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Antioxidants
Special Issues
Multi-Target Profile of Antioxidant Compounds, including Repurposing and Combination Strategies
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Multi-Target Profile of Antioxidant Compounds, including Repurposing and Combination Strategies

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (30 September 2024) | Viewed by 11584

Special Issue Editor

Dr. Roberta Rocca

E-Mail Website
Guest Editor
Dipartimento di Scienze della Salute, Università “Magna Graecia” di Catanzaro, Campus “Salvatore Venuta”, Viale Europa, 88100 Catanzaro, Italy
Interests: docking; nucleic acids; drug design; molecular modeling; molecular dynamics; virtual screening; drug repurposing; natural products
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer, neurodegenerative disorders and stroke are just some examples of multifactorial diseases and often oxidative stress is a common event that occurs. Currently, there is no efficient and effective cure for these diseases; consequently, researchers have taken advantage of the multi-targeting drug approach to design molecules which may be developed as useful agents for their treatment. In this scenario, in silico techniques are considered as useful and powerful tools to enhance rational drug design in the medicinal chemistry field. The discovery, design, synthesis and biological evaluation of multi-targeting molecules combining antioxidant and/or anti-inflammatory properties are expected to be beneficial in the treatment of different multifactorial diseases.

The aim of the current Special Issue is to cover promising, recent, and novel research trends in the polypharmacologic field, focusing on antioxidant compounds. In particular, advancements in the design and synthesis of novel polypharmacological agents, especially those that highlight new strategies and approaches, are appreciated. Additionally, repurposing or the discovery of new mechanisms of action for antioxidants compounds are considered.

We welcome original research, review, mini review and perspective articles on themes including, but not limited to:

  • the development of new multi-target antioxidant entities;
  • multi-target rational drug design of antioxidant molecules;
  • drug repurposing proposals of antioxidant compounds;
  • discovery of off-target effects for antioxidant compounds;
  • application of different approaches to polypharmacology;
  • rational design and synthesis of hybrid compounds.

Dr. Roberta Rocca
Guest Editor

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

  • polypharmacology
  • multi-target ligands
  • rational drug design
  • repurposing
  • off-target effects
  • computational techniques

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Published Papers (8 papers)

