Cellular Redox Homeostasis

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Antioxidants antioxidants	6.0	10.6	2012	16.9 Days	CHF 2900
Cells cells	5.1	9.9	2012	17 Days	CHF 2700
International Journal of Molecular Sciences ijms	4.9	8.1	2000	16.8 Days	CHF 2900

22 pages, 3466 KiB

Open AccessArticle

Glutathione–Hemin/Hematin Adduct Formation to Disintegrate Cytotoxic Oxidant Hemin/Hematin in Human K562 Cells and Red Blood Cells’ Hemolysates: Impact of Glutathione on the Hemolytic Disorders and Homeostasis

by Sofia K. Georgiou-Siafis, Martina K. Samiotaki, Vassilis J. Demopoulos, George Panayotou and Asterios S. Tsiftsoglou

Antioxidants 2022, 11(10), 1959; https://doi.org/10.3390/antiox11101959 - 30 Sep 2022

Cited by 10 | Viewed by 4551

Abstract

Hemin, an oxidized form of heme, acts as potent oxidant to regulate glutathione (GSH) content in pro-erythroid K562 nucleated cells, via activation of the KEAP1/NRF2 defensive signaling pathway. Moreover, GSH, as an essential metabolite, is involved in the regulation of cell-redox homeostasis and [...] Read more.

Hemin, an oxidized form of heme, acts as potent oxidant to regulate glutathione (GSH) content in pro-erythroid K562 nucleated cells, via activation of the KEAP1/NRF2 defensive signaling pathway. Moreover, GSH, as an essential metabolite, is involved in the regulation of cell-redox homeostasis and proposed to scavenge cytotoxic free heme, which is released from hemoglobin of damaged red blood cells (RBCs) during different hemolytic disorders. In the present study, we aimed to uncover the molecular mechanism by which GSH inhibits hemin-induced cytotoxicity (HIC) by affecting hemin’s structural integrity in K562 cells and in RBC hemolysates. GSH, along with other thiols (cysteine, thioglycolic acid, and mercaptoethanol) altered the spectrum of hemin, while each of them co-added with hemin in cultures of K562 cells prevented HIC and growth arrest and markedly reduced the intracellular level of hemin. In addition, GSH endogenous levels served as a barrier to HIC in K562 cells, as shown by the depletion in GSH. LC-MS/MS analysis of the in vitro reaction between hemin and GSH revealed at least five different isomers of GSH–hemin adducts, as well as hydroxy derivatives as reaction products, which are characterized by unique mass spectra (MS). The latter allowed the detection of adducts in human RBC hemolysates. Based on these findings, we proposed a molecular mechanism via which GSH prevents HIC and structurally disintegrates heme. An analogous reaction was observed in RBC hemolysates via direct inter-reaction between hematin (ferric and hydroxide heme) released from hemoglobin and GSH. Overall, GSH–hematin adducts could be considered as novel entities of the human metabolome of RBCs in hemolytic disorders. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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18 pages, 2328 KiB

Open AccessArticle

Profiling the Site of Protein CoAlation and Coenzyme A Stabilization Interactions

by Maria-Armineh Tossounian, Maria Baczynska, William Dalton, Charlie Newell, Yilin Ma, Sayoni Das, Jonathan Alexis Semelak, Dario Ariel Estrin, Valeriy Filonenko, Madia Trujillo, Sew Yeu Peak-Chew, Mark Skehel, Franca Fraternali, Christine Orengo and Ivan Gout

Antioxidants 2022, 11(7), 1362; https://doi.org/10.3390/antiox11071362 - 14 Jul 2022

Cited by 14 | Viewed by 4356

Abstract

Coenzyme A (CoA) is a key cellular metabolite known for its diverse functions in metabolism and regulation of gene expression. CoA was recently shown to play an important antioxidant role under various cellular stress conditions by forming a disulfide bond with proteins, termed [...] Read more.

Coenzyme A (CoA) is a key cellular metabolite known for its diverse functions in metabolism and regulation of gene expression. CoA was recently shown to play an important antioxidant role under various cellular stress conditions by forming a disulfide bond with proteins, termed CoAlation. Using anti-CoA antibodies and liquid chromatography tandem mass spectrometry (LC-MS/MS) methodologies, CoAlated proteins were identified from various organisms/tissues/cell-lines under stress conditions. In this study, we integrated currently known CoAlated proteins into mammalian and bacterial datasets (CoAlomes), resulting in a total of 2093 CoAlated proteins (2862 CoAlation sites). Functional classification of these proteins showed that CoAlation is widespread among proteins involved in cellular metabolism, stress response and protein synthesis. Using 35 published CoAlated protein structures, we studied the stabilization interactions of each CoA segment (adenosine diphosphate (ADP) moiety and pantetheine tail) within the microenvironment of the modified cysteines. Alternating polar-non-polar residues, positively charged residues and hydrophobic interactions mainly stabilize the pantetheine tail, phosphate groups and the ADP moiety, respectively. A flexible nature of CoA is observed in examined structures, allowing it to adapt its conformation through interactions with residues surrounding the CoAlation site. Based on these findings, we propose three modes of CoA binding to proteins. Overall, this study summarizes currently available knowledge on CoAlated proteins, their functional distribution and CoA–protein stabilization interactions. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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22 pages, 1920 KiB

Open AccessReview

Emerging Evidence of the Significance of Thioredoxin-1 in Hematopoietic Stem Cell Aging

by Shaima Jabbar, Parker Mathews and Yubin Kang

Antioxidants 2022, 11(7), 1291; https://doi.org/10.3390/antiox11071291 - 29 Jun 2022

Cited by 4 | Viewed by 2852

Abstract

The United States is undergoing a demographic shift towards an older population with profound economic, social, and healthcare implications. The number of Americans aged 65 and older will reach 80 million by 2040. The shift will be even more dramatic in the extremes [...] Read more.

The United States is undergoing a demographic shift towards an older population with profound economic, social, and healthcare implications. The number of Americans aged 65 and older will reach 80 million by 2040. The shift will be even more dramatic in the extremes of age, with a projected 400% increase in the population over 85 years old in the next two decades. Understanding the molecular and cellular mechanisms of ageing is crucial to reduce ageing-associated disease and to improve the quality of life for the elderly. In this review, we summarized the changes associated with the ageing of hematopoietic stem cells (HSCs) and what is known about some of the key underlying cellular and molecular pathways. We focus here on the effects of reactive oxygen species and the thioredoxin redox homeostasis system on ageing biology in HSCs and the HSC microenvironment. We present additional data from our lab demonstrating the key role of thioredoxin-1 in regulating HSC ageing. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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23 pages, 1874 KiB

Open AccessReview

Ferroptosis and Its Emerging Role in Pre-Eclampsia

by Zhixian Chen, Jianfeng Gan, Mo Zhang, Yan Du and Hongbo Zhao

Antioxidants 2022, 11(7), 1282; https://doi.org/10.3390/antiox11071282 - 28 Jun 2022

Cited by 23 | Viewed by 4662

Abstract

Iron is essential for cell survival, and iron deficiency is a known risk factor for many reproductive diseases. Paradoxically, such disorders are also more common in cases of iron overload. Here, we evaluated the role of ferroptosis in women’s health, particularly focusing on [...] Read more.

Iron is essential for cell survival, and iron deficiency is a known risk factor for many reproductive diseases. Paradoxically, such disorders are also more common in cases of iron overload. Here, we evaluated the role of ferroptosis in women’s health, particularly focusing on pre-eclampsia (PE). PE is a multisystem disorder and is one of the leading causes of maternal and perinatal morbidity and mortality, especially when the condition is of early onset. Nevertheless, the exact etiological mechanism of PE remains unclear. Interestingly, ferroptosis, as a regulated iron-dependent cell death pathway, involves a lethal accumulation of lipid peroxides and shares some characteristics with PE pathophysiology. In this review, we comprehensively reviewed and summarized recent studies investigating the molecular mechanisms involved in the regulation and execution of ferroptosis, as well as ferroptosis mechanisms in the pathology of PE. We propose that ferroptosis not only plays an important role in PE, but may also become a novel therapeutic target for PE. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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15 pages, 1303 KiB

Open AccessReview

Cold Argon Athmospheric Plasma for Biomedicine: Biological Effects, Applications and Possibilities

by Andrew K. Martusevich, Alexandra V. Surovegina, Ivan V. Bocharin, Vladimir V. Nazarov, Inessa A. Minenko and Mikhail Yu. Artamonov

Antioxidants 2022, 11(7), 1262; https://doi.org/10.3390/antiox11071262 - 27 Jun 2022

Cited by 29 | Viewed by 3612

Abstract

Currently, plasma medicine is a synthetic direction that unites the efforts of specialists of various profiles. For the successful formation of plasma medicine, it is necessary to solve a large complex of problems, including creating equipment for generating cold plasma, revealing the biological [...] Read more.

Currently, plasma medicine is a synthetic direction that unites the efforts of specialists of various profiles. For the successful formation of plasma medicine, it is necessary to solve a large complex of problems, including creating equipment for generating cold plasma, revealing the biological effects of this effect, as well as identifying and justifying the most promising areas of its application. It is known that these biological effects include antibacterial and antiviral activity, the ability to stimulate hemocoagulation, pro-regenerative properties, etc. The possibility of using the factor in tissue engineering and implantology is also shown. Based on this, the purpose of this review was to form a unified understanding of the biological effects and biomedical applications of argon cold plasma. The review shows that cold plasma, like any other physical and chemical factors, has dose dependence, and the variable parameter in this case is the exposure of its application. One of the significant characteristics determining the specificity of the cold plasma effect is the carrier gas selection. This gas carrier is not just an ionized medium but modulates the response of biosystems to it. Finally, the perception of cold plasma by cellular structures can be carried out by activating a special molecular biosensor, the functioning of which significantly depends on the parameters of the medium (in the field of plasma generation and the cell itself). Further research in this area can open up new prospects for the effective use of cold plasma. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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18 pages, 4423 KiB

Open AccessArticle

A Mutation in Endogenous saRNA miR-23a Influences Granulosa Cells Response to Oxidative Stress

by Siqi Wang, Yuqi Li, Qiang Zeng, Liu Yang, Xing Du and Qifa Li

Antioxidants 2022, 11(6), 1174; https://doi.org/10.3390/antiox11061174 - 15 Jun 2022

Cited by 10 | Viewed by 2567

Abstract

Phenotypes are the result of the interaction between the gene and the environment, so the response of individuals with different genotypes to an environment is variable. Here, we reported that a mutation in miR-23a influences granulosa cells (GCs) response to oxidative stress, a [...] Read more.

