ER‐anchored CRTH2 antagonizes collagen biosynthesis and organ fibrosis via binding LARP6

Zuo, Shengkai; Wang, Bei; Liu, Jiao; Kong, Deping; Cui, Hui Song; Jia, Yao-Nan; Wang, Chenyao; Xu, Xin; Chen, Guilin; Wang, Yuanyang; Yang, Linlin; Zhang, Kai; Ai, Ding; Du, Jie; Shen, Yujun; Yu, Ying

doi:10.15252/embj.2020107403

Cited by 21 publications

(14 citation statements)

References 64 publications

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“…MK-886, an inhibitor of the 5-lipoxygenase-activating protein (FLAP), could suppress leukotriene biosynthesis and reduce choroidal neovascularization in age-related macular degeneration models [ 35 ]. Literature reviews show that bumetanide has a promising effect in many diseases, including organ fibrosis, neonatal epilepsy, and heart failure [ 36 ]. Harmalol, a beta carboline alkaloid, can induce apoptosis in HepG2 via binding to DNA sequences [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Potential Key Biomarkers and Immune Infiltration in Oral Lichen Planus

et al. 2022

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Background. Oral lichen planus (OLP) is a chronic autoimmune oral mucosal disease that seriously affects the life quality of the patients. But till now, the exact etiology and pathogenesis of OLP remain unclear. Our study is aimed at finding the key molecules and pathways involved in the pathogenesis mechanisms of OLP, providing more effective therapeutic strategies for OLP. Methods. Data from GSE52130 were downloaded from GEO datasets for analysis. Then, we carried out enrichment analysis of the differentially expressed genes (DEGs) using Gene Ontology (GO) and KEGG pathway analyses. Next, the CIBERSORT algorithm was used to assess immune cell infiltration in OLP patients. Furthermore, we also constructed a protein-protein interaction network using STRING and Cytoscape and simultaneously sought potential transcription factors plug-in including MCODE CytoHubba and iRegulon. In addition, ROC analysis was employed to assess the diagnostic performance of these hub genes. Lastly, we identified 6 promising novel drugs to treat OLP through Connectivity Map. Results. We illustrated that 255 DEGs were mainly enriched in the focal adhesion pathway and metabolism pathways. Besides, Cibersort analysis showed that M1 macrophages, T follicular helper cells, and T regulatory cells are more infiltrated in OLP samples. In addition, ROC analysis demonstrated that these hub genes owned higher diagnostic value in OLP, in which SPRR1B had the highest diagnostic value. And we also predicted that SOX7 was the most relevant transcription factor of those hub genes. Lastly, through the CMap database, we identified 6 small molecules as possible treatment drugs of OLP. Conclusion. Our research identified that SPRR1B could be used as potential biomarkers for the early diagnosis of OLP. In addition, as a chronic autoimmune oral mucosal disease, OLP has different infiltration types of immune cells. Furthermore, 6 small molecules were proposed as promising novel treatment drugs for OLP patients. Therefore, our research may provide new impetus for the development of effective OLP biological treatment options.

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Section: Discussionmentioning

confidence: 99%

Identification of Potential Key Biomarkers and Immune Infiltration in Oral Lichen Planus

et al. 2022

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“…This finding may make its utilization in antifibrotic therapy more feasible [ 44 – 46 ]. It was demonstrated in an in vitro experiment by Zuo et al [ 47 ] that bumetanide could inhibit collagen biosynthesis in fibroblasts by targeting the interaction of CRTH2 and LARP6, resulting in the treatment of organ fibrosis, suggesting that bumetanide may alleviate symptoms of IC/BPS patients by inhibiting bladder fibrosis. The molecular docking method was applied to bumetanide and the IC/BPS signature gene RASGRP1, where the low binding free energy performed good affinity between ligand and binding sites, suggesting that bumetanide may be a potent inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Identification of Immune-Related Genes and Small-Molecule Drugs in Interstitial Cystitis/Bladder Pain Syndrome Based on the Integrative Machine Learning Algorithms and Molecular Docking