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Research

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21 pages, 3910 KiB  
Article
Hit Identification and Functional Validation of Novel Dual Inhibitors of HDAC8 and Tubulin Identified by Combining Docking and Molecular Dynamics Simulations
by Antonio Curcio, Roberta Rocca, Federica Chiera, Maria Eugenia Gallo Cantafio, Ilenia Valentino, Ludovica Ganino, Pierpaolo Murfone, Angela De Simone, Giulia Di Napoli, Stefano Alcaro, Nicola Amodio and Anna Artese
Antioxidants 2024, 13(11), 1427; https://doi.org/10.3390/antiox13111427 - 20 Nov 2024
Viewed by 256
Abstract
Chromatin organization, which is under the control of histone deacetylases (HDACs), is frequently deregulated in cancer cells. Amongst HDACs, HDAC8 plays an oncogenic role in different neoplasias by acting on both histone and non-histone substrates. Promising anti-cancer strategies have exploited dual-targeting drugs that [...] Read more.
Chromatin organization, which is under the control of histone deacetylases (HDACs), is frequently deregulated in cancer cells. Amongst HDACs, HDAC8 plays an oncogenic role in different neoplasias by acting on both histone and non-histone substrates. Promising anti-cancer strategies have exploited dual-targeting drugs that inhibit both HDAC8 and tubulin. These drugs have shown the potential to enhance the outcome of anti-cancer treatments by simultaneously targeting multiple pathways critical to disease onset and progression. In this study, a structure-based virtual screening (SBVS) of 96403 natural compounds was performed towards the four Class I HDAC isoforms and tubulin. Using molecular docking and molecular dynamics simulations (MDs), we identified two molecules that could selectively interact with HDAC8 and tubulin. CNP0112925 (arundinin), bearing a polyphenolic structure, was confirmed to inhibit HDAC8 activity and tubulin organization, affecting breast cancer cell viability and triggering mitochondrial superoxide production and apoptosis. Full article
(This article belongs to the Special Issue Multi-Target Profile of Antioxidant Compounds, including Repurposing and Combination Strategies)
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23 pages, 4370 KiB  
Article
Multiple Mechanisms of Action of Sulfodyne®, a Natural Antioxidant, against Pathogenic Effects of SARS-CoV-2 Infection
by Paul-Henri Romeo, Laurine Conquet, Sébastien Messiaen, Quentin Pascal, Stéphanie G. Moreno, Anne Bravard, Jacqueline Bernardino-Sgherri, Nathalie Dereuddre-Bosquet, Xavier Montagutelli, Roger Le Grand, Vanessa Petit and Federica Ferri
Antioxidants 2024, 13(9), 1083; https://doi.org/10.3390/antiox13091083 - 4 Sep 2024
Viewed by 1193
Abstract
Few therapeutic options are available to treat COVID-19. The KEAP1/NRF2 pathway, the major redox-responsive pathway, has emerged as a potential therapeutic target for COVID-19 as it regulates redox homeostasis and inflammation that are altered during SARS-CoV-2 infection. Here, we characterized the effects of [...] Read more.
Few therapeutic options are available to treat COVID-19. The KEAP1/NRF2 pathway, the major redox-responsive pathway, has emerged as a potential therapeutic target for COVID-19 as it regulates redox homeostasis and inflammation that are altered during SARS-CoV-2 infection. Here, we characterized the effects of NRF2-agonist Sulfodyne®, a stabilized natural Sulforaphane, in cellular and animal models of SARS-CoV-2 infection. In pulmonary or colonic epithelial cell lines, Sulfodyne® elicited a more efficient inhibition of SARS-CoV-2 replication than NRF2-agonists DMF and CDDO. This antiviral activity was not dependent on NRF2 but was associated with the regulation of several metabolic pathways, including the inhibition of ER stress and mTOR signaling, which are activated during SARS-CoV-2 infection. Sulfodyne® also decreased SARS-CoV-2 mediated inflammatory responses by inhibiting the delayed induction of IFNB1 and type I IFN-stimulated genes in infected epithelial cell lines and by reducing the activation of human by-stander monocytes recruited after SARS-CoV-2 infection. In K18-hACE2 mice infected with SARS-CoV-2, Sulfodyne® treatment reduced both early lung viral load and disease severity by fine-tuning IFN-beta levels. Altogether, these results provide evidence for multiple mechanisms that underlie the antiviral and anti-inflammatory activities of Sulfodyne® and pinpoint Sulfodyne® as a potent therapeutic agent against pathogenic effects of SARS-CoV-2 infection. Full article
(This article belongs to the Special Issue Multi-Target Profile of Antioxidant Compounds, including Repurposing and Combination Strategies)
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38 pages, 9055 KiB  
Article
A Multi-Target Pharmacological Correction of a Lipoyltransferase LIPT1 Gene Mutation in Patient-Derived Cellular Models