Phenotypes are the result of the interaction between the gene and the environment, so the response of individuals with different genotypes to an environment is variable. Here, we reported that a mutation in miR-23a influences granulosa cells (GCs) response to oxidative stress, a common mechanism of environmental factors affecting female reproduction. We showed that nuclear miR-23a is a pro-apoptotic miRNA in porcine GCs through the activation of the transcription and function of NORHA, a long non-coding RNA (lncRNA) induces GC apoptosis and responses to oxidative stress. Mechanistically, miR-23a acts as an endogenous small activating RNA (saRNA) to alter histone modifications of the NORHA promoter through the direct binding to its core promoter. A C > T mutation was identified at −398 nt of the miR-23a core promoter, which created a novel binding site for the transcription factor SMAD4 and recruited the transcription repressor SMAD4 to inhibit miR-23a transcription and function in GCs. Notably, g.−398C > T mutation in the miR-23a promoter reduced GCs response to oxidative stress. In addition, g.−398C > T mutation was significantly associated with sow fertility traits. In short, our findings preliminarily revealed the genetic basis of individual differences in the response to oxidative stress from the perspective of a single mutation and identified miR-23a as a candidate gene for the environmental adaptation to oxidative stress. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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16 pages, 4951 KiB

Open AccessArticle

Reactive Oxygen Species Distribution Involved in Stipe Gradient Elongation in the Mushroom Flammulina filiformis

by Junjie Yan, Julia Chekanova, Yuanyuan Liu, Bingcheng Gan, Ying Long, Xing Han, Zongjun Tong, Juan Miao, Lingdan Lian, Baogui Xie and Fang Liu

Cells 2022, 11(12), 1896; https://doi.org/10.3390/cells11121896 - 11 Jun 2022

Cited by 14 | Viewed by 3118

Abstract

The mushroom stipe raises the pileus above the substrate into a suitable position for dispersing spores. The stipe elongates at different speeds along its length, with the rate of elongation decreasing in a gradient from the top to the base. However, the molecular [...] Read more.

The mushroom stipe raises the pileus above the substrate into a suitable position for dispersing spores. The stipe elongates at different speeds along its length, with the rate of elongation decreasing in a gradient from the top to the base. However, the molecular mechanisms underlying stipe gradient elongation are largely unknown. Here, we used the model basidiomycete mushroom Flammulina filiformis to investigate the mechanism of mushroom stipe elongation and the role of reactive oxygen species (ROS) signaling in this process. Our results show that O₂⁻ and H₂O₂ exhibit opposite gradient distributions in the stipe, with higher O₂⁻ levels in the elongation region (ER), and higher H₂O₂ levels in the stable region (SR). Moreover, NADPH-oxidase-encoding genes are up-regulated in the ER, have a function in producing O₂⁻, and positively regulate stipe elongation. Genes encoding manganese superoxide dismutase (MnSOD) are up-regulated in the SR, have a function in producing H₂O_2, and negatively regulate stipe elongation. Altogether, our data demonstrate that ROS (O₂⁻/H₂O₂) redistribution mediated by NADPH oxidase and MnSODs is linked to the gradient elongation of the F. filiformis stipe. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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20 pages, 1638 KiB

Open AccessReview

Reactive Oxygen Species in Regulating Lymphangiogenesis and Lymphatic Function

by Bhupesh Singla, Ravi Varma Aithabathula, Sonia Kiran, Shweta Kapil, Santosh Kumar and Udai P. Singh

Cells 2022, 11(11), 1750; https://doi.org/10.3390/cells11111750 - 26 May 2022

Cited by 18 | Viewed by 4562

Abstract

The lymphatic system is pivotal for immunosurveillance and the maintenance of tissue homeostasis. Lymphangiogenesis, the formation of new lymphatic vessels from pre-existing vessels, has both physiological and pathological roles. Recent advances in the molecular mechanisms regulating lymphangiogenesis have opened a new area of [...] Read more.

The lymphatic system is pivotal for immunosurveillance and the maintenance of tissue homeostasis. Lymphangiogenesis, the formation of new lymphatic vessels from pre-existing vessels, has both physiological and pathological roles. Recent advances in the molecular mechanisms regulating lymphangiogenesis have opened a new area of research on reparative lymphangiogenesis for the treatment of various pathological disorders comprising neurological disorders, cardiac repair, autoimmune disease, obesity, atherosclerosis, etc. Reactive oxygen species (ROS) produced by the various cell types serve as signaling molecules in several cellular mechanisms and regulate various aspects of growth-factor-mediated responses, including lymphangiogenesis. The ROS, including superoxide anion, hydrogen peroxide, and nitric oxide, play both beneficial and detrimental roles depending upon their levels and cellular microenvironment. Low ROS levels are essential for lymphangiogenesis. On the contrary, oxidative stress due to enhanced ROS generation and/or reduced levels of antioxidants suppresses lymphangiogenesis via promoting lymphatic endothelial cell apoptosis and death. In this review article, we provide an overview of types and sources of ROS, discuss the role of ROS in governing lymphangiogenesis and lymphatic function, and summarize the role of lymphatics in various diseases. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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8 pages, 1207 KiB

Open AccessArticle

Thyroid Disorders in Patients Treated with Dimethyl Fumarate for Multiple Sclerosis: A Retrospective Observational Study

by Cédric O. Renaud, Panos G. Ziros, Amandine Mathias, Caroline Pot and Gerasimos P. Sykiotis

Antioxidants 2022, 11(5), 1015; https://doi.org/10.3390/antiox11051015 - 21 May 2022

Cited by 3 | Viewed by 3263

Abstract

Background: Dimethyl fumarate (DMF), a drug used for the treatment of multiple sclerosis (MS) and psoriasis, has been shown to activate the Keap1/Nrf2 antioxidant response. Nrf2 exerts pleiotropic roles in the thyroid gland; among others, single nucleotide polymorphisms (SNPs) in the gene encoding [...] Read more.

Background: Dimethyl fumarate (DMF), a drug used for the treatment of multiple sclerosis (MS) and psoriasis, has been shown to activate the Keap1/Nrf2 antioxidant response. Nrf2 exerts pleiotropic roles in the thyroid gland; among others, single nucleotide polymorphisms (SNPs) in the gene encoding Nrf2 modulate the risk of Hashimoto’s thyroiditis (HT), suggesting that pharmacological activation of Nrf2 might also be protective. However, a patient with acute exacerbation of HT after starting DMF for MS was recently reported, raising questions about the thyroidal safety of Nrf2 activators. Methods: In a retrospective observational study, we investigated the prevalence and incidence of thyroid disorders (TD) among 163 patients with MS treated with DMF. Results: Only 7/163 patients (4.3%) were diagnosed with functional TD; most (5/163, 3.0%) were diagnosed before DMF treatment. Functional TD were diagnosed under or after DMF in only 2 patients (1.2%). Under DMF, one patient developed transient mild hypothyroidism with negative thyroid autoantibodies. After DMF discontinuation, another patient developed hyperthyroidism due to Graves’ disease. No patient developed thyroid structural disease under or after DMF. Conclusions: The very low incidence of functional TD indicates an overall very good thyroid tolerance of DMF, arguing against screening for TD in MS patients considered for or treated with DMF, and supporting the further study of Nrf2 activators for the prevention and treatment of TD. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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26 pages, 1643 KiB

Open AccessReview

Connexin Mutations and Hereditary Diseases

by Yue Qiu, Jianglin Zheng, Sen Chen and Yu Sun

Int. J. Mol. Sci. 2022, 23(8), 4255; https://doi.org/10.3390/ijms23084255 - 12 Apr 2022

Cited by 31 | Viewed by 6079

Abstract

Inherited diseases caused by connexin mutations are found in multiple organs and include hereditary deafness, congenital cataract, congenital heart diseases, hereditary skin diseases, and X-linked Charcot–Marie–Tooth disease (CMT1X). A large number of knockout and knock-in animal models have been used to study the [...] Read more.

Inherited diseases caused by connexin mutations are found in multiple organs and include hereditary deafness, congenital cataract, congenital heart diseases, hereditary skin diseases, and X-linked Charcot–Marie–Tooth disease (CMT1X). A large number of knockout and knock-in animal models have been used to study the pathology and pathogenesis of diseases of different organs. Because the structures of different connexins are highly homologous and the functions of gap junctions formed by these connexins are similar, connexin-related hereditary diseases may share the same pathogenic mechanism. Here, we analyze the similarities and differences of the pathology and pathogenesis in animal models and find that connexin mutations in gap junction genes expressed in the ear, eye, heart, skin, and peripheral nerves can affect cellular proliferation and differentiation of corresponding organs. Additionally, some dominant mutations (e.g., Cx43 p.Gly60Ser, Cx32 p.Arg75Trp, Cx32 p.Asn175Asp, and Cx32 p.Arg142Trp) are identified as gain-of-function variants in vivo, which may play a vital role in the onset of dominant inherited diseases. Specifically, patients with these dominant mutations receive no benefits from gene therapy. Finally, the complete loss of gap junctional function or altered channel function including permeability (ions, adenosine triphosphate (ATP), Inositol 1,4,5-trisphosphate (IP3), Ca²⁺, glucose, miRNA) and electric activity are also identified in vivo or in vitro. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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16 pages, 1340 KiB

Open AccessReview

Involvement of Oxidative Stress in Protective Cardiac Functions of Calprotectin

by Luc Rochette, Geoffrey Dogon, Eve Rigal, Marianne Zeller, Yves Cottin and Catherine Vergely

Cells 2022, 11(7), 1226; https://doi.org/10.3390/cells11071226 - 5 Apr 2022

Cited by 6 | Viewed by 3665

Abstract

Calprotectin (CLP) belonging to the S-100 protein family is a heterodimeric complex (S100A8/S100A9) formed by two binding proteins. Upon cell activation, CLP stored in neutrophils is released extracellularly in response to inflammatory stimuli and acts as damage-associated molecular patterns (DAMPs). S100A8 and S100A9 [...] Read more.

