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Antioxidants
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Pharmacology of Antioxidants
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Pharmacology of Antioxidants

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Natural and Synthetic Antioxidants".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 55489

Special Issue Editors

Prof. Dr. László Dux

E-Mail Website
Guest Editor
Department of Biochemistry, Faculty of Medicine, University of Szeged, Szeged, Hungary
Interests: Adaptation of contractile tissues in health and disease, calcium regulation in muscle contraction, Factors influencing muscle regeneration in exercise and aging, prevention of tissue damage, Standardization and quality control of analytical methods in Clinical Biochemistry
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Bruno Podesser

E-Mail Website
Guest Editor
Center for Biomedical Research, Medical University of Vienna, Vienna, Austria
Interests: myocardial protection; pressure and volume overload; extracellular matrix; remodeling

Special Issue Information

Dear Colleagues,

Oxidation and reduction, basically the release and uptake of electrons, are essential phenomena in life. Our molecular systems, cellular and subcellular components are more prone to be damaged by unwanted oxidation than by reduction due to our oxidative atmosphere. This oxidative damage is even more aggravated by the generation of Reactive Oxygen and Nitrogen Species and /or by Free Oxygen Radicals. Natural and synthetic Antioxidants are known to be useful in preventing and alleviating these damages in almost all areas of medical sciences. Although generally considered advantageous, in some molecular systems, the proper functionality requires the oxidised state of certain substances, making antioxidants unnecessary, even harmful under certain conditions. A deeper understanding of the pharmacology, the molecular mechanism of natural and synthetic antioxidants may promote and help the effective application thereof in particular areas of cardiovascular diseases, during exercise and aging in skeletal and heart muscles, as well as in neurological disorders, diabetes mellitus, and cancerous processes.

The present issue aims to collect and document new findings in the pharmacology of natural and synthetic antioxidants, old and new, to promote and support their application in the most important areas of recent day’s human medicine. 

Prof. Dr. László Dux
Prof. Dr. Bruno Podesser
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Molecular action of antioxidants and natural antioxidants
  • New signaling mechanisms in ROS/RNS generation
  • Preventive application of antioxidants
  • Oxidative damage in skeletal and heart muscles
  • Oxidative stress during myocardial ischemia/reperfusion and in heart failure
  • Antioxidants in diabetes prevention and therapy
  • Antioxidants in neurological disorders
  • Aging and antioxidants
  • Oxidative stress in cancer therapy
  • Nitric oxide—a natural scavenger
  • Natural antioxidants

Published Papers (18 papers)

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24 pages, 4112 KiB  
Article
Preclinical Characterization of Antioxidant Quinolyl Nitrone QN23 as a New Candidate for the Treatment of Ischemic Stroke
by Emma Martínez-Alonso, Alejandro Escobar-Peso, Alicia Aliena-Valero, Germán Torregrosa, Mourad Chioua, Rocío Fernández-Serra, Daniel González-Nieto, Youness Ouahid, Juan B. Salom, Jaime Masjuan, José Marco-Contelles and Alberto Alcázar
Antioxidants 2022, 11(6), 1186; https://doi.org/10.3390/antiox11061186 - 16 Jun 2022
Cited by 6 | Viewed by 2327
Abstract
Nitrones are encouraging drug candidates for the treatment of oxidative stress-driven diseases such as acute ischemic stroke (AIS). In a previous study, we found a promising quinolylnitrone, QN23, which exerted a neuroprotective effect in neuronal cell cultures subjected to oxygen–glucose deprivation and in [...] Read more.
Nitrones are encouraging drug candidates for the treatment of oxidative stress-driven diseases such as acute ischemic stroke (AIS). In a previous study, we found a promising quinolylnitrone, QN23, which exerted a neuroprotective effect in neuronal cell cultures subjected to oxygen–glucose deprivation and in experimental models of cerebral ischemia. In this paper, we update the biological and pharmacological characterization of QN23. We describe the suitability of intravenous administration of QN23 to induce neuroprotection in transitory four-vessel occlusion (4VO) and middle cerebral artery occlusion (tMCAO) experimental models of brain ischemia by assessing neuronal death, apoptosis induction, and infarct area, as well as neurofunctional outcomes. QN23 significantly decreased the neuronal death and apoptosis induced by the ischemic episode in a dose-dependent manner and showed a therapeutic effect when administered up to 3 h after post-ischemic reperfusion onset, effects that remained 11 weeks after the ischemic episode. In addition, QN23 significantly reduced infarct volume, thus recovering the motor function in a tMCAO model. Remarkably, we assessed the antioxidant activity of QN23 in vivo using dihydroethidium as a molecular probe for radical species. Finally, we describe QN23 pharmacokinetic parameters. All these results pointing to QN23 as an interesting and promising preclinical candidate for the treatment of AIS. Full article
(This article belongs to the Special Issue Pharmacology of Antioxidants)
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15 pages, 2349 KiB  
Article
Hydroxytyrosol Prevents Doxorubicin-Induced Oxidative Stress and Apoptosis in Cardiomyocytes
by Ivana Sirangelo, Maria Liccardo and Clara Iannuzzi
Antioxidants 2022, 11(6), 1087; https://doi.org/10.3390/antiox11061087 - 30 May 2022
Cited by 9 | Viewed by 2310
Abstract
Doxorubicin (Dox) is a highly effective chemotherapeutic agent employed in the handling of hematological and solid tumors. The effective use of Dox in cancer therapy has been seriously limited due to its well-known cardiotoxic side effects, mainly mediated by oxidative damage. Therefore, the [...] Read more.
