Editorial

3 pages, 188 KiB

Open AccessEditorial

Redox-Active Molecules as Therapeutic Agents

by Ana Sofia Fernandes

Antioxidants 2022, 11(5), 1004; https://doi.org/10.3390/antiox11051004 - 20 May 2022

Cited by 1 | Viewed by 1287

Oxidative stress and altered redox signaling have been described in a plethora of pathological conditions, such as inflammation, cardiovascular diseases, diabetes, cancer, and neurodegenerative disorders, among others [...] Full article

(This article belongs to the Special Issue Redox-Active Molecules as Therapeutic Agents)

Research

Jump to: Editorial, Review

23 pages, 3887 KiB

Open AccessArticle

Curcumin and Carnosic Acid Cooperate to Inhibit Proliferation and Alter Mitochondrial Function of Metastatic Prostate Cancer Cells

by Saniya Ossikbayeva, Marina Khanin, Yoav Sharoni, Aviram Trachtenberg, Sultan Tuleukhanov, Richard Sensenig, Slava Rom, Michael Danilenko and Zulfiya Orynbayeva

Antioxidants 2021, 10(10), 1591; https://doi.org/10.3390/antiox10101591 - 11 Oct 2021

Cited by 13 | Viewed by 2813

Abstract

Anticancer activities of plant polyphenols have been demonstrated in various models of neoplasia. However, evidence obtained in numerous in vitro studies indicates that proliferation arrest and/or killing of cancer cells require quite high micromolar concentrations of polyphenols that are difficult to reach in [...] Read more.

Anticancer activities of plant polyphenols have been demonstrated in various models of neoplasia. However, evidence obtained in numerous in vitro studies indicates that proliferation arrest and/or killing of cancer cells require quite high micromolar concentrations of polyphenols that are difficult to reach in vivo and can also be (geno)toxic to at least some types of normal cells. The ability of certain polyphenols to synergize with one another at low concentrations can be used as a promising strategy to effectively treat human malignancies. We have recently reported that curcumin and carnosic acid applied at non-cytotoxic concentrations synergistically cooperate to induce massive apoptosis in acute myeloid leukemia cells, but not in normal hematopoietic and non-hematopoietic cells, via sustained cytosolic calcium overload. Here, we show that the two polyphenols can also synergistically suppress the growth of DU145 and PC-3 metastatic prostate cancer cell cultures. However, instead of cell killing, the combined treatment induced a marked inhibition of cell proliferation associated with G₀/G₁ cell cycle arrest. This was preceded by transient elevation of cytosolic calcium levels and prolonged dissipation of the mitochondrial membrane potential, without generating oxidative stress, and was associated with defective oxidative phosphorylation encompassing mitochondrial dysfunction. The above effects were concomitant with a significant downregulation of mRNA and protein expression of the oncogenic kinase SGK1, the mitochondria-hosted mTOR component. In addition, a moderate decrease in SGK1 phosphorylation at Ser422 was observed in polyphenol-treated cells. The mTOR inhibitor rapamycin produced a similar reduction in SGK1 mRNA and protein levels as well as phosphorylation. Collectively, our findings suggest that the combination of curcumin and carnosic acid at potentially bioavailable concentrations may effectively target different types of cancer cells by distinct modes of action. This and similar combinations merit further exploration as an anticancer modality. Full article

(This article belongs to the Special Issue Redox-Active Molecules as Therapeutic Agents)

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11 pages, 978 KiB

Open AccessArticle

Effects of Lippia citriodora Leaf Extract on Lipid and Oxidative Blood Profile of Volunteers with Hypercholesterolemia: A Preliminary Study

by Antonella Angiolillo, Deborah Leccese, Marisa Palazzo, Francesco Vizzarri, Donato Casamassima, Carlo Corino and Alfonso Di Costanzo

Antioxidants 2021, 10(4), 521; https://doi.org/10.3390/antiox10040521 - 27 Mar 2021

Cited by 3 | Viewed by 2003

Abstract

Lippia citriodora is a plant traditionally used for its anti-inflammatory, antioxidant and antispasmodic effects, as well as for additional biological activities proven in cell culture, animal studies and a small number of human clinical trials. The plant has also shown a marked improvement [...] Read more.

