Integrated systematic pharmacology analysis and experimental validation to reveal the mechanism of action of Semen aesculi on inflammatory bowel diseases

Li, Min; Wang, Fang; Zhang, Ce; Li, Min-An; Li, Yuchen; Fu, Fenghua

doi:10.1016/j.jep.2022.115627

Cited by 8 publications

(2 citation statements)

References 46 publications

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“…However, when the intestinal mucosal barrier becomes compromised, a phenomenon commonly referred to as “leaky gut,” it results in the translocation of luminal components, including lipopolysaccharides (LPS) and diamine oxidase (DAO), into the bloodstream [ 36 ]. Elevated levels of LPS and DAO in the serum have been documented in various studies, providing evidence for the existence of this intestinal permeability in patients with IBD [ 37 ]. In this study, we discovered that NGR1 significantly downregulated the elevated levels of serum DAO, LPS, and FITC-Dextran in colitis mice.…”

Section: Discussionmentioning

confidence: 99%

Notoginsenoside R1 promotes Lgr5+ stem cell and epithelium renovation in colitis mice via activating Wnt/β-Catenin signaling

Yu,

Gao,

et al. 2024

Acta Pharmacol Sin

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Inflammatory bowel disease (IBD) is characterized by persistent damage to the intestinal barrier and excessive inflammation, leading to increased intestinal permeability. Current treatments of IBD primarily address inflammation, neglecting epithelial repair. Our previous study has reported the therapeutic potential of notoginsenoside R1 (NGR1), a characteristic saponin from the root of Panax notoginseng, in alleviating acute colitis by reducing mucosal inflammation. In this study we investigated the reparative effects of NGR1 on mucosal barrier damage after the acute injury stage of DSS exposure. DSS-induced colitis mice were orally treated with NGR1 (25, 50, 125 mg·kg−1·d−1) for 10 days. Body weight and rectal bleeding were daily monitored throughout the experiment, then mice were euthanized, and the colon was collected for analysis. We showed that NGR1 administration dose-dependently ameliorated mucosal inflammation and enhanced epithelial repair evidenced by increased tight junction proteins, mucus production and reduced permeability in colitis mice. We then performed transcriptomic analysis on rectal tissue using RNA-sequencing, and found NGR1 administration stimulated the proliferation of intestinal crypt cells and facilitated the repair of epithelial injury; NGR1 upregulated ISC marker Lgr5, the genes for differentiation of intestinal stem cells (ISCs), as well as BrdU incorporation in crypts of colitis mice. In NCM460 human intestinal epithelial cells in vitro, treatment with NGR1 (100 μM) promoted wound healing and reduced cell apoptosis. NGR1 (100 μM) also increased Lgr5+ cells and budding rates in a 3D intestinal organoid model. We demonstrated that NGR1 promoted ISC proliferation and differentiation through activation of the Wnt signaling pathway. Co-treatment with Wnt inhibitor ICG-001 partially counteracted the effects of NGR1 on crypt Lgr5+ ISCs, organoid budding rates, and overall mice colitis improvement. These results suggest that NGR1 alleviates DSS-induced colitis in mice by promoting the regeneration of Lgr5+ stem cells and intestinal reconstruction, at least partially via activation of the Wnt/β-Catenin signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Notoginsenoside R1 promotes Lgr5+ stem cell and epithelium renovation in colitis mice via activating Wnt/β-Catenin signaling

Yu,

Gao,

et al. 2024

Acta Pharmacol Sin

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“…The literature verification revealed that Escin (rank 3) and Ozanimod (rank 9) have literature support for use in the treatment of Crohn's disease. Escin is the main bioactive ingredient Article Title of Semen aesculi, which improves intestinal barrier dysfunction of IBD via Akt/NF-κB signaling pathway [38]. Ozanimod is a once-daily sphingosine 1phosphate receptor modulator for the treatment of inflammatory bowel disease and was approved by the FDA.…”

Section: Prnet Found Natural Compounds Against Colorectal Cancermentioning

confidence: 99%

Predicting transcriptional responses to novel chemical perturbations using deep generative model

Zhao,

Qi,

Zhao

et al. 2024

Preprint

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Understanding transcriptional responses to chemical perturbations is central for drug discovery, but exhaustive experimental high-throughput screening of disease and compound combinations is unfeasible. To overcome this limitation, here we present a perturbation-conditioned deep generative model named PRnet for predicting transcriptional responses to novel chemical perturbations that were never experimentally perturbed at bulk and single-cell levels. Evaluation indicated that PRnet outperformed alternative methods in predicting responses across novel compounds, pathways, and cell lines. PRnet enables gene-level response interpretation and novel compounds screening for diseases based on gene signatures. PRnet further identified and experimentally tested novel compounds candidates against small cell lung cancer and colorectal cancer. Lastly, PRnet generated a large-scale integration atlas of perturbation profiles, covering 88 cell lines and 52 tissues perturbed by various screening compound libraries. PRnet provided a robust and scalable candidate recommendation workflow and has successfully recommended drug candidates for 233 different diseases based on the atlas. Overall, PRnet is an effective and valuable tool for cell- and gene-based therapeutics screening.

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AHR, a novel inhibitory immune checkpoint receptor, is a potential therapeutic target for chemoresistant glioblastoma

Tan

Zhao

Wang

et al. 2023

J Cancer Res Clin Oncol

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Integrated systematic pharmacology analysis and experimental validation to reveal the mechanism of action of Semen aesculi on inflammatory bowel diseases

Cited by 8 publications

References 46 publications

Notoginsenoside R1 promotes Lgr5+ stem cell and epithelium renovation in colitis mice via activating Wnt/β-Catenin signaling

Notoginsenoside R1 promotes Lgr5+ stem cell and epithelium renovation in colitis mice via activating Wnt/β-Catenin signaling

Predicting transcriptional responses to novel chemical perturbations using deep generative model

AHR, a novel inhibitory immune checkpoint receptor, is a potential therapeutic target for chemoresistant glioblastoma

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