Antioxidants

Research

20 pages, 2143 KiB

Open AccessArticle

Next-Generation Sequencing Advances the Genetic Diagnosis of Cerebral Cavernous Malformation (CCM)

by Valerio Benedetti, Rosalia Canzoneri, Andrea Perrelli, Carlo Arduino, Andrea Zonta, Alfredo Brusco and Saverio Francesco Retta

Antioxidants 2022, 11(7), 1294; https://doi.org/10.3390/antiox11071294 - 29 Jun 2022

Cited by 7 | Viewed by 2929

Abstract

Cerebral Cavernous Malformation (CCM) is a cerebrovascular disease of genetic origin that predisposes to seizures, focal neurological deficits and fatal intracerebral hemorrhage. It may occur sporadically or in familial forms, segregating as an autosomal dominant condition with incomplete penetrance and highly variable expressivity. [...] Read more.

Cerebral Cavernous Malformation (CCM) is a cerebrovascular disease of genetic origin that predisposes to seizures, focal neurological deficits and fatal intracerebral hemorrhage. It may occur sporadically or in familial forms, segregating as an autosomal dominant condition with incomplete penetrance and highly variable expressivity. Its pathogenesis has been associated with loss-of-function mutations in three genes, namely KRIT1 (CCM1), CCM2 and PDCD10 (CCM3), which are implicated in defense mechanisms against oxidative stress and inflammation. Herein, we screened 21 Italian CCM cases using clinical exome sequencing and found six cases (~29%) with pathogenic variants in CCM genes, including a large 145–256 kb genomic deletion spanning the KRIT1 gene and flanking regions, and the KRIT1 c.1664C>T variant, which we demonstrated to activate a donor splice site in exon 16. The segregation of this cryptic splicing mutation was studied in a large Italian family (five affected and seven unaffected cases), and showed a largely heterogeneous clinical presentation, suggesting the implication of genetic modifiers. Moreover, by analyzing ad hoc gene panels, including a virtual panel of 23 cerebrovascular disease-related genes (Cerebro panel), we found two variants in NOTCH3 and PTEN genes, which could contribute to the abnormal oxidative stress and inflammatory responses to date implicated in CCM disease pathogenesis. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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12 pages, 2297 KiB

Open AccessArticle

Lipid-Coated Nanocrystals as a Tool for Improving the Antioxidant Activity of Resveratrol

by Monica Argenziano, Irfan Aamer Ansari, Elisabetta Muntoni, Rita Spagnolo, Anna Scomparin and Roberta Cavalli

Antioxidants 2022, 11(5), 1007; https://doi.org/10.3390/antiox11051007 - 20 May 2022

Cited by 8 | Viewed by 2640

Abstract

Trans-resveratrol, a polyphenolic phytoalexin found in various plant sources, has been the focus of increasing attention in recent years because of its role in the prevention of many human diseases, and particularly because of its antioxidant properties. However, the in vivo effect [...] Read more.

Trans-resveratrol, a polyphenolic phytoalexin found in various plant sources, has been the focus of increasing attention in recent years because of its role in the prevention of many human diseases, and particularly because of its antioxidant properties. However, the in vivo effect of trans-resveratrol after oral administration is negligible when compared to its efficacy in vitro, due to its low bioavailability. Moreover, it presents stability issues as it is an extremely photosensitive compound when exposed to light. This work aims to develop lipid-coated nanocrystals in order to improve the antioxidant activity and bioavailability of trans-resveratrol. Lipid-coated trans-resveratrol nanocrystals with sizes lower than 500 nm, spherical shapes and smooth surfaces were obtained via a milling method. They showed a faster dissolution rate than the coarse trans-resveratrol powder. The antioxidant properties of trans-resveratrol were not impaired by the milling process. The in vivo pharmacokinetics of lipid-coated trans-resveratrol nanocrystals were evaluated after oral administration to rats, with a commercial Phytosome^® formulation being used for comparison purposes. An increase in the trans-resveratrol area under the curve was observed and the lipid-coated nanocrystal formulation led to an enhancement in the oral bioavailability of the compound. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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18 pages, 8003 KiB

Open AccessArticle

Coriolus Versicolor Downregulates TLR4/NF-κB Signaling Cascade in Dinitrobenzenesulfonic Acid-Treated Mice: A Possible Mechanism for the Anti-Colitis Effect

by Daniela Impellizzeri, Roberta Fusco, Tiziana Genovese, Marika Cordaro, Ramona D’Amico, Angela Trovato Salinaro, Maria Laura Ontario, Sergio Modafferi, Salvatore Cuzzocrea, Rosanna Di Paola, Vittorio Calabrese and Rosalba Siracusa

Antioxidants 2022, 11(2), 406; https://doi.org/10.3390/antiox11020406 - 17 Feb 2022

Cited by 15 | Viewed by 3588

Abstract

Inflammatory bowel diseases (IBDs) are disorders characterized by chronic inflammation of the intestinal tract. The focus of the present study was to examine the effect of the fungus Coriolus versicolor (CV), underlining its correlation with Toll-like receptors 4 (TLR4) and nuclear [...] Read more.

Inflammatory bowel diseases (IBDs) are disorders characterized by chronic inflammation of the intestinal tract. The focus of the present study was to examine the effect of the fungus Coriolus versicolor (CV), underlining its correlation with Toll-like receptors 4 (TLR4) and nuclear factor erythroid 2-related factor 2 (Nrf2); we aim to evaluate its anti-inflammatory and antioxidant effect in mice exposed to experimental colitis. The model was induced in mice by colon instillation of dinitrobenzenesulfonic acid (DNBS), CV was administered orally (200 mg per kg) daily for 4 days. On day 4, the animals were killed, and the tissues collected for histological, biochemical, and molecular analyses. Four days after DNBS administration, CC motif chemokine ligand 2 (CCL2), prostaglandin E2 (PGE2), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) production increased in association with damage to the colon. Neutrophil infiltration, as assessed by myeloperoxidase (MPO) activity, in the mucosa was associated with overexpression of P-selectin and intercellular adhesion molecule 1 (ICAM1). Immunohistochemistry for nitrotyrosine and poly-(ADP-Ribose)-polymerase (PARP) showed evident stain in the inflamed colon. Treatment with CV significantly reduced the appearance of colon changes and weight loss. These effects were associated with a remarkable ability of CV to reduce the expression of TLR4 and modulate the pathway of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). This improved the colon architecture, reduced MPO activity, the release of proinflammatory cytokines, the presence of nitrotyrosine, and the hyperactivation of PARP, as well as the up-regulation of P-selectin and ICAM1. Furthermore, we studied the action of CV on the Nrf2/HO-1 pathway, which is important for maintaining redox balance, demonstrating that CV by significantly increasing both enzymes is able to counteract the oxidative stress induced by DNBS. Taken together, our results clearly show that this natural compound can be considered as a possible dietary supplement against colitis. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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18 pages, 2942 KiB

Open AccessArticle

Insulin-like Growth Factor II Prevents MPP+ and Glucocorticoid Mitochondrial-Oxidative and Neuronal Damage in Dopaminergic Neurons

by Silvia Claros, Pablo Cabrera, Nadia Valverde, Silvana Y. Romero-Zerbo, Manuel Víctor López-González, Kirill Shumilov, Alicia Rivera, Jose Pavia, Elisa Martín-Montañez and María Garcia-Fernandez

Antioxidants 2022, 11(1), 41; https://doi.org/10.3390/antiox11010041 - 24 Dec 2021

Cited by 6 | Viewed by 3361

Abstract

Stress seems to contribute to Parkinson’s disease (PD) neuropathology, probably by dysregulation of the hypothalamic–pituitary–adrenal axis. Key factors in this pathophysiology are oxidative stress and mitochondrial dysfunction and neuronal glucocorticoid-induced toxicity. The insulin-like growth factor II (IGF-II), a pleiotropic hormone, has shown antioxidant [...] Read more.

