Dataset Information

Inhibition of Fibroblast Activation in Uterine Leiomyoma by Components of Rhizoma Curcumae and Rhizoma Sparganii.

ABSTRACT: Background: The herbs Rhizoma Curcumae and Rhizoma Sparganii (RCRS) are often used in traditional Chinese medicine for the treatment of uterine leiomyoma (UL). The effectiveness of RCRS for the treatment of UL has been confirmed in our previous studies. Purpose: This study aimed to investigate the molecular mechanism by which RCRS inhibits the activation of fibroblast activation protein (FAP) and prevents UL in rats. Study Design and Methods: A Sprague Dawley (SD) rat model of UL was established via estrogen and progesterone load combined with external stimulation. Histological analyses, enzyme-linked immunosorbent assays, and western blotting were performed to evaluate the effect of RCRS on UL and elucidate its mechanism of action. Results: Our data showed that the treatment of SD rats with RCRS significantly reduced the expression of extracellular matrix component collagen, FAP, and transforming growth factor beta (a FAP-activating factor) and the phosphorylation of the cell proliferation pathway-related signaling factors AKT/MEK/ERK. Conclusion: Our results suggest that RCRS is effective in the prevention and treatment of UL in rats, and RCRS may exert its functions by inhibiting the activation of tumor-associated fibroblasts and cell proliferation and by improving the tumor extracellular matrix.

SUBMITTER: Feng Y

PROVIDER: S-EPMC7957009 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Inhibition of Fibroblast Activation in Uterine Leiomyoma by Components of Rhizoma Curcumae and Rhizoma Sparganii.

Feng Yewen Y Zhao Yumin Y Li Yao Y Peng Teng T Kuang Yu Y Shi Xingming X Wang Gang G Peng Fu F Yu Chenghao C

Frontiers in public health 20210301

Background: The herbs Rhizoma Curcumae and Rhizoma Sparganii (RCRS) are often used in traditional Chinese medicine for the treatment of uterine leiomyoma (UL). The effectiveness of RCRS for the treatment of UL has been confirmed in our previous studies. Purpose: This study aimed to investigate the molecular mechanism by which RCRS inhibits the activation of fibroblast activation protein (FAP) and prevents UL in rats. Study Design and Methods: A Sprague Dawley ( ...[more]

PMID: 33732680

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Project description:BackgroundLung cancer has a poor prognosis and a high mortality rate, and patients may develop multidrug resistance. Sparganii Rhizoma-Curcumae Rhizoma (HCSC), the classic herbal drug combination of traditional Chinese medicine (TCM), is commonly used in treating tumors, but its molecular mechanism is still unclear.MethodWe explored the possible mechanisms underlying the antitumor effect of HCSC using network pharmacology. The bioactive components of HCSC and their targets were collected from the TCM Systems Pharmacology (TCMSP) database and PharmMapper. Gene Ontology (GO) and KEGG enrichment analyses were performed; the GeneMANIA platform was used for the functional enrichment analysis of the core targets and their neighboring genes. Molecular docking was performed between the bioactive components and core targets. HCSC freeze-dried powder was prepared, and the bioactive components were verified by liquid chromatography- (LC-) mass spectrometry (MS). Human lung adenocarcinoma H1975 cells were cultured to verify in vitro the molecular mechanism of action of HCSC in treating lung cancer, as predicted by network pharmacology. Finally, we used the Symmap database to predict the relationship between the herb and TCM syndrome.ResultA total of seven bioactive components were identified by network pharmacological analysis. Through enrichment analyses, it was found that the mechanism of action mainly involved mitochondrial-mediated caspase-dependent cell apoptosis signaling pathways. The results of molecular docking showed that the bioactive components in HCSC have a good affinity with the target proteins (ALB, BCL2L1, ESR1, HRAS, MAP2K1, MAPK14, and SIRT1). LC-MS confirmed that formononetin and bisdemethoxycurcumin were present in the HCSC freeze-dried powder, consistent with the prediction. The results of in vitro experiments on NCI-H1975 cells confirmed that HCSC can upregulate the mitochondrial-mediated caspase-dependent apoptosis signaling pathway by inducing the cleavage of caspase-3, caspase-9, and PARP, consistent with the network pharmacology prediction. Further, the qi deficiency and blood stasis associated with TCM syndrome can be treated with HCSC.

