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

Deadline for manuscript submissions: closed (20 May 2025) | Viewed by 16647

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Dr. Marija Plješa-Ercegovac

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Guest Editor

Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
Interests: oxidative stress; glutathione transferases; redox biology; urologic oncology; COVID

Special Issue Information

Dear Colleagues,

It is well established that oxidative stress plays an important role in severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection. Indeed, significant alterations in redox homeostasis, due to altered antioxidant capacity, have been shown to contribute to the vicious cycle of inflammation and oxidative stress in COVID-19. Furthermore, oxidative stress and the impaired expression of antioxidant enzymes, as well as cytoprotective proteins under the control of the antioxidative response element in the DNA, have been suggested as the molecular basis of long-COVID. Since antioxidants have the ability to counteract the action of oxidants by scavenging reactive oxygen species (ROS) and by inhibiting oxidant-generating enzymes, various antioxidants have been proposed as “anti-SARS-CoV-2 agents”. However, further studies are needed to clarify the role of antioxidants as potential therapeutic strategies for both the prevention and treatment of acute COVID-19, as well as long-COVID.

Prof. Dr. Marija S. Plješa-Ercegovac
Guest Editor

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Keywords

antioxidants
epidemic
COVID-19
oxidative stress
antioxidant capacity
vitamins
human diseases

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Published Papers (9 papers)

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Research

28 pages, 2360 KB

Open AccessArticle

Cobalt(II) Complexes of 4′-Bromo-Fenamic Acid: Antioxidant Properties, Antibacterial Activity, and Interaction with DNA and Albumins

by Georgios Malis, Christina N. Banti, Alexia Tialiou, Michael R. Reithofer, Antonios G. Hatzidimitriou, Sotiris K. Hadjikakou, Konstantina C. Fylaktakidou and George Psomas

Int. J. Mol. Sci. 2025, 26(19), 9787; https://doi.org/10.3390/ijms26199787 - 8 Oct 2025

Viewed by 271

Abstract

The reaction of 4′–bromo-fenamic acid, a bromo-derivative of fenamic acid (the scaffold of the fenamate non-steroidal anti-inflammatory drugs), with Co(II) in the absence or presence of various nitrogen-donor ligands yielded nine novel, neutral mononuclear Co(II) complexes. These complexes were characterized by physicochemical and spectroscopic techniques and single-crystal X-ray crystallography. The biological evaluation of the compounds focused on their antioxidant and antimicrobial efficacy, as well as their interaction with calf-thymus DNA, pBR322 plasmid DNA (in the absence or presence of diverse irradiations) and serum albumins. The complexes have shown significant antioxidant activity since they can scavenge 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) radicals (up to 96.48 ± 0.07%) and reduce H₂O₂ (up to 96.93 ± 0.53%). Antimicrobial testing revealed that the complexes were more active than free 4′-bromo-fenamic acid with four of them classified as bactericidal agents against selected bacterial strains. The compounds can interact with calf-thymus DNA via intercalation, and the calculated DNA-binding constants are on the 10⁶ M⁻¹ order. The plasmid DNA-cleavage ability of the compounds is strongly enhanced under UVA irradiation (photocleavage > 90%). In addition, the compounds can bind tightly and reversibly to serum albumins with binding constants in the 10⁵ M⁻¹ range. Full article

(This article belongs to the Special Issue Focus on Antioxidants and Human Diseases)

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14 pages, 2329 KB

Open AccessArticle

FBXO22 Suppresses Oxidative Stress-Induced ASK1 Activation and Cell Death via Ubiquitination-Dependent Degradation of TRIM48

by Naoki Kashiwabara, Keita Nagaoka, Kenshin Nakajima, Hiroki Tsukamoto, Yoshihisa Tomioka, Isao Naguro, Hidenori Ichijo, Takuya Noguchi, Yusuke Hirata and Atsushi Matsuzawa

Int. J. Mol. Sci. 2025, 26(19), 9472; https://doi.org/10.3390/ijms26199472 - 27 Sep 2025