Stress seems to contribute to Parkinson’s disease (PD) neuropathology, probably by dysregulation of the hypothalamic–pituitary–adrenal axis. Key factors in this pathophysiology are oxidative stress and mitochondrial dysfunction and neuronal glucocorticoid-induced toxicity. The insulin-like growth factor II (IGF-II), a pleiotropic hormone, has shown antioxidant and neuroprotective effects in some neurodegenerative disorders. Our aim was to examine the protective effect of IGF-II on a dopaminergic cellular combined model of PD and mild to moderate stress measuring oxidative stress parameters, mitochondrial and neuronal markers, and signalling pathways. IGF-II counteracts the mitochondrial-oxidative damage produced by the toxic synergistic effect of corticosterone and 1-methyl-4-phenylpyridinium, protecting dopaminergic neurons from death and neurodegeneration. IGF-II promotes PKC activation and nuclear factor (erythroid-derived 2)-like 2 antioxidant response in a glucocorticoid receptor-dependent pathway, preventing oxidative cell damage and maintaining mitochondrial function. Thus, IGF-II is a potential therapeutic tool for treatment and prevention of disease progression in PD patients suffering mild to moderate emotional stress. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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22 pages, 2685 KiB

Open AccessArticle

On the Antioxidant Properties of L-Kynurenine: An Efficient ROS Scavenger and Enhancer of Rat Brain Antioxidant Defense

by Daniela Ramírez Ortega, Perla Eugenia Ugalde Muñiz, Tonali Blanco Ayala, Gustavo Ignacio Vázquez Cervantes, Rafael Lugo Huitrón, Benjamín Pineda, Dinora Fabiola González Esquivel, Gonzalo Pérez de la Cruz, José Pedraza Chaverrí, Laura Sánchez Chapul, Saúl Gómez-Manzo and Verónica Pérez de la Cruz

Antioxidants 2022, 11(1), 31; https://doi.org/10.3390/antiox11010031 - 24 Dec 2021

Cited by 23 | Viewed by 4030

Abstract

L-kynurenine (L-KYN) is an endogenous metabolite, that has been used as a neuroprotective strategy in experimental models. The protective effects of L-KYN have been attributed mainly to kynurenic acid (KYNA). However, considering that L-KYN is prone to oxidation, this redox property may play [...] Read more.

L-kynurenine (L-KYN) is an endogenous metabolite, that has been used as a neuroprotective strategy in experimental models. The protective effects of L-KYN have been attributed mainly to kynurenic acid (KYNA). However, considering that L-KYN is prone to oxidation, this redox property may play a substantial role in its protective effects. The aim of this work was to characterize the potential impact of the redox properties of L-KYN, in both synthetic and biological systems. First, we determined whether L-KYN scavenges reactive oxygen species (ROS) and prevents DNA and protein oxidative degradation in synthetic systems. The effect of L-KYN and KYNA (0.1–100 µM) on redox markers (ROS production, lipoperoxidation and cellular function) was compared in rat brain homogenates when exposed to FeSO₄ (10 µM). Then, the effect of L-KYN administration (75 mg/kg/day for 5 days) on the GSH content and the enzymatic activity of glutathione reductase (GR) and glutathione peroxidase (GPx) was determined in rat brain tissue. Finally, brain homogenates from rats pretreated with L-KYN were exposed to pro-oxidants and oxidative markers were evaluated. The results show that L-KYN is an efficient scavenger of ^●OH and ONOO⁻, but not O₂^●– or H₂O₂ and that it prevents DNA and protein oxidative degradation in synthetic systems. L-KYN diminishes the oxidative effect induced by FeSO₄ on brain homogenates at lower concentrations (1 µM) when compared to KYNA (100 µM). Furthermore, the sub-chronic administration of L-KYN increased the GSH content and the activity of both GR and GPx, and also prevented the oxidative damage induced by the ex vivo exposure to pro-oxidants. Altogether, these findings strongly suggest that L-KYN can be considered as a potential endogenous antioxidant. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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19 pages, 3179 KiB

Open AccessArticle

The Atrophic Effect of 1,25(OH)₂ Vitamin D₃ (Calcitriol) on C2C12 Myotubes Depends on Oxidative Stress

by Tommaso Raiteri, Ivan Zaggia, Simone Reano, Andrea Scircoli, Laura Salvadori, Flavia Prodam and Nicoletta Filigheddu

Antioxidants 2021, 10(12), 1980; https://doi.org/10.3390/antiox10121980 - 12 Dec 2021

Cited by 9 | Viewed by 4149

Abstract

Dysfunctional mitochondrial metabolism has been linked to skeletal muscle loss in several physio-pathological states. Although it has been reported that vitamin D (VD) supports cellular redox homeostasis by maintaining normal mitochondrial functions, and VD deficiency often occurs in conditions associated with skeletal muscle [...] Read more.

Dysfunctional mitochondrial metabolism has been linked to skeletal muscle loss in several physio-pathological states. Although it has been reported that vitamin D (VD) supports cellular redox homeostasis by maintaining normal mitochondrial functions, and VD deficiency often occurs in conditions associated with skeletal muscle loss, the efficacy of VD supplementation to overcome muscle wasting is debated. Investigations on the direct effects of VD metabolites on skeletal muscle using C2C12 myotubes have revealed an unexpected pro-atrophic activity of calcitriol (1,25VD), while its upstream metabolites cholecalciferol (VD3) and calcidiol (25VD) have anti-atrophic effects. Here, we investigated if the atrophic effects of 1,25VD on myotubes depend on its activity on mitochondrial metabolism. The impact of 1,25VD and its upstream metabolites VD3 and 25VD on mitochondria dynamics and the activity of C2C12 myotubes was evaluated by measuring mitochondrial content, architecture, metabolism, and reactive oxygen species (ROS) production. We found that 1,25VD induces atrophy through protein kinase C (PKC)-mediated ROS production, mainly of extramitochondrial origin. Consistent with this, cotreatment with the antioxidant N-acetylcysteine (NAC), but not with the mitochondria-specific antioxidant mitoTEMPO, was sufficient to blunt the atrophic activity of 1,25VD. In contrast, VD3 and 25VD have antioxidant properties, suggesting that the efficacy of VD supplementation might result from the balance between atrophic pro-oxidant (1,25VD) and protective antioxidant (VD3 and 25VD) metabolites. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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13 pages, 3051 KiB

Open AccessArticle

Amyloid-β 25-35 Induces Neurotoxicity through the Up-Regulation of Astrocytic System X_c⁻

by Veronica D’Ezio, Marco Colasanti and Tiziana Persichini

Antioxidants 2021, 10(11), 1685; https://doi.org/10.3390/antiox10111685 - 26 Oct 2021

Cited by 17 | Viewed by 2351

Abstract

Amyloid-β (Aβ) deposition, a hallmark of Alzheimer’s disease, is known to induce free radical production and oxidative stress, leading to neuronal damage. During oxidative stress, several cell types (including astrocytes) can activate the nuclear factor erythroid 2-related factor 2 (Nrf2), a regulator of [...] Read more.

Amyloid-β (Aβ) deposition, a hallmark of Alzheimer’s disease, is known to induce free radical production and oxidative stress, leading to neuronal damage. During oxidative stress, several cell types (including astrocytes) can activate the nuclear factor erythroid 2-related factor 2 (Nrf2), a regulator of several phase II detoxifying and antioxidant genes, such as the System X_c⁻ subunit xCT. Here, we studied (i) the effect of the Aβ fragment 25-35 (Aβ_25-35) on Nrf2-dependent System X_c⁻ expression in U373 human astroglial cells and (ii) the effect of Aβ_25-35-induced astrocytic response on neuronal cell viability using an in vitro co-culture system. We found that Aβ_25-35 was able to activate an antioxidant response in astrocytes, by inducing both Nrf2 activation and System X_c⁻ up-regulation. However, this astrocytic response caused an enhanced cell mortality of co-cultured SH-SY5Y cells, taken as a neuronal model. Consistently, the specific System X_c⁻ inhibitor sulfasalazine prevented the increase of both neuronal mortality and extracellular glutamate levels, thus indicating that the neurotoxic effect was due to an augmented release of glutamate through the transporter. The involvement of NMDA receptor activation in this pathway was also demonstrated using the specific inhibitor MK801 that completely restored neuronal viability at the control levels. The present study sheds light on the Nrf2/system X_c⁻ pathway in the toxicity induced by Aβ_25-35 and may help to better understand the involvement of astrocytes in neuronal death during Alzheimer’s disease. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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15 pages, 1405 KiB

Open AccessArticle

Inhibition of Peroxiredoxin 6 PLA2 Activity Decreases Oxidative Stress and the Severity of Acute Lung Injury in the Mouse Cecal Ligation and Puncture Model

by Aron B. Fisher, Chandra Dodia, Jian-Qin Tao, Sheldon I. Feinstein and Shampa Chatterjee

Antioxidants 2021, 10(11), 1676; https://doi.org/10.3390/antiox10111676 - 24 Oct 2021

Cited by 8 | Viewed by 2459

Abstract

The use of agents to inhibit the production of reactive oxygen species (ROS) has been proposed for the treatment of Acute Lung Injury (ALI). However, this approach also inhibits the bactericidal activity of polymorphonuclear leucocytes (PMN) and other cells, raising the possibility of [...] Read more.