Doxorubicin (Dox) is a highly effective chemotherapeutic agent employed in the handling of hematological and solid tumors. The effective use of Dox in cancer therapy has been seriously limited due to its well-known cardiotoxic side effects, mainly mediated by oxidative damage. Therefore, the identification of an effective and safe antagonist against Dox-induced cardiotoxicity remains a challenge. In this respect, as plant polyphenols have attracted considerable interest due to their antioxidant properties and good safety profile, hydroxytyrosol (HT), the major phenolic compound in olive oil, could be a potential candidate due to its remarkable antioxidant and anticancer powers. In this study, the effect of HT was tested on Dox-induced cardiotoxicity by using a combination of biochemical and cellular biology techniques. Interestingly, HT was able to counteract Dox-induced cytotoxicity in cardiomyocytes by acting on the SOD2 level and the oxidative response, as well as on apoptotic mechanisms mediated by Bcl-2/Bax. At the same time, HT did not to interfere with the antitumorigenic properties of Dox in osteosarcoma cells. This study identifies new, beneficial properties for HT and suggests that it might be a promising molecule for the development of additional therapeutic approaches aimed at preventing anthracycline-related cardiotoxicity and improving long-term outcomes in antineoplastic treatments. Full article
(This article belongs to the Special Issue Pharmacology of Antioxidants)
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24 pages, 4593 KiB  
Article
The Antioxidant Activity of Thymus serpyllum Extract Protects against the Inflammatory State and Modulates Gut Dysbiosis in Diet-Induced Obesity in Mice
by Antonio Jesús Ruiz-Malagón, María Jesús Rodríguez-Sojo, Laura Hidalgo-García, José Alberto Molina-Tijeras, Federico García, Ivo Pischel, Miguel Romero, Juan Duarte, Patricia Diez-Echave, María Elena Rodríguez-Cabezas, Alba Rodríguez-Nogales and Julio Gálvez
Antioxidants 2022, 11(6), 1073; https://doi.org/10.3390/antiox11061073 - 28 May 2022
Cited by 9 | Viewed by 3077
Abstract
Nowadays, there is an increasing interest in alternative therapies in the treatment of metabolic syndrome that combine efficacy and safety profiles. Therefore, this study aimed to evaluate the effect of an extract of Thymus serpyllum, containing rosmarinic acid, on high-fat diet (HFD)-induced [...] Read more.
Nowadays, there is an increasing interest in alternative therapies in the treatment of metabolic syndrome that combine efficacy and safety profiles. Therefore, this study aimed to evaluate the effect of an extract of Thymus serpyllum, containing rosmarinic acid, on high-fat diet (HFD)-induced obesity mice, highlighting the impact of its antioxidant activity on the inflammatory status and gut dysbiosis. The extract was administered daily (50, 100 and 150 mg/kg) in HFD-fed mice. The treatment reduced body weight gain, glucose and lipid metabolic profiles. Moreover, the extract ameliorated the inflammatory status, with the c-Jun N-terminal kinases (JUNK) pathway being involved, and showed a significant antioxidant effect by the reduction of radical scavenging activity and the mitigation of lipid peroxidation. Moreover, the extract was able to modulate the altered gut microbiota, restoring microbial richness and diversity, and augmenting the counts of short-chain fatty acid producing bacteria, which have been associated with the maintenance of gut permeability and weight regulation. In conclusion, the antioxidant activity of Thymus serpyllum extract displayed a positive impact on obesity and its metabolic alterations, also reducing systemic inflammation. These effects may be mediated by modulation of the gut microbiota. Full article
(This article belongs to the Special Issue Pharmacology of Antioxidants)
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13 pages, 2143 KiB  
Article
Ultrafine Diesel Exhaust Particles Induce Apoptosis of Oligodendrocytes by Increasing Intracellular Reactive Oxygen Species through NADPH Oxidase Activation
by Ji Young Kim, Jin-Hee Kim, Yong-Dae Kim and Je Hoon Seo
Antioxidants 2022, 11(5), 1031; https://doi.org/10.3390/antiox11051031 - 23 May 2022
Cited by 6 | Viewed by 2147
Abstract
Diesel exhaust particles (DEPs) are a main contributor to air pollution. Ultrafine DEPs can cause neurodegenerative diseases by increasing intracellular reactive oxygen species (ROS). Compared with other cells in the brain, oligodendrocytes responsible for myelination are more susceptible to oxidative stress. However, the [...] Read more.
Diesel exhaust particles (DEPs) are a main contributor to air pollution. Ultrafine DEPs can cause neurodegenerative diseases by increasing intracellular reactive oxygen species (ROS). Compared with other cells in the brain, oligodendrocytes responsible for myelination are more susceptible to oxidative stress. However, the mechanisms underlying ROS generation in oligodendrocytes and the susceptibility of oligodendrocytes to ROS by ultrafine DEPs remain unclear. Herein, we examined the effects of excessive ROS generated by NOX2, an isoform of the NADPH oxidase family, after exposure to ultrafine DEPs (200 μg/mL) on the survival of two types of oligodendrocytes—oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes (mOLs)––isolated from the brain of neonatal rats. In addition, mice were exposed to ultrafine DEP suspension (20 μL, 0.4 mg/mL) via the nasal route for 1 week, after which the expression of NOX2 and cleaved caspase-3 was examined in the white matter of the cerebellum. Exposure to DEPs significantly increased NOX2 expression and ROS generation in OPCs and mOLs. OPCs and mOLs clearly exhibited viability reduction, and a significant change in p53, Bax, Bcl-2, and cleaved caspase-3 expression, after DEP exposure. In contrast, treatment with berberine (BBR), an NOX2 inhibitor, significantly mitigated these effects. In mice exposed to DEP, the presence of NOX2-positive and cleaved caspase-3-positive oligodendrocytes was demonstrated in the cerebellar white matter; NOX2 and cleaved caspase-3 expression in the cerebellum lysates was significantly increased. BBR treatment returned expression of these proteins to control levels. These results demonstrate that the susceptibility of OPCs and mOLs to ultrafine DEPs is, at least in part, caused by excessive ROS produced by NOX2 and the sequential changes in the expression of p53, Bax, Bcl-2, and cleaved caspase-3. Overall, NOX2 inhibitor enhances the survival of two types of oligodendrocytes. Full article
(This article belongs to the Special Issue Pharmacology of Antioxidants)
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16 pages, 5229 KiB  
Article
Synergistic Antiproliferation of Cisplatin and Nitrated [6,6,6]Tricycle Derivative (SK2) for a Combined Treatment of Oral Cancer Cells
by Sheng-Chieh Wang, Ching-Yu Yen, Jun-Ping Shiau, Meng-Yang Chang, Ming-Feng Hou, Jiiang-Huei Jeng, Jen-Yang Tang and Hsueh-Wei Chang
Antioxidants 2022, 11(5), 926; https://doi.org/10.3390/antiox11050926 - 8 May 2022
Cited by 4 | Viewed by 1847
Abstract
SK2, a nitrated [6,6,6]tricycle derivative with an n-butyloxy group, showed selective antiproliferation effects on oral cancer but not on normal oral cells. This investigation assessed for the first time the synergistic antiproliferation potential of cisplatin/SK2 in oral cancer cells. Cell viability assay [...] Read more.