Calprotectin (CLP) belonging to the S-100 protein family is a heterodimeric complex (S100A8/S100A9) formed by two binding proteins. Upon cell activation, CLP stored in neutrophils is released extracellularly in response to inflammatory stimuli and acts as damage-associated molecular patterns (DAMPs). S100A8 and S100A9 possess both anti-inflammatory and anti-bacterial properties. The complex is a ligand of the toll-like receptor 4 (TLR4) and receptor for advanced glycation end (RAGE). At sites of infection and inflammation, CLP is a target for oxidation due to its co-localization with neutrophil-derived oxidants. In the heart, oxidative stress (OS) responses and S100 proteins are closely related and intimately linked through pathophysiological processes. Our review summarizes the roles of S100A8, S100A9 and CLP in the inflammation in relationship with vascular OS, and we examine the importance of CLP for the mechanisms driving in the protection of myocardium. Recent evidence interpreting CLP as a critical modulator during the inflammatory response has identified this alarmin as an interesting drug target. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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19 pages, 2126 KiB

Open AccessReview

Metabolic Stress and Mitochondrial Dysfunction in Ataxia-Telangiectasia

by Goutham Narayanan Subramanian, Abrey Jie Yeo, Magtouf Hnaidi Gatei, David John Coman and Martin Francis Lavin

Antioxidants 2022, 11(4), 653; https://doi.org/10.3390/antiox11040653 - 28 Mar 2022

Cited by 13 | Viewed by 3769

Abstract

The ataxia-telangiectasia mutated (ATM) protein kinase is, as the name implies, mutated in the human genetic disorder ataxia-telangiectasia (A-T). This protein has its “finger in many pies”, being responsible for the phosphorylation of many thousands of proteins in different signaling pathways in its [...] Read more.

The ataxia-telangiectasia mutated (ATM) protein kinase is, as the name implies, mutated in the human genetic disorder ataxia-telangiectasia (A-T). This protein has its “finger in many pies”, being responsible for the phosphorylation of many thousands of proteins in different signaling pathways in its role in protecting the cell against a variety of different forms of stress that threaten to perturb cellular homeostasis. The classical role of ATM is the protection against DNA damage, but it is evident that it also plays a key role in maintaining cell homeostasis in the face of oxidative and other forms of non-DNA damaging stress. The presence of ATM is not only in the nucleus to cope with damage to DNA, but also in association with other organelles in the cytoplasm, which suggests a greater protective role. This review attempts to address this greater role of ATM in protecting the cell against both external and endogenous damage. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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15 pages, 15058 KiB

Open AccessArticle

Molecular Hydrogen Enhances Proliferation of Cancer Cells That Exhibit Potent Mitochondrial Unfolded Protein Response

by Tomoya Hasegawa, Mikako Ito, Satoru Hasegawa, Masaki Teranishi, Koki Takeda, Shuto Negishi, Hiroshi Nishiwaki, Jun-ichi Takeda, Tyler W. LeBaron and Kinji Ohno

Int. J. Mol. Sci. 2022, 23(5), 2888; https://doi.org/10.3390/ijms23052888 - 7 Mar 2022

Cited by 14 | Viewed by 23112

Abstract

Molecular hydrogen ameliorates pathological states in a variety of human diseases, animal models, and cell models, but the effects of hydrogen on cancer have been rarely reported. In addition, the molecular mechanisms underlying the effects of hydrogen remain mostly unelucidated. We found that [...] Read more.

Molecular hydrogen ameliorates pathological states in a variety of human diseases, animal models, and cell models, but the effects of hydrogen on cancer have been rarely reported. In addition, the molecular mechanisms underlying the effects of hydrogen remain mostly unelucidated. We found that hydrogen enhances proliferation of four out of seven human cancer cell lines (the responders). The proliferation-promoting effects were not correlated with basal levels of cellular reactive oxygen species. Expression profiling of the seven cells showed that the responders have higher gene expression of mitochondrial electron transport chain (ETC) molecules than the non-responders. In addition, the responders have higher mitochondrial mass, higher mitochondrial superoxide, higher mitochondrial membrane potential, and higher mitochondrial spare respiratory capacity than the non-responders. In the responders, hydrogen provoked mitochondrial unfolded protein response (mtUPR). Suppression of cell proliferation by rotenone, an inhibitor of mitochondrial ETC complex I, was rescued by hydrogen in the responders. Hydrogen triggers mtUPR and induces cell proliferation in cancer cells that have high basal and spare mitochondrial ETC activities. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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17 pages, 2280 KiB

Open AccessArticle

Antioxidant and Antiaging Properties of a Novel Synergistic Nutraceutical Complex: Readouts from an In Cellulo Study and an In Vivo Prospective, Randomized Trial

by Sophia Athanasopoulou, Marianna Kapetanou, Michel Georges Magouritsas, Nikoletta Mougkolia, Polykseni Taouxidou, Michael Papacharalambous, Fotios Sakellaridis and Efstathios Gonos

Antioxidants 2022, 11(3), 468; https://doi.org/10.3390/antiox11030468 - 26 Feb 2022

Cited by 2 | Viewed by 3851

Abstract

Aging is a dynamic procedure that is developed in multiple layers and characterized by distinct hallmarks. The use of biomarkers that target different hallmarks of aging is substantial in predicting adverse outcomes during the aging process, implementing specifically designed antiaging interventions and monitoring [...] Read more.

Aging is a dynamic procedure that is developed in multiple layers and characterized by distinct hallmarks. The use of biomarkers that target different hallmarks of aging is substantial in predicting adverse outcomes during the aging process, implementing specifically designed antiaging interventions and monitoring responses to these interventions. The present study aimed to develop a novel composition of plant extracts, comprising identified active ingredients that synergistically target different hallmarks of aging in cellulo and in vivo. The selected single extracts and the developed composition were tested through a powerful set of biomarkers that we have previously identified and studied. The composition of selected extracts simultaneously increased cellular lifespan, reduced the cellular oxidative load and enhanced antioxidant defense mechanisms by increasing proteasome activity and content. In addition, the combination prevented telomere attrition and preserved optimum DNA methylation levels. Remarkably, biomarker profiling of healthy volunteers who received the identified combination in the form of a nutritional supplement within the frame of a prospective, randomized, controlled 3-month trial revealed an unprecedented antioxidant capacity in humans. In conclusion, our results support the notion that interventions with specifically designed combinations of natural compounds targeting multiple hallmarks of aging represent an effective way to improve healthspan and well-being. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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12 pages, 6480 KiB

Open AccessArticle

Neuronal Pnn Deficiency Increases Oxidative Stress and Exacerbates Cerebral Ischemia/Reperfusion Injury in Mice

by Shu-Yuan Hsu, Chih-Hung Chen, Sujira Mukda and Steve Leu

Antioxidants 2022, 11(3), 466; https://doi.org/10.3390/antiox11030466 - 26 Feb 2022

Cited by 7 | Viewed by 3269

Abstract

Cerebral stroke remains one of the leading causes of death worldwide. Ischemic stroke caused by the sudden loss of blood flow in brain is the major type of cerebral stroke. In addition to necrotic cell death in the ischemic core region, neuronal apoptosis [...] Read more.

Cerebral stroke remains one of the leading causes of death worldwide. Ischemic stroke caused by the sudden loss of blood flow in brain is the major type of cerebral stroke. In addition to necrotic cell death in the ischemic core region, neuronal apoptosis is usually observed in the ischemic penumbra. Pnn, a multi-functional protein, participates in cellular proliferation, migration, differentiation, apoptosis as well as cell–cell interaction through its abilities in regulating gene transcription and mRNA processing. Our recent studies have demonstrated that Pnn has a cell type-specific distribution manner in neural cells under ischemic injury and plays a protective role in astrocytes against ischemic stress. In this study, we generated an inducible neuron-specific Pnn deficiency mouse model to further investigate the physiological role of Pnn in neurons. To directly examine the role of neuronal Pnn in ischemic stress, four weeks after induction of Pnn deficiency in neurons, middle cerebral artery occlusion (MCAO) was applied to induce cerebral ischemia/reperfusion in mice. In the cerebrum and hippocampus with neuronal Pnn depletion, the expression of SRSF2, a mRNA splicing regulator, was increased, while the expression of SRSF1, a functional antagonist of SRSF2, was reduced. Expression levels of ROS generators (NOX-1 and NOX-2) and antioxidant proteins (GR, HO-1, NQO-1) were upregulated in brain tissue with loss of neuronal Pnn, echoing an increase in oxidized proteins in cortical and hippocampal neurons. Furthermore, the expression of DNA damage marker, p53bp1, was found in the choroid plexus of mice with neuronal Pnn depletion. In mice with MCAO, compared to wild type mice, both increased cerebral infarcted area and elevated expressions of proapoptotic proteins were found in mice with neuronal Pnn depletion. In conclusion, Pnn deficiency increases oxidative stress in neurons and exacerbates cerebral ischemia/reperfusion injury in mice. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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24 pages, 4504 KiB

Open AccessArticle

A Comprehensive Evaluation of Salt Tolerance in Tomato (Var. Ailsa Craig): Responses of Physiological and Transcriptional Changes in RBOH’s and ABA Biosynthesis and Signalling Genes

by Abdul Raziq, Yu Wang, Atta Mohi Ud Din, Jin Sun, Sheng Shu and Shirong Guo

Int. J. Mol. Sci. 2022, 23(3), 1603; https://doi.org/10.3390/ijms23031603 - 29 Jan 2022

Cited by 30 | Viewed by 5475

Abstract

Salinity is a ubiquitous stressor, depleting osmotic potential and affecting the tomato seedlings’ development and productivity. Considering this critical concern, we explored the salinity response in tomato seedlings by evaluating them under progressive salt stress duration (0, 3, 6, and 12 days). Intriguingly, [...] Read more.