Lippia citriodora is a plant traditionally used for its anti-inflammatory, antioxidant and antispasmodic effects, as well as for additional biological activities proven in cell culture, animal studies and a small number of human clinical trials. The plant has also shown a marked improvement in blood lipid profile in some animal species. In the present preliminary study, we investigated the effect of a leaf extract on lipid and oxidative blood profile of hypercholesterolemic volunteers. Twelve adults received Lippia citriodora extract caps, containing 23% phenylpropanoids, (100 mg, once a day) for 16 weeks. Selected blood lipids and plasma oxidative markers were measured at baseline and after 4, 8 and 16 weeks of treatment. Compared with baseline, total cholesterol levels significantly decreased and high-density lipoprotein cholesterol increased, while low-density lipoprotein cholesterol and triglycerides showed only a downward trend. Oxidative status was improved due to a decrease in the concentration of total oxidant status, reactive oxygen metabolites and malondialdehyde, and a significant increase in ferric reducing ability of plasma, vitamin A and vitamin E. These preliminary results suggest that dietary supplementation with Lippia citriodora extract can improve the lipid profile, enhance blood antioxidant power, and could be a valuable natural compound for the management of human hypercholesterolemia. Full article

(This article belongs to the Special Issue Redox-Active Molecules as Therapeutic Agents)

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21 pages, 1621 KiB

Open AccessArticle

In Vivo Bioavailability of Selenium in Selenium-Enriched Streptococcus thermophilus and Enterococcus faecium in CD IGS Rats

by Gabriela Krausova, Antonin Kana, Marek Vecka, Ivana Hyrslova, Barbora Stankova, Vera Kantorova, Iva Mrvikova, Martina Huttl and Hana Malinska

Antioxidants 2021, 10(3), 463; https://doi.org/10.3390/antiox10030463 - 16 Mar 2021

Cited by 19 | Viewed by 2569

Abstract

The selenium (Se) enrichment of yeasts and lactic acid bacteria (LAB) has recently emerged as a novel concept; the individual health effects of these beneficial microorganisms are combined by supplying the essential micronutrient Se in a more bioavailable and less toxic form. This [...] Read more.

The selenium (Se) enrichment of yeasts and lactic acid bacteria (LAB) has recently emerged as a novel concept; the individual health effects of these beneficial microorganisms are combined by supplying the essential micronutrient Se in a more bioavailable and less toxic form. This study investigated the bioavailability of Se in the strains Enterococcus faecium CCDM 922A (EF) and Streptococcus thermophilus CCDM 144 (ST) and their respective Se-enriched forms, SeEF and SeST, in a CD (SD-Sprague Dawley) IGS rat model. Se-enriched LAB administration resulted in higher Se concentrations in the liver and kidneys of rats, where selenocystine was the prevalent Se species. The administration of both Se-enriched strains improved the antioxidant status of the animals. The effect of the diet was more pronounced in the heart tissue, where a lower glutathione reductase content was observed, irrespective of the Se fortification in LAB. Interestingly, rats fed diets with EF and SeEF had higher glutathione reductase activity. Reduced concentrations of serum malondialdehyde were noted following Se supplementation. Diets containing Se-enriched strains showed no macroscopic effects on the liver, kidneys, heart, and brain and had no apparent influence on the basic parameters of the lipid metabolism. Both the strains tested herein showed potential for further applications as promising sources of organically bound Se and Se nanoparticles. Full article

(This article belongs to the Special Issue Redox-Active Molecules as Therapeutic Agents)

