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14 pages, 1499 KiB

Open AccessArticle

Sustained Systemic Antioxidative Effects of Intermittent Theta Burst Stimulation beyond Neurodegeneration: Implications in Therapy in 6-Hydroxydopamine Model of Parkinson’s Disease

by Milica Zeljkovic Jovanovic, Jelena Stanojevic, Ivana Stevanovic, Milica Ninkovic, Nadezda Nedeljkovic and Milorad Dragic

Antioxidants 2024, 13(2), 218; https://doi.org/10.3390/antiox13020218 - 08 Feb 2024

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Abstract

Parkinson’s disease (PD) is manifested by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and caudoputamen (Cp), leading to the development of motor and non-motor symptoms. The contribution of oxidative stress to the development and progression of PD [...] Read more.

Parkinson’s disease (PD) is manifested by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and caudoputamen (Cp), leading to the development of motor and non-motor symptoms. The contribution of oxidative stress to the development and progression of PD is increasingly recognized. Experimental models show that strengthening antioxidant defenses and reducing pro-oxidant status may have beneficial effects on disease progression. In this study, the neuroprotective potential of intermittent theta burst stimulation (iTBS) is investigated in a 6-hydroxydopamine (6-OHDA)-induced PD model in rats seven days after intoxication which corresponds to the occurrence of first motor symptoms. Two-month-old male Wistar rats were unilaterally injected with 6-OHDA to mimic PD pathology and were subsequently divided into two groups to receive either iTBS or sham stimulation for 21 days. The main oxidative parameters were analyzed in the caudoputamen, substantia nigra pars compacta, and serum. iTBS treatment notably mitigated oxidative stress indicators, simultaneously increasing antioxidative parameters in the caudoputamen and substantia nigra pars compacta well after 6-OHDA-induced neurodegeneration process was over. Serum analysis confirmed the systemic effect of iTBS with a decrease in oxidative markers and an increase in antioxidants. Prolonged iTBS exerts a modulatory effect on oxidative/antioxidant parameters in the 6-OHDA-induced PD model, suggesting a potential neuroprotective benefit, even though at this specific time point 6-OHDA-induced oxidative status was unaltered. These results emphasize the need to further explore the mechanisms of iTBS and argue in favor of considering it as a therapeutic intervention in PD and related neurodegenerative diseases. Full article

(This article belongs to the Special Issue Cellular ROS and Antioxidants: Physiological and Pathological Role)

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21 pages, 10326 KiB

Open AccessArticle

The Binding of HSPA8 and Mitochondrial ALDH2 Mediates Oxygen-Glucose Deprivation-Induced Fibroblast Senescence

by Wenting Hui, Tongtong Song, Ling Yu and Xia Chen

Antioxidants 2024, 13(1), 42; https://doi.org/10.3390/antiox13010042 - 25 Dec 2023

Viewed by 1124

Abstract

Cellular senescence refers to the permanent and irreversible cessation of the cell cycle. Recently, it has gained significant interest as a promising target for preventing cardiovascular diseases. Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that has been closely linked with an increased [...] Read more.

Cellular senescence refers to the permanent and irreversible cessation of the cell cycle. Recently, it has gained significant interest as a promising target for preventing cardiovascular diseases. Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that has been closely linked with an increased risk of cardiovascular diseases. In this study, bioinformatics analysis revealed that the signaling pathway for fibroblast senescence is significantly activated in mice after myocardial infarction (MI), and that ALDH2 might be a crucial molecule responsible for inducing this change. Therefore, we created an NIH3T3 fibroblast cell line oxygen-glucose deprivation (OGD) model to replicate the conditions of MI in vitro. We further revealed that decreased ALDH2 enzyme activity is a critical factor that affects fibroblast senescence after OGD, and the activation of ALDH2 can improve the mitochondrial damage caused by OGD. We identified Heat Shock 70-kDa Protein 8 (HSPA8) as an interacting protein of ALDH2 through co-immunoprecipitation (Co-IP) and mass spectrometry (MS) detection. Subsequently, our studies showed that HSPA8 translocates to the mitochondria after OGD, potentially binding to ALDH2 and inhibiting its enzyme activity. By transfecting siRNA to inhibit HSPA8 expression in cells, it was found that ALDH2 enzyme activity can be significantly increased, and the senescence characteristics induced by OGD in NIH3T3 cells can be improved. In conclusion, the data from this study suggest that HSPA8, in conjunction with ALDH2, could regulate fibroblast senescence after oxygen-glucose deprivation, providing a new direction and foundation for effectively intervening in fibroblast senescence after myocardial infarction. Full article

(This article belongs to the Special Issue Cellular ROS and Antioxidants: Physiological and Pathological Role)

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17 pages, 8116 KiB

Open AccessArticle

Relationship between Aspartame-Induced Cerebral Cortex Injury and Oxidative Stress, Inflammation, Mitochondrial Dysfunction, and Apoptosis in Sprague Dawley Rats

by Jureeporn U-pathi, Yen-Chia Yeh, Chia-Wen Chen, Eddy E. Owaga and Rong-Hong Hsieh

Antioxidants 2024, 13(1), 2; https://doi.org/10.3390/antiox13010002 - 19 Dec 2023

Viewed by 1349

Abstract

There are emerging concerns about the potential cerebral cortex injury from aspartame due to the accumulation of the various neurotoxic metabolic components in the central nervous system after long-term dietary exposure. The aim of this study was to evaluate the effect of oral [...] Read more.