Salinity is a ubiquitous stressor, depleting osmotic potential and affecting the tomato seedlings’ development and productivity. Considering this critical concern, we explored the salinity response in tomato seedlings by evaluating them under progressive salt stress duration (0, 3, 6, and 12 days). Intriguingly, besides the adverse effect of salt stress on tomato growth the findings exhibited a significant role of tomato antioxidative system, RBOH genes, ABA biosynthesis, and signaling transcription factor for establishing tolerance to salinity stress. For instance, the activities of enzymatic and non-enzymatic antioxidants continued to incline positively with the increased levels of reactive oxygen species (O₂^•−, H₂O₂), MDA, and cellular damage, suggesting the scavenging capacity of tomato seedlings against salt stress. Notably, the RBOH transcription factors activated the hydrogen peroxide-mediated signalling pathway that induced the detoxification mechanisms in tomato seedlings. Consequently, the increased gene expression of antioxidant enzymes and the corresponding ratio of non-enzymatic antioxidants AsA-GSH suggested the modulation of antioxidants to survive the salt-induced oxidative stress. In addition, the endogenous ABA level was enhanced under salinity stress, indicating higher ABA biosynthesis and signalling gene expression. Subsequently, the upregulated transcript abundance of ABA biosynthesis and signalling-related genes suggested the ABA-mediated capacity of tomato seedlings to regulate homeostasis under salt stress. The current findings have revealed fascinating responses of the tomato to survive the salt stress periods, in order to improve the abiotic stress tolerance in tomato. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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15 pages, 2177 KiB

Open AccessArticle

Sacsin Deletion Induces Aggregation of Glial Intermediate Filaments

by Fernanda Murtinheira, Mafalda Migueis, Ricardo Letra-Vilela, Mickael Diallo, Andrea Quezada, Cláudia A. Valente, Abel Oliva, Carmen Rodriguez, Vanesa Martin and Federico Herrera

Cells 2022, 11(2), 299; https://doi.org/10.3390/cells11020299 - 16 Jan 2022

Cited by 9 | Viewed by 4030

Abstract

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder commonly diagnosed in infants and characterized by progressive cerebellar ataxia, spasticity, motor sensory neuropathy and axonal demyelination. ARSACS is caused by mutations in the SACS gene that lead to truncated or defective [...] Read more.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder commonly diagnosed in infants and characterized by progressive cerebellar ataxia, spasticity, motor sensory neuropathy and axonal demyelination. ARSACS is caused by mutations in the SACS gene that lead to truncated or defective forms of the 520 kDa multidomain protein, sacsin. Sacsin function is exclusively studied on neuronal cells, where it regulates mitochondrial network organization and facilitates the normal polymerization of neuronal intermediate filaments (i.e., neurofilaments and vimentin). Here, we show that sacsin is also highly expressed in astrocytes, C6 rat glioma cells and N9 mouse microglia. Sacsin knockout in C6 cells (C6^Sacs−/−) induced the accumulation of the glial intermediate filaments glial fibrillary acidic protein (GFAP), nestin and vimentin in the juxtanuclear area, and a concomitant depletion of mitochondria. C6^Sacs−/− cells showed impaired responses to oxidative challenges (Rotenone) and inflammatory stimuli (Interleukin-6). GFAP aggregation is also associated with other neurodegenerative conditions diagnosed in infants, such as Alexander disease or Giant Axonal Neuropathy. Our results, and the similarities between these disorders, reinforce the possible connection between ARSACS and intermediate filament-associated diseases and point to a potential role of glia in ARSACS pathology. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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28 pages, 1804 KiB

Open AccessEditor’s ChoiceReview

Revisiting the Oxidation of Flavonoids: Loss, Conservation or Enhancement of Their Antioxidant Properties

by Hernan Speisky, Fereidoon Shahidi, Adriano Costa de Camargo and Jocelyn Fuentes

Antioxidants 2022, 11(1), 133; https://doi.org/10.3390/antiox11010133 - 7 Jan 2022

Cited by 152 | Viewed by 11215

Abstract

Flavonoids display a broad range of health-promoting bioactivities. Among these, their capacity to act as antioxidants has remained most prominent. The canonical reactive oxygen species (ROS)-scavenging mode of the antioxidant action of flavonoids relies on the high susceptibility of their phenolic moieties to [...] Read more.

Flavonoids display a broad range of health-promoting bioactivities. Among these, their capacity to act as antioxidants has remained most prominent. The canonical reactive oxygen species (ROS)-scavenging mode of the antioxidant action of flavonoids relies on the high susceptibility of their phenolic moieties to undergo oxidation. As a consequence, upon reaction with ROS, the antioxidant capacity of flavonoids is severely compromised. Other phenol-compromising reactions, such as those involved in the biotransformation of flavonoids, can also markedly affect their antioxidant properties. In recent years, however, increasing evidence has indicated that, at least for some flavonoids, the oxidation of such residues can in fact markedly enhance their original antioxidant properties. In such apparent paradoxical cases, the antioxidant activity arises from the pro-oxidant and/or electrophilic character of some of their oxidation-derived metabolites and is exerted by activating the Nrf2–Keap1 pathway, which upregulates the cell’s endogenous antioxidant capacity, and/or, by preventing the activation of the pro-oxidant and pro-inflammatory NF-κB pathway. This review focuses on the effects that the oxidative and/or non-oxidative modification of the phenolic groups of flavonoids may have on the ability of the resulting metabolites to promote direct and/or indirect antioxidant actions. Considering the case of a metabolite resulting from the oxidation of quercetin, we offer a comprehensive description of the evidence that increasingly supports the concept that, in the case of certain flavonoids, the oxidation of phenolics emerges as a mechanism that markedly amplifies their original antioxidant properties. An overlooked topic of great phytomedicine potential is thus unraveled. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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21 pages, 4971 KiB

Open AccessArticle

Cis-9, Trans-11 CLA Alleviates Lipopolysaccharide-Induced Depression of Fatty Acid Synthesis by Inhibiting Oxidative Stress and Autophagy in Bovine Mammary Epithelial Cells

by Nana Ma, Guozhen Wei, Hongzhu Zhang, Hongyu Dai, Animesh Chandra Roy, Xiaoli Shi, Guangjun Chang and Xiangzhen Shen

Antioxidants 2022, 11(1), 55; https://doi.org/10.3390/antiox11010055 - 27 Dec 2021

Cited by 24 | Viewed by 3942

Abstract

Lipopolysaccharide (LPS) is the dominating endotoxin of Gram-negative bacteria, which can cause mastitis. Bovine mammary epithelial cells (BMECs), as major components of the mammary gland, usually suffer LPS challenge. Cis-9, trans-11 conjugated linoleic acid (CLA) has been reported to have anti-inflammatory characteristics, while [...] Read more.

Lipopolysaccharide (LPS) is the dominating endotoxin of Gram-negative bacteria, which can cause mastitis. Bovine mammary epithelial cells (BMECs), as major components of the mammary gland, usually suffer LPS challenge. Cis-9, trans-11 conjugated linoleic acid (CLA) has been reported to have anti-inflammatory characteristics, while its anti-oxidative ability to maintain cellular homeostasis in BMECs under LPS challenge is limited. Therefore, we studied whether cis-9, trans-11 CLA can restore the disturbance of cellular homeostasis indicated by the redox status and autophagy level caused by LPS and have an effect on cellular function- milk fat metabolism. For oxidative stress, LPS challenge promoted the formation of reactive oxygen species (ROS) and thiobarbituric acid reactive substances (TBARS) and decreased the concentration of glutathione. Anti-oxidative signaling regulated by transcription factor nuclear factor, erythroid 2 like 2 (Nrf2) was also depressed by LPS at the mRNA and protein level. However, cis-9, trans-11 CLA pretreatment downregulated the formation of ROS and TBARS and upregulated the expression of antioxidative enzymes. As a part of innate immunity, autophagy was also motivated by LPS challenge, while CLA decreased the autophagy level. LPS and H₂O₂ inhibited milk fat synthesis-related transcription factor sterol regulatory element binding protein (SREBP1), peroxisome proliferator activated receptor gamma (PPARG) and their downstream enzymes. Furthermore, 50 uM cis-9, trans-11 CLA promoted the mRNA and protein abundance of milk fat synthesis-related genes and lipid droplet formation in BMECs. In conclusion, LPS challenge disturbed the cellular homeostasis and depressed milk fat synthesis in BMECs; while cis-9, trans-11 CLA alleviated oxidative stress and decreased autophagy level, thus promoting milk fat synthesis, which offers a natural therapeutic strategy for mastitis. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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13 pages, 2107 KiB

Open AccessArticle

Catalase Overexpression Drives an Aggressive Phenotype in Glioblastoma

by Susanne Flor, Claudia R. Oliva, Md Yousuf Ali, Kristen L. Coleman, Jeremy D. Greenlee, Karra A. Jones, Varun Monga and Corinne E. Griguer

Antioxidants 2021, 10(12), 1988; https://doi.org/10.3390/antiox10121988 - 14 Dec 2021

Cited by 21 | Viewed by 4041

Abstract

Glioblastoma remains the deadliest form of brain cancer, largely because these tumors become resistant to standard of care treatment with radiation and chemotherapy. Intracellular production of reactive oxygen species (ROS) is necessary for chemo- and radiotherapy-induced cytotoxicity. Here, we assessed whether antioxidant catalase [...] Read more.

Glioblastoma remains the deadliest form of brain cancer, largely because these tumors become resistant to standard of care treatment with radiation and chemotherapy. Intracellular production of reactive oxygen species (ROS) is necessary for chemo- and radiotherapy-induced cytotoxicity. Here, we assessed whether antioxidant catalase (CAT) affects glioma cell sensitivity to temozolomide and radiation. Using The Cancer Genome Atlas database, we found that CAT mRNA expression is upregulated in glioma tumor tissue compared with non-tumor tissue, and the level of expression negatively correlates with the overall survival of patients with high-grade glioma. In U251 glioma cells, CAT overexpression substantially decreased the basal level of hydrogen peroxide, enhanced anchorage-independent cell growth, and facilitated resistance to the chemotherapeutic drug temozolomide and ionizing radiation. Importantly, pharmacological inhibition of CAT activity reduced the proliferation of glioma cells isolated from patient biopsy samples. Moreover, U251 cells overexpressing CAT formed neurospheres in neurobasal medium, whereas control cells did not, suggesting that the radio- and chemoresistance conferred by CAT may be due in part to the enrichment of glioma stem cell populations. Finally, CAT overexpression significantly decreased survival in an orthotopic mouse model of glioma. These results demonstrate that CAT regulates chemo- and radioresistance in human glioma. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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14 pages, 6788 KiB

Open AccessArticle

Ellagic Acid Modulates the Amyloid Precursor Protein Gene via Superoxide Dismutase Regulation in the Entorhinal Cortex in an Experimental Alzheimer’s Model

by Wafaa S. Ramadan and Saleh Alkarim

Cells 2021, 10(12), 3511; https://doi.org/10.3390/cells10123511 - 13 Dec 2021

Cited by 15 | Viewed by 3563

Abstract

Patients suffering from Alzheimer’s disease (AD) are still increasing worldwide. The development of (AD) is related to oxidative stress and genetic factors. This study investigated the therapeutic effects of ellagic acid (EA) on the entorhinal cortex (ERC), which plays a major role in [...] Read more.

