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Redox Homeostasis and Oxidative Stress in Human Metabolism and Disease

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

Deadline for manuscript submissions: 20 March 2025 | Viewed by 14066

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Special Issue Editors

Prof. Dr. Alina Woźniak

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Department of Medical Biology and Biochemistry, Faculty of Medicine, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 24 Karłowicza St., 85-092 Bydgoszcz, Poland
Interests: reactive oxygen species; oxidative stress; antioxidants; lipid peroxidation; exercise biochemistry; cryostimulation; parasitology
Special Issues, Collections and Topics in MDPI journals

Dr. Jaroslaw Nuszkiewicz

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Department of Medical Biology and Biochemistry, Faculty of Medicine, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 24 Karłowicza St., 85-092 Bydgoszcz, Poland
Interests: reactive oxygen species; oxidative stress; antioxidants; oncology; metabolic diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The finely tuned equilibrium of redox reactions forms the bedrock of many cellular functions underlying key metabolic processes and influencing the health of tissues and organs. This balance, critical for cell functionality, is frequently compromised in a myriad of diseases, including metabolic disorders, degenerative conditions and various other pathophysiological states. Perturbations in redox homeostasis often result from an imbalance between the production of reactive oxygen species (ROS) and antioxidant response mechanisms. At physiological levels, ROS serve as pivotal signaling molecules in a wide range of metabolic activities. However, excessive ROS accumulation can deleteriously perturb metabolic functions, instigating a diseased state and accelerating its progression. Furthermore, the intimate relationship between redox dynamics and human metabolism becomes even more complex when considering the influence of exogenous factors. These agents, in varied concentrations, can either maintain a redox equilibrium, thereby aiding metabolic function, or disrupt it, exacerbating oxidative stress. A deeper grasp of these multifaceted interactions is crucial not only for understanding disease etiology, but also devising innovative therapeutic interventions and preventive measures.

In this vein, this Special Issue invites submissions of original research articles that shed light on the intricate dance of redox signaling within metabolic contexts, both in health and disease. Articles highlighting the potential therapeutic strategies targeting redox imbalances in metabolic disorders are particularly encouraged. Additionally, comprehensive review articles that evaluate and dissect the current knowledge landscape pertaining to the theme are most welcome.

Prof. Dr. Alina Woźniak
Dr. Jaroslaw Nuszkiewicz
Guest Editors

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Keywords

antioxidants
biomarkers
cellular functions
disease etiology
disease progression
metabolic disorders
metabolic signaling
oxidative stress
pathophysiological states
reactive oxygen species
redox homeostasis
redox signaling

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Published Papers (9 papers)

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Research

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17 pages, 1367 KiB

Open AccessArticle

Plasma Redox Balance in Advanced-Maternal-Age Pregnant Women and Effects of Plasma on Umbilical Cord Mesenchymal Stem Cells

by Elena Grossini, Carmen Imma Aquino, Sakthipriyan Venkatesan, Libera Troìa, Eleonora Tizzoni, Federica Fumagalli, Daniela Ferrante, Rosanna Vaschetto, Valentino Remorgida and Daniela Surico

Int. J. Mol. Sci. 2024, 25(9), 4869; https://doi.org/10.3390/ijms25094869 - 29 Apr 2024

Cited by 4 | Viewed by 1050

Abstract

Pregnancy at advanced maternal age (AMA) is a condition of potential risk for the development of maternal–fetal complications with possible repercussions even in the long term. Here, we analyzed the changes in plasma redox balance and the effects of plasma on human umbilical cord mesenchymal cells (hUMSCs) in AMA pregnant women (patients) at various timings of pregnancy. One hundred patients and twenty pregnant women younger than 40 years (controls) were recruited and evaluated at various timings during pregnancy until after delivery. Plasma samples were used to measure the thiobarbituric acid reactive substances (TBARS), glutathione and nitric oxide (NO). In addition, plasma was used to stimulate the hUMSCs, which were tested for cell viability, reactive oxygen species (ROS) and NO release. The obtained results showed that, throughout pregnancy until after delivery in patients, the levels of plasma glutathione and NO were lower than those of controls, while those of TBARS were higher. Moreover, plasma of patients reduced cell viability and NO release, and increased ROS release in hUMSCs. Our results highlighted alterations in the redox balance and the presence of potentially harmful circulating factors in plasma of patients. They could have clinical relevance for the prevention of complications related to AMA pregnancy. Full article