There are emerging concerns about the potential cerebral cortex injury from aspartame due to the accumulation of the various neurotoxic metabolic components in the central nervous system after long-term dietary exposure. The aim of this study was to evaluate the effect of oral aspartame consumption on cerebral cortex injury in the rat brain, and further evaluate the various underlying molecular mechanisms, with a special focus on oxidative stress, inflammation, mitochondrial dysfunction, and apoptosis pathways. Sprague Dawley rats (nineteen, female) were randomly sub-divided into three groups: (i) normal diet with vehicle: control group (five rats), (ii) low dose of aspartame group (LA): seven rats received 30 mg/kg body weight (bw) daily doses of aspartame, (iii) high dose of aspartame group (HA): seven rats received 60 mg/kg bw daily doses of aspartame. After 8 weeks, the LA and HA groups showed lower expression levels of brain-derived neurotrophic factor (BDNF), antioxidant enzyme activity (SOD2, CAT), antioxidant marker (Nrf2), inflammatory response (IκB), mitochondrial biogenesis (Sirt1, PGC1α, Nrf1, TFAM), mitochondrial DNA (mtDNA) copy number, and apoptosis-related proteins (Bax, Caspase-3) expressions. Aspartame administration also elevated oxidative stress levels (Malondialdehyde, MDA), 8-hydroxy-2-deoxy guanosine (8-OHdG), PGE₂ and COX-2 expressions, pro-inflammatory cytokines (TNFα, IL6, IL1β), antioxidant marker expression (Keap1), inflammatory responses (iNOS, NFκB), and glial fibrillary acidic protein (GFAP) levels in the cerebral cortex of the rats, thereby contributing to the reduced survival of pyramidal cells and astrocyte glial cells of the cerebral cortex. Therefore, these findings imply that aspartame-induced neurotoxicity in rats’ cerebral cortex could be regulated through four mechanisms: inflammation, enhanced oxidant stress, decreased mitochondrial biogenesis, and apoptosis pathways. Full article

(This article belongs to the Special Issue Cellular ROS and Antioxidants: Physiological and Pathological Role)

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24 pages, 4204 KiB

Open AccessArticle

Near-Infrared Light Exposure Triggers ROS to Downregulate Inflammatory Cytokines Induced by SARS-CoV-2 Spike Protein in Human Cell Culture

by Blanche Aguida, Marie-Marthe Chabi, Soria Baouz, Rhys Mould, Jimmy D. Bell, Marootpong Pooam, Sebastien André, Dominique Archambault, Margaret Ahmad and Nathalie Jourdan

Antioxidants 2023, 12(10), 1824; https://doi.org/10.3390/antiox12101824 - 02 Oct 2023

Cited by 1 | Viewed by 2378

Abstract

The leading cause of mortality from SARS-CoV-2 is an exaggerated host immune response, triggering cytokine storms, multiple organ failure and death. Current drug- and vaccine-based therapies are of limited efficacy against novel viral variants. Infrared therapy is a non-invasive and safe method that [...] Read more.

The leading cause of mortality from SARS-CoV-2 is an exaggerated host immune response, triggering cytokine storms, multiple organ failure and death. Current drug- and vaccine-based therapies are of limited efficacy against novel viral variants. Infrared therapy is a non-invasive and safe method that has proven effective against inflammatory conditions for over 100 years. However, its mechanism of action is poorly understood and has not received widespread acceptance. We herein investigate whether near-infrared (NIR) light exposure in human primary alveolar and macrophage cells could downregulate inflammatory cytokines triggered by the SARS-CoV-2 spike (S) protein or lipopolysaccharide (LPS), and via what underlying mechanism. Our results showed a dramatic reduction in pro-inflammatory cytokines within days of NIR light treatment, while anti-inflammatory cytokines were upregulated. Mechanistically, NIR light stimulated mitochondrial metabolism, induced transient bursts in reactive oxygen species (ROS) and activated antioxidant gene transcription. These, in turn, downregulated ROS and inflammatory cytokines. A causal relationship was shown between the induction of cellular ROS by NIR light exposure and the downregulation of inflammatory cytokines triggered by SARS-CoV-2 S. If confirmed by clinical trials, this method would provide an immediate defense against novel SARS-CoV-2 variants and other inflammatory infectious diseases. Full article

(This article belongs to the Special Issue Cellular ROS and Antioxidants: Physiological and Pathological Role)

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14 pages, 2081 KiB

Open AccessArticle

DUOX2-Induced Oxidative Stress Inhibits Intestinal Angiogenesis through MMP3 in a Low-Birth-Weight Piglet Model

by Dongbin Zou, Yun Yang, Fengjie Ji, Renlong Lv, Tieshan Xu and Chengjun Hu

Antioxidants 2023, 12(10), 1800; https://doi.org/10.3390/antiox12101800 - 25 Sep 2023

Cited by 1 | Viewed by 1125

Abstract

Intestinal vessels play a critical role in nutrient absorption, whereas the effect and mechanism of low birth weight (LBW) on its formation remain unclear. Here, twenty newborn piglets were assigned to the control (CON) group (1162 ± 98 g) and LBW group (724 [...] Read more.

