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Oxidative Stress and Antioxidants in Hypoxia and Human Pathophysiology Settings: Novel Pharmacological Targets

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

Deadline for manuscript submissions: closed (10 March 2024) | Viewed by 8166

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Special Issue Editor

Dr. Rodrigo L. Castillo

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Guest Editor

1. Departamento de Medicina Interna Oriente, Facultad de Medicina, Universidad de Chile, Santiago 7500922, Chile
2. Unidad de Paciente Crítico, Hospital del Salvador, Santiago 7500922, Chile
Interests: cardiovascular physiology and pathophysiology; animal models of intermittent hypoxia; cardiotoxicity; internal medicine; clinical trial

Special Issue Information

Dear Colleagues,

Hypoxic (HI) injury is defined as the worsening of organ/cellular dysfunction and cell death following reduction in blood flow due to organ targeting or increases in oxygen consumption in a related tissue. Restoration of blood flow is essential to salvage ischemic tissues. However, reperfusion itself causes further damage, contributing to reversible and irreversible changes in tissue viability and organ function, the basic pathophysiology of ischemia-reperfusion (IR) injury, especially oxidative stress, and cell death mechanism. When the blood supply is re-established, local inflammation and oxidative stress production increase, leading to secondary injury. Cell damage induced by prolonged ischemia must be distinguished from IR injury. It occurs in a wide range of organ systems, including the heart, lung, kidney, and brain. It may involve not only the ischemic organ itself but may also induce systemic damage to distant organs, potentially leading to multisystem organ failure, as different animal models have shown. Similar responses are seen in a human context, in patients exposed to acute and chronic hypoxia, from populations living in environments with low oxygen pressure, such as mountains (or high altitudes), to those suffering from conditions that induce hypoxia, such as what occurs at the cerebral and myocardial level with ischemic pathologies. Moreover, in some cancers, such as breast and colon, modulation of oxidative stress and tissue hypoxia could have a distant effect, for example, in the induction of cardiotoxicity.

This Special Issue is focused on the following topics:

-Current concepts of pathophysiology and therapies in cardiac HI and pharmacological preconditioning;

-Mechanisms of liver preconditioning in animal and clinical models of HI and IR injury;

-Current concepts of pathophysiology and therapies in cerebral HI and IR injury;

-Current concepts of anthracycline-induced cardiotoxicity in breast cancer: role of tumor microenvironment;

-Ex vivo models to reduce HI injury in organs for transplantation: role of antioxidants;

-Role of hypoxia in cardiovascular programing: mechanisms and potential therapeutic target with antioxidants;

-Role of microRNAs in the regulation of cardiac HI injury: animals and clinical settings.

Dr. Rodrigo L. Castillo
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

tissue hypoxia
reperfusion injury
hypoxic preconditioning
oxidative stress
antioxidants
hypoxic programing
microRNA
clinical hypoxic settings

Published Papers (7 papers)

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Research

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24 pages, 9238 KiB

Open AccessArticle

The Reducing Agent Dithiothreitol Modulates the Ventilatory Responses That Occur in Freely Moving Rats during and following a Hypoxic–Hypercapnic Challenge

by Paulina M. Getsy, Gregory A. Coffee, Walter J. May, Santhosh M. Baby, James N. Bates and Stephen J. Lewis

Antioxidants 2024, 13(4), 498; https://doi.org/10.3390/antiox13040498 - 22 Apr 2024

Viewed by 444

Abstract

The present study examined the hypothesis that changes in the oxidation–reduction state of thiol residues in functional proteins play a major role in the expression of the ventilatory responses in conscious rats that occur during a hypoxic–hypercapnic (HH) gas challenge and upon return to room air. A HH gas challenge in vehicle-treated rats elicited robust and sustained increases in minute volume (via increases in frequency of breathing and tidal volume), peak inspiratory and expiratory flows, and inspiratory and expiratory drives while minimally affecting the non-eupneic breathing index (NEBI). The HH-induced increases in these parameters, except for frequency of breathing, were substantially diminished in rats pre-treated with the potent and lipophilic disulfide-reducing agent, L,D-dithiothreitol (100 µmol/kg, IV). The ventilatory responses that occurred upon return to room air were also substantially different in dithiothreitol-treated rats. In contrast, pre-treatment with a substantially higher dose (500 µmol/kg, IV) of the lipophilic congener of the monosulfide, N-acetyl-L-cysteine methyl ester (L-NACme), only minimally affected the expression of the above-mentioned ventilatory responses that occurred during the HH gas challenge or upon return to room air. The effectiveness of dithiothreitol suggests that the oxidation of thiol residues occurs during exposure to a HH gas challenge and that this process plays an essential role in allowing for the expression of the post-HH excitatory phase in breathing. However, this interpretation is contradicted by the lack of effects of L-NACme. This apparent conundrum may be explained by the disulfide structure affording unique functional properties to dithiothreitol in comparison to monosulfides. More specifically, the disulfide structure may give dithiothreitol the ability to alter the conformational state of functional proteins while transferring electrons. It is also possible that dithiothreitol is simply a more efficient reducing agent following systemic injection, although one interpretation of the data is that the effects of dithiothreitol are not due to its reducing ability. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Hypoxia and Human Pathophysiology Settings: Novel Pharmacological Targets)

