Telmisartan inhibits microglia-induced neurotoxic A1 astrocyte conversion via PPARγ-mediated NF-κB/p65 degradation.

Astrocytes are crucially involved in neuroinflammation. Activated astrocytes exhibit at least two phenotypes, A1 (neurotoxic) and A2 (neuroprotective). The A1 phenotype is the major reactive astrocyte phenotype involved in aging and neurodegenerative diseases. Telmisartan, which is an antihypertensive agent, is a promising neuroprotective agent. This study aimed to investigate the effects of telmisartan on the phenotype of reactive astrocytes. Astrocytes were activated by culturing with the conditioned medium derived from lipopolysaccharide-stimulated microglia. This conditioned medium induced early, transient A2 astrocyte conversion (within 24 h) and late, sustained A1 conversion (beginning at 24 h and lasting up to 7 days), with a concomitant increase in the production of pro-inflammatory cytokines (interleukin [IL]-1ß, tumor necrosis factor [TNF]α, and IL-6) and phosphorylation of nuclear factor-κB (NF-κB)/p65. Telmisartan treatment promoted and inhibited A2 and A1 conversion, respectively. Telmisartan reduced total and phosphorylated p65 protein levels. Losartan, a specific angiotensin II type-1 receptor (AT1R) blocker, did not influence the reactive state of astrocytes. Additionally, AT1R activation by angiotensin II did not induce the expression of pro-inflammatory cytokines and A1/A2 markers, indicating that the AT1R signaling pathway is not involved in the astrocyte-mediated inflammatory response. A peroxisome proliferator-activated receptor γ (PPARγ) antagonist reversed the effects of telmisartan. Moreover, telmisartan-induced p65 downregulation was reversed by the proteasome inhibitor MG132. These results indicate that telmisartan suppresses activated microglia-induced neurotoxic A1 astrocyte conversion through p65 degradation. Our findings contribute towards the elucidation of the anti-inflammatory activity of telmisartan in brain disorders.

Local and systemic effects of IDH mutations on primary glioma patients.

Adult gliomas are divided into isocitrate dehydrogenase (IDH) wild-type and IDH mutant subtypes according to the new 2021 World Health Organization classification system. However, the local and systemic effects of IDH mutations on primary glioma patients are not well illustrated. Retrospective analysis, immune-cell infiltration analysis, meta-analysis, and immunohistochemistry assay were applied in the present study. The results from our cohort showed that IDH mutant gliomas own a lower proliferating rate compared to that in wild-type gliomas. Patients with mutant IDH exhibited a higher frequency of seizures in both our cohort and the cohort from the meta-analysis. Mutations in IDH result in lower levels of intra-tumour but higher levels of circulating CD4+ and CD8+ T lymphocytes. Levels of neutrophils in both intra-tumour and circulating blood were lower in IDH mutant gliomas. Moreover, IDH mutant glioma patients receiving radiotherapy in combination with chemotherapy exhibited better overall survival with respect to radiotherapy alone. Mutations in IDH alters the local and circulating immune microenvironment, and increases the sensitivity of tumour cell to chemotherapy.

Palmitoyl transferases act as potential regulators of tumor-infiltrating immune cells and glioma progression.

High immune-cell infiltration in glioblastomas (GBMs) leads to immunotherapy resistance. Emerging evidence has shown that zinc finger Asp-His-His-Cyc-type (ZDHHC) palmitoyl transferases participate in regulating tumor progression and the immune microenvironment. In the present study, a large cohort of patients with gliomas from The Cancer Genome Atlas (TCGA) and Rembrandt databases was included to perform omics analysis of ZDHHCs in gliomas. CCK-8, flow cytometry, quantitative real-time PCR, western blotting, and transwell assays were performed to determine the effects of ZDHHC inhibition on glioma cells and microglia. We found that five (ZDHHC11, ZDHHC12, ZDHHC15, ZDHHC22, and ZDHHC23) out of 23 ZDHHCs were aberrantly expressed in gliomas and might play their roles through the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. Further results indicated that inhibition of ZDHHCs with 2-bromopalmitate (2-BP) suppressed glioma-cell viability and autophagy, as well as promoted apoptosis. Targeting ZDHHCs also promoted the sensitivity of glioma cells to temozolomide (TMZ) chemotherapy. In addition, the inhibition of ZDHHCs weakened the migratory ability of microglia induced by glioma cells in vitro and in vivo. Taken together, our findings suggest that the inhibition of ZDHHCs suppresses glioma-cell viability and microglial infiltration. Targeting ZDHHCs may be promising for glioma treatments.

Osteopontin improves sensitivity to tyrosine kinase inhibitor in lung adenocarcinoma in vitro by promoting epidermal growth factor receptor phosphorylation.

