Role of reactive oxygen species and mitochondrial damage in rheumatoid arthritis and targeted drugs

Jing, Weiyao; Liu, Cui; Chenghong, Su; Limei, Liu; Chen, Ping; Li, Xiangjun; Xinghua, Zhang; Yuan, Bo; Wang, Haidong; Xiaozheng, Du

doi:10.3389/fimmu.2023.1107670

Cited by 45 publications

(29 citation statements)

References 304 publications

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“…This endoplasmic reticulum stress may promote the progression of RA through the proliferation of synovial cells and the production of pro-inflammatory cytokines ( de Seabra Rodrigues Dias et al, 2021 ; Floudas et al, 2022 ; Miglioranza Scavuzzi and Holoshitz, 2022 ). Wulf et al pointed out that oxidative stress in mitochondria can produce many reactive oxygen species (ROS) ( Jing et al, 2023 ). At high concentrations, free radicals and their derivatives are harmful to the organism and destroy all the main components of the cell.…”

Section: Discussionmentioning

confidence: 99%

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RETRACTED: Bioinformatics analysis based on crucial genes of endothelial cells in rheumatoid

Zhou

2023

Front. Genet.

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Objectives: Synovial neovascularization is an early and remarkable event that promotes the development of rheumatoid arthritis (RA) synovial hyperplasia. This study aimed to find potential diagnostic markers and molecular therapeutic targets for RA at the mRNA molecular level.Method: We download the expression profile dataset GSE46687 from the gene expression ontology (GEO) microarray, and used R software to screen out the differentially expressed genes between the normal group and the disease group. Then we performed functional enrichment analysis, used the STRING database to construct a protein-protein interaction (PPI) network, and identify candidate crucial genes, infiltration of the immune cells and targeted molecular drug.Results: Rheumatoid arthritis datasets included 113 differentially expressed genes (DEGs) including 104 upregulated and 9 downregulated DEGs. The enrichment analysis of genes shows that the differential genes are mainly enriched in condensed chromosomes, ribosomal subunits, and oxidative phosphorylation. Through PPI network analysis, seven crucial genes were identified: RPS13, RPL34, RPS29, RPL35, SEC61G, RPL39L, and RPL37A. Finally, we find the potential compound drug for RA.Conclusion: Through this method, the pathogenesis of RA endothelial cells was further explained. It provided new therapeutic targets, but the relationship between these genes and RA needs further research to be validated in the future.

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Section: Discussionmentioning

confidence: 99%

“…This Floudas et al, 2022;Miglioranza Scavuzzi and Holoshitz, 2022). Wulf et al pointed out that oxidative stress in mitochondria can produce many reactive oxygen species (ROS) (Jing et al, 2023). At high concentrations, free radicals and their derivatives are harmful to the organism and destroy all the main components of the cell.…”

Section: Figurementioning

confidence: 99%

RETRACTED: Bioinformatics analysis based on crucial genes of endothelial cells in rheumatoid

Zhou

2023

Front. Genet.

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“…We all know that oxidative stress is associated with inflammation and both factors are closely linked to RA, oxidative stress affects immune cell metabolic processes and promotes inflammation in RA, 15 Therefore, some traditional medications operate through a new mechanism of inhibiting oxidative stress and increasing antioxidants to alleviate clinical symptoms in patients with RA 16 . The results of our study demonstrated elevated MDA expression and significantly decreased SOD and TAOC expression in the serum of RA patients, suggesting an imbalance of oxidative homeostasis and immune inflammatory response in RA patients.…”

Section: Discussionmentioning

confidence: 99%

Exploring the effect of LncRNA DANCR to regulate the Keap1‐Nrf2/ARE pathway on oxidative stress in rheumatoid arthritis

Cai,

Sun,

Wang

et al. 2024

Immunity Inflam & Disease

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IntroductionAberrant expression of long noncoding RNAs (LncRNAs) can regulate oxidative stress in rheumatoid arthritis (RA). This study focused on investigating the effects of LncRNA differentiation antagonizing nonprotein coding RNA (DANCR) regulation of Keap1‐Nrf2/ARE pathway on inflammation and oxidative stress in RA.MethodsThe levels of LncRNA DANCR/miR‐486‐3p/Keap1 in peripheral blood of 30 RA groups and 30 normal subjects were examined, and the association of LncRNA DANCR with inflammatory indicators of RA was investigated. We stimulated fibroblast‐like synoviocytes (FLS) from RA patients with tumor necrosis factor α and subsequently performed in vitro cellular assays to construct overexpression plasmids and small interfering RNAs of LncRNA DANCR to investigate the relationship between LncRNA DANCR and FLSs viability and migration in RA, as well as the effects on cellular oxidative stress factors and Keap1‐Nrf2/ARE pathway; molecular biology analysis was used to predict microRNAs that can bind LncRNA DANCR, and luciferase verified the binding sites of LncRNA DANCR with Keap1 and miR‐486‐3p; to further refine the gene and protein expression results, we used reverse transcription‐quantitative polymerase chain reaction and immunoblotting assays.ResultsIn both groups of peripheral blood mononuclear cells, the expression levels of LncRNA DANCR and Keap1 messenger RNA were higher in the RA group than in the normal control group, and the opposite was true for miR‐486‐3p; LncRNA DANCR was positively correlated with total antioxidant capacity (TAOC), IL6, IL17, malondialdehyde (MDA), but not with IL11, rheumatoid factor, cyclic citrullinated peptide, superoxide dismutase (SOD), with 28‐joint disease activity score, reactive oxygen species, C‐reactive protein, and erythrocyte sedimentation rate were negatively correlated; overexpression of LncRNA DANCR stimulated the Keap1‐Nrf2/ARE pathway, decreased the expression of IL10, SOD, TAOC, and increased the expression levels of MDA, IL11, IL‐17, PD‐L1, and silencing of LncRNA DANCR was the opposite, but knockdown of miR‐486‐3p or overexpression of keap1 reversed the expression of the above‐mentioned inflammatory and oxidative factors. In addition, pcDNA‐DANCR clearly showed stronger cell invasion and migration ability and exacerbated its inflammatory response, which may be related to the regulatory role of miR‐486‐3p and Keap1‐Nrf2/ARE signaling pathway, and we verified their targeting relationship using dual luciferase, showing that DANCR could regulate Keap1‐Nrf2/ARE through miR‐486‐3p modulates the Keap1‐Nrf2/ARE pathway and affects inflammatory and oxidative responses in RA patients.ConclusionThe low‐expressed LncRNA DANCR may regulate the Keap1‐Nrf2/ARE pathway and suppress the inflammatory and oxidative responses in RA patients.

