NGS study of glucocorticoids response genes in inflammatory bowel disease patients

Skrzypczak-Zielińska, Marzena; Gabryel, Marcin; Marszalek, Daria; Dobrowolska, Agnieszka; Słomski, Ryszard

doi:10.5114/aoms.2019.84470

Cited by 9 publications

(9 citation statements)

References 40 publications

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“…Another study showed that the combination of glucocorticoid receptor (GR) and FKBP5 (the cg25114611 annotated to the FKBP5 gene) mutational analyses could help to identify subgroups of CD with higher chances of benefitting from glucocorticoid treatment ( Maltese et al, 2012 ). FKBP5 revealed a significant impact on the glucocorticoid treatment response, which could result in valuable pharmacogenetic biomarkers after being confirmed in other populations and in functional studies ( Skrzypczak-Zielinska et al, 2021 ). In addition, Tobi et al (2018) illustrated that DNA methylation acted as a mediator of the association between prenatal adversity and risk factors for metabolic disease, and it has been shown that methylation of cg09349128 was associated with the expression of PIM3, a gene implicated in cell growth and energy metabolism ( Beharry et al, 2011 ) and glucose-stimulated insulin secretion in β cells ( Vlacich et al, 2010 ).…”

Section: Discussionmentioning

confidence: 94%

High-Dimensional DNA Methylation Mediates the Effect of Smoking on Crohn’s Disease

Wang

Xia

2022

Front. Genet.

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Epigenome-wide mediation analysis aims to identify high-dimensional DNA methylation at cytosine–phosphate–guanine (CpG) sites that mediate the causal effect of linking smoking with Crohn’s disease (CD) outcome. Studies have shown that smoking has significant detrimental effects on the course of CD. So we assessed whether DNA methylation mediates the association between smoking and CD. Among 103 CD cases and 174 controls, we estimated whether the effects of smoking on CD are mediated through DNA methylation CpG sites, which we referred to as causal mediation effect. Based on the causal diagram, we first implemented sure independence screening (SIS) to reduce the pool of potential mediator CpGs from a very large to a moderate number; then, we implemented variable selection with de-sparsifying the LASSO regression. Finally, we carried out a comprehensive mediation analysis and conducted sensitivity analysis, which was adjusted for potential confounders of age, sex, and blood cell type proportions to estimate the mediation effects. Smoking was significantly associated with CD under odds ratio (OR) of 2.319 (95% CI: 1.603, 3.485, p < 0.001) after adjustment for confounders. Ninety-nine mediator CpGs were selected from SIS, and then, seven candidate CpGs were obtained by de-sparsifying the LASSO regression. Four of these CpGs showed statistical significance, and the average causal mediation effects (ACME) were attenuated from 0.066 to 0.126. Notably, three significant mediator CpGs had absolute sensitivity parameters of 0.40, indicating that these mediation effects were robust even when the assumptions were slightly violated. Genes (BCL3 and FKBP5) harboring these four CpGs were related to CD. These findings suggest that changes in methylation are involved in the mechanism by which smoking increases risk of CD.

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Section: Discussionmentioning

confidence: 94%

High-Dimensional DNA Methylation Mediates the Effect of Smoking on Crohn’s Disease

Wang

Xia

2022

Front. Genet.

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“…In the present study, construction of the drug–compound–target–disease and PPI networks showed that the HSP90AA1 gene was the key intersecting gene between both. This gene was found to be associated with the glucocorticoid response and severity of fatigue in patients with CD ( Grimstad et al, 2020 ; Skrzypczak-Zielinska et al, 2021 ). Molecular docking showed that the protein encoded by the HSP90AA1 gene bound to aureusidin, the bioactive compound of P. chinensis , which had various anti-inflammatory effects on inflammation-related diseases ( Ren et al, 2020 ; Yang et al, 2020 ; Yang et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacology-Based Strategy to Identify the Pharmacological Mechanisms of Pulsatilla Decoction against Crohn’s Disease

