Paradoxical Roles of Antioxidant Enzymes: Basic Mechanisms and Health Implications

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated from aerobic metabolism, as a result of accidental electron leakage as well as regulated enzymatic processes. Because ROS/RNS can induce oxidative injury and act in redox signaling, enzymes metabolizing them will inherently promote either health or disease, depending on the physiological context. It is thus misleading to consider conventionally called antioxidant enzymes to be largely, if not exclusively, health protective. Because such a notion is nonetheless common, we herein attempt to rationalize why this simplistic view should be avoided. First we give an updated summary of physiological phenotypes triggered in mouse models of overexpression or knockout of major antioxidant enzymes. Subsequently, we focus on a series of striking cases that demonstrate “paradoxical” outcomes, i.e., increased fitness upon deletion of antioxidant enzymes or disease triggered by their overexpression. We elaborate mechanisms by which these phenotypes are mediated via chemical, biological, and metabolic interactions of the antioxidant enzymes with their substrates, downstream events, and cellular context. Furthermore, we propose that novel treatments of antioxidant enzyme-related human diseases may be enabled by deliberate targeting of dual roles of the pertaining enzymes. We also discuss the potential of “antioxidant” nutrients and phytochemicals, via regulating the expression or function of antioxidant enzymes, in preventing, treating, or aggravating chronic diseases. We conclude that “paradoxical” roles of antioxidant enzymes in physiology, health, and disease derive from sophisticated molecular mechanisms of redox biology and metabolic homeostasis. Simply viewing antioxidant enzymes as always being beneficial is not only conceptually misleading but also clinically hazardous if such notions underpin medical treatment protocols based on modulation of redox pathways.

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Reactive Nitrogen Species: Molecular Mechanisms and Potential Significance in Health and Disease

Antioxidants and Redox Signaling ◽

10.1089/ars.2007.1993 ◽

2009 ◽

Vol 11 (3) ◽

pp. 669-702 ◽

Cited By ~ 95

Author(s):

M. Carmen Martínez ◽

Ramaroson Andriantsitohaina

Keyword(s):

Reactive Nitrogen Species ◽

Molecular Mechanisms ◽

Reactive Nitrogen ◽

Nitrogen Species ◽

Potential Significance ◽

Health And Disease

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Cadherin Signaling in Cancer and Autoimmune Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms222413358 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13358

Author(s):

Margherita Sisto ◽

Domenico Ribatti ◽

Sabrina Lisi

Keyword(s):

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Cell Trafficking ◽

Cellular Functions ◽

Cytoskeletal Organization ◽

Mesenchymal Transition ◽

Cellular Processes ◽

Cellular Context ◽

Health And Disease ◽

Mediate Cell

Cadherins mediate cell–cell adhesion through a dynamic process that is strongly dependent on the cellular context and signaling. Cadherin regulation reflects the interplay between fundamental cellular processes, including morphogenesis, proliferation, programmed cell death, surface organization of receptors, cytoskeletal organization, and cell trafficking. The variety of molecular mechanisms and cellular functions regulated by cadherins suggests that we have only scratched the surface in terms of clarifying the functions mediated by these versatile proteins. Altered cadherins expression is closely connected with tumorigenesis, epithelial–mesenchymal transition (EMT)-dependent fibrosis, and autoimmunity. We review the current understanding of how cadherins contribute to human health and disease, considering the mechanisms of cadherin involvement in diseases progression, as well as the clinical significance of cadherins as therapeutic targets.

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Astrocytes in health and disease

Orvosi Hetilap ◽

10.1556/oh.2007.27892 ◽

2007 ◽

Vol 148 (15) ◽

pp. 697-702 ◽

Cited By ~ 2

Author(s):

Marianna Murányi ◽

Zsombor Lacza

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Free Radicals ◽

Molecular Mechanisms ◽

Neuronal Dysfunction ◽

Supporting Cells ◽

Neuronal Synapses ◽

Health And Disease ◽

Novel Targets ◽

Therapeutic Tools

It is now known that astrocytes are not merely supporting cells but they also play an important role in neuronal funcions. Astrocytes tightly ensheat neuronal synapses and regulate the excitation of neurons by uptaking neurotransmitters; reglulate the cerebral blood flow, cerebral fluid volume and extracellular concentrations of ions. They also supply fuel in the form of lactate and provide free radical scavangers such as glutathione for active neurons. These facts indicate that impaired function of astrocytes may lead to neuronal dysfunction. After brain injury (stroke, trauma or tumors) astrocytes are swollen and release active molecules such as glutamate or free radicals resulting in neuronal dysfunction. Thus, investigation of the molecular mechanisms of astrocyte function may reveal novel targets for the development of therapeutic tools in neuronal diseases.

