MS and LC-MS/MS. The best extraction conditions for polyphenolic (2.86 mg gallic acid equivalents/g WMF) and tocopherolic compounds (29.4 µg/g WMF) were acetone with 40% water content (N20) and acetone with 20% water content (N15), respectively. Although the total tocopherol concentrations were lower than in other Juglans regia parts, most of the total tocopherol quantity was provided by the highly biologically active δ-tocopherol (84%). Significant quantities of quercetin (101.9 µg/g), hyperoside (2662.9 µg/g), quercitrin (405.7 µg/g), and isoquercitrin (1293.7 µg/g) were determined in WMF (N20). Both extracts inhibited the enzymatic activity of α-glucosidase and tyrosinase; however, an increased inhibition was observed for N20, the extract with the higher polyphenolic content. Conversely, N15 had higher anticancerous activity on the cell lines used, with a moderate selectivity towards the cancerous phenotype being observed for both extracts. At non-cytotoxic concentrations, both extracts displayed good antioxidant activities in cellular cultures, decreasing basal and H₂O₂-induced oxidative stress. This is the first characterization of both hydrophilic and lipophilic phytochemicals in WMF extracts. The outcomes of our study reveal that walnut male flowers have strong biological activities, thus justifying further research to demonstrate their usefulness in the food, pharmaceutical, and/or cosmetic industries. Full article

(This article belongs to the Special Issue Anti-Inflammatory and Antioxidant Advances on Bioactive Compounds Derived from Plants and Foods in Honor of Professor Carlo Franchini on the Occasion of His Retirement)

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18 pages, 2567 KiB

Open AccessArticle

Hyperoxidation of Peroxiredoxins and Effects on Physiology of Drosophila

by Austin McGinnis, Vladimir I. Klichko, William C. Orr and Svetlana N. Radyuk

Antioxidants 2021, 10(4), 606; https://doi.org/10.3390/antiox10040606 - 15 Apr 2021

Cited by 5 | Viewed by 2707

Abstract

The catalytic activity of peroxiredoxins (Prx) is determined by the conserved peroxidatic cysteine (Cys_P), which reacts with peroxides to form sulfenic acid (Cys-SOH). Under conditions of oxidative stress, Cys_P is oxidized to catalytically inactive sulfinic (Cys-SO₂) and sulfonic [...] Read more.

The catalytic activity of peroxiredoxins (Prx) is determined by the conserved peroxidatic cysteine (Cys_P), which reacts with peroxides to form sulfenic acid (Cys-SOH). Under conditions of oxidative stress, Cys_P is oxidized to catalytically inactive sulfinic (Cys-SO₂) and sulfonic (Cys-SO₃) forms. The Cys-SO₂ form can be reduced in a reaction catalyzed by sulfiredoxin (Srx). To explore the physiological significance of peroxiredoxin overoxidation, we investigated daily variations in the oxidation state of 2-Cys peroxiredoxins in flies of different ages, or under conditions when the pro-oxidative load is high. We found no statistically significant changes in the 2-Cys Prxs monomer:dimer ratio, which indirectly reflects changes in the Prx catalytic activity. However, we found daily variations in Prx-SO_2/3 that were more pronounced in older flies as well as in flies lacking Srx. Unexpectedly, the srx mutant flies did not exhibit a diminished survivorship under normal or oxidative stress conditions. Moreover, the srx mutant was characterized by a higher physiological activity. In conclusion, catalytically inactive forms of Prx-SO_2/3 serve not only as a marker of cellular oxidative burden, but may also play a role in an adaptive response, leading to a positive effect on the physiology of Drosophila melanogaster. Full article

(This article belongs to the Special Issue Peroxiredoxin)

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21 pages, 3331 KiB

Open AccessArticle

Plasma Treated Water Solutions in Cancer Treatments: The Contrasting Role of RNS

by Eloisa Sardella, Valeria Veronico, Roberto Gristina, Loris Grossi, Savino Cosmai, Marinella Striccoli, Maura Buttiglione, Francesco Fracassi and Pietro Favia

Antioxidants 2021, 10(4), 605; https://doi.org/10.3390/antiox10040605 - 14 Apr 2021

Cited by 31 | Viewed by 3422

Abstract

Plasma Treated Water Solutions (PTWS) recently emerged as a novel tool for the generation of Reactive Oxygen and Nitrogen Species (ROS and RNS) in liquids. The presence of ROS with a strong oxidative power, like hydrogen peroxide (H₂O₂), has [...] Read more.