(This article belongs to the Special Issue Redox Homeostasis and Oxidative Stress in Human Metabolism and Disease)

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Figure 1
Glutathione (GSH, (A)), malonyldialdeide (MDA, (B)) and nitric oxide (NO, (C)) in umbilical cord plasma older (AMA > 40 yrs) and younger (Cntrl < 40 yrs) pregnant women collected at delivery. MDA was measured through the TBARS assay. T2: at the delivery. The results are expressed as median and range of different measurements. Square brackets indicate significance between groups (p < 0.05). Full article ">Figure 2
Effects of plasma taken from pregnant women older (patients) and younger than 40 years (controls) on cell viability (A), reactive oxygen species (ROS) release (B) and nitric oxide (NO) release (C) in hUMSCs. The bars represent the effects of plasma of all 10 patients and all 5 controls at various time points. T0: at 11–13 weeks of gestational age; T1: at 20–22 weeks of gestational age; T3: before Cesarean section or at 48–72 h after the delivery. The results are the median and range of repeated experiments. Untreated cells: non-treated hUMSCs. * p < 0.05 vs. untreated cells; a: p < 0.05 vs. T3 controls; square brackets indicate significance between the groups (p < 0.05). Full article ">Figure 3
Flowchart describing advanced-maternal-age (AMA) pregnant women that underwent the analysis of plasma redox balance and NO at various time points. Full article ">Figure 4
Flowchart describing the controls that underwent the analysis of plasma redox balance and NO at various time points. Full article ">Figure 5
Experiments on hUMSCs. hUMSCs: human umbilical cord mesenchymal stem cells. Full article ">

13 pages, 2792 KiB

Open AccessCommunication

Oxidative Stress Markers and Histopathological Changes in Selected Organs of Mice Infected with Murine Norovirus 1 (MNV-1)

by Paulina Janicka, Dominika Stygar, Elżbieta Chełmecka, Piotr Kuropka, Arkadiusz Miążek, Aleksandra Studzińska, Aleksandra Pogorzelska, Katarzyna Pala and Barbara Bażanów

Int. J. Mol. Sci. 2024, 25(7), 3614; https://doi.org/10.3390/ijms25073614 - 23 Mar 2024

Viewed by 1290

Abstract

This paper describes the effects of murine norovirus (MNV) infection on oxidative stress and histopathological changes in mice. This study uses histopathological assays, enzymatic and non-enzymatic antioxidant markers, and total oxidative status and capacity (TOS, TAC). The results suggest that MNV infection can lead to significant changes with respect to the above-mentioned parameters in various organs. Specifically, reduced superoxide dismutase (SOD), Mn superoxide dismutase (MnSOD), catalase (CAT), and glutathione reductase (GR) activities were observed in liver tissues, while higher MnSOD activity was observed in kidney tissues of MNV-infected mice when compared to the control. GR activity was lower in all tissues of MNV-infected mice tested, with the exception of lung tissue. This study also showed that norovirus infection led to increased TOS levels in the brain and liver and TAC levels in the brain, while TOS levels were significantly reduced in the kidneys. These changes may be due to the production of reactive oxygen species (ROS) caused by the viral infection. ROS can damage cells and contribute to oxidative stress. These studies help us to understand the pathogenesis of MNV infection and its potential effects on oxidative stress and histopathological changes in mice, and pave the way for further studies of the long-term effects of MNV infection. Full article

(This article belongs to the Special Issue Redox Homeostasis and Oxidative Stress in Human Metabolism and Disease)

