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Modulation of Oxidative Stress: Molecular and Pharmacological Aspects

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (29 February 2020) | Viewed by 47152

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Prof. Dr. Luciano Saso

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Faculty of Pharmacy and Medicine, Sapienza University of Rome, 00185 Rome, Italy
Interests: pharmacology; therapeutic modulators of oxidative stress
Special Issues, Collections and Topics in MDPI journals

Dr. Ritushree Kukreti

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CSIR-Institute of Genomics and Integrative Biology, Delhi, India
Interests: Identification and characterization of genes involved in drug responses and functional validation for establishment of biomarkers of biomedical importance

Prof. Sibel Suzen

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Faculty of Pharmacy, University of Ankara, Ankara, Turkey
Interests: pharmaceutical chemistry; Nrf2

Special Issue Information

Dear Colleagues,

Oxidative stress is a physiological phenomenon but can also play an etiopathogenetic role in a variety of conditions, including cardiovascular diseases, neurodegenerative diseases, epilepsy, and cancer. Recently, the role of antioxidants has been significantly redefined. The hypothesis that “classical antioxidants” (radical scavengers) could always be beneficial for human health has not been confirmed by several epidemiological and clinical studies. Possible reasons of the failure of the current antioxidant therapies, including methodological pitfalls in drug development and delivery, lack of good biological markers to select the patients, etc., have been reviewed elsewhere (1, 2). We currently believe that, rather than “antioxidants”, it is more appropriate to develop “modulators of oxidative stress” such as activators or inhibitors of the nuclear erythroid-related factor 2 (Nrf2), because, depending on the condition to treat, it could be more beneficial to either reduce or increase the oxidative stress. In this Special Issue, the main aspects of the modulation of oxidative stress, with special attention to Nrf2 (3), will be examined.

1: Saso L, Firuzi O. Pharmacological applications of antioxidants: lights and shadows. Curr Drug Targets. 2014;15(13):1177-99.

2: Firuzi O, Miri R, Tavakkoli M, Saso L. Antioxidant therapy: current status and future prospects. Curr Med Chem. 2011;18(25):3871-88.

3. Sova M and Saso L. Drug Des Devel Ther. 2018 Sep 25;12:3181-3197.Design and development of Nrf2 modulators for cancer chemoprevention and therapy: a review.

Prof. Dr. Luciano Saso
Dr. Ritushree Kukreti
Prof. Sibel Suzen
Guest Editors

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Keywords

Antioxidants
Modulators of oxidative stress
Activators or inhibitors of the nuclear erythroid-related factor 2 (Nrf2)
Cancer
Epilepsy

Published Papers (10 papers)

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Research

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17 pages, 4682 KiB

Open AccessArticle

The Anti-Inflammatory and Antioxidant Effects of Sodium Propionate

by Alessia Filippone, Marika Lanza, Michela Campolo, Giovanna Casili, Irene Paterniti, Salvatore Cuzzocrea and Emanuela Esposito

Int. J. Mol. Sci. 2020, 21(8), 3026; https://doi.org/10.3390/ijms21083026 - 24 Apr 2020

Cited by 36 | Viewed by 4670

Abstract

The major end-products of dietary fiber fermentation by gut microbiota are the short-chain fatty acids (SCFAs) acetate, propionate, and butyrate, which have been shown to modulate host metabolism via effects on metabolic pathways at different tissue sites. Several studies showed the inhibitory effects of sodium propionate (SP) on nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. We carried out an in vitro model of inflammation on the J774-A1 cell line, by stimulation with lipopolysaccharide (LPS) and H₂O₂, followed by the pre-treatment with SP at 0.1, 1 mM and 10 mM. To evaluate the effect on acute inflammation and superoxide anion-induced pain, we performed a model of carrageenan (CAR)-induced rat paw inflammation and intraplantar injection of KO₂ where rats received SP orally (10, 30, and 100 mg/kg). SP decreased in concentration-dependent-manner the expression of cicloxigenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) following LPS stimulation. SP was able to enhance anti-oxidant enzyme production such as manganese superoxide dismutase (MnSOD) and heme oxygenase-1 (HO-1) following H₂O₂ stimulation. In in vivo models, SP (30 and 100 mg/kg) reduced paw inflammation and tissue damage after CAR and KO₂ injection. Our results demonstrated the anti-inflammatory and anti-oxidant properties of SP; therefore, we propose that SP may be an effective strategy for the treatment of inflammatory diseases. Full article