SK2, a nitrated [6,6,6]tricycle derivative with an n-butyloxy group, showed selective antiproliferation effects on oral cancer but not on normal oral cells. This investigation assessed for the first time the synergistic antiproliferation potential of cisplatin/SK2 in oral cancer cells. Cell viability assay at 24 h showed that a low dose of combined cisplatin/SK2 (10 μM/10 μg/mL) provided more antiproliferation than cisplatin or SK2 alone. Cisplatin/SK2 triggered also more apoptosis inductions in terms of subG1 accumulation, annexin V, pancaspase, and caspase 3/8/9 measurements. Moreover, cisplatin/SK2 provided more oxidative stress and DNA damage in oral cancer cells than independent treatments. Oxidative stress inhibitors rescued the cisplatin/SK2-induced antiproliferation and oxidative stress generation. Moreover, cisplatin/SK2 induced more antiproliferation, apoptosis, oxidative stress, and DNA damage in oral cancer cells than in normal oral cells (S-G). In conclusion, low-dose cisplatin/SK2 combined treatment promoted selective and synergistic antiproliferation in oral cancer cells depending on oxidative-stress-associated responses. Full article
(This article belongs to the Special Issue Pharmacology of Antioxidants)
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21 pages, 3774 KiB  
Article
Investigating a Curcumin-Loaded PLGA-PEG-PLGA Thermo-Sensitive Hydrogel for the Prevention of Alzheimer’s Disease
by Yi-Wen Lin, Chih-Hsiang Fang, Ching-Yun Yang, Ya-Jyun Liang and Feng-Huei Lin
Antioxidants 2022, 11(4), 727; https://doi.org/10.3390/antiox11040727 - 7 Apr 2022
Cited by 14 | Viewed by 3213
Abstract
In Alzheimer’s disease (AD), the most common cause of dementia, patients generally forget to take pills or skip medication due to side effects, affecting the treatment efficacy. In this study, we combined a poly(lactic-co-glycolic acid), (PLGA)-poly(ethylene glycol), and (PEG)-PLGA thermo-sensitive hydrogel with curcumin [...] Read more.
In Alzheimer’s disease (AD), the most common cause of dementia, patients generally forget to take pills or skip medication due to side effects, affecting the treatment efficacy. In this study, we combined a poly(lactic-co-glycolic acid), (PLGA)-poly(ethylene glycol), and (PEG)-PLGA thermo-sensitive hydrogel with curcumin (PGC) to deliver an intramuscular injection that could continuously release curcumin and maintain it at a constant level in blood to prevent AD development or progression. We evaluated the drug release profile and cytotoxicity of PGC and its effects on AD pathology through in vitro and in vivo studies and on cognitive function through an aluminum-chloride-induced AD rat model. In the in vitro study, PGC exhibited a lack of cytotoxicity, excellent anti-inflammatory and antioxidant properties, and microglial modulation. In the Morris water maze test, the PGC injection-administered AD rats presented well-focused searching behavior with the shortest swimming path and longest retention times in the quadrant where the platform was initially located. Furthermore, PGC reduced amyloid-beta aggregation and deposition and significantly increased hippocampal activity. This study demonstrated that intramuscular PGC injection can effectively prevent AD development or progression in rats without inducing toxicity; therefore, this strategy could help overcome the present challenges in AD management in humans. Full article
(This article belongs to the Special Issue Pharmacology of Antioxidants)
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16 pages, 4589 KiB  
Article
Zebrafish Model-Based Assessment of Indoxyl Sulfate-Induced Oxidative Stress and Its Impact on Renal and Cardiac Development
by Paul Wei-Hua Tang, Ping-Hsun Wu, Yi-Ting Lin, Chen-Hao Chiu, Tien-Li Cheng, Wen-Hui Guan, Hugo You-Hsien Lin, Kun-Tai Lee, Yau-Hung Chen, Chien-Chih Chiu and Wangta Liu
Antioxidants 2022, 11(2), 400; https://doi.org/10.3390/antiox11020400 - 16 Feb 2022
Cited by 11 | Viewed by 3555
Abstract
Kidney disease patients may have concurrent chronic kidney disease-associated mineral bone disorder and hypertension. Cardiovascular disease (CVD) and neuropathy occur due to kidney failure-induced accumulation of uremic toxins in the body. Indoxyl sulfate (IS), a product of indole metabolism in the liver, is [...] Read more.
