Antioxidants

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21 pages, 3582 KiB

Open AccessArticle

Activation of the MAC1-ERK1/2-NOX2 Pathway Is Required for LPS-Induced Sustaining Reactive Microgliosis, Chronic Neuroinflammation and Neurodegeneration

by Shih-Heng Chen, Shuangyu Han, Chih-Fen Hu, Ran Zhou, Yun Gao, Dezhen Tu, Huiming Gao, Jing Feng, Yubao Wang, Ru-Band Lu and Jau-Shyong Hong

Antioxidants 2022, 11(6), 1202; https://doi.org/10.3390/antiox11061202 - 20 Jun 2022

Cited by 3 | Viewed by 2307

Abstract

Recent studies suggest that improper resolution of acute neuroinflammation may lead to long-lasting low-grade chronic neuroinflammation and drive progressive neurodegeneration. However, the molecular mechanism underlying the transition from acute to chronic neuroinflammation remains unclear. The main purpose of this study was to search [...] Read more.

Recent studies suggest that improper resolution of acute neuroinflammation may lead to long-lasting low-grade chronic neuroinflammation and drive progressive neurodegeneration. However, the molecular mechanism underlying the transition from acute to chronic neuroinflammation remains unclear. The main purpose of this study was to search for potential pathways mediating LPS-elicited chronic neuroinflammation and resultant neurodegeneration. Using microglia cultures prepared from C57BL/6J, MAC1-deficient, and MyD88-deficient mice, the initial study showed that activation of TLR-4 is not sufficient for maintaining chronic neuroinflammation despite its essential role in LPS-initiated acute neuroinflammation. Opposite to TLR-4, our studies showed significantly reduced intensity of chronic neuroinflammation, oxidative stress, and progressive loss of nigral dopaminergic neurons in MAC1-deficient neuron/glial cultures or mice stimulated with LPS. Mechanistic studies revealed the essential role ERK1/2 activation in chronic neuroinflammation-elicited neurodegeneration, which was demonstrated by using an ERK1/2 inhibitor in neuron-glial cultures. Taken together, we propose a key role of the MAC1-NOX2-ERK1/2 signaling pathway in the initiation and maintenance of low-grade chronic neuroinflammation. Continuing ERK1/2 phosphorylation and NOX2 activation form a vicious feedforward cycle in microglia to maintain the low-grade neuroinflammation and drive neurodegeneration. Full article

(This article belongs to the Special Issue Redox Regulation in Inflammation and Disease)

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17 pages, 2538 KiB

Open AccessArticle

Nucleoredoxin Plays a Key Role in the Maintenance of Retinal Pigmented Epithelium Differentiation

by Mariana I. Holubiec, Juan I. Romero, Claudia Urbainsky, Manuela Gellert, Pablo Galeano, Francisco Capani, Christopher Horst Lillig and Eva-Maria Hanschmann

Antioxidants 2022, 11(6), 1106; https://doi.org/10.3390/antiox11061106 - 1 Jun 2022

Cited by 1 | Viewed by 2240

Abstract

Nucleoredoxin (Nrx) belongs to the Thioredoxin protein family and functions in redox-mediated signal transduction. It contains the dithiol active site motif Cys-Pro-Pro-Cys and interacts and regulates different proteins in distinct cellular pathways. Nrx was shown to be catalytically active in the insulin assay [...] Read more.

Nucleoredoxin (Nrx) belongs to the Thioredoxin protein family and functions in redox-mediated signal transduction. It contains the dithiol active site motif Cys-Pro-Pro-Cys and interacts and regulates different proteins in distinct cellular pathways. Nrx was shown to be catalytically active in the insulin assay and recent findings indicate that Nrx functions, in fact, as oxidase. Here, we have analyzed Nrx in the mammalian retina exposed to (perinatal) hypoxia-ischemia/reoxygenation, combining ex vivo and in vitro models. Our data show that Nrx regulates cell differentiation, which is important to (i) increase the number of glial cells and (ii) replenish neurons that are lost following the hypoxic insult. Nrx is essential to maintain cell morphology. These regulatory changes are related to VEGF but do not seem to be linked to the Wnt/β-catenin pathway, which is not affected by Nrx knock-down. In conclusion, our results strongly suggest that hypoxia-ischemia could lead to alterations in the organization of the retina, related to changes in RPE cell differentiation. Nrx may play an essential role in the maintenance of the RPE cell differentiation state via the regulation of VEGF release. Full article

