scholarly journals Exploring the Modulatory Mechanism of Eleng Capsule in the Treatment of Endometriosis Based on Integrated Strategy of Transcriptomics Combined With Network Pharmacology

2020 ◽  
Author(s):  
Weilin Zheng ◽  
Jie Wang ◽  
Jiangyong Gu ◽  
Jiayi Wu ◽  
Tao Wang ◽  
...  
Keyword(s):  
Chinese Medicine ◽  
Signaling Pathway ◽  
Rna Sequencing ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Targets ◽  
Gene Set Enrichment Analysis ◽  
Mass Spectrometry Analysis ◽  
Network Pharmacology ◽  
Mesenchymal Transition ◽  
Tof Ms

Abstract BackgroundEndometriosis causes severe chronic pelvic pain and infertility. Chinese medicine plays an active role in the treatment of endometriosis. ELeng Capsule(ELC) is a Chinese medicine formula used for the treatment of endometriosis for several years. The previous studies have shown that ELC inhibits endometriosis. However, the mechanisms of action of ELC have not been characterized. In this study, network pharmacology and mRNA transcriptome analysis were used to study various therapeutic targets in ELC.Methods Ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry analysis(UPLC-Q-TOF/MS) was used to identify the compounds in ELC.And network pharmacology was used to analyze the network of targets and identified compounds of ELC. Apoptosis was assessed using the terminal deoxynucleotidyl transferase (TdT) deoxyuridine 5'-triphosphate (dUTP) nick-end labeling (TUNEL) assay.The protein expression of VEGFA,VEGFB,VEGFC and α-SMA in the ectopic endometrium were identified by immunohistochemistry(IHC).The level of VEGFA,VEGFB and IL1-β in serum were used by ELISA. Further, RNA-sequencing was used to identify differentially expressed genes (DEGs) in ELC. Biological functions and pathways were determined through the Gene Ontology(GO) and Kyoto encyclopedia of genes and genomes pathway(KEGG) analyses. In addition, Gene Set Enrichment Analysis (GSEA) analysis was used to further analyze the genetic network and modular genetics. ResultsWe had identified 26 new bioactive compounds in ELeng Capsule by UPLC-Q-TOF/MS analysis. The KEGG pathways of ELC associtaed targets related to neuroactive ligand-receptor interaction, the toll-like receptor signaling pathway, and the vascular endothelial growth factor signaling pathway by network pharmacology analysis.Further, ELC could induce cell apoptosis, inhibit angiogenesis through reduce the expression of VEGFA and VEGFC, and inhibit the fibrosis through reduce the expression of α-SMA in ectopic lesions(P＜0.05). In addition, the development of endometriosis in the rat model may be related to mechanisms of inflammation,epithelial-mesenchymal transition(EMT) by RNA-sequencing. And the targets in the treatment of ELC were predominantly associated with actin and cytoskeleton,EMT,focal adhesion,and inflammatory immunity based on the DEGs analysis. In additon, the GSEA analysis showed that the treatment of ELC was associated with the Notch signaling pathway, Hippo signaling pathway, etc.ConclusionELeng Capsules exerted beneficial effects against endometriosis, potentially by induce apoptosis,modulating the angiogenesis,cytoskeleton, epithelial-mesenchymal transition(EMT), and cell junction-associated pathways,etc. These findings could provide evidence for an innovative treatment strategy and novel therapeutic targets for endometriosis.

scholarly journals Exploration of the Modulatory Property Mechanism of ELeng Capsule in the Treatment of Endometriosis Using Transcriptomics Combined With Systems Network Pharmacology

2021 ◽  
Vol 12 ◽  
Author(s):  
Weilin Zheng ◽  
Jie Wang ◽  
Jiayi Wu ◽  
Tao Wang ◽  
Yangxue Huang ◽  
...  
Keyword(s):  
Chinese Medicine ◽  
Signaling Pathway ◽  
Epithelial Mesenchymal Transition ◽  
Active Role ◽  
Mapk Signaling ◽  
Network Pharmacology ◽  
Receptor Interaction ◽  
Mesenchymal Transition ◽  
Beneficial Effects ◽  
Function Modules

