Nintedanib Alleviates Experimental Colitis by Inhibiting CEBPB/PCK1 and CEBPB/EFNA1 Pathways

Li, Hailong; Li, Jinhe; Tu, Xiao; Yin, Hu; Yang, Ying; Gu, Xiaoting; Jin, Ge; Cao, Hailong; Zhou, Honggang; Yang, Cheng

doi:10.3389/fphar.2022.904420

Cited by 9 publications

(12 citation statements)

References 55 publications

(62 reference statements)

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“…MMP25 can degrade ECM proteins and promote embryonic growth and development, ovulation, uterine degeneration, and wound healing [26]. CEBPB participates in tumorigenesis and apoptosis, proliferation and differentiation, and systemic in ammatory response by regulating the gene transcription of target cells [27]. CRISPLD2 is a glucocorticoid responsive gene, regulating immune response [28].…”

Section: Discussionmentioning

confidence: 99%

The analysis of bioinformatics uncovers the interaction genes and immune connection between the fracture and CRPS

Kong,

Wang,

Guo

et al. 2024

Preprint

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Background Patients with fractures are known to have an increased susceptibility to the development of complex regional pain syndrome (CRPS), yet the precise underlying mechanism of this condition remains inadequately understood. The objective of this study is to identify shared genes between fracture and CRPS and explore their potential molecular mechanisms. Methods The raw data pertaining to facture and CRPS were obtained from the Gene Expression Omnibus (GEO) datasets. Venn plots were utilized to extract the differentially expressed genes (DEGs) that were shared between facture and CRPS. Subsequently, functional enrichment analyses were conducted on these shared genes to identify significant biological functions. The PPI network was employed to visualize the network of the shared genes, and the hub genes were identified using MCODE. The levels of immune infiltration in fracture and CRPS were evaluated using the CIBERSORT algorithm, and the relationship between hub genes and immune cell infiltration was investigated. Additionally, the expression levels of hub genes were examined to explore potential phenotypic subgroups in fractures and CRPS, and the infiltration of immune cells was analyzed across different subcategories. Results A comprehensive analysis revealed the presence of 13 overlapping genes among the DEGs in the fracture and CRPS datasets. The outcomes of functional enrichment analysis suggest that these shared genes primarily participate in immune-related pathways. Furthermore, our investigation identified five hub genes that exhibited up-regulation in both CRPS and fracture patients when compared to healthy individuals. The analysis of immune infiltration revealed an increase in various immune cell populations among patients diagnosed with CRPS and fractures. Furthermore, the hub genes exhibited strong associations with multiple infiltrating immune cells. Based on their shared gene expression profiles, patients with fractures and CRPS were classified into two distinct clusters, namely C1 and C2. Conclusion Our study reveals a close relationship between fracture and CRPS from crosstalk genes, providing clues to further explore the interaction and therapy for fracture and CRPS.

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Section: Discussionmentioning

confidence: 99%

The analysis of bioinformatics uncovers the interaction genes and immune connection between the fracture and CRPS

Kong,

Wang,

Guo

et al. 2024

Preprint

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“…Furthermore, it has been observed that the down-regulation of EFNA1 expression exerts inhibitory effects on the three-dimensional growth of HT29 colon cancer cells [ 31 ]. Previous studies have also reported that exhibits a therapeutic effect in experimental colitis by inhibiting the CEBPB/PCK1 and CEBPB/EFNA1 pathways, which are associated with the PI3K-Akt and P38 MAPK pathways [ 32 ]. CRNG disruption and overexpression, in conjunction with KITLG, have been observed to interact and engage in viral and pathogenic infections in PK-15 cells [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Analysis of PDCoV-Infected HIEC-6 Cells and Enrichment Pathways PI3K-Akt and P38 MAPK

