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1.
J Periodontal Res ; 59(1): 104-118, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37971162

RESUMO

BACKGROUND AND OBJECTIVE: Atrial fibrillation (AF) and periodontitis, both classified under chronic inflammatory diseases, share common etiologies, including genetic factors and immune pathways. However, the exact mechanisms are still poorly understood. This study aimed to explore the potential common genes and immune characteristics between AF and periodontitis. METHODS: Gene expression datasets for AF and periodontitis were downloaded from the Gene Expression Omnibus (GEO) database. Differential expression analysis was used to identify common genes in the training set. Functional analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, were conducted to elucidate the underlying mechanisms. Hub genes were further screened based on expression levels, receiver operating characteristic (ROC) curves, and least absolute shrinkage and selection operator (LASSO) regression. Then, based on the expression levels and ROC values of the hub genes in the validation set, the target genes were identified. Finally, immune cell infiltration analysis was performed on the AF and periodontitis datasets in the training set using the "CIBERSORT" R package. The relationships between target genes, infiltrating immune cells, and inflammatory factors were also investigated. In addition, AF susceptibility, atrial fibrosis, inflammatory infiltration, and RGS1 protein expression in rat models of periodontitis were assessed through in vivo electrophysiology experiments, Masson's trichrome staining, hematoxylin-eosin staining, immunohistochemistry, and western blotting, respectively. RESULTS: A total of 21 common genes were identified between AF and periodontitis among the differentially expressed genes. After evaluating gene expression levels, ROC curves, and LASSO analysis, four significant genes between AF and periodontitis were identified, namely regulator of G-protein signaling 1 (RGS1), annexin A6 (ANXA6), solute carrier family 27 member 6 (SLC27A6), and ficolin 1 (FCN1). Further validation confirmed that RGS1 was the optimal shared target gene for AF and periodontitis. Immune cell infiltration analysis revealed that neutrophils and T cells play an important role in the pathogenesis of both diseases. RGS1 showed a significant positive correlation with activated memory CD4 T cells and gamma-delta T cells and a negative correlation with CD8 T cells and regulatory T cells in both training sets. Moreover, RGS1 was positively correlated with classical pro-inflammatory cytokines IL1ß and IL6. In periodontitis rat models, AF susceptibility, atrial fibrosis, and inflammatory infiltration were significantly increased, and RGS1 expression in the atrial tissue was upregulated. CONCLUSION: A common gene between AF and periodontitis, RGS1 appears central in linking the two conditions. Immune and inflammatory responses may underlie the interaction between AF and periodontitis.


Assuntos
Fibrilação Atrial , Animais , Ratos , Fibrilação Atrial/genética , Western Blotting , Linfócitos T CD8-Positivos , Biologia Computacional , Fibrose
2.
Int Immunopharmacol ; 138: 112550, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-38941671

