Utilizing a structure-based virtual screening approach to discover potential LSD1 inhibitors.

BACKGROUND: Lysine-specific demethylase 1 (LSD1) is highly expressed in a variety of malignant tumors, rendering it a crucial epigenetic target for anti-tumor therapy. Therefore, the inhibition of LSD1 activity has emerged as a promising innovative therapeutic approach for targeted cancer treatment. METHODS: In our study, we employed innovative structure-based drug design methods to meticulously select compounds from the ZINC15 database. Utilizing virtual docking, we evaluated docking scores and binding modes to identify potential inhibitors. To further validate our findings, we harnessed molecular dynamic simulations and conducted meticulous biochemical experiments to deeply analyze the binding interactions between the protein and compounds. RESULTS: Our results showcased that ZINC10039815 exhibits an exquisite binding mode with LSD1, fitting perfectly into the active pocket and forming robust interactions with multiple critical residues of the protein. CONCLUSIONS: With its significant inhibitory effect on LSD1 activity, ZINC10039815 emerges as a highly promising candidate for the development of novel LSD1 inhibitors.

Significance of NotchScore and JAG1 in predicting prognosis and immune response of low-grade glioma.

Introduction: Low-grade glioma (LGG) is a prevalent malignant tumor in the intracranial region. Despite the advancements in treatment methods for this malignancy over the past decade, significant challenges still persist in the form of drug resistance and tumor recurrence. The Notch signaling pathway plays essential roles in many physiological processes as well as in cancer development. However, the significance of the pathway and family genes in LGG are poorly understood. Methods: We conducted gene expression profiling analysis using the TCGA dataset to investigate the gene set associated with the Notch signaling pathway. we have proposed a metric called "NotchScore" that quantifies the strength of the Notch signaling pathway and enables us to assess its significance in predicting prognosis and immune response in LGG. We downregulated JAG1 in low-grade gliomas to assess its influence on the proliferation and migration of these tumors. Ultimately, we determined the impact of the transcription factor VDR on the transcription of PDL1 through chip-seq data analysis. Results: Our findings indicate that tumors with a higher NotchScore, exhibit poorer prognosis, potentially due to their ability to evade the anti-tumor effects of immune cells by expressing immune checkpoints. Among the genes involved in the Notch signaling pathway, JAG1 has emerged as the most representative in terms of capturing the characteristics of both NotchScore and Notch pathways. The experimental results demonstrate that silencing JAG1 yielded a significant decrease in tumor cell proliferation in LGG cell lines. Our study revealed mechanisms by which tumors evade the immune system through the modulation of PDL1 transcription levels via the PI3K-Akt signaling pathway. Additionally, JAG1 potentially influences PDL1 in LGG by regulating the PI3K-Akt signaling pathway and the expression of the transcription factor VDR. Discussion: These findings contribute to our understanding of immune evasion by tumors in LGG. The insights gained from this research may have implications for the development of therapeutic interventions for LGG.

LncRNA AGPG Confers Endocrine Resistance in Breast Cancer by Promoting E2F1 Activity.

Resistance to endocrine therapy represents a major concern for patients with estrogen receptor α-positive (ERα+) breast cancer. Endocrine therapy resistance is commonly mediated by activated E2F signaling. A better understanding of the mechanisms governing E2F1 activity in resistant cells could reveal strategies for overcoming resistance. Here, we identified the long noncoding RNA (lncRNA) actin gamma 1 pseudogene 25 (AGPG) as a regulator of E2F1 activity in endocrine-resistant breast cancer. Expression of AGPG was increased in endocrine-resistant breast cancer cells, which was driven by epigenomic activation of an enhancer. AGPG was also abnormally upregulated in patient breast tumors, especially in the luminal B subtype, and high AGPG expression was associated with poor survival of patients with ERα+ breast cancer receiving endocrine therapy. The upregulation of AGPG mediated resistance to endocrine therapy and cyclin-dependent kinase 4/6 inhibition in breast cancer cells. Mechanistically, AGPG physically interacted with PURα, thus releasing E2F1 from PURα and leading to E2F1 signaling activation in ERα+ breast cancer cells. In patients with breast cancer, E2F1 target genes were positively and negatively correlated with expression of AGPG and PURα, respectively. Coadministration of chemically modified AGPG siRNA and tamoxifen strongly suppressed tumor growth in endocrine-resistant cell line-derived xenografts. Together, these results demonstrate that AGPG can drive endocrine therapy resistance and indicate that it is a promising biomarker and potential therapeutic target in breast cancer. SIGNIFICANCE: Blockade of formation of the PURα/E2F1 complex by lncRNA AGPG activates E2F1 and promotes endocrine resistance, providing potential strategies for combatting endocrine-resistant breast cancer.

