Chemically modified small interfering RNA targeting Hedgehog signaling pathway for rheumatoid arthritis therapy

Lin, Lang; Zhu, Shangling; Huang, Hongyu; Wu, Lin-Ping; Huang, Jianlin

doi:10.1016/j.omtn.2022.12.008

Cited by 5 publications

(3 citation statements)

References 57 publications

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“…The hedgehog signaling pathway is a highly conserved pathway that plays a critical role in embryonic development [ 34 , 35 ]. The study provided evidence that the utilization of chemically modified siRNA (si-S1A3-Chol) that targets the Hedgehog signaling pathway could serve as a promising therapeutic approach for RA44 [ 36 ]. Furthermore, the administration of Anti-TNFα treatment was found to reduce the elevated levels of serum Indian Hedgehog in individuals with ankylosing spondylitis and impact the expression of Hedgehog pathway target genes with functional significance [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

A compendium of mitochondrial molecular characteristics provides novel perspectives on the treatment of rheumatoid arthritis patients

Wang,

Gao,

Wang

et al. 2023

J Transl Med

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Rheumatoid arthritis (RA) is an autoimmune disease that exhibits a high degree of heterogeneity, marked by unpredictable disease flares and significant variations in the response to available treatments. The lack of optimal stratification for RA patients may be a contributing factor to the poor efficacy of current treatment options. The objective of this study is to elucidate the molecular characteristics of RA through the utilization of mitochondrial genes and subsequently construct and authenticate a diagnostic framework for RA. Mitochondrial proteins were obtained from the MitoCarta database, and the R package limma was employed to filter for differentially expressed mitochondrial genes (MDEGs). Metascape was utilized to perform enrichment analysis, followed by an unsupervised clustering algorithm using the ConsensuClusterPlus package to identify distinct subtypes based on MDEGs. The immune microenvironment, biological pathways, and drug response were further explored in these subtypes. Finally, a multi-biomarker-based diagnostic model was constructed using machine learning algorithms. Utilizing 88 MDEGs present in transcript profiles, it was possible to classify RA patients into three distinct subtypes, each characterized by unique molecular and cellular signatures. Subtype A exhibited a marked activation of inflammatory cells and pathways, while subtype C was characterized by the presence of specific innate lymphocytes. Inflammatory and immune cells in subtype B displayed a more modest level of activation (Wilcoxon test P < 0.05). Notably, subtype C demonstrated a stronger correlation with a superior response to biologics such as infliximab, anti-TNF, rituximab, and methotrexate/abatacept (P = 0.001) using the fisher test. Furthermore, the mitochondrial diagnosis SVM model demonstrated a high degree of discriminatory ability in distinguishing RA in both training (AUC = 100%) and validation sets (AUC = 80.1%). This study presents a pioneering analysis of mitochondrial modifications in RA, offering a novel framework for patient stratification and potentially enhancing therapeutic decision-making.

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Section: Discussionmentioning

confidence: 99%

A compendium of mitochondrial molecular characteristics provides novel perspectives on the treatment of rheumatoid arthritis patients

Wang,

Gao,

Wang

et al. 2023

J Transl Med

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“…Rheumatoid arthritis (RA) is a prevalent inflammatory autoimmune disorder distinguished by inflammation of the synovium and resultant joint damage 1 . Activated fibroblastic synoviocytes (FLS), and inflammatory and oxidative factors are found to be involved in the inflammatory mechanisms of RA during the bone destruction and synovitis of RA 2 . Oxidative stress generates excessive free radicals that oxidize other molecules in the body, for example, excessive free radicals in RA patients reduce the antioxidant level of the body and accelerate the progression of bone destruction 3 .…”

Section: Introductionmentioning

confidence: 99%

“… 1 Activated fibroblastic synoviocytes (FLS), and inflammatory and oxidative factors are found to be involved in the inflammatory mechanisms of RA during the bone destruction and synovitis of RA. 2 Oxidative stress generates excessive free radicals that oxidize other molecules in the body, for example, excessive free radicals in RA patients reduce the antioxidant level of the body and accelerate the progression of bone destruction. 3 We demonstrated that the low expression of LINC00638 regulates the Nrf2/HO‐1 signaling pathway, triggering inflammation in RA and influencing its oxidative stress response.…”

Section: Introductionmentioning

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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Overcoming delivery barriers for RNA therapeutics in the treatment of rheumatoid arthritis

Zhang,

Li,

Jiang

et al. 2023

European Journal of Pharmaceutics and Biopharmaceutics

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Chemically modified small interfering RNA targeting Hedgehog signaling pathway for rheumatoid arthritis therapy

Cited by 5 publications

References 57 publications

A compendium of mitochondrial molecular characteristics provides novel perspectives on the treatment of rheumatoid arthritis patients

A compendium of mitochondrial molecular characteristics provides novel perspectives on the treatment of rheumatoid arthritis patients

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

Overcoming delivery barriers for RNA therapeutics in the treatment of rheumatoid arthritis

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