Downregulation of lncRNA EPB41L4A-AS1 Mediates Activation of MYD88-Dependent NF-κB Pathway in Diabetes-Related Inflammation

Wang, Ziqing; Liao, Weijie; Liu, Fuhai; Yang, Tingpeng; Xie, Weidong; Liao, Meijian; Gu, Dayong; Zhang, Yaou

doi:10.2147/dmso.s280765

Cited by 15 publications

(14 citation statements)

References 33 publications

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“…The expression of EPB41L4A-AS1 is reduced under high glucose and inflammatory stimulation at the cellular level, which promotes the expression of IL-1 β and IL-8 [ 54 ]. EPB41L4A-AS1 knockdown promotes the upregulation of myeloid differentiation factor 88 (MYD88) expression by enhancing the enrichment of H3K9me3 in the MYD88 promoter.…”

Section: The Role and Function Of Lncrnas In Diabetic Inflammationmentioning

confidence: 99%

“…Liu et al [ 90 ] found that knockdown of MALAT1 can ameliorate diabetic retinopathy by reducing microvascular leakage and retinal inflammation. Wang et al [ 54 ] found that EPB41L4A-AS1 knockdown promotes the inflammatory reaction by promoting glycolysis [ 113 ]. The lncRNAs involved in inflammatory signaling pathways, particularly in pathways involving JAK/STAT, NF-kB, p38/MAPK, and other targets, have been extensively investigated.…”

Section: The Role and Function Of Lncrnas In Diabetic Inflammationmentioning

confidence: 99%

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Molecular Mechanisms and Functions of lncRNAs in the Inflammatory Reaction of Diabetes Mellitus

Huang

2021

International Journal of Endocrinology

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Diabetes is a chronic inflammatory state, and several studies have shown that the mechanisms of insulin resistance and abnormal islet β-cell function in diabetes are closely related to inflammatory reactions. Inflammation plays a critical role in diabetic complications. Long noncoding RNAs (lncRNAs), a new area of genomic research for gene regulation, have complex biological functions in various aspects of cellular biological activity. Recent studies have shown that lncRNAs are associated with the regulation of inflammatory responses in various ways, including at the epigenetic, transcriptional, and posttranscriptional levels. This paper presents a brief review of studies on the mechanisms of lncRNAs in diabetic inflammation. The purpose of this article is to determine the role of lncRNAs in the process of diabetic inflammation and to provide new strategies for the use of lncRNAs in the treatments for diabetic inflammation.

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Section: The Role and Function Of Lncrnas In Diabetic Inflammationmentioning

confidence: 99%

Section: The Role and Function Of Lncrnas In Diabetic Inflammationmentioning

confidence: 99%

Molecular Mechanisms and Functions of lncRNAs in the Inflammatory Reaction of Diabetes Mellitus

Huang

2021

International Journal of Endocrinology

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“…EPB41L4A-AS1 was first reported as a protein-coding gene named TIGA1 related to cell proliferation [ 9 ]; later studies demonstrated that EPB41L4A-AS1 mainly functioned as a lncRNA associated with cell metabolism and immune response [ 7 , 10 , 11 ], and its downregulation in cancer cells induced glutamine dependency and promoted glycolysis [ 7 ]. Interestingly, it has been shown that downregulation of EPB41L4A-AS1 in placental trophoblast cells could inhibit the Warburg effect essential for fast growth of placental trophoblast cells leading to recurrent miscarriages [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of EPB41L4A-AS1 mediated the brain aging and neurodegenerative diseases via damaging synthesis of NAD+ and ATP

Yang

Wang²,

Liao³

et al. 2021

Cell Biosci

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Background Aging and neurodegenerative diseases are typical metabolic-related processes. As a metabolism-related long non-coding RNA, EPB41L4A-AS has been reported to be potentially involved in the development of brain aging and neurodegenerative diseases. In this study, we sought to reveal the mechanisms of EPB41L4A-AS in aging and neurodegenerative diseases. Methods Human hippocampal gene expression profiles downloaded from the Genotype-Tissue Expression database were analyzed to obtain age-stratified differentially expressed genes; a weighted correlation network analysis algorithm was then used to construct a gene co-expression network of these differentially expressed genes to obtain gene clustering modules. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, protein–protein interaction network, and correlation analysis were used to reveal the role of EPB41L4A-AS1. The mechanism was verified using Gene Expression Omnibus dataset GSE5281 and biological experiments (construction of cell lines, Real-time quantitative PCR, Western blot, measurement of ATP and NAD+ levels, nicotinamide riboside treatment, Chromatin Immunoprecipitation) in neurons and glial-derived cells. Results EPB41L4A-AS1 was downregulated in aging and Alzheimer's disease. EPB41L4A-AS1 related genes were found to be enriched in the electron transport chain and NAD+ synthesis pathway. Furthermore, these genes were highly associated with neurodegenerative diseases and positively correlated with EPB41L4A-AS1. In addition, biological experiments proved that the downregulation of EPB41L4A-AS1 could reduce the expression of these genes via histone H3 lysine 27 acetylation, resulting in decreased NAD+ and ATP levels, while EPB41L4A-AS1 overexpression and nicotinamide riboside treatment could restore the NAD+ and ATP levels. Conclusions Downregulation of EPB41L4A-AS1 not only disturbs NAD+ biosynthesis but also affects ATP synthesis. As a result, the high demand for NAD+ and ATP in the brain cannot be met, promoting the development of brain aging and neurodegenerative diseases. However, overexpression of EPB41L4A-AS1 and nicotinamide riboside, a substrate of NAD+ synthesis, can reduce EPB41L4A-AS1 downregulation-mediated decrease of NAD+ and ATP synthesis. Our results provide new perspectives on the mechanisms underlying brain aging and neurodegenerative diseases.