A Comprehensive Analysis Revealing FBXW9 as a Potential Prognostic and Immunological Biomarker in Breast Cancer.

The WD40 repeat-containing F-box proteins (FBXWs) family belongs to three major classes of F-box proteins. Consistent with the function of other F-box proteins, FBXWs are E3 ubiquitin ligases to mediate protease-dependent protein degradation. However, the roles of several FBXWs remain elusive. In the present study, via integrative analysis of transcriptome profiles from The Cancer Genome Atlas (TCGA) datasets, we found that FBXW9 was upregulated in the majority of cancer types, including breast cancer. FBXW expression was correlated with the prognosis of patients with various types of cancers, especially for FBXW4, 5, 9, and 10. Moreover, FBXWs were associated with infiltration of immune cells, and expression of FBXW9 was associated with poor prognosis of patients receiving anti-PD1 therapy. We predicted several substrates of FBXW9, and TP53 was the hub gene in the list. Downregulation of FBXW9 increased the expression of p21, a target of TP53, in breast cancer cells. FBXW9 was also strongly correlated with cancer cell stemness, and genes correlated with FBXW9 were associated with several MYC activities according to gene enrichment analysis in breast cancer. Cell-based assays showed that silencing of FBXW9 inhibited cell proliferation and cell cycle progression in breast cancer cells. Our study highlights the potential role of FBXW9 as a biomarker and promising target for patients with breast cancer.

IFN-α-2b Reduces Postoperative Arthrofibrosis in Rats by Inhibiting Fibroblast Proliferation and Migration through STAT1/p21 Signaling Pathway.

Objective: To investigate the effect of IFN-α-2b in preventing postoperative arthrofibrosis in rats, its antiproliferation effect on fibroblasts in vitro, and its molecular mechanism. Methods: The rat model of arthrofibrosis was established and treated with different concentrations of drugs. Knee specimens were collected for histological and immunohistochemical staining to observe the effect of IFN-α-2b on arthrofibrosis in rats. The biological information was further mined according to the database data, and the possible regulatory mechanism of IFN-α-2b on fibroblasts was analyzed. The inhibitory effect of IFN-α-2b on fibroblast proliferation and migration in vitro was detected by cell counting kit-8 (CCK-8), immunofluorescence analysis, cell cycle test, EdU assay, wound healing test, and Transwell method, and the analysis results were verified by Western blotting method. Results: The test results of rat knee joint specimens showed that IFN-α-2b significantly inhibited the degree of fibrosis after knee joint surgery, the number of fibroblasts in the operation area was less than that of the control group, and the expression of collagen and proliferation-related proteins decreased. In vitro experimental results show that IFN-α-2b can inhibit the proliferation and migration of fibroblasts. According to the results of database analysis, it is suggested that the STAT1/P21 pathway may be involved, and it has been verified and confirmed by Western blotting and other related methods. Conclusion: IFN-α-2b can reduce surgery-induced arthrofibrosis by inhibiting fibroblast proliferation and migration, which may be related to the regulation of STAT1/p21 signaling pathway.

Integrative analyses of bulk microarray data to discover genes, pathways, and immune infiltration characteristics associated with targeting of Ewing sarcoma.