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Figure 1
Histopathological changes in the lungs and kidneys. Lungs: Example pictures of lymphocyte infiltration in the control group and on the 3rd day. Note the presence of lymphoreticular tissue present (arrow) next to the bronchiole in the control group as well as in the alveoli on the 3rd day. Similar changes were found in individuals from other groups. Mag 100×. Kidneys: Example pictures of lymphocyte infiltration in animals on the 3rd, 4th, and 7th days. Mild lymphocyte infiltration (arrow) under the kidney capsule and between proximal tubules on the 4th day. Similar changes were observed in other time periods and in the control group. Fourth day—Mag 200×, seventh—Mag 400×. Scale bar—control and 7th day—25 µm, scale bar—3rd and 4th days—100 µm. These changes were considered not to be associated with norovirus. Full article ">Figure 2
Histopathological changes in the liver. Control group—normal structure of hepatocytes surrounding the central vein (arrow). Mag 400×. Mild lymphocyte infiltration around the blood vessel (arrow) after 3rd (Mag 400×) and 4th days. ((Mag 200×).After the 7th day, lymphocyte infiltration in the hepatic stroma (arrow). Mag 400×. Scale bar—25 µm. Full article ">Figure 3
Histopathological changes in the midbrain. Control group—numerous blood vessels in the midbrain (arrow). Mag 200×. After 3rd and 4th days—perivascular infiltration of lymphocytes in the white matter (arrow). Mag 400×. (D) after the 7th day, mild perivascular lymphocyte infiltration in white matter (arrow). Mag 400×. Scale bar—25 µm. Full article ">Figure 4
Histopathological changes in the cerebellum. Control group—normal image of unaltered cortex covered with pia matter. Mag 400×. On the 3rd day, 4th day, and 7th day—perivascular infiltration of lymphocytes in the white matter (arrow). Mag 400×. Scale bar—25 µm. Full article ">

16 pages, 986 KiB

Open AccessArticle

Preliminary Report on the Influence of Acute Inflammation on Adiponectin Levels in Older Inpatients with Different Nutritional Status

by Jakub Husejko, Marcin Gackowski, Jakub Wojtasik, Dominika Strzała, Maciej Pesta, Katarzyna Mądra-Gackowska, Jarosław Nuszkiewicz, Alina Woźniak, Mariusz Kozakiewicz and Kornelia Kędziora-Kornatowska

Int. J. Mol. Sci. 2024, 25(4), 2016; https://doi.org/10.3390/ijms25042016 - 7 Feb 2024

Cited by 1 | Viewed by 1287

Abstract

Inflammation can be triggered by a variety of factors, including pathogens, damaged cells, and toxic compounds. It is a biological response of the immune system, which can be successfully assessed in clinical practice using some molecular substances. Because adiponectin, a hormone released by adipose tissue, influences the development of inflammation, its evaluation as a potential measure of inflammation in clinical practice is justified. In the present contribution, statistical comparison of adiponectin concentration and selected molecular substances recognized in clinical practice as measures of inflammation were utilized to demonstrate whether adipose tissue hormones, as exemplified by adiponectin, have the potential to act as a measure of rapidly changing inflammation when monitoring older hospitalized patients in the course of bacterial infection. The study showed no statistically significant differences in adiponectin levels depending on the rapidly changing inflammatory response in its early stage. Interestingly, the concentration of adiponectin is statistically significantly higher in malnourished patients than in people with normal nutritional levels, assessed based on the MNA. According to the results obtained, adiponectin is not an effective measure of acute inflammation in clinical practice. However, it may serve as a biomarker of malnutrition in senile individuals. Full article

(This article belongs to the Special Issue Redox Homeostasis and Oxidative Stress in Human Metabolism and Disease)

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Review

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15 pages, 723 KiB

Open AccessReview

The Role of Selected Elements in Oxidative Stress Protection: Key to Healthy Fertility and Reproduction

by Marcin Wróblewski, Weronika Wróblewska and Marta Sobiesiak

Int. J. Mol. Sci. 2024, 25(17), 9409; https://doi.org/10.3390/ijms25179409 - 29 Aug 2024

Cited by 1 | Viewed by 1411

Abstract

Oxidative stress and its relationship to fertility and reproduction is a topic of interest in medicine, especially in the context of the effects of trace elements and micronutrients. Oxidative stress occurs when there is an excess of free radicals in the body, which can lead to cell and tissue damage. Free radicals are reactive oxygen species (ROS) that can be formed as a result of normal metabolic processes, as well as under the influence of external factors such as environmental pollution, UV radiation, and diet. Oxidative stress has a significant impact on fertility. In men, it can lead to DNA damage in sperm, which can result in reduced semen quality, reduced sperm motility and increased numbers of defective sperm, and free radical damage to sperm cell membranes causing a reduction in the number of available sperm. In women, oxidative stress can affect the quality of female reproductive cells, which can lead to problems with their maturation and with embryo implantation in the uterus and can also affect ovarian function and disrupt hormonal regulation of the menstrual cycle. A proper balance of trace elements and micronutrients is key to protecting against oxidative stress and maintaining reproductive health. Supplementation with appropriate elements such as zinc, selenium, copper, manganese, chromium, and iron can help reduce oxidative stress and improve fertility. This work discusses the effects of selected elements on oxidative stress parameters specifically in terms of fertility and reproduction. Full article

