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Antioxidants and redox signalling
Mary Ann Liebert, Inc.
Antioxidants and redox signalling

Mary Ann Liebert, Inc.

1523-0864

Antioxidants and redox signalling/Journal Antioxidants and redox signalling
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    Structure and Function of Redox-Sensitive Superfolder Green Fluorescent Protein Variant

    Christoph G.W. GertzenAnna Katharina SchuhThomas NietzelStefan Rahlfs...
    18页
    查看更多>>摘要：Aims: Genetically encoded green fluorescent protein (GFP)-based redox biosensors are widely used to monitor specific and dynamic redox processes in living cells. Over the last few years, various biosensors for a variety of applications were engineered and enhanced to match the organism and cellular environments, which should be investigated. In this context, the unicellular intraerythrocytic parasite Plasmodium, the causative agent of malaria, represents a challenge, as the small size of the organism results in weak fluorescence signals that complicate precise measurements, especially for cell compartment-specific observations. To address this, we have functionally and structurally characterized an enhanced redox biosensor superfolder roGFP2 (sfroGFP2).Results: SfroGFP2 retains roGFP2-like behavior, yet with improved fluorescence intensity (FI) in cellulo. SfroGFP2-based redox biosensors are pH insensitive in a physiological pH range and show midpoint potentials comparable with roGFP2-based redox biosensors. Using crystallography and rigidity theory, we identified the superfolding mutations as being responsible for improved structural stability of the biosensor in a redox-sensitive environment, thus explaining the improved FI in cellulo.Innovation: This work provides insight into the structure and function of GFP-based redox biosensors. It describes an improved redox biosensor (sfroGFP2) suitable for measuring oxidizing effects within small cells where applicability of other redox sensor variants is limited.Conclusion: Improved structural stability of sfroGFP2 gives rise to increased FI in cellulo. Fusion to hGrx1 (human glutaredoxin-1) provides the hitherto most suitable biosensor for measuring oxidizing effects in Plasmodium. This sensor is of major interest for studying glutathione redox changes in small cells, as well as subcellular compartments in general. Antioxid. Redox Signal. 37, 1–18.
      原文链接:
    • NSTL
    • Mary Ann Liebert, Inc

    Anthracycline-Induced Atrial Structural and Electrical Remodeling Characterizes Early Cardiotoxicity and Contributes to Atrial Conductive Instability and Dysfunction

    Ruopeng TanTao CongGuiwen XuZhujing Hao...
    21页
    查看更多>>摘要：Aims: Cancer patients treated with anthracyclines are susceptible to atrial fibrillation (AF), while the mechanisms remain unclear. Due to sudden and unpredictable features, prediction of anthracycline-induced AF at early phase is difficult. Clinically, we tested whether anthracycline-induced early atrial remodeling in patients could be detected by echocardiography. Experimentally, we investigated the mechanisms of doxorubicin-induced atrial remodeling and AF in mice, and the protective effects of dexrazoxane and antioxidants.Methods and Results: Postsurgery breast cancer patients with an anthracycline-containing or anthracycline exclusion regimen were recruited for echocardiography before chemotherapy, and 3 and 6 months after chemotherapy. Mice were injected with doxorubicin or vehicle (5 mg/kg/week, 4 weeks), and left atrial diameter, electrical transmission, and AF inducibility were measured. Meanwhile, the level of reactive oxygen species (ROS), activity of antioxidant enzymes, cardiomyocyte size, vacuolization, inflammation, and fibrosis were also measured in mouse atria. The therapeutic effects of dexrazoxane and antioxidants on doxorubicin-induced changes in the aforementioned parameters were also determined. While ventricular parameters and functions were unchanged in cancer patients receiving anthracyclines before and after chemotherapy, left atrial reservoir and conduit function were decreased at 3 months postchemotherapy versus prechemotherapy. Doxorubicin-induced susceptibility to AF occurred in mice before onset of ventricular dysfunction. Doxorubicin-induced AF was via inducing structural remodeling (cardiomyocyte death, hypotrophy, and vacuolization) and electrical remodeling (reduction and redistribution of connexin 43) in atria, which was effectively prevented by dexrazoxane or antioxidants through inhibiting ROS generation or enhancing ROS elimination.Innovation and Conclusion: AF inducibility was induced after doxorubicin injection, which can be inhibited by repressing the ROS level. Antioxid. Redox Signal. 37, 19–39.The Clinical Trial Registration number is PJ-KS-KY-2019-73.
      原文链接:
    • NSTL
    • Mary Ann Liebert, Inc

    Reversal of Epigenetic Peroxisome Proliferator-Activated Receptor-γ Suppression by Diacerein Alleviates Oxidative Stress and Osteoarthritis in Mice