(This article belongs to the Special Issue Redox Regulation in Inflammation and Disease)

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15 pages, 3715 KiB

Open AccessArticle

S1P/S1P₂ Signaling Axis Regulates Both NLRP3 Upregulation and NLRP3 Inflammasome Activation in Macrophages Primed with Lipopolysaccharide

by Chi-Ho Lee and Ji Woong Choi

Antioxidants 2021, 10(11), 1706; https://doi.org/10.3390/antiox10111706 - 27 Oct 2021

Cited by 11 | Viewed by 2870

Abstract

The activation of NLRP3 inflammasome is a key factor for various inflammatory diseases. Here, we provide experimental evidence supporting the regulatory role of sphingosine-1-phosphate (S1P) in NLRP3 inflammasome activation in mouse bone-marrow-derived macrophages (BMDMs), along with the S1P receptor subtype involved and underlying [...] Read more.

The activation of NLRP3 inflammasome is a key factor for various inflammatory diseases. Here, we provide experimental evidence supporting the regulatory role of sphingosine-1-phosphate (S1P) in NLRP3 inflammasome activation in mouse bone-marrow-derived macrophages (BMDMs), along with the S1P receptor subtype involved and underlying regulatory mechanisms. During the priming stage, S1P induced NLRP3 upregulation in BMDMs only when primed with lipopolysaccharide (LPS). In this event, S1P₂, but not S1P₁, was involved based on the attenuated NLRP3 upregulation with JTE013 (S1P₂ antagonist) or S1P₂ knockdown. During the activation stage, S1P induced NLRP3 inflammasome activation in LPS-primed BMDMs via caspase-1 activation, interleukin 1β maturation, apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, and IL-1β secretion. Such NLRP3 inflammasome activation was blocked by either pharmacological inhibition or genetic knockdown of S1P₂. NF-κB, PI3K/Akt, and ERK1/2 were identified as effector pathways underlying S1P/S1P₂ signaling in the regulation of NLRP3 upregulation in LPS-primed BMDMs. Further, reactive oxygen species (ROS) production was dependent on the S1P/S1P₂ signaling axis in these cells, and the ROS generated regulate NLRP3 inflammasome activation, but not NLRP3 priming. Collectively, our findings suggest that S1P promotes NLRP3 upregulation and NLRP3 inflammasome activation in LPS-primed BMDMs via S1P₂ and subsequent effector pathways. Full article

(This article belongs to the Special Issue Redox Regulation in Inflammation and Disease)

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18 pages, 38715 KiB

Open AccessArticle

Salvianolic Acid C Protects against Cisplatin-Induced Acute Kidney Injury through Attenuation of Inflammation, Oxidative Stress and Apoptotic Effects and Activation of the CaMKK–AMPK–Sirt1-Associated Signaling Pathway in Mouse Models

by Liang-Hsuan Chien, Chien-Ta Wu, Jeng-Shyan Deng, Wen-Ping Jiang, Wen-Chin Huang and Guan-Jhong Huang

Antioxidants 2021, 10(10), 1620; https://doi.org/10.3390/antiox10101620 - 15 Oct 2021

Cited by 25 | Viewed by 4018

Abstract

Acute kidney injury (AKI) is a sudden reduction in kidney activity and has a high mortality rate. Salvianolic acid C (SAC), one of the main polyphenolic components of Salvia miltiorrhiza, displays significant pharmacologically active effects. An animal model of cisplatin-induced kidney injury [...] Read more.