Intestinal vessels play a critical role in nutrient absorption, whereas the effect and mechanism of low birth weight (LBW) on its formation remain unclear. Here, twenty newborn piglets were assigned to the control (CON) group (1162 ± 98 g) and LBW group (724 ± 31 g) according to their birth weight. Results showed that the villus height and the activity of maltase in the jejunum were lower in the LBW group than in the CON group. LBW group exhibited a higher oxidative stress level and impaired mitochondrial function in the jejunum and was lower than the CON group in the intestinal vascular density. To investigate the role of oxidative stress in intestinal angiogenesis, H₂O₂ was employed to induce oxidative stress in porcine intestinal epithelial cells (IPEC-J2). The results showed that the conditioned media from IPEC-J2 with H₂O₂ treatment decreased the angiogenesis of porcine vascular endothelial cells (PVEC). Transcriptome analysis revealed that a higher expression level of dual oxidase 2 (DUOX2) was found in the intestine of LBW piglets. Knockdown of DUOX2 in IPEC-J2 increased the proliferation and decreased the oxidative stress level. In addition, conditioned media from IPEC-J2 with DUOX2-knockdown was demonstrated to promote the angiogenesis of PVEC. Mechanistically, the knockdown of DUOX2 decreased the reactive oxygen species (ROS) level, thus increasing the angiogenesis in a matrix metalloproteinase 3 (MMP3) dependent manner. Conclusively, our results indicated that DUOX2-induced oxidative stress inhibited intestinal angiogenesis through MMP3 in a LBW piglet model. Full article

(This article belongs to the Special Issue Cellular ROS and Antioxidants: Physiological and Pathological Role)

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18 pages, 5231 KiB

Open AccessArticle

Artemisia gmelinii Extract Attenuates Particulate Matter-Induced Neutrophilic Inflammation in a Mouse Model of Lung Injury

by Hyeon-Ji Song, Dong-Uk Shin, Ji-Eun Eom, Kyung Min Lim, Eun Yeong Lim, Young In Kim, Ha-Jung Kim, Ju Hye Song, MyeongKuk Shim, HyeonJeong Choe, Gun-Dong Kim, So-Young Lee and Hee Soon Shin

Antioxidants 2023, 12(8), 1591; https://doi.org/10.3390/antiox12081591 - 09 Aug 2023

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Abstract

Particulate matter (PM) induces and augments oxidative stress and inflammation, leading to respiratory diseases. Although Artemisia gmelinii Weber ex Stechm has antioxidant and anti-inflammatory effects, there are no reports on whether Artemisia gmelinii extract (AGE) regulates lung inflammation in a PM-induced model. Thus, [...] Read more.

Particulate matter (PM) induces and augments oxidative stress and inflammation, leading to respiratory diseases. Although Artemisia gmelinii Weber ex Stechm has antioxidant and anti-inflammatory effects, there are no reports on whether Artemisia gmelinii extract (AGE) regulates lung inflammation in a PM-induced model. Thus, we investigated the protective effects of AGE using a PM-induced mouse lung inflammation model. AGE significantly decreased the expression of inflammatory chemokines, neutrophil extracellular trap formation, and the total number of inflammatory cells in the bronchoalveolar lavage fluid (BALF). Furthermore, AGE attenuated lung inflammation through the suppression of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/mitogen-activated protein kinase (MAPK) signaling pathway, while promoting the nuclear factor erythroid-2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) signaling pathway in lung tissues. Concordant with these observations, AGE suppressed inflammatory cytokines, chemokines, reactive oxygen species, NETosis, myeloperoxidase, and neutrophil elastase by decreasing the mRNA expression of High mobility group box 1, Runt-related transcription factor 1, and Kruppel-like factor 6 in differentiated HL-60 cells. In summary, our data demonstrated that AGE suppresses PM-induced neutrophil infiltration, lung damage, and pulmonary inflammation by suppressing NF-κB/MAPK signaling pathways and enhancing the NRF2/HO-1 signaling pathway. These findings suggest that AGE administration is an effective approach for preventing and treating PM-induced respiratory inflammation. Full article

(This article belongs to the Special Issue Cellular ROS and Antioxidants: Physiological and Pathological Role)

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22 pages, 2138 KiB

Open AccessArticle

Radical-Driven Methane Formation in Humans Evidenced by Exogenous Isotope-Labeled DMSO and Methionine

by Frank Keppler, Mihály Boros and Daniela Polag

Antioxidants 2023, 12(7), 1381; https://doi.org/10.3390/antiox12071381 - 04 Jul 2023

Cited by 1 | Viewed by 1106

Abstract

Methane (CH₄), which is produced endogenously in animals and plants, was recently suggested to play a role in cellular physiology, potentially influencing the signaling pathways and regulatory mechanisms involved in nitrosative and oxidative stress responses. In addition, it was proposed that [...] Read more.

