A module of multifactor‐mediated dysfunction guides the molecular typing of coronary heart disease

Li, Yuewei; Mei, Lin; Wang, Kangjie; Zhan, Ya-Qing; Gu, Wenli; Gao, Guanghao; Huang, Yuna; Chen, Yangxin; Huang, Tao; Wang, Jingfeng

doi:10.1002/mgg3.1415

Cited by 5 publications

(4 citation statements)

References 27 publications

(30 reference statements)

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“…It should be noted that hyporesponsiveness of the immune system and an anti-inflammatory effects were suggested upon activation of HCAR3 [47,48]. It was also indicated that HCAR3 could be involved in sepsis [49] and coronary heart disease [50]. A single study identified HCAR3 as a potential target in colorectal cancer [51].…”

Section: Discussionmentioning

confidence: 99%

Alterations in Kynurenine and NAD+ Salvage Pathways during the Successful Treatment of Inflammatory Bowel Disease Suggest HCAR3 and NNMT as Potential Drug Targets

Wnorowski

Wnorowska

Kurzepa

et al. 2021

IJMS

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A meta-analysis of publicly available transcriptomic datasets was performed to identify metabolic pathways profoundly implicated in the progression and treatment of inflammatory bowel disease (IBD). The analysis revealed that genes involved in tryptophan (Trp) metabolism are upregulated in Crohn’s disease (CD) and ulcerative colitis (UC) and return to baseline after successful treatment with infliximab. Microarray and mRNAseq profiles from multiple experiments confirmed that enzymes responsible for Trp degradation via the kynurenine pathway (IDO1, KYNU, IL4I1, KMO, and TDO2), receptor of Trp metabolites (HCAR3), and enzymes catalyzing NAD+ turnover (NAMPT, NNMT, PARP9, CD38) were synchronously coregulated in IBD, but not in intestinal malignancies. The modeling of Trp metabolite fluxes in IBD indicated that changes in gene expression shifted intestinal Trp metabolism from the synthesis of 5-hydroxytryptamine (5HT, serotonin) towards the kynurenine pathway. Based on pathway modeling, this manifested in a decline in mucosal Trp and elevated kynurenine (Kyn) levels, and fueled the production of downstream metabolites, including quinolinate, a substrate for de novo NAD+ synthesis. Interestingly, IBD-dependent alterations in Trp metabolites were normalized in infliximab responders, but not in non-responders. Transcriptomic reconstruction of the NAD+ pathway revealed an increased salvage biosynthesis and utilization of NAD+ in IBD, which normalized in patients successfully treated with infliximab. Treatment-related changes in NAD+ levels correlated with shifts in nicotinamide N-methyltransferase (NNMT) expression. This enzyme helps to maintain a high level of NAD+-dependent proinflammatory signaling by removing excess inhibitory nicotinamide (Nam) from the system. Our analysis highlights the prevalent deregulation of kynurenine and NAD+ biosynthetic pathways in IBD and gives new impetus for conducting an in-depth examination of uncovered phenomena in clinical studies.

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Section: Discussionmentioning

confidence: 99%

Alterations in Kynurenine and NAD+ Salvage Pathways during the Successful Treatment of Inflammatory Bowel Disease Suggest HCAR3 and NNMT as Potential Drug Targets

Wnorowski

Wnorowska

Kurzepa

et al. 2021

IJMS

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“…Ferritin heavy chain 1 (FTH1), a major intracellular iron storage protein, is a substrate of ferroptosis, which emerges to play vital roles in coronary atherosclerotic heart disease [ 7 ]. Li et al have reported that FTH1 is significantly up-regulated in blood samples of coronary atherosclerotic heart disease patients [ 33 ]. HIF1A rs2057482 polymorphism is related to the occurrence of coronary heart disease and some metabolic parameters and cardiovascular risk factors [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Construction and validation of molecular subtypes of coronary artery disease based on ferroptosis-related genes