Kidney disease patients may have concurrent chronic kidney disease-associated mineral bone disorder and hypertension. Cardiovascular disease (CVD) and neuropathy occur due to kidney failure-induced accumulation of uremic toxins in the body. Indoxyl sulfate (IS), a product of indole metabolism in the liver, is produced from tryptophan by the intestinal flora and is ultimately excreted through the kidneys. Hemodialysis helps renal failure patients eliminate many nephrotoxins, except for IS, which leads to a poor prognosis. Although the impacts of IS on cardiac and renal development have been well documented using mouse and rat models, other model organisms, such as zebrafish, have rarely been studied. The zebrafish genome shares at least 70% similarity with the human genome; therefore, zebrafish are ideal model organisms for studying vertebrate development, including renal development. In this study, we aimed to investigate the impact of IS on the development of zebrafish embryos, especially cardiac and renal development. At 24 h postfertilization (hpf), zebrafish were exposed to IS at concentrations ranging from 2.5 to 10 mM. IS reduced survival and the hatching rate, caused cardiac edema, increased mortality, and shortened the body length of zebrafish embryos. In addition, IS decreased heart rates and renal function. IS affected zebrafish development via the ROS and MAPK pathways, which subsequently led to inflammation in the embryos. The results suggest that IS interferes with cardiac and renal development in zebrafish embryos, providing new evidence about the toxicity of IS to aquatic organisms and new insights for the assessment of human health risks. Accordingly, we suggest that zebrafish studies can ideally complement mouse model studies to allow the simultaneous and comprehensive investigation of the physiological impacts of uremic endotheliotoxins, such as IS, on cardiac and renal development. Full article
(This article belongs to the Special Issue Pharmacology of Antioxidants)
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16 pages, 4156 KiB  
Article
Therapeutic Potential of Perillaldehyde in Ameliorating Vulvovaginal Candidiasis by Reducing Vaginal Oxidative Stress and Apoptosis
by Lei Chen, Fei Wang, Su Qu, Xiaona He, Yongxin Zhu, Yi Zhou, Kunlong Yang, Yong-Xin Li, Man Liu, Xue Peng and Jun Tian
Antioxidants 2022, 11(2), 178; https://doi.org/10.3390/antiox11020178 - 18 Jan 2022
Cited by 11 | Viewed by 2423
Abstract
Vulvovaginal candidiasis (VVC) is one of the most frequent diseases induced by Candida albicans (C. albicans) during pregnancy, which results in enormous pain to women and their partners in daily life. Perillaldehyde (PAE), a natural monoterpenoid, has significant anti-microbial, anti-inflammatory and [...] Read more.
Vulvovaginal candidiasis (VVC) is one of the most frequent diseases induced by Candida albicans (C. albicans) during pregnancy, which results in enormous pain to women and their partners in daily life. Perillaldehyde (PAE), a natural monoterpenoid, has significant anti-microbial, anti-inflammatory and anti-oxidation effects. Reactive oxygen species (ROS) are key factors for the host to resist the invasion of fungi. However, excess ROS can cause additional damage independent of the pathogen itself, and the mechanism of ROS in VVC has not been investigated. In this murine study, we revealed that C. albicans infection increased the expression of NADPH oxidase 2 (NOX2) and the content of malonaldehyde (MDA). C. albicans inhibited the activity of antioxidant enzymes in the vagina, including superoxide dismutase (SOD), Catalase (CAT), glutathione peroxidase (GSH-PX) and heme oxygenase (HO-1), which were returned to normal levels after treatment with PAE. Furthermore, PAE inhibited the activities of Keap1 and promoted Nrf2 transfer from cytoplasm to nucleus, which were mediated by excessive accumulation of ROS in the VVC mice. In this study, we also indicated that PAE inhibited the apoptosis of vagina cells via Caspase 9- Caspase 7-PARP pathway and prevented the release of IL-1ꞵ in VVC mice. In summary, this study revealed that the treatment of VVC in mice with PAE might be mediated by inhibition of ROS, and established the therapeutic potential of PAE as an antifungal agent for the treatment of VVC. Full article
(This article belongs to the Special Issue Pharmacology of Antioxidants)
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16 pages, 4592 KiB  
Article
Obacunone Retards Renal Cyst Development in Autosomal Dominant Polycystic Kidney Disease by Activating NRF2
by Zhiwei Qiu, Jinzhao He, Guangying Shao, Jiaqi Hu, Xiaowei Li, Hong Zhou, Min Li and Baoxue Yang
Antioxidants 2022, 11(1), 38; https://doi.org/10.3390/antiox11010038 - 24 Dec 2021
Cited by 5 | Viewed by 5500
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disease characterized by progressive enlargement of fluid-filled cysts derived from renal tubular epithelial cells, which has become the fourth leading cause of end-stage renal diseases. Currently, treatment options for ADPKD remain limited. The [...] Read more.
Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disease characterized by progressive enlargement of fluid-filled cysts derived from renal tubular epithelial cells, which has become the fourth leading cause of end-stage renal diseases. Currently, treatment options for ADPKD remain limited. The purpose of this study was to discover an effective therapeutic drug for ADPKD. With virtual screening, Madin-Darby canine kidney (MDCK) cyst model, embryonic kidney cyst model and kidney-specific Pkd1 knockout mouse (PKD) model, we identified obacunone as a candidate compound for ADPKD drug discovery from a natural antioxidant compound library. In vitro experiments showed that obacunone significantly inhibited cyst formation and expansion of MDCK cysts and embryonic kidney cysts in a dose-dependent manner. In vivo, obacunone treatment significantly reduced the renal cyst development in PKD mice. Western blot and morphological analysis revealed that obacunone served as a NRF2 activator in ADPKD, which suppressed lipid peroxidation by up-regulating GPX4 and finally restrained excessive cell proliferation by down-regulating mTOR and MAPK signaling pathways. Experimental data demonstrated obacunone as an effective renal cyst inhibitor for ADPKD, indicating that obacunone might be developed into a therapeutic drug for ADPKD treatment. Full article
(This article belongs to the Special Issue Pharmacology of Antioxidants)
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13 pages, 2165 KiB  
Article
Long-Term PDE-5A Inhibition Improves Myofilament Function in Left and Right Ventricular Cardiomyocytes through Partially Different Mechanisms in Diabetic Rat Hearts
by Beáta Bódi, Árpád Kovács, Hajnalka Gulyás, Lilla Mártha, Attila Tóth, Csaba Mátyás, Bálint András Barta, Attila Oláh, Béla Merkely, Tamás Radovits and Zoltán Papp
Antioxidants 2021, 10(11), 1776; https://doi.org/10.3390/antiox10111776 - 6 Nov 2021
Cited by 2 | Viewed by 2007
Abstract
Heart failure with preserved ejection fraction (HFpEF) and right ventricular (RV) dysfunction are frequent complications of diabetic cardiomyopathy. Here we aimed to characterize RV and left ventricular (LV) remodeling and its prevention by vardenafil (a long-acting phosphodiesterase-5A (PDE-5A) inhibitor) administration in a diabetic [...] Read more.
Heart failure with preserved ejection fraction (HFpEF) and right ventricular (RV) dysfunction are frequent complications of diabetic cardiomyopathy. Here we aimed to characterize RV and left ventricular (LV) remodeling and its prevention by vardenafil (a long-acting phosphodiesterase-5A (PDE-5A) inhibitor) administration in a diabetic HFpEF model. Zucker Diabetic Fatty (ZDF) and control, ZDF Lean (Lean) male rats received 10 mg/kg vardenafil (ZDF + Vard; Lean + Vard) per os, on a daily basis for a period of 25 weeks. In vitro force measurements, biochemical and histochemical assays were employed to assess cardiomyocyte function and signaling. Vardenafil treatment increased cyclic guanosine monophosphate (cGMP) levels and decreased 3-nitrotyrosine (3-NT) levels in the left and right ventricles of ZDF animals, but not in Lean animals. Cardiomyocyte passive tension (Fpassive) was higher in LV and RV cardiomyocytes of ZDF rats than in those receiving preventive vardenafil treatment. Levels of overall titin phosphorylation did not differ in the four experimental groups. Maximal Ca2+-activated force (Fmax) of LV and RV cardiomyocytes were preserved in ZDF animals. Ca2+-sensitivity of isometric force production (pCa50) was significantly higher in LV (but not in RV) cardiomyocytes of ZDF rats than in their counterparts in the Lean or Lean + Vard groups. In accordance, the phosphorylation levels of cardiac troponin I (cTnI) and myosin binding protein-C (cMyBP-C) were lower in LV (but not in RV) cardiomyocytes of ZDF animals than in their counterparts of the Lean or Lean + Vard groups. Vardenafil treatment normalized pCa50 values in LV cardiomyocytes, and it decreased pCa50 below control levels in RV cardiomyocytes in the ZDF + Vard group. Our data illustrate partially overlapping myofilament protein alterations for LV and RV cardiomyocytes in diabetic rat hearts upon long-term PDE-5A inhibition. While uniform patterns in cGMP, 3-NT and Fpassive levels predict identical effects of vardenafil therapy for the diastolic function in both ventricles, the uneven cTnI, cMyBP-C phosphorylation levels and pCa50 values implicate different responses for the systolic function. Full article
(This article belongs to the Special Issue Pharmacology of Antioxidants)
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17 pages, 2737 KiB  
Article
Two Benzene Rings with a Boron Atom Comprise the Core Structure of 2-APB Responsible for the Anti-Oxidative and Protective Effect on the Ischemia/Reperfusion-Induced Rat Heart Injury
by Yan-Cheng Shen, Yan-Jhih Shen, Wen-Sen Lee, Michael Yu-Chih Chen, Wei-Chia Tu and Kun-Ta Yang
Antioxidants 2021, 10(11), 1667; https://doi.org/10.3390/antiox10111667 - 22 Oct 2021
Cited by 3 | Viewed by 1819
Abstract
To identify the core structure of 2-aminoethoxydiphenyl borate (2-APB) responsible for the anti-oxidative and protective effect on the ischemia/reperfusion (I/R)-induced heart injury, various 2-APB analogues were analyzed, and several antioxidant assays were performed. Cell viability was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Myocardial [...] Read more.