Patients suffering from Alzheimer’s disease (AD) are still increasing worldwide. The development of (AD) is related to oxidative stress and genetic factors. This study investigated the therapeutic effects of ellagic acid (EA) on the entorhinal cortex (ERC), which plays a major role in episodic memory, in the brains of an AD rat model. AD was induced using AlCl₃ (50 mg/kg orally for 4 weeks). Rats were divided into four groups: control, AD model, EA (treated with 50 mg/kg EA orally for 4 weeks), and ADEA (AD rats treated with EA after AlCl₃ was stopped) groups. All rats were investigated for episodic memory using the novel object recognition test (NORT), antioxidant serum biomarkers, lipid peroxidation, histopathology of the ERC, and quantitative PCR for the superoxide dismutase (SOD) gene. EA therapy in AD rats significantly increased the discrimination index for NORT and the levels of SOD, glutathione, and total antioxidant capacity. Lipid peroxidation products were decreased, and the neurofibrillary tangles and neuritic plaques in the ERC sections were reduced after EA administration. The decrease in ERC thickness in the AD group, caused by caspase-3-mediated apoptosis and neurotoxicity due to amyloid precursor protein, was modulated by the increased SOD mRNA expression. Adjustment of the ERC antioxidant environment and decreased oxidative stress under EA administration enhanced SOD expression, resulting in the modulation of amyloid precursor protein toxicity and caspase-3-mediated apoptosis, thereby restoring episodic memory. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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18 pages, 4277 KiB

Open AccessArticle

l-Arginine Alleviates LPS-Induced Oxidative Stress and Apoptosis via Activating SIRT1-AKT-Nrf2 and SIRT1-FOXO3a Signaling Pathways in C2C12 Myotube Cells

by Ye Zhao, Qin Jiang, Xuefei Zhang, Xiaoxiao Zhu, Xia Dong, Linyuan Shen, Shunhua Zhang, Lili Niu, Lei Chen, Ming Zhang, Jun Jiang, Daiwen Chen and Li Zhu

Antioxidants 2021, 10(12), 1957; https://doi.org/10.3390/antiox10121957 - 7 Dec 2021

Cited by 30 | Viewed by 5175

Abstract

l-arginine (l-Arg) has been reported to possess a wide range of functions, including anti-inflammatory, anti-oxidative, and anti-apoptosis. However, the role of l-Arg in LPS-induced muscle injury and its potential protective mechanism has not been well elucidated. This study aimed [...] Read more.

l-arginine (l-Arg) has been reported to possess a wide range of functions, including anti-inflammatory, anti-oxidative, and anti-apoptosis. However, the role of l-Arg in LPS-induced muscle injury and its potential protective mechanism has not been well elucidated. This study aimed to investigate the effects of l-Arg on the LPS-induced oxidative stress and apoptosis in differentiated C2C12 myotube cells. Our results demonstrated that myotube cells treated with 0.2 mg/mL LPS significantly decreased cell viability. l-Arg treatment significantly suppressed LPS induced ROS accumulation and cell apoptosis. Furthermore, l-Arg improved antioxidant-related enzymes’ activities; increased antioxidant ability via Akt-Nrf2 signaling pathway; maintained the mitochondrial membrane potential (MMP); and enhanced FOXO3a expression, leading to a decrease in the mitochondrial-associated apoptotic proteins. In addition, l-Arg exposure dramatically increased the mRNA and protein expressions of SIRT1. The cytoprotective effect of l-Arg was restricted by the SIRT1 inhibitor EX527, which led to an increase in ROS level, apoptosis rate, and decreased cell MMP. The results also demonstrated that EX527 treatment significantly eliminated the effect of l-Arg on LPS-induced oxidative damage and mitochondria-mediated cell apoptosis. Our findings revealed that l-Arg could be used as a potential nutraceutical in reducing muscle injury via regulating SIRT1-Akt-Nrf2 and SIRT1-FOXO3a-mitochondria apoptosis signaling pathways. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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17 pages, 3217 KiB

Open AccessArticle

The Mechanism of Leptin on Inhibiting Fibrosis and Promoting Browning of White Fat by Reducing ITGA5 in Mice

by Yuexia Liu, Yizhou Li, Juntong Liang, Zhuwen Sun, Qiong Wu, Yongnian Liu and Chao Sun

Int. J. Mol. Sci. 2021, 22(22), 12353; https://doi.org/10.3390/ijms222212353 - 16 Nov 2021

Cited by 17 | Viewed by 3521

Abstract

Leptin is a small molecule protein secreted by adipocytes, which can promote white fat browning through activating the hypothalamic nervous system and inhibiting downstream signaling pathways. Moreover, white fat browning has been proven to alleviate fat tissue fibrosis. This study explores the mechanism [...] Read more.

Leptin is a small molecule protein secreted by adipocytes, which can promote white fat browning through activating the hypothalamic nervous system and inhibiting downstream signaling pathways. Moreover, white fat browning has been proven to alleviate fat tissue fibrosis. This study explores the mechanism of leptin in regulating adipose tissue fibrosis and white fat browning. After treating mice with leptin, we screened out the recombinant integrin alpha 5 (ITGA5) through proteomics sequencing, which may play a role in adipose tissue fibrosis. Through real-time quantitative PCR (qPCR), western blotting (WB), hematoxylin-eosin (HE) staining, Masson’s trichrome, immunofluorescence, immunohistochemistry, etc., the results showed that after leptin treated adipocytes, the expression of fibrosis-related genes and ITGA5 was significantly down-regulated in adipocytes. We constructed fibrosis model through transforming growth factor-β (TGF-β) and a high-fat diet (HFD), and treated with ITGA5 overexpression vector and interference fragments. The results indicated the expression of fibrosis-related genes were significantly down-regulated after interfering with ITGA5. After treating adipocytes with wortmannin, fibrosis-related gene expression was inhibited after overexpression of ITGA5. Moreover, after injecting mice with leptin, we also found that leptin significantly up-regulated the expression of adipose tissue browning-related genes. Overall, our research shows that leptin can inhibit the activation of phosphatidylinositol 3 kinase (PI3K)-protein kinase B (AKT) signaling pathway by reducing the expression of ITGA5, which could alleviate adipose tissue fibrosis, and further promote white fat browning. Our research provides a theoretical basis for further research on the effect of leptin in fibrosis-related adipose tissue metabolism. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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25 pages, 6258 KiB

Open AccessArticle

RALBP1 in Oxidative Stress and Mitochondrial Dysfunction in Alzheimer’s Disease

by Sanjay Awasthi, Ashly Hindle, Neha A. Sawant, Mathew George, Murali Vijayan, Sudhir Kshirsagar, Hallie Morton, Lloyd E. Bunquin, Philip T. Palade, J. Josh Lawrence, Hafiz Khan, Chhanda Bose, P. Hemachandra Reddy and Sharda P. Singh

Cells 2021, 10(11), 3113; https://doi.org/10.3390/cells10113113 - 10 Nov 2021

Cited by 16 | Viewed by 4241

Abstract

The purpose of our study is to understand the role of the RALBP1 gene in oxidative stress (OS), mitochondrial dysfunction and cognition in Alzheimer’s disease (AD) pathogenesis. The RALPB1 gene encodes the 76 kDa protein RLIP76 (Rlip). Rlip functions as a stress-responsive/protective transporter [...] Read more.

The purpose of our study is to understand the role of the RALBP1 gene in oxidative stress (OS), mitochondrial dysfunction and cognition in Alzheimer’s disease (AD) pathogenesis. The RALPB1 gene encodes the 76 kDa protein RLIP76 (Rlip). Rlip functions as a stress-responsive/protective transporter of glutathione conjugates (GS-E) and xenobiotic toxins. We hypothesized that Rlip may play an important role in maintaining cognitive function. The aim of this study is to determine whether Rlip deficiency in mice is associated with AD-like cognitive and mitochondrial dysfunction. Brain tissue obtained from cohorts of wildtype (WT) and Rlip^+/− mice were analyzed for OS markers, expression of genes that regulate mitochondrial fission/fusion, and synaptic integrity. We also examined mitochondrial ultrastructure in brains obtained from these mice and further analyzed the impact of Rlip deficiency on gene networks of AD, aging, stress response, mitochondrial function, and CREB signaling. Our studies revealed a significant increase in the levels of OS markers and alterations in the expression of genes and proteins involved in mitochondrial biogenesis, dynamics and synapses in brain tissues from these mice. Furthermore, we compared the cognitive function of WT and Rlip^+/− mice. Behavioral, basic motor and sensory function tests in Rlip^+/− mice revealed cognitive decline, similar to AD. Gene network analysis indicated dysregulation of stress-activated gene expression, mitochondrial function and CREB signaling genes in the Rlip^+/− mouse brain. Our results suggest that Rlip deficiency-associated increases in OS and mitochondrial dysfunction could contribute to the development or progression of OS-related AD processes. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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14 pages, 1975 KiB

Open AccessArticle

Mitochondrial Dysfunction in Cardiorenal Syndrome 3: Renocardiac Effect of Vitamin C

by Raquel Silva Neres-Santos, Carolina Victoria Cruz Junho, Karine Panico, Wellington Caio-Silva, Joana Claudio Pieretti, Juliana Almeida Tamashiro, Amedea Barozzi Seabra, César Augusto João Ribeiro and Marcela Sorelli Carneiro-Ramos

Cells 2021, 10(11), 3029; https://doi.org/10.3390/cells10113029 - 5 Nov 2021

Cited by 14 | Viewed by 3306

Abstract

Cardiorenal syndrome (CRS) is a pathological link between the kidneys and heart, in which an insult in a kidney or heart leads the other organ to incur damage. CRS is classified into five subtypes, and type 3 (CRS3) is characterized by acute kidney [...] Read more.

