A sialyltransferases-related gene signature serves as a potential predictor of prognosis and therapeutic response for bladder cancer.

BACKGROUND: Aberrant glycosylation, catalyzed by the specific glycosyltransferase, is one of the dominant features of cancers. Among the glycosyltransferase subfamilies, sialyltransferases (SiaTs) are an essential part which has close linkages with tumor-associated events, such as tumor growth, metastasis and angiogenesis. Considering the relationship between SiaTs and cancer, the current study attempted to establish an effective prognostic model with SiaTs-related genes (SRGs) to predict patients' outcome and therapeutic responsiveness of bladder cancer. METHODS: RNA-seq data, clinical information and genomic mutation data were downloaded (TCGA-BLCA and GSE13507 datasets). The comprehensive landscape of the 20 SiaTs was analyzed, and the differentially expressed SiaTs-related genes were screened with "DESeq2" R package. ConsensusClusterPlus was applied for clustering, following with survival analysis with Kaplan-Meier curve. The overall survival related SRGs were determined with univariate Cox proportional hazards regression analysis, and the least absolute shrinkage and selection operator (LASSO) regression analysis was performed to generate a SRGs-related prognostic model. The predictive value was estimated with Kaplan-Meier plot and the receiver operating characteristic (ROC) curve, which was further validated with the constructed nomogram and decision curve. RESULTS: In bladder cancer tissues, 17 out of the 20 SiaTs were differentially expressed with CNV changes and somatic mutations. Two SiaTs_Clusters were determined based on the expression of the 20 SiaTs, and two gene_Clusters were identified based on the expression of differentially expressed genes between SiaTs_Clusters. The SRGs-related prognostic model was generated with 7 key genes (CD109, TEAD4, FN1, TM4SF1, CDCA7L, ATOH8 and GZMA), and the accuracy for outcome prediction was validated with ROC curve and a constructed nomogram. The SRGs-related prognostic signature could separate patients into high- and low-risk group, where the high-risk group showed poorer outcome, more abundant immune infiltration, and higher expression of immune checkpoint genes. In addition, the risk score derived from the SRGs-related prognostic model could be utilized as a predictor to evaluate the responsiveness of patients to the medical therapies. CONCLUSIONS: The SRGs-related prognostic signature could potentially aid in the prediction of the survival outcome and therapy response for patients with bladder cancer, contributing to the development of personalized treatment and appropriate medical decisions.

Combining bioinformatics and machine learning to identify common mechanisms and biomarkers of chronic obstructive pulmonary disease and atrial fibrillation.

Background: Patients with chronic obstructive pulmonary disease (COPD) often present with atrial fibrillation (AF), but the common pathophysiological mechanisms between the two are unclear. This study aimed to investigate the common biological mechanisms of COPD and AF and to search for important biomarkers through bioinformatic analysis of public RNA sequencing databases. Methods: Four datasets of COPD and AF were downloaded from the Gene Expression Omnibus (GEO) database. The overlapping genes common to both diseases were screened by WGCNA analysis, followed by protein-protein interaction network construction and functional enrichment analysis to elucidate the common mechanisms of COPD and AF. Machine learning algorithms were also used to identify key biomarkers. Co-expression analysis, "transcription factor (TF)-mRNA-microRNA (miRNA)" regulatory networks and drug prediction were performed for key biomarkers. Finally, immune cell infiltration analysis was performed to evaluate further the immune cell changes in the COPD dataset and the correlation between key biomarkers and immune cells. Results: A total of 133 overlapping genes for COPD and AF were obtained, and the enrichment was mainly focused on pathways associated with the inflammatory immune response. A key biomarker, cyclin dependent kinase 8 (CDK8), was identified through screening by machine learning algorithms and validated in the validation dataset. Twenty potential drugs capable of targeting CDK8 were obtained. Immune cell infiltration analysis revealed the presence of multiple immune cell dysregulation in COPD. Correlation analysis showed that CDK8 expression was significantly associated with CD8+ T cells, resting dendritic cell, macrophage M2, and monocytes. Conclusions: This study highlights the role of the inflammatory immune response in COPD combined with AF. The prominent link between CDK8 and the inflammatory immune response and its characteristic of not affecting the basal expression level of nuclear factor kappa B (NF-kB) make it a possible promising therapeutic target for COPD combined with AF.