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Lighting a path: genetic studies pinpoint neurodevelopmental mechanisms in autism and related disorders

Dialogues in Clinical Neuroscience ◽

10.31887/10.31887/dcns.2012.14.3/mpescosolido ◽

2012 ◽

Vol 14 (3) ◽

pp. 239-252

Keyword(s):

Molecular Mechanisms ◽

Protein Localization ◽

Regulation Of Gene Expression ◽

Neuronal Cell ◽

Mrna Splicing ◽

Genetic Mutations ◽

Scaffolding Proteins ◽

Molecular Processes ◽

Genetic Studies ◽

Novel Treatments

In this review, we outline critical molecular processes that have been implicated by discovery of genetic mutations in autism. These mechanisms need to be mapped onto the neurodevelopment step(s) gone awry that may be associated with cause in autism. Molecular mechanisms include: (i) regulation of gene expression; (ii) pre-mRNA splicing; (iii) protein localization, translation, and turnover; (iv) synaptic transmission; (v) cell signaling; (vi) the functions of cytoskeletal and scaffolding proteins; and (vii) the function of neuronal cell adhesion molecules. While the molecular mechanisms appear broad, they may converge on only one of a few steps during neurodevelopment that perturbs the structure, function, and/or plasticity of neuronal circuitry. While there are many genetic mutations involved, novel treatments may need to target only one of few developmental mechanisms.

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DNA Methylation Profiles of Tph1A and BDNF in Gut and Brain of L. Rhamnosus-Treated Zebrafish

Biomolecules ◽

10.3390/biom11020142 ◽

2021 ◽

Vol 11 (2) ◽

pp. 142

Author(s):

Mariella Cuomo ◽

Luca Borrelli ◽

Rosa Della Monica ◽

Lorena Coretti ◽

Giulia De Riso ◽

...

Keyword(s):

Dna Methylation ◽

Molecular Mechanisms ◽

The Past ◽

Targeted Analysis ◽

Lack Of Information ◽

High Resolution Power ◽

Resolution Level ◽

Health And Disease ◽

High Doses ◽

The Brain

The bidirectional microbiota–gut–brain axis has raised increasing interest over the past years in the context of health and disease, but there is a lack of information on molecular mechanisms underlying this connection. We hypothesized that change in microbiota composition may affect brain epigenetics leading to long-lasting effects on specific brain gene regulation. To test this hypothesis, we used Zebrafish (Danio Rerio) as a model system. As previously shown, treatment with high doses of probiotics can modulate behavior in Zebrafish, causing significant changes in the expression of some brain-relevant genes, such as BDNF and Tph1A. Using an ultra-deep targeted analysis, we investigated the methylation state of the BDNF and Tph1A promoter region in the brain and gut of probiotic-treated and untreated Zebrafishes. Thanks to the high resolution power of our analysis, we evaluated cell-to-cell methylation differences. At this resolution level, we found slight DNA methylation changes in probiotic-treated samples, likely related to a subgroup of brain and gut cells, and that specific DNA methylation signatures significantly correlated with specific behavioral scores.

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Novel Treatments and Technologies Applied to the Cure of Neuroblastoma

Children ◽

10.3390/children8060482 ◽

2021 ◽

Vol 8 (6) ◽

pp. 482

Author(s):

Irene Paraboschi ◽

Laura Privitera ◽

Gabriela Kramer-Marek ◽

John Anderson ◽

Stefano Giuliani

Keyword(s):

Research Effort ◽

Treatment Strategies ◽

Adverse Outcomes ◽

Treatment Protocols ◽

Ongoing Research ◽

Hematopoietic Stem ◽

Novel Treatments ◽

Therapeutic Modalities ◽

High Risk Disease ◽

Novel Treatment Strategies

Neuroblastoma (NB) is the most common extracranial solid tumour in childhood, accounting for approximately 15% of all cancer-related deaths in the paediatric population1. It is characterised by heterogeneous clinical behaviour in neonates and often adverse outcomes in toddlers. The overall survival of children with high-risk disease is around 40–50% despite the aggressive treatment protocols consisting of intensive chemotherapy, surgery, radiation therapy and hematopoietic stem cell transplantation2,3. There is an ongoing research effort to increase NB’s cellular and molecular biology knowledge to translate essential findings into novel treatment strategies. This review aims to address new therapeutic modalities emerging from preclinical studies offering a unique translational opportunity for NB treatment.