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17 pages, 12726 KiB

Open AccessArticle

Protective and Regenerative Effects of Reconstituted HDL on Human Rotator Cuff Fibroblasts under Hypoxia: An In Vitro Study

by Ra Jeong Kim and Hyung Bin Park

Antioxidants 2024, 13(4), 497; https://doi.org/10.3390/antiox13040497 - 22 Apr 2024

Viewed by 507

Abstract

Hypoxia and hypo-high-density lipoproteinemia (hypo-HDLemia) are proposed risk factors for rotator cuff tear. HDL is recognized for its potential benefits in ischemia-driven angiogenesis and wound healing. Nevertheless, research on the potential benefits of reconstituted HDL (rHDL) on human rotator cuff fibroblasts (RCFs) under hypoxia is limited. This study investigates the cytoprotective and regenerative effects of rHDL, as well as N-acetylcysteine (NAC), vitamin C (Vit C), and HDL on human RCFs under hypoxic conditions. Sixth-passage human RCFs were divided into normoxia, hypoxia, and hypoxia groups pretreated with antioxidants (NAC, Vit C, rHDL, HDL). Hypoxia was induced by 1000 µM CoCl₂. In the hypoxia group compared to the normoxia group, there were significant increases in hypoxia-inducible factor-1α (HIF-1α), heme oxygenase-1 (HO-1), and Bcl-2/E1B-19kDa interacting protein 3 (BNIP3) expressions, along with reduced cell viability, elevated reactive oxygen species (ROS) production, apoptosis rate, expressions of cleaved caspase-3, cleaved poly ADP-ribose polymerase-1 (PARP-1), vascular endothelial growth factors (VEGF), and matrix metalloproteinase-2 (MMP-2), as well as decreased collagen I and III production, and markedly lower cell proliferative activity (p ≤ 0.039). These responses were significantly mitigated by pretreatment with rHDL (p ≤ 0.046). This study suggests that rHDL can enhance cell proliferation and collagen I and III production while reducing apoptosis in human RCFs under hypoxic conditions. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Hypoxia and Human Pathophysiology Settings: Novel Pharmacological Targets)

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12 pages, 4708 KiB

Open AccessArticle

Serelaxin Protects H9c2 Cardiac Myoblasts against Hypoxia and Reoxygenation-Induced Damage through Activation of AMP Kinase/Sirtuin1: Further Insight into the Molecular Mechanisms of the Cardioprotection of This Hormone

by Virginia Zizi, Matteo Becatti, Daniele Bani and Silvia Nistri

Antioxidants 2024, 13(2), 163; https://doi.org/10.3390/antiox13020163 - 27 Jan 2024

Viewed by 932

Abstract

Serelaxin (RLX), namely the human recombinant Relaxin-2 hormone, protects the heart from ischemia/reperfusion (I/R)-induced damage due to its anti-inflammatory, anti-apoptotic and antioxidant properties. RLX acts by binding to its specific RXFP1 receptor whereby it regulates multiple transduction pathways. In this in vitro study, we offer the first evidence for the involvement of the AMP kinase/Sirtuin1 (AMPK/SIRT1) pathway in the protection by RLX against hypoxia/reoxygenation (H/R)-induced damage in H9c2 cells. The treatment of the H/R-exposed cells with RLX (17 nmol L⁻¹) enhanced SIRT1 expression and activity. The inhibition of SIRT1 signaling with EX527 (10 µmol L⁻¹) reduced the beneficial effect of the hormone on mitochondrial efficiency and cell apoptosis. Moreover, RLX upregulated the AMPK pathway, as shown by the increase in the expression of phospho-AMPK-activated protein. Finally, AMPK pathway inhibition by Compound C (10 and 20 μmol L⁻¹) abrogated the increase in SIRT1 expression induced by RLX, thus suggesting the involvement of the AMPK pathway in this effect of RLX. These results strengthen the concept that RLX exerts its cardioprotective effects against H/R-induced injury through multiple pathways which also include AMPK/SIRT1. These new findings support the use of RLX or RLX-derived molecules as a promising therapeutic for those diseases in which I/R and oxidative stress play a pathogenic role. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Hypoxia and Human Pathophysiology Settings: Novel Pharmacological Targets)