(This article belongs to the Special Issue Redox Homeostasis and Oxidative Stress in Human Metabolism and Disease)

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29 pages, 1154 KiB

Open AccessReview

Environmental and Genetic Determinants of Ankylosing Spondylitis

by Rafał Bilski, Piotr Kamiński, Daria Kupczyk, Sławomir Jeka, Jędrzej Baszyński, Halina Tkaczenko and Natalia Kurhaluk

Int. J. Mol. Sci. 2024, 25(14), 7814; https://doi.org/10.3390/ijms25147814 - 17 Jul 2024

Cited by 2 | Viewed by 2230

Abstract

Exposure to heavy metals and lifestyle factors like smoking contribute to the production of free oxygen radicals. This fact, combined with a lowered total antioxidant status, can induce even more damage in the development of ankylosing spondylitis (AS). Despite the fact that some researchers are looking for more genetic factors underlying AS, most studies focus on polymorphisms within the genes encoding the human leukocyte antigen (HLA) system. The biggest challenge is finding the effective treatment of the disease. Genetic factors and the influence of oxidative stress, mineral metabolism disorders, microbiota, and tobacco smoking seem to be of great importance for the development of AS. The data contained in this review constitute valuable information and encourage the initiation and development of research in this area, showing connections between inflammatory disorders leading to the pathogenesis of AS and selected environmental and genetic factors. Full article

(This article belongs to the Special Issue Redox Homeostasis and Oxidative Stress in Human Metabolism and Disease)

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16 pages, 799 KiB

Open AccessReview

The Current State of Knowledge Regarding the Genetic Predisposition to Sports and Its Health Implications in the Context of the Redox Balance, Especially Antioxidant Capacity

by Paweł Sutkowy, Martyna Modrzejewska, Marta Porzych and Alina Woźniak

Int. J. Mol. Sci. 2024, 25(13), 6915; https://doi.org/10.3390/ijms25136915 - 24 Jun 2024

Viewed by 970

Abstract

The significance of physical activity in sports is self-evident. However, its importance is becoming increasingly apparent in the context of public health. The constant desire to improve health and performance suggests looking at genetic predispositions. The knowledge of genes related to physical performance can be utilized initially in the training of athletes to assign them to the appropriate sport. In the field of medicine, this knowledge may be more effectively utilized in the prevention and treatment of cardiometabolic diseases. Physical exertion engages the entire organism, and at a basic physiological level, the organism’s responses are primarily related to oxidant and antioxidant reactions due to intensified cellular respiration. Therefore, the modifications involve the body adjusting to the stresses, especially oxidative stress. The consequence of regular exercise is primarily an increase in antioxidant capacity. Among the genes considered, those that promote oxidative processes dominate, as they are associated with energy production during exercise. What is missing, however, is a look at the other side of the coin, which, in this case, is antioxidant processes and the genes associated with them. It has been demonstrated that antioxidant genes associated with increased physical performance do not always result in increased antioxidant capacity. Nevertheless, it seems that maintaining the oxidant–antioxidant balance is the most important thing in this regard. Full article

(This article belongs to the Special Issue Redox Homeostasis and Oxidative Stress in Human Metabolism and Disease)

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36 pages, 2067 KiB

Open AccessReview

Immunogenetic and Environmental Factors in Age-Related Macular Disease

by Sylwia Brodzka, Jędrzej Baszyński, Katarzyna Rektor, Karolina Hołderna-Bona, Emilia Stanek, Natalia Kurhaluk, Halina Tkaczenko, Grażyna Malukiewicz, Alina Woźniak and Piotr Kamiński

Int. J. Mol. Sci. 2024, 25(12), 6567; https://doi.org/10.3390/ijms25126567 - 14 Jun 2024