Viewed by 399

Abstract

TRIM48 is a human-specific tripartite motif (TRIM) family protein with E3 ubiquitin ligase activity that plays a significant role in the oxidative stress response and tumor suppression. However, the mechanisms regulating TRIM48 expression remain unknown. In this study, we demonstrate that TRIM48 is targeted for ubiquitination-dependent degradation by S-phase kinase-associated protein 1 (Skp1)-Cullin1 (Cul1)-F-box protein (SCF) ubiquitin ligase complex, containing F-box protein 22 (FBXO22) as a substrate recognition subunit. We found that TRIM48 is a rapid turnover protein, as evidenced by the fast and drastic decrease in its protein expression level in the presence of a protein synthesis inhibitor cycloheximide, which was suppressed by knocking down either Skp1, Cul1 or FBXO22. Exogenous FBXO22 expression promoted K48-linked polyubiquitination and degradation of TRIM48. FBXO22 deficiency accelerated oxidative stress-induced activation of apoptosis signal-regulating kinase 1 (ASK1) and cell death, which was reversed by additional TRIM48 knockdown. Collectively, our findings identify the FBXO22 SCF complex as a key negative regulator of TRIM48-driven ASK1-activation and cell death under oxidative stress. The dysregulation of this axis may underlie human-specific pathologies, such as tumorigenesis and oxidative stress-associated disorders, highlighting its potential as a target for novel therapeutic interventions. Full article

(This article belongs to the Special Issue Focus on Antioxidants and Human Diseases)

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31 pages, 2653 KB

Open AccessArticle

Protective Antioxidant Potential of Argan Oil Versus Other Edible Oils in LPS-Challenged Mouse Heart and Kidney

by Soufiane Rabbaa, Habiba Bouchab, Mounia Tahri-Joutey, Yassir Laaziouez, Youness Limami, Vivien Pires, Boubker Nasser, Pierre Andreoletti, Mustapha Cherkaoui-Malki and Riad El Kebbaj

Int. J. Mol. Sci. 2025, 26(17), 8300; https://doi.org/10.3390/ijms26178300 - 27 Aug 2025

Viewed by 830

Abstract

Oxidative stress plays a key role in tissue damage during inflammation, highlighting the need for effective antioxidant interventions. This study investigates the antioxidant potential of argan oil (AO)—obtained from Argania spinosa (L.) Skeels almonds—in comparison with olive oil (OO), cactus seed oil (CSO), and colza oil (CO). Quantitative analyses of total polyphenols and pigments—including chlorophylls, carotenoids, and xanthophylls—were conducted alongside antioxidant capacity assessments via DPPH, ABTS, and FRAP assays. The methanolic fraction consistently demonstrated the highest phenolic concentration and antioxidant efficacy across all oils. To establish in vivo relevance, a male C57BL/6J mouse model of acute oxidative stress was induced by lipopolysaccharide (LPS) administration. Pretreatment with oils significantly modulated key oxidative stress biomarkers—SOD, CAT, GPx activities, GSH levels, and lipid peroxidation (MDA)—in both heart and kidney. LPS challenge induced marked oxidative imbalance, notably increasing enzymatic activity and MDA levels, while depleting GSH in the heart and elevating it in the kidney. However, pretreatment with oils effectively restored redox homeostasis, with AO showing particularly potent effects and a stronger regulatory effect observed in the kidney. Hierarchical clustering of z-score-normalized heatmaps revealed distinct oxidative stress signatures, clearly separating LPS-treated heart and kidney tissues from other groups due to heightened oxidative markers. In contrast, oil-treated and oil-combined-with-LPS groups clustered closer to the control, underscoring the protective effect of oils against LPS-induced oxidative stress, with efficiency varying by oil type. Pearson correlation analysis, complemented by multivariate principal component analysis (PCA), further emphasized strong positive associations between antioxidant enzymes (SOD, CAT, GPx) and MDA levels, while GSH exhibited tissue-specific behavior—negatively correlated in the heart but positively in the kidney—highlighting divergent redox regulation between organs. Collectively, AO demonstrated robust cardioprotective and nephroprotective properties, supporting its potential as a natural dietary strategy against inflammation-induced oxidative stress. Full article

(This article belongs to the Special Issue Focus on Antioxidants and Human Diseases)