Plasma Treated Water Solutions (PTWS) recently emerged as a novel tool for the generation of Reactive Oxygen and Nitrogen Species (ROS and RNS) in liquids. The presence of ROS with a strong oxidative power, like hydrogen peroxide (H₂O₂), has been proposed as the main effector for the cancer-killing properties of PTWS. A protective role has been postulated for RNS, with nitric oxide (NO) being involved in the activation of antioxidant responses and cell survival. However, recent evidences proved that NO-derivatives in proper mixtures with ROS in PTWS could enhance rather than reduce the selectivity of PTWS-induced cancer cell death through the inhibition of specific antioxidant cancer defenses. In this paper we discuss the formation of RNS in different liquids with a Dielectric Barrier Discharge (DBD), to show that NO is absent in PTWS of complex composition like plasma treated (PT)-cell culture media used for in vitro experiments, as well as its supposed protective role. Nitrite anions (NO₂^-) instead, present in our PTWS, were found to improve the selective death of Saos2 cancer cells compared to EA.hy926 cells by decreasing the cytotoxic threshold of H₂O₂ to non-toxic values for the endothelial cell line. Full article

(This article belongs to the Special Issue Paradox Role of Oxidative Stress in Cancer: State of the Art)

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17 pages, 1531 KiB

Open AccessReview

Is Premenstrual Syndrome Associated with Inflammation, Oxidative Stress and Antioxidant Status? A Systematic Review of Case–Control and Cross-Sectional Studies

by Dominika Granda, Maria Karolina Szmidt and Joanna Kaluza

Antioxidants 2021, 10(4), 604; https://doi.org/10.3390/antiox10040604 - 14 Apr 2021

Cited by 34 | Viewed by 7317

Abstract

Premenstrual syndrome (PMS) is a cyclically occurring combination of various symptoms, leading to decreased life quality among approximately 30% of women of childbearing age. PMS etiology remains unknown; however, there are some suggestions that inappropriate inflammatory response and oxidative stress are involved. This [...] Read more.

Premenstrual syndrome (PMS) is a cyclically occurring combination of various symptoms, leading to decreased life quality among approximately 30% of women of childbearing age. PMS etiology remains unknown; however, there are some suggestions that inappropriate inflammatory response and oxidative stress are involved. This study aimed to systematically review case–control and cross-sectional studies investigating inflammation markers, oxidative stress, and antioxidant status among women with PMS and controls. The study protocol was registered with PROSPERO (no. CRD42020178545), and the authors followed the guidelines for performing a systemic review recommended by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). By searching PubMed and Scopus databases (up to 8 January 2021), six case–control studies and five cross-sectional studies of medium or high quality were classified to the review. The systematic review included 652 women with PMS and 678 controls, for whom 36 eligible markers were determined. Limited evidence indicates increased levels of inflammatory parameters and suggests decreased antioxidant status in PMS women. Insufficient data with inconsistent results made it impossible to formulate a firm conclusion on the contribution of oxidative stress in PMS occurrence. To acknowledge the role of inflammation, oxidative stress, and antioxidant status in the pathophysiology of PMS, further research with case–control design and large study groups is needed. Full article

(This article belongs to the Section Health Outcomes of Antioxidants and Oxidative Stress)

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20 pages, 3928 KiB

Open AccessArticle

Melatonin Targets Metabolism in Head and Neck Cancer Cells by Regulating Mitochondrial Structure and Function

by Ana Guerra-Librero, Beatriz I. Fernandez-Gil, Javier Florido, Laura Martinez-Ruiz, César Rodríguez-Santana, Ying-Qiang Shen, José M. García-Verdugo, Alba López-Rodríguez, Iryna Rusanova, Alfredo Quiñones-Hinojosa, Darío Acuña-Castroviejo, Jordi Marruecos, Tomás De Haro and Germaine Escames

Antioxidants 2021, 10(4), 603; https://doi.org/10.3390/antiox10040603 - 14 Apr 2021

Cited by 27 | Viewed by 6063

Abstract

Metabolic reprogramming, which is characteristic of cancer cells that rapidly adapt to the hypoxic microenvironment and is crucial for tumor growth and metastasis, is recognized as one of the major mechanisms underlying therapeutic resistance. Mitochondria, which are directly involved in metabolic reprogramming, are [...] Read more.

