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Cellular Redox Mechanisms in Inflammation and Programmed Cell Death

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

Deadline for manuscript submissions: 20 September 2024 | Viewed by 6645

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Dr. Irina I. Vlasova

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Institute for Regenerative Medicine, Sechenov First Moscow State Medical University, 119435 Moscow, Russia
Interests: innate immunity; neutrophils; macrophages; reactive oxygen species; peroxidases

Special Issue Information

Dear Colleagues,

Redox reactions play an important role in the regulation of physiological processes. Cellular redox balance can vary widely dependently on cell activity and homeostatic capacity, as well as exposure to stress factors. Normally, redox reactions are strictly controlled; however, during inflammation and programmed cell death (e.g., apoptosis and ferroptosis), increased oxidant production and redox dysregulation contribute to cell injury, culminating in cell demise. Even in these extreme conditions, there are regulatory factors that control the poorly balanced redox processes and limit the spreading of cell death and tissue damage. Notably, inflammatory responses and cell death programs include three stages: initiation, progression, and termination (or cell removal). At all stages, reactive oxygen species and redox enzymes are the key players in the regulation of physiological processes.

The research topics of this Special Issue on redox mechanisms involved in the regulation of inflammation and programmed forms of cell death include the following:

The radical-generating activity of neutrophils and macrophages in the initiation stage of inflammation.
The enzymatically controlled production and dismutation of redox-active molecules: NADPH-oxidase (and other Nox), myeloperoxidase, superoxide dismutases, etc.
The iron-dependent oxidation of cellular lipids and the synthesis of lipid mediators.
NO• as a regulator of inflammation and cell death.
Enzymatic and non-enzymatic antioxidants that contribute to the suppression of oxidative stress (thioredoxin family proteins, glutathione peroxidases/reductases, etc.)
Redox signaling aimed at the removal of dead and damaged cells, and phagocyte redox-activity.

We welcome the submission of research reports, reviews, and mini-reviews that are within the scope of these subjects.

Dr. Irina I. Vlasova
Guest Editor

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Keywords

neutrophils
macrophages
reactive oxygen species
nitric oxide
redox-active enzymes
lipid oxidation
inflammatory response
apoptosis
ferroptosis

Published Papers (7 papers)

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Research

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19 pages, 2321 KiB

Open AccessArticle

Polyphenols from Maackia amurensis Heartwood Protect Neuronal Cells from Oxidative Stress and Prevent Herpetic Infection

by Darya V. Tarbeeva, Evgeny A. Pislyagin, Ekaterina S. Menchinskaya, Dmitrii V. Berdyshev, Natalya V. Krylova, Olga V. Iunikhina, Anatoliy I. Kalinovskiy, Mikhail Y. Shchelkanov, Natalia P. Mishchenko, Dmitry L. Aminin and Sergey A. Fedoreyev

Int. J. Mol. Sci. 2024, 25(8), 4142; https://doi.org/10.3390/ijms25084142 - 09 Apr 2024

Viewed by 279

Abstract

Here, we continued the investigation of anti-HSV-1 activity and neuroprotective potential of 14 polyphenolic compounds isolated from Maackia amurensis heartwood. We determined the absolute configurations of asymmetric centers in scirpusin A (13) and maackiazin (10) as 7R,8R and 1″S,2″S, respectively. We showed that dimeric stilbens maackin (9) and scirpusin A (13) possessed the highest anti-HSV-1 activity among polyphenols 1–14. We also studied the effect of polyphenols 9 and 13 on the early stages of HSV-1 infection. Direct interaction with the virus (virucidal activity) was the main mechanism of the antiviral activity of these compounds. The neuroprotective potential of polyphenolic compounds from M. amurensis was studied using models of 6-hydroxydopamine (6-OHDA)-and paraquat (PQ)-induced neurotoxicity. A dimeric stilbene scirpusin A (13) and a flavonoid liquiritigenin (6) were shown to be the most active compounds among the tested polyphenols. These compounds significantly increased the viability of 6-OHDA-and PQ-treated Neuro-2a cells, elevated mitochondrial membrane potential and reduced the intracellular ROS level. We also found that scirpusin A (13), liquiritigenin (6) and retusin (3) considerably increased the percentage of live Neuro-2a cells and decreased the number of early apoptotic cells. Scirpusin A (13) was the most promising compound possessing both anti-HSV-1 activity and neuroprotective potential. Full article

(This article belongs to the Special Issue Cellular Redox Mechanisms in Inflammation and Programmed Cell Death)