Alpha-lipoic acid activates AMPK to protect against oxidative stress and apoptosis in rats with diabetic peripheral neuropathy.

PURPOSE: To investigate the AMPK pathway-mediated effect of alpha-lipoic acid (ALA) on the dorsal root ganglia (DRGs) of rats with diabetic peripheral neuropathy (DPN) and to attempt to elucidate the underlying mechanism. METHODS: Sprague-Dawley rats (n = 15) were randomly divided into three groups. The control group was fed a standard diet, and the other groups were fed a high-carbohydrate/high-fat diet. Diabetes was established by a single streptozotocin (STZ) (30 mg/kg) injection, and control rats were injected with an equal volume of citrate buffer. ALA (60 mg/kg/day) was administered for 12 weeks. The nerve conduction velocity (NCV) of the sciatic nerve was measured. Glutathione (GSH) and malondialdehyde (MDA) concentrations in serum were measured with the thiobarbituric acid method and biochemistry. Pathological changes in the rat DRGs were observed. AMPK, phospho-AMPK (p-AMPK), nuclear factor erythroid-2-related factor 2 (Nrf2), phospho-nuclear factor erythroid-2-related factor 2 (p-Nrf2), heme oxygenase 1 (HO-1), quinone oxidoreductase 1 (NQO1), Forkhead box O3 (FoxO3a), phospho-Forkhead box O3 (p-FoxO3a), and Bcl-2 interacting mediator of cell death (Bim) expression levels were assessed by immunohistochemistry and western blotting. RESULTS: ALA improved the motor NCV (MNCV) and sensory NCV (SNCV) of rats with DPN and reduced their mechanical pain threshold. ALA increased serum GSH concentrations and decreased serum MDA concentrations. Additionally, AMPK was activated by ALA. Nrf2, p-Nrf2, HO-1, and NQO1 expression was upregulated, while FoxO3a, p-FoxO3a, and Bim expression was downregulated. ALA reduced oxidative stress and apoptosis in DRG. CONCLUSION: ALA alleviates DPN and improves peripheral nerve function. ALA reduces oxidative stress by activating Nrf2 through AMPK and inhibits FoxO3a and Bim thereby reducing neuronal apoptosis.

Astragaloside IV Inhibits Mitochondrial-Dependent Apoptosis of the Dorsal Root Ganglion in Diabetic Peripheral Neuropathy Rats Through Modulation of the SIRT1/p53 Signaling Pathway.

PURPOSE: To investigate the effect of astragaloside IV (AS-IV) on mitochondrial-dependent apoptosis in the dorsal root ganglion of diabetic peripheral neuropathy (DPN) rats through the SIRT1/p53 pathway. METHODS: Diabetic rat model was induced by high-carbohydrate/high-fat diet and intraperitoneal injection of STZ. Diabetic rats were divided into three groups (n =16 per group): DPN group, AS-IV group (60mg/kg/d) and α-lipoic acid (ALA) group (60mg/kg/d). Weight and blood glucose levels were monitored every 4 weeks for 12 weeks. DPN was evaluated using the Von Frey Filaments Test and nerve conduction velocity. The dorsal root ganglia of rats were isolated and the pathological changes of mitochondria were observed by electron microscopy. The activity of mitochondrial electron transport chain complex, mitochondrial membrane potential, malonaldehyde (MDA) and glutathione (GSH) levels were measured. Neural apoptosis was detected using the Terminal Deoxynucleotidyl Nick-End Labeling (TUNEL) assay kit. The cleaved caspase-3, major proteins in the SIRT1/p53 pathway, including SIRT1, acetyl p53, Drp1, BAX, and BCL-2, were detected using immunohistochemistry and Western blot. Gene expression of major proteins in the SIRT1/p53 pathway was also detected. RESULTS: After 12 weeks of treatment, AS-IV and ALA did not significantly affect body weight or fasting glucose levels, but reduced mechanical abnormal pain in DPN and improved nerve conduction velocity. AS-IV and ALA increased the level of GSH and decreased the level of MDA. Both AS-IV and ALA can reduce mitochondrial damage, improve mitochondrial electron transport chain complex activity and mitochondrial membrane potential, and reduce the percentages of positive cells with DNA fragmentation and the expression of cleaved caspase-3 protein. AS-IV and ALA up-regulated the expression of SIRT1 and down-regulated the expression of acetyl-p53, Drp1 and the ratio of BAX to BCL-2. Changes in gene expression were similar. CONCLUSION: AS-IV can reduce the occurrence of mitochondrial-dependent apoptosis by regulating the SIRT1/p53 pathway. It has a similar therapeutic effect as ALA and is therefore a promising drug for the potential treatment of DPN.