(This article belongs to the Special Issue Modulation of Oxidative Stress: Molecular and Pharmacological Aspects)

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13 pages, 1623 KiB

Open AccessArticle

The Protective Effect of Dabigatran and Rivaroxaban on DNA Oxidative Changes in a Model of Vascular Endothelial Damage with Oxidized Cholesterol

by Ewelina Woźniak, Marlena Broncel, Bożena Bukowska and Paulina Gorzelak-Pabiś

Int. J. Mol. Sci. 2020, 21(6), 1953; https://doi.org/10.3390/ijms21061953 - 13 Mar 2020

Cited by 20 | Viewed by 4653

Abstract

Background: Atherosclerotic plaques are unstable, and their release may result in thrombosis; therefore, currently, antiplatelet therapy with anticoagulants is recommended for the treatment of acute coronary syndrome. The aim of this study was to assess the effect of oxidized cholesterol on human umbilical vascular endothelial cells (HUVECs). The study also examines the protective and repairing effect of dabigatran and rivaroxaban in a model of vascular endothelial damage with 25-hydroxycholesterol (25-OHC). Methods: HUVECs were treated with compounds induce DNA single-strand breaks (SSBs) using the comet assay. Oxidative DNA damage was detected using endonuclease III (Nth) or human 8 oxoguanine DNA glycosylase (hOOG1). Reactive oxygen species (ROS) formation was determined using flow cytometry. Results: 25-hydroxycholesterol caused DNA SSBs, induced oxidative damage and increased ROS in the HUVECs; ROS level was lowered by dabigatran and rivaroxaban. Only dabigatran was able to completely repair the DNA SSBs induced by oxysterol. Dabigatran was able to reduce the level of oxidative damage of pyrimidines induced by oxysterol to the level of control cells. Conclusions: Observed changes strongly suggest that the tested anticoagulants induced indirect repair of DNA by inhibiting ROS production. Furthermore, dabigatran appears to have a higher antioxidant activity than rivaroxaban. Full article

(This article belongs to the Special Issue Modulation of Oxidative Stress: Molecular and Pharmacological Aspects)

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19 pages, 3840 KiB

Open AccessArticle

The Effect of Schisandra chinensis Baillon on Cross-Talk between Oxidative Stress, Endoplasmic Reticulum Stress, and Mitochondrial Signaling Pathway in Testes of Varicocele-Induced SD Rat

by Keshab Kumar Karna, Bo Ram Choi, Min-Ji Kim, Hye Kyung Kim and Jong Kwan Park

Int. J. Mol. Sci. 2019, 20(22), 5785; https://doi.org/10.3390/ijms20225785 - 17 Nov 2019

Cited by 34 | Viewed by 5536

Abstract

Schisandra chinensis Baillon (SC) has been utilized for its antioxidants and anti-inflammatory activities in a broad variety of medical applications. However; SC uses for improving fertility in males and related disorders with proper scientific validation remain obscure. The present study aimed to investigate the effects of SC on varicocele (VC)-induced testicular dysfunction and the potential molecular mechanism associated with VC-induced germ cell apoptosis. The male Sprague–Dawley rats were equally divided into four groups consisting of 10 rats in a normal control group (CTR), a control group administered SC 200 mg/kg (SC 200), a varicocele-induced control group (VC), and a varicocele-induced group administered SC 200 mg/kg (VC + SC 200). Rats were administrated 200 mg/kg SC once daily for 28 days after induction of varicocele rats and sham controls. At the end of the treatment period, body and reproductive organ weight, sperm parameters, histopathological damages, proinflammatory cytokines, apoptosis markers, biomarkers of oxidative stress, endoplasmic reticulum (ER) stress, and steroidogenic acute regulatory protein (StAR) were evaluated. The effects of SC extract on human sperm motility were also analyzed. SC treatment reduces VC-induced testicular dysfunction by significantly increasing testicular weight, sperm count and sperm motility, serum testosterone level, Johnsen score, spermatogenic cell density, testicular superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase level, and steroidogenic acute regulatory protein (StAR) level. Furthermore, the effects of SC on malondialdehyde (MDA) level, reactive oxygen species (ROS)/reactive nitrogen species (RNS) level, apoptotic index, serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, Glucose-regulated protein-78 (Grp 78), phosphorylated c-Jun-N-terminal kinase (p-JNK), phosphorylated inositol-requiring transmembrane kinase/endoribonuclease 1α (p-IRE1α), cleaved caspase 3, and Bax:Bcl2 in VC-induced rats were significantly decreased. Treatment with SC extracts also increased sperm motility in human sperm. Our findings suggest that the SC ameliorate testicular dysfunction in VC-induced rats via crosstalk between oxidative stress, ER stress, and mitochondrial-mediated testicular germ cell apoptosis signaling pathways. SC promotes spermatogenesis by upregulating abnormal sex hormones and decreasing proinflammatory cytokines (interleukin-6; TNF-α). Full article