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14 pages, 2637 KB

Open AccessArticle

Aβ₄₀ Improves Cerebrovascular Endothelial Function via NOX4-Dependent Hydrogen Peroxide Release

by Elizabeth Heller, Lindsey McGurran, Joseph K. Brown, Kathleen Love, Matthew Hobbs, Jeong Sook Kim-Han and Byung Hee Han

Int. J. Mol. Sci. 2025, 26(14), 6759; https://doi.org/10.3390/ijms26146759 - 15 Jul 2025

Viewed by 668

Abstract

Alzheimer’s disease (AD) is associated with an abnormal accumulation of amyloid β (Aβ) fibrils in the brain parenchyma and cerebrovasculature, which leads to cognitive impairment and cerebrovascular dysfunction. Cerebrovascular endothelial cells play a crucial role in regulating cerebral blood flow, vascular permeability, and neurovascular function. Reactive oxygen species (ROS), particularly those generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), contribute to vascular dysfunction and amyloid deposition in the Alzheimer’s disease (AD) brain. However, the role of the NOX4 isoform in AD pathogenesis remains to be examined. In the present study, we found that NOX4 among the NOX isoforms is predominantly expressed in bEnd.3 mouse brain endothelial cells. Treatment with Aβ₄₀ significantly enhanced the release of H₂O₂ and NO, and increased the endothelial cell viability. To test the involvement of NOX4 in Aβ₄₀-induced H₂O₂ production, we utilized pharmacological inhibitors of NOX isoforms. Aβ₄₀-induced H₂O₂ production was attenuated in the presence of the pan-NOX inhibitor, apocynin, or the NOX1/4-selective inhibitors, setanaxib and GKT136901. Since only the NOX4 isoform is expressed in bEnd.3 cells, these results indicate that NOX4 is responsible for the release of H₂O₂ stimulated by Aβ₄₀. Taken together, the present study demonstrated that Aβ₄₀ peptide exerts beneficial effects in bEnd.3 endothelial cells via the NOX4-dependent mechanism. Full article

(This article belongs to the Special Issue Focus on Antioxidants and Human Diseases)

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14 pages, 5400 KB

Open AccessArticle

Therapeutic Potential of CHCHD2 in Ischemia–Reperfusion Injury: Mechanistic Insights into Nrf2-Dependent Antioxidant Defense in HK2 Cells

by Yajie Hao and Xiaoshuang Zhou

Int. J. Mol. Sci. 2025, 26(13), 6089; https://doi.org/10.3390/ijms26136089 - 25 Jun 2025

Viewed by 539

Abstract

Acute kidney injury (AKI) resulting from ischemia/reperfusion (I/R) poses a significant clinical challenge due to its high mortality and complex pathophysiology. Here, the protective actions of Coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) in carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-induced adenosine triphosphate depletion and recovery (ATP-D/R) injury in human kidney-2 (HK2) cells are examined. During ATP-D/R, expression levels of CHCHD2 were significantly reduced. The overexpression of CHCHD2 substantially reduced the levels of ROS, lipid peroxidation, apoptosis, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL), whereas the knockdown of CHCHD2 exacerbated cellular injury. Mechanistic studies further demonstrated that overexpression of CHCHD2 restored Nrf2 expression under ATP-D/R conditions, facilitated its nuclear translocation, and upregulated the downstream antioxidant enzyme HO-1. In contrast, the knockdown of Nrf2 reduced the cytoprotective actions of CHCHD2. These findings indicate that CHCHD2 reduces cellular damage by enhancing antioxidant defenses and reducing apoptosis through activating the Nrf2 axis, underscoring its potential as a therapeutic target for AKI. Full article

(This article belongs to the Special Issue Focus on Antioxidants and Human Diseases)

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12 pages, 292 KB

Open AccessArticle

GPX3 Variant Genotype Affects the Risk of Developing Severe Forms of COVID-19

by Marko Markovic, Jovan Ranin, Zoran Bukumiric, Djurdja Jerotic, Ana Savic-Radojevic, Marija Pljesa-Ercegovac, Tatjana Djukic, Marko Ercegovac, Milika Asanin, Ivana Milosevic, Goran Stevanovic, Tatjana Simic, Vesna Coric and Marija Matic

