AIMSRecurrent miscarriage (RM) plagues 1 %-5 % women of childbearing age. Facing the limitations of clinical treatment, its pathological mechanism remains to be clarified.METHODSDecidual tissues of three induced abortions and three RM were collected for transcriptome sequencing. The pathological features of RM were identified by differential expression genes (DEGs) analysis, GSEA, GO and KEGG analysis, and a protein-protein interaction network was constructed for DEGs, and six algorithms were used to identify hub genes. In addition, the immune characteristics of RM patients were identified by CIBERSORT, and the correlation between them and hub genes was analyzed. Furthermore, in single-cell level, different cells were grouped according to the expression level of hub genes, and the expression ratio and abundance of hub genes in different cells and their regulation on cell function were explored.RESULTSTranscriptome sequencing of patients with RM showed that a large number of genes were down-regulated, which was related to fibroblast proliferation, epithelial cell migration, female pregnancy and cell chemotaxis. Fifteen hub genes were identified by constructing a protein-protein interaction network, among which DUSP1, NR4A1 and THBS1 were involved in cell migration and chemotaxis. Immune cell infiltration analysis showed that the infiltration of T cells, macrophages and NK cells was abnormal, and there was a significant correlation with hub genes. Moreover, we found that compared with the expression of DUSP1, the non-expression of DUSP1 will reduce the extracellular matrix formation of fibroblasts and the chemotaxis of macrophages. At the same time, it is worth noting that the expression ratio and abundance of hub genes are decreased in epithelial cells, fibroblasts, macrophages and NK cells. Furthermore, single-cell analysis and in vitro and in vivo experiments show that DUSP1 and NR4A1 are low-expressed in different cells of RM patients, which is accompanied by the inhibition of fibroblast proliferation and macrophage chemotaxis. Drug prediction and screening based on hub genes show that Cinobufagin and calmidazolium are expected to be candidate drugs for RM.CONCLUSIONHub genes such as DUSP1, NR4A1 and THBS1 participate in RM by regulating epithelial cell migration, fibroblast proliferation and macrophage chemotaxis, which will provide new insight for the diagnosis and targeted therapy of RM.

01 Nov 2024·Biotechnology and Genetic Engineering Reviews

Cinobufacini suppresses malignant behaviors of endometrial cancer by regulating NF-κB pathway

Article

Author: Liu, Xiaoyun ; Sun, Mengyi ; Xu, Yintao ; Han, Xiaodao

Cinobufagin has inhibitory effects on various tumors, but there are few studies on gynecological tumors. This study explored the function and molecular mechanism of cinobufagin in endometrial cancer (EC). Different concentrations of cinobufagin treated EC cells (Ishikawa and HEC-1). Clone formation, methyl thiazolyl tetrazolium (MTT), flow cytometry, and transwell assays were used to detect malignant behaviors. A Western blot assay was performed to detect protein expression. Cinobufacini was sensitive to the inhibition of EC cell proliferation in a time- and concentration-dependent manner. Meanwhile, EC cell apoptosis was induced by cinobufacini. In addition, cinobufacini impaired the invasive and migratory abilities of EC cells. More importantly, cinobufacini blocked the nuclear factor kappa beta (NF-κB) pathway in EC by inhibiting p-IkBα and p-p65 expression. Cinobufacini suppresses malignant behaviors of EC by blocking the NF-κB pathway.

01 Oct 2024·Phytomedicine

Multi-omics reveals bufadienolide Q-markers of Bufonis Venenum based on antitumor activity and cardiovascular toxicity in zebrafish

Article

Author: Zhao, Haiyu ; Xia, Bo ; Si, Nan ; Bian, Baolin ; Liu, Huining ; Wang, Huijun ; Sun, Bo ; Jiang, Shan ; Wang, Hongjie ; Chen, Lihua ; Yang, Jiaying ; Liu, Yuyang ; Wei, Xiaolu

BACKGROUNDBufonis Venenum (BV) is a traditional animal-based Chinese medicine with therapeutic effects against cancer. However, its clinical use is significantly restricted due to associated cardiovascular risks. BV's value in China's market is typically assessed based on "content priority," focusing on indicator components. However, these components of BV possess both antitumor activity and toxicity, and the correlation between the antitumor activity and toxicity of BV has not yet been elucidated.PURPOSEThis study employs an integrated multi-omics approach to identify bufadienolide Q-markers and explore the correlation between BV's antitumor activity and toxicity. The aim is to establish a more comprehensive method for BV's quality.METHODSNormal zebrafish and HepG2 xenograft zebrafish were chosen as activity and toxicity evaluation models. Ultra-high performance liquid chromatography (UHPLC) coupled with a linear ion trap orbitrap (LTQ-Orbitrap) mass spectrometry was used to quantify eight batches of BV and key "toxic and effective" components were screened out. Transcriptomic and metabolomic analyses were performed to elucidate the regulatory mechanisms underlying the antitumor activity and cardiovascular toxicity of the key components in BV.RESULTSEight key "toxic and effective" compounds were identified: resibufogenin, cinobufagin, arenobufagin, bufotalin, bufalin, gamabufotalin, desacetylcinobufagin, and telocinobufagin. The findings showed that bufalin and cinobufagin interfered with calcium homeostasis through CaV and CaSR, induced cardiotoxicity, and upregulated CASP9 to activate myocardial cell apoptosis. However, desacetylcinobufagin exhibited greater potential in terms of anti-tumor effects. Combining the results of untargeted and targeted metabolomics revealed that desacetylcinobufagin could have a callback effect on differential lipids and correct abnormal energy and amino acid metabolism caused by cancer, similar to cinobufagin and bufalin. Microscale thermophoresis (MST) ligand binding measurements also showed that the binding of desacetylcinobufagin to GPX4 has a more potent ability to induce ferroptosis in tumor cells compared to cinobufagin.CONCLUSIONAn innovative evaluation method based on the zebrafish was developed to investigate the relationship between the toxicity and efficacy of BV. This study identified toxicity and activity Q-markers and explored the mechanism between the two effects of BV. The research data could offer valuable insights into the efficacy of BV. Additionally, desacetylcinobufagin, an active ingredient with low toxicity, was found to enhance the quality of BV.

100 Deals associated with Cinobufagin Oral Liquid

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Indication	Country/Location	Organization	Date
Hepatitis B, Chronic	CN	Anhui China Resources Jinchan Pharmaceutical Co., Ltd.	21 Sep 2020
Neoplasms	CN	Anhui China Resources Jinchan Pharmaceutical Co., Ltd.	21 Sep 2020

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