To identify the core structure of 2-aminoethoxydiphenyl borate (2-APB) responsible for the anti-oxidative and protective effect on the ischemia/reperfusion (I/R)-induced heart injury, various 2-APB analogues were analyzed, and several antioxidant assays were performed. Cell viability was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Myocardial infarct size was quantified using triphenyl tetrazolium chloride (TTC) staining. The levels of tumor necrosis factor-alpha (TNF-α) and cleaved-caspase-3 protein were evaluated as an indicator for the anti-inflammatory and anti-apoptotic effect, respectively. Our data show that 2-APB, diphenylborinic anhydride (DPBA) and 3-(diphenylphosphino)-1-propylamine (DP3A) all exerted the anti-oxidative activity, but only 2-APB and DPBA can scavenge H2O2. 2-APB and DPBA can potently inhibit hydrogen peroxide (H2O2)- and hypoxanthine/xanthine oxidase (HX/XOD)-induced increases in intracellular H2O2 and H9c2 cell death. 2-APB and DPBA were able to decrease the I/R-induced adult rat cardiomyocytes death, myocardial infarct size, and the levels of malondialdehyde (MDA) and creatine kinase-MB (CK-MB). Our results suggest that the two benzene rings with a boron atom comprise the core structure of 2-APB responsible for the anti-oxidative effect mediated through the reaction with H2O2 and generation of phenolic compounds, which in turn reduced the I/R-induced oxidative stress and injury in the rat heart. Full article
(This article belongs to the Special Issue Pharmacology of Antioxidants)
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21 pages, 2679 KiB  
Article
Assessing the Potential of Nutraceuticals as Geroprotectors on Muscle Performance and Cognition in Aging Mice
by Zoltán Singlár, Péter Szentesi, János Fodor, Ágnes Angyal, László Csernoch and Mónika Sztretye
Antioxidants 2021, 10(9), 1415; https://doi.org/10.3390/antiox10091415 - 4 Sep 2021
Cited by 1 | Viewed by 2849
Abstract
Aging and frailty are associated with a decline in muscle force generation, which is a direct consequence of reduced muscle quantity and quality. Among the leading contributors to aging is the generation of reactive oxygen species, the byproducts of terminal oxidation. Their negative [...] Read more.
Aging and frailty are associated with a decline in muscle force generation, which is a direct consequence of reduced muscle quantity and quality. Among the leading contributors to aging is the generation of reactive oxygen species, the byproducts of terminal oxidation. Their negative effects can be moderated via antioxidant supplementation. Krill oil and astaxanthin (AX) are nutraceuticals with a variety of health promoting, geroprotective, anti-inflammatory, anti-diabetic and anti-fatigue effects. In this work, we examined the functional effects of these two nutraceutical agents supplemented via pelleted chow in aging mice by examining in vivo and in vitro skeletal muscle function, along with aspects of intracellular and mitochondrial calcium homeostasis, as well as cognition and spatial memory. AX diet regimen limited weight gain compared to the control group; however, this phenomenon was not accompanied by muscle tissue mass decline. On the other hand, both AX and krill oil supplementation increased force production without altering calcium homeostasis during excitation-contraction coupling mechanism or mitochondrial calcium uptake processes. We also provide evidence of improved spatial memory and learning ability in aging mice because of krill oil supplementation. Taken together, our data favors the application of antioxidant nutraceuticals as geroprotectors to improve cognition and healthy aging by virtue of improved skeletal muscle force production. Full article
(This article belongs to the Special Issue Pharmacology of Antioxidants)
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14 pages, 4210 KiB  
Article
Necrostatin-1 Prevents Ferroptosis in a RIPK1- and IDO-Independent Manner in Hepatocellular Carcinoma
by Hanna Yuk, Md Abdullah, Do-Hyung Kim, Haeseung Lee and Seung-Jin Lee
Antioxidants 2021, 10(9), 1347; https://doi.org/10.3390/antiox10091347 - 25 Aug 2021
Cited by 25 | Viewed by 5690
Abstract
Ferroptosis is caused by the iron-mediated accumulation of lipid peroxidation, which is distinct from apoptosis and necroptosis. Necrostatin-1 inhibits receptor-interacting serine/threonine-protein kinase 1 (RIPK1) to initiate necroptosis; it also inhibits indoleamine 2,3-dioxygenase (IDO) to regulate tumor immunity. However, few studies have examined the [...] Read more.
Ferroptosis is caused by the iron-mediated accumulation of lipid peroxidation, which is distinct from apoptosis and necroptosis. Necrostatin-1 inhibits receptor-interacting serine/threonine-protein kinase 1 (RIPK1) to initiate necroptosis; it also inhibits indoleamine 2,3-dioxygenase (IDO) to regulate tumor immunity. However, few studies have examined the off-target effect of necrostatin-1 on the ferroptosis pathway. The present study examined whether necrostatin-1 could interrupt ferroptosis induced by system xc- inhibitors (sulfasalazine and erastin) and a glutathione peroxidase 4 inhibitor (RSL3) in Huh7 and SK-HEP-1 cells. Necrostatin-1 completely prevented decreases in cell viability induced by sulfasalazine and erastin; it partially blunted decreases in cell viability induced by RSL3. Necrostatin-1, ferrostatin-1, and deferoxamine repressed sulfasalazine-provoked membrane permeabilization, as detected by 7-aminoactinomycin D staining and lipid peroxidation measured using a C11-BODIPY probe. However, other RIPK1 inhibitors (necrostatin-1s and GSK2982772) and an IDO inhibitor (1-methyl-D-tryptophan) did not recover the decrease in cell viability induced by sulfasalazine. Necrostatin-1 potentiated sulfasalazine-induced expression of xCT, a catalytic subunit of system xc- in these cells. These results demonstrated that necrostatin-1 blocked ferroptosis through a mechanism independent from RIPK1 and IDO inhibition in Huh7 and SK-HEP-1 cells, indicating that its antioxidant activity should be considered when using necrostatin-1 as a RIPK1 inhibitor. Full article
(This article belongs to the Special Issue Pharmacology of Antioxidants)
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14 pages, 5193 KiB  
Article
Left Ventricular SGLT1 Protein Expression Correlates with the Extent of Myocardial Nitro-Oxidative Stress in Rats with Pressure and Volume Overload-Induced Heart Failure
by Alex Ali Sayour, Mihály Ruppert, Attila Oláh, Kálmán Benke, Bálint András Barta, Eszter Zsáry, Haoran Ke, Eszter Mária Horváth, Béla Merkely and Tamás Radovits
Antioxidants 2021, 10(8), 1190; https://doi.org/10.3390/antiox10081190 - 26 Jul 2021
Cited by 5 | Viewed by 2142
Abstract
Myocardial sodium-glucose cotransporter 1 (SGLT1) has been shown to be upregulated in humans with heart failure (HF) with or without diabetes. In vitro studies have linked SGLT1 to increased nitro-oxidative stress in cardiomyocytes. We aimed to assess the relation between left ventricular (LV) [...] Read more.