et al. 2022

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Purpose: To explore pharmacological mechanisms of Pulsatilla decoction (PD) against Crohn’s disease (CD) via network pharmacology analysis followed by experimental validation.Methods: Public databases were searched to identify bioactive compounds and related targets of PD as well as related genes in patients with CD. Analyses using the drug–compound–target–disease network, the protein–protein interaction (PPI) network, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to predict the core targets and pathways of PD against CD. Colon tissue resected from patients with CD and tissue samples from a mouse model of CD fibrosis treated with PD were assessed to verify the major targets of PD in CD predicted by network pharmacologic analysis.Results: A search of the targets of bioactive compounds in PD and targets in CD identified 134 intersection targets. The target HSP90AA1, which was common to the drug–compound–target–disease and PPI networks, was used to simulate molecular docking with the corresponding bioactive compound. GO and KEGG enrichment analyses showed that multiple targets in the antifibrotic pathway were enriched and could be experimentally validated in CD patients and in a mouse model of CD fibrosis. Assays of colon tissues from CD patients showed that intestinal fibrosis was greater in stenoses than in nonstenoses, with upregulation of p-AKT, AKT, p-mTOR, mTOR, p-ERK1/2, ERK1/2, p-PKC, and PKC targets. Treatment of CD fibrosis mice with PD reduced the degree of fibrosis, with downregulation of the p-AKT, AKT, p-mTOR, mTOR, p-ERK1/2, ERK1/2, and PKC targets.Conclusion: Network pharmacology analysis was able to predict bioactive compounds in PD and their potential targets in CD. Several of these targets were validated experimentally, providing insight into the pharmacological mechanisms underlying the biological activities of PD in patients with CD.

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“…MAPK14, an isoform of serine/threonine-specific kinase (SAPKs) is a major subfamily of mitogen-activated protein kinase, which plays an important role in TNF-alpha production ( 66 ). Patients with mutated MAPK14 showed adverse therapeutic effects when treated with glucocorticoid, suggesting that MAPK14 is a potential biomarker to predict therapeutic responses ( 67 ). Research has found that UC patients with high MAPK14 expression experience more severe abdominal pain than patients with low MAPK14 expression ( 68 ).…”

Section: Discussionmentioning

confidence: 99%

Hedysarum multijugum Maxim treats ulcerative colitis through the PI3K-AKT and TNF signaling pathway according to network pharmacology and molecular docking

Zhang¹,

Chong²,

Xie³

et al. 2022

Ann Transl Med

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Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) that prevails mainly in western countries. Due to the unknown etiology of UC, the purpose of treatments has predominantly comprised symptomatic and pain relief. With extensive research focusing on the pathogenesis of UC, various novel treatments have emerged, although their efficiency has remained unsatisfactory. Hedysarum multijugum Maxim (HMM), a crucial constituent of traditional Chinese medicine, has a broad application in many diseases and has been found beneficial for UC patients.Methods: In this study, network pharmacology and molecular docking analyses were applied to explore the potential mechanism of HMM treating UC. Active ingredients of HMM and target genes were acquired from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP).UC-related genes were obtained from three disease databases. Common genes were selected from these two gene sets, and a compound-genes network was drawn by Cytoscape. Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO) enrichment, and protein-protein interaction (PPI) analyses were performed to identify the essential pathways and proteins in UC.Results: A total of 121 genes were found related to UC and targeted by HMM. The GO and KEGG analyses showed that these genes were associated with inflammation and immune signaling pathways and inflammation-related biological processes (BP) such as the tumor necrosis factor (TNF) and PI3K-AKT signaling pathways. Four active ingredients (quercetin, kaempferol, formononetin, and isorhamnetin) and five genes (RELA, MAPK14, MAPK1, JUN, AKT1) were reserved after screening. Molecular docking further showed that the receptor had a high binding affinity with HMM active ingredients.Conclusions: This study revealed that HMM treats UC through four active ingredients (quercetin, kaempferol, formononetin, and isorhamnetin) targeting five hub genes (RELA, MAPK14, MAPK1, JUN, AKT1) by regulating the PI3K-AKT1 and TNF signaling pathways.

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NGS study of glucocorticoids response genes in inflammatory bowel disease patients

Cited by 9 publications

References 40 publications

High-Dimensional DNA Methylation Mediates the Effect of Smoking on Crohn’s Disease

High-Dimensional DNA Methylation Mediates the Effect of Smoking on Crohn’s Disease

Network Pharmacology-Based Strategy to Identify the Pharmacological Mechanisms of Pulsatilla Decoction against Crohn’s Disease

Hedysarum multijugum Maxim treats ulcerative colitis through the PI3K-AKT and TNF signaling pathway according to network pharmacology and molecular docking

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