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16 pages, 3260 KiB

Open AccessArticle

Comparison of Anti-Oxidative Effect of Human Adipose- and Amniotic Membrane-Derived Mesenchymal Stem Cell Conditioned Medium on Mouse Preimplantation Embryo Development

by Kihae Ra, Hyun Ju Oh, Eun Young Kim, Sung Keun Kang, Jeong Chan Ra, Eui Hyun Kim, Se Chang Park and Byeong Chun Lee

Antioxidants 2021, 10(2), 268; https://doi.org/10.3390/antiox10020268 - 09 Feb 2021

Cited by 4 | Viewed by 2787

Abstract

Oxidative stress is a major cause of damage to the quantity and quality of embryos produced in vitro. Antioxidants are usually supplemented to protect embryos from the suboptimal in vitro culture (IVC) environment. Amniotic membrane-derived mesenchymal stem cells (AMSC) have emerged as a [...] Read more.

Oxidative stress is a major cause of damage to the quantity and quality of embryos produced in vitro. Antioxidants are usually supplemented to protect embryos from the suboptimal in vitro culture (IVC) environment. Amniotic membrane-derived mesenchymal stem cells (AMSC) have emerged as a promising regenerative therapy, and their paracrine factors with anti-oxidative effects are present in AMSC conditioned medium (CM). We examined the anti-oxidative potential of human AMSC-CM treatment during IVC on mouse preimplantation embryo development and antioxidant gene expression in the forkhead box O (FoxO) pathway. AMSC-CM (10%) was optimal for overall preimplantation embryo developmental processes and upregulated the expression of FoxOs and their downstream antioxidants in blastocysts (BL). Subsequently, compared to adipose-derived mesenchymal stem cell (ASC)-CM, AMSC-CM enhanced antioxidant gene expression and intracellular GSH levels in the BL. Total antioxidant capacity and SOD activity were greater in AMSC-CM than in ASC-CM. Furthermore, SOD and catalase were more active in culture medium supplemented with AMSC-CM than in ASC-CM. Lastly, the anti-apoptotic effect of AMSC-CM was observed with the regulation of apoptosis-related genes and mitochondrial membrane potential in BL. In conclusion, the present study established AMSC-CM treatment at an optimal concentration as a novel antioxidant intervention for assisted reproduction. Full article

(This article belongs to the Special Issue Redox-Active Molecules as Therapeutic Agents)

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20 pages, 22429 KiB

Open AccessArticle

Activation of NRF2 and ATF4 Signaling by the Pro-Glutathione Molecule I-152, a Co-Drug of N-Acetyl-Cysteine and Cysteamine

by Rita Crinelli, Carolina Zara, Luca Galluzzi, Gloria Buffi, Chiara Ceccarini, Michael Smietana, Michele Mari, Mauro Magnani and Alessandra Fraternale

Antioxidants 2021, 10(2), 175; https://doi.org/10.3390/antiox10020175 - 26 Jan 2021

Cited by 12 | Viewed by 3615

Abstract

I-152 combines two pro-glutathione (GSH) molecules, namely N-acetyl-cysteine (NAC) and cysteamine (MEA), to improve their potency. The co-drug efficiently increases/replenishes GSH levels in vitro and in vivo; little is known about its mechanism of action. Here we demonstrate that I-152 not only supplies [...] Read more.