(This article belongs to the Special Issue Modulation of Oxidative Stress: Molecular and Pharmacological Aspects)

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26 pages, 10738 KiB

Open AccessArticle

The Antioxidant and Antiproliferative Activities of 1,2,3-Triazolyl-L-Ascorbic Acid Derivatives

by Anja Harej, Andrijana Meščić Macan, Višnja Stepanić, Marko Klobučar, Krešimir Pavelić, Sandra Kraljević Pavelić and Silvana Raić-Malić

Int. J. Mol. Sci. 2019, 20(19), 4735; https://doi.org/10.3390/ijms20194735 - 24 Sep 2019

Cited by 15 | Viewed by 3180

Abstract

The novel 4-substituted 1,2,3-triazole L-ascorbic acid (L-ASA) conjugates with hydroxyethylene spacer as well as their conformationally restricted 4,5-unsaturated analogues were synthesized as potential antioxidant and antiproliferative agents. An evaluation of the antioxidant activity of novel compounds showed that the majority of the 4,5-unsaturated L-ASA derivatives showed a better antioxidant activity compared to their saturated counterparts. m-Hydroxyphenyl (7j), p-pentylphenyl (7k) and 2-hydroxyethyl (7q) substituted 4,5-unsaturated 1,2,3-triazole L-ASA derivatives exhibited very efficient and rapid (within 5 min) 2,2-diphenyl-1-picrylhydrazyl (DPPH^•) radical scavenging activity (7j, 7k: IC₅₀ = 0.06 mM; 7q: IC₅₀ = 0.07 mM). In vitro scavenging activity data were supported by in silico quantum-chemical modelling. Thermodynamic parameters for hydrogen-atom transfer and electron-transfer radical scavenging pathways of anions deprotonated at C2-OH or C3-OH groups of L-ASA fragments were calculated. The structure activity analysis (SAR) through principal component analysis indicated radical scavenging activity by the participation of OH group with favorable reaction parameters: the C3-OH group of saturated C4-C5(OH) derivatives and the C2-OH group of their unsaturated C4=C5 analogues. The antiproliferative evaluation showed that p-bromophenyl (4e: IC₅₀ = 6.72 μM) and p-pentylphenyl-substituted 1,2,3-triazole L-ASA conjugate (4k: IC₅₀ = 26.91 μM) had a selective cytotoxic effect on breast adenocarcinoma MCF-7 cells. Moreover, compound 4e did not inhibit the growth of foreskin fibroblasts (IC₅₀ > 100 μM). In MCF-7 cells treated with 4e, a significant increase of hydroxylated hypoxia-inducible transcription factor 1 alpha (HIF-1α) expression and decreased expression of nitric oxide synthase 2 (NOS2) were observed, suggesting the involvement of 4e in the HIF-1α signaling pathway for its strong growth-inhibition effect on MCF-7 cells. Full article

(This article belongs to the Special Issue Modulation of Oxidative Stress: Molecular and Pharmacological Aspects)