Endometriosis is a common gynecological disease and causes severe chronic pelvic pain and infertility. Growing evidence showed that traditional Chinese medicine (TCM) plays an active role in the treatment of endometriosis. ELeng Capsule (ELC) is a Chinese medicine formula used for the treatment of endometriosis for several years. However, the mechanisms of ELC have not been fully characterized. In this study, network pharmacology and mRNA transcriptome analysis were used to study various therapeutic targets in ELC. As a result, 40 compounds are identified, and 75 targets overlapped with endometriosis-related proteins. The mechanism of ELC for the treatment of endometriosis is based on the function modules of inducing apoptosis, inhibiting angiogenesis, and regulating immunity mainly through signaling molecules and interaction (neuroactive ligand–receptor interaction), immune system–associated pathways (toll-like receptor signaling pathway), vascular endothelial growth factor (VEGF) signaling, and MAPK signaling pathway based on network pharmacology. In addition, based on RNA-sequence analysis, we found that the mechanism of ELC was predominantly associated with the regulation of the function modules of actin and cytoskeleton, epithelial–mesenchymal transition (EMT), focal adhesion, and immunity-associated pathways. In conclusion, ELC exerted beneficial effects on endometriosis, and the potential mechanism could be realized through functional modules, such as inducing apoptosis and regulating angiogenesis, cytoskeleton, and EMT. This work not only provides insights into the therapeutic mechanism of TCM for treating endometriosis but also offers an efficient way for drug discovery and development from herbal medicine.

scholarly journals YTHDF1 promotes hepatocellular carcinoma progression via activating PI3K/AKT/mTOR signaling pathway and inducing epithelial-mesenchymal transition

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Xiangyuan Luo ◽  
Mengdie Cao ◽  
Fan Gao ◽  
Xingxing He
Keyword(s):  
Signaling Pathway ◽  
Rna Binding ◽  
Epithelial Mesenchymal Transition ◽  
Mtor Signaling ◽  
Gene Set Enrichment Analysis ◽  
Migration And Invasion ◽  
Mtor Signaling Pathway ◽  
Promoting Effect ◽  
Mesenchymal Transition ◽  
Hcc Cells

Abstract Background N6-methyladenosine (m6A) modification, as the most abundant RNA modification, widely participates in the physiological process and is involved in multiple disease progression, especially cancer. YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) is a pivotal m6A “reader” protein, which has been reported in multiple cancers. However, the role and molecular mechanism of YTHDF1 in HCC are still not fully elucidated. Methods Based on various bioinformatics databases, q-RT PCR, western blot, and a tissue microarray containing 90 HCC samples, we examined the expression of YTHDF1 in HCC. Then, we applied the loss-of-function experiments to explore the role of YTHDF1 in HCC by in vitro and in vivo assays. Finally, we performed the gene set enrichment analysis (GSEA) to predict the potential signaling pathway of YTHDF1 involved in HCC and further verified this prediction. Results YTHDF1 was overexpressed in HCC and associated with HCC grade. Depletion of YTHDF1 markedly impaired the proliferation, migration, invasion, and cell cycle process of HCC cells. Mechanistically, YTHDF1 promoted the growth of HCC cells via activating the PI3K/AKT/mTOR signaling pathway. Moreover, we also demonstrated that the epithelial-mesenchymal transition (EMT) mediated the promoting effect of YTHDF1 on the migration and invasion of HCC cells. Conclusions YTHDF1 contributes to the progression of HCC by activating PI3K/AKT/mTOR signaling pathway and inducing EMT.

scholarly journals Network pharmacology evaluation of the active ingredients and potential targets of XiaoLuoWan for application to uterine fibroids

2020 ◽  
Vol 40 (12) ◽  
Author(s):  
Yonghui Yu ◽  
Fang Yang ◽  
Hong Liu
Keyword(s):  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Calcium Signaling ◽  
Signaling Pathway ◽  
Uterine Fibroids ◽  
Therapeutic Targets ◽  
Network Pharmacology ◽  
Therapeutic Effects ◽  
Active Ingredients ◽  
Calcium Signaling Pathway

Abstract XiaoLuoWan (XLW) is a classical formula in traditional Chinese medicine (TCM) that has satisfactory therapeutic effects for uterine fibroids (UFs). However, its underlying mechanisms remain unclear. To elucidate the pharmacological actions of XLW in treating UFs, an ingredient–target–disease framework was proposed based on network pharmacology strategies. The active ingredients in XLW and their putative targets were obtained from the TCM systems pharmacology database and analysis platform (TCMSP) and Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine (BATMAN-TCM) platforms. The known therapeutic targets of UFs were acquired from the DigSee and DrugBank databases. Then, the links between putative XLW targets and therapeutic UF targets were identified to establish interaction networks by Cytoscape. Finally, Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of overlapping gene targets were performed in the STRING database and visualized in R software. In total, 9 active compounds were obtained from 74 ingredients, with 71 curative targets predicted in XLW. Moreover, 321 known therapeutic targets were closely related to UFs, with 29 targets overlapping with XLW and considered interacting genes. Pathway enrichment revealed that the calcium signaling pathway was significantly enriched and the mitogen-activated protein kinase (MAPK) signaling pathway, cAMP signaling pathway, cancer and vascular smooth muscle contraction pathways, cGMP-PKG signaling pathway, and AGE-RAGE signaling pathway were closely associated with XLW intervention for UFs. In conclusion, the network pharmacology detection identified 9 available chemicals as the active ingredients in XLW that may relieve UFs by regulating 29 target genes involved in the calcium signaling pathway, MAPK pathway and cAMP pathway. Network pharmacology analyses may provide more convincing evidence for the investigation of classical TCM prescriptions, such as XLW.