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14 pages, 4386 KiB

Open AccessArticle

Endoplasmic Reticulum Stress Induces Vasodilation in Liver Vessels That Is Not Mediated by Unfolded Protein Response

by Sergejs Zavadskis, Anna Shiganyan, Andrea Müllebner, Johannes Oesterreicher, Wolfgang Holnthoner, Johanna Catharina Duvigneau and Andrey V. Kozlov

Int. J. Mol. Sci. 2024, 25(7), 3865; https://doi.org/10.3390/ijms25073865 - 30 Mar 2024

Viewed by 479

Abstract

There is a growing body of evidence that ER stress and the unfolded protein response (UPR) play a key role in numerous diseases. Impaired liver perfusion and ER stress often accompany each other in liver diseases. However, the exact impact of ER stress and UPR on the hepatic perfusion is not fully understood. The aim of this study was to disclose the effect of ER stress and UPR on the size of liver vessels and on the levels of Ca²⁺ and nitric oxide (NO), critical regulators of vascular tonus. This study was carried out in precisely cut liver tissue slices. Confocal microscopy was used to create 3D images of vessels. NO levels were determined either using either laser scan microscopy (LSM) in cells or by NO-analyser in medium. Ca²⁺ levels were analysed by LSM. We show that tunicamycin, an inducer of ER stress, acts similarly with vasodilator acetylcholine. Both exert a similar effect on the NO and Ca²⁺ levels; both induce significant vasodilation. Notably, this vasodilative effect persisted despite individual inhibition of UPR pathways—ATF-6, PERK, and IRE1—despite confirming the activation of UPR. Experiments with HUVEC cells showed that elevated NO levels did not result from endothelial NO synthase (eNOS) activation. Our study suggests that tunicamycin-mediated ER stress induces liver vessel vasodilation in an NO-dependent manner, which is mediated by intracellular nitrodilator-activatable NO store (NANOS) in smooth muscle cells rather than by eNOS. Full article

(This article belongs to the Special Issue Cellular Redox Mechanisms in Inflammation and Programmed Cell Death)

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25 pages, 18837 KiB

Open AccessArticle

Radical-Generating Activity, Phagocytosis, and Mechanical Properties of Four Phenotypes of Human Macrophages

by Shakir K. Suleimanov, Yuri M. Efremov, Timofey O. Klyucherev, Emin L. Salimov, Aligeydar A. Ragimov, Peter S. Timashev and Irina I. Vlasova

Int. J. Mol. Sci. 2024, 25(3), 1860; https://doi.org/10.3390/ijms25031860 - 03 Feb 2024

Viewed by 778

Abstract

Macrophages are the major players and orchestrators of inflammatory response. Expressed proteins and secreted cytokines have been well studied for two polar macrophage phenotypes—pro-inflammatory M1 and anti-inflammatory regenerative M2, but little is known about how the polarization modulates macrophage functions. In this study, we used biochemical and biophysical methods to compare the functional activity and mechanical properties of activated human macrophages differentiated from monocyte with GM-CSF (M0_GM) and M-CSF (M0_M) and polarized into M1 and M2 phenotypes, respectively. Unlike GM-CSF, which generates dormant cells with low activity, M-CSF confers functional activity on macrophages. M0_M and M2 macrophages had very similar functional characteristics—high reactive oxygen species (ROS) production level, and higher phagocytosis and survival compared to M1, while M1 macrophages showed the highest radical-generating activity but the lowest phagocytosis and survival among all phenotypes. All phenotypes decreased their height upon activation, but only M1 and M2 cells increased in stiffness, which can indicate a decrease in the migration ability of these cells and changes in their interactions with other cells. Our results demonstrated that while mechanical properties differ between M0 and polarized cells, all four phenotypes of monocyte-derived macrophages differ in their functional activities, namely in cytokine secretion, ROS production, and phagocytosis. Within the broad continuum of human macrophages obtained in experimental models and existing in vivo, there is a diversity of phenotypes with varying combinations of both markers and functional activities. Full article

(This article belongs to the Special Issue Cellular Redox Mechanisms in Inflammation and Programmed Cell Death)

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12 pages, 1023 KiB

Open AccessArticle

Influence of Microbiota-Related Metabolites Associated with Inflammation and Sepsis on the Peroxidase Activity of Cyclooxygenase in Healthy Human Monocytes and Acute Monocytic Leukemia Cells

by Natalia Beloborodova, Roman Fadeev and Nadezhda Fedotcheva

Int. J. Mol. Sci. 2023, 24(22), 16244; https://doi.org/10.3390/ijms242216244 - 13 Nov 2023