PURPOSE: Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) improve the prognosis of lung adenocarcinoma (LUAD). However, the factors affecting its clinical efficacy remain unclear. This study aimed to determine the correlation between Osteopontin (OPN) and EGFR, and explore the inhibitory effect of first-generation TKI gefitinib on LUAD cells. METHODS: The correlation between OPN and EGFR was determined through bioinformatics technology, and the clinical information as well as samples of related patients were collected to verify the relationship between them. Using three different NSCLC cell lines A549, H1299 and PC9, we studied the effects of OPN expression and EGFR phosphorylation on the first-generation TKI's efficacy in vitro. RESULTS: Our data revealed that OPN staining positively linked to a more advanced clinical stage. Compared with the control group, LUAD cells with elevated OPN levels are more sensitive to the growth inhibitory effect of TKI. Knocking down of OPN decreased the response of cells to gefitinib. Besides, OPN also upregulated the phosphorylation of EGFR, thereby affecting the effect of TKI. CONCLUSION: OPN enhanced the sensitivity of LUAD cells to gefitinib by promoting EGFR phosphorylation. OPN may be a potential target for evaluating TKI efficacy and a potential target for molecular therapy.

Identification and Validation of a Novel Prognosis Prediction Model in Adrenocortical Carcinoma by Integrative Bioinformatics Analysis, Statistics, and Machine Learning.

Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis. Thus, we aimed to establish a potential gene model for prognosis prediction of patients with ACC. First, weighted gene co-expression network (WGCNA) was constructed to screen two key modules (blue: P = 5e-05, R^2 = 0.65; red: P = 4e-06, R^2 = -0.71). Second, 93 survival-associated genes were identified. Third, 11 potential prognosis models were constructed, and two models were further selected. Survival analysis, receiver operating characteristic curve (ROC), Cox regression analysis, and calibrate curve were performed to identify the best model with great prognostic value. Model 2 was further identified as the best model [training set: P < 0.0001; the area under curve (AUC) value was higher than in any other models showed]. We further explored the prognostic values of genes in the best model by analyzing their mutations and copy number variations (CNVs) and found that MKI67 altered the most (12%). CNVs of the 14 genes could significantly affect the relative mRNA expression levels and were associated with survival of ACC patients. Three independent analyses indicated that all the 14 genes were significantly associated with the prognosis of patients with ACC. Six hub genes were further analyzed by constructing a PPI network and validated by AUC and concordance index (C-index) calculation. In summary, we constructed and validated a prognostic multi-gene model and found six prognostic biomarkers, which may be useful for predicting the prognosis of ACC patients.

Dysregulation of miR-138-5p/RPS6KA1-AP2M1 Is Associated With Poor Prognosis in AML.

Acute myeloid leukemia (AML) is a malignant disease of hematopoietic stem/progenitor cells, and most AML patients are in a severe state. Internal tandem duplication mutations in FLT3 gene (FLT3-ITD) detected in AML stem cells account for 20-30 percent of AML patients. In this study, we attempted to study the impact of the interaction of FLT3-ITD mutation and the CXCL12/CXCR4 axis in AML, and the possible mechanisms caused by the impact by bioinformatics. Gene set variation analysis (GSVA) revealed that the PI3K-Akt-mTOR pathway positively correlated with the status of FLT3-ITD mutation. Multiple survival analyses were performed on TCGA-AML to screen the prognostic-related genes, and RPS6KA1 and AP2M1 are powerful prognostic candidates for overall survival in AML. WGCNA, KEGG/GO analysis, and the functional roles of RPS6KA1 and AP2M1 in AML were clarified by correlation analysis. We found that the expression levels of RPS6KA1 and AP2M1 were significantly associated with chemoresistance of AML, and the CXCL12/CXCR4 axis would regulate RPS6KA1/AP2M1 expression. Besides, miR-138-5p, regulated by the CXCL12/CXCR4 axis, was the common miRNA target of RPS6KA1 and AP2M1. Taken together, the interaction of FLT3-ITD mutation and the CXCL12/CXCR4 axis activated the PI3K-Akt-mTOR pathway, and the increased expression of RPS6KA1 and AP2M1 caused by hsa-miR-138-5p downregulation regulates the multi-resistance gene expression leading to drug indications.

Analysis of the Interaction Network of Hub miRNAs-Hub Genes, Being Involved in Idiopathic Pulmonary Fibers and Its Emerging Role in Non-small Cell Lung Cancer.

Idiopathic pulmonary fibrosis (IPF) is a fibrotic interstitial lung disease with lesions confined to the lungs. To identify meaningful microRNA (miRNA) and gene modules related to the IPF progression, GSE32537 (RNA-sequencing data) and GSE32538 (miRNA-sequencing data) were downloaded and processed, and then weighted gene co-expression network analysis (WGCNA) was applied to construct gene co-expression networks and miRNA co-expression networks. GSE10667, GSE70866, and GSE27430 were used to make a reasonable validation for the results and evaluate the clinical significance of the genes and the miRNAs. Six hub genes (COL3A1, COL1A2, OGN, COL15A1, ASPN, and MXRA5) and seven hub miRNAs (hsa-let-7b-5p, hsa-miR-26a-5p, hsa-miR-25-3p, hsa-miR-29c-3p, hsa-let-7c-5p, hsa-miR-29b-3p, and hsa-miR-26b-5p) were clarified and validated. Meanwhile, iteration network of hub miRNAs-hub genes was constructed, and the emerging role of the network being involved in non-small cell lung cancer (NSCLC) was also analyzed by several webtools. The expression levels of hub genes were different between normal lung tissues and NSCLC tissues. Six genes (COL3A1, COL1A2, OGN, COL15A1, ASPN, and MXRA5) and three miRNAs (hsa-miR-29c-3p, hsa-let-7c-5p, and hsa-miR-29b-3p) were related to the survival time of lung adenocarcinoma (LUAD). The interaction network of hub miRNAs-hub genes might provide common mechanisms involving in IPF and NSCLC. More importantly, useful clues were provided for clinical treatment of both diseases based on novel molecular advances.

