Mammalian Metallothionein-2A and Oxidative Stress

Ling, Xue-Bin; Wei, Hongwei; Wang, Jun; Kong, Yue-Qiong; Wu, Yu-You; Guo, Junli; Li, Tianfa; Li, Ji-Ke

doi:10.3390/ijms17091483

Cited by 93 publications

(69 citation statements)

References 103 publications

(126 reference statements)

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“…32 Increased extracellular levels of GABA, released by interneurons for example, lead to astrocytic Ca2 + elevations mediated by GABAb receptor activation. 39 Mitochondrial mechanisms involved in VWM pathophysiology corroborate recent findings in primary astrocytes of Eif2b5 R132H/R132H mice indicating that an impaired oxidative phosphorylation in these cells is compensated by increased mitochondrial content and glycolysis. 32 This confirms earlier findings that neuronal dysfunction in VWM should not be overlooked.…”

Section: Discussionsupporting

confidence: 81%

Astrocyte Subtype Vulnerability in Stem Cell Models of Vanishing White Matter

Leferink

Dooves

Hillen

et al. 2019

Annals of Neurology

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Objective: Astrocytes have gained attention as important players in neurological disease. In line with their heterogeneous character, defects in specific astrocyte subtypes have been identified. Leukodystrophy vanishing white matter (VWM) shows selective vulnerability in white matter astrocytes, but the underlying mechanisms remain unclear. Induced pluripotent stem cell technology is being extensively explored in studies of pathophysiology and regenerative medicine. However, models for distinct astrocyte subtypes for VWM are lacking, thereby hampering identification of disease-specific pathways. Methods: Here, we characterize human and mouse pluripotent stem cell-derived gray and white matter astrocyte subtypes to generate an in vitro VWM model. We examined morphology and functionality, and used coculture methods, high-content microscopy, and RNA sequencing to study VWM cultures. Results: We found intrinsic vulnerability in specific astrocyte subpopulations in VWM. When comparing VWM and control cultures, white matter-like astrocytes inhibited oligodendrocyte maturation, and showed affected pathways in both human and mouse cultures, involving the immune system and extracellular matrix. Interestingly, human white matter-like astrocytes presented additional, human-specific disease mechanisms, such as neuronal and mitochondrial functioning. Interpretation: Astrocyte subtype cultures revealed disease-specific pathways in VWM. Cross-validation of human-and mouse-derived protocols identified human-specific disease aspects. This study provides new insights into VWM disease mechanisms, which helps the development of in vivo regenerative applications, and we further present strategies to study astrocyte subtype vulnerability in neurological disease.

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Section: Discussionsupporting

confidence: 81%

Astrocyte Subtype Vulnerability in Stem Cell Models of Vanishing White Matter

Leferink

Dooves

Hillen

et al. 2019

Annals of Neurology

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“…The DEX induced up-regulation of HMGA2 may be a compensatory mechanism to antagonize TM cell senescence. Metallothionein 2A ( MT2A ), a metal binding enzyme, plays a role in anti-oxidant, anti-apoptosis, detoxification and anti-inflammation [59]. It is also a GR-inducible gene in hepatic cells [60].…”

Section: Discussionmentioning

confidence: 99%

A Comparison of Gene Expression Profiles between Glucocorticoid Responder and Non-Responder Bovine Trabecular Meshwork Cells Using RNA Sequencing