Metabolic reprogramming, which is characteristic of cancer cells that rapidly adapt to the hypoxic microenvironment and is crucial for tumor growth and metastasis, is recognized as one of the major mechanisms underlying therapeutic resistance. Mitochondria, which are directly involved in metabolic reprogramming, are used to design novel mitochondria-targeted anticancer agents. Despite being targeted by melatonin, the functional role of mitochondria in melatonin’s oncostatic activity remains unclear. In this study, we aim to investigate the role of melatonin in mitochondrial metabolism and its functional consequences in head and neck cancer. We analyzed the effects of melatonin on head and neck squamous cell carcinoma (HNSCC) cell lines (Cal-27 and SCC-9), which were treated with 100, 500, and 1500 µM of melatonin for 1, 3, and 5 days, and found a connection between a change of metabolism following melatonin treatment and its effects on mitochondria. Our results demonstrate that melatonin induces a shift to an aerobic mitochondrial metabolism that is associated with changes in mitochondrial morphology, function, fusion, and fission in HNSCC. We found that melatonin increases oxidative phosphorylation (OXPHOS) and inhibits glycolysis in HNSCC, resulting in increased ROS production, apoptosis, and mitophagy, and decreased cell proliferation. Our findings highlight new molecular pathways involved in melatonin’s oncostatic activity, suggesting that it could act as an adjuvant agent in a potential therapy for cancer patients. We also found that high doses of melatonin, such as those used in this study for its cytotoxic impact on HNSCC cells, might lead to additional effects through melatonin receptors. Full article

(This article belongs to the Special Issue Melatonin and Related Compounds: Antioxidant and Anti-inflammatory Actions)

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16 pages, 9725 KiB

Open AccessArticle

Oxidative Stress and Inflammatory Markers in Abdominal Aortic Aneurysm

by David Sánchez-Infantes, Meritxell Nus, Miquel Navas-Madroñal, Joan Fité, Belén Pérez, Antonio J. Barros-Membrilla, Begoña Soto, José Martínez-González, Mercedes Camacho, Cristina Rodriguez, Ziad Mallat and María Galán

Antioxidants 2021, 10(4), 602; https://doi.org/10.3390/antiox10040602 - 14 Apr 2021

Cited by 44 | Viewed by 4656

Abstract

Abdominal aortic aneurysm (AAA) is increasing due to aging of the population and is a major cause of death among the elderly. Ultrasound screening programs are useful in early diagnosis, but aneurysm size is not always a good predictor of rupture. Our aim [...] Read more.

Abdominal aortic aneurysm (AAA) is increasing due to aging of the population and is a major cause of death among the elderly. Ultrasound screening programs are useful in early diagnosis, but aneurysm size is not always a good predictor of rupture. Our aim was to analyze the value of circulating molecules related to oxidative stress and inflammation as new biomarkers to assist the management of AAA. The markers were quantified by ELISA, and their expression in the aneurysmal wall was studied by real-time PCR and by immunostaining. Correlation analysis of the studied markers with aneurysm diameter and peak wall stress (PWS), obtained by finite element analysis, and multivariate regression analysis to assess potential confounding factors were performed. Our study shows an extensive inflammatory infiltration in the aneurysmal wall, mainly composed by T-cells, macrophages and B-cells and altered levels of reactive oxygen species (ROS), IgM, IgG, CD38, GDF15, S100A4 and CD36 in plasma and in the aneurysmal tissue of AAA patients compared with controls. Circulating levels of IgG, CD38 and GDF15 positively correlated with abdominal aortic diameter, and CD38 was correlated with PWS. Our data show that altered levels of IgG, CD38 and GDF15 have potential diagnostic value in the assessment of AAA. Full article

(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease and Comorbidities)

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19 pages, 1775 KiB

Open AccessReview

Factors Differentiating the Antioxidant Activity of Macular Xanthophylls in the Human Eye Retina

by Justyna Widomska, Wieslaw I. Gruszecki and Witold K. Subczynski

Antioxidants 2021, 10(4), 601; https://doi.org/10.3390/antiox10040601 - 14 Apr 2021

Cited by 18 | Viewed by 4205

Abstract

Macular xanthophylls, which are absorbed from the human diet, accumulate in high concentrations in the human retina, where they efficiently protect against oxidative stress that may lead to retinal damage. In addition, macular xanthophylls are uniquely spatially distributed in the retina. The zeaxanthin [...] Read more.