Myocardial sodium-glucose cotransporter 1 (SGLT1) has been shown to be upregulated in humans with heart failure (HF) with or without diabetes. In vitro studies have linked SGLT1 to increased nitro-oxidative stress in cardiomyocytes. We aimed to assess the relation between left ventricular (LV) SGLT1 expression and the extent of nitro-oxidative stress in two non-diabetic rat models of chronic heart failure (HF) evoked by either pressure (TAC, n = 12) or volume overload (ACF, n = 12). Sham-operated animals (Sham-T and Sham-A, both n = 12) served as controls. Both TAC and ACF induced characteristic LV structural and functional remodeling. Western blotting revealed that LV SGLT1 protein expression was significantly upregulated in both HF models (both p < 0.01), whereas the phosphorylation of ERK1/2 was decreased only in ACF; AMPKα activity was significantly reduced in both models. The protein expression of the Nox4 NADPH oxidase isoform was increased in both TAC and ACF compared with respective controls (both p < 0.01), showing a strong positive correlation with SGLT1 expression (r = 0.855, p < 0.001; and r = 0.798, p = 0.001, respectively). Furthermore, SGLT1 protein expression positively correlated with the extent of myocardial nitro-oxidative stress in failing hearts assessed by 3-nitrotyrosin (r = 0.818, p = 0.006) and 4-hydroxy-2-nonenal (r = 0.733, p = 0.020) immunostaining. Therefore, LV SGLT1 protein expression was upregulated irrespective of the nature of chronic hemodynamic overload, and correlated significantly with the expression of Nox4 and with the level of myocardial nitro-oxidative stress, suggesting a pathophysiological role of SGLT1 in HF. Full article
(This article belongs to the Special Issue Pharmacology of Antioxidants)
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16 pages, 6288 KiB  
Article
Balanced Intense Exercise Training Induces Atrial Oxidative Stress Counterbalanced by the Antioxidant System and Atrial Hypertrophy That Is Not Associated with Pathological Remodeling or Arrhythmogenicity
by Attila Oláh, Bálint András Barta, Alex Ali Sayour, Mihály Ruppert, Eszter Virág-Tulassay, Julianna Novák, Zoltán V. Varga, Péter Ferdinandy, Béla Merkely and Tamás Radovits
Antioxidants 2021, 10(3), 452; https://doi.org/10.3390/antiox10030452 - 15 Mar 2021
Cited by 6 | Viewed by 2371
Abstract
Although regular exercise training is associated with cardiovascular benefits, the increased risk of atrial arrhythmias has been observed after vigorous exercise and has been related to oxidative stress. We aimed at investigating exercise-induced atrial remodeling in a rat model of an athlete’s heart [...] Read more.
Although regular exercise training is associated with cardiovascular benefits, the increased risk of atrial arrhythmias has been observed after vigorous exercise and has been related to oxidative stress. We aimed at investigating exercise-induced atrial remodeling in a rat model of an athlete’s heart and determining sex-specific differences. Age-matched young adult rats were divided into female exercised, female control, male exercised, and male control groups. After exercised animals completed a 12-week-long swim training protocol, echocardiography and in vivo cardiac electrophysiologic investigation were performed. Additionally, atrial histological and gene expression analyses were carried out. Post-mortem atrial weight data and histological examination confirmed marked atrial hypertrophy. We found increased atrial gene expression of antioxidant enzymes along with increased nitro-oxidative stress. No gene expression alteration was found regarding markers of pathological remodeling, apoptotic, proinflammatoric, and profibrotic processes. Exercise training was associated with a prolonged right atrial effective refractory period. We could not induce arrhythmias by programmed stimulation in any groups. We found decreased expression of potassium channels. Female gender was associated with lower profibrotic expression and collagen density. Long-term, balanced exercise training-induced atrial hypertrophy is not associated with harmful electrical remodeling, and no inflammatory or profibrotic response was observed in the atrium of exercised rats. Full article
(This article belongs to the Special Issue Pharmacology of Antioxidants)
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16 pages, 2233 KiB  
Article
Preventive Effects of Anthraquinones Isolated from an Endophytic Fungus, Colletotrichum sp. JS-0367 in Tumor Necrosis Factor-α-Stimulated Damage of Human Dermal Fibroblasts
by Sullim Lee, Quynh Nhu Nguyen, Hung Manh Phung, Sang Hee Shim, Daeyoung Kim, Gwi Seo Hwang and Ki Sung Kang
Antioxidants 2021, 10(2), 200; https://doi.org/10.3390/antiox10020200 - 30 Jan 2021
Cited by 6 | Viewed by 2725
Abstract
Reactive oxygen species (ROS) are a major causative factor of inflammatory responses and extracellular matrix degradation. ROS also cause skin aging and diverse cutaneous lesions. Therefore, antioxidants that inhibit the generation of ROS may be beneficial in the relief of skin aging and [...] Read more.