Int. J. Mol. Sci. 2023, 24(22), 16151; https://doi.org/10.3390/ijms242216151 - 10 Nov 2023

Cited by 4 | Viewed by 2398

Abstract

In SARS-CoV-2 infection, excessive activation of the immune system intensively increases reactive oxygen species levels, causing harmful hyperinflammatory and oxidative state cumulative effects which may contribute to COVID-19 severity. Therefore, we assumed that antioxidant genetic profile, independently and complemented with laboratory markers, modulates COVID-19 severity. The study included 265 COVID-19 patients. Polymorphism of GSTM1, GSTT1, Nrf2 rs6721961, GSTM3 rs1332018, GPX3 rs8177412, GSTP1 rs1695, GSTO1 rs4925, GSTO2 rs156697, SOD2 rs4880 and GPX1 rs1050450 genes was determined with appropriate PCR-based methods. Inflammation (interleukin-6, CRP, fibrinogen, ferritin) and organ damage (urea, creatinine, transaminases and LDH) markers, complete blood count and coagulation status (d-dimer, fibrinogen) were measured. We found significant association for COVID-19 progression for patients with lymphocytes below 1.0 × 10⁹/L (OR = 2.97, p = 0.002). Increased IL-6 and CRP were also associated with disease progression (OR = 8.52, p = 0.001, and OR = 10.97, p < 0.001, respectively), as well as elevated plasma AST and LDH (OR = 2.25, p = 0.021, and OR = 4.76, p < 0.001, respectively). Of all the examined polymorphisms, we found significant association with the risk of developing severe forms of COVID-19 for GPX3 rs8177412 variant genotype (OR = 2.42, p = 0.032). This finding could be of particular importance in the future, complementing other diagnostic tools for prediction of COVID-19 disease course. Full article

(This article belongs to the Special Issue Focus on Antioxidants and Human Diseases)

22 pages, 5153 KB

Open AccessArticle

Pharmacogenomic Landscape of Ivermectin and Selective Antioxidants: Exploring Gene Interplay in the Context of Long COVID

by Ying-Fei Yang and Sher Singh

Int. J. Mol. Sci. 2023, 24(20), 15471; https://doi.org/10.3390/ijms242015471 - 23 Oct 2023

Cited by 1 | Viewed by 5048

Abstract

COVID-19 pandemic has caused widespread panic and fear among the global population. As such, repurposing drugs are being used as viable therapeutic options due to the limited effective treatments for Long COVID symptoms. Ivermectin is one of the emerging repurposed drugs that has been shown effective to have antiviral effects in clinical trials. In addition, antioxidant compounds are also gaining attention due to their capabilities of reducing inflammation and severity of symptoms. Due to the absence of knowledge in pharmacogenomics and modes of actions in the human body for these compounds, this study aims to provide a pharmacogenomic profile for the combination of ivermectin and six selected antioxidants (epigallocatechin gallate (EGCG), curcumin, sesamin, anthocyanins, quercetin, and N-acetylcysteine (NAC)) as potentially effective regimens for long COVID symptoms. Results showed that there were 12 interacting genes found among the ivermectin, 6 antioxidants, and COVID-19. For network pharmacology, the 12 common interacting genes/proteins had the highest associations with Pertussis pathway, AGE-RAGE signaling pathway in diabetic complications, and colorectal cancer in the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Disease analyses also revealed that the top three relevant diseases with COVID-19 infections were diabetes mellitus, ischemia, reperfusion injury. We also identified 6 potential target microRNAs (miRNAs) of the 12 commonly curated genes used as molecular biomarkers for COVID-19 treatments. The established pharmacogenomic network, disease analyses, and identified miRNAs could facilitate developments of effective regimens for chronic sequelae of COVID-19 especially in this post-pandemic era. However, further studies and clinical trials are needed to substantiate the effectiveness and dosages for COVID-19 treatments. Full article

(This article belongs to the Special Issue Focus on Antioxidants and Human Diseases)