Viewed by 838

Abstract

The human microbiota produces metabolites that can enter the bloodstream and exert systemic effects on various functions in both healthy and pathological states. We have studied the participation of microbiota-related metabolites in bacterial infection by examining their influence on the activity of cyclooxygenase (COX) as a key enzyme of inflammation. The influence of aromatic microbial metabolites, derivatives of phenylalanine (phenylpropionic acid, PPA), tyrosine (4-hydroxyphenyllactic acid, HPLA), and tryptophan (indolacetic acids, IAA), the concentrations of which in the blood change notably during sepsis, was evaluated. Also, the effect of itaconic acid (ITA) was studied, which is formed in macrophages under the action of bacterial lipopolysaccharides (LPS) and appears in the blood in the early stages of infection. Metabiotic acetyl phosphate (AcP) as a strong acetylating agent was also tested. The activity of COX was measured via the TMPD oxidation colorimetric assay using the commercial pure enzyme, cultured healthy monocytes, and the human acute monocytic leukemia cell line THP-1. All metabolites in the concentration range of 100–500 μM lowered the activity of COX. The most pronounced inhibition was observed on the commercial pure enzyme, reaching up to 40% in the presence of AcP and 20–30% in the presence of the other metabolites. On cell lysates, the effect of metabolites was preserved, although it significantly decreased, probably due to their interaction with other targets subject to redox-dependent and acetylation processes. The possible contribution of the redox-dependent action of microbial metabolites was confirmed by assessing the activity of the enzyme in the presence of thiol reagents and in model conditions, when the COX-formed peroxy intermediate was replaced with tert-butyl hydroperoxide (TBH). The data show the involvement of the microbial metabolites in the regulation of COX activity, probably due to their influence on the peroxidase activity of the enzyme. Full article

(This article belongs to the Special Issue Cellular Redox Mechanisms in Inflammation and Programmed Cell Death)

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14 pages, 317 KiB

Open AccessArticle

Impact of Hypoxia–Hyperoxia Exposures on Cardiometabolic Risk Factors and TMAO Levels in Patients with Metabolic Syndrome

by Afina Bestavashvili, Oleg Glazachev, Shabnam Ibragimova, Alexander Suvorov, Alexandros Bestavasvili, Shevket Ibraimov, Xinliang Zhang, Yong Zhang, Chavdar Pavlov, Elena Syrkina, Abram Syrkin and Philipp Kopylov

Int. J. Mol. Sci. 2023, 24(19), 14498; https://doi.org/10.3390/ijms241914498 - 24 Sep 2023

Viewed by 1152

Abstract

Along with the known risk factors of cardiovascular diseases (CVDs) constituting metabolic syndrome (MS), the gut microbiome and some of its metabolites, in particular trimethylamine-N-oxide (TMAO), are actively discussed. A prolonged stay under natural hypoxic conditions significantly and multi-directionally changes the ratio of gut microbiome strains and their metabolites in feces and blood, which is the basis for using hypoxia preconditioning for targeted effects on potential risk factors of CVD. A prospective randomized study included 65 patients (32 females) with MS and optimal medical therapy. Thirty-three patients underwent a course of 15 intermittent hypoxic–hyperoxic exposures (IHHE group). The other 32 patients underwent sham procedures (placebo group). Before and after the IHHE course, patients underwent liver elastometry, biochemical blood tests, and blood and fecal sampling for TMAO analysis (tandem mass spectrometry). No significant dynamics of TMAO were detected in both the IHHE and sham groups. In the subgroup of IHHE patients with baseline TMAO values above the reference (TMAO ≥ 5 μmol/l), there was a significant reduction in TMAO plasma levels. But the degree of reduction in total cholesterol (TCh), low-density lipoprotein (LDL), and regression of liver steatosis index was more pronounced in patients with initially normal TMAO values. Despite significant interindividual variations, in the subgroup of IHHE patients with MS and high baseline TMAO values, there were more significant reductions in cardiometabolic and hepatic indicators of MS than in controls. More research is needed to objectify the prognostic role of TMAO and the possibilities of its correction using hypoxia adaptation techniques. Full article

(This article belongs to the Special Issue Cellular Redox Mechanisms in Inflammation and Programmed Cell Death)

22 pages, 12028 KiB

Open AccessArticle

Inhibition of Ferroptosis Enables Safe Rewarming of HEK293 Cells following Cooling in University of Wisconsin Cold Storage Solution

by Lucas P. Gartzke, Koen D. W. Hendriks, Femke Hoogstra-Berends, Christian P. Joschko, Anne-Lise Strandmoe, Pieter C. Vogelaar, Guido Krenning and Robert H. Henning

Int. J. Mol. Sci. 2023, 24(13), 10939; https://doi.org/10.3390/ijms241310939 - 30 Jun 2023