Macular xanthophylls, which are absorbed from the human diet, accumulate in high concentrations in the human retina, where they efficiently protect against oxidative stress that may lead to retinal damage. In addition, macular xanthophylls are uniquely spatially distributed in the retina. The zeaxanthin concentration (including the lutein metabolite meso-zeaxanthin) is ~9-fold greater than lutein concentration in the central fovea. These numbers do not correlate at all with the dietary intake of xanthophylls, for which there is a dietary zeaxanthin-to-lutein molar ratio of 1:12 to 1:5. The unique spatial distributions of macular xanthophylls—lutein, zeaxanthin, and meso-zeaxanthin—in the retina, which developed during evolution, maximize the protection of the retina provided by these xanthophylls. We will correlate the differences in the spatial distributions of macular xanthophylls with their different antioxidant activities in the retina. Can the major protective function of macular xanthophylls in the retina, namely antioxidant actions, explain their evolutionarily determined, unique spatial distributions? In this review, we will address this question. Full article

(This article belongs to the Special Issue Carotenoids, Oxidative Stress and Disease)

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24 pages, 1685 KiB

Open AccessReview

Therapeutic Potential and Immunomodulatory Role of Coenzyme Q₁₀ and Its Analogues in Systemic Autoimmune Diseases

by Chary López-Pedrera, José Manuel Villalba, Alejandra Mª Patiño-Trives, Maria Luque-Tévar, Nuria Barbarroja, Mª Ángeles Aguirre, Alejandro Escudero-Contreras and Carlos Pérez-Sánchez

Antioxidants 2021, 10(4), 600; https://doi.org/10.3390/antiox10040600 - 13 Apr 2021

Cited by 21 | Viewed by 7005

Abstract

Coenzyme Q₁₀ (CoQ₁₀) is a mitochondrial electron carrier and a powerful lipophilic antioxidant located in membranes and plasma lipoproteins. CoQ₁₀ is endogenously synthesized and obtained from the diet, which has raised interest in its therapeutic potential against pathologies related [...] Read more.

Coenzyme Q₁₀ (CoQ₁₀) is a mitochondrial electron carrier and a powerful lipophilic antioxidant located in membranes and plasma lipoproteins. CoQ₁₀ is endogenously synthesized and obtained from the diet, which has raised interest in its therapeutic potential against pathologies related to mitochondrial dysfunction and enhanced oxidative stress. Novel formulations of solubilized CoQ₁₀ and the stabilization of reduced CoQ₁₀ (ubiquinol) have improved its bioavailability and efficacy. Synthetic analogues with increased solubility, such as idebenone, or accumulated selectively in mitochondria, such as MitoQ, have also demonstrated promising properties. CoQ₁₀ has shown beneficial effects in autoimmune diseases. Leukocytes from antiphospholipid syndrome (APS) patients exhibit an oxidative perturbation closely related to the prothrombotic status. In vivo ubiquinol supplementation in APS modulated the overexpression of inflammatory and thrombotic risk-markers. Mitochondrial abnormalities also contribute to immune dysregulation and organ damage in systemic lupus erythematosus (SLE). Idebenone and MitoQ improved clinical and immunological features of lupus-like disease in mice. Clinical trials and experimental models have further demonstrated a therapeutic role for CoQ₁₀ in Rheumatoid Arthritis, multiple sclerosis and type 1 diabetes. This review summarizes the effects of CoQ₁₀ and its analogs in modulating processes involved in autoimmune disorders, highlighting the potential of these therapeutic approaches for patients with immune-mediated diseases. Full article

(This article belongs to the Special Issue Health Effects of Coenzyme Q10)

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Antioxidants, Volume 10, Issue 4 (April 2021) – 129 articles

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