Suppression of Long Non-Coding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) Potentiates Cell Apoptosis and Drug Sensitivity to Taxanes and Adriamycin in Breast Cancer.

BACKGROUND The long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is expressed highly in various types of tumors. Moreover, the tumor-initiating role of MALAT1 has been probed in the context of breast cancer. This study was set to investigate the regulatory role of MALAT1 on the chemosensitivity of breast cancer cells to taxanes (Tax) and adriamycin (Adr). MATERIAL AND METHODS Following the measurement of MALAT1 expression in patients with breast cancer by means of qRT-PCR, the connection between the MALAT1 expression pattern and the prognosis of breast cancer patients as well as the molecular typing of breast cancer patients was analyzed using Kaplan-Meier survival analysis and receiver operating characteristic (ROC) curves. Next, the analysis between the expression of MALAT1 and the clinical symptoms of breast cancer patients was carried out. Subsequently, we generated taxane-resistant MCF-7 cells (MCF-7/Tax) and purchased Adr-resistant MCF-7 cells (MCF-7/Adr). Finally, the proliferation, apoptosis and drug resistance of resistant and parental cells were evaluated after transfection of silencing MALAT1 into these cells. RESULTS MALAT1 was highly expressed in the breast cancer tissues. Moreover, patients with relative overexpression of MALAT1 had worse prognosis. MALAT1 expression was remarkably promoted in MCF-7/Tax and MCF-7/Adr cells, whose sensitivity to Tax and Adr was enhanced following MALAT1 knockdown. CONCLUSIONS MALAT1 was elevated in breast cancer tissues and MCF-7-resistant cells, relative to corresponding controls and downregulation of MALAT1 inhibited the growth and chemoresistance of breast cancer cells to Tax and Adr.

MiR-524-5p Suppresses Migration, Invasion, and EMT Progression in Breast Cancer Cells Through Targeting FSTL1.

Background: The effects of miR-524-5p on breast cancer (BC) have not been investigated, though studies show that miR-524-5p has an anticancer function. Thus, this study investigated the effects of miR-524-5p on BC cells and its potential molecular mechanism. Materials and Methods: The expression of miR-524-5p from the collected BC samples was determined. Cell counting kit-8 (CCK-8) assay was performed to examine the effect of miR-524-5p on BC cells viability. The target for miR-524-5p was predicted by bioinformatics and further verified by luciferase assay. Wound healing assay and transwell assay were performed to determine cell migration and invasion of BC cells. The expressions of Follistatin-like 1 (FSTL1) and related proteins in epithelial-mesenchymal transition (EMT) were detected by Western blotting and quantitative real-time polymerase chain reaction. Results: MiR-524-5p was low-expressed in BC samples, and upregulation of miR-524-5p suppressed BC cell viability, migration, and invasion. FSTL1 was predicted as a target for miR-524-5p. In addition, overexpressed FSTL1 effectively abolished the effect of miR-524-5p on inhibiting FSTL1 expression, and reversed the inhibitory effects of miR-524-5p on the migration, invasion of BC cells as well as the effect of miR-524-5p on regulating the expressions of matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), E-cadherin, and N-cadherin. Conclusions: Our findings suggest that miR-524-5p targeting FSTL1 adversely affects the progression of migration, invasion, and EMT of BC cells, thus, miR-524-5p is possibly a target for BC treatment.