Cardiorenal syndrome (CRS) is a pathological link between the kidneys and heart, in which an insult in a kidney or heart leads the other organ to incur damage. CRS is classified into five subtypes, and type 3 (CRS3) is characterized by acute kidney injury as a precursor to subsequent cardiovascular changes. Mitochondrial dysfunction and oxidative and nitrosative stress have been reported in the pathophysiology of CRS3. It is known that vitamin C, an antioxidant, has proven protective capacity for cardiac, renal, and vascular endothelial tissues. Therefore, the present study aimed to assess whether vitamin C provides protection to heart and the kidneys in an in vivo CRS3 model. The unilateral renal ischemia and reperfusion (IR) protocol was performed for 60 min in the left kidney of adult mice, with and without vitamin C treatment, immediately after IR or 15 days after IR. Kidneys and hearts were subsequently collected, and the following analyses were conducted: renal morphometric evaluation, serum urea and creatinine levels, high-resolution respirometry, amperometry technique for NO measurement, gene expression of mitochondrial dynamic markers, and NOS. The analyses showed that the left kidney weight was reduced, urea and creatinine levels were increased, mitochondrial oxygen consumption was reduced, NO levels were elevated, and Mfn2 expression was reduced after 15 days of IR compared to the sham group. Oxygen consumption and NO levels in the heart were also reduced. The treatment with vitamin C preserved the left kidney weight, restored renal function, reduced NO levels, decreased iNOS expression, elevated constitutive NOS isoforms, and improved oxygen consumption. In the heart, oxygen consumption and NO levels were improved after vitamin C treatment, whereas the three NOS isoforms were overexpressed. These data indicate that vitamin C provides protection to the kidneys and some beneficial effects to the heart after IR, indicating it may be a preventive approach against cardiorenal insults. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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13 pages, 4226 KiB

Open AccessArticle

Identification and Function of Apicoplast Glutaredoxins in Neospora caninum

by Xingju Song, Xu Yang, Zhu Ying, Heng Zhang, Jing Liu and Qun Liu

Int. J. Mol. Sci. 2021, 22(21), 11946; https://doi.org/10.3390/ijms222111946 - 4 Nov 2021

Cited by 5 | Viewed by 2435

Abstract

Glutaredoxins (GRXs), important components of the intracellular thiol redox system, are involved in multiple cellular processes. In a previous study, we identified five GRXs in the apicomplexan parasite, Neospora caninum. In the present study, we confirmed that the GRXs S14 and C5 [...] Read more.

Glutaredoxins (GRXs), important components of the intracellular thiol redox system, are involved in multiple cellular processes. In a previous study, we identified five GRXs in the apicomplexan parasite, Neospora caninum. In the present study, we confirmed that the GRXs S14 and C5 are located in the apicoplast, which suggests unique functions for these proteins. Although single-gene deficiency did not affect the growth of parasites, a double knockout (Δgrx S14Δgrx C5) significantly reduced their reproductive capacity. However, there were no significant changes in redox indices (GSH/GSSG ratio, reactive oxygen species and hydroxyl radical levels) in double-knockout parasites, indicating that grx S14 and grx C5 are not essential for maintaining the redox balance in parasite cells. Key amino acid mutations confirmed that the Cys²⁰³ of grx S14 and Cys^253/256 of grx C5 are important for parasite growth. Based on comparative proteomics, 79 proteins were significantly downregulated in double-knockout parasites, including proteins mainly involved in the electron transport chain, the tricarboxylic acid cycle and protein translation. Collectively, GRX S14 and GRX C5 coordinate the growth of parasites. However, considering their special localization, the unique functions of GRX S14 and GRX C5 need to be further studied. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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31 pages, 1612 KiB

Open AccessReview

Mitochondria in Diabetic Kidney Disease

by Amna Ayesha Ahmad, Shayna Odeal Draves and Mariana Rosca

Cells 2021, 10(11), 2945; https://doi.org/10.3390/cells10112945 - 29 Oct 2021

Cited by 67 | Viewed by 8277

Abstract

Diabetic kidney disease (DKD) is the leading cause of end stage renal disease (ESRD) in the USA. The pathogenesis of DKD is multifactorial and involves activation of multiple signaling pathways with merging outcomes including thickening of the basement membrane, podocyte loss, mesangial expansion, [...] Read more.

Diabetic kidney disease (DKD) is the leading cause of end stage renal disease (ESRD) in the USA. The pathogenesis of DKD is multifactorial and involves activation of multiple signaling pathways with merging outcomes including thickening of the basement membrane, podocyte loss, mesangial expansion, tubular atrophy, and interstitial inflammation and fibrosis. The glomerulo-tubular balance and tubule-glomerular feedback support an increased glomerular filtration and tubular reabsorption, with the latter relying heavily on ATP and increasing the energy demand. There is evidence that alterations in mitochondrial bioenergetics in kidney cells lead to these pathologic changes and contribute to the progression of DKD towards ESRD. This review will focus on the dialogue between alterations in bioenergetics in glomerular and tubular cells and its role in the development of DKD. Alterations in energy substrate selection, electron transport chain, ATP generation, oxidative stress, redox status, protein posttranslational modifications, mitochondrial dynamics, and quality control will be discussed. Understanding the role of bioenergetics in the progression of diabetic DKD may provide novel therapeutic approaches to delay its progression to ESRD. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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20 pages, 4015 KiB

Open AccessArticle

Docosahexaenoic Acid Inhibits Cell Proliferation through a Suppression of c-Myc Protein in Pancreatic Ductal Adenocarcinoma Cells

by Jia-Ning Syu, Der-Yen Lee, Hung-Chang Hung, Chia-Ying Li, Hung-Yu Lin, En-Pei Isabel Chiang, Yi-Heng Chen, Shu-Ming Huang and Feng-Yao Tang

Antioxidants 2021, 10(11), 1721; https://doi.org/10.3390/antiox10111721 - 28 Oct 2021

Cited by 1 | Viewed by 2331

Abstract

Treatment of pancreatic cancer by inhibiting the aberrant activation of the survival signaling pathways has received considerable attention. We investigated the probable action of DHA on the suppression of cell proliferation in human pancreatic ductal adenocarcinoma (PDAC) cells. Our results demonstrated that DHA [...] Read more.

Treatment of pancreatic cancer by inhibiting the aberrant activation of the survival signaling pathways has received considerable attention. We investigated the probable action of DHA on the suppression of cell proliferation in human pancreatic ductal adenocarcinoma (PDAC) cells. Our results demonstrated that DHA dose-dependently inhibited cell proliferation through an induction of cell cycle arrest in human PDAC cells. DHA suppressed the expression of phosphorylated-Rb (p-Rb), cyclin D1, cyclin E, cyclin A, E2F1 and c-Myc proteins. Blocking the activation of STAT3 signaling pathway led to an inactivation of CAMKII and increased phosphorylation of c-Myc (T58) protein accompanied with decreased expression of c-Myc protein. Treatment of DHA effectively inhibited cell survival through decreased phosphorylation levels of EGFR, STAT3 and CAMKII proteins. The mechanisms of action were associated with increased phosphorylation levels of c-Myc (T58) and instability of c-Myc proteins. DHA inhibited cell survival through an increased GSSG/GSH ratio and oxidative stress level in HPAF-II cells. DHA induced cell apoptosis through increased expression of Bax, c-caspase 3 and c-PARP proteins in HPAF-II cells. Moreover, treatment of DHA significantly inhibited nucleotide synthesis. In conclusion, DHA might significantly suppress the proliferation of PDAC cells and therefore have potential as an anti-cancer therapeutic agent. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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21 pages, 3102 KiB

Open AccessArticle

Lineage-Selective Disturbance of Early Human Hematopoietic Progenitor Cell Differentiation by the Commonly Used Plasticizer Di-2-ethylhexyl Phthalate via Reactive Oxygen Species: Fatty Acid Oxidation Makes the Difference

by Lars Kaiser, Isabel Quint, René Csuk, Manfred Jung and Hans-Peter Deigner

Cells 2021, 10(10), 2703; https://doi.org/10.3390/cells10102703 - 9 Oct 2021

Cited by 5 | Viewed by 4509

Abstract

Exposure to ubiquitous endocrine-disrupting chemicals (EDCs) is a major public health concern. We analyzed the physiological impact of the EDC, di-2-ethylhexyl phthalate (DEHP), and found that its metabolite, mono-2-ethylhexyl phthalate (MEHP), had significant adverse effects on myeloid hematopoiesis at environmentally relevant concentrations. An [...] Read more.

Exposure to ubiquitous endocrine-disrupting chemicals (EDCs) is a major public health concern. We analyzed the physiological impact of the EDC, di-2-ethylhexyl phthalate (DEHP), and found that its metabolite, mono-2-ethylhexyl phthalate (MEHP), had significant adverse effects on myeloid hematopoiesis at environmentally relevant concentrations. An analysis of the underlying mechanism revealed that MEHP promotes increases in reactive oxygen species (ROS) by reducing the activity of superoxide dismutase in all lineages, possibly via its actions at the aryl hydrocarbon receptor. This leads to a metabolic shift away from glycolysis toward the pentose phosphate pathway and ultimately results in the death of hematopoietic cells that rely on glycolysis for energy production. By contrast, cells that utilize fatty acid oxidation for energy production are not susceptible to this outcome due to their capacity to uncouple ATP production. These responses were also detected in non-hematopoietic cells exposed to alternate inducers of ROS. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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17 pages, 34859 KiB

Open AccessArticle

Hepatocyte-Specific Deficiency of BAP31 Amplified Acetaminophen-Induced Hepatotoxicity via Attenuating Nrf2 Signaling Activation in Mice

by Jie Zhao, Xiaotong Lv, Yan Huo, Xiaodi Hu, Xiaochen Li, Shizhuo Sun, Xin Zhao, Xuewei Kong and Jialin Xu

Int. J. Mol. Sci. 2021, 22(19), 10788; https://doi.org/10.3390/ijms221910788 - 5 Oct 2021

Cited by 1 | Viewed by 3193

Abstract

Liver-specific deficiency of B-cell receptor-associated protein 31 knockout mice (BAP31-LKO) and the littermates were injected with acetaminophen (APAP), markers of liver injury, and the potential molecular mechanisms were determined. In response to APAP overdose, serum aspartate aminotransferase and alanine aminotransferase levels were increased [...] Read more.