by David Gómez-Fernández, Ana Romero-González, Juan M. Suárez-Rivero, Paula Cilleros-Holgado, Mónica Álvarez-Córdoba, Rocío Piñero-Pérez, José Manuel Romero-Domínguez, Diana Reche-López, Alejandra López-Cabrera, Salvador Ibáñez-Mico, Marta Castro de Oliveira, Andrés Rodríguez-Sacristán, Susana González-Granero, José Manuel García-Verdugo and José A. Sánchez-Alcázar
Antioxidants 2024, 13(8), 1023; https://doi.org/10.3390/antiox13081023 - 22 Aug 2024
Viewed by 1165
Abstract
Mutations in the lipoyltransferase 1 (LIPT1) gene are rare inborn errors of metabolism leading to a fatal condition characterized by lipoylation defects of the 2-ketoacid dehydrogenase complexes causing early-onset seizures, psychomotor retardation, abnormal muscle tone, severe lactic acidosis, and increased urine [...] Read more.
Mutations in the lipoyltransferase 1 (LIPT1) gene are rare inborn errors of metabolism leading to a fatal condition characterized by lipoylation defects of the 2-ketoacid dehydrogenase complexes causing early-onset seizures, psychomotor retardation, abnormal muscle tone, severe lactic acidosis, and increased urine lactate, ketoglutarate, and 2-oxoacid levels. In this article, we characterized the disease pathophysiology using fibroblasts and induced neurons derived from a patient bearing a compound heterozygous mutation in LIPT1. A Western blot analysis revealed a reduced expression of LIPT1 and absent expression of lipoylated pyruvate dehydrogenase E2 (PDH E2) and alpha-ketoglutarate dehydrogenase E2 (α-KGDH E2) subunits. Accordingly, activities of PDH and α-KGDH were markedly reduced, associated with cell bioenergetics failure, iron accumulation, and lipid peroxidation. In addition, using a pharmacological screening, we identified a cocktail of antioxidants and mitochondrial boosting agents consisting of pantothenate, nicotinamide, vitamin E, thiamine, biotin, and α-lipoic acid, which is capable of rescuing LIPT1 pathophysiology, increasing the LIPT1 expression and lipoylation of mitochondrial proteins, improving cell bioenergetics, and eliminating iron overload and lipid peroxidation. Furthermore, our data suggest that the beneficial effect of the treatment is mainly mediated by SIRT3 activation. In conclusion, we have identified a promising therapeutic approach for correcting LIPT1 mutations. Full article
(This article belongs to the Special Issue Multi-Target Profile of Antioxidant Compounds, including Repurposing and Combination Strategies)
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15 pages, 3476 KiB  
Article
Apomorphine Suppresses the Progression of Steatohepatitis by Inhibiting Ferroptosis
by Hiroshi Maeda, Kouichi Miura, Kenichi Aizawa, Oyunjargal Bat-Erdene, Miho Sashikawa-Kimura, Eri Noguchi, Masako Watanabe, Naoya Yamada, Hitoshi Osaka, Naoki Morimoto and Hironori Yamamoto
Antioxidants 2024, 13(7), 805; https://doi.org/10.3390/antiox13070805 - 2 Jul 2024
Cited by 1 | Viewed by 961
Abstract
The role of ferroptosis in steatohepatitis development is largely unknown. We investigated (1) whether hepatocyte ferroptosis occurs in a gene-modified steatohepatitis model without modifying dietary components, (2) whether ferroptosis occurs at an early stage of steatohepatitis, and (3) whether apomorphine, recently reported as [...] Read more.
The role of ferroptosis in steatohepatitis development is largely unknown. We investigated (1) whether hepatocyte ferroptosis occurs in a gene-modified steatohepatitis model without modifying dietary components, (2) whether ferroptosis occurs at an early stage of steatohepatitis, and (3) whether apomorphine, recently reported as a ferroptosis inhibitor, can ameliorate steatohepatitis. Hepatocyte-specific PTEN KO mice were used. Huh 7 and primary cultured hepatocytes isolated from the mice were used in this study. The number of dead cells increased in 10-week-old PTEN KO mice. This cell death was suppressed by the administration of ferroptosis inhibitor ferrostatin-1 for 2 weeks. Apomorphine also ameliorated the severity of steatohepatitis. Treatment with ferroptosis inhibitors, including apomorphine, decreases the level of lipid peroxidase. Apomorphine suppressed cell death induced by RSL-3 (a ferroptosis inducer), which was not suppressed by apoptosis or necroptosis inhibitors. Apomorphine showed a radical trapping capacity with much more potent activity than ferrostatin-1 and Trolox, a soluble form of vitamin E. In addition, apomorphine activated nrf2 and its downstream genes, including HO-1 and xCT. In conclusion, ferroptosis occurs in steatohepatitis from an early stage in PTEN KO mice. In addition, apomorphine ameliorates the severity of steatohepatitis by inhibiting ferroptosis. Full article