The use of agents to inhibit the production of reactive oxygen species (ROS) has been proposed for the treatment of Acute Lung Injury (ALI). However, this approach also inhibits the bactericidal activity of polymorphonuclear leucocytes (PMN) and other cells, raising the possibility of aggravating lung injury in ALI associated with bacterial infection. We used the cecal ligation and puncture (CLP) model of ALI associated with sepsis to investigate the effect of inhibiting NADPH oxidase 2 (NOX2)-derived ROS production, the main source of ROS in lungs. A phospholipase A₂ inhibitor called peroxiredoxin 6 inhibitory peptide-2 (PIP-2) was used to inhibit NOX2 activation; the peptide prevents liberation of Rac, a necessary NOX2 co-factor. At 18 h after intravenous treatment with 2 µg PIP-2 /gram body weight (wt), the number of colony-forming bacteria in lungs and peritoneal fluid of mice with CLP was approximately doubled as compared to untreated mice. Treatment with 10 µg PIP-2/g body wt resulted in 100% mortality within 18 h. Antibiotic treatment abolished both the increase in lung bacteria with low dose PIP-2 and the increased mortality with high dose PIP-2. Treatment with PIP-2 plus antibiotics resulted in significantly improved lung histology, decreased PMN infiltration, decreased lung fluid accumulation, and decreased oxidative lung injury compared to antibiotics alone. We conclude that the administration of PIP-2 provides partial protection against lung injury in a model of ALI due to bacterial infection, while concurrent antibiotic treatment abolishes the deleterious effects of PIP-2 on lung bacterial clearance. These results suggest that addition of PIP-2 to the antibiotic regimen is beneficial for treatment of ALI associated with bacterial infection. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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15 pages, 8245 KiB

Open AccessArticle

Malaria Pigment Hemozoin Impairs GM-CSF Receptor Expression and Function by 4-Hydroxynonenal

by Oleksii Skorokhod, Valentina Barrera, Giorgia Mandili, Federica Costanza, Elena Valente, Daniela Ulliers and Evelin Schwarzer

Antioxidants 2021, 10(8), 1259; https://doi.org/10.3390/antiox10081259 - 6 Aug 2021

Cited by 5 | Viewed by 2848

Abstract

Malarial pigment hemozoin (HZ) generates the lipoperoxidation product 4-hydroxynonenal (4-HNE), which is known to cause dysregulation of the immune response in malaria. The inhibition of granulocyte macrophage colony-stimulating factor (GM-CSF)-dependent differentiation of dendritic cells (DC) by HZ and 4-HNE was previously described in [...] Read more.

Malarial pigment hemozoin (HZ) generates the lipoperoxidation product 4-hydroxynonenal (4-HNE), which is known to cause dysregulation of the immune response in malaria. The inhibition of granulocyte macrophage colony-stimulating factor (GM-CSF)-dependent differentiation of dendritic cells (DC) by HZ and 4-HNE was previously described in vitro, and the GM-CSF receptor (GM-CSF R) was hypothesised to be a primary target of 4-HNE in monocytes. In this study, we show the functional impact of HZ on GM-CSF R in monocytes and monocyte-derived DC by (i) impairing GM-CSF binding by 50 ± 9% and 65 ± 14%, respectively (n = 3 for both cell types); (ii) decreasing the expression of GM-CSF R functional subunit (CD116) on monocyte’s surface by 36 ± 11% (n = 6) and in cell lysate by 58 ± 16% (n = 3); and (iii) binding of 4-HNE to distinct amino acid residues on CD116. The data suggest that defective DC differentiation in malaria is caused by GM-CSF R dysregulation and GM-CSF R modification by lipoperoxidation product 4-HNE via direct interaction with its CD116 subunit. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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14 pages, 2480 KiB

Open AccessArticle

Dual Mechanisms of Cardiac Action Potential Prolongation by 4-Oxo-Nonenal Increasing the Risk of Arrhythmia; Late Na⁺ Current Induction and hERG K⁺ Channel Inhibition

by Seong-Woo Choi, Ming-Zhe Yin, Na-Kyeong Park, Joo-Han Woo and Sung-Joon Kim

Antioxidants 2021, 10(7), 1139; https://doi.org/10.3390/antiox10071139 - 19 Jul 2021

Cited by 1 | Viewed by 2713

Abstract

4-Oxo-nonenal (4-ONE) is an endogenous lipid peroxidation product that is more reactive than 4-hydroxy-nonenal (4-HNE). We previously reported the arrhythmic potential of 4-HNE by suppression of cardiac human Ether-a-go-go Related Gene (hERG) K⁺ channels with prolonged action potential duration (APD) in cardiomyocytes. [...] Read more.

4-Oxo-nonenal (4-ONE) is an endogenous lipid peroxidation product that is more reactive than 4-hydroxy-nonenal (4-HNE). We previously reported the arrhythmic potential of 4-HNE by suppression of cardiac human Ether-a-go-go Related Gene (hERG) K⁺ channels with prolonged action potential duration (APD) in cardiomyocytes. Here, we illustrate the higher arrhythmic risk of 4-ONE by modulating the cardiac hNa_V1.5 channel currents (I_NaV). Although the peak amplitude of I_NaV was not significantly changed by 4-ONE up to 10 μM, the rate of I_NaV inactivation was slowed, and the late Na⁺ current (I_NaL) became larger by 10 μM 4-ONE. The chemical modification of specific residues in hNa_V1.5 by 4-ONE was identified using MS-fingerprinting analysis. In addition to the changes in I_NaV, 4-ONE decreased the delayed rectifier K⁺ channel currents including the hERG current. The L-type Ca²⁺ channel current was decreased, whereas its inactivation was slowed by 4-ONE. The APD prolongation by 10 μM of 4-ONE was more prominent than that by 100 μM of 4-HNE. In the computational in silico cardiomyocyte simulation analysis, the changes of I_NaL by 4-ONE significantly exacerbated the risk of arrhythmia exhibited by the TdP marker, qNet. Our study suggests an arrhythmogenic effect of 4-ONE on cardiac ion channels, especially hNa_V1.5. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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20 pages, 4010 KiB

Open AccessArticle

A Novel mRNA-Mediated and MicroRNA-Guided Approach to Specifically Eradicate Drug-Resistant Hepatocellular Carcinoma Cell Lines by Se-Methylselenocysteine

by Arun Kumar Selvam, Rim Jawad, Roberto Gramignoli, Adnane Achour, Hugh Salter and Mikael Björnstedt

Antioxidants 2021, 10(7), 1094; https://doi.org/10.3390/antiox10071094 - 7 Jul 2021

Cited by 9 | Viewed by 3089

Abstract

Despite progress in the treatment of non-visceral malignancies, the prognosis remains poor for malignancies of visceral organs and novel therapeutic approaches are urgently required. We evaluated a novel therapeutic regimen based on treatment with Se-methylselenocysteine (MSC) and concomitant tumor-specific induction of Kynurenine aminotransferase [...] Read more.

Despite progress in the treatment of non-visceral malignancies, the prognosis remains poor for malignancies of visceral organs and novel therapeutic approaches are urgently required. We evaluated a novel therapeutic regimen based on treatment with Se-methylselenocysteine (MSC) and concomitant tumor-specific induction of Kynurenine aminotransferase 1 (KYAT1) in hepatocellular carcinoma (HCC) cell lines, using either vector-based and/or lipid nanoparticle-mediated delivery of mRNA. Supplementation of MSC in KYAT1 overexpressed cells resulted in significantly increased cytotoxicity, due to ROS formation, as compared to MSC alone. Furthermore, microRNA antisense-targeted sites for miR122, known to be widely expressed in normal hepatocytes while downregulated in hepatocellular carcinoma, were added to specifically limit cytotoxicity in HCC cells, thereby limiting the off-target effects. KYAT1 expression was significantly reduced in cells with high levels of miR122 supporting the concept of miR-guided induction of tumor-specific cytotoxicity. The addition of alpha-ketoacid favored the production of methylselenol, enhancing the cytotoxic efficacy of MSC in HCC cells, with no effects on primary human hepatocytes. Altogether, the proposed regimen offers great potential to safely and specifically target hepatic tumors that are currently untreatable. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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15 pages, 2176 KiB

Open AccessArticle

Vitamin C Cytotoxicity and Its Effects in Redox Homeostasis and Energetic Metabolism in Papillary Thyroid Carcinoma Cell Lines

by Laura Tronci, Gabriele Serreli, Cristina Piras, Daniela Virginia Frau, Tinuccia Dettori, Monica Deiana, Federica Murgia, Maria Laura Santoru, Martina Spada, Vera Piera Leoni, Julian Leether Griffin, Roberta Vanni, Luigi Atzori and Paola Caria

Antioxidants 2021, 10(5), 809; https://doi.org/10.3390/antiox10050809 - 20 May 2021

Cited by 16 | Viewed by 4564

Abstract

High-dose of vitamin C (L-ascorbic acid, ascorbate) exhibits anti-tumoral effects, primarily mediated by pro-oxidant mechanisms. This cytotoxic effect is thought to affect the reciprocal crosstalk between redox balance and cell metabolism in different cancer types. Vitamin C also inhibits the growth of papillary [...] Read more.

