Integrating network pharmacology, molecular docking and experimental verification to explore the therapeutic effect and potential mechanism of nomilin against triple-negative breast cancer.

BACKGROUND: Nomilin is a limonoid compound known for its multiple biological activities, but its role in triple negative breast cancer (TNBC) remains unclear. This study aims to uncover the potential therapeutic effect of nomilin on TNBC and elucidate the specific mechanism of its action. METHODS: We employed weighted gene co-expression network analysis (WGCNA), differential expression analysis, and the GeneCards database to identify potential targets for TNBC. Simultaneously, we utilized the Swiss Target Prediction, ChEMBL, and STITCH databases to identify potential targets of nomilin. The core targets and mechanisms of nomilin against TNBC were predicted through protein-protein interaction (PPI) network analysis, molecular docking, and enrichment analysis. The results of the network pharmacology were corroborated by conducting experiments. RESULTS: A total of 17,204 TNBC targets were screened, and 301 potential targets of nomilin were identified. Through the PPI network, eight core targets of nomilin against TNBC were pinpointed, namely BCL2, Caspase3, CyclinD1, EGFR, HSP90AA1, KRAS, PARP1, and TNF. Molecular docking, molecular dynamics simulation and proteome microarray revealed that nomilin exhibits strong binding activity to these core proteins. Enrichment analysis results indicated that the anti-TNBC effect of nomilin is associated with PI3K/Akt pathway. In vitro and in vivo experiments have demonstrated that nomilin inhibits TNBC cell proliferation and migration while promoting cell apoptosis through the PI3K/Akt pathway. CONCLUSION: For the first time, the research effectively discovered the objectives and mechanisms of nomilin in combating TNBC using network pharmacology, molecular docking, molecular dynamics simulation, proteome microarray and experimental confirmation, presenting a hopeful approach for treating TNBC.

CircZFR promotes colorectal cancer progression via stabilizing BCLAF1 and regulating the miR-3127-5p/RTKN2 axis.

Aberrant expression of circular RNAs (circRNAs) is frequently linked to colorectal cancer (CRC). Here, we identified circZFR as a promising biomarker for CRC diagnosis and prognosis. CircZFR was upregulated in CRC tissues and serum exosomes and its level was linked to cancer incidence, advanced-stages, and metastasis. In both in vitro and in vivo settings, circZFR promoted the growth and spread while suppressing apoptosis of CRC. Exosomes with circZFR overexpression promoted the proliferation and migration of cocultured CRC cells. Mechanistically, epithelial splicing regulatory protein 1 (ESRP1) in CRC cells may enhance the production of circZFR. BCL2-associated transcription factor 1 (BCLAF1) bound to circZFR, which prevented its ubiquitinated degradation. Additionally, circZFR sponged miR-3127-5p to boost rhotekin 2 (RTKN2) expression. Our TCP1-CD-QDs nanocarrier was able to carry and deliver circZFR siRNA (si-circZFR) to the vasculature of CRC tissues and cells, which inhibited the growth of tumors in patient-derived xenograft (PDX) models. Taken together, our results show that circZFR is an oncogenic circRNA, which promotes the development and spread of CRC in a BCLAF1 and miR-3127-5p-dependent manner. CircZFR is a possible serum biopsy marker for the diagnosis and a desirable target for further treatment of CRC.

microRNA-15a-5p suppresses hypoxia-induced tumor growth and chemoresistance in bladder cancer by binding to eIF5A2.