Methane (CH₄), which is produced endogenously in animals and plants, was recently suggested to play a role in cellular physiology, potentially influencing the signaling pathways and regulatory mechanisms involved in nitrosative and oxidative stress responses. In addition, it was proposed that the supplementation of CH₄ to organisms may be beneficial for the treatment of several diseases, including ischemia, reperfusion injury, and inflammation. However, it is still unclear whether and how CH₄ is produced in mammalian cells without the help of microorganisms, and how CH₄ might be involved in physiological processes in humans. In this study, we produced the first evidence of the principle that CH₄ is formed non-microbially in the human body by applying isotopically labeled methylated sulfur compounds, such as dimethyl sulfoxide (DMSO) and methionine, as carbon precursors to confirm cellular CH₄ formation. A volunteer applied isotopically labeled (²H and ¹³C) DMSO on the skin, orally, and to blood samples. The monitoring of stable isotope values of CH₄ convincingly showed the conversion of the methyl groups, as isotopically labeled CH₄ was formed during all experiments. Based on these results, we considered several hypotheses about endogenously formed CH₄ in humans, including physiological aspects and stress responses involving reactive oxygen species (ROS). While further and broader validation studies are needed, the results may unambiguously serve as a proof of concept for the endogenous formation of CH₄ in humans via a radical-driven process. Furthermore, these results might encourage follow-up studies to decipher the potential physiological role of CH₄ and its bioactivity in humans in more detail. Of particular importance is the potential to monitor CH₄ as an oxidative stress biomarker if the observed large variability of CH₄ in breath air is an indicator of physiological stress responses and immune reactions. Finally, the potential role of DMSO as a radical scavenger to counteract oxidative stress caused by ROS might be considered in the health sciences. DMSO has already been investigated for many years, but its potential positive role in medical use remains highly uncertain. Full article

(This article belongs to the Special Issue Cellular ROS and Antioxidants: Physiological and Pathological Role)

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20 pages, 12226 KiB

Open AccessArticle

EGCG Attenuates CA1 Neuronal Death by Regulating GPx1, NF-κB S536 Phosphorylation and Mitochondrial Dynamics in the Rat Hippocampus following Status Epilepticus

by Ji-Eun Kim, Tae-Hyun Kim and Tae-Cheon Kang

Antioxidants 2023, 12(4), 966; https://doi.org/10.3390/antiox12040966 - 20 Apr 2023

Cited by 1 | Viewed by 1383

Abstract

Epigallocatechin-3-gallate (EGCG) is an antioxidant that directly scavenges reactive oxygen species (ROS) and inhibits pro-oxidant enzymes. Although EGCG protects hippocampal neurons from status epilepticus (SE, a prolonged seizure activity), the underlying mechanisms are not fully understood. As the preservation of mitochondrial dynamics is [...] Read more.

Epigallocatechin-3-gallate (EGCG) is an antioxidant that directly scavenges reactive oxygen species (ROS) and inhibits pro-oxidant enzymes. Although EGCG protects hippocampal neurons from status epilepticus (SE, a prolonged seizure activity), the underlying mechanisms are not fully understood. As the preservation of mitochondrial dynamics is essential for cell viability, it is noteworthy to elucidate the effects of EGCG on impaired mitochondrial dynamics and the related signaling pathways in SE-induced CA1 neuronal degeneration, which are yet unclear. In the present study, we found that EGCG attenuated SE-induced CA1 neuronal death, accompanied by glutathione peroxidase-1 (GPx1) induction. EGCG also abrogated mitochondrial hyperfusion in these neurons by the preservation of extracellular signal-regulated kinase 1/2 (ERK1/2)–dynamin-related protein 1 (DRP1)-mediated mitochondrial fission, independent of c-Jun N-terminal kinase (JNK) activity. Furthermore, EGCG abolished SE-induced nuclear factor-κB (NF-κB) serine (S) 536 phosphorylation in CA1 neurons. ERK1/2 inhibition by U0126 diminished the effect of EGCG on neuroprotection and mitochondrial hyperfusion in response to SE without affecting GPx1 induction and NF-κB S536 phosphorylation, indicating that the restoration of ERK1/2–DRP1-mediated fission may be required for the neuroprotective effects of EGCG against SE. Therefore, our findings suggest that EGCG may protect CA1 neurons from SE insults through GPx1–ERK1/2–DRP1 and GPx1–NF-κB signaling pathways, respectively. Full article

(This article belongs to the Special Issue Cellular ROS and Antioxidants: Physiological and Pathological Role)