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16 pages, 3348 KiB

Open AccessArticle

Nitroxide—HMP—Protects Human Trophoblast HTR-8/SVneo Cells from H₂O₂-Induced Oxidative Stress by Reducing the HIF1A Signaling Pathway

by Diana Pintye, Réka Eszter Sziva, Maxim Mastyugin, Marianna Török, Sonako Jacas, Agnes Lo, Saira Salahuddin and Zsuzsanna K. Zsengellér

Antioxidants 2023, 12(8), 1578; https://doi.org/10.3390/antiox12081578 - 8 Aug 2023

Cited by 2 | Viewed by 1693

Abstract

Preeclampsia (PE) is a pregnancy-specific syndrome affecting 5–7% of patients. There is no effective treatment available. Early abnormal placental development is associated with oxidative stress (OS) and a release of reactive oxygen species (ROS) in the placenta. This phenomenon leads to downstream signaling, Hypoxia Inducible Factor 1A (HIF1A) stabilization and transcription of the anti-angiogenic factors soluble fms-like tyrosine kinase 1 (sFLT1) and soluble endoglin (sEng), which are known to cause endothelial and trophoblast dysfunction and cardinal features of PE: hypertension, proteinuria and, in severe cases, eclampsia. We tested whether 3-(Hydroxymethyl)-1-oxy-2,2,5,5-tetramethylpyrrolidine (HMP)—a nitroxide-type antioxidant molecule—can reduce placental OS and mitigate PE symptoms in vitro. We induced OS in human trophoblast (HTR-8/SVneo) cells with hydrogen peroxide (H₂O₂) and assessed whether modulating cell redox function with HMP reduces cell injury, mitochondrial stress and HIF1A and sFLT1 production. Pre-treatment with HMP reduced mitochondrial-derived ROS production, restored LC3B expression and reduced HIF1A and sFLT1 expression in H₂O₂-exposed HTR-8/SVneo trophoblast cells. HMP improved the mitochondrial electron chain enzyme activity, indicating that a reduction in OS alleviates mitochondrial stress and also reduces anti-angiogenic responses. In reducing placental trophoblast OS, HMP presents a potential novel therapeutic approach for the treatment of PE. Future investigation is warranted regarding the in vivo use of HMP. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Hypoxia and Human Pathophysiology Settings: Novel Pharmacological Targets)

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Review

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33 pages, 2109 KiB

Open AccessReview

Modulating Nitric Oxide: Implications for Cytotoxicity and Cytoprotection

by Igor Belenichev, Olena Popazova, Nina Bukhtiyarova, Dmytro Savchenko, Valentyn Oksenych and Oleksandr Kamyshnyi

Antioxidants 2024, 13(5), 504; https://doi.org/10.3390/antiox13050504 - 23 Apr 2024

Viewed by 418

Abstract

Despite the significant progress in the fields of biology, physiology, molecular medicine, and pharmacology; the designation of the properties of nitrogen monoxide in the regulation of life-supporting functions of the organism; and numerous works devoted to this molecule, there are still many open questions in this field. It is widely accepted that nitric oxide (^•NO) is a unique molecule that, despite its extremely simple structure, has a wide range of functions in the body, including the cardiovascular system, the central nervous system (CNS), reproduction, the endocrine system, respiration, digestion, etc. Here, we systematize the properties of ^•NO, contributing in conditions of physiological norms, as well as in various pathological processes, to the mechanisms of cytoprotection and cytodestruction. Current experimental and clinical studies are contradictory in describing the role of ^•NO in the pathogenesis of many diseases of the cardiovascular system and CNS. We describe the mechanisms of cytoprotective action of ^•NO associated with the regulation of the expression of antiapoptotic and chaperone proteins and the regulation of mitochondrial function. The most prominent mechanisms of cytodestruction—the initiation of nitrosative and oxidative stresses, the production of reactive oxygen and nitrogen species, and participation in apoptosis and mitosis. The role of ^•NO in the formation of endothelial and mitochondrial dysfunction is also considered. Moreover, we focus on the various ways of pharmacological modulation in the nitroxidergic system that allow for a decrease in the cytodestructive mechanisms of ^•NO and increase cytoprotective ones. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Hypoxia and Human Pathophysiology Settings: Novel Pharmacological Targets)