Acute kidney injury (AKI) is a sudden reduction in kidney activity and has a high mortality rate. Salvianolic acid C (SAC), one of the main polyphenolic components of Salvia miltiorrhiza, displays significant pharmacologically active effects. An animal model of cisplatin-induced kidney injury was used to study the potential of SAC to improve AKI. First, SAC was administered intraperitoneally in mice for 10 consecutive days, and then cisplatin was administered intraperitoneally on day 7 to establish a nephrotoxicity mouse model. SAC mitigated renal histological changes, blood creatinine (CRE) and blood urea nitrogen (BUN) production and the levels of inflammatory mediators in the cisplatin-induced AKI. Furthermore, malondialdehyde (MDA) levels were reduced and glutathione (GSH) was increased after intraperitoneal injection (i.p.) administration of SAC. In addition, based on Western blot data, SAC reduced the expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) activation in mouse renal tissues. Finally, SAC diminished the level of TLR-4 expression and enhanced the production of several antioxidative enzymes (superoxidase dismutase (SOD1), glutathione peroxidase (GPx3), catalase, nuclear-factor-erythroid-2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1)), Sirtuin 1 (Sirt1), p-AMP-activated protein kinase (AMPK) and p-Ca²⁺/calmodulin-dependent protein kinase kinase (CaMKK). In addition, Sirt1 inhibition (EX 527) inverted the effect of SAC against cisplatin-induced nephrotoxicity. Collectively, SAC provides a therapeutic target with promising clinical potential after cisplatin treatment by attenuating oxidative stress and inflammation. Full article

(This article belongs to the Special Issue Redox Regulation in Inflammation and Disease)

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16 pages, 3032 KiB

Open AccessArticle

Pseurotin D Induces Apoptosis through Targeting Redox Sensitive Pathways in Human Lymphoid Leukemia Cells

by Eva Mosejová, Rebeka Bosnjakovic, Lukáš Kubala and Ondřej Vašíček

Antioxidants 2021, 10(10), 1576; https://doi.org/10.3390/antiox10101576 - 5 Oct 2021

Cited by 4 | Viewed by 2348

Abstract

Chronic lymphocytic leukemia (CLL) is the most prevalent lymphoid malignancy in many geographical regions of the world. Pseurotin D, a secondary metabolite of fungi, represents a group of bioactive natural products with a newly ascribed range of interesting biological activities. The purpose of [...] Read more.

Chronic lymphocytic leukemia (CLL) is the most prevalent lymphoid malignancy in many geographical regions of the world. Pseurotin D, a secondary metabolite of fungi, represents a group of bioactive natural products with a newly ascribed range of interesting biological activities. The purpose of this study was to bring new insights into the mechanism behind the effects of pseurotin D on MEC-1 cells as a representative CLL cell line, with a particular focus on selected signaling pathways important in the proliferation of cells and targeting mitochondrial metabolism. Our results showed that pseurotin D was able to significantly inhibit the proliferation of MEC-1 cells and arrested them in the G2/M cell cycle phase. In addition, pseurotin D was able to induce apoptosis. We found that all of these effects were associated with a change in mitochondrial membrane potential and the production of mitochondrial reactive oxygen species (ROS). We showed for the first time that pseurotin D suppresses MEC-1 cell proliferation and induces apoptotic cell death via induction of the collapse of the mitochondria respiratory chain and the ROS-related caspase pathway. Our results show the pseurotins family as promising compounds which could serve as a basis for the development of new compounds in the treatment of lymphoma. Full article

(This article belongs to the Special Issue Redox Regulation in Inflammation and Disease)

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Review

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24 pages, 2014 KiB

Open AccessReview

Changing Perspectives from Oxidative Stress to Redox Signaling—Extracellular Redox Control in Translational Medicine

by Paola Loreto Palacio, José R. Godoy, Orhan Aktas and Eva-Maria Hanschmann

Antioxidants 2022, 11(6), 1181; https://doi.org/10.3390/antiox11061181 - 16 Jun 2022

Cited by 16 | Viewed by 3701

Abstract

Extensive research has changed the understanding of oxidative stress that has been linked to every major disease. Today we distinguish oxidative eu- and distress, acknowledging that redox modifications are crucial for signal transduction in the form of specific thiol switches. Long underestimated, reactive [...] Read more.