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13 pages, 4048 KB

Open AccessArticle

Improving Soluble Expression of SARS-CoV-2 Spike Priming Protease TMPRSS2 with an Artificial Fusing Protein

by Xiao Ye, Xue Ling, Min Wu, Guijie Bai, Meng Yuan and Lang Rao

Int. J. Mol. Sci. 2023, 24(13), 10475; https://doi.org/10.3390/ijms241310475 - 22 Jun 2023

Viewed by 3092

Abstract

SARS-CoV-2 relies on the recognition of the spike protein by the host cell receptor ACE2 for cellular entry. In this process, transmembrane serine protease 2 (TMPRSS2) plays a pivotal role, as it acts as the principal priming agent catalyzing spike protein cleavage to initiate the fusion of the cell membrane with the virus. Thus, TMPRSS2 is an ideal pharmacological target for COVID-19 therapy development, and the effective production of high–quality TMPRSS2 protein is essential for basic and pharmacological research. Unfortunately, as a mammalian–originated protein, TMPRSS2 could not be solubly expressed in the prokaryotic system. In this study, we applied different protein engineering methods and found that an artificial protein XXA derived from an antifreeze protein can effectively promote the proper folding of TMPRSS2, leading to a significant improvement in the yield of its soluble form. Our study also showed that the fused XXA protein did not influence the enzymatic catalytic activity; instead, it greatly enhanced TMPRSS2′s thermostability. Therefore, our strategy for increasing TMPRSS2 expression would be beneficial for the large–scale production of this stable enzyme, which would accelerate aniti–SARS-CoV-2 therapeutics development. Full article

(This article belongs to the Special Issue Focus on Antioxidants and Human Diseases)

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14 pages, 2217 KB

Open AccessArticle

Antioxidant Genetic Variants Modify Echocardiography Indices in Long COVID

by Milika Asanin, Marko Ercegovac, Gordana Krljanac, Tatjana Djukic, Vesna Coric, Djurdja Jerotic, Marija Pljesa-Ercegovac, Marija Matic, Ivana Milosevic, Mihajlo Viduljevic, Goran Stevanovic, Jovan Ranin, Tatjana Simic, Zoran Bukumiric and Ana Savic-Radojevic

Int. J. Mol. Sci. 2023, 24(12), 10234; https://doi.org/10.3390/ijms241210234 - 16 Jun 2023

Cited by 5 | Viewed by 2238

Abstract

Although disturbance of redox homeostasis might be responsible for COVID-19 cardiac complications, this molecular mechanism has not been addressed yet. We have proposed modifying the effects of antioxidant proteins polymorphisms (superoxide dismutase 2 (SOD2), glutathione peroxidase 1 (GPX1), glutathione peroxidase 3 (GPX3) and nuclear factor erythroid 2-related factor 2, (Nrf2)) in individual susceptibility towards the development of cardiac manifestations of long COVID-19. The presence of subclinical cardiac dysfunction was assessed via echocardiography and cardiac magnetic resonance imaging in 174 convalescent COVID-19 patients. SOD2, GPX1, GPX3 and Nrf2 polymorphisms were determined via the appropriate PCR methods. No significant association of the investigated polymorphisms with the risk of arrhythmia development was found. However, the carriers of variant GPX1*T, GPX3*C or Nrf2*A alleles were more than twice less prone for dyspnea development in comparison with the carriers of the referent ones. These findings were even more potentiated in the carriers of any two variant alleles of these genes (OR = 0.273, and p = 0.016). The variant GPX alleles were significantly associated with left atrial and right ventricular echocardiographic parameters, specifically LAVI, RFAC and RV-EF (p = 0.025, p = 0.009, and p = 0.007, respectively). Based on the relation between the variant SOD2*T allele and higher levels of LV echocardiographic parameters, EDD, LVMI and GLS, as well as troponin T (p = 0.038), it can be proposed that recovered COVID-19 patients, who are the carriers of this genetic variant, might have subtle left ventricular systolic dysfunction. No significant association between the investigated polymorphisms and cardiac disfunction was observed when cardiac magnetic resonance imaging was performed. Our results on the association between antioxidant genetic variants and long COVID cardiological manifestations highlight the involvement of genetic propensity in both acute and long COVID clinical manifestations. Full article

(This article belongs to the Special Issue Focus on Antioxidants and Human Diseases)

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