In various malignant tumors (including bladder cancer) poor prognosis is associated with hypoxia and therapeutic resistance. Evidence indicates that in bladder cancer, microRNAs (miRNAs) have vital functions in acquired drug resistance. However, the involvement of miRNAs in hypoxia-mediated bladder cancer doxorubicin (Dox) resistance is unknown. Herein, we showed that hypoxia and Dox treatment downregulated miR-15a-5p expression. Using UM-UC-3 and J82 bladder cancer cell lines and in vivo mouse models of bladder cancer, we confirmed that miR-15a-5p arrests tumor cell growth and Dox resistance in vitro and in vivo. Furthermore, we determined the interaction between miR-15a-5p and eukaryotic translation initiation factor 5A-2 (eIF5A2) using dual luciferase reporters and quantitative real-time reverse transcription polymerase chain reaction assays. We also showed that a miR-15a-5p agomir repressed EIF5A2 expression in bladder cancer cells, thereby inhibiting the epithelial-mesenchymal transition (EMT) induced by Dox or hypoxia. Moreover, ectopic expression of miR-15a-5p abrogated eIF5A2-mediated Dox resistance in bladder cancer cells. Collectively, these data indicated that hypoxia promotes tumor growth and chemoresistance through the HIF-1α/miR-15a-5p/eIFTA2/EMT pathway. This new finding not only has implications for improving our understanding of the Dox resistance process during bladder cancer progression but also indicates that the miR-15a-5p agomir is a promising tool to prevent Dox resistance in patients with bladder cancer.

Construction and validation of a novel algorithm based on oncosis-related lncRNAs comprising the immune landscape and prediction of colorectal cancer prognosis.

Colorectal cancer (CRC) has high morbidity and mortality, particularly if diagnosed at an advanced stage. Although there have been several studies on CRC, few have investigated the relationship between oncosis and CRC. Thus, the purpose of the present study was to identify oncosis-related long noncoding RNAs (lncRNAs) and to establish a clinical prognostic model. Original data were acquired from The Cancer Genome Atlas database and PubMed. Differentially expressed oncosis-related lncRNAs (DEorlncRNAs) were identified and were subsequently formed into pairs. Next, a series of tests and analyses, including both univariate and multivariate analyses, as well as Lasso and Cox regression analyses, were performed to establish a receiver operating characteristic curve. A cut-off point was subsequently used to divide the samples into groups labelled as high- or low-risk. Thus, a model was established and evaluated in several dimensions. Six pairs of DEorlncRNAs associated with prognosis according to the algorithm were screened out and the CRC cases were divided into high- and low-risk groups. Significant differences between patients in the different risk groups were observed for several traits, including survival outcomes, clinical pathology characteristics, immune cell infiltration status and drug sensitivity. In addition, PCR and flow cytometry were performed to further verify the model. In summary, a new risk model algorithm based on six pairs of DEorlncRNAs in CRC, which does not require specific data regarding the level of gene expression, was established and validated. This algorithm may be used to predict patient prognosis, immune cell infiltration and drug sensitivity.

Autophagy inhibits the mesenchymal stem cell aging induced by D-galactose through ROS/JNK/p38 signalling.

Autophagy and cellular senescence are two critical responses of mammalian cells to stress and may have a direct relationship given that they respond to the same set of stimuli, including oxidative stress, DNA damage, and telomere shortening. Mesenchymal stem cells (MSCs) have emerged as reliable cell sources for stem cell transplantation and are currently being tested in numerous clinical trials. However, the effects of autophagy on MSC senescence and corresponding mechanisms have not been fully evaluated. Several studies demonstrated that autophagy level increases in aging MSCs and the downregulation of autophagy can delay MSC senescence, which is inconsistent with most studies that showed autophagy could play a protective role in stem cell senescence. To further study the relationship between autophagy and MSC senescence and explore the effects and mechanisms of premodulated autophagy on MSC senescence, we induced the up- or down-regulation of autophagy by using rapamycin (Rapa) or 3-methyladenine, respectively, before MSC senescence induced by D-galactose (D-gal). Results showed that pretreatment with Rapa for 24 hours remarkably alleviated MSC aging induced by D-gal and inhibited ROS generation. p-Jun N-terminal kinases (JNK) and p-38 expression were also clearly decreased in the Rapa group. Moreover, the protective effect of Rapa on MSC senescence can be abolished by enhancing the level of ROS, and p38 inhibitor can reverse the promoting effect of H2 O2 on MSC senescence. In summary, the present study indicates that autophagy plays a protective role in MSC senescence induced by D-gal, and ROS/JNK/p38 signalling plays an important mediating role in autophagy-delaying MSC senescence.