Cited by 3 | Viewed by 1208

Abstract

Age-related macular degeneration (AMD) is a chronic disease, which often develops in older people, but this is not the rule. AMD pathogenesis changes include the anatomical and functional complex. As a result of damage, it occurs, in the retina and macula, among other areas. These changes may lead to partial or total loss of vision. This disease can occur in two clinical forms, i.e., dry (progression is slowly and gradually) and exudative (wet, progression is acute and severe), which usually started as dry form. A coexistence of both forms is possible. AMD etiology is not fully understood. Extensive genetic studies have shown that this disease is multifactorial and that genetic determinants, along with environmental and metabolic-functional factors, are important risk factors. This article reviews the impact of heavy metals, macro- and microelements, and genetic factors on the development of AMD. We present the current state of knowledge about the influence of environmental factors and genetic determinants on the progression of AMD in the confrontation with our own research conducted on the Polish population from Kuyavian-Pomeranian and Lubusz Regions. Our research is concentrated on showing how polluted environments of large agglomerations affects the development of AMD. In addition to confirming heavy metal accumulation, the growth of risk of acute phase factors and polymorphism in the genetic material in AMD development, it will also help in the detection of new markers of this disease. This will lead to a better understanding of the etiology of AMD and will help to establish prevention and early treatment. Full article

(This article belongs to the Special Issue Redox Homeostasis and Oxidative Stress in Human Metabolism and Disease)

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21 pages, 3463 KiB

Open AccessReview

Unraveling the Role of Reactive Oxygen Species in T Lymphocyte Signaling

by Karsten Gülow, Deniz Tümen, Philipp Heumann, Stephan Schmid, Arne Kandulski, Martina Müller and Claudia Kunst

Int. J. Mol. Sci. 2024, 25(11), 6114; https://doi.org/10.3390/ijms25116114 - 1 Jun 2024

Cited by 4 | Viewed by 1410

Abstract

Reactive oxygen species (ROS) are central to inter- and intracellular signaling. Their localized and transient effects are due to their short half-life, especially when generated in controlled amounts. Upon T cell receptor (TCR) activation, regulated ROS signaling is primarily initiated by complexes I and III of the electron transport chain (ETC). Subsequent ROS production triggers the activation of nicotinamide adenine dinucleotide phosphate oxidase 2 (NADPH oxidase 2), prolonging the oxidative signal. This signal then engages kinase signaling cascades such as the mitogen-activated protein kinase (MAPK) pathway and increases the activity of REDOX-sensitive transcription factors such as nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1). To limit ROS overproduction and prevent oxidative stress, nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant proteins such as superoxide dismutases (SODs) finely regulate signal intensity and are capable of terminating the oxidative signal when needed. Thus, oxidative signals, such as T cell activation, are well-controlled and critical for cellular communication. Full article

(This article belongs to the Special Issue Redox Homeostasis and Oxidative Stress in Human Metabolism and Disease)