    Xingren ChenXiaobo ZhuJian DongFang Chen...
    14页
    查看更多>>摘要：Aims: The pathogenesis of osteoarthritis (OA) is characterized by oxidative stress (OS) and sustained inflammation that are substantially associated with epigenetic DNA methylation alterations of osteogenic gene expression. Diacerein as an anthraquinone anti-OA drug exhibits multiple chondroprotective properties, but less clarified pharmacological actions. Since anthraquinone contain an epigenetic modulating property, in this study we investigate whether the anti-OA functions of diacerein involve DNA methylation modulation and antioxidant signaling.Results: The OA mice incurred by destabilization of medial meniscus exhibited marked suppression of peroxisome proliferator-activated receptor-gamma (PPARγ), a chondroprotective transcription factor with anti-inflammation and OS-balancing properties, aberrant upregulations of DNA methyltransferase (DNMT)1/3a, and PPARγ promoter hypermethylation in knee joint cartilage. Diacerein treatment mitigated the cartilage damage and significantly inhibited the DNMT1/3a upregulation, the PPARγ promoter hypermethylation, and the PPARγ loss, and it effectively corrected the adverse expression of antioxidant enzymes and inflammatory cytokines. In cultured chondrocytes, diacerein reduced the interleukin-1β-induced PPARγ suppression and the abnormal expression of its downstream antioxidant enzymes in a gain of DNMT and PPARγ inhibition-sensitive manner, and in PPARγ knockout mice, the anti-OA effects of diacerein were significantly reduced.Innovation: Our work reveals a novel anti-OA pharmacological property of diacerein and identifies the aberrant DNMT elevation and the resultant PPARγ suppression as an important epigenetic pathway that mediates diacerein's anti-OA activities.Conclusion: DNA methylation aberration and the resultant PPARγ suppression contribute significantly to epigenetic OA pathogenesis, and targeting PPARγ suppression via DNA demethylation is an important component of diacerein's anti-OA functions. Antioxid. Redox Signal. 37, 40–53.
      原文链接:
    • NSTL
    • Mary Ann Liebert, Inc

    Specialized Pro-Resolving Mediators Derived from N-3 Polyunsaturated Fatty Acids: Role in Metabolic Syndrome and Related Complications

    Laurent DubéSchohraya SpahisKarelle Lacha?neAndreanne Lemieux...
    30页
    查看更多>>摘要：Significance: Metabolic syndrome (MetS) prevalence continues to grow and represents a serious public health issue worldwide. This multifactorial condition carries the risk of hastening the development of type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases (CVD). Another troubling aspect of MetS is the requirement of poly-pharmacological therapy not devoid of side effects. Therefore, there is an urgent need for prospecting alternative nutraceuticals as effective therapeutic agents for MetS.Recent Advances: Currently, there is an increased interest in understanding the regulation of metabolic derangements by specialized pro-resolving lipid mediators (SPMs), especially those derived from the long chain n-3 polyunsaturated fatty acids.Critical Issues: The SPMs are recognized as efficient modulators that are capable of inhibiting the production of pro-inflammatory cytokines, blocking neutrophil activation/recruitment, and inducing non-phlogistic (anti-inflammatory) activation of macrophage engulfment and removal of apoptotic inflammatory cells and debris. The aim of the present review is precisely to first underline key concepts relative to SPM functions before focusing on their status and actions on MetS components (e.g., obesity, glucose dysmetabolism, hyperlipidemia, hypertension) and complications such as T2D, NAFLD, and CVD.Future Directions: Valuable data from preclinical and clinical investigations have emphasized the SPM functions and influence on oxidative stress- and inflammation-related MetS. Despite these promising findings obtained without compromising host defense, additional efforts are needed to evaluate their potential therapeutic applications and further develop practical tools to monitor their bioavailability to cope with cardiometabolic disorders. Antioxid. Redox Signal. 37, 54–83.
      原文链接:
    • NSTL
    • Mary Ann Liebert, Inc

    The Role of Perivascular Adipose Tissue-Derived Hydrogen Sulfide in the Control of Vascular Homeostasis