(This article belongs to the Special Issue Multi-Target Profile of Antioxidant Compounds, including Repurposing and Combination Strategies)
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26 pages, 4855 KiB  
Article
Dexborneol Amplifies Pregabalin’s Analgesic Effect in Mouse Models of Peripheral Nerve Injury and Incisional Pain
by Zhen Shen, Yun-Dan Guo, Ming-Ze Tang, Ping Zhou, Yu-Xin Su, Hao-Ran Shen, Tao Li, Wei Jiang, Yan-Xing Han, Cai Tie, Jing-Jing Cui, Tian-Le Gao and Jian-Dong Jiang
Antioxidants 2024, 13(7), 803; https://doi.org/10.3390/antiox13070803 - 2 Jul 2024
Cited by 1 | Viewed by 1196
Abstract
Pregabalin is a medication primarily used in the treatment of neuropathic pain and anxiety disorders, owing to its gabapentinoid properties. Pregabalin monotherapy faces limitations due to its variable efficacy and dose-dependent adverse reactions. In this study, we conducted a comprehensive investigation into the [...] Read more.
Pregabalin is a medication primarily used in the treatment of neuropathic pain and anxiety disorders, owing to its gabapentinoid properties. Pregabalin monotherapy faces limitations due to its variable efficacy and dose-dependent adverse reactions. In this study, we conducted a comprehensive investigation into the potentiation of pregabalin’s analgesic effects by dexborneol, a neuroprotective bicyclic monoterpenoid compound. We performed animal experiments where pain models were induced using two methods: peripheral nerve injury, involving axotomy and ligation of the tibial and common peroneal nerves, and incisional pain through a longitudinal incision in the hind paw, while employing a multifaceted methodology that integrates behavioral pharmacology, molecular biology, neuromorphology, and lipidomics to delve into the mechanisms behind this potentiation. Dexborneol was found to enhance pregabalin’s efficacy by promoting its transportation to the central nervous system, disrupting self-amplifying vicious cycles via the reduction of HMGB1 and ATP release, and exerting significant anti-oxidative effects through modulation of central lipid metabolism. This combination therapy not only boosted pregabalin’s analgesic property but also notably decreased its side effects. Moreover, this therapeutic cocktail exceeded basic pain relief, effectively reducing neuroinflammation and glial cell activation—key factors contributing to persistent and chronic pain. This study paves the way for more tolerable and effective analgesic options, highlighting the potential of dexborneol as an adjuvant to pregabalin therapy. Full article
(This article belongs to the Special Issue Multi-Target Profile of Antioxidant Compounds, including Repurposing and Combination Strategies)
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12 pages, 38099 KiB  
Article
Anticancer Effects of High Glucosinolate Synthesis Lines of Brassica rapa on Colorectal Cancer Cells
by Jung Sun Kim, Sanghee Han, Hail Kim, So Youn Won, Hyun Woo Park, Hyunjin Choi, Minji Choi, Min Young Lee, In Jin Ha and Seok-Geun Lee
Antioxidants 2022, 11(12), 2463; https://doi.org/10.3390/antiox11122463 - 14 Dec 2022
Cited by 5 | Viewed by 1820
Abstract
Chemoprevention is a method of health control in modern industrialized societies. Traditional breeding (hybridization) has been widely used to produce new (sub)species with beneficial phenotypes. Previously, we produced a number of doubled haploid (DH) lines of Brassica rapa with a high glucosinolate (GSL) [...] Read more.
Chemoprevention is a method of health control in modern industrialized societies. Traditional breeding (hybridization) has been widely used to produce new (sub)species with beneficial phenotypes. Previously, we produced a number of doubled haploid (DH) lines of Brassica rapa with a high glucosinolate (GSL) content. In this study, we evaluated the anticancer activities of extracts from three selected high-GSL (HGSL)-containing DH lines (DHLs) of Brassica rapa in human colorectal cancer (CRC) cells. The three HGSL DHL extracts showed anti-proliferative activities in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assay and pro-apoptotic activities in the cell cycle or annexin V analysis with the induction of pro-apoptotic protein expression in CRC cells. Mechanistically, HGSL DHL extracts inhibited the NF-κB and ERK pathways, leading to a reduction in the nuclear localization of NF-κB p65. In addition, reactive oxygen species were induced by HGSL DHL extract treatment in CRC cells. In conclusion, our data suggest that the newly developed HGSL DHLs possess enhanced anticancer activities and are potentially helpful as a daily vegetable supplement with chemopreventive activities. Full article
(This article belongs to the Special Issue Multi-Target Profile of Antioxidant Compounds, including Repurposing and Combination Strategies)
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Review