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16 pages, 21990 KiB

Open AccessArticle

KDELC2 Upregulates Glioblastoma Angiogenesis via Reactive Oxygen Species Activation and Tumor-Associated Macrophage Proliferation

by Yu-Ling Tsai, Ying Chen, Ying-Chuan Chen and Wen-Chiuan Tsai

Antioxidants 2023, 12(4), 923; https://doi.org/10.3390/antiox12040923 - 13 Apr 2023

Cited by 3 | Viewed by 1660

Abstract

Glioblastoma is notorious for its rapid progression and neovascularization. In this study, it was found that KDEL (Lys-Asp-Glu-Leu) containing 2 (KDELC2) stimulated vasculogenic factor expression and induced human umbilical vein endothelial cell (HUVEC) proliferation. The NLRP3 inflammasome and autophagy activation via hypoxic inducible [...] Read more.

Glioblastoma is notorious for its rapid progression and neovascularization. In this study, it was found that KDEL (Lys-Asp-Glu-Leu) containing 2 (KDELC2) stimulated vasculogenic factor expression and induced human umbilical vein endothelial cell (HUVEC) proliferation. The NLRP3 inflammasome and autophagy activation via hypoxic inducible factor 1 alpha (HIF-1α) and mitochondrial reactive oxygen species (ROS) production was also confirmed. The application of the NLRP3 inflammasome inhibitor MCC950 and autophagy inhibitor 3-methyladenine (3-MA) indicated that the above phenomenon activation correlated with an endothelial overgrowth. Furthermore, KDELC2 suppression decreased the endoplasmic reticulum (ER) stress factors’ expression. The ER stress inhibitors, such as salubrinal and GSK2606414, significantly suppressed HUVEC proliferation, indicating that ER stress promotes glioblastoma vascularization. Finally, shKDELC2 glioblastoma-conditioned medium (CM) stimulated TAM polarization and induced THP-1 cells to transform into M1 macrophages. In contrast, THP-1 cells co-cultured with compensatory overexpressed (OE)-KDELC2 glioblastoma cells increased IL-10 secretion, a biomarker of M2 macrophages. HUVECs co-cultured with shKDELC2 glioblastoma-polarized THP-1 cells were less proliferative, demonstrating that KDELC2 promotes angiogenesis. Mito-TEMPO and MCC950 increased caspase-1p20 and IL-1β expression in THP-1 macrophages, indicating that mitochondrial ROS and autophagy could also interrupt THP-1-M1 macrophage polarization. In conclusion, mitochondrial ROS, ER stress, and the TAMs resulting from OE-KDELC2 glioblastoma cells play important roles in upregulating glioblastoma angiogenesis. Full article

(This article belongs to the Special Issue Cellular ROS and Antioxidants: Physiological and Pathological Role)

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15 pages, 5976 KiB

Open AccessArticle

Increased Renal Medullary NOX-4 in Female but Not Male Mice during the Early Phase of Type 1 Diabetes: Potential Role of ROS in Upregulation of TGF-β1 and Fibronectin in Collecting Duct Cells

by Felipe Casado-Barragán, Geraldine Lazcano-Páez, Paulina E. Larenas, Monserrat Aguirre-Delgadillo, Fernanda Olivares-Aravena, Daniela Witto-Oyarce, Camila Núñez-Allimant, Katherin Silva, Quynh My Nguyen, Pilar Cárdenas, Modar Kassan and Alexis A. Gonzalez

Antioxidants 2023, 12(3), 729; https://doi.org/10.3390/antiox12030729 - 16 Mar 2023

Viewed by 2191

Abstract

Chronic diabetes mellitus (DM) can lead to kidney damage associated with increased reactive oxygen species (ROS), proteinuria, and tubular damage. Altered protein expression levels of transforming growth factor-beta 1 (TGF-β1), fibronectin, and renal NADPH oxidase (NOX-4) are associated with the profibrotic phenotype in [...] Read more.

Chronic diabetes mellitus (DM) can lead to kidney damage associated with increased reactive oxygen species (ROS), proteinuria, and tubular damage. Altered protein expression levels of transforming growth factor-beta 1 (TGF-β1), fibronectin, and renal NADPH oxidase (NOX-4) are associated with the profibrotic phenotype in renal tubular cells. NOX-4 is one of the primary sources of ROS in the diabetic kidney and responsible for the induction of profibrotic factors in collecting duct (CD) cells. The renal medulla is predominantly composed of CDs; in DM, these CD cells are exposed to high glucose (HG) load. Currently there is no published literature describing the expression of these markers in the renal medulla in male and female mice during the early phase of DM, or the role of NOX-4-induced ROS. Our aim was to evaluate changes in transcripts and protein abundances of TGF-β1, fibronectin, and NOX-4 along with ROS levels in renal medullary tissues from male and female mice during a short period of streptozotocin (STZ)-induced type 1 DM and the effect of HG in cultured CD cells. CF-1 mice were injected with or without a single dose of STZ (200 mg/kg) and euthanized at day 6. STZ females showed higher expression of fibronectin and TGF-β1 when compared to control mice of either gender. Interestingly, STZ female mice showed a >30-fold increase on mRNA levels and a 3-fold increase in protein levels of kidney medullary NOX-4. Both male and female STZ mice showed increased intrarenal ROS. In primary cultures of inner medullary CD cells exposed to HG over 48 h, the expression of TGF-β1, fibronectin, and NOX-4 were augmented. M-1 CD cells exposed to HG showed increased ROS, fibronectin, and TGF-β1; this effect was prevented by NOX-4 inhibition. Our data suggest that at as early as 6 days of STZ-induced DM, the expression of profibrotic markers TGF-β1 and fibronectin increases in renal medullary CD cells. Antioxidants mechanisms in male and female in renal medullary tissues seems to be differentially regulated by the actions of NOX-4. Full article