Prognostic Factors Analysis and Nomogram Construction of Dual Primary Lung Cancer: A Population Study.

As a special type of lung cancer, multiple primary lung cancer (MPLC) has unique biological characteristics, and its research remains limited. The aim of our research was to identify prognostic factors and construct a prognostic nomogram of dual primary lung cancer (DPLC). A population cohort study of patients with DPLC was conducted using the extracted data from the Surveillance, Epidemiology, and End Results (SEER) database. Relevant survival variables were identified using the Cox proportional hazard model. Prognostic nomogram was performed and its predictive performance was validated via the modeling and validating cohort data. Additionally, propensity score matching (PSM) was also applied to evaluate whether surgery affected the OS of this study population. 5411 eligible DPLC patients were included in this study cohort, with 41.0% of 3-year OS rate and 27.7% of 5-year OS rate. Age, sex, race, grade, stage, lymph node (LN) metastasis, histological type, primary site, and surgery were considered to be prognostic factors of OS. The C-indexes of the established nomogram were 0.70 (95% CI (0.69, 0.71)) in the modeling group and 0.70 (95% CI (0.68, 0.72)) in the validation group, which showed an ideal model discrimination ability. AUC and calibration plots of 3- and 5-year OS also proved the good performance of the established nomogram. After 1 : 1 PSM, surgery can potentially reduce the risk of OS (HR = 0.63, 95% CI: 0.56-0.72) of DPLC. The prognostic nomogram with reliable performance was developed to predict 3- and 5-year OS rates, which could assist clinicians to make more reasonable survival prediction for DPLC patients. For patients without absolute surgical contraindications, surgery should be actively considered.

Screening and Functional Analysis of Hub MicroRNAs Related to Tumor Development in Colon Cancer.

Various microRNAs (miRNAs) are of importance in the development of colon cancer, but most of the mechanisms of the miRNAs are still unclear. In order to clarify the hub miRNAs and their roles in colon cancer development, GSE98406 was used to screen hub miRNAs by bioinformatics analysis. 46 DE-miRNAs (14 were upregulated and 32 were downregulated) and 1738 target genes of DE-miRNAs were ascertained. miRNAs-gene-networks and miRNAs-GO-networks were built to get more knowledge about the function of candidate miRNAs. After validation, three miRNAs (miR-17-5p, miR-182-5p and miR-200a-3p) were recognized to be hub miRNAs associated with the progression of colon cancer. More importantly, the hub miRNAs and the putative targets genes might be new diagnostic and therapeutic targets for colon cancer in the future.

Effects of hub genes on the clinicopathological and prognostic features of lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is a common malignancy; however, the majority of its underlying molecular mechanisms remain unknown. In the present study, weighted gene co-expression network analysis was applied to construct gene co-expression networks for the GSE19804 dataset, in order to screen hub genes associated with the pathogenesis of LUAD. In addition, with the aid of the Database for Annotation, Visualization and Integrated Discovery, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes, pathway enrichment analyses were performed on the genes in the selected module. Using the GSE40791 dataset and The Cancer Genome Atlas database, the hub genes were identified. It was discovered that the turquoise module was the most significant module associated with the tumor stage of LUAD. After performing functional enrichment analyses, it was indicated that the turquoise module was mainly enriched in signal transduction. Additionally, at the transcriptional and translational level, nine hub genes were identified and validated: Carbonic anhydrase 4 (CA4), platelet and endothelial cell adhesion molecule 1 (PECAM1), DnaJ member B4 (DNAJB4), advanced glycosylation end-product specific receptor (AGER), GTPase, IMAP family member 6 (GIMAP6), chromosome 10 open reading frame 54 (C10orf54), dedicator of cytokinesis 4 (DOCK4), Golgi membrane protein 1 (GOLM1) and platelet activating factor acetylhydrolase 1b catalytic subunit 3 (PAFAH1B3). CA4, PECAM1, DNAJB4, AGER, GIMAP6, C10orf54 and DOCK4 were expressed at lower levels in the tumor samples, whereas GOLM1 and PAFAH1B3 were highly expressed in tumor samples. In addition, all hub genes were associated with prognosis. In conclusion, one module and nine genes were recognized to be associated with the tumor stage of LUAD. These findings may enhance the understanding of the progression and prognosis of LUAD.