High-dose of vitamin C (L-ascorbic acid, ascorbate) exhibits anti-tumoral effects, primarily mediated by pro-oxidant mechanisms. This cytotoxic effect is thought to affect the reciprocal crosstalk between redox balance and cell metabolism in different cancer types. Vitamin C also inhibits the growth of papillary thyroid carcinoma (PTC) cells, although the metabolic and redox effects remain to be fully understood. To shed light on these aspects, PTC-derived cell lines harboring the most common genetic alterations characterizing this tumor were used. Cell viability, apoptosis, and the metabolome were explored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test (MTT), flow cytometry, and UHPLC/MS. Changes were observed in redox homeostasis, with increased reactive oxygen species (ROS) level and perturbation in antioxidants and electron carriers, leading to cell death by both apoptosis and necrosis. The oxidative stress contributed to the metabolic alterations in both glycolysis and TCA cycle. Our results confirm the pro-oxidant effect of vitamin C as relevant in triggering the cytotoxicity in PTC cells and suggest that inhibition of glycolysis and alteration of TCA cycle via NAD⁺ depletion can play an important role in this mechanism of PTC cancer cell death. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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16 pages, 2889 KiB

Open AccessArticle

Butterfly Pea Flower (Clitoria ternatea Linn.) Extract Ameliorates Cardiovascular Dysfunction and Oxidative Stress in Nitric Oxide-Deficient Hypertensive Rats

by Putcharawipa Maneesai, Metee Iampanichakul, Nisita Chaihongsa, Anuson Poasakate, Prapassorn Potue, Siwayu Rattanakanokchai, Sarawoot Bunbupha, Petcharat Chiangsaen and Poungrat Pakdeechote

Antioxidants 2021, 10(4), 523; https://doi.org/10.3390/antiox10040523 - 27 Mar 2021

Cited by 21 | Viewed by 8168

Abstract

In this study, we examine whether Clitoria ternatea Linn. (CT) can prevent Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced cardiac and vascular dysfunction in rats. Male Sprague Dawley rats were given L-NAME (40 mg/kg, drinking water) and orally administered with CT extract (300 mg/kg/day) or [...] Read more.

In this study, we examine whether Clitoria ternatea Linn. (CT) can prevent Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced cardiac and vascular dysfunction in rats. Male Sprague Dawley rats were given L-NAME (40 mg/kg, drinking water) and orally administered with CT extract (300 mg/kg/day) or lisinopril (2.5 mg/kg/day) for 5 weeks. The main phytochemical components of the CT extract were found to be flavonoids. The CT extract alleviated the high blood pressure in rats receiving L-NAME. Decreased vasorelaxation responses to acetylcholine and enhanced contractile responses to sympathetic nerve stimulation in aortic rings and mesenteric vascular beds of L-NAME treated rats were ameliorated by CT extract supplementation. Left ventricular hypertrophy and dysfunction were developed in L-NAME rats, which were partially prevented by CT extract treatment. The CT extract alleviated upregulated endothelial nitric oxide synthase expression, decreased plasma nitrate/nitrite levels, and increased oxidative stress in L-NAME rats. It suppressed high levels of serum angiotensin-converting enzyme activity, plasma angiotensin II, and cardiac angiotensin II type 1 receptor, NADPH oxidases 2, nuclear factor-kappa B, and tumor necrosis factor-alpha expression. The CT extract, therefore, partially prevented L-NAME-induced hypertension and cardiovascular alterations in rats. These effects might be related to a reduction in the oxidative stress and renin–angiotensin system activation due to L-NAME in rats. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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22 pages, 6731 KiB

Open AccessArticle

IL17A Depletion Affects the Metabolism of Macrophages Treated with Gemcitabine

by Cecilia Roux, Gianluca Mucciolo, Joanna Kopecka, Francesco Novelli, Chiara Riganti and Paola Cappello

Antioxidants 2021, 10(3), 422; https://doi.org/10.3390/antiox10030422 - 10 Mar 2021

Cited by 4 | Viewed by 4314

Abstract

Background: Interleukin (IL)17A is a member of the IL17 cytokine family, which is released by both immune and non-immune cells such as tumor and stromal cells into the tumor microenvironment. IL17 receptors are also widely expressed in different type of cells. Among all [...] Read more.

Background: Interleukin (IL)17A is a member of the IL17 cytokine family, which is released by both immune and non-immune cells such as tumor and stromal cells into the tumor microenvironment. IL17 receptors are also widely expressed in different type of cells. Among all the members, IL17A is the most controversial in regulating tumor immunity. Here, we investigated how IL17A inhibition modulated macrophage differentiation and metabolism in the presence or absence of gemcitabine. Gemcitabine is the gold standard drug for treating pancreatic cancer and can increase macrophage antitumoral activities. Results: We observed some unique features of macrophages polarized in the absence of IL17A, in terms of RNA and protein expression of typical phenotypic markers, and we demonstrated that this paralleled specific changes in their metabolism and functions, such as the induction of an antitumor response. Interestingly, these features were almost maintained or enhanced when macrophages were treated with gemcitabine. We also demonstrated that the anti-IL17A antibody effectively reproduced features of macrophages derived from IL17A knock-out mice. Conclusion: Overall, we provide a proof-of-concept that combining an anti-IL17A antibody with gemcitabine may represent an effective strategy to modulate macrophages and enhance the anti-tumor response, especially in pancreatic cancer where gemcitabine is widely used. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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27 pages, 4626 KiB

Open AccessArticle

Anxiolytic, Promnesic, Anti-Acetylcholinesterase and Antioxidant Effects of Cotinine and 6-Hydroxy-L-Nicotine in Scopolamine-Induced Zebrafish (Danio rerio) Model of Alzheimer’s Disease

by Razvan Stefan Boiangiu, Marius Mihasan, Dragos Lucian Gorgan, Bogdan Alexandru Stache and Lucian Hritcu

Antioxidants 2021, 10(2), 212; https://doi.org/10.3390/antiox10020212 - 1 Feb 2021

Cited by 27 | Viewed by 5315

Abstract

Cotinine (COT) and 6-hydroxy-L-nicotine (6HLN) are two nicotinic derivatives that possess cognitive-improving abilities and antioxidant properties in different rodent models of Alzheimer’s disease (AD), eluding the side-effects of nicotine (NIC), the parent molecule. In the current study, we evaluated the impact of COT [...] Read more.

Cotinine (COT) and 6-hydroxy-L-nicotine (6HLN) are two nicotinic derivatives that possess cognitive-improving abilities and antioxidant properties in different rodent models of Alzheimer’s disease (AD), eluding the side-effects of nicotine (NIC), the parent molecule. In the current study, we evaluated the impact of COT and 6HLN on memory deterioration, anxiety, and oxidative stress in the scopolamine (SCOP)-induced zebrafish model of AD. For this, COT and 6HLN were acutely administered by immersion to zebrafish that were treated with SCOP before testing. The memory performances were assessed in Y-maze and object discrimination (NOR) tasks, while the anxiety-like behavior was evaluated in the novel tank diving test (NTT). The acetylcholinesterase (AChE) activity and oxidative stress were measured from brain samples. The RT-qPCR analysis was used to evaluate the npy, egr1, bdnf, and nrf2a gene expression. Our data indicated that both COT and 6HLN attenuated the SCOP-induced anxiety-like behavior and memory impairment and reduced the oxidative stress and AChE activity in the brain of zebrafish. Finally, RT-qPCR analysis indicated that COT and 6HLN increased the npy, egr1, bdnf, and nrf2a gene expression. Therefore, COT and 6HLN could be used as tools for improving AD conditions. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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14 pages, 3177 KiB

Open AccessArticle

Inter-Relationship between Platelet-Derived Microparticles and Oxidative Stress in Patients with Venous Thromboembolism

by Salvatore Santo Signorelli, Gea Oliveri Conti, Maria Fiore, Maria Grazia Elfio, Antonio Cristaldi, Ilenia Nicolosi, Pietro Zuccarello, Luca Zanoli, Agostino Gaudio, Domenico Di Raimondo and Margherita Ferrante

Antioxidants 2020, 9(12), 1217; https://doi.org/10.3390/antiox9121217 - 2 Dec 2020

Cited by 7 | Viewed by 2199

Abstract

Background: Hypercoagulative conditions play a key role in venous thromboembolism (VTE). Inflammation is currently linked to VTE, but the potential role of circulating microparticles and oxidative stress (OxS) must be elucidated. The aim of this study was to evaluate platelet-derived microparticles and surrogate [...] Read more.