I-152 combines two pro-glutathione (GSH) molecules, namely N-acetyl-cysteine (NAC) and cysteamine (MEA), to improve their potency. The co-drug efficiently increases/replenishes GSH levels in vitro and in vivo; little is known about its mechanism of action. Here we demonstrate that I-152 not only supplies GSH precursors, but also activates the antioxidant kelch-like ECH-associated protein 1/nuclear factor E2-related factor 2 (KEAP1/NRF2) pathway. The mechanism involves disulfide bond formation between KEAP1 cysteine residues, NRF2 stabilization and enhanced expression of the γ-glutamil cysteine ligase regulatory subunit. Accordingly, a significant increase in GSH levels, not reproduced by treatment with NAC or MEA alone, was found. Compared to its parent compounds, I-152 delivered NAC more efficiently within cells and displayed increased reactivity to KEAP1 compared to MEA. While at all the concentrations tested, I-152 activated the NRF2 pathway; high doses caused co-activation of activating transcription factor 4 (ATF4) and ATF4-dependent gene expression through a mechanism involving Atf4 transcriptional activation rather than preferential mRNA translation. In this case, GSH levels tended to decrease over time, and a reduction in cell proliferation/survival was observed, highlighting that there is a concentration threshold which determines the transition from advantageous to adverse effects. This body of evidence provides a molecular framework for the pro-GSH activity and dose-dependent effects of I-152 and shows how synergism and cross reactivity between different thiol species could be exploited to develop more potent drugs. Full article

(This article belongs to the Special Issue Redox-Active Molecules as Therapeutic Agents)

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18 pages, 3810 KiB

Open AccessArticle

Unique Cellular and Biochemical Features of Human Mitochondrial Peroxiredoxin 3 Establish the Molecular Basis for Its Specific Reaction with Thiostrepton

by Kimberly J. Nelson, Terri Messier, Stephanie Milczarek, Alexis Saaman, Stacie Beuschel, Uma Gandhi, Nicholas Heintz, Terrence L. Smalley, Jr., W. Todd Lowther and Brian Cunniff

Antioxidants 2021, 10(2), 150; https://doi.org/10.3390/antiox10020150 - 20 Jan 2021

Cited by 9 | Viewed by 2881

Abstract

A central hallmark of tumorigenesis is metabolic alterations that increase mitochondrial reactive oxygen species (mROS). In response, cancer cells upregulate their antioxidant capacity and redox-responsive signaling pathways. A promising chemotherapeutic approach is to increase ROS to levels incompatible with tumor cell survival. Mitochondrial [...] Read more.

A central hallmark of tumorigenesis is metabolic alterations that increase mitochondrial reactive oxygen species (mROS). In response, cancer cells upregulate their antioxidant capacity and redox-responsive signaling pathways. A promising chemotherapeutic approach is to increase ROS to levels incompatible with tumor cell survival. Mitochondrial peroxiredoxin 3 (PRX3) plays a significant role in detoxifying hydrogen peroxide (H₂O₂). PRX3 is a molecular target of thiostrepton (TS), a natural product and FDA-approved antibiotic. TS inactivates PRX3 by covalently adducting its two catalytic cysteine residues and crosslinking the homodimer. Using cellular models of malignant mesothelioma, we show here that PRX3 expression and mROS levels in cells correlate with sensitivity to TS and that TS reacts selectively with PRX3 relative to other PRX isoforms. Using recombinant PRXs 1–5, we demonstrate that TS preferentially reacts with a reduced thiolate in the PRX3 dimer at mitochondrial pH. We also show that partially oxidized PRX3 fully dissociates to dimers, while partially oxidized PRX1 and PRX2 remain largely decameric. The ability of TS to react with engineered dimers of PRX1 and PRX2 at mitochondrial pH, but inefficiently with wild-type decameric protein at cytoplasmic pH, supports a novel mechanism of action and explains the specificity of TS for PRX3. Thus, the unique structure and propensity of PRX3 to form dimers contribute to its increased sensitivity to TS-mediated inactivation, making PRX3 a promising target for prooxidant cancer therapy. Full article

(This article belongs to the Special Issue Redox-Active Molecules as Therapeutic Agents)

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15 pages, 10712 KiB

Open AccessArticle

Withanolide C Inhibits Proliferation of Breast Cancer Cells via Oxidative Stress-Mediated Apoptosis and DNA Damage

by Tzu-Jung Yu, Jen-Yang Tang, Li-Ching Lin, Wan-Ju Lien, Yuan-Bin Cheng, Fang-Rong Chang, Fu Ou-Yang and Hsueh-Wei Chang