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16 pages, 3341 KiB

Open AccessArticle

Quinacrine-Mediated Inhibition of Nrf2 Reverses Hypoxia-Induced 5-Fluorouracil Resistance in Colorectal Cancer

by Ha Gyeong Kim, Chan Woo Kim, Don Haeng Lee, Jae-Seon Lee, Eun-Taex Oh and Heon Joo Park

Int. J. Mol. Sci. 2019, 20(18), 4366; https://doi.org/10.3390/ijms20184366 - 05 Sep 2019

Cited by 21 | Viewed by 3454

Abstract

5-Fluorouracil (5-FU) is an important chemotherapeutic agent for the systemic treatment of colorectal cancer (CRC), but its effectiveness against CRC is limited by increased 5-FU resistance caused by the hypoxic tumor microenvironment. The purpose of our study was to assess the feasibility of using quinacrine (QC) to increase the efficacy of 5-FU against CRC cells under hypoxic conditions. QC reversed the resistance to 5-FU induced by hypoxia in CRC cell lines, as determined using ATP-Glo cell viability assays and clonogenic survival assays. Treatment of cells with 5-FU under hypoxic conditions had no effect on the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a regulator of cellular resistance to oxidative stress, whereas treatment with QC alone or in combination with 5-FU reduced Nrf2 expression in all CRC cell lines tested. Overexpression of Nrf2 effectively prevented the increase in the number of DNA double-strand breaks induced by QC alone or in combination with 5-FU. siRNA-mediated c-Jun N-terminal kinase-1 (JNK1) knockdown inhibited the QC-mediated Nrf2 degradation in CRC cells under hypoxic conditions. The treatment of CRC xenografts in mice with the combination of QC and 5-FU was more effective in suppressing tumor growth than QC or 5-FU alone. QC increases the susceptibility of CRC cells to 5-FU under hypoxic conditions by enhancing JNK1-dependent Nrf2 degradation. Full article

(This article belongs to the Special Issue Modulation of Oxidative Stress: Molecular and Pharmacological Aspects)

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14 pages, 7608 KiB

Open AccessArticle

Dapagliflozin Prevents NOX- and SGLT2-Dependent Oxidative Stress in Lens Cells Exposed to Fructose-Induced Diabetes Mellitus

by Ying-Ying Chen, Tsung-Tien Wu, Chiu-Yi Ho, Tung-Chen Yeh, Gwo-Ching Sun, Ya-Hsin Kung, Tzyy-Yue Wong, Ching-Jiunn Tseng and Pei-Wen Cheng

Int. J. Mol. Sci. 2019, 20(18), 4357; https://doi.org/10.3390/ijms20184357 - 05 Sep 2019

Cited by 34 | Viewed by 5304

Abstract

Purpose: Cataracts in patients with diabetes mellitus (DM) are a major cause of blindness in developed and developing countries. This study aims to examine whether the generation of reactive oxygen species (ROS) via the increased expression of glucose transporters (GLUTs) and the receptor for advanced glycation end products (RAGE) influences the cataract development in DM. Methods: Lens epithelial cells (LECs) were isolated during cataract surgery from patients without DM or with DM, but without diabetic retinopathy. In a rat model, fructose (10% fructose, 8 or 12 weeks) with or without dapagliflozin (1.2 mg/day, 2 weeks) treatment did induce DM, as verified by blood pressure and serum parameter measurements. Immunofluorescence stainings and immunoblottings were used to quantify the protein levels. Endogenous O₂˙¯ production in the LECs was determined in vivo with dihydroethidium stainings. Results: We investigated that GLUT levels in LECs differed significantly, thus leading to the direct enhancement of RAGE-associated superoxide generation in DM patients with cataracts. Superoxide production was significantly higher in LECs from rats with fructose-induced type 2 DM, whereas treatment with the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin prevented this effect in fructose-fed rats. Protein expression levels of the sodium/glucose cotransporter 2 (SGLT2), GLUT1, GLUT5, the nicotinamide adenine dinucleotide phosphate reduced form (NADPH) oxidase subunit p67-phox, NOX2/4 and RAGE were upregulated in fructose-fed animals, whereas dapagliflozin treatment reversed these effects. Conclusions: In rats with fructose-induced DM, dapagliflozin downregulates RAGE-induced NADPH oxidase expression in LECs via the inactivation of GLUTs and a reduction in ROS generation. These novel findings suggest that the SGLT2 inhibitor dapagliflozin may be a candidate for the pharmacological prevention of cataracts in patients with DM. Full article