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Circadian Blood Pressure Rhythm in Cardiovascular and Renal Health and Disease

Biomolecules ◽

10.3390/biom11060868 ◽

2021 ◽

Vol 11 (6) ◽

pp. 868

Author(s):

Jiayang Zhang ◽

Ruoyu Sun ◽

Tingting Jiang ◽

Guangrui Yang ◽

Lihong Chen

Keyword(s):

Blood Pressure ◽

Circadian Rhythm ◽

Molecular Mechanisms ◽

Current Understanding ◽

Renal Outcomes ◽

Circadian Blood Pressure ◽

Health And Disease ◽

The Relationship

Blood pressure (BP) follows a circadian rhythm, it increases on waking in the morning and decreases during sleeping at night. Disruption of the circadian BP rhythm has been reported to be associated with worsened cardiovascular and renal outcomes, however the underlying molecular mechanisms are still not clear. In this review, we briefly summarized the current understanding of the circadian BP regulation and provided therapeutic overview of the relationship between circadian BP rhythm and cardiovascular and renal health and disease.

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Friend or Foe: Paradoxical Roles of Autophagy in Gliomagenesis

Cells ◽

10.3390/cells10061411 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1411

Author(s):

Don Carlo Ramos Batara ◽

Moon-Chang Choi ◽

Hyeon-Uk Shin ◽

Hyunggee Kim ◽

Sung-Hak Kim

Keyword(s):

Brain Tumor ◽

Glioblastoma Multiforme ◽

Cancer Biology ◽

Molecular Mechanisms ◽

Primary Brain Tumor ◽

Molecular Target ◽

Therapeutic Strategies ◽

Homeostatic Mechanism ◽

Cellular Context ◽

Cellular Components

Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor in adults, with a poor median survival of approximately 15 months after diagnosis. Despite several decades of intensive research on its cancer biology, treatment for GBM remains a challenge. Autophagy, a fundamental homeostatic mechanism, is responsible for degrading and recycling damaged or defective cellular components. It plays a paradoxical role in GBM by either promoting or suppressing tumor growth depending on the cellular context. A thorough understanding of autophagy’s pleiotropic roles is needed to develop potential therapeutic strategies for GBM. In this paper, we discussed molecular mechanisms and biphasic functions of autophagy in gliomagenesis. We also provided a summary of treatments for GBM, emphasizing the importance of autophagy as a promising molecular target for treating GBM.

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RNA–Binding Protein HuD as a Versatile Factor in Neuronal and Non–Neuronal Systems

Biology ◽

10.3390/biology10050361 ◽

2021 ◽

Vol 10 (5) ◽

pp. 361

Author(s):

Myeongwoo Jung ◽

Eun-Kyung Lee

Keyword(s):

Gene Expression ◽

Neural Plasticity ◽

Molecular Mechanisms ◽

Neuronal Development ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Novel Treatments ◽

Target Mrnas ◽

Neuronal Systems

HuD (also known as ELAVL4) is an RNA–binding protein belonging to the human antigen (Hu) family that regulates stability, translation, splicing, and adenylation of target mRNAs. Unlike ubiquitously distributed HuR, HuD is only expressed in certain types of tissues, mainly in neuronal systems. Numerous studies have shown that HuD plays essential roles in neuronal development, differentiation, neurogenesis, dendritic maturation, neural plasticity, and synaptic transmission by regulating the metabolism of target mRNAs. However, growing evidence suggests that HuD also functions as a pivotal regulator of gene expression in non–neuronal systems and its malfunction is implicated in disease pathogenesis. Comprehensive knowledge of HuD expression, abundance, molecular targets, and regulatory mechanisms will broaden our understanding of its role as a versatile regulator of gene expression, thus enabling novel treatments for diseases with aberrant HuD expression. This review focuses on recent advances investigating the emerging role of HuD, its molecular mechanisms of target gene regulation, and its disease relevance in both neuronal and non–neuronal systems.

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