Antioxidants 2020, 9(9), 873; https://doi.org/10.3390/antiox9090873 - 16 Sep 2020

Cited by 15 | Viewed by 2817

Abstract

Some withanolides, particularly the family of steroidal lactones, show anticancer effects, but this is rarely reported for withanolide C (WHC)—especially anti-breast cancer effects. The subject of this study is to evaluate the ability of WHC to regulate the proliferation of breast cancer cells, [...] Read more.

Some withanolides, particularly the family of steroidal lactones, show anticancer effects, but this is rarely reported for withanolide C (WHC)—especially anti-breast cancer effects. The subject of this study is to evaluate the ability of WHC to regulate the proliferation of breast cancer cells, using both time and concentration in treatment with WHC. In terms of ATP depletion, WHC induced more antiproliferation to three breast cancer cell lines, SKBR3, MCF7, and MDA-MB-231, than to normal breast M10 cell lines. SKBR3 and MCF7 cells showing higher sensitivity to WHC were used to explore the antiproliferation mechanism. Flow cytometric apoptosis analyses showed that subG1 phase and annexin V population were increased in breast cancer cells after WHC treatment. Western blotting showed that cleaved forms of the apoptotic proteins poly (ADP-ribose) polymerase (c-PARP) and cleaved caspase 3 (c-Cas 3) were increased in breast cancer cells. Flow cytometric oxidative stress analyses showed that WHC triggered reactive oxygen species (ROS) and mitochondrial superoxide (MitoSOX) production as well as glutathione depletion. In contrast, normal breast M10 cells showed lower levels of ROS and annexin V expression than breast cancer cells. Flow cytometric DNA damage analyses showed that WHC triggered γH2AX and 8-oxo-2′-deoxyguanosine (8-oxodG) expression in breast cancer cells. Moreover, N-acetylcysteine (NAC) pretreatment reverted oxidative stress-mediated ATP depletion, apoptosis, and DNA damage. Therefore, WHC kills breast cancer cells depending on oxidative stress-associated mechanisms. Full article

(This article belongs to the Special Issue Redox-Active Molecules as Therapeutic Agents)

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24 pages, 2299 KiB

Open AccessArticle

Bioprospection of Natural Sources of Polyphenols with Therapeutic Potential for Redox-Related Diseases

by Regina Menezes, Alexandre Foito, Carolina Jardim, Inês Costa, Gonçalo Garcia, Rita Rosado-Ramos, Sabine Freitag, Colin James Alexander, Tiago Fleming Outeiro, Derek Stewart and Cláudia N. Santos

Antioxidants 2020, 9(9), 789; https://doi.org/10.3390/antiox9090789 - 26 Aug 2020

Cited by 9 | Viewed by 3654

Abstract

Plants are a reservoir of high-value molecules with underexplored biomedical applications. With the aim of identifying novel health-promoting attributes in underexplored natural sources, we scrutinized the diversity of (poly)phenols present within the berries of selected germplasm from cultivated, wild, and underutilized Rubus species. [...] Read more.

Plants are a reservoir of high-value molecules with underexplored biomedical applications. With the aim of identifying novel health-promoting attributes in underexplored natural sources, we scrutinized the diversity of (poly)phenols present within the berries of selected germplasm from cultivated, wild, and underutilized Rubus species. Our strategy combined the application of metabolomics, statistical analysis, and evaluation of (poly)phenols’ bioactivity using a yeast-based discovery platform. We identified species as sources of (poly)phenols interfering with pathological processes associated with redox-related diseases, particularly, amyotrophic lateral sclerosis, cancer, and inflammation. In silico prediction of putative bioactives suggested cyanidin–hexoside as an anti-inflammatory molecule which was validated in yeast and mammalian cells. Moreover, cellular assays revealed that the cyanidin moiety was responsible for the anti-inflammatory properties of cyanidin–hexoside. Our findings unveiled novel (poly)phenolic bioactivities and illustrated the power of our integrative approach for the identification of dietary (poly)phenols with potential biomedical applications. Full article