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“…EPB41L4A-AS1 was rst reported as a protein-coding gene, named TIGA1 related to cell proliferation [9], but now it is found that EPB41L4A-AS1 mainly functions as a lncRNA which is associated with cell metabolism and immune response [7,10,11]. In cancer cells, downregulation of EPB41L4A-AS1 induces glutamine dependency and promotes glycolysis [7].…”

Section: Introductionmentioning

confidence: 99%

“…In placental trophoblast cells, the downregulation of EPB41L4A-AS1 inhibits the Warburg effect which is needed for fast growth of placental trophoblast cells and causes recurrent miscarriage [10]. Furthermore, down-regulation of EPB41L4A-AS1 can activate the MYD88-Dependent NF-κB pathway in diabetes-related in ammation [11].…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of EPB41L4A-AS1 mediated the brain aging and neurodegenerative diseases via damaging synthesis of NAD+ and ATP

Yang

Wang

Liao

et al. 2021

Preprint

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Background: Long noncoding RNA EPB41L4A-AS1 plays a very important role in metabolism. Aging and neurodegenerative diseases are typical metabolic-related processes. As a metabolism-related lncRNA, EPB41L4A-AS may be involved in the development of brain aging and neurodegenerative diseases. In this study, we aim to reveal the mechanism of EPB41L4A-AS in aging and neurodegenerative diseases.Methods: Age-related differential expression analysis was applied on the gene expression profile of the hippocampus in the Genotype-Tissue Expression database to obtain age-related differentially expressed genes and the weighted correlation network analysis algorithm was used to construct a gene co-expression network for age-related differentially expressed genes to obtain different gene clustering modules. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, protein-protein interaction network, and correlation analysis were used to reveal the mechanism of EPB41L4A-AS1. The mechanism was verified using Gene Expression Omnibus profile GSE5281 and biology experiments (construction of cell lines, Real-time quantitative PCR, Western blot, measurement of ATP and NAD+ levels, nicotinamide riboside treatment, Chromatin Immunoprecipitation) in neurons and glial-derived cells.Results: EPB41L4A-AS1 is down-regulated in aging and Alzheimer’s disease. EPB41L4A-AS1 related genes are genes of the electron transport chain and NAD+ synthesis pathway. Furthermore, these genes are highly related to neurodegenerative diseases and EPB41L4A-AS1 has a positive correlation with them. In addition, biology experiments proved that the down-regulation of EPB41L4A-AS1 can reduce the expression of these genes via modification of the acetylation of lysine 27 on histone 3, resulting in the down-regulation of NAD+ and ATP levels, while the overexpression of EPB41L4A-AS1 and nicotinamide riboside treatment can restore the levels of NAD+ and ATP.Conclusions: Down-regulation of EPB41L4A-AS1 not only disturbs NAD+ biosynthesis but also affects ATP production. As a result, the high demand of brain for NAD+ and ATP can not be met, which promotes the development of brain aging and neurodegenerative diseases. However, overexpression of EPB41L4A-AS1 and nicotinamide riboside, a substrate of NAD+ synthesis, can reduce EPB41L4A-AS1 down-regulation mediated decrease of NAD+ and ATP synthesis. Our results provide a new perspective on brain aging and neurodegenerative diseases.

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Downregulation of lncRNA EPB41L4A-AS1 Mediates Activation of MYD88-Dependent NF-κB Pathway in Diabetes-Related Inflammation

Cited by 15 publications

References 33 publications

Molecular Mechanisms and Functions of lncRNAs in the Inflammatory Reaction of Diabetes Mellitus

Molecular Mechanisms and Functions of lncRNAs in the Inflammatory Reaction of Diabetes Mellitus

Down-regulation of EPB41L4A-AS1 mediated the brain aging and neurodegenerative diseases via damaging synthesis of NAD+ and ATP

Down-regulation of EPB41L4A-AS1 mediated the brain aging and neurodegenerative diseases via damaging synthesis of NAD+ and ATP

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