(This article belongs to the Special Issue Cellular ROS and Antioxidants: Physiological and Pathological Role)

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13 pages, 2439 KiB

Open AccessArticle

Expression of the H₂O₂ Biosensor roGFP-Tpx1.C169S in Fission and Budding Yeasts and Jurkat Cells to Compare Intracellular H₂O₂ Levels, Transmembrane Gradients, and Response to Metals

by Laura de Cubas, Jorge Mallor, Víctor Herrera-Fernández, José Ayté, Rubén Vicente and Elena Hidalgo

Antioxidants 2023, 12(3), 706; https://doi.org/10.3390/antiox12030706 - 13 Mar 2023

Viewed by 1619

Abstract

Intracellular hydrogen peroxide (H₂O₂) levels can oscillate from low, physiological concentrations, to intermediate, signaling ones, and can participate in toxic reactions when overcoming certain thresholds. Fluorescent protein-based reporters to measure intracellular H₂O₂ have been developed in [...] Read more.

Intracellular hydrogen peroxide (H₂O₂) levels can oscillate from low, physiological concentrations, to intermediate, signaling ones, and can participate in toxic reactions when overcoming certain thresholds. Fluorescent protein-based reporters to measure intracellular H₂O₂ have been developed in recent decades. In particular, the redox-sensitive green fluorescent protein (roGFP)-based proteins fused to peroxiredoxins are among the most sensitive H₂O₂ biosensors. Using fission yeast as a model system, we recently demonstrated that the gradient of extracellular-to-intracellular peroxides through the plasma membrane is around 300:1, and that the concentration of physiological H₂O₂ is in the low nanomolar range. Here, we have expressed the very sensitive probe roGFP2-Tpx1.C169S in two other model systems, budding yeast and human Jurkat cells. As in fission yeast, the biosensor is ~40–50% oxidized in these cell types, suggesting similar peroxide steady-state levels. Furthermore, probe oxidation upon the addition of extracellular peroxides is also quantitatively similar, suggesting comparable plasma membrane H₂O₂ gradients. Finally, as a proof of concept, we have applied different concentrations of zinc to all three model systems and have detected probe oxidation, demonstrating that an excess of this metal can cause fluctuations of peroxides, which are moderate in yeasts and severe in mammalian cells. We conclude that the principles governing H₂O₂ fluxes are very similar in different model organisms. Full article

(This article belongs to the Special Issue Cellular ROS and Antioxidants: Physiological and Pathological Role)

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15 pages, 2574 KiB

Open AccessArticle

Methane Admixture Protects Liver Mitochondria and Improves Graft Function after Static Cold Storage and Reperfusion

by Tamara Horváth, Lilla Sándor, Bálint Baráth, Tibor Donka, Bence Baráth, Árpád Mohácsi, Kurszán Dávid Jász, Petra Hartmann and Mihály Boros

Antioxidants 2023, 12(2), 271; https://doi.org/10.3390/antiox12020271 - 25 Jan 2023

Cited by 2 | Viewed by 1453

Abstract

Mitochondria are targets of cold ischemia-reperfusion (IR), the major cause of cell damage during static cold preservation of liver allografts. The bioactivity of methane (CH₄) has recently been recognized in various hypoxic and IR conditions as having influence on many aspects [...] Read more.

Mitochondria are targets of cold ischemia-reperfusion (IR), the major cause of cell damage during static cold preservation of liver allografts. The bioactivity of methane (CH₄) has recently been recognized in various hypoxic and IR conditions as having influence on many aspects of mitochondrial biology. We therefore hypothesized that cold storage of liver grafts in CH₄-enriched preservation solution can provide an increased defence against organ dysfunction in a preclinical rat model of liver transplantation. Livers were preserved for 24 h in cold histidine–tryptophan–ketoglutarate (HTK) or CH₄-enriched HTK solution (HTK-CH₄) (n = 24 each); then, viability parameters were monitored for 60 min during normothermic isolated reperfusion and perfusate and liver tissue were collected. The oxidative phosphorylation capacity and extramitochondrial Ca²⁺ movement were measured by high resolution respirometry. Oxygen and glucose consumption increased significantly while hepatocellular damage was decreased in the HTK-CH₄ grafts compared to the HTK group. Mitochondrial oxidative phosphorylation capacity was more preserved (128.8 ± 31.5 pmol/s/mL vs 201.3 ± 54.8 pmol/s/mL) and a significantly higher Ca²⁺ flux was detected in HTK-CH₄ storage (2.9 ± 0.1 mV/s) compared to HTK (2.3 ± 0.09 mV/s). These results demonstrate the direct effect of CH₄ on hepatic mitochondrial function and extramitochondrial Ca²⁺ fluxes, which may have contributed to improved graft functions and a preserved histomorphology after cold IR. Full article