(This article belongs to the Special Issue Redox-Active Molecules as Therapeutic Agents)

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19 pages, 2991 KiB

Open AccessArticle

The Phosphodiesterase Type 5 Inhibitor Sildenafil Improves DNA Stability and Redox Homeostasis in Systemic Sclerosis Fibroblasts Exposed to Reactive Oxygen Species

by Luigi Di Luigi, Guglielmo Duranti, Ambra Antonioni, Paolo Sgrò, Roberta Ceci, Clara Crescioli, Stefania Sabatini, Andrea Lenzi, Daniela Caporossi, Francesco Del Galdo, Ivan Dimauro and Cristina Antinozzi

Antioxidants 2020, 9(9), 786; https://doi.org/10.3390/antiox9090786 - 25 Aug 2020

Cited by 13 | Viewed by 2680

Abstract

Systemic sclerosis (SSc) is a multi-system connective tissue disease characterized by the increased deposition of extracellular matrix proteins such as collagen and fibronectin. Although the pathogenesis is not completely understood, a number of studies suggest that free radicals could be the major contributors [...] Read more.

Systemic sclerosis (SSc) is a multi-system connective tissue disease characterized by the increased deposition of extracellular matrix proteins such as collagen and fibronectin. Although the pathogenesis is not completely understood, a number of studies suggest that free radicals could be the major contributors to the disease. Indeed, different studies demonstrated how oxidative stress could contribute to the fibrotic process activation at the level of the skin and visceral organs. Emerging evidences highlight the beneficial effects of sildenafil, a phosphodiesterase type 5 inhibitor (PDE5i), which protects different cell lines from the cell damage induced by reactive oxygen species (ROS). These data make sildenafil a good candidate for therapeutic treatment aimed to protect biological macromolecules against oxidative damage, thus preserving cell viability. The purpose of this study was to evaluate the sensitivity of SSc dermal fibroblasts to an oxidative insult and the ability for sildenafil to prevent/reduce the DNA damage due to ROS action. Additionally, we evaluated the capacity for sildenafil to influence redox homeostasis and cytotoxicity, as well as cell proliferation and cell cycle progression. We demonstrated that SSc fibroblasts have an increased sensitivity to a pro-oxidant environment in comparison to healthy controls. The sildenafil treatment reduced ROS-induced DNA damage, counteracted the negative effects of ROS on cell viability and proliferation, and promoted the activity of specific enzymes involved in redox homeostasis maintenance. To our knowledge, in this report, we demonstrate, for the first time, that sildenafil administration prevents ROS-induced instability in human dermal fibroblasts isolated by SSc patients. These results expand the use of PDE5i as therapeutic agents in SSc by indicating a protective role in tissue damage induced by oxidative insult. Full article

(This article belongs to the Special Issue Redox-Active Molecules as Therapeutic Agents)

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18 pages, 4580 KiB

Open AccessArticle

Impact of the APE1 Redox Function Inhibitor E3330 in Non-Small Cell Lung Cancer Cells Exposed to Cisplatin: Increased Cytotoxicity and Impairment of Cell Migration and Invasion

by Rita Manguinhas, Ana S. Fernandes, João G. Costa, Nuno Saraiva, Sérgio P. Camões, Nuno Gil, Rafael Rosell, Matilde Castro, Joana P. Miranda and Nuno G. Oliveira

Antioxidants 2020, 9(6), 550; https://doi.org/10.3390/antiox9060550 - 24 Jun 2020

Cited by 21 | Viewed by 3661

Abstract

Elevated expression levels of the apurinic/apyrimidinic endonuclease 1 (APE1) have been correlated with the more aggressive phenotypes and poor prognosis of non-small cell lung cancer (NSCLC). This study aimed to assess the impact of the inhibition of the redox function of APE1 with [...] Read more.