Extensive research has changed the understanding of oxidative stress that has been linked to every major disease. Today we distinguish oxidative eu- and distress, acknowledging that redox modifications are crucial for signal transduction in the form of specific thiol switches. Long underestimated, reactive species and redox proteins of the Thioredoxin (Trx) family are indeed essential for physiological processes. Moreover, extracellular redox proteins, low molecular weight thiols and thiol switches affect signal transduction and cell–cell communication. Here, we highlight the impact of extracellular redox regulation for health, intermediate pathophenotypes and disease. Of note, recent advances allow the analysis of redox changes in body fluids without using invasive and expensive techniques. With this new knowledge in redox biochemistry, translational strategies can lead to innovative new preventive and diagnostic tools and treatments in life sciences and medicine. Full article

(This article belongs to the Special Issue Redox Regulation in Inflammation and Disease)

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24 pages, 6443 KiB

Open AccessReview

Is Nucleoredoxin a Master Regulator of Cellular Redox Homeostasis? Its Implication in Different Pathologies

by Osiris Germán Idelfonso-García, Brisa Rodope Alarcón-Sánchez, Verónica Rocío Vásquez-Garzón, Rafael Baltiérrez-Hoyos, Saúl Villa-Treviño, Pablo Muriel, Héctor Serrano, Julio Isael Pérez-Carreón and Jaime Arellanes-Robledo

Antioxidants 2022, 11(4), 670; https://doi.org/10.3390/antiox11040670 - 30 Mar 2022

Cited by 12 | Viewed by 3923

Abstract

Nucleoredoxin (NXN), an oxidoreductase enzyme, contributes to cellular redox homeostasis by regulating different signaling pathways in a redox-dependent manner. By interacting with seven proteins so far, namely disheveled (DVL), protein phosphatase 2A (PP2A), phosphofructokinase-1 (PFK1), translocation protein SEC63 homolog (SEC63), myeloid differentiation primary [...] Read more.

Nucleoredoxin (NXN), an oxidoreductase enzyme, contributes to cellular redox homeostasis by regulating different signaling pathways in a redox-dependent manner. By interacting with seven proteins so far, namely disheveled (DVL), protein phosphatase 2A (PP2A), phosphofructokinase-1 (PFK1), translocation protein SEC63 homolog (SEC63), myeloid differentiation primary response gene-88 (MYD88), flightless-I (FLII), and calcium/calmodulin-dependent protein kinase II type alpha (CAMK2A), NXN is involved in the regulation of several key cellular processes, including proliferation, organogenesis, cell cycle progression, glycolysis, innate immunity and inflammation, motility, contraction, protein transport into the endoplasmic reticulum, neuronal plasticity, among others; as a result, NXN has been implicated in different pathologies, such as cancer, alcoholic and polycystic liver disease, liver fibrogenesis, obesity, Robinow syndrome, diabetes mellitus, Alzheimer’s disease, and retinitis pigmentosa. Together, this evidence places NXN as a strong candidate to be a master redox regulator of cell physiology and as the hub of different redox-sensitive signaling pathways and associated pathologies. This review summarizes and discusses the current insights on NXN-dependent redox regulation and its implication in different pathologies. Full article

(This article belongs to the Special Issue Redox Regulation in Inflammation and Disease)

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14 pages, 3928 KiB

Open AccessReview

Role of Nitric Oxide and Protein S-Nitrosylation in Ischemia-Reperfusion Injury

by Hyang-Mi Lee, Ji Woong Choi and Min Sik Choi

Antioxidants 2022, 11(1), 57; https://doi.org/10.3390/antiox11010057 - 27 Dec 2021

Cited by 12 | Viewed by 3702

Abstract

Ischemia-reperfusion injury (IRI) is a process in which damage is induced in hypoxic tissue when oxygen supply is resumed after ischemia. During IRI, restoration of reduced nitric oxide (NO) levels may alleviate reperfusion injury in ischemic organs. The protective mechanism of NO is [...] Read more.

Ischemia-reperfusion injury (IRI) is a process in which damage is induced in hypoxic tissue when oxygen supply is resumed after ischemia. During IRI, restoration of reduced nitric oxide (NO) levels may alleviate reperfusion injury in ischemic organs. The protective mechanism of NO is due to anti-inflammatory effects, antioxidant effects, and the regulation of cell signaling pathways. On the other hand, it is generally known that S-nitrosylation (SNO) mediates the detrimental or protective effect of NO depending on the action of the nitrosylated target protein, and this is also applied in the IRI process. In this review, the effect of each change of NO and SNO during the IRI process was investigated. Full article

(This article belongs to the Special Issue Redox Regulation in Inflammation and Disease)

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