(This article belongs to the Special Issue Cellular ROS and Antioxidants: Physiological and Pathological Role)

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18 pages, 10989 KiB

Open AccessArticle

Dioscin Protects against Cisplatin-Induced Acute Kidney Injury by Reducing Ferroptosis and Apoptosis through Activating Nrf2/HO-1 Signaling

by Shuang Wang, Yingce Zheng, Shengzi Jin, Yunwei Fu and Yun Liu

Antioxidants 2022, 11(12), 2443; https://doi.org/10.3390/antiox11122443 - 11 Dec 2022

Cited by 9 | Viewed by 2180

Abstract

Acute kidney injury (AKI) is a clinical syndrome with high morbidity and mortality worldwide, and there is currently no effective means to prevent it. Dioscin is naturally present in the dioscoreaceae plants and has antioxidant and anti-inflammatory effects. Here, we found that dioscin [...] Read more.

Acute kidney injury (AKI) is a clinical syndrome with high morbidity and mortality worldwide, and there is currently no effective means to prevent it. Dioscin is naturally present in the dioscoreaceae plants and has antioxidant and anti-inflammatory effects. Here, we found that dioscin is protective against cisplatin-induced AKI. Pathological and ultrastructural observations revealed that dioscin reduced renal tissue lesions and mitochondrial damage. Furthermore, dioscin markedly suppressed reactive oxygen species and malondialdehyde levels in the kidneys of AKI rats and increased the contents of glutathione and catalase. In addition, dioscin dramatically reduced the number of apoptotic cells and the expression of pro-apoptotic proteins in rat kidneys and human renal tubular epithelial cells (HK2). Conversely, the protein levels of anti-ferroptosis including GPX4 and FSP1 in vivo and in vitro were significantly enhanced after dioscin treatment. Mechanistically, dioscin promotes the entry of Nrf2 into the nucleus and regulates the expression of downstream HO-1 to exert renal protection. However, the nephroprotective effect of dioscin was weakened after inhibiting Nrf2 in vitro and in vivo. In conclusion, dioscin exerts a reno-protective effect by decreasing renal oxidative injury, apoptosis and ferroptosis through the Nrf2/HO-1 signaling pathway, providing a new insight into AKI prevention. Full article

(This article belongs to the Special Issue Cellular ROS and Antioxidants: Physiological and Pathological Role)

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27 pages, 2368 KiB

Open AccessReview

Reactive Oxygen Species and Strategies for Antioxidant Intervention in Acute Respiratory Distress Syndrome

by Eun Yeong Lim, So-Young Lee, Hee Soon Shin and Gun-Dong Kim

Antioxidants 2023, 12(11), 2016; https://doi.org/10.3390/antiox12112016 - 18 Nov 2023

Viewed by 1384

Abstract

Acute respiratory distress syndrome (ARDS) is a life-threatening pulmonary condition characterized by the sudden onset of respiratory failure, pulmonary edema, dysfunction of endothelial and epithelial barriers, and the activation of inflammatory cascades. Despite the increasing number of deaths attributed to ARDS, a comprehensive [...] Read more.

Acute respiratory distress syndrome (ARDS) is a life-threatening pulmonary condition characterized by the sudden onset of respiratory failure, pulmonary edema, dysfunction of endothelial and epithelial barriers, and the activation of inflammatory cascades. Despite the increasing number of deaths attributed to ARDS, a comprehensive therapeutic approach for managing patients with ARDS remains elusive. To elucidate the pathological mechanisms underlying ARDS, numerous studies have employed various preclinical models, often utilizing lipopolysaccharide as the ARDS inducer. Accumulating evidence emphasizes the pivotal role of reactive oxygen species (ROS) in the pathophysiology of ARDS. Both preclinical and clinical investigations have asserted the potential of antioxidants in ameliorating ARDS. This review focuses on various sources of ROS, including NADPH oxidase, uncoupled endothelial nitric oxide synthase, cytochrome P450, and xanthine oxidase, and provides a comprehensive overview of their roles in ARDS. Additionally, we discuss the potential of using antioxidants as a strategy for treating ARDS. Full article

(This article belongs to the Special Issue Cellular ROS and Antioxidants: Physiological and Pathological Role)

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29 pages, 2465 KiB

Open AccessReview

Mitochondrial Volume Regulation and Swelling Mechanisms in Cardiomyocytes

by Xavier R. Chapa-Dubocq, Keishla M. Rodríguez-Graciani, Nelson Escobales and Sabzali Javadov

Antioxidants 2023, 12(8), 1517; https://doi.org/10.3390/antiox12081517 - 28 Jul 2023

Cited by 2 | Viewed by 1685

Abstract

Mitochondrion, known as the “powerhouse” of the cell, regulates ion homeostasis, redox state, cell proliferation and differentiation, and lipid synthesis. The inner mitochondrial membrane (IMM) controls mitochondrial metabolism and function. It possesses high levels of proteins that account for ~70% of the membrane [...] Read more.