Viewed by 1252

Abstract

The prolonged cooling of cells results in cell death, in which both apoptosis and ferroptosis have been implicated. Preservation solutions such as the University of Wisconsin Cold Storage Solution (UW) encompass approaches addressing both. The use of UW improves survival and thus extends preservation limits, yet it remains unclear how exactly organ preservation solutions exert their cold protection. Thus, we explored cooling effects on lipid peroxidation and adenosine triphosphate (ATP) levels and the actions of blockers of apoptosis and ferroptosis, and of compounds enhancing mitochondrial function. Cooling and rewarming experiments were performed in a cellular transplantation model using Human Embryonic Kidney (HEK) 293 cells. Cell viability was assessed by neutral red assay. Lipid peroxidation levels were measured by Western blot against 4-Hydroxy-Nonenal (4HNE) and the determination of Malondialdehyde (MDA). ATP was measured by luciferase assay. Cooling beyond 5 h in Dulbecco’s Modified Eagle Medium (DMEM) induced complete cell death in HEK293, whereas cooling in UW preserved ~60% of the cells, with a gradual decline afterwards. Cooling-induced cell death was not precluded by inhibiting apoptosis. In contrast, the blocking of ferroptosis by Ferrostatin-1 or maintaining of mitochondrial function by the 6-chromanol SUL150 completely inhibited cell death both in DMEM- and UW-cooled cells. Cooling for 24 h in UW followed by rewarming for 15 min induced a ~50% increase in MDA, while concomitantly lowering ATP by >90%. Treatment with SUL150 of cooled and rewarmed HEK293 effectively precluded the increase in MDA and preserved normal ATP in both DMEM- and UW-cooled cells. Likewise, treatment with Ferrostatin-1 blocked the MDA increase and preserved the ATP of rewarmed UW HEK293 cells. Cooling-induced HEK293 cell death from hypothermia and/or rewarming was caused by ferroptosis rather than apoptosis. UW slowed down ferroptosis during hypothermia, but lipid peroxidation and ATP depletion rapidly ensued upon rewarming, ultimately resulting in complete cell death. Treatment throughout UW cooling with small-molecule Ferrostatin-1 or the 6-chromanol SUL150 effectively prevented ferroptosis, maintained ATP, and limited lipid peroxidation in UW-cooled cells. Counteracting ferroptosis during cooling in UW-based preservation solutions may provide a simple method to improve graft survival following cold static cooling. Full article

(This article belongs to the Special Issue Cellular Redox Mechanisms in Inflammation and Programmed Cell Death)

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Review

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16 pages, 1781 KiB

Open AccessReview

Pathological Interplay between Inflammation and Mitochondria Aggravates Glutamate Toxicity

by Annette Vaglio-Garro, Andrey V. Kozlov, Yuliya D. Smirnova and Adelheid Weidinger

Int. J. Mol. Sci. 2024, 25(4), 2276; https://doi.org/10.3390/ijms25042276 - 14 Feb 2024

Viewed by 983

Abstract

Mitochondrial dysfunction and glutamate toxicity are associated with neural disorders, including brain trauma. A review of the literature suggests that toxic and transmission actions of neuronal glutamate are spatially and functionally separated. The transmission pathway utilizes synaptic GluN2A receptors, rapidly released pool of glutamate, evoked release of glutamate mediated by Synaptotagmin 1 and the amount of extracellular glutamate regulated by astrocytes. The toxic pathway utilizes extrasynaptic GluN2B receptors and a cytoplasmic pool of glutamate, which results from the spontaneous release of glutamate mediated by Synaptotagmin 7 and the neuronal 2-oxoglutarate dehydrogenase complex (OGDHC), a tricarboxylic acid (TCA) cycle enzyme. Additionally, the inhibition of OGDHC observed upon neuro-inflammation is due to an excessive release of reactive oxygen/nitrogen species by immune cells. The loss of OGDHC inhibits uptake of glutamate by mitochondria, thus facilitating its extracellular accumulation and stimulating toxic glutamate pathway without affecting transmission. High levels of extracellular glutamate lead to dysregulation of intracellular redox homeostasis and cause ferroptosis, excitotoxicity, and mitochondrial dysfunction. The latter affects the transmission pathway demanding high-energy supply and leading to cell death. Mitochondria aggravate glutamate toxicity due to impairments in the TCA cycle and become a victim of glutamate toxicity, which disrupts oxidative phosphorylation. Thus, therapies targeting the TCA cycle in neurological disorders may be more efficient than attempting to preserve mitochondrial oxidative phosphorylation. Full article

(This article belongs to the Special Issue Cellular Redox Mechanisms in Inflammation and Programmed Cell Death)

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