Background: Hypercoagulative conditions play a key role in venous thromboembolism (VTE). Inflammation is currently linked to VTE, but the potential role of circulating microparticles and oxidative stress (OxS) must be elucidated. The aim of this study was to evaluate platelet-derived microparticles and surrogate OxS biomarkers in patients diagnosed with VTE through a case–control study. Methods: Platelet-derived microparticles (MPs), pro-thrombinase-induced clotting time assay (PiCT), phospholipids (PLPs), malondialdehyde (MDA), 4-hydroxynonenale (4-HNE), thiobarbituric acid reactive substances (TBARs), superoxide dismutase (SOD), and galectin-3 (Gal-3) were measured in VTE patients and in healthy controls. Results: PLPs, 4-HNE, TBARs, and Gal-3 were higher in VTE patients compared to controls; conversely, SOD was lower. A significant non-linear regression between OxS biomarkers and the markers of platelet degranulation was found. Conclusion: Our results suggest that OxS and platelet degranulation are concomitant pathophysiological mechanisms in VTE. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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Review

Jump to: Research, Other

28 pages, 1120 KiB

Open AccessReview

Hormesis and Oxidative Distress: Pathophysiology of Reactive Oxygen Species and the Open Question of Antioxidant Modulation and Supplementation

by Mariapaola Nitti, Barbara Marengo, Anna Lisa Furfaro, Maria Adelaide Pronzato, Umberto Maria Marinari, Cinzia Domenicotti and Nicola Traverso

Antioxidants 2022, 11(8), 1613; https://doi.org/10.3390/antiox11081613 - 19 Aug 2022

Cited by 18 | Viewed by 4181

Abstract

Alterations of redox homeostasis leads to a condition of resilience known as hormesis that is due to the activation of redox-sensitive pathways stimulating cell proliferation, growth, differentiation, and angiogenesis. Instead, supraphysiological production of reactive oxygen species (ROS) exceeds antioxidant defence and leads to [...] Read more.

Alterations of redox homeostasis leads to a condition of resilience known as hormesis that is due to the activation of redox-sensitive pathways stimulating cell proliferation, growth, differentiation, and angiogenesis. Instead, supraphysiological production of reactive oxygen species (ROS) exceeds antioxidant defence and leads to oxidative distress. This condition induces damage to biomolecules and is responsible or co-responsible for the onset of several chronic pathologies. Thus, a dietary antioxidant supplementation has been proposed in order to prevent aging, cardiovascular and degenerative diseases as well as carcinogenesis. However, this approach has failed to demonstrate efficacy, often leading to harmful side effects, in particular in patients affected by cancer. In this latter case, an approach based on endogenous antioxidant depletion, leading to ROS overproduction, has shown an interesting potential for enhancing susceptibility of patients to anticancer therapies. Therefore, a deep investigation of molecular pathways involved in redox balance is crucial in order to identify new molecular targets useful for the development of more effective therapeutic approaches. The review herein provides an overview of the pathophysiological role of ROS and focuses the attention on positive and negative aspects of antioxidant modulation with the intent to find new insights for a successful clinical application. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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21 pages, 1920 KiB

Open AccessReview

Hepatic Myofibroblasts: A Heterogeneous and Redox-Modulated Cell Population in Liver Fibrogenesis

by Claudia Bocca, Francesca Protopapa, Beatrice Foglia, Marina Maggiora, Stefania Cannito, Maurizio Parola and Erica Novo

Antioxidants 2022, 11(7), 1278; https://doi.org/10.3390/antiox11071278 - 28 Jun 2022

Cited by 11 | Viewed by 2073

Abstract

During chronic liver disease (CLD) progression, hepatic myofibroblasts (MFs) represent a unique cellular phenotype that plays a critical role in driving liver fibrogenesis and then fibrosis. Although they could originate from different cell types, MFs exhibit a rather common pattern of pro-fibrogenic phenotypic [...] Read more.

During chronic liver disease (CLD) progression, hepatic myofibroblasts (MFs) represent a unique cellular phenotype that plays a critical role in driving liver fibrogenesis and then fibrosis. Although they could originate from different cell types, MFs exhibit a rather common pattern of pro-fibrogenic phenotypic responses, which are mostly elicited or sustained both by oxidative stress and reactive oxygen species (ROS) and several mediators (including growth factors, cytokines, chemokines, and others) that often operate through the up-regulation of the intracellular generation of ROS. In the present review, we will offer an overview of the role of MFs in the fibrogenic progression of CLD from different etiologies by focusing our attention on the direct or indirect role of ROS and, more generally, oxidative stress in regulating MF-related phenotypic responses. Moreover, this review has the purpose of illustrating the real complexity of the ROS modulation during CLD progression. The reader will have to keep in mind that a number of issues are able to affect the behavior of the cells involved: a) the different concentrations of reactive species, b) the intrinsic state of the target cells, as well as c) the presence of different growth factors, cytokines, and other mediators in the extracellular microenvironment or of other cellular sources of ROS. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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21 pages, 6830 KiB

Open AccessReview

Antioxidant Activity of Natural Hydroquinones

by Rosa M. Giner, José Luis Ríos and Salvador Máñez

Antioxidants 2022, 11(2), 343; https://doi.org/10.3390/antiox11020343 - 9 Feb 2022

Cited by 22 | Viewed by 4544

Abstract

Secondary metabolites derived from hydroquinone are quite rare in nature despite the original simplicity of its structure, especially when compared to other derivatives with which it shares biosynthetic pathways. However, its presence in a prenylated form is somewhat relevant, especially in the marine [...] Read more.

Secondary metabolites derived from hydroquinone are quite rare in nature despite the original simplicity of its structure, especially when compared to other derivatives with which it shares biosynthetic pathways. However, its presence in a prenylated form is somewhat relevant, especially in the marine environment, where it is found in different algae and invertebrates. Sometimes, more complex molecules have also been identified, as in the case of polycyclic diterpenes, such as those possessing an abietane skeleton. In every case, the presence of the dihydroxy group in the para position gives them antioxidant capacity, through its transformation into para-quinones.This review focuses on natural hydroquinones with antioxidant properties referenced in the last fifteen years. This activity, which has been generally demonstrated in vitro, should lead to relevant pharmacological properties, through its interaction with enzymes, transcription factors and other proteins, which may be particularly relevant for the prevention of degenerative diseases of the central nervous system, or also in cancer and metabolic or immune diseases. As a conclusion, this review has updated the pharmacological potential of hydroquinone derivatives, despite the fact that only a small number of molecules are known as active principles in established medicinal plants. The highlights of the present review are as follows: (a) sesquiterpenoid zonarol and analogs, whose activity is based on the stimulation of the Nrf2/ARE pathway, have a neuroprotective effect; (b) the research on pestalotioquinol and analogs (aromatic ene-ynes) in the pharmacology of atherosclerosis is of great value, due to their agonistic interaction with LXRα; and (c) prenylhydroquinones with a selective effect on tyrosine nitration or protein carbonylation may be of interest in the control of post-translational protein modifications, which usually appear in chronic inflammatory diseases. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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16 pages, 1119 KiB

Open AccessReview

Physical Activity vs. Redox Balance in the Brain: Brain Health, Aging and Diseases

by Paweł Sutkowy, Alina Woźniak, Celestyna Mila-Kierzenkowska, Karolina Szewczyk-Golec, Roland Wesołowski, Marta Pawłowska and Jarosław Nuszkiewicz

Antioxidants 2022, 11(1), 95; https://doi.org/10.3390/antiox11010095 - 30 Dec 2021

Cited by 19 | Viewed by 3951

Abstract

It has been proven that physical exercise improves cognitive function and memory, has an analgesic and antidepressant effect, and delays the aging of the brain and the development of diseases, including neurodegenerative disorders. There are even attempts to use physical activity in the [...] Read more.

It has been proven that physical exercise improves cognitive function and memory, has an analgesic and antidepressant effect, and delays the aging of the brain and the development of diseases, including neurodegenerative disorders. There are even attempts to use physical activity in the treatment of mental diseases. The course of most diseases is strictly associated with oxidative stress, which can be prevented or alleviated with regular exercise. It has been proven that physical exercise helps to maintain the oxidant–antioxidant balance. In this review, we present the current knowledge on redox balance in the organism and the consequences of its disruption, while focusing mainly on the brain. Furthermore, we discuss the impact of physical activity on aging and brain diseases, and present current recommendations and directions for further research in this area. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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18 pages, 2789 KiB

Open AccessReview

Usefulness of Melatonin and Other Compounds as Antioxidants and Epidrugs in the Treatment of Head and Neck Cancer

by Joaquín Guerra and Jesús Devesa

Antioxidants 2022, 11(1), 35; https://doi.org/10.3390/antiox11010035 - 24 Dec 2021

Cited by 11 | Viewed by 4049

Abstract

Along with genetic mutations, aberrant epigenetic alterations are the initiators of head and neck cancer carcinogenesis. Currently, several drugs are being developed to correct these epigenetic alterations, known as epidrugs. Some compounds with an antioxidant effect have been shown to be effective in [...] Read more.