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28 pages, 2359 KiB

Open AccessReview

Oxidative Stress Induced by Lipotoxicity and Renal Hypoxia in Diabetic Kidney Disease and Possible Therapeutic Interventions: Targeting the Lipid Metabolism and Hypoxia

by Seung Yun Chae, Yaeni Kim and Cheol Whee Park

Antioxidants 2023, 12(12), 2083; https://doi.org/10.3390/antiox12122083 - 6 Dec 2023

Cited by 1 | Viewed by 1779

Abstract

Oxidative stress, a hallmark pathophysiological feature in diabetic kidney disease (DKD), arises from the intricate interplay between pro-oxidants and anti-oxidants. While hyperglycemia has been well established as a key contributor, lipotoxicity emerges as a significant instigator of oxidative stress. Lipotoxicity encompasses the accumulation of lipid intermediates, culminating in cellular dysfunction and cell death. However, the mechanisms underlying lipotoxic kidney injury in DKD still require further investigation. The key role of cell metabolism in the maintenance of cell viability and integrity in the kidney is of paramount importance to maintain proper renal function. Recently, dysfunction in energy metabolism, resulting from an imbalance in oxygen levels in the diabetic condition, may be the primary pathophysiologic pathway driving DKD. Therefore, we aim to shed light on the pivotal role of oxidative stress related to lipotoxicity and renal hypoxia in the initiation and progression of DKD. Multifaceted mechanisms underlying lipotoxicity, including oxidative stress with mitochondrial dysfunction, endoplasmic reticulum stress activated by the unfolded protein response pathway, pro-inflammation, and impaired autophagy, are delineated here. Also, we explore potential therapeutic interventions for DKD, targeting lipotoxicity- and hypoxia-induced oxidative stress. These interventions focus on ameliorating the molecular pathways of lipid accumulation within the kidney and enhancing renal metabolism in the face of lipid overload or ameliorating subsequent oxidative stress. This review highlights the significance of lipotoxicity, renal hypoxia-induced oxidative stress, and its potential for therapeutic intervention in DKD. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Hypoxia and Human Pathophysiology Settings: Novel Pharmacological Targets)

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13 pages, 1600 KiB

Open AccessReview

Protein Carbonylation as a Biomarker of Oxidative Stress and a Therapeutic Target in Neonatal Brain Damage

by José Martínez-Orgado, María Martínez-Vega, Laura Silva, Angela Romero, María de Hoz-Rivera, María Villa and Aarón del Pozo

Antioxidants 2023, 12(10), 1839; https://doi.org/10.3390/antiox12101839 - 10 Oct 2023

Cited by 2 | Viewed by 1318

Abstract

Oxidative stress (OS) constitutes a pivotal factor within the mechanisms underlying brain damage, for which the immature brain is particularly vulnerable. This vulnerability is caused by the abundance of immature oligodendrocytes in the immature brain, which are highly susceptible to OS-induced harm. Consequently, any injurious process involving OS within the immature brain can lead to long-term myelination impairment. Among the detrimental repercussions of OS, protein carbonylation stands out as a prominently deleterious consequence. Noteworthy elevation of protein carbonylation is observable across diverse models of neonatal brain injury, following both diffuse and focal hypoxic–ischemic insults, as well as intraventricular hemorrhage, in diverse animal species encompassing rodents and larger mammals, and at varying stages of brain development. In the immature brain, protein carbonylation manifests as a byproduct of reactive nitrogen species, bearing profound implications for cell injury, particularly in terms of inflammation amplification. Moreover, protein carbonylation appears as a therapeutic target for mitigating neonatal brain damage. The administration of a potent antioxidant, such as cannabidiol, yields substantial neuroprotective effects. These encompass the reduction in cerebral damage, restoration of neurobehavioral performance, and preservation of physiological myelination. Such effects are linked to the modulation of protein carbonylation. The assessment of protein carbonylation emerges as a reliable method for comprehending the intricate mechanisms underpinning damage and neuroprotection within neonatal brain injury. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Hypoxia and Human Pathophysiology Settings: Novel Pharmacological Targets)

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