Elevated expression levels of the apurinic/apyrimidinic endonuclease 1 (APE1) have been correlated with the more aggressive phenotypes and poor prognosis of non-small cell lung cancer (NSCLC). This study aimed to assess the impact of the inhibition of the redox function of APE1 with E3330 either alone or in combination with cisplatin in NSCLC cells. For this purpose, complementary endpoints focusing on cell viability, apoptosis, cell cycle distribution, and migration/invasion were studied. Cisplatin decreased the viability of H1975 cells in a time- and concentration-dependent manner, with IC₅₀ values of 9.6 µM for crystal violet assay and 15.9 µM for 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. E3330 was clearly cytotoxic for concentrations above 30 µM. The co-incubation of E3330 and cisplatin significantly decreased cell viability compared to cisplatin alone. Regarding cell cycle distribution, cisplatin led to an increase in sub-G1, whereas the co-treatment with E3330 did not change this profile, which was then confirmed in terms of % apoptotic cells. In addition, the combination of E3330 and cisplatin at low concentrations decreased collective and chemotactic migration, and also chemoinvasion, by reducing these capabilities up to 20%. Overall, these results point to E3330 as a promising compound to boost cisplatin therapy that warrants further investigation in NSCLC. Full article

(This article belongs to the Special Issue Redox-Active Molecules as Therapeutic Agents)

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Review

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20 pages, 6836 KiB

Open AccessReview

Fighting Oxidative Stress with Sulfur: Hydrogen Sulfide in the Renal and Cardiovascular Systems

by Joshua J. Scammahorn, Isabel T. N. Nguyen, Eelke M. Bos, Harry Van Goor and Jaap A. Joles

Antioxidants 2021, 10(3), 373; https://doi.org/10.3390/antiox10030373 - 02 Mar 2021

Cited by 39 | Viewed by 4743

Abstract

Hydrogen sulfide (H₂S) is an essential gaseous signaling molecule. Research on its role in physiological and pathophysiological processes has greatly expanded. Endogenous enzymatic production through the transsulfuration and cysteine catabolism pathways can occur in the kidneys and blood vessels. Furthermore, non-enzymatic [...] Read more.

Hydrogen sulfide (H₂S) is an essential gaseous signaling molecule. Research on its role in physiological and pathophysiological processes has greatly expanded. Endogenous enzymatic production through the transsulfuration and cysteine catabolism pathways can occur in the kidneys and blood vessels. Furthermore, non-enzymatic pathways are present throughout the body. In the renal and cardiovascular system, H₂S plays an important role in maintaining the redox status at safe levels by promoting scavenging of reactive oxygen species (ROS). H₂S also modifies cysteine residues on key signaling molecules such as keap1/Nrf2, NFκB, and HIF-1α, thereby promoting anti-oxidant mechanisms. Depletion of H₂S is implicated in many age-related and cardiorenal diseases, all having oxidative stress as a major contributor. Current research suggests potential for H₂S-based therapies, however, therapeutic interventions have been limited to studies in animal models. Beyond H₂S use as direct treatment, it could improve procedures such as transplantation, stem cell therapy, and the safety and efficacy of drugs including NSAIDs and ACE inhibitors. All in all, H₂S is a prime subject for further research with potential for clinical use. Full article

(This article belongs to the Special Issue Redox-Active Molecules as Therapeutic Agents)

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27 pages, 1792 KiB

Open AccessReview

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

by Sepideh Mirzaei, Ali Zarrabi, Farid Hashemi, Amirhossein Zabolian, Hossein Saleki, Negar Azami, Soodeh Hamzehlou, Mahdi Vasheghani Farahani, Kiavash Hushmandi, Milad Ashrafizadeh, Haroon Khan and Alan Prem Kumar