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Figure 1
Schematic representation of oxidative signaling in T cells. Stimulation of the T cell receptor (TCR) leads to phosphorylation and activation of tyrosine kinase ZAP70, which phosphorylates LAT. Consequently, LAT recruits PLCγ1, which generates inositol 3,4,5-triphosphate (IP3) and diacylglycerol (DAG). At this point, the activation-induced signal diverges. IP3 is responsible for releasing Ca2+ into the cytosol. DAG activates the RAS guanyl-releasing protein 1 (RAS-GRP) and PKCθ. RAS-GRP activates Rat sarcoma (RAS) and subsequent kinase signaling. PKCθ induces ROS release via the mitochondria. Both signals are essential for the induction of activation-induced gene expression in T cells. Mitochondrial ROS release is a prerequisite for the induction of NADPH oxidase 2. ROS generation via NADPH oxidase 2 leads to a sustained oxidative signal. The figure was created with <a href="http://BioRender.com" target="_blank">BioRender.com</a> (accessed on 31 May 2024). Full article ">Figure 2
Complex I (CI) releases O2•− into the mitochondrial matrix, where most of it is converted to H2O2. However, certain conditions can lead to increased H2O2 production through other reactions. This high H2O2 production induces MnSOD, which further accelerates the conversion of O2•− to H2O2. As a result, fewer alternative reactions leading to H2O2 formation occur. Overall, this leads to reduced H2O2 production and a downregulation of the oxidative signal. The figure was created with BioRender.com. Full article ">Figure 3
After TCR stimulation, PLCγ1 generates 3,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 induces Ca2+ influx into the cytosol and activates NF-AT via calcineurin. Simultaneously, DAG activates PKCθ. PKCθ most likely phosphorylates ADPGK. ADPGK induces a redirection of glycolysis, allowing electrons to be directly transferred to ubiquinone via GPD2. From there, electrons can be retrogradely directed towards Complex I of the ETC and forward directed to Complex III. At these complexes, ROS is released, activating REDOX-sensitive transcription factors and inducing the expression of specific genes essential for T cell activation. The figure was created with BioRender.com. Full article ">Figure 4
Overview of T cell subsets. CD8+ T cells, also known as cytotoxic T lymphocytes (CTLs), are a vital component of the adaptive immune system. Their primary function is to identify and destroy infected or malignant cells. CD4+ T cells, also known as helper T cells, are crucial for orchestrating the immune response. They assist other immune cells by releasing cytokines that regulate the activity, growth, and differentiation of various immune cells. CD4+ can further be divided into Th1 cells (expressing T-box expressed in T cells [T-bet]), Th2 cells (expressing the GATA binding protein 3 [GATA3]), Th17 cells (expressing the RAR-related orphan receptor gamma t [RORγt]), and T regulatory cells (Treg; expressing elevated levels of (Forkhead-Box-Protein P3 [FOXP3]). Th1 cells promote cell-mediated immunity by activating macrophages and cytotoxic T cells. They are crucial for defending against intracellular pathogens like viruses and certain bacteria. Th2 cells support humoral immunity by stimulating B cells to produce antibodies. They are important for combating extracellular parasites and allergens. Th17 cells are involved in defending against extracellular bacteria and fungi. They also play a role in autoimmune diseases by promoting inflammation. Tregs maintain immune tolerance by suppressing immune responses, preventing autoimmune diseases, and controlling inflammation. The figure was created with BioRender.com. Full article ">Figure 5
ROS-induced oxidation of free thiol groups activates MAP kinase kinase kinases (MAPKKKs), which phosphorylate MAPKK and, subsequently, MAPK. This signaling pathway is further amplified by the oxidation of MAPK phosphatases, which are inhibited by oxidation of a thiol residue in their active site, resulting in full activation of the MAPK cascade. OX = oxidation, P = phosphorylation. The figure was created with BioRender.com. Full article ">Figure 6
The role of oxidative signals in the activation of NF-κB. The inhibitor of NF-κB (IκB) is phosphorylated by the IκB kinase (IKK) complex. Additionally, a pro-oxidative environment in the cytosol causes IκB to become oxidized. Both phosphorylation and oxidation result in the accelerated degradation of IκB, so NF-κB is released. The free NF-κB can now translocate to the nucleus. Oxidation further accelerates this translocation. The oxidation of NF-κB is enabled by a shift in the cytosolic REDOX homeostasis towards a pro-oxidative state, induced by the oxidative signal. In the nucleus, NF-κB must be reduced again to enable optimal DNA binding. This is primarily achieved by Thioredoxin 1 (TRX1). The figure was created with BioRender.com 4.3.3. Nuclear Factor of Activated t cells (NF-AT). Full article ">Figure 7
After TCR stimulation, two signaling pathways are induced via 3,4,5-triphosphate (IP3) and diacylglycerol (DAG). The IP3-dependent pathway leads to Ca2+ release into the cytosol, activating NF-AT. The DAG-dependent pathway activates PKCθ and induces an oxidative signal via Complex I and III of the mitochondrial electron transport chain (ETC). Additionally, the MAPK signaling pathway is induced via PKCθ. The oxidative signal originating from mitochondrial ETC amplifies the MAPK signaling pathway and activates the redox-sensitive transcription factors AP1, NF-κB, and Nrf2. AP1 and NF-κB, together with NF-AT, create the minimal requirement for T cell activation. Conversely, Nrf2, by inducing antioxidant proteins, contributes to the control and potential termination of the oxidative signal. The figure was created with BioRender.com Oxidative signals in T cells are essential for the initiation of a T cell immune response. Several publications and data have addressed the induction of oxidative signals by TCR stimulation and the mechanisms by which these signals are generated. However, the role of co-stimulation in oxidative signaling is not well understood. This represents a knowledge gap that urgently needs to be investigated in detail. Full article ">