scholarly journals Piezo1 Promoted Hepatocellular Carcinoma Progression and EMT Through Activating TGF-β Signaling by Recruiting Rab5c

2021 ◽  
Author(s):  
Yiming Li ◽  
Cong Xu ◽  
Bo Sun ◽  
Fangjing Zhong ◽  
Momo Cao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Epithelial Mesenchymal Transition ◽  
Independent Study ◽  
Gene Set Enrichment Analysis ◽  
Mechanism Study ◽  
Mesenchymal Transition

Abstract Background Piezo1 plays critical roles in vascular development during early embryogenesis. However, the function of Piezo1 in hepatocellular carcinoma (HCC) remain elusive. This study aimed to explore the function and mechanisms of Piezo1 in HCC. Methods qRT-PCR, western blot and immunohistochemistry analyses were used to determine Piezo1 expression in HCC samples and cell lines. The clinical significance of Piezo1 was assessed in two independent study cohorts containing 280 patients with HCC. Gene set enrichment analysis (GSEA) was performed to explore the signaling pathway of Piezo1. A series of in vitro and in vivo experiments were used to determine the role and molecular mechanism of Piezo1 in HCC progression. Results Piezo1 expression was significantly upregulated in HCC tissues and cell lines. High Piezo1 expression was closely correlated with aggressive clinicopathological features, poor clinical outcomes of HCC patients. Moreover, knockdown of Piezo1 in HCCLM3 and Hep3B cells significantly inhibited proliferation, migration, invasion and epithelial–mesenchymal transition (EMT) of HCC cells in vitro, and tumor growth, EMT and metastasis in vivo. Further mechanism study indicated that these phenotypic and function changes were mediated by TGF-β signaling pathway. Finally, we proved that Piezo1 exerted its tumor promotion effect by recruiting Rab5c to activating TGF-β signaling pathway. Conclusions We proved Piezo1 promotes progression of hepatocellular carcinoma via TGF-β signaling, which may serve as a novel prognostic predictor and the potential therapeutic target for HCC patients.

scholarly journals Genome-Wide Lymphocytic mRNA Sequencing to Identify Epithelial-Mesenchymal Transition Mechanism in Silicosis

2021 ◽  
Author(s):  
Hai bin Li ◽  
Lin Zhang ◽  
Yi Guan ◽  
Yingzheng Zhao ◽  
Ning Li ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Signaling Pathway ◽  
Peripheral Blood ◽  
Epithelial Mesenchymal Transition ◽  
Janus Kinase ◽  
Gene Set Enrichment Analysis ◽  
Healthy Controls ◽  
Blood Samples ◽  
Mesenchymal Transition ◽  
Transition Mechanism

Abstract Background Lymphocytes are immune cells that play dual roles in the pathogenesis of silicosis. Epithelial-mesenchymal transition (EMT), a vital phenomenon in the pathogenesis of silicosis, is regulated by cytokines, chemokines, and other molecules secreted by lymphocytes; however, the underlying regulatory mechanism is unclear. Here, we investigated the role of lymphocytes in EMT in silicosis. Methods Three patients with silicosis and three healthy controls that underwent pre-job physical examination were recruited; fasting venous blood samples were collected and lymphocytes were separated by Ficoll. High-throughput sequencing technology and bioinformatic analysis were used to identify specific genes and signaling pathways. The results were verified through the detection of related indices of peripheral blood samples. Results The baseline characteristics of subjects from silicosis group were matched with those of healthy controls. In comparison with healthy controls, patients with silicosis showed 1915 dysregulated genes that were thought to participate in various biological processes, including angiogenesis, tissue repair, cell proliferation, invasion, migration, and EMT. Protein-protein interaction analysis grouped these genes into three hub targets, including phosphoinositide 3-kinase (PI3K), integrin beta 1 (ITGB1), and integrin-linked protein kinase (ILK). Gene set enrichment analysis (GSEA) confirmed that PI3K, ITGB1, and ILK were tightly associated with EMT through the Wnt signaling pathway, Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling pathway, and cell adhesion molecular pathway. ITGB1 is a member of the adhesion molecule family. The identified genes were verified through the detection of soluble adhesion molecules in peripheral blood samples of patients with silicosis and healthy subjects. Conclusion Dysregulation of PI3K, ITGB1, and ILK in lymphocytes may contribute to EMT via JAK-STAT, Wnt, and cell adhesion molecular pathways in patients with silicosis.

