TMEA, a Polyphenol in Sanguisorba officinalis, Promotes Thrombocytopoiesis by Upregulating PI3K/Akt Signaling.
Ontology highlight
ABSTRACT:
SUBMITTER: Li H
PROVIDER: S-EPMC8416095 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveEstrogen is an important hormone affecting angiogenesis in women and is important for female physical development. Menopausal women are prone to serious cardiovascular and cerebrovascular diseases when estrogen is significantly reduced. Bone marrow mesenchymal stem cells (BMSC) have potential roles in processes such as angiogenesis and remodeling. This study is to investigate the effect of 17β-estradiol on BMSC angiogenic differentiation and its underlying molecular mechanism, and to provide a basis for the treatment of microvascular diseases.MethodsEnrichment analysis of apoptosis, migration or angiogenesis processes and molecular mechanisms of BMSC treated with 17β-estradiol was performed to screen core proteins and perform molecular docking validation. Human MSCs were cultured in vitro to examine the effect of 17β-estradiol on BMSC migration or angiogenic differentiation.Results17β-estradiol acted on 48 targets of BMSC and was involved in regulating 52 cell migration processes or 17 angiogenesis processes through 66 KEGG pathways such as PI3K-Akt, MAPK, etc. 17β-estradiol bound tightly to 10 core proteins including APP, NTRK1, EGFR, and HSP90AA1. 17β-estradiol promoted cell scratch area closure rate and CD31 expression in BMSCs, downregulated BMSC apoptosis rate, and promoted Akt and p-Akt protein expression in BMSC.Conclusion17β-estradiol binds to FN1, MCM2, XPO1, NTRK1 and other proteins to initiate PI3K-Akt, MAPK and other signaling pathways, so as to regulate BMSC to promote or remodel angiogenesis, verifying that 17β-estradiol up-regulates PI3K-Akt signaling pathway to promote BMSC angiogenic differentiation.
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Project description:BackgroundOur previous bioinformatics-based study found that midkine (MDK) was associated with poor prognosis of glioblastoma (GBM). However, the mechanism of MDK in GBM remains elusive.MethodsA public GBM-related dataset and GBM tissues from our center were used validate the aberrant expression of MDK in GBM at the RNA and protein levels. The relationship between MDK expression and survival of GBM patients was also explored through survival analysis. Subsequently, we identified MDK-related GBM-specific genes using differential expression analysis. Functional enrichment analyses were performed to reveal their potential biological functions. CCK-8, 5-ethynyl-2'-deoxyuridine, and Matrigel-transwell assays were performed in GBM cell lines in which MDK was knocked out or overexpressed in order assess the effects of MDK on proliferation, migration, and invasion of GBM cells. Western blotting was performed to detect candidate proteins.ResultsOur study showed MDK is a promising diagnostic and prognostic biomarker for GBM because it is highly expressed in the disease and it is associated with poor prognosis. MDK is involved in various cancer-related pathways, such as PI3K-Akt signaling, the cell cycle, and VEGF signaling. A comprehensive transcriptional regulatory network was constructed to show the potential pathways through which MDK may be involved in GBM. In vitro, Overexpression of MDK augmented proliferation, migration, and invasion of GBM cell lines, whereas suppression of MDK led to the opposite effects. Furthermore, our study confirmed that MDK promotes the progression of GBM by activating the PI3K-Akt signaling pathway.ConclusionsOur present study proposes that MDK promotes GBM by activating the PI3K-Akt signaling pathway, and it describes a potential regulatory network involved.
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Project description:BackgroundRing finger protein 135 (RNF135) is an E3 ubiquitin ligase that has been implicated in the tumorigenesis of multiple human malignancies. However, whether RNF135 plays a role in the development of human osteosarcoma (OS) remains unknown.MethodsRNF135 expression in 20 human OS and 20 human osteochondroma specimens were evaluated by means of immunohistochemistry staining. The effects of shRNA-mediated RNF135 knockdown on human OS cell growth and apoptosis were evaluated through a panel of in vitro studies on cell proliferation, colony formation, exposure of phosphatidylserine on the cell surface, and caspase 3/7 activation. The protein levels of PI3K, AKT, and p-AKT were determined by western blot analysis.ResultsWe detected significantly higher RNF135 levels in human OS tissues than human osteochondroma tissues. In in vitro studies, shRNA-mediated RNF135 knockdown in human OS cells inhibited proliferation and induced apoptosis. In addition, RNF135 knockdown reduced PI3K and p-AKT protein levels and activated caspase 3 and 7.ConclusionsThese results supported that RNF135 contributes to human OS development through PI3K/AKT-dependent mechanisms. Targeting RNF135 may provide a new therapeutic approach for treating this human malignancy.