Antioxidants 2021, 10(3), 349; https://doi.org/10.3390/antiox10030349 - 26 Feb 2021

Cited by 73 | Viewed by 8117

Abstract

Doxorubicin (DOX) is extensively applied in cancer therapy due to its efficacy in suppressing cancer progression and inducing apoptosis. After its discovery, this chemotherapeutic agent has been frequently used for cancer therapy, leading to chemoresistance. Due to dose-dependent toxicity, high concentrations of DOX [...] Read more.

Doxorubicin (DOX) is extensively applied in cancer therapy due to its efficacy in suppressing cancer progression and inducing apoptosis. After its discovery, this chemotherapeutic agent has been frequently used for cancer therapy, leading to chemoresistance. Due to dose-dependent toxicity, high concentrations of DOX cannot be administered to cancer patients. Therefore, experiments have been directed towards revealing underlying mechanisms responsible for DOX resistance and ameliorating its adverse effects. Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling is activated to increase levels of reactive oxygen species (ROS) in cells to protect them against oxidative stress. It has been reported that Nrf2 activation is associated with drug resistance. In cells exposed to DOX, stimulation of Nrf2 signaling protects cells against cell death. Various upstream mediators regulate Nrf2 in DOX resistance. Strategies, both pharmacological and genetic interventions, have been applied for reversing DOX resistance. However, Nrf2 induction is of importance for alleviating side effects of DOX. Pharmacological agents with naturally occurring compounds as the most common have been used for inducing Nrf2 signaling in DOX amelioration. Furthermore, signaling networks in which Nrf2 is a key player for protection against DOX adverse effects have been revealed and are discussed in the current review. Full article

(This article belongs to the Special Issue Redox-Active Molecules as Therapeutic Agents)

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16 pages, 1413 KiB

Open AccessReview

LOXL2 Inhibitors and Breast Cancer Progression

by Sandra Ferreira, Nuno Saraiva, Patrícia Rijo and Ana S. Fernandes

Antioxidants 2021, 10(2), 312; https://doi.org/10.3390/antiox10020312 - 19 Feb 2021

Cited by 53 | Viewed by 5494

Abstract

LOX (lysyl oxidase) and lysyl oxidase like-1–4 (LOXL 1–4) are amine oxidases, which catalyze cross-linking reactions of elastin and collagen in the connective tissue. These amine oxidases also allow the cross-link of collagen and elastin in the extracellular matrix of tumors, facilitating the [...] Read more.

LOX (lysyl oxidase) and lysyl oxidase like-1–4 (LOXL 1–4) are amine oxidases, which catalyze cross-linking reactions of elastin and collagen in the connective tissue. These amine oxidases also allow the cross-link of collagen and elastin in the extracellular matrix of tumors, facilitating the process of cell migration and the formation of metastases. LOXL2 is of particular interest in cancer biology as it is highly expressed in some tumors. This protein also promotes oncogenic transformation and affects the proliferation of breast cancer cells. LOX and LOXL2 inhibition have thus been suggested as a promising strategy to prevent metastasis and invasion of breast cancer. BAPN (β-aminopropionitrile) was the first compound described as a LOX inhibitor and was obtained from a natural source. However, novel synthetic compounds that act as LOX/LOXL2 selective inhibitors or as dual LOX/LOX-L inhibitors have been recently developed. In this review, we describe LOX enzymes and their role in promoting cancer development and metastases, with a special focus on LOXL2 and breast cancer progression. Moreover, the recent advances in the development of LOXL2 inhibitors are also addressed. Overall, this work contextualizes and explores the importance of LOXL2 inhibition as a promising novel complementary and effective therapeutic approach for breast cancer treatment. Full article

(This article belongs to the Special Issue Redox-Active Molecules as Therapeutic Agents)

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