RESUMO

BACKGROUND: Sepsis is considered a high risk factor for new-onset atrial fibrillation (NOAF), with neutrophil extracellular traps (NETs) being implicated in the pathogenesis of numerous diseases. However, the precise role of NETs and NETs-related genes (NRGs) in the occurrence of NOAF in sepsis remains inadequately elucidated. The objective of this study was to identify hub NRGs connecting sepsis and AF, and to investigate the potential association between NETs and NOAF in sepsis. METHODS: The AF and sepsis microarray datasets were retrieved from the Gene Expression Omnibus (GEO) database for analysis of shared pathophysiological mechanisms and NRGs implicated in both sepsis and AF using bioinformatics techniques. The CIBERSORT algorithm was employed to assess immune cell infiltration and identify common immune characteristics in these diseases. Additionally, a rat model of lipopolysaccharide (LPS)-induced sepsis was utilized to investigate the association between NETs, NRGs, and sepsis-induced AF. Western blotting, enzyme-linked immunosorbent assay, hematoxylin-eosin staining, immunohistochemistry, and immunofluorescence were employed to assess the expression of NRGs, the formation of NETs, and the infiltration of neutrophils. Electrophysiological analysis and multi-electrode array techniques were utilized to examine the vulnerability and conduction heterogeneity of AF in septic rats. Furthermore, intervention was conducted in LPS-induced sepsis rats using DNase I, a pharmacological agent that specifically targets NETs, in order to assess its impact on neutrophil infiltration, NETs formation, hub NRGs protein expression, and AF vulnerability. RESULTS: A total of 61 commonly differentially expressed genes (DEGs) and four hub DE-NRGs were identified in the context of sepsis and AF. Functional enrichment analysis revealed that these DEGs were predominantly associated with processes related to inflammation and immunity. Immune infiltration analysis further demonstrated the presence of immune infiltrating cells, specifically neutrophil infiltration, in both sepsis and AF. Additionally, a positive correlation was observed between the relative expression of the four hub DE-NRGs and neutrophil infiltration. In rats with LPS-induced sepsis, we observed a notable upregulation in the expression of four DE-NRGs, the formation of NETs, and infiltration of neutrophils in atrial tissue. Through electrophysiological assessments, we identified heightened vulnerability to AF, reduced atrial surface conduction velocity, and increased conduction heterogeneity in LPS-induced sepsis rats. Notably, these detrimental effects can be partially ameliorated by treatment with DNase I. CONCLUSIONS: Through bioinformatics analysis and experimental validation, we identified four hub NRGs in sepsis and AF. Subsequent experiments indicated that the formation of NETs in the atria may contribute to the pathogenesis of NOAF in sepsis. These discoveries offer potential novel targets and insights for the prevention and treatment of NOAF in sepsis.


Assuntos
Fibrilação Atrial , Armadilhas Extracelulares , Lipopolissacarídeos , Neutrófilos , Ratos Sprague-Dawley , Sepse , Animais , Armadilhas Extracelulares/imunologia , Sepse/imunologia , Sepse/genética , Fibrilação Atrial/genética , Fibrilação Atrial/imunologia , Fibrilação Atrial/induzido quimicamente , Ratos , Masculino , Neutrófilos/imunologia , Humanos , Modelos Animais de Doenças , Desoxirribonuclease I/metabolismo , Desoxirribonuclease I/genética
3.
J Zhejiang Univ Sci B ; 24(7): 632-649, 2023 Jul 15.
Artigo em Inglês, Zh | MEDLINE | ID: mdl-37455139

RESUMO

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia seen in clinical settings, which has been associated with substantial rates of mortality and morbidity. However, clinically available drugs have limited efficacy and adverse effects. We aimed to investigate the mechanisms of action of andrographolide (Andr) with respect to AF. We used network pharmacology approaches to investigate the possible therapeutic effect of Andr. To define the role of Andr in AF, HL-1 cells were pro-treated with Andr for 1 h before rapid electronic stimulation (RES) and rabbits were pro-treated for 1 d before rapid atrial pacing (RAP). Apoptosis, myofibril degradation, oxidative stress, and inflammation were determined. RNA sequencing (RNA-seq) was performed to investigate the relevant mechanism. Andr treatment attenuated RAP-induced atrial electrophysiological changes, inflammation, oxidative damage, and apoptosis both in vivo and in vitro. RNA-seq indicated that oxidative phosphorylation played an important role. Transmission electron microscopy and adenosine triphosphate (ATP) content assay respectively validated the morphological and functional changes in mitochondria. The translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus and the molecular docking suggested that Andr might exert a therapeutic effect by influencing the Keap1-Nrf2 complex. In conclusions, this study revealed that Andr is a potential preventive therapeutic drug toward AF via activating the translocation of Nrf2 to the nucleus and the upregulation of heme oxygenase-1 (HO-1) to promote mitochondrial bioenergetics.


Assuntos
Fibrilação Atrial , Animais , Coelhos , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/prevenção & controle , Fibrilação Atrial/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Transdução de Sinais , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/farmacologia , Simulação de Acoplamento Molecular , Estresse Oxidativo , Metabolismo Energético , Mitocôndrias/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Heme Oxigenase-1
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