PURPOSE: To explore transcriptome and immunological features of patients with Ewing sarcoma (ES) using all publicly available microarray data. METHODS: Data of 479 ES tissues were integrated and normalized. Gene expression, immune infiltration, and cancer-specific pathways were analyzed. Genes of interest were knocked down, followed by cell proliferation and colony formation assays. RESULTS: Consistent with the previous reports of differential expressed genes (DEGs) in ES, our analysis identified CCND1, HMCN1, and NKX2-2 were among the most highly expressed, while TWNC1, MYBPC1, and CKM were among the lowest expressed genes. GO, KEGG, and GSEA enrichment analysis identified that the DEGs related to bone and muscle functioning, those that contributed to crucial cellular, and metabolism pathways such as actin binding, apoptosis, TCA cycle, and cell cycle were also significantly enriched. Immune infiltration analysis discovered that many T cell subsets including CD4T, CD8 T, and Gamma delta T cells were highly infiltrated, while monocytes and B cells were less infiltrated in tumors. A total of 138 genes were both significantly up-regulated in tumors and associated with decreased survival, while 38 significantly down-regulated genes were associated with increased survival, many of which were previously reported as oncogenes and tumor suppressors in ES and other cancers. Silencing of four newly identified top ranked up-regulated genes with decreased survivals in ES inhibited proliferation and colony formation of ES cells. CONCLUSION: This study may provide a clear representative transcriptome profile of ES, providing diagnostic biomarkers, pathways, and immune infiltrative characteristics targets for ES.

Quercetin inhibits fibroblasts proliferation and reduces surgery-induced epidural fibrosis via the autophagy-mediated PI3K/Akt/mTOR pathway.

Epidural fibrosis (EF) is a serious complication when the patients suffer from operations of lumbar laminectomy. It is reported that quercetin plays a positive role in the prevention of various fibrotic diseases. However, the role of quercetin in the prevention of epidural fibrosis (EF) and its possible mechanism are unclear. Fibroblast proliferation is considered to be the main cause of epidural fibrosis.Autophagy is a lysosomal degradation pathway that is essential for survival, differentiation, development, and homeostasis.Although autophagy has been associated with fibrosis of different tissues, the effect of autophagy on epidural fibrosis is still unknown.The aim of this study was to investigate the function and mechanism of autophagy induced by quercetin, a polyphenol derived from plants. In vivo, the effect of quercetin on reducing epidural fibrosis was confirmed via histological staining and immunohistochemical analysis. The results showed that quercetin had significant suppressive effects on epidural fibrosis following laminectomy in rats.In vitro,, cell counting kit-8 (CCK-8), Western blot analysis, immunofluorescence and Edu staining, TUNEL staining and transmission electron microscopy were used to detect the effects of quercetin on the proliferation and apoptosis of fibroblasts and explore the possible signal transduction pathway. Results indicated that quercetin could induce autophagy and inhibit proliferation in fibroblasts. In conclusion, Quercetin could regulate fibroblast proliferation, apoptosis, migration and other biological behaviors through autophagy, thereby preventing epidural fibrosis. The specific corresponding pathway may be the PI3K/Akt/mTOR signaling pathway.

IFN-α-2b Inhibits the Proliferation and Migration of Fibroblasts via the TGFß/Smad Signaling Pathway to Reduce Postoperative Epidural Fibrosis.

Epidural fibrosis after lumbar laminectomy refers to a serious complication, and excessive proliferation of fibroblasts is considered the major factor. Interferon-alpha-2b (IFN-α-2b) can exert antiviral and antiproliferative effects, which has been suggested to effectively prevent several fibrotic diseases. However, the effect of IFN-α-2b on the prevention of epidural fibrosis (EF) and its possible mechanism remain unclear. In this study, in vitro and in vivo experiments were performed to examine the possible mechanism of IFN-α-2b for preventing EF. Cell counting kit-8 (CCK-8), cell cycle test, Edu incorporation, wound healing assay, transwell test, and Western blotting assay were performed to investigate the inhibitory effect of IFN-α-2b on the proliferation and migration of fibroblasts in vitro. As indicated from the results, IFN-α-2b was capable of inhibiting proliferation and migration of fibroblasts and inhibiting the activity of the transforming growth factor ß (TGFß)/Smad signaling pathway. In vivo, the effect of IFN-α-2b on the reduction of EF was determined by performing histological macroscopic evaluation and histological and immunohistochemical staining. As suggested from the results, IFN-α-2b significantly inhibited EF after laminectomy. As revealed from the mentioned results, IFN-α-2b may have a promising application for preventing EF in the future.