    Emma MitidieriCarlotta TurnaturiDomenico VanacoreRaffaella Sorrentino...
    14页
    查看更多>>摘要：Significance: Emerging evidence suggests that perivascular adipose tissue (PVAT) has a relevant role in the control of vascular tone in physiology and pathology. Healthy PVAT has anticontractile, anti-inflammatory, and antioxidative actions. Accumulating data from both human and experimental animal models indicate that PVAT dysfunction is conceivably coupled to cardiovascular diseases, and it is associated with vascular inflammation, oxidative stress, and arterial remodeling. Therefore, “healthy” PVAT may constitute a novel therapeutic target for the prevention and treatment of cardiovascular diseases.Recent Advances: Hydrogen sulfide (H2S) has been recognized as a vascular anti-contractile factor released from PVAT. The enzymes deputed to H2S biosynthesis are variously expressed in PVAT and strictly dependent on the vascular bed and species. Metabolic and cardiovascular diseases can alter the morphological and secretory characteristics of PVAT, influencing also the H2S signaling. Here, we discuss the role of PVAT-derived H2S in healthy conditions and its relevance in alterations occurring in vascular disorders.Critical Issues: We discuss how a better understanding may help in the prevention of vascular dysfunction related to alteration in PVAT-released H2S as well as the importance of the interplay between PVAT and H2S.Future Directions: We propose future directions to evaluate the contribution of each enzyme involved in H2S biosynthesis and their alteration/switch occurring in vascular disorders and the remaining challenges in investigating the role of H2S. Antioxid. Redox Signal. 37, 84–97.
      原文链接:
    • NSTL
    • Mary Ann Liebert, Inc

    Modulatory Role of Carbon Monoxide on the Inflammatory Response and Oxidative Stress Linked to Gastrointestinal Disorders

    André Luiz dos Reis BarbosaLucas Antonio Duarte NicolauJand-Venes Rolim MedeirosMarcellus Henrique Loiola Ponte Souza...
    17页
    查看更多>>摘要：Significance: Carbon monoxide (CO) is an endogenous gaseous mediator that plays an important role in maintaining gastrointestinal (GI) tract homeostasis, acting in mucosal defense, and providing negative modulation of pathophysiological markers of clinical conditions.Recent Advances: Preclinical studies using animal models and/or cell culture show that CO can modulate the inflammatory response and oxidative stress in GI mucosal injuries and pathological conditions, reducing proinflammatory cytokines and reactive oxygen species, while increasing antioxidant defense mechanisms.Critical Issues: CO has potent anti-inflammatory and antioxidant effects. The defense mechanisms of the GI tract are subject to aggression by different chemical agents (e.g., drugs and ethanol) as well as complex and multifactorial diseases, with inflammation and oxidative stress as strong triggers for the deleterious effects. Thus, it is possible that CO acts on a variety of molecules involved in the inflammatory and oxidative signaling cascades, as well as reinforcing several defense mechanisms that maintain GI homeostasis.Future Directions: CO-based therapies are promising tools for the treatment of GI disorders, such as gastric and intestinal injuries, inflammatory bowel disease, and pancreatitis. Therefore, it is necessary to develop safe and selective CO-releasing agents and/or donor drugs to facilitate effective treatments and methods for analysis of CO levels that are simple and inexpensive. Antioxid. Redox Signal. 37, 98–114.
      原文链接:
    • NSTL
    • Mary Ann Liebert, Inc

    Targeting Oxidative Stress and Inflammatory Response for Blood–Brain Barrier Protection in Intracerebral Hemorrhage

    Shengpan ChenLingzhi LiChao PengChunjing Bian...
    20页
    查看更多>>摘要：Significance: Blood–brain barrier (BBB) disruption is a major pathological change after intracerebral hemorrhage (ICH) and is both the cause and result of oxidative stress and of the immune response post-ICH. These processes contribute to ICH-induced brain injury.Recent Advances: After the breakdown of cerebral vessels, blood components, including erythrocytes and their metabolites, thrombin, and fibrinogen, can access the cerebral parenchyma through the compromised BBB, triggering oxidative stress and inflammatory cascades. These aggravate BBB disruption and contribute to further infiltration of blood components, resulting in a vicious cycle that exacerbates brain edema and neurological injury after ICH. Experimental and clinical studies have highlighted the role of BBB disruption in ICH-induced brain injury.Critical Issues: In this review, we focus on the strategies to protect the BBB in ICH. Specifically, we summarize the evidence and the underlying mechanisms, including the ICH-induced process of oxidative stress and inflammatory response, and we highlight the potential therapeutic targets to protect BBB integrity after ICH.Future Directions: Future studies should probe the mechanism of ferroptosis as well as oxidative stress-inflammation coupling in BBB disruption after ICH and investigate the effects of antioxidants and immunomodulatory agents in more ICH clinical trials. Antioxid. Redox Signal. 37, 115–134.
      原文链接:
    • NSTL
    • Mary Ann Liebert, Inc

    Biological Sex As a Critical Variable in CD4+ Effector T Cell Function in Preclinical Models of Multiple Sclerosis

