Discovery and identification of EIF2AK2 as a direct key target of berberine for anti-inflammatory effects

Wei, Wei; Zeng, Qingpeng; Wang, Yan; Guo, Xixi; Fan, Tianyun; Li, Yinghong; Deng, Hongkui; Zhao, Liping; Zhang, Xintong; Liu, Yonghua; Shi, Yulong; Zhu, Jingyang; Ma, Xican; Wang, Yanxiang; Jiang, Jian‐Dong; Song, Dan–Qing

doi:10.1016/j.apsb.2022.12.009

Cited by 21 publications

(6 citation statements)

References 55 publications

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“…The cytokine TNF- α substantially contributes to the pathogenesis of psoriasis, and it harbors a potent target for psoriasis treatment 1 , 6 . Herein, a TNF- α induced L929 cell death model was developed to evaluate the TNF- α inhibitory capacity of 1 and 2 31 , 32 , 33 , 34 . As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Spirohypertones A and B as potent antipsoriatics: Tumor necrosis factor-α inhibitors with unprecedented chemical architectures

Duan,

Sun,

et al. 2024

Acta Pharmaceutica Sinica B

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Section: Resultsmentioning

confidence: 99%

Spirohypertones A and B as potent antipsoriatics: Tumor necrosis factor-α inhibitors with unprecedented chemical architectures

Duan,

Sun,

et al. 2024

Acta Pharmaceutica Sinica B

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“…Omics approaches facilitate research on the mode of action of drugs, especially pinpointing the unknown mode of action for further studies. − Although compound C20 showed outstanding in vitro fungicidal activity against R. solani, its in vivo activity was poor.…”

Section: Resultsmentioning

confidence: 99%

Fungicidal Activity of New Pyrrolo[2,3-d]thiazoles and Their Potential Action on the Tryptophan Metabolic Pathway and Wax Biosynthesis

Zhang,

Li,

Yang

et al. 2024

J. Agric. Food Chem.

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The main challenge in the development of agrochemicals is the lack of new leads and/or targets. It is critical to discover new molecular targets and their corresponding ligands. YZK-C22, which contains a 1,2,3-thiadiazol-[1,2,4]triazolo [3,4b][1,3,4]thiadiazole skeleton, is a fungicide lead compound with broad-spectrum fungicidal activity. Previous studies suggested that the [1,2,4]triazolo [3,4-b][1,3,4]thiadiazole scaffold exhibited good antifungal activity. Inspired by this, a series of pyrrolo[2,3d]thiazole derivatives were designed and synthesized through a bioisosteric strategy. Compounds C1, C9, and C20 were found to be more active against Rhizoctonia solani than the positive control YZK-C22. More than half of the target compounds provided favorable activity against Botrytis cinerea, where the EC 50 values of compounds C4, C6, C8, C10, and C20 varied from 1.17 to 1.77 μg/mL. Surface plasmon resonance and molecular docking suggested that in vitro potent compounds C9 and C20 have a new mode of action instead of acting as pyruvate kinase inhibitors. Transcriptome analysis revealed that compound C20 can impact the tryptophan metabolic pathway, cutin, suberin, and wax biosynthesis of B. cinerea. Overall, pyrrolo[2,thiazole is discovered as a new fungicidal lead structure with a potential new mode of action for further exploration.

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“…Additionally, the analysis revealed that the gene expression profile in Epi1.2 cells is consistent with inflammatory responses. This profile includes the expression of RAI14, DDIT4, VGLL4, CD46, EIF2AK2, and REL [28][29][30][31][32]. Furthermore, these cells were also enriched in fibrosis-associated genes, such as TRIM2 and REL.…”

Section: Epi12 Cells With a Distinct Immune And Profibrotic Functiona...mentioning

confidence: 99%

DPSCs regulate epithelial-T cell interactions in oral submucous fibrosis

Wang,

Zhang,

Meng

et al. 2024

Stem Cell Res Ther

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Background Oral submucous fibrosis (OSF) is a precancerous lesion characterized by fibrous tissue deposition, the incidence of which correlates positively with the frequency of betel nut chewing. Prolonged betel nut chewing can damage the integrity of the oral mucosal epithelium, leading to chronic inflammation and local immunological derangement. However, currently, the underlying cellular events driving fibrogenesis and dysfunction are incompletely understood, such that OSF has few treatment options with limited therapeutic effectiveness. Dental pulp stem cells (DPSCs) have been recognized for their anti-inflammatory and anti-fibrosis capabilities, making them promising candidates to treat a range of immune, inflammatory, and fibrotic diseases. However, the application of DPSCs in OSF is inconclusive. Therefore, this study aimed to explore the pathogenic mechanism of OSF and, based on this, to explore new treatment options. Methods A human cell atlas of oral mucosal tissues was compiled using single-cell RNA sequencing to delve into the underlying mechanisms. Epithelial cells were reclustered to observe the heterogeneity of OSF epithelial cells and their communication with immune cells. The results were validated in vitro, in clinicopathological sections, and in animal models. In vivo, the therapeutic effect and mechanism of DPSCs were characterized by histological staining, immunohistochemical staining, scanning electron microscopy, and atomic force microscopy. Results A unique epithelial cell population, Epi1.2, with proinflammatory and profibrotic functions, was predominantly found in OSF. Epi1.2 cells also induced the fibrotic process in fibroblasts by interacting with T cells through receptor-ligand crosstalk between macrophage migration inhibitory factor (MIF)-CD74 and C-X-C motif chemokine receptor 4 (CXCR4). Furthermore, we developed OSF animal models and simulated the clinical local injection process in the rat buccal mucosa using DPSCs to assess their therapeutic impact and mechanism. In the OSF rat model, DPSCs demonstrated superior therapeutic effects compared with the positive control (glucocorticoids), including reducing collagen deposition and promoting blood vessel regeneration. DPSCs mediated immune homeostasis primarily by regulating the numbers of KRT19 + MIF + epithelial cells and via epithelial-stromal crosstalk. Conclusions Given the current ambiguity surrounding the cause of OSF and the limited treatment options available, our study reveals that epithelial cells and their crosstalk with T cells play an important role in the mechanism of OSF and suggests the therapeutic promise of DPSCs.

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Discovery and identification of EIF2AK2 as a direct key target of berberine for anti-inflammatory effects

Cited by 21 publications

References 55 publications

Spirohypertones A and B as potent antipsoriatics: Tumor necrosis factor-α inhibitors with unprecedented chemical architectures

Spirohypertones A and B as potent antipsoriatics: Tumor necrosis factor-α inhibitors with unprecedented chemical architectures

Fungicidal Activity of New Pyrrolo[2,3-d]thiazoles and Their Potential Action on the Tryptophan Metabolic Pathway and Wax Biosynthesis

DPSCs regulate epithelial-T cell interactions in oral submucous fibrosis

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