Mitochondrion, known as the “powerhouse” of the cell, regulates ion homeostasis, redox state, cell proliferation and differentiation, and lipid synthesis. The inner mitochondrial membrane (IMM) controls mitochondrial metabolism and function. It possesses high levels of proteins that account for ~70% of the membrane mass and are involved in the electron transport chain, oxidative phosphorylation, energy transfer, and ion transport, among others. The mitochondrial matrix volume plays a crucial role in IMM remodeling. Several ion transport mechanisms, particularly K⁺ and Ca²⁺, regulate matrix volume. Small increases in matrix volume through IMM alterations can activate mitochondrial respiration, whereas excessive swelling can impair the IMM topology and initiates mitochondria-mediated cell death. The opening of mitochondrial permeability transition pores, the well-characterized phenomenon with unknown molecular identity, in low- and high-conductance modes are involved in physiological and pathological increases of matrix volume. Despite extensive studies, the precise mechanisms underlying changes in matrix volume and IMM structural remodeling in response to energy and oxidative stressors remain unknown. This review summarizes and discusses previous studies on the mechanisms involved in regulating mitochondrial matrix volume, IMM remodeling, and the crosstalk between these processes. Full article

(This article belongs to the Special Issue Cellular ROS and Antioxidants: Physiological and Pathological Role)

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12 pages, 1004 KiB

Open AccessReview

Effect of 8-Hydroxyguanine DNA Glycosylase 1 on the Function of Immune Cells

by Weiran Zhang, Ranwei Zhong, Xiangping Qu, Yang Xiang and Ming Ji

Antioxidants 2023, 12(6), 1300; https://doi.org/10.3390/antiox12061300 - 19 Jun 2023

Viewed by 1472

Abstract

Excess reactive oxygen species (ROS) can cause an imbalance between oxidation and anti-oxidation, leading to the occurrence of oxidative stress in the body. The most common product of ROS-induced base damage is 8-hydroxyguanine (8-oxoG). Failure to promptly remove 8-oxoG often causes mutations during [...] Read more.

Excess reactive oxygen species (ROS) can cause an imbalance between oxidation and anti-oxidation, leading to the occurrence of oxidative stress in the body. The most common product of ROS-induced base damage is 8-hydroxyguanine (8-oxoG). Failure to promptly remove 8-oxoG often causes mutations during DNA replication. 8-oxoG is cleared from cells by the 8-oxoG DNA glycosylase 1 (OGG1)-mediated oxidative damage base excision repair pathway so as to prevent cells from suffering dysfunction due to oxidative stress. Physiological immune homeostasis and, in particular, immune cell function are vulnerable to oxidative stress. Evidence suggests that inflammation, aging, cancer, and other diseases are related to an imbalance in immune homeostasis caused by oxidative stress. However, the role of the OGG1-mediated oxidative damage repair pathway in the activation and maintenance of immune cell function is unknown. This review summarizes the current understanding of the effect of OGG1 on immune cell function. Full article

(This article belongs to the Special Issue Cellular ROS and Antioxidants: Physiological and Pathological Role)

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15 pages, 823 KiB

Open AccessReview

Pleiotropic Signaling by Reactive Oxygen Species Concerted with Dietary Phytochemicals and Microbial-Derived Metabolites as Potent Therapeutic Regulators of the Tumor Microenvironment

by Toshiyuki Murai and Satoru Matsuda

Antioxidants 2023, 12(5), 1056; https://doi.org/10.3390/antiox12051056 - 06 May 2023

Cited by 4 | Viewed by 1894

Abstract

The excessive generation of reactive oxygen species (ROS) plays a pivotal role in the pathogenesis of diseases. ROS are central to cellular redox regulation and act as second messengers to activate redox-sensitive signals. Recent studies have revealed that certain sources of ROS can [...] Read more.

The excessive generation of reactive oxygen species (ROS) plays a pivotal role in the pathogenesis of diseases. ROS are central to cellular redox regulation and act as second messengers to activate redox-sensitive signals. Recent studies have revealed that certain sources of ROS can be beneficial or harmful to human health. Considering the essential and pleiotropic roles of ROS in basic physiological functions, future therapeutics should be designed to modulate the redox state. Dietary phytochemicals, microbiota, and metabolites derived from them can be expected to be developed as drugs to prevent or treat disorders in the tumor microenvironment. Full article

(This article belongs to the Special Issue Cellular ROS and Antioxidants: Physiological and Pathological Role)

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