Along with genetic mutations, aberrant epigenetic alterations are the initiators of head and neck cancer carcinogenesis. Currently, several drugs are being developed to correct these epigenetic alterations, known as epidrugs. Some compounds with an antioxidant effect have been shown to be effective in preventing these malignant lesions and in minimizing the complications derived from cytotoxic treatment. Furthermore, in vitro and in vivo studies show a promising role in the treatment of head and neck squamous cell carcinoma (HNSCC). This is the case of supplements with DNA methylation inhibitory function (DNMTi), such as epigallocatechin gallate, sulforaphane, and folic acid; histone deacetylase inhibitors (HDACi), such as sodium butyrate and melatonin or histone acetyltransferase inhibitors (HATi), such as curcumin. The objective of this review is to describe the role of some antioxidants and their epigenetic mechanism of action, with special emphasis on melatonin and butyric acid given their organic production, in the prevention and treatment of HNSCC. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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30 pages, 1530 KiB

Open AccessReview

Oxidative Stress-Related Mechanisms in Melanoma and in the Acquired Resistance to Targeted Therapies

by Stefania Pizzimenti, Simone Ribero, Marie Angele Cucci, Margherita Grattarola, Chiara Monge, Chiara Dianzani, Giuseppina Barrera and Giuliana Muzio

Antioxidants 2021, 10(12), 1942; https://doi.org/10.3390/antiox10121942 - 3 Dec 2021

Cited by 44 | Viewed by 4906

Abstract

Melanoma is a highly aggressive cancer with the poorest prognosis, representing the deadliest form of skin cancer. Activating mutations in BRAF are the most frequent genetic alterations, present in approximately 50% of all melanoma cases. The use of specific inhibitors towards mutant BRAF [...] Read more.

Melanoma is a highly aggressive cancer with the poorest prognosis, representing the deadliest form of skin cancer. Activating mutations in BRAF are the most frequent genetic alterations, present in approximately 50% of all melanoma cases. The use of specific inhibitors towards mutant BRAF variants and MEK, a downstream signaling target of BRAF in the MAPK pathway, has significantly improved progression-free and overall survival in advanced melanoma patients carrying BRAF mutations. Nevertheless, despite these improvements, resistance still develops within the first year of therapy in around 50% of patients, which is a significant problem in managing BRAF-mutated advanced melanoma. Understanding these mechanisms is one of the mainstreams of the research on BRAFi/MEKi acquired resistance. Both genetic and epigenetic mechanisms have been described. Moreover, in recent years, oxidative stress has emerged as another major force involved in all the phases of melanoma development, from initiation to progression until the onsets of the metastatic phenotype and chemoresistance, and has thus become a target for therapy. In the present review, we discuss the current knowledge on oxidative stress and its signaling in melanoma, as well as the oxidative stress-related mechanisms in the acquired resistance to targeted therapies. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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18 pages, 1723 KiB

Open AccessReview

Iron Overload, Oxidative Stress, and Ferroptosis in the Failing Heart and Liver

by Daniele Mancardi, Mariarosa Mezzanotte, Elisa Arrigo, Alice Barinotti and Antonella Roetto

Antioxidants 2021, 10(12), 1864; https://doi.org/10.3390/antiox10121864 - 24 Nov 2021

Cited by 90 | Viewed by 7696

Abstract

Iron accumulation is a key mediator of several cytotoxic mechanisms leading to the impairment of redox homeostasis and cellular death. Iron overload is often associated with haematological diseases which require regular blood transfusion/phlebotomy, and it represents a common complication in thalassaemic patients. Major [...] Read more.

Iron accumulation is a key mediator of several cytotoxic mechanisms leading to the impairment of redox homeostasis and cellular death. Iron overload is often associated with haematological diseases which require regular blood transfusion/phlebotomy, and it represents a common complication in thalassaemic patients. Major damages predominantly occur in the liver and the heart, leading to a specific form of cell death recently named ferroptosis. Different from apoptosis, necrosis, and autophagy, ferroptosis is strictly dependent on iron and reactive oxygen species, with a dysregulation of mitochondrial structure/function. Susceptibility to ferroptosis is dependent on intracellular antioxidant capacity and varies according to the different cell types. Chemotherapy-induced cardiotoxicity has been proven to be mediated predominantly by iron accumulation and ferroptosis, whereas there is evidence about the role of ferritin in protecting cardiomyocytes from ferroptosis and consequent heart failure. Another paradigmatic organ for transfusion-associated complication due to iron overload is the liver, in which the role of ferroptosis is yet to be elucidated. Some studies report a role of ferroptosis in the initiation of hepatic inflammation processes while others provide evidence about an involvement in several pathologies including immune-related hepatitis and acute liver failure. In this manuscript, we aim to review the literature to address putative common features between the response to ferroptosis in the heart and liver. A better comprehension of (dys)similarities is pivotal for the development of future therapeutic strategies that can be designed to specifically target this type of cell death in an attempt to minimize iron-overload effects in specific organs. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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25 pages, 1599 KiB

Open AccessReview

Coenzyme Q at the Hinge of Health and Metabolic Diseases

by Juan Diego Hernández-Camacho, Laura García-Corzo, Daniel José Moreno Fernández-Ayala, Plácido Navas and Guillermo López-Lluch

Antioxidants 2021, 10(11), 1785; https://doi.org/10.3390/antiox10111785 - 8 Nov 2021

Cited by 17 | Viewed by 5710

Abstract

Coenzyme Q is a unique lipidic molecule highly conserved in evolution and essential to maintaining aerobic metabolism. It is endogenously synthesized in all cells by a very complex pathway involving a group of nuclear genes that share high homology among species. This pathway [...] Read more.

Coenzyme Q is a unique lipidic molecule highly conserved in evolution and essential to maintaining aerobic metabolism. It is endogenously synthesized in all cells by a very complex pathway involving a group of nuclear genes that share high homology among species. This pathway is tightly regulated at transcription and translation, but also by environment and energy requirements. Here, we review how coenzyme Q reacts within mitochondria to promote ATP synthesis and also integrates a plethora of metabolic pathways and regulates mitochondrial oxidative stress. Coenzyme Q is also located in all cellular membranes and plasma lipoproteins in which it exerts antioxidant function, and its reaction with different extramitochondrial oxidoreductases contributes to regulate the cellular redox homeostasis and cytosolic oxidative stress, providing a key factor in controlling various apoptosis mechanisms. Coenzyme Q levels can be decreased in humans by defects in the biosynthesis pathway or by mitochondrial or cytosolic dysfunctions, leading to a highly heterogeneous group of mitochondrial diseases included in the coenzyme Q deficiency syndrome. We also review the importance of coenzyme Q levels and its reactions involved in aging and age-associated metabolic disorders, and how the strategy of its supplementation has had benefits for combating these diseases and for physical performance in aging. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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19 pages, 400 KiB

Open AccessReview

Peroxisome Proliferator-Activated Receptors (PPARs) and Oxidative Stress in Physiological Conditions and in Cancer

by Giuliana Muzio, Giuseppina Barrera and Stefania Pizzimenti

Antioxidants 2021, 10(11), 1734; https://doi.org/10.3390/antiox10111734 - 29 Oct 2021

Cited by 44 | Viewed by 3731

Abstract

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor superfamily. Originally described as “orphan nuclear receptors”, they can bind both natural and synthetic ligands acting as agonists or antagonists. In humans three subtypes, PPARα, β/δ, γ, are encoded by different genes, show [...] Read more.

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor superfamily. Originally described as “orphan nuclear receptors”, they can bind both natural and synthetic ligands acting as agonists or antagonists. In humans three subtypes, PPARα, β/δ, γ, are encoded by different genes, show tissue-specific expression patterns, and contribute to the regulation of lipid and carbohydrate metabolisms, of different cell functions, including proliferation, death, differentiation, and of processes, as inflammation, angiogenesis, immune response. The PPAR ability in increasing the expression of various antioxidant genes and decreasing the synthesis of pro-inflammatory mediators, makes them be considered among the most important regulators of the cellular response to oxidative stress conditions. Based on the multiplicity of physiological effects, PPAR involvement in cancer development and progression has attracted great scientific interest with the aim to describe changes occurring in their expression in cancer cells, and to investigate the correlation with some characteristics of cancer phenotype, including increased proliferation, decreased susceptibility to apoptosis, malignancy degree and onset of resistance to anticancer drugs. This review focuses on mechanisms underlying the antioxidant and anti-inflammatory properties of PPARs in physiological conditions, and on the reported beneficial effects of PPAR activation in cancer. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

17 pages, 739 KiB

Open AccessReview

Oxidative Stress in Preterm Newborns

by Chiara Lembo, Giuseppe Buonocore and Serafina Perrone

Antioxidants 2021, 10(11), 1672; https://doi.org/10.3390/antiox10111672 - 23 Oct 2021

Cited by 75 | Viewed by 4574

Abstract

Preterm babies are highly susceptible to oxidative stress (OS) due to an imbalance between the oxidant and antioxidant systems. The generation of free radicals (FR) induces oxidative damage to multiple body organs and systems. OS is the main factor responsible for the development [...] Read more.