Reactive oxygen species (ROS) are a major causative factor of inflammatory responses and extracellular matrix degradation. ROS also cause skin aging and diverse cutaneous lesions. Therefore, antioxidants that inhibit the generation of ROS may be beneficial in the relief of skin aging and diseases. We investigated the anti-skin aging effect of anthraquinones from cultures of Colletotrichum sp., an endophytic fungus isolated from Morus alba L. using human dermal fibroblasts (HDFs). We preferentially evaluated the preventive effects of anti-oxidative anthraquinones (1, 4) against the generation of ROS, nitric oxide (NO), and prostaglandins-E2 (PGE2). Among them, 1,3-dihydroxy-2,8-dimethoxy-6-methylanthraquinone (1) suppressed the generation of ROS, NO, and PGE2 in tumor necrosis factor-alpha (TNF-α)-stimulated HDFs. Compound 1 reversed the TNF-induced increase in matrix metalloproteinase (MMP)-1 and a decrease in procollagen I α1 (COLIA1). It also suppressed inducible NO synthase, cyclooxygenase-2, interleukin (IL)-1β, IL-6, and IL-8, which upregulate inflammatory reactions. Mechanistically, compound 1 suppressed nuclear factor-κB, activator protein 1, and mitogen-activated protein kinases in TNF-α-stimulated HDFs. These results suggest that compound 1 may be beneficial for improving skin aging and diverse cutaneous lesions. Full article
(This article belongs to the Special Issue Pharmacology of Antioxidants)
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Review

Jump to: Research

17 pages, 1769 KiB  
Review
Impacts of Oxidative Stress and PI3K/AKT/mTOR on Metabolism and the Future Direction of Investigating Fucoidan-Modulated Metabolism
by Jun-Ping Shiau, Ya-Ting Chuang, Yuan-Bin Cheng, Jen-Yang Tang, Ming-Feng Hou, Ching-Yu Yen and Hsueh-Wei Chang
Antioxidants 2022, 11(5), 911; https://doi.org/10.3390/antiox11050911 - 6 May 2022
Cited by 27 | Viewed by 3852
Abstract
The critical factors for regulating cancer metabolism are oxidative stress and phosphoinositide-3-kinase/AKT serine-threonine kinase/mechanistic target of the rapamycin kinase (PI3K/AKT/mTOR). However, the metabolic impacts of oxidative stress and PI3K/AKT/mTOR on individual mechanisms such as glycolysis (Warburg effect), pentose phosphate pathway (PPP), fatty acid [...] Read more.
The critical factors for regulating cancer metabolism are oxidative stress and phosphoinositide-3-kinase/AKT serine-threonine kinase/mechanistic target of the rapamycin kinase (PI3K/AKT/mTOR). However, the metabolic impacts of oxidative stress and PI3K/AKT/mTOR on individual mechanisms such as glycolysis (Warburg effect), pentose phosphate pathway (PPP), fatty acid synthesis, tricarboxylic acid cycle (TCA) cycle, glutaminolysis, and oxidative phosphorylation (OXPHOS) are complicated. Therefore, this review summarizes the individual and interacting functions of oxidative stress and PI3K/AKT/mTOR on metabolism. Moreover, natural products providing oxidative stress and PI3K/AKT/mTOR modulating effects have anticancer potential. Using the example of brown algae-derived fucoidan, the roles of oxidative stress and PI3K/AKT/mTOR were summarized, although their potential functions within diverse metabolisms were rarely investigated. We propose a potential application that fucoidan may regulate oxidative stress and PI3K/AKT/mTOR signaling to modulate their associated metabolic regulations. This review sheds light on understanding the impacts of oxidative stress and PI3K/AKT/mTOR on metabolism and the future direction of metabolism-based cancer therapy of fucoidan. Full article
(This article belongs to the Special Issue Pharmacology of Antioxidants)
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32 pages, 3057 KiB  
Review
Pharmacology of Catechins in Ischemia-Reperfusion Injury of the Heart
by Kristína Ferenczyová, Lucia Kindernay, Jana Vlkovičová, Barbora Kaločayová, Tomáš Rajtík and Monika Barteková
Antioxidants 2021, 10(9), 1390; https://doi.org/10.3390/antiox10091390 - 30 Aug 2021
Cited by 11 | Viewed by 3881
Abstract
Catechins represent a group of polyphenols that possesses various beneficial effects in the cardiovascular system, including protective effects in cardiac ischemia-reperfusion (I/R) injury, a major pathophysiology associated with ischemic heart disease, myocardial infarction, as well as with cardioplegic arrest during heart surgery. In [...] Read more.
Catechins represent a group of polyphenols that possesses various beneficial effects in the cardiovascular system, including protective effects in cardiac ischemia-reperfusion (I/R) injury, a major pathophysiology associated with ischemic heart disease, myocardial infarction, as well as with cardioplegic arrest during heart surgery. In particular, catechin, (−)-epicatechin, and epigallocatechin gallate (EGCG) have been reported to prevent cardiac myocytes from I/R-induced cell damage and I/R-associated molecular changes, finally, resulting in improved cell viability, reduced infarct size, and improved recovery of cardiac function after ischemic insult, which has been widely documented in experimental animal studies and cardiac-derived cell lines. Cardioprotective effects of catechins in I/R injury were mediated via multiple molecular mechanisms, including inhibition of apoptosis; activation of cardioprotective pathways, such as PI3K/Akt (RISK) pathway; and inhibition of stress-associated pathways, including JNK/p38-MAPK; preserving mitochondrial function; and/or modulating autophagy. Moreover, regulatory roles of several microRNAs, including miR-145, miR-384-5p, miR-30a, miR-92a, as well as lncRNA MIAT, were documented in effects of catechins in cardiac I/R. On the other hand, the majority of results come from cell-based experiments and healthy small animals, while studies in large animals and studies including comorbidities or co-medications are rare. Human studies are lacking completely. The dosages of compounds also vary in a broad scale, thus, pharmacological aspects of catechins usage in cardiac I/R are inconclusive so far. Therefore, the aim of this focused review is to summarize the most recent knowledge on the effects of catechins in cardiac I/R injury and bring deep insight into the molecular mechanisms involved and dosage-dependency of these effects, as well as to outline potential gaps for translation of catechin-based treatments into clinical practice. Full article
(This article belongs to the Special Issue Pharmacology of Antioxidants)
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