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Project description:Sanguisorba officinalis L., a traditional Chinese medicine (TCM) called DiYu (DY) in China, has a strong tradition of utilization as a scorching, blood-cooling, and hemostatic medication, and was used for cancer prevention and treatment due to its potential immune-enhancing and hematological toxicity-reducing effects. Previous studies have reported significant effects of DY on cancers including colorectal cancer (CRC), which is one of the most common malignancies worldwide. The first-line cure 5-fluorouracil (5-FU) plays decisive commerce in the sedative of CRC as a clinically available chemotherapeutic agent. One of the primary causes of cancer treatment failure is the acquisition of chemotherapy drug resistance. In order to successfully combat the emergence of chemoresistance, it is essential to identify herbs or traditional Chinese medicine that have adjuvant therapeutic effects on CRC. Therefore, this study aimed to determine whether DY could improve the sensitivity, conquer the chemoresistance of 5-FU-resistant CRC cells, and investigate its intrinsic mechanism.Materials and methodsMTT, Hoechst 33258 staining, and flow cytometry assays were used to determine the anticancer activity of DY alone or in combination with 5-FU against 5-FU-resistant CRC cells (RKO-R and HCT15-R) and wound healing assays were conducted to detect cell migration. Transcriptomic techniques were carried out to explore the effect and mechanism of DY on drug-resistant CRC cells. Western Blot and RT q-PCR assays were performed to validate the mechanism by which DY overcomes drug-resistant CRC cells.ResultsThese results indicated that DY alone or in combination with 5-FU significantly inhibited the proliferation and the migration of resistant CRC cells, and potentiated the susceptibility of 5-FU to drug-resistant CRC cells. GO and KEGG enrichment analysis showed that the mechanisms of drug resistance in CRC cells and DY against drug-resistant CRC cells highly overlapped, involved in the modulation of biological processes such as cell migration, positive regulation of protein binding and cytoskeleton, and MAPK (Ras-ERK-MEK), PI3K/Akt, and other signaling pathways. Moreover, DY can mediate the expression of p-R-Ras, p-ERK1/2, p-MEK1/2, p-PI3K, p-AKT, HIF-1A and VEGFA proteins. In addition, DY significantly suppressed the expression of AKT3, NEDD9, BMI-1, and CXCL1 genes in resistant CRC cells.ConclusionIn conclusion, DY could inhibit the proliferation and migration of 5-FU-resistant cells and strengthen the sensitivity of 5-FU to CRC-resistant cells. Furthermore, DY may prevail over chemoresistance through the Ras/MEK/ERK and PI3K/Akt pathways. These findings imply that DY may be a potential drug for clinical treatment or adjuvant treatment of drug-resistant CRC.
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Project description:PurposeThe PI3K/Akt signaling axis contributes to the dysregulation of many dominant features in breast cancer including cell proliferation, survival, metabolism, motility, and genomic instability. While multiple studies have demonstrated that basal-like or triple-negative breast tumors have uniformly high PI3K/Akt activity, genomic alterations that mediate dysregulation of this pathway in this subset of highly aggressive breast tumors remain to be determined.MethodsIn this study, we present an integrated genomic analysis based on the use of a PI3K gene expression signature as a framework to analyze orthogonal genomic data from human breast tumors, including RNA expression, DNA copy number alterations, and protein expression. In combination with data from a genome-wide RNA-mediated interference screen in human breast cancer cell lines, we identified essential genetic drivers of PI3K/Akt signaling.ResultsOur in silico analyses identified SOX4 amplification as a novel modulator of PI3K/Akt signaling in breast cancers and in vitro studies confirmed its role in regulating Akt phosphorylation.ConclusionsTaken together, these data establish a role for SOX4-mediated PI3K/Akt signaling in breast cancer and suggest that SOX4 may represent a novel therapeutic target and/or biomarker for current PI3K family therapies.
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Project description:BackgroundHepatocellular carcinoma is one of the most common and deadly cancers. The aim of this study was to elucidate the role of tRNA methyltransferase 6 (TRMT6) during HCC progression.MethodsThe role of TRMT6 in the progression and prognosis of HCC was confirmed by analysis of online databases and clinical human samples. The effects of up-regulation or down-regulation of TRMT6 on HCC cell proliferation and PI3K/AKT pathway-related protein expressions were verified. The molecular mechanism was investigated in vivo by constructing subcutaneous xenograft tumor model.ResultsTRMT6 was overexpressed in HCC tissues and associated with Tumour-Node-Metastasis (TNM) stage, primary tumor (T) and regional lymph node (N) classification. TRMT6 expressions in HCC cell lines were higher than that in normal liver cell. TRMT6 overexpression can promote HCC cell proliferation, increase the number of S phase cells. Interference with TRMT6 reduced the PI3K/AKT pathway-related protein expressions, and was reversed by the addition of IGF1. Interference with TRMT6 inhibited tumor growth in vivo and was related to PI3K/AKT pathway.ConclusionsOverexpression of TRMT6 promote HCC cell proliferation in vivo and in vitro through PI3K/AKT/mTOR axis, which provides a potential choice for the treatment of HCC in clinical practice.
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Project description:BackgroundNon-small cell lung cancer (NSCLC), the most prevalent type of human lung cancer, is characterized by many molecular abnormalities. SH2B1, a member of the SH2-domain containing family, have recently been shown to act as tumor activators in multiple cancers. The objective of this study was to investigate the role SH2B1 and the underlying molecular mechanism in NSCLC.MethodsCell functional analysis and cell line-derived xenograft model were performed to determine SH2B1 potential roles on NSCLC cell proliferation in vitro and in vivo. In vitro assays were performed to identify signal molecular mechanisms. Subsequently, 104 patients with NSCLC undergoing primary surgical resection were recruited to evaluated expression of SH2B1 and Akt/mTOR signaling markers by immunohistochemical staining to determine their clinicopathologic significance.ResultsModulation of SH2B1 expression levels had distinct effects on cell proliferation, cell cycle and apoptosis in the NSCLC cell lines A549 and H1299. At the molecular level, overexpression of SH2B1 resulted in the upregulation of the Akt/mTOR markers, p-Akt and p-mTOR, and downregulation of PTEN to promote NSCLC cell proliferation, while silencing SH2B1 had the opposite effect. In human NSCLC specimens, SH2B1 expression levels were positively associated with Akt/mTOR signaling pathway markers.ConclusionsThe SH2B1/Akt/mTOR/PTEN axis is required for regulating NSCLC cell proliferation and might prove to be a promising strategy for restraining tumor progression in NSCLC patients.
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