16 pages, 2981 KiB

Open AccessReview

The Role of Glutathione in Age-Related Macular Degeneration (AMD)

Int. J. Mol. Sci. 2024, 25(8), 4158; https://doi.org/10.3390/ijms25084158 - 9 Apr 2024

Cited by 6 | Viewed by 2091

Abstract

Age-related macular degeneration (AMD) is a chronic disease that usually develops in older people. Pathogenetic changes in this disease include anatomical and functional complexes. Harmful factors damage the retina and macula. These changes may lead to partial or total loss of vision. The disease can occur in two clinical forms: dry (the progression is slow and gentle) and exudative (wet—progression is acute and severe), which usually starts in the dry form; however, the coexistence of both forms is possible. The etiology of AMD is not fully understood, and the precise mechanisms of the development of this illness are still unknown. Extensive genetic studies have shown that AMD is a multi-factorial disease and that genetic determinants, along with external and internal environmental and metabolic-functional factors, are important risk factors. This article reviews the role of glutathione (GSH) enzymes engaged in maintaining the reduced form and polymorphism in glutathione S-transferase theta-1 (GSTT1) and glutathione S-transferase mu-1 (GSTM1) in the development of AMD. We only chose papers that confirmed the influence of the parameters on the development of AMD. Because GSH is the most important antioxidant in the eye, it is important to know the influence of the enzymes and genetic background to ensure an optimal level of glutathione concentration. Numerous studies have been conducted on how the glutathione system works till today. This paper presents the current state of knowledge about the changes in GSH, GST, GR, and GPx in AMD. GST studies clearly show increased activity in ill people, but for GPx, the results relating to activity are not so clear. Depending on the research, the results also suggest higher and lower GPx activity in patients with AMD. The analysis of polymorphisms in GST genes confirmed that mutations lead to weaker antioxidant barriers and may contribute to the development of AMD; unfortunately, a meta-analysis and some research did not confirm that connection. Unspecific results of many of the parameters that make up the glutathione system show many unknowns. It is so important to conduct further research to understand the exact mechanism of defense functions of glutathione against oxidative stress in the human eye. Full article

(This article belongs to the Special Issue Redox Homeostasis and Oxidative Stress in Human Metabolism and Disease)

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The figure shows the two different clinical forms of macular degeneration (modified from the work of Nayyar et al. (2020) [<a href="#B7-ijms-25-04158" class="html-bibr">7</a>]). Full article ">Figure 2
The figure shows the risk factors for age-related macular degeneration (AMD). CFH: complement H activity; ApoE: apolipoprotein E; ARMS2: age-related maculopathy susceptibility 2 (modified from the work of Hyttinen et al. (2023) [<a href="#B9-ijms-25-04158" class="html-bibr">9</a>]). Full article ">Figure 3
The figure shows the enzymes involved during glutathione synthesis and metabolism in the retina. AC: amacrine cell; BPC: bipolar cell; GC: ganglion cell; GCL: ganglion cell layer; γGCL: γ-glutamate cysteine ligase; G6PD: glucose-6-phosphate dehydrogenase; 6PG: 6-phosphogluconate; GPx: glutathione peroxidase; GR: glutathione reductase; GS: glutathione synthase; GSH: glutathione; ROD: rhodopsin; HC: horizontal cell; INL: inner nuclear layer; IPL: inner plexiform layer; IOSP: inner and outer segments of photoreceptors; NF: nerve fiber; ONL: outer nuclear layer; OPL: outer plexiform layer; protein-S2: protein-S−S; protein (SH)2: protein-SH; RPE: retinal pigment epithelium; TR: thioredoxin reductase; TRX (SH)2: thioredoxin; TRX-S2: oxidized thioredoxin (modified from the work of McBean et al. (2015) [<a href="#B48-ijms-25-04158" class="html-bibr">48</a>]). Full article ">Figure 4
The figure shows the genes and their associations with AMD pathogenesis. Cellular functions, e.g., apoptotic, tumorigenesis, homologous recombination, angiogenesis, and inflammation are regulated by genes that stimulate the cardinal features of AMD abnormalities. Question marks symbolize the expected role of factors in the processes involved in AMD’s development (modified from the work of Anand et al. (2016) [<a href="#B95-ijms-25-04158" class="html-bibr">95</a>]). Full article ">

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