Liver-specific deficiency of B-cell receptor-associated protein 31 knockout mice (BAP31-LKO) and the littermates were injected with acetaminophen (APAP), markers of liver injury, and the potential molecular mechanisms were determined. In response to APAP overdose, serum aspartate aminotransferase and alanine aminotransferase levels were increased in BAP31-LKO mice than in wild-type controls, accompanied by enhanced liver necrosis. APAP-induced apoptosis and mortality were increased. Hepatic glutathione was decreased (1.60 ± 0.31 μmol/g tissue in WT mice vs. 0.85 ± 0.14 μmol/g tissue in BAP31-LKO mice at 6 h, p < 0.05), along with reduced glutathione reductase activity and superoxide dismutase; while malondialdehyde was significantly induced (0.41 ± 0.03 nmol/mg tissue in WT mice vs. 0.50 ± 0.05 nmol/mg tissue in BAP31-LKO mice for 6 h, p < 0.05). JNK signaling activation and APAP-induced hepatic inflammation were increased in BAP31-LKO mice. The mechanism research revealed that BAP31-deficiency decreased Nrf2 mRNA stability (half-life of Nrf2 mRNA decreased from ~1.3 h to ~40 min) and miR-223 expression, led to reduced nuclear factor erythroid 2-related factor 2 (Nrf2) signaling activation and antioxidant genes induction. BAP31-deficiency decreased mitochondrial membrane potentials, reduced mitochondria-related genes expression, and resulted in mitochondrial dysfunction in the liver. Conclusions: BAP31-deficiency reduced the antioxidant response and Nrf2 signaling activation via reducing Nrf2 mRNA stabilization, enhanced JNK signaling activation, hepatic inflammation, and apoptosis, amplified APAP-induced hepatotoxicity in mice. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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17 pages, 29840 KiB

Open AccessArticle

BACE1 Inhibition Increases Susceptibility to Oxidative Stress by Promoting Mitochondrial Damage

by Carolina Francelin, Sayak K. Mitter, Qingwen Qian, Sandeep Kumar Barodia, Colin Ip, Xiaoping Qi, Hongmei Gu, Judith Quigley, Matthew S. Goldberg, Maria B. Grant and Michael E. Boulton

Antioxidants 2021, 10(10), 1539; https://doi.org/10.3390/antiox10101539 - 28 Sep 2021

Cited by 8 | Viewed by 2977

Abstract

BACE1 is a key enzyme facilitating the generation of neurotoxic β-amyloid (Aβ) peptide. However, given that BACE1 has multiple substrates we explored the importance of BACE1 in the maintenance of retinal pigment epithelial (RPE) cell homeostasis under oxidative stress. Inhibition of BACE1 reduced [...] Read more.

BACE1 is a key enzyme facilitating the generation of neurotoxic β-amyloid (Aβ) peptide. However, given that BACE1 has multiple substrates we explored the importance of BACE1 in the maintenance of retinal pigment epithelial (RPE) cell homeostasis under oxidative stress. Inhibition of BACE1 reduced mitochondrial membrane potential, increased mitochondrial fragmentation, and increased cleaved caspase-3 expression in cells under oxidative stress. BACE1 inhibition also resulted in significantly lower levels of mitochondrial fusion proteins OPA1 and MFN1 suggesting a higher rate of mitochondrial fission while increasing the levels of mitophagic proteins Parkin and PINK1 and autophagosome numbers. In contrast, BACE2 had minimal effect on cellular response to oxidative stress. In summary, our results emphasize the importance of BACE1 in augmenting cellular defense against oxidative stress by protecting mitochondrial dynamics. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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12 pages, 2281 KiB

Open AccessArticle

Fursultiamine Prevents Drug-Induced Ototoxicity by Reducing Accumulation of Reactive Oxygen Species in Mouse Cochlea

by Ye-Ri Kim, Tae-Jun Kwon, Un-Kyung Kim, In-Kyu Lee, Kyu-Yup Lee and Jeong-In Baek

Antioxidants 2021, 10(10), 1526; https://doi.org/10.3390/antiox10101526 - 26 Sep 2021

Cited by 8 | Viewed by 4528

Abstract

Drug-induced hearing loss is a major type of acquired sensorineural hearing loss. Cisplatin and aminoglycoside antibiotics have been known to cause ototoxicity, and excessive accumulation of intracellular reactive oxygen species (ROS) are suggested as the common major pathology of cisplatin- and aminoglycoside antibiotics-induced [...] Read more.

Drug-induced hearing loss is a major type of acquired sensorineural hearing loss. Cisplatin and aminoglycoside antibiotics have been known to cause ototoxicity, and excessive accumulation of intracellular reactive oxygen species (ROS) are suggested as the common major pathology of cisplatin- and aminoglycoside antibiotics-induced ototoxicity. Fursultiamine, also called thiamine tetrahydrofurfuryl disulfide, is a thiamine disulfide derivative that may have antioxidant effects. To evaluate whether fursultiamine can prevent cisplatin- and kanamycin-induced ototoxicity, we investigated their preventive potential using mouse cochlear explant culture system. Immunofluorescence staining of mouse cochlear hair cells showed that fursultiamine pretreatment reduced cisplatin- and kanamycin-induced damage to both inner and outer hair cells. Fursultiamine attenuated mitochondrial ROS accumulation as evidenced by MitoSOX Red staining and restored mitochondrial membrane potential in a JC-1 assay. In addition, fursultiamine pretreatment reduced active caspase-3 and TUNEL signals after cisplatin or kanamycin treatment, indicating that fursultiamine decreased apoptotic hair cell death. This study is the first to show a protective effect of fursultiamine against cisplatin- and aminoglycoside antibiotics-induced ototoxicity. Our results suggest that fursultiamine could act as an antioxidant and anti-apoptotic agent against mitochondrial oxidative stress.in cochlear hair cells. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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17 pages, 6363 KiB

Open AccessArticle

Impact of Wheat Streak Mosaic Virus on Peroxisome Proliferation, Redox Reactions, and Resistance Responses in Wheat

by Lidiya Mishchenko, Taras Nazarov, Alina Dunich, Ivan Mishchenko, Olga Ryshchakova, Ivan Motsnyi, Anna Dashchenko, Lidiya Bezkrovna, Yaroslav Fanin, Olga Molodchenkova and Andrei Smertenko

Int. J. Mol. Sci. 2021, 22(19), 10218; https://doi.org/10.3390/ijms221910218 - 23 Sep 2021

Cited by 13 | Viewed by 3780

Abstract

Although peroxisomes play an essential role in viral pathogenesis, and viruses are known to change peroxisome morphology, the role of genotype in the peroxisomal response to viruses remains poorly understood. Here, we analyzed the impact of wheat streak mosaic virus (WSMV) on the [...] Read more.

Although peroxisomes play an essential role in viral pathogenesis, and viruses are known to change peroxisome morphology, the role of genotype in the peroxisomal response to viruses remains poorly understood. Here, we analyzed the impact of wheat streak mosaic virus (WSMV) on the peroxisome proliferation in the context of pathogen response, redox homeostasis, and yield in two wheat cultivars, Patras and Pamir, in the field trials. We observed greater virus content and yield losses in Pamir than in Patras. Leaf chlorophyll and protein content measured at the beginning of flowering were also more sensitive to WSMV infection in Pamir. Patras responded to the WSMV infection by transcriptional up-regulation of the peroxisome fission genes PEROXIN 11C (PEX11C), DYNAMIN RELATED PROTEIN 5B (DRP5B), and FISSION1A (FIS1A), greater peroxisome abundance, and activation of pathogenesis-related proteins chitinase, and β-1,3-glucanase. Oppositely, in Pamir, WMSV infection suppressed transcription of peroxisome biogenesis genes and activity of chitinase and β-1,3-glucanase, and did not affect peroxisome abundance. Activity of ROS scavenging enzymes was higher in Patras than in Pamir. Thus, the impact of WMSV on peroxisome proliferation is genotype-specific and peroxisome abundance can be used as a proxy for the magnitude of plant immune response. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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18 pages, 4448 KiB

Open AccessArticle

H₂O₂-Mediated Oxidative Stress Enhances Cystathionine γ-Lyase-Derived H₂S Synthesis via a Sulfenic Acid Intermediate

by Jun Wang, Guanya Jia, Heng Li, Shasha Yan, Jing Qian, Xin Guo, Ge Li, Haizhen Qi, Zhilong Zhu, Yanjun Wu, Weijuan He and Weining Niu

Antioxidants 2021, 10(9), 1488; https://doi.org/10.3390/antiox10091488 - 18 Sep 2021

Cited by 11 | Viewed by 3366

Abstract

Hydrogen sulfide (H₂S), which is generated mainly by cystathionine γ-lyase (CSE) in the cardiovascular system, plays a pivotal role in a wide range of physiological and pathological processes. However, the regulatory mechanism of the CSE/H₂S system is poorly [...] Read more.

Hydrogen sulfide (H₂S), which is generated mainly by cystathionine γ-lyase (CSE) in the cardiovascular system, plays a pivotal role in a wide range of physiological and pathological processes. However, the regulatory mechanism of the CSE/H₂S system is poorly understood. Herein, we show that oxidation induces the disulfide bond formation between Cys252 and Cys255 in the CXXC motif, thus stimulating the H₂S-producing activity of CSE. The activity of oxidized CSE is approximately 2.5 fold greater than that of the reduced enzyme. Molecular dynamics and molecular docking suggest that the disulfide bond formation induces the conformational change in the active site of CSE and consequently increases the affinity of the enzyme for the substrate L-cysteine. Mass spectrometry and mutagenesis studies further established that the residue Cys255 is crucial for oxidation sensing. Oxidative stress-mediated sulfenylation of Cys255 leads to a sulfenic acid intermediate that spontaneously forms an intramolecular disulfide bond with the vicinal thiol group of Cys252. Moreover, we demonstrate that exogenous hydrogen peroxide (H₂O₂) and endogenous H₂O₂ triggered by vascular endothelial growth factor (VEGF) promote cellular H₂S production through the enhancement of CSE activity under oxidative stress conditions. By contrast, incubation with H₂O₂ or VEGF did not significantly enhance cellular H₂S production in the presence of PEG-catalase, an enzymatic cell-permeable H₂O₂ scavenger with high H₂O₂ specificity. Taken together, we report a new posttranslational modification of CSE that provides a molecular mechanism for H₂O₂/H₂S crosstalk in cells under oxidative stress. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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24 pages, 9567 KiB

Open AccessArticle

7S,15R-Dihydroxy-16S,17S-Epoxy-Docosapentaenoic Acid, a Novel DHA Epoxy Derivative, Inhibits Colorectal Cancer Stemness through Repolarization of Tumor-Associated Macrophage Functions and the ROS/STAT3 Signaling Pathway

by Lifang Wang, Hack Sun Choi, Yan Su, Binna Lee, Jae Jun Song, Yong-Suk Jang and Jeong-Woo Seo

Antioxidants 2021, 10(9), 1459; https://doi.org/10.3390/antiox10091459 - 14 Sep 2021

Cited by 11 | Viewed by 3595

Abstract

Colorectal cancer is a highly malignant cancer that is inherently resistant to many chemotherapeutic drugs owing to the complicated tumor-supportive microenvironment (TME). Tumor-associated macrophages (TAM) are known to mediate colorectal cancer metastasis and relapse and are therefore a promising therapeutic target. In the [...] Read more.