Preterm babies are highly susceptible to oxidative stress (OS) due to an imbalance between the oxidant and antioxidant systems. The generation of free radicals (FR) induces oxidative damage to multiple body organs and systems. OS is the main factor responsible for the development of typical premature infant diseases, such as bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, intraventricular hemorrhage, periventricular leukomalacia, kidney damage, eryptosis, and also respiratory distress syndrome and patent ductus arteriosus. Many biomarkers have been detected to early identify newborns at risk of developing a free radical-mediated disease and to investigate new antioxidant strategies. This review reports the current knowledge on OS in the preterm newborns and the newest findings concerning the use of OS biomarkers as diagnostic tools, as well as in implementing antioxidant therapeutic strategies for the prevention and treatment of these diseases and their sequelae. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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16 pages, 855 KiB

Open AccessReview

Oxidative Stress and Beta Amyloid in Alzheimer’s Disease. Which Comes First: The Chicken or the Egg?

by Elena Tamagno, Michela Guglielmotto, Valeria Vasciaveo and Massimo Tabaton

Antioxidants 2021, 10(9), 1479; https://doi.org/10.3390/antiox10091479 - 16 Sep 2021

Cited by 110 | Viewed by 9534

Abstract

The pathogenesis of Alzheimer’s disease involves β amyloid (Aβ) accumulation known to induce synaptic dysfunction and neurodegeneration. The brain’s vulnerability to oxidative stress (OS) is considered a crucial detrimental factor in Alzheimer’s disease. OS and Aβ are linked to each other because Aβ [...] Read more.

The pathogenesis of Alzheimer’s disease involves β amyloid (Aβ) accumulation known to induce synaptic dysfunction and neurodegeneration. The brain’s vulnerability to oxidative stress (OS) is considered a crucial detrimental factor in Alzheimer’s disease. OS and Aβ are linked to each other because Aβ induces OS, and OS increases the Aβ deposition. Thus, the answer to the question “which comes first: the chicken or the egg?” remains extremely difficult. In any case, the evidence for the primary occurrence of oxidative stress in AD is attractive. Thus, evidence indicates that a long period of gradual oxidative damage accumulation precedes and results in the appearance of clinical and pathological AD symptoms, including Aβ deposition, neurofibrillary tangle formation, metabolic dysfunction, and cognitive decline. Moreover, oxidative stress plays a crucial role in the pathogenesis of many risk factors for AD. Alzheimer’s disease begins many years before its symptoms, and antioxidant treatment can be an important therapeutic target for attacking the disease. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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12 pages, 845 KiB

Open AccessReview

Fast Antioxidant Reaction of Polyphenols and Their Metabolites

by Janusz M. Gebicki and Thomas Nauser

Antioxidants 2021, 10(8), 1297; https://doi.org/10.3390/antiox10081297 - 17 Aug 2021

Cited by 26 | Viewed by 3881

Abstract

The negative correlation between diets rich in fruits and vegetables and the occurrence of cardiovascular disease, stroke, cancer, atherosclerosis, cognitive impairment and other deleterious conditions is well established, with flavonoids and other polyphenols held to be partly responsible for the beneficial effects. Initially, [...] Read more.

The negative correlation between diets rich in fruits and vegetables and the occurrence of cardiovascular disease, stroke, cancer, atherosclerosis, cognitive impairment and other deleterious conditions is well established, with flavonoids and other polyphenols held to be partly responsible for the beneficial effects. Initially, these effects were explained by their antioxidant ability, but the low concentrations of polyphenols in tissues and relatively slow reaction with free radicals suggested that, instead, they act by regulating cell signalling pathways. Here we summarise results demonstrating that the abandonment of an antioxidant role for food polyphenols is based on incomplete knowledge of the mechanism of the polyphenol-free radical reaction. New kinetic measurements show that the reaction is up to 1000 times faster than previously reported and lowers the damaging potential of the radicals. The results also show that the antioxidant action does not require phenolic groups, but only a carbon-centred free radical and an aromatic molecule. Thus, not only food polyphenols but also many of their metabolites are effective antioxidants, significantly increasing the antioxidant protection of cells and tissues. By restoring an important antioxidant role for food polyphenols, the new findings provide experimental support for the advocacy of diets rich in plant-derived food. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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20 pages, 1388 KiB

Open AccessReview

Oxidized LDLs as Signaling Molecules

by Jean-Marc Zingg, Adelina Vlad and Roberta Ricciarelli

Antioxidants 2021, 10(8), 1184; https://doi.org/10.3390/antiox10081184 - 26 Jul 2021

Cited by 32 | Viewed by 5883

Abstract

Levels of oxidized low-density lipoproteins (oxLDLs) are usually low in vivo but can increase whenever the balance between formation and scavenging of free radicals is impaired. Under normal conditions, uptake and degradation represent the physiological cellular response to oxLDL exposure. The uptake of [...] Read more.

Levels of oxidized low-density lipoproteins (oxLDLs) are usually low in vivo but can increase whenever the balance between formation and scavenging of free radicals is impaired. Under normal conditions, uptake and degradation represent the physiological cellular response to oxLDL exposure. The uptake of oxLDLs is mediated by cell surface scavenger receptors that may also act as signaling molecules. Under conditions of atherosclerosis, monocytes/macrophages and vascular smooth muscle cells highly exposed to oxLDLs tend to convert to foam cells due to the intracellular accumulation of lipids. Moreover, the atherogenic process is accelerated by the increased expression of the scavenger receptors CD36, SR-BI, LOX-1, and SRA in response to high levels of oxLDL and oxidized lipids. In some respects, the effects of oxLDLs, involving cell proliferation, inflammation, apoptosis, adhesion, migration, senescence, and gene expression, can be seen as an adaptive response to the rise of free radicals in the vascular system. Unlike highly reactive radicals, circulating oxLDLs may signal to cells at more distant sites and possibly trigger a systemic antioxidant defense, thus elevating the role of oxLDLs to that of signaling molecules with physiological relevance. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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19 pages, 1274 KiB

Open AccessReview

The Controversial Role of 24-S-Hydroxycholesterol in Alzheimer’s Disease

by Paola Gamba, Serena Giannelli, Erica Staurenghi, Gabriella Testa, Barbara Sottero, Fiorella Biasi, Giuseppe Poli and Gabriella Leonarduzzi

Antioxidants 2021, 10(5), 740; https://doi.org/10.3390/antiox10050740 - 7 May 2021

Cited by 44 | Viewed by 4954

Abstract

The development of Alzheimer’s disease (AD) is influenced by several events, among which the dysregulation of cholesterol metabolism in the brain plays a major role. Maintenance of brain cholesterol homeostasis is essential for neuronal functioning and brain development. To maintain the steady-state level, [...] Read more.

The development of Alzheimer’s disease (AD) is influenced by several events, among which the dysregulation of cholesterol metabolism in the brain plays a major role. Maintenance of brain cholesterol homeostasis is essential for neuronal functioning and brain development. To maintain the steady-state level, excess brain cholesterol is converted into the more hydrophilic metabolite 24-S-hydroxycholesterol (24-OHC), also called cerebrosterol, by the neuron-specific enzyme CYP46A1. A growing bulk of evidence suggests that cholesterol oxidation products, named oxysterols, are the link connecting altered cholesterol metabolism to AD. It has been shown that the levels of some oxysterols, including 27-hydroxycholesterol, 7β-hydroxycholesterol and 7-ketocholesterol, significantly increase in AD brains contributing to disease progression. In contrast, 24-OHC levels decrease, likely due to neuronal loss. Among the different brain oxysterols, 24-OHC is certainly the one whose role is most controversial. It is the dominant oxysterol in the brain and evidence shows that it represents a signaling molecule of great importance for brain function. However, numerous studies highlighted the potential role of 24-OHC in favoring AD development, since it promotes neuroinflammation, amyloid β (Aβ) peptide production, oxidative stress and cell death. In parallel, 24-OHC has been shown to exert several beneficial effects against AD progression, such as preventing tau hyperphosphorylation and Aβ production. In this review we focus on the current knowledge of the controversial role of 24-OHC in AD pathogenesis, reporting a detailed overview of the findings about its levels in different AD biological samples and its noxious or neuroprotective effects in the brain. Given the relevant role of 24-OHC in AD pathophysiology, its targeting could be useful for disease prevention or slowing down its progression. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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20 pages, 2575 KiB

Open AccessReview

Reactive Oxygen Species-Induced TRPM2-Mediated Ca²⁺ Signalling in Endothelial Cells

by Ran Ding, Ya-Ling Yin and Lin-Hua Jiang

Antioxidants 2021, 10(5), 718; https://doi.org/10.3390/antiox10050718 - 3 May 2021

Cited by 24 | Viewed by 3723

Abstract

Endothelial cells form the innermost layer of blood vessels with a fundamental role as the physical barrier. While regulation of endothelial cell function by reactive oxygen species (ROS) is critical in physiological processes such as angiogenesis, endothelial function is a major target for [...] Read more.