(This article belongs to the Special Issue Modulation of Oxidative Stress: Molecular and Pharmacological Aspects)

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17 pages, 3673 KiB

Open AccessArticle

Intermedin in Paraventricular Nucleus Attenuates Ang II-Induced Sympathoexcitation through the Inhibition of NADPH Oxidase-Dependent ROS Generation in Obese Rats with Hypertension

by Ying Kang, Lei Ding, Hangbing Dai, Fangzheng Wang, Hong Zhou, Qing Gao, Xiaoqing Xiong, Feng Zhang, Tianrun Song, Yan Yuan, Guoqing Zhu and Yebo Zhou

Int. J. Mol. Sci. 2019, 20(17), 4217; https://doi.org/10.3390/ijms20174217 - 28 Aug 2019

Cited by 26 | Viewed by 3347

Abstract

Increased reactive oxygen species (ROS) induced by angiotensin II (Ang II) in the paraventricular nucleus (PVN) play a critical role in sympathetic overdrive in hypertension (OH). Intermedin (IMD), a bioactive peptide, has extensive clinically prospects in preventing and treating cardiovascular diseases. The study was designed to test the hypothesis that IMD in the PVN can inhibit the generation of ROS caused by Ang II for attenuating sympathetic nerve activity (SNA) and blood pressure (BP) in rats with obesity-related hypertension (OH). Male Sprague-Dawley rats (160–180 g) were used to induce OH by feeding of a high-fat diet (42% kcal as fat) for 12 weeks. The dynamic changes of sympathetic outflow were evaluated as the alterations of renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to certain chemicals. The results showed that the protein expressions of Ang II type 1 receptor (AT1R), calcitonin receptor-like receptor (CRLR) and receptor activity-modifying protein 2 (RAMP2) and RAMP3 were markedly increased, but IMD was much lower in OH rats when compared to control rats. IMD itself microinjection into PVN not only lowered SNA, NADPH oxidase activity and ROS level, but also decreased Ang II-caused sympathetic overdrive, and increased NADPH oxidase activity, ROS levels and mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) activation in OH rats. However, those effects were mostly blocked by the adrenomedullin (AM) receptor antagonist AM22-52 pretreatment. The enhancement of SNA caused by Ang II can be significantly attenuated by the pretreatment of AT1R antagonist lorsatan, superoxide scavenger Tempol and NADPH oxidase inhibitor apocynin (Apo) in OH rats. ERK activation inhibitor U0126 in the PVN reversed Ang II-induced enhancement of SNA, and Apo and IMD pretreatment in the PVN decreased Ang II-induced ERK activation. Chronic IMD administration in the PVN resulted in significant reductions in basal SNA and BP in OH rats. Moreover, IMD lowered NADPH oxidase activity and ROS level in the PVN; reduced the protein expressions of AT1R and NADPH oxidase subunits NOX2 and NOX4, and ERK activation in the PVN; and decreased Ang II levels-inducing sympathetic overactivation. These results indicated that IMD via AM receptors in the PVN attenuates SNA and hypertension, and decreases Ang II-induced enhancement of SNA through the inhibition of NADPH oxidase activity and ERK activation. Full article

(This article belongs to the Special Issue Modulation of Oxidative Stress: Molecular and Pharmacological Aspects)

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Review

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21 pages, 484 KiB

Open AccessReview

Redox-Modulating Agents in the Treatment of Viral Infections

by Paola Checconi, Marta De Angelis, Maria Elena Marcocci, Alessandra Fraternale, Mauro Magnani, Anna Teresa Palamara and Lucia Nencioni

Int. J. Mol. Sci. 2020, 21(11), 4084; https://doi.org/10.3390/ijms21114084 - 08 Jun 2020