Colorectal cancer is a highly malignant cancer that is inherently resistant to many chemotherapeutic drugs owing to the complicated tumor-supportive microenvironment (TME). Tumor-associated macrophages (TAM) are known to mediate colorectal cancer metastasis and relapse and are therefore a promising therapeutic target. In the current study, we first confirmed the anti-inflammatory effect of 7S,15R-dihydroxy-16S,17S-epoxy-docosapentaenoic acid (diHEP-DPA), a novel DHA dihydroxy derivative synthesized in our previous work. We found that diHEP-DPA significantly reduced lipopolysaccharide (LPS)-induced inflammatory cytokines secretion of THP1 macrophages, IL-6, and TNF-α. As expected, diHEP-DPA also modulated TAM polarization, as evidenced by decreased gene and protein expression of the TAM markers, CD206, CD163, VEGF, and TGF-β1. During the polarization process, diHEP-DPA treatment decreased the concentration of TGF-β1, IL-1β, IL-6, and TNF-α in culture supernatants via inhibiting the NF-κB pathway. Moreover, diHEP-DPA blocked immunosuppression by reducing the expression of SIRPα in TAMs and CD47 in colorectal cancer cells. Knowing that an inflammatory TME largely serves to support epithelial-mesenchymal transition (EMT) and cancer stemness, we tested whether diHEP-DPA acted through polarization of TAMs to regulate these processes. The intraperitoneally injected diHEP-DPA inhibited tumor growth when administered alone or in combination with 5-fluorouracil (5-FU) chemotherapy in vivo. We further found that diHEP-DPA effectively reversed TAM-conditioned medium (TCCM)-induced EMT and enhanced colorectal cancer stemness, as evidenced by its inhibition of colorectal cancer cell migration, invasion and expression of EMT markers, as well as cancer cell tumorspheres formation, without damaging colorectal cancer cells. DiHEP-DPA reduced the population of aldehyde dehydrogenase (ALDH)-positive cells and expression of colorectal stemness marker proteins (CD133, CD44, and Sox2) by modulating TAM polarization. Additionally, diHEP-DPA directly inhibited cancer stemness by inducing the production of reactive oxygen species (ROS), which, in turn, reduced the phosphorylation of nuclear signal transducer and activator of transcription 3 (STAT3). These data collectively suggest that diHEP-DPA has the potential for development as an anticancer agent against colorectal cancer. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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23 pages, 2226 KiB

Open AccessReview

The Role of HO-1 and Its Crosstalk with Oxidative Stress in Cancer Cell Survival

by Shih-Kai Chiang, Shuen-Ei Chen and Ling-Chu Chang

Cells 2021, 10(9), 2401; https://doi.org/10.3390/cells10092401 - 13 Sep 2021

Cited by 126 | Viewed by 8600

Abstract

Heme oxygenases (HOs) act on heme degradation to produce carbon monoxide (CO), free iron, ferritin, and biliverdin. Upregulation of cellular HO-1 levels is signature of oxidative stress for its downstream effects particularly under pro-oxidative status. Subcellular traffics of HO-1 to different organelles constitute [...] Read more.

Heme oxygenases (HOs) act on heme degradation to produce carbon monoxide (CO), free iron, ferritin, and biliverdin. Upregulation of cellular HO-1 levels is signature of oxidative stress for its downstream effects particularly under pro-oxidative status. Subcellular traffics of HO-1 to different organelles constitute a network of interactions compromising a variety of effectors such as pro-oxidants, ROS, mitochondrial enzymes, and nucleic transcription factors. Some of the compartmentalized HO-1 have been demonstrated as functioning in the progression of cancer. Emerging data show the multiple roles of HO-1 in tumorigenesis from pathogenesis to the progression to malignancy, metastasis, and even resistance to therapy. However, the role of HO-1 in tumorigenesis has not been systematically addressed. This review describes the crosstalk between HO-1 and oxidative stress, and following redox regulation in the tumorigenesis. HO-1-regulated signaling pathways are also summarized. This review aims to integrate basic information and current progress of HO-1 in cancer research in order to enhance the understandings and facilitate following studies. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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24 pages, 1957 KiB

Open AccessReview

Lutein as a Modulator of Oxidative Stress-Mediated Inflammatory Diseases

by Yu Jin Ahn and Hyeyoung Kim

Antioxidants 2021, 10(9), 1448; https://doi.org/10.3390/antiox10091448 - 13 Sep 2021

Cited by 97 | Viewed by 9500

Abstract

Lutein is a xanthophyll carotenoid obtained from various foods, such as dark green leafy vegetables and egg yolk. Lutein has antioxidant activity and scavenges reactive oxygen species such as singlet oxygen and lipid peroxy radicals. Oxidative stress activates inflammatory mediators, leading to the [...] Read more.

Lutein is a xanthophyll carotenoid obtained from various foods, such as dark green leafy vegetables and egg yolk. Lutein has antioxidant activity and scavenges reactive oxygen species such as singlet oxygen and lipid peroxy radicals. Oxidative stress activates inflammatory mediators, leading to the development of metabolic and inflammatory diseases. Thus, recent basic and clinical studies have investigated the anti-inflammatory effects of lutein based on its antioxidant activity and modulation of oxidant-sensitive inflammatory signaling pathways. Lutein suppresses activation of nuclear factor-kB and signal transducer and activator of transcription 3, and induction of inflammatory cytokines (interleukin-1β, interleukin-6, monocyte chemoattratant protein-1, tumor necrosis factor-α) and inflammatory enzymes (cyclooxygenase-2, inducible nitric oxide synthase). It also maintains the content of endogenous antioxidant (glutathione) and activates nuclear factor erythroid 2–related factor 2 (Nrf2) and Nrf2 signaling-related antioxidant enzymes (hemeoxygenase-1, NAD(P)H: quinone oxidoreductase 1, glutathione-s-transferase, glutathione peroxidase, superoxide dismutase, catalase). In this review, we have discussed the current knowledge regarding the anti-inflammatory function of lutein against inflammatory diseases in various organs, including neurodegenerative disorders, eye diseases, diabetic retinopathy, osteoporosis, cardiovascular diseases, skin diseases, liver injury, obesity, and colon diseases. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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17 pages, 6748 KiB

Open AccessArticle

Peroxiredoxin 1 Controls Ovulation and Ovulated Cumulus–Oocyte Complex Activity through TLR4-Derived ERK1/2 Signaling in Mice

by Hyo-Jin Park, Bokyung Kim, Deog-Bon Koo and Dong-Seok Lee

Int. J. Mol. Sci. 2021, 22(17), 9437; https://doi.org/10.3390/ijms22179437 - 30 Aug 2021

Cited by 13 | Viewed by 2964

Abstract

Peroxiredoxins (PRDXs) are expressed in the ovary and during ovulation. PRDX1 activity related to the immuno-like response during ovulation is unknown. We investigated the roles of Prdx1 on TLR4 and ERK1/2 signaling from the ovulated cumulus–oocyte complex (COC) using Prdx1-knockout (K/O) and [...] Read more.

Peroxiredoxins (PRDXs) are expressed in the ovary and during ovulation. PRDX1 activity related to the immuno-like response during ovulation is unknown. We investigated the roles of Prdx1 on TLR4 and ERK1/2 signaling from the ovulated cumulus–oocyte complex (COC) using Prdx1-knockout (K/O) and wild-type (WT) mice. Ovulated COCs were collected 12 and 16 h after pregnant mare serum gonadotropin/hCG injection. PRDX1 protein expression and COC secretion factors (Il-6, Tnfaip6, and Ptgs2) increased 16 h after ovulated COCs of the WT mice were obtained. We treated the ovulated COCs in mice with LPS (0.5 μg/mL) or hyaluronidase (Hya) (10 units/mL) to induce TLR4 activity. Intracellular reactive oxygen species (ROS), cumulus cell apoptosis, PRDX1, TLR4/P38/ERK1/2 protein expression, and COC secretion factors’ mRNA levels increased in LPS- and Hya-treated COCs. The ERK inhibitor (U0126) and Prdx1 siRNA affected TLR4/ERK1/2 expression. The number and cumulus expansion of ovulated COCs by ROS were impaired in Prdx1 K/O mice but not in WT ones. Prdx1 gene deletion induced TLR4/P38/ERK1/2 expression and cumulus expansion genes. These results show the controlling roles of PRDX1 for TLR4/P38/ERK1/2 signaling activity in ovulated mice and the interlink of COCs with ovulation. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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18 pages, 2936 KiB

Open AccessArticle

Genome-Wide Identification and Transcriptional Expression Analysis of Annexin Genes in Capsicum annuum and Characterization of CaAnn9 in Salt Tolerance

by Xiaoxia Wu, Yan Ren, Hailong Jiang, Yan Wang, Jiaxing Yan, Xiaoying Xu, Fucai Zhou and Haidong Ding

Int. J. Mol. Sci. 2021, 22(16), 8667; https://doi.org/10.3390/ijms22168667 - 12 Aug 2021

Cited by 6 | Viewed by 3063

Abstract

Annexin (Ann) is a polygenic, evolutionarily conserved, calcium-dependent and phospholipid-binding protein family, which plays key roles in plant growth, development, and stress response. However, a comprehensive understanding of CaAnn genes of pepper (Capsicum annuum) at the genome-wide level is limited. Based [...] Read more.

Annexin (Ann) is a polygenic, evolutionarily conserved, calcium-dependent and phospholipid-binding protein family, which plays key roles in plant growth, development, and stress response. However, a comprehensive understanding of CaAnn genes of pepper (Capsicum annuum) at the genome-wide level is limited. Based on the available pepper genomic information, we identified 15 members of the CaAnn gene family. Phylogenetic analysis showed that CaAnn proteins could be categorized into four different orthologous groups. Real time quantitative RT-PCR analysis showed that the CaAnn genes were tissue-specific and were widely expressed in pepper leaves after treatments with cold, salt, and drought, as well as exogenously applied MeJA and ABA. In addition, the function of CaAnn9 was further explored using the virus-induced gene silencing (VIGS) technique. CaAnn9-silenced pepper seedlings were more sensitive to salt stress, reflected by the degradation of chlorophyll, the accumulation of reactive oxygen species (ROS), and the decrease of antioxidant defense capacity. This study provides important information for further study of the role of pepper CaAnn genes and their coding proteins in growth, development, and environmental responses. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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