Endothelial cells form the innermost layer of blood vessels with a fundamental role as the physical barrier. While regulation of endothelial cell function by reactive oxygen species (ROS) is critical in physiological processes such as angiogenesis, endothelial function is a major target for interruption by oxidative stress resulting from generation of high levels of ROS in endothelial cells by various pathological factors and also release of ROS by neutrophils. TRPM2 is a ROS-sensitive Ca²⁺-permeable channel expressed in endothelial cells of various vascular beds. In this review, we provide an overview of the TRPM2 channel and its role in mediating ROS-induced Ca²⁺ signaling in endothelial cells. We discuss the TRPM2-mediated Ca²⁺ signaling in vascular endothelial growth factor-induced angiogenesis and in post-ischemic neovascularization. In particular, we examine the accumulative evidence that supports the role of TRPM2-mediated Ca²⁺ signaling in endothelial cell dysfunction caused by various oxidative stress-inducing factors that are associated with tissue inflammation, obesity and diabetes, as well as air pollution. These findings provide new, mechanistic insights into ROS-mediated regulation of endothelial cells in physiology and diseases. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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20 pages, 2259 KiB

Open AccessReview

Phenotypic Modulation of Macrophages and Vascular Smooth Muscle Cells in Atherosclerosis—Nitro-Redox Interconnections

by Justine Bonetti, Alessandro Corti, Lucie Lerouge, Alfonso Pompella and Caroline Gaucher

Antioxidants 2021, 10(4), 516; https://doi.org/10.3390/antiox10040516 - 26 Mar 2021

Cited by 26 | Viewed by 5826

Abstract

Monocytes/macrophages and vascular smooth muscle cells (vSMCs) are the main cell types implicated in atherosclerosis development, and unlike other mature cell types, both retain a remarkable plasticity. In mature vessels, differentiated vSMCs control the vascular tone and the blood pressure. In response to [...] Read more.

Monocytes/macrophages and vascular smooth muscle cells (vSMCs) are the main cell types implicated in atherosclerosis development, and unlike other mature cell types, both retain a remarkable plasticity. In mature vessels, differentiated vSMCs control the vascular tone and the blood pressure. In response to vascular injury and modifications of the local environment (inflammation, oxidative stress), vSMCs switch from a contractile to a secretory phenotype and also display macrophagic markers expression and a macrophagic behaviour. Endothelial dysfunction promotes adhesion to the endothelium of monocytes, which infiltrate the sub-endothelium and differentiate into macrophages. The latter become polarised into M1 (pro-inflammatory), M2 (anti-inflammatory) or Mox macrophages (oxidative stress phenotype). Both monocyte-derived macrophages and macrophage-like vSMCs are able to internalise and accumulate oxLDL, leading to formation of “foam cells” within atherosclerotic plaques. Variations in the levels of nitric oxide (NO) can affect several of the molecular pathways implicated in the described phenomena. Elucidation of the underlying mechanisms could help to identify novel specific therapeutic targets, but to date much remains to be explored. The present article is an overview of the different factors and signalling pathways implicated in plaque formation and of the effects of NO on the molecular steps of the phenotypic switch of macrophages and vSMCs. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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18 pages, 1032 KiB

Open AccessReview

Control of Oxidative Stress in Cancer Chemoresistance: Spotlight on Nrf2 Role

by Giuseppina Barrera, Marie Angele Cucci, Margherita Grattarola, Chiara Dianzani, Giuliana Muzio and Stefania Pizzimenti

Antioxidants 2021, 10(4), 510; https://doi.org/10.3390/antiox10040510 - 25 Mar 2021

Cited by 55 | Viewed by 4848

Abstract

Chemoresistance represents the main obstacle to cancer treatment with both conventional and targeted therapy. Beyond specific molecular alterations, which can lead to targeted therapy, metabolic remodeling, including the control of redox status, plays an important role in cancer cell survival following therapy. Although [...] Read more.

Chemoresistance represents the main obstacle to cancer treatment with both conventional and targeted therapy. Beyond specific molecular alterations, which can lead to targeted therapy, metabolic remodeling, including the control of redox status, plays an important role in cancer cell survival following therapy. Although cancer cells generally have a high basal reactive oxygen species (ROS) level, which makes them more susceptible than normal cells to a further increase of ROS, chemoresistant cancer cells become highly adapted to intrinsic or drug-induced oxidative stress by upregulating their antioxidant systems. The antioxidant response is principally mediated by the transcription factor Nrf2, which has been considered the master regulator of antioxidant and cytoprotective genes. Nrf2 expression is often increased in several types of chemoresistant cancer cells, and its expression is mediated by diverse mechanisms. In addition to Nrf2, other transcription factors and transcriptional coactivators can participate to maintain the high antioxidant levels in chemo and radio-resistant cancer cells. The control of expression and function of these molecules has been recently deepened to identify which of these could be used as a new therapeutic target in the treatment of tumors resistant to conventional therapy. In this review, we report the more recent advances in the study of Nrf2 regulation in chemoresistant cancers and the role played by other transcription factors and transcriptional coactivators in the control of antioxidant responses in chemoresistant cancer cells. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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41 pages, 8471 KiB

Open AccessSystematic Review

Role of Photobiomodulation Therapy in Modulating Oxidative Stress in Temporomandibular Disorders. A Systematic Review and Meta-Analysis of Human Randomised Controlled Trials

by Reem Hanna, Snehal Dalvi, René Jean Bensadoun and Stefano Benedicenti

Antioxidants 2021, 10(7), 1028; https://doi.org/10.3390/antiox10071028 - 25 Jun 2021

Cited by 27 | Viewed by 6787

Abstract

This systematic review and meta-analysis (PROSPERO registration; ref CRD 42020198921) aimed to govern photobiomodulation therapy (PBMT) efficacy in temporomandibular disorder (TMD). PRISMA guidelines and Cochrane Collaboration recommendations were followed. Differences in pain reduction assessment by qualitative measurement with visual analogue scale (VAS), pain [...] Read more.

This systematic review and meta-analysis (PROSPERO registration; ref CRD 42020198921) aimed to govern photobiomodulation therapy (PBMT) efficacy in temporomandibular disorder (TMD). PRISMA guidelines and Cochrane Collaboration recommendations were followed. Differences in pain reduction assessment by qualitative measurement with visual analogue scale (VAS), pain pressure threshold (PPT) and maximum mouth opening (MMO) were calculated with 95% confidence intervals and pooled in a random effects model with a subgroup analysis, evaluating the role of follow-up duration. Heterogeneity was analysed using Q and I² tests. Publication bias was assessed by visual examination of funnel plot symmetry. Qualitative analysis revealed 46% of the 44 included studies showed a high risk of bias. Meta-analysis on 32 out of 44 studies revealed statistically significant intergroup differences (SSID) for VAS (SMD = −0.55; 95% CI = −0.82 to −0.27; Z = 3.90 (p < 0.001)), PPT (SMD = −0.45; 95% CI = −0.89 to 0.00; Z = 1.97 (p = 0.05)) and MMO (SMD = −0.45; 95% CI = −0.89 to 0.00; Z = 1.97 (p = 0.05)), favouring PBMT compared to control treatment strategies. Sensitivity analysis revealed SSID (SMD = −0.53; 95% CI = −0.73 to −0.32; Z = 5.02 (p < 0.0001)) with low heterogeneity (Τ² = 0.02; χ² = 16.03 (p = 0.31); I² = 13%). Hence, this review, for first time, proposed suggested recommendations for PBMT protocols and methodology for future extensive TMD research. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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9 pages, 390 KiB

Open AccessSystematic Review

Oxidative Stress Biomarkers in Chronic Obstructive Pulmonary Disease Exacerbations: A Systematic Review

by Elisabetta Zinellu, Angelo Zinellu, Alessandro G. Fois, Maria Carmina Pau, Valentina Scano, Barbara Piras, Ciriaco Carru and Pietro Pirina

Antioxidants 2021, 10(5), 710; https://doi.org/10.3390/antiox10050710 - 29 Apr 2021

Cited by 16 | Viewed by 3349

Abstract

Background: Chronic Obstructive Pulmonary Disease (COPD) is a progressive disease characterized by a not fully reversible airflow limitation associated with an abnormal inflammatory response. Exacerbations of COPD are of major importance in the acceleration of disease progression, in healthcare costs, and negatively affect [...] Read more.

Background: Chronic Obstructive Pulmonary Disease (COPD) is a progressive disease characterized by a not fully reversible airflow limitation associated with an abnormal inflammatory response. Exacerbations of COPD are of major importance in the acceleration of disease progression, in healthcare costs, and negatively affect the patient’s quality of life. Exacerbations are characterized by a further increase in the airway inflammation likely driven by oxidative stress. In order to deepen the knowledge about this topic, several studies have focused on oxidative stress biomarkers levels. This review summarizes the literature findings about oxidative stress biomarkers in exacerbated COPD patients compared to ones in the stable state. Methods: a systematic search in electronic databases Pubmed, Web of Science, Scopus and Google Scholar from inception to January 2021, was conducted using the terms: “oxidative stress”, “chronic obstructive pulmonary disease” or “COPD”, “exacerbation”. Results: 23 studies were selected for the systematic review. They showed the presence of an imbalance between oxidant and antioxidant molecules in favor of the former in exacerbation of COPD. Conclusions: future studies using standardized methods in better characterized population are needed. However, this review suggests that targeting oxidative stress could be useful in monitoring the disease progression in COPD patients and especially in those more susceptible to exacerbations. Full article

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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