Cited by 80 | Viewed by 5001

Abstract

Viruses use cell machinery to replicate their genome and produce viral proteins. For this reason, several intracellular factors, including the redox state, might directly or indirectly affect the progression and outcome of viral infection. In physiological conditions, the redox balance between oxidant and antioxidant species is maintained by enzymatic and non-enzymatic systems, and it finely regulates several cell functions. Different viruses break this equilibrium and induce an oxidative stress that in turn facilitates specific steps of the virus lifecycle and activates an inflammatory response. In this context, many studies highlighted the importance of redox-sensitive pathways as novel cell-based targets for therapies aimed at blocking both viral replication and virus-induced inflammation. In the review, we discuss the most recent findings in this field. In particular, we describe the effects of natural or synthetic redox-modulating molecules in inhibiting DNA or RNA virus replication as well as inflammatory pathways. The importance of the antioxidant transcription factor Nrf2 is also discussed. Most of the data reported here are on influenza virus infection. We believe that this approach could be usefully applied to fight other acute respiratory viral infections characterized by a strong inflammatory response, like COVID-19. Full article

(This article belongs to the Special Issue Modulation of Oxidative Stress: Molecular and Pharmacological Aspects)

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18 pages, 3933 KiB

Open AccessReview

Oxidative Stress: Role and Response of Short Guanine Tracts at Genomic Locations

by Anju Singh, Ritushree Kukreti, Luciano Saso and Shrikant Kukreti

Int. J. Mol. Sci. 2019, 20(17), 4258; https://doi.org/10.3390/ijms20174258 - 30 Aug 2019

Cited by 46 | Viewed by 4979

Abstract

Over the decades, oxidative stress has emerged as a major concern to biological researchers. It is involved in the pathogenesis of various lifestyle-related diseases such as hypertension, diabetes, atherosclerosis, and neurodegenerative diseases. The connection between oxidative stress and telomere shortening via oxidative guanine lesion is well documented. Telomeres are confined to guanine rich ends of chromosomes. Owing to its self-association properties, it adopts G-quadruplex structures and hampers the overexpression of telomerase in the cancer cells. Guanine, being the most oxidation prone nucleobase, when structured in G-quadruplex entity, is found to respond peculiarly towards oxidative stress. Interestingly, this non-Watson–Crick structural feature exists abundantly in promoters of various oncogenes, exons and other genomic locations. The involvement of G-quadruplex architecture in oncogene promoters is well recognized in gene regulation processes. Development of small molecules aimed to target G-quadruplex structures, have found to alter the overexpression of oncogenes. The interaction may lead to the obstruction of diseased cell having elevated level of reactive oxygen species (ROS). Thus, presence of short guanine tracts (Gn) forming G-quadruplexes suggests its critical role in oxidative genome damage. Present review is a modest attempt to gain insight on the association of oxidative stress and G-quadruplexes, in various biological processes. Full article

(This article belongs to the Special Issue Modulation of Oxidative Stress: Molecular and Pharmacological Aspects)

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17 pages, 605 KiB

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Pharmacological Applications of Nrf2 Inhibitors as Potential Antineoplastic Drugs

by Pelin Telkoparan-Akillilar, Sibel Suzen and Luciano Saso

Int. J. Mol. Sci. 2019, 20(8), 2025; https://doi.org/10.3390/ijms20082025 - 24 Apr 2019

Cited by 47 | Viewed by 6113

Abstract

Oxidative stress (OS) is associated with many diseases ranging from cancer to neurodegenerative disorders. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is one of the most effective cytoprotective controller against OS. Modulation of Nrf2 pathway constitutes a remarkable strategy in the antineoplastic treatments. A big number of Nrf2-antioxidant response element activators have been screened for use as chemo-preventive drugs in OS associated diseases like cancer even though activation of Nrf2 happens in a variety of cancers. Research proved that hyperactivation of the Nrf2 pathway produces a situation that helps the survival of normal as well as malignant cells, protecting them against OS, anticancer drugs, and radiotherapy. In this review, the modulation of the Nrf2 pathway, anticancer activity and challenges associated with the development of an Nrf2-based anti-cancer treatment approaches are discussed. Full article

(This article belongs to the Special Issue Modulation of Oxidative Stress: Molecular and Pharmacological Aspects)

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