Project description:Recent studies concerning products that originate from natural plants have sought to clarify active ingredients, which both explains the mechanisms of the function and aids in quality control during production. As a traditional functional plant, Curcumae Rhizoma (CR) has been proven to be effective in promoting blood circulation and removing blood stasis. However, the components that play a role in its huge compound library are still unclear. The present study aimed to develop a high-throughput screening method to identify thrombin inhibitors in CR and validate them by in vitro and in vivo experiments. The effect of CR on thrombin in HUVECs cells was determined by ELISA, then an affinity-ultrafiltration-UPLC-Q-Exactive Orbitrap/MS approach was applied. Agatroban and adenosine were used as positive and negative drugs respectively to verify the reliability of the established method. The in vitro activity of the compounds was determined by specific substrate S-2238. The in vivo effect of the active ingredients was determined using zebrafish. Molecular docking was used to understand the internal interactions between compounds and enzymes. ELISA results showed that CR had an inhibitory effect on thrombin. The screening method established in this paper is reliable, by which a total of 15 active compounds were successfully identified. This study is the first to report that C7, 8, and 11 have in vitro thrombin-inhibitory activity and significantly inhibit thrombosis in zebrafish models at a safe dose. Molecular docking studies were employed to analyze the possible active binding sites, with the results suggesting that compound 16 is likely a better thrombin inhibitor compared with the other compounds. Based on the affinity-ultrafiltration-UPLC-Q-Exactive Orbitrap/MS approach, a precisely targeted therapy method using bio-active compounds from CR might be successfully established, which also provides a valuable reference for targeted therapy, mechanism exploration, and the quality control of traditional herbal medicine.

Project description:BackgroundUterine leiomyomas (UL) are the most common benign tumor in women of reproductive age. Their pathology remains unclear, which hampers the development of safe and effective treatments. Raising evidence suggests epigenetics as a main mechanism involved in tumor development. Histone modification is a key component in the epigenetic regulation of gene expression. Specifically, the histone mark H3K4me3, which promotes gene expression, is altered in many tumors. In this study, we aimed to identify if the histone modification H3K4me3 regulates the expression of genes involved in uterine leiomyoma pathogenesis.MethodsProspective study integrating RNA-seq (n = 48) and H3K4me3 CHIP-seq (n = 19) data of uterine leiomyomas versus their adjacent myometrium. Differentially expressed genes (FDR < 0.01, log2FC > 1 or < - 1) were selected following DESeq2, edgeR, and limma analysis. Their differential methylation and functional enrichment (FDR < 0.05) were respectively analyzed with limma and ShinyGO.ResultsCHIP-seq data showed a global suppression of H3K4me3 in uterine leiomyomas versus their adjacent myometrial tissue (p-value< 2.2e-16). Integrating CHIP-seq and RNA-seq data highlighted that transcription of 696/922 uterine leiomyoma-related differentially expressed genes (DEG) (FDR < 0.01, log2FC > 1 or < - 1) was epigenetically mediated by H3K4me3. Further, 50 genes were differentially trimethylated (FDR < 0.05), including 33 hypertrimethylated/upregulated, and 17 hypotrimethylated/downregulated genes. Functional enrichment analysis of the latter showed dysregulation of neuron-related processes and synapsis-related cellular components in uterine leiomyomas, and a literature review study of these DEG found additional implications with tumorigenesis (i.e. aberrant proliferation, invasion, and dysregulation of Wnt/β-catenin, and TGF-β pathways). Finally, SATB2, DCX, SHOX2, ST8SIA2, CAPN6, and NPTX2 proto-oncogenes were identified among the hypertrimethylated/upregulated DEG, while KRT19, ABCA8, and HOXB4 tumor suppressor genes were identified among hypotrimethylated/downregulated DEG.ConclusionsH3K4me3 instabilities alter the expression of oncogenes and tumor suppressor genes, inducing aberrant proliferation, and dysregulated Wnt/β-catenin, and TGF-β pathways, that ultimately promote uterine leiomyoma progression. The reversal of these histone modifications may be a promising new therapeutic alternative for uterine leiomyoma patients.

Dataset Information

Inhibition of Fibroblast Activation in Uterine Leiomyoma by Components of Rhizoma Curcumae and Rhizoma Sparganii.

Publications

Inhibition of Fibroblast Activation in Uterine Leiomyoma by Components of <i>Rhizoma Curcumae</i> and <i>Rhizoma Sparganii</i>.

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