et al. 2017

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The most common ocular side effect of glucocorticoid (GC) therapy is GC-induced ocular hypertension (OHT) and GC-induced glaucoma (GIG). GC-induced OHT occurs in about 40% of the general population, while the other 60% are resistant. This study aims to determine the genes and pathways involved in differential GC responsiveness in the trabecular meshwork (TM). Using paired bovine eyes, one eye was perfusion-cultured with 100nM dexamethasone (DEX), while the fellow eye was used to establish a bovine TM (BTM) cell strain. Based on maximum IOP change in the perfused eye, the BTM cell strain was identified as a DEX-responder or non-responder strain. Three responder and three non-responder BTM cell strains were cultured, treated with 0.1% ethanol or 100nM DEX for 7 days. RNA and proteins were extracted for RNA sequencing (RNAseq), qPCR, and Western immunoblotting (WB), respectively. Data were analyzed using the human and bovine genome databases as well as Tophat2 software. Genes were grouped and compared using Student’s t-test. We found that DEX induced fibronectin expression in responder BTM cells but not in non-responder cells using WB. RNAseq showed between 93 and 606 differentially expressed genes in different expression groups between responder and non-responder BTM cells. The data generated by RNAseq were validated using qPCR. Pathway analyses showed 35 pathways associated with differentially expressed genes. These genes and pathways may play important roles in GC-induced OHT and will help us to better understand differential ocular responsiveness to GCs.

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“…NADPH:quinone oxidoreductase-1 (NQO1), a cytoplasmic 2-electron reductase, also acts as an antioxidant by preventing the generation of ROS via 1-electron reduction of quinones. Other biological antioxidants include ascorbic acid (vitamin C), vitamin E, melatonin and the metallothioneins (MT) (16), a family of small cysteine-rich proteins that localize to the membrane of the Golgi apparatus. In addition to protecting cells from toxic metals such as Zn, MTs protect against oxidative stress via their cysteine residues that scavenge ROS such as • OH and • O 2 − (17).…”

Section: The Basal Antioxidant Responsementioning

confidence: 99%

Defenses against Pro-oxidant Forces - Maintenance of Cellular and Genomic Integrity and Longevity

2018

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There has been enormous recent progress in understanding how human cells respond to oxidative stress, such as that caused by exposure to ionizing radiation. We have witnessed a significant deciphering of the events that underlie how antioxidant responses counter pro-oxidant damage to key biological targets in all cellular compartments, including the genome and mitochondria. These cytoprotective responses include: 1. The basal cellular repertoire of antioxidant capabilities and its supporting cast of facilitator enzymes; and 2. The inducible phase of the antioxidant response, notably that mediated by the Nrf2 transcription factor. There has also been frenetic progress in defining how reactive electrophilic species swamp existing protective mechanisms to augment DNA damage, events that are embodied in the cellular “DNA-damage response”, including cell cycle checkpoint activation and DNA repair, which occur on a time scale of hours to days, as well as the implementation of cellular responses such as apoptosis, autophagy, senescence and reprograming that extend the time period of damage sensing and response into weeks, months and years. It has become apparent that, in addition to the initial oxidative insult, cells typically undergo further waves of secondary reactive oxygen/nitrogen species generation, DNA damage and signaling and that these may reemerge long after the initial events have subsided, probably being driven, at least in part, by persisting DNA damage. These reactive oxygen/nitrogen species are an integral part of the pathological consequences of radiation exposure and may persist across multiple cell divisions. Because of the pervasive nature of oxidative stress, a cell will manifest different responses in different subcellular compartments and to different levels of stress injury. Aspects of these compartmentalized responses can involve the same proteins (such as ATM, p53 and p21) but in different functional guises, e.g., in cytoplasmic versus nuclear responses or in early-versus late-phase events. Many of these responses involve gene activation and new protein synthesis as well as a plethora of post-translational modifications of both basal and induced response proteins. It is these responses that we focus on in this review.

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Mammalian Metallothionein-2A and Oxidative Stress

Cited by 93 publications

References 103 publications

Astrocyte Subtype Vulnerability in Stem Cell Models of Vanishing White Matter

Astrocyte Subtype Vulnerability in Stem Cell Models of Vanishing White Matter

A Comparison of Gene Expression Profiles between Glucocorticoid Responder and Non-Responder Bovine Trabecular Meshwork Cells Using RNA Sequencing

Defenses against Pro-oxidant Forces - Maintenance of Cellular and Genomic Integrity and Longevity

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