Jiang

Xinqing

Al-Danakh

et al. 2022

Journal of Immunology Research

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Background. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic, severely distressing clinical syndrome characterized by bladder pain and pressure perceptions. The origin and pathophysiology of IC/BPS are currently unclear, making it difficult to diagnose and formulate successful treatments. Our study is aimed at investigating the role of immune-related genes in the diagnosis, progression, and therapy of IC/BPS. Method. The gene expression datasets GSE11783, GSE11839, GSE28242, and GSE57560 were retrieved from the GEO database for further analysis. Immune-related IC/BPS differentially expressed genes (DEGs) were identified by limma. Three distinct machine learning approaches, least absolute shrinkage and selection operator (LASSO), support vector machine–recursive feature elimination (SVM-RFE), and random forest (RF), were used to find the immune-related IC characteristic genes. Nomogram and receiving operator curves (ROC) were plotted to measure characteristic effectiveness. Using the CMap database and the molecular docking approach, potential small-molecule medicines were found and verified. Consensus cluster analysis was also performed to separate the IC/BPS samples into immunological subtypes. Results. A total of 24 immune-related IC/BPS-DEGs were identified. When compared to the normal control group, the IC/BPS cohort had significantly more immune cell infiltration. Integrative machine learning methods discovered 5 IC/BPS characteristic genes (RASGRP1, PPBP, RBP4, CR2, and PROS2) that may predict IC/BPS diagnosis and immune cell infiltration. Furthermore, two immunological subgroups with substantial variations in immune cell infiltration across IC/BPS samples were identified, which were named cluster1 and cluster2, with the hallmark genes having greater expression in cluster2. Finally, bumetanide was shown to have the potential to be a medication for the treatment of IC/BPS, and it performed well in terms of its molecular binding with RASGRP1. Conclusion. We found and validated 5 immune-related IC/BPS genes (RASGRP1, PPBP, RBP4, CR2, and PROS2) and 2 IC/BPS immune subtypes. In addition, bumetanide was discovered to be a potential drug for treating IC/BPS, which may provide new insight into the diagnosis and immune therapy of IC/BPS patients.

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“…CFs were isolated by enzymatic digestion and were cultured in full DMEM medium as previously described [19][20][21]. CFs isolated from male neonatal C57BL/6J mice (1-3 days) were cultured under normal glucose with 10% fetal bovine serum to the second generation before treatment.…”

Section: Cell Culture and Treatmentmentioning

confidence: 99%

Fibroblast-specific activation of Rnd3 protects against cardiac remodeling in diabetic cardiomyopathy via suppression of Notch and TGF-β signaling

Zhang¹,

Cao²,

Zheng³

et al. 2022

Theranostics

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Rationale: Extracellular matrix (ECM) remodeling, a key pathological feature in diabetic cardiomyopathy (DCM), is triggered by oxidative stress, inflammation, and various metabolic disorders in the heart. Cardiac fibroblasts (CFs) are the primary source of ECM proteins and the ultimate effector cells in ECM remodeling. CFs are turned on and differentiated into myofibroblasts in response to profibrotic signaling. Rnd3 is a small Rho-GTPase involved in the regulation of cell-cycle distribution, cell migration, and cell morphogenesis. Emerging evidence suggests a link between Rnd3 expression and onset of cardiovascular diseases. However, the role of Rnd3 in DCM remains unknown. Methods: Flow cytometry was employed to separate different types of cardiac cells. Type 2 diabetes mellitus was established in Rnd3 fibroblast-specific knockout and transgenic mice. RNA sequencing and chromatin immunoprecipitation assay were used to discern signaling pathways involved. Results: Rnd3 expression was reduced in cardiac tissues of diabetic mice, with CFs being the primary cell type. Fibroblast-specific upregulation of Rnd3 in vivo was protective against DCM, whereas Rnd3 downregulation in fibroblasts accentuated cardiac oxidative stress, fibrosis, ventricular remodeling, and dysfunction. Moreover, in vitro Rnd3 overexpression significantly attenuated reactive oxygen species production, CF migration and proliferation under high levels of glucose (35 mmol/L) and palmitic acid (500 µmol/L) challenge. Furthermore, RNA sequencing indicated that Notch and TGF-β signaling were significantly suppressed upon Rnd3 overexpression. Mechanistically, Rnd3 regulated Notch and TGF-β signaling by interacting with NICD and ROCK1, respectively. Specifically, glucotoxicity and lipotoxicity control Rnd3 expression by regulating the binding of Nr1H2 and Rnd3 promoter. Conclusions: Our findings provide compelling evidence in that fibroblast-specific activation of Rnd3 protects against cardiac remodeling in DCM, indicating promises of targeting Rnd3 in the treatment of DCM.

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ER‐anchored CRTH2 antagonizes collagen biosynthesis and organ fibrosis via binding LARP6

Cited by 21 publications

References 64 publications

Identification of Potential Key Biomarkers and Immune Infiltration in Oral Lichen Planus

Identification of Potential Key Biomarkers and Immune Infiltration in Oral Lichen Planus

Identification of Immune-Related Genes and Small-Molecule Drugs in Interstitial Cystitis/Bladder Pain Syndrome Based on the Integrative Machine Learning Algorithms and Molecular Docking

Fibroblast-specific activation of Rnd3 protects against cardiac remodeling in diabetic cardiomyopathy via suppression of Notch and TGF-β signaling

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