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26 pages, 1881 KiB  
Review
Application of Antioxidant Compounds in Bone Defect Repair
by Jiajia Wang, Yubing Zhang, Qingming Tang, Yinan Zhang, Ying Yin and Lili Chen
Antioxidants 2024, 13(7), 789; https://doi.org/10.3390/antiox13070789 - 28 Jun 2024
Cited by 1 | Viewed by 1193
Abstract
Bone defects caused by trauma, tumor resection, and infections are significant clinical challenges. Excessive reactive oxygen species (ROS) usually accumulate in the defect area, which may impair the function of cells involved in bone formation, posing a serious challenge for bone repair. Due [...] Read more.
Bone defects caused by trauma, tumor resection, and infections are significant clinical challenges. Excessive reactive oxygen species (ROS) usually accumulate in the defect area, which may impair the function of cells involved in bone formation, posing a serious challenge for bone repair. Due to the potent ROS scavenging ability, as well as potential anti-inflammatory and immunomodulatory activities, antioxidants play an indispensable role in the maintenance and protection of bone health and have gained increasing attention in recent years. This narrative review aims to give an overview of the main research directions on the application of antioxidant compounds in bone defect repair over the past decade. In addition, the positive effects of various antioxidants and their biomaterial delivery systems in bone repair are summarized to provide new insights for exploring antioxidant-based strategies for bone defect repair. Full article
(This article belongs to the Special Issue Multi-Target Profile of Antioxidant Compounds, including Repurposing and Combination Strategies)
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18 pages, 1366 KiB  
Review
A Critical Appraisal of the Protective Activity of Polyphenolic Antioxidants against Iatrogenic Effects of Anticancer Chemotherapeutics
by Rosa Purgatorio, Angelina Boccarelli, Leonardo Pisani, Modesto de Candia, Marco Catto and Cosimo D. Altomare
Antioxidants 2024, 13(1), 133; https://doi.org/10.3390/antiox13010133 - 22 Jan 2024
Cited by 4 | Viewed by 2519
Abstract
Polyphenolic compounds, encompassing flavonoids (e.g., quercetin, rutin, and cyanidin) and non-flavonoids (e.g., gallic acid, resveratrol, and curcumin), show several health-related beneficial effects, which include antioxidant, anti-inflammatory, hepatoprotective, antiviral, and anticarcinogenic properties, as well as the prevention of coronary heart diseases. Polyphenols have also [...] Read more.
Polyphenolic compounds, encompassing flavonoids (e.g., quercetin, rutin, and cyanidin) and non-flavonoids (e.g., gallic acid, resveratrol, and curcumin), show several health-related beneficial effects, which include antioxidant, anti-inflammatory, hepatoprotective, antiviral, and anticarcinogenic properties, as well as the prevention of coronary heart diseases. Polyphenols have also been investigated for their counteraction against the adverse effects of common anticancer chemotherapeutics. This review evaluates the outcomes of clinical studies (and related preclinical data) over the last ten years, with a focus on the use of polyphenols in chemotherapy as auxiliary agents acting against oxidative stress toxicity induced by antitumor drugs. While further clinical studies are needed to establish adequate doses and optimal delivery systems, the improvement in polyphenols’ metabolic stability and bioavailability, through the implementation of nanotechnologies that are currently being investigated, could improve therapeutic applications of their pharmaceutical or nutraceutical preparations in tumor chemotherapy. Full article
(This article belongs to the Special Issue Multi-Target Profile of Antioxidant Compounds, including Repurposing and Combination Strategies)
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