Ding¹,

Long²,

An³

et al. 2022

BMC Cardiovasc Disord

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Background This study aims to construct a reliable diagnostic model for coronary artery disease (CAD) patients and explore its potential mechanism by consensus molecular subtypes of ferroptosis-related genes. Methods GSE12288 and GSE20680 were downloaded from Gene Expression Omnibus database. CAD patients were divided into different molecular subtypes according to the expression level of ferroptosis-related genes. Then, the distribution of differentially expressed genes, functional annotations and immune infiltration cells between the two subtypes were compared. Finally, a prognostic model of ferroptosis-related genes in CAD was constructed and verified. Results Two different molecular subtypes of CAD were obtained according to the expression level of ferroptosis-related genes. Then, a total of 1944 differentially expressed genes (DEGs) were found, among which, 236 genes were up-regulated and 1708 genes were down-regulated. In addition, 43 DEGs were ferroptosis-related genes. Functional enrichment analysis showed that these DEGs between two subtypes of CAD were mainly enriched in immune-related pathways and processes, such as T cell receptor, mTOR, NOD-like receptor and Toll-like receptor signaling pathways. We also found that 21 immune cells were significantly changed between two subtypes of CAD. The LASSO method was performed to identify and construct the 16 ferroptosis-related genes-based diagnostic signature. Diagnostic efficiency of diagnostic signature measured by AUC in the training set and validation cohort was 0.971 and 0.899, respectively. Conclusions This study contributes to a more comprehensive understanding of the mechanism of ferroptosis-related genes in CAD.

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“…As a bioinformatics approach, WGCNA was utilized to create a scale-free network according to gene expression profiles [ 13 ]. All genes in a module are groups of genes with similar patterns of expression [ 14 ].…”

Section: Methodsmentioning

confidence: 99%

Identification and validation of glomerulotubular crosstalk genes mediating IgA nephropathy by integrated bioinformatics

Bai

2022

BMC Nephrol

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Background IgA nephropathy (IgAN), which has been reported as the most prevalent glomerulonephritis globally, is the major contributor to end-stage renal diseases. This bioinformatics study aimed to explore glomerulotubular crosstalk genes and dysregulated pathways relating to the pathogenesis of IgAN. Methods The microarray datasets from the Gene Expression Omnibus (GEO) database were searched. Weighted gene co-expression network analysis (WGCNA) and differentially expressed genes (DEGs) of both glomeruli and tubulointerstitium were conducted individually. The co-expression gene modules of glomeruli and tubulointerstitium were compared via gene function enrichment analysis. Subsequently, the crosstalk co-expression network was constructed via the STRING database and key genes were mined from the crosstalk network. Finally, key genes were validated using another GEO dataset (GSE99340) containing RNA-seq data of IgAN and lupus nephritis, and their potential diagnostic values were shown using receiver operating characteristic (ROC) analysis. Results Five hundred eighty-three DEGs and eight modules were identified in glomerular samples, while 272 DEGs and four modules were in tubulointerstitial samples. There were 119 overlapping DEGs between the two groups. Among the distinctive modules, four modules in glomeruli and one module in tubulointerstitium were positively associated with IgAN. While four modules in glomeruli and two modules in tubulointerstitium were negatively associated with IgAN. The top ten key genes screened by CytoHubba were ITGAM, ALB, TYROBP, ITGB2, CYBB, HCK, CSF1R, LAPTM5, FN1, and CTSS. Compared with lupus nephritis, there were significant differences in the expression levels of CYBB, CTSS and TYROBP (P < 0.05), while other key genes showed no significant difference. Meanwhile, CYBB, CTSS, and TYROBP demonstrated possible diagnostic significance. Conclusions The crosstalk genes confirmed in this study may provide novel insight into the pathogenesis of IgAN. Immune-related pathways are associated with both glomerular and tubulointerstitial injuries in IgAN. The glomerulotubular crosstalk might perform a role in the pathogenesis of IgAN.

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A module of multifactor‐mediated dysfunction guides the molecular typing of coronary heart disease

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 5 publications

References 27 publications

Alterations in Kynurenine and NAD+ Salvage Pathways during the Successful Treatment of Inflammatory Bowel Disease Suggest HCAR3 and NNMT as Potential Drug Targets

Alterations in Kynurenine and NAD+ Salvage Pathways during the Successful Treatment of Inflammatory Bowel Disease Suggest HCAR3 and NNMT as Potential Drug Targets

Construction and validation of molecular subtypes of coronary artery disease based on ferroptosis-related genes

Identification and validation of glomerulotubular crosstalk genes mediating IgA nephropathy by integrated bioinformatics

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