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“…6 Fibroblast-like synoviocytes (FLS) are the primary effect cells sustaining joint inflammation, angiogenesis, and cartilage destruction. 7 During RA activity, FLS produces a multitude of angiogenic factors, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which pathologically alter endothelial cell activity and promote joint angiogenesis. This exacerbates RA severity by contributing to synovial hyperplasia and inflammation.…”

Section: Introductionmentioning

confidence: 99%

“…Angiogenesis is crucial for various physiological processes, including embryonic development, wound healing, and tissue regeneration, as well as pathophysiological conditions like cancer and inflammation 6 . Fibroblast‐like synoviocytes (FLS) are the primary effect cells sustaining joint inflammation, angiogenesis, and cartilage destruction 7 . During RA activity, FLS produces a multitude of angiogenic factors, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which pathologically alter endothelial cell activity and promote joint angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

LncRNA HOTAIR regulates the PI3K/AKT pathway via the miR‐126‐3p/PIK3R2 axis to participate in synovial angiogenesis in rheumatoid arthritis

Liu,

Wang,

Huang

et al. 2023

Immunity Inflam & Disease

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BackgroundThe abnormal expression of long noncoding RNA (LncRNA) HOTAIR has been associated with synovial angiogenesis in rheumatoid arthritis (RA). The aim of this study is to investigate whether LncRNA HOTAIR plays a role in synovial angiogenesis in RA by regulating the phosphoinositide 3‐kinase/protein kinase B (PI3K/AKT) pathway through the miR‐126‐3p/PIK3R2 axis.MethodsIn this study, we conducted in vitro experiments by designing overexpression plasmids and small interfering RNAs targeting LncRNA HOTAIR and then transfected them into rheumatoid arthritis fibroblast‐like synoviocytes (RA‐FLS). We then co‐cultured the RA‐FLS with human umbilical vein endothelial cells (HUVEC) to establish a RA‐FLS‐induced HUVEC model. We investigated the effects of LncRNA HOTAIR on the proliferation, migration, lumen forming ability of HUVEC, as well as the expression of synovial endothelial cell markers, angiogenic factors, and the PI3K/AKT pathway. To validate the interactions between LncRNA HOTAIR, miR‐126‐3p, and PIK3R2, we used bioinformatics and luciferase reporter experiments. We also employed real‐time fluorescence quantitative, Western blotanalysis, and immunofluorescence techniques to analyze the target genes and proteins.ResultsThe expression of LncRNA HOTAIR was upregulated in HUVEC induced by RA‐FLS. The overexpression of LncRNA HOTAIR significantly increased the expression of vascular endothelial growth factor, basic fibroblast growth factor, CD34, and CD105 in HUVEC, promoting their proliferation, migration, and lumen formation. At the same time, the overexpression of LncRNA HOTAIR inhibited the expression of miR‐126‐3p, promoted the expression of PIK3R2, activated the PI3K/AKT pathway, and promoted the expression of PI3K, AKT and phosphorylated‐AKT, while the silence of LncRNA HOTAIR reversed these expressions. Bioinformatics and double luciferase reporter gene experiments confirmed the targeting relationship among LncRNA HOTAIR, miR‐126‐3p, and PIK3R2. Finally, the rescue experiments showed that PI3K agonists could reverse the inhibitory effect of silent LncRNA HOTAIR on HUVEC.ConclusionLncRNA HOTAIR has the potential to activate the PI3K/AKT pathway, likely through the regulatory axis involving miR‐126‐3p/PIK3R2, consequently contributing to synovial angiogenesis in RA.

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Role of reactive oxygen species and mitochondrial damage in rheumatoid arthritis and targeted drugs

Cited by 45 publications

References 304 publications

RETRACTED: Bioinformatics analysis based on crucial genes of endothelial cells in rheumatoid

RETRACTED: Bioinformatics analysis based on crucial genes of endothelial cells in rheumatoid

Exploring the effect of LncRNA DANCR to regulate the Keap1‐Nrf2/ARE pathway on oxidative stress in rheumatoid arthritis

LncRNA HOTAIR regulates the PI3K/AKT pathway via the miR‐126‐3p/PIK3R2 axis to participate in synovial angiogenesis in rheumatoid arthritis

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