    Muhammad UmairMohamed Reda FazaziManu Rangachari
    15页
    查看更多>>摘要：Significance: T cells play a pivotal role in maintaining adaptive immune responses against pathogens. However, misdirected T cell responses against self-tissues may lead to autoimmune disease. Biological sex has profound effects on T cell function and is an important determinant of disease incidence and severity in autoimmune diseases such as multiple sclerosis (MS).Recent Advances: Many autoimmune diseases skew toward higher female incidence, including MS; however, it is has become increasingly more accepted that men living with MS are more prone to developing a progressive disease course and to having worsened disease outcomes.Critical Issues: In this review, we discuss what is known about the role of biological sex on T cell development and differentiation, examining evidence that male sex can augment T helper 17 (Th17) responses. Next, we outline what is known about sex differences in animal models of MS, and about the distinct roles played by sex hormones versus sex chromosomes in pathogenesis in these models. Finally, we discuss recent advances that examine the molecular basis for worsened disease outcomes in males, with a particular focus on the role played by Th17 cells in these models.Future Directions: Better understanding the role of biological sex in T cell function may pave the way to effective personalized treatment strategies in MS and other autoimmune diseases. Antioxid. Redox Signal. 37, 135–149.
      原文链接:
    • NSTL
    • Mary Ann Liebert, Inc

    Dysregulation of Iron Homeostasis in the Central Nervous System and the Role of Ferroptosis in Neurodegenerative Disorders

    Samuel DavidPriya JhelumFari RyanSuh Young Jeong...
    21页
    查看更多>>摘要：Significance: Iron accumulation occurs in the central nervous system (CNS) in a variety of neurological conditions as diverse as spinal cord injury, stroke, multiple sclerosis, Parkinson's disease, and others. Iron is a redox-active metal that gives rise to damaging free radicals if its intracellular levels are not controlled or if it is not properly sequestered within cells. The accumulation of iron occurs due to dysregulation of mechanisms that control cellular iron homeostasis.Recent Advances: The molecular mechanisms that regulate cellular iron homeostasis have been revealed in much detail in the past three decades, and new advances continue to be made. Understanding which aspects of iron homeostasis are dysregulated in different conditions will provide insights into the causes of iron accumulation and iron-mediated tissue damage. Recent advances in iron-dependent lipid peroxidation leading to cell death, called ferroptosis, has provided useful insights that are highly relevant for the lipid-rich environment of the CNS.Critical Issues: This review examines the mechanisms that control normal cellular iron homeostasis, the dysregulation of these mechanisms in neurological disorders, and more recent work on how iron can induce tissue damage via ferroptosis.Future Directions: Quick and reliable tests are needed to determine if and when ferroptosis contributes to the pathogenesis of neurological disorders. In addition, there is need to develop better druggable agents to scavenge lipid radicals and reduce CNS damage for neurological conditions for which there are currently few effective treatments. Antioxid. Redox Signal. 37, 150–170.
      原文链接:
    • NSTL
    • Mary Ann Liebert, Inc

    Tetrahydrobiopterin in Cell Function and Death Mechanisms

    Jeannette Vasquez-VivarZhongjie ShiSidhartha Tan
    13页
    查看更多>>摘要：Significance: Tetrahydrobiopterin (BH4) is most well known as a required cofactor for enzymes regulating cellular redox homeostasis, aromatic amino acid metabolism, and neurotransmitter synthesis. Less well known are the effects dependent on the cofactor's availability, factors governing its synthesis and recycling, redox implications of the cofactor itself, and protein–protein interactions that underlie cell death. This review provides an understanding of the recent advances implicating BH4 in the mechanisms of cell death and suggestions of possible therapeutic interventions.Recent Advances: The levels of BH4 often reflect the sum of synthetic and recycling enzyme activities. Enhanced expression of GTP cyclohydrolase, the rate-limiting enzyme in biosynthesis, increases BH4, leading to improved cell function and survival. Pharmacologically increasing BH4 levels has similar beneficial effects, leading to enhanced production of neurotransmitters and nitric oxide or reducing oxidant levels. The GTP cyclohydrolase-BH4 pairing has been implicated in a type of cell death, ferroptosis. At the cellular level, BH4 counteracts anticancer therapies directed to enhance ferroptosis via glutathione peroxidase 4 (GPX4) activity inhibition.Critical Issues: Because of the multitude of intertwined mechanisms, a clear relationship between BH4 and cell death is not well understood yet. The possibility that the cofactor directly influences cell viability has not been excluded in previous studies when modulating BH4-producing enzymes.Future Directions: The importance of cellular BH4 variations and BH4 biosynthetic enzymes to cell function and viability makes it essential to better characterize temporal changes, cofactor activity, and the influence on redox status, which in turn would help develop novel therapies. Antioxid. Redox Signal. 37, 171–183.
      原文链接:
    • NSTL
    • Mary Ann Liebert, Inc