scholarly journals Crk and CrkL as Therapeutic Targets for Cancer Treatment

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 739
Author(s):  
Taeju Park
Keyword(s):  
Tumor Cell ◽  
Cancer Treatment ◽  
Epithelial Mesenchymal Transition ◽  
Human Cancer ◽  
Therapeutic Targets ◽  
Viral Oncoprotein ◽  
Mesenchymal Transition ◽  
Chemotherapy Drugs ◽  
Cell Functions

Crk and CrkL are cellular counterparts of the viral oncoprotein v-Crk. Crk and CrkL are overexpressed in many types of human cancer, correlating with poor prognosis. Furthermore, gene knockdown and knockout of Crk and CrkL in tumor cell lines suppress tumor cell functions, including cell proliferation, transformation, migration, invasion, epithelial-mesenchymal transition, resistance to chemotherapy drugs, and in vivo tumor growth and metastasis. Conversely, overexpression of tumor cells with Crk or CrkL enhances tumor cell functions. Therefore, Crk and CrkL have been proposed as therapeutic targets for cancer treatment. However, it is unclear whether Crk and CrkL make distinct or overlapping contributions to tumor cell functions in various cancer types because Crk or CrkL have been examined independently in most studies. Two recent studies using colorectal cancer and glioblastoma cells clearly demonstrated that Crk and CrkL need to be ablated individually and combined to understand distinct and overlapping roles of the two proteins in cancer. A comprehensive understanding of individual and overlapping roles of Crk and CrkL in tumor cell functions is necessary to develop effective therapeutic strategies. This review systematically discusses crucial functions of Crk and CrkL in tumor cell functions and provides new perspectives on targeting Crk and CrkL in cancer therapy.

scholarly journals CHN1 promotes epithelial–mesenchymal transition via the Akt/GSK-3β/Snail pathway in cervical carcinoma

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Haoqi Zhao ◽  
Lan Wang ◽  
Shufang Wang ◽  
Xihua Chen ◽  
Min Liang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Lymph Node ◽  
Signaling Pathway ◽  
Cervical Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Xenograft Tumor ◽  
Mesenchymal Transition ◽  
Gsk 3Β ◽  
Related Proteins

Abstract Background Metastasis and invasion are crucial in determining the mortality of cervical carcinoma (CC) patients. The epithelial–mesenchymal transition (EMT) is now a universal explanation for the mechanisms of tumor metastasis. Α-chimeric protein (α-chimaerin, CHN1) plays an important role in the regulation of signal transduction and development. However, the molecular regulatory relationships between CHN1 and CC progression in relation to EMT have not yet been identified. Methods The expression of CHN1 in CC tissues, adjacent tissues, and lymph node metastases from CC patients was detected by immunohistochemistry. Upregulation and knockdown of CHN1 were achieved by transfection of CC cells. The effect of CHN1 on cell proliferation was determined by CCK-8 and plate clone formation assays. Changes in migration and invasion capabilities were evaluated using scratch migration and transwell invasion assays. The effect of CHN1 overexpression and interference on xenograft tumor growth was determined by tumor weight and pathological analyses. The expression of EMT-related mRNAs was measured by qRT-PCR in transfected CC cells. EMT-related proteins and Akt/GSK-3β/Snail signaling pathway-related proteins were also evaluated by western blotting. Results CHN1 was overexpressed in CC tissues and was associated with lymph node metastasis and low survival in CC patients. Overexpression of CHN1 promoted cell proliferation, migration, and invasion in CC cells. In contrast, silencing of CHN1 inhibited these phenomena. Overexpression of CHN1 promoted tumor formation in an in vivo xenograft tumor mouse model, with increased tumor volumes and weights. In addition, CHN1 induced the expression of EMT-related transcription factors, accompanied by the decreased expression of epithelial markers and increased expression of mesenchymal markers. The Akt/GSK-3β/Snail signaling pathway was activated by overexpression of CHN1 in vitro, and activation of this pathway was inhibited by the signaling pathway inhibitor LY294002. Conclusion These results suggest that CHN1 promotes the development and progression of cervical carcinoma via the Akt/GSK-3β/Snail pathway by inducing EMT.

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