Jiang,

Zhang,

et al. 2024

Viruses

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Porcine Deltacoronavirus (PDCoV) is a newly identified coronavirus that causes severe intestinal lesions in piglets. However, the understanding of how PDCoV interacts with human hosts is limited. In this study, we aimed to investigate the interactions between PDCoV and human intestinal cells (HIEC-6) by analyzing the transcriptome at different time points post-infection (12 h, 24 h, 48 h). Differential gene analysis revealed a total of 3560, 5193, and 4147 differentially expressed genes (DEGs) at 12 h, 24 h, and 48 h, respectively. The common genes among the DEGs at all three time points were enriched in biological processes related to cytokine production, extracellular matrix, and cytokine activity. KEGG pathway analysis showed enrichment of genes involved in the p53 signaling pathway, PI3K-Akt signaling pathway, and TNF signaling pathway. Further analysis of highly expressed genes among the DEGs identified significant changes in the expression levels of BUB1, DDIT4, ATF3, GBP2, and IRF1. Comparison of transcriptome data at 24 h with other time points revealed 298 DEGs out of a total of 6276 genes. KEGG analysis of these DEGs showed significant enrichment of pathways related to viral infection, specifically the PI3K-Akt and P38 MAPK pathways. Furthermore, the genes EFNA1 and KITLG, which are associated with viral infection, were found in both enriched pathways, suggesting their potential as therapeutic or preventive targets for PDCoV infection. The enhancement of PDCoV infection in HIEC-6 was observed upon inhibition of the PI3K-Akt and P38 MAPK signaling pathways using sophoridine. Overall, these findings contribute to our understanding of the molecular mechanisms underlying PDCoV infection in HIEC-6 cells and provide insights for developing preventive and therapeutic strategies against PDCoV infection.

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“…In our model, PCK1 pathway is activated by the IL6-IL6R interaction in the liver, which is feeds back to the lung pathogenesis of IPF via KNG1-BDKRB1 pathway. Recently, nintedanib, one of the two FDA-approved IPF therapeutics, is shown to attenuate experimental colitis via inhibiting the PCK1 pathway 43 . This study suggests that a part of the therapeutic effect of nintedanib on IPF is via the inhibition of the PCK1 pathway.…”

Section: The Inter-organ Mechanism Of Ipfmentioning

confidence: 99%

Latent inter-organ mechanism of idiopathic pulmonary fibrosis unveiled by a generative computational approach

Kozawa

Tejima

Takagi

et al. 2023

Preprint

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Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by complex lung pathogenesis affecting approximately three million people worldwide. While the molecular and cellular details of the IPF mechanism is emerging, our current understanding is centered around the lung itself. On the other hand, many human diseases are the products of complex multi-organ interactions. Hence, we postulate that a dysfunctional crosstalk of the lung with other organs plays a causative role in the onset, progression and/or complications of IPF. In this study, we employed a generative computational approach to identify such inter-organ mechanism of IPF. The approach works as follows: 1) To find unexpected relatedness of IPF to other diseases of non-lung organs and to identify molecular features that define such relatedness, 2) To identify differentially expressed genes between the lung tissues of IPF vs. those of non-IPF pulmonary disease patients, 3) To detect ligand-receptor relationships across multiple organs and their upstream and downstream signaling pathways in 1) and 2), 4) To generate a map of the inter-organ IPF mechanism with the molecular and cellular resolution. This approach found unexpected molecular relatedness of IPF to neoplasm, diabetes, Alzheimer′s disease, obesity, atherosclerosis, and arteriosclerosis. Furthermore, as a potential mechanism underlying this relatedness, we uncovered a putative molecular crosstalk system across the lung and the liver. In this inter-organ system, a secreted protein, kininogen 1, from hepatocytes in the liver interacts with its receptor, bradykinin receptor B1 in the lung. This ligand-receptor interaction across the liver and the lung leads to the activation of calmodulin pathways in the lung, leading to the activation of interleukin 6 and phosphoenolpyruvate carboxykinase 1 pathway across these organs. Furthermore, we retrospectively identified several pre-clinical and clinical evidence supporting this inter-organ mechanism of IPF. In conclusion, such feedforward and feedback system across the lung and the liver provides a unique opportunity for the development of the treatment and/or diagnosis of IPF. Furthermore, the result illustrates a generative computational framework for machine-mediated synthesis of mechanisms that facilitates and complements the traditional experimental approaches in biomedical sciences.

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Nintedanib Alleviates Experimental Colitis by Inhibiting CEBPB/PCK1 and CEBPB/EFNA1 Pathways

Cited by 9 publications

References 55 publications

The analysis of bioinformatics uncovers the interaction genes and immune connection between the fracture and CRPS

The analysis of bioinformatics uncovers the interaction genes and immune connection between the fracture and CRPS

Transcriptomic Analysis of PDCoV-Infected HIEC-6 Cells and Enrichment Pathways PI3K-Akt and P38 MAPK

Latent inter-organ mechanism of idiopathic pulmonary fibrosis unveiled by a generative computational approach

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