Exploring potential genes and mechanisms linking erectile dysfunction and depression.

Background: The clinical correlation between erectile dysfunction (ED) and depression has been revealed in cumulative studies. However, the evidence of shared mechanisms between them was insufficient. This study aimed to explore common transcriptomic alterations associated with ED and depression. Materials and methods: The gene sets associated with ED and depression were collected from the Gene Expression Omnibus (GEO) database. Comparative analysis was conducted to obtain common genes. Using R software and other appropriate tools, we conducted a range of analyses, including function enrichment, interactive network creation, gene cluster analysis, and transcriptional and post-transcriptional signature profiling. Candidate hub crosslinks between ED and depression were selected after external validation and molecular experiments. Furthermore, subpopulation location and disease association of hub genes were explored. Results: A total of 85 common genes were identified between ED and depression. These genes strongly correlate with cell adhesion, redox homeostasis, reactive oxygen species metabolic process, and neuronal cell body. An interactive network consisting of 80 proteins and 216 interactions was thereby developed. Analysis of the proteomic signature of common genes highlighted eight major shared genes: CLDN5, COL7A1, LDHA, MAP2K2, RETSAT, SEMA3A, TAGLN, and TBC1D1. These genes were involved in blood vessel morphogenesis and muscle cell activity. A subsequent transcription factor (TF)-miRNA network showed 47 TFs and 88 miRNAs relevant to shared genes. Finally, CLDN5 and TBC1D1 were well-validated and identified as the hub crosslinks between ED and depression. These genes had specific subpopulation locations in the corpus cavernosum and brain tissue, respectively. Conclusion: Our study is the first to investigate common transcriptomic alterations and the shared biological roles of ED and depression. The findings of this study provide insights into the referential molecular mechanisms underlying the co-existence between depression and ED.

Comprehensive analysis of biological landscape of oxidative stress-related genes in diabetic erectile dysfunction.

Oxidative stress plays a pivotal role in the pathogenesis of diabetic erectile dysfunction, while specific mechanisms have not been illuminated. The study aims to reveal the genetic expression patterns of oxidative stress in diabetic erectile dysfunction. Transcriptome data of diabetic erectile dysfunction and oxidative stress-related genes (OSRGs) in the Gene Expression Omnibus database were downloaded and analyzed based on differential expression. Functional enrichment analyses were conducted to clarify the biological functions. A protein interaction framework was established, and significant gene profiles were validated in the cavernous endothelial cells, clinical patients, and rat models. A miRNA-OSRGs network was predicted and validated. The results were analyzed using Student's t-test. The analysis screened 203 differentially expressed OSRGs (p < 0.05), which had a close association with oxidoreductase activities, glutathione metabolism, and autophagy. A four-gene signature comprised of EPS8L2 (p = 0.044), GSTA3 (p = 0.015), LOX (p < 0.001) and MGST1 (p = 0.002) was well validated and regarded as the hub OSRGs. Compared with the control group, notable increases and decreases were observed in the expressions of GSTA3 (3.683 ± 0.636 vs. 0.416 ± 0.507) and LOX (2.104 ± 1.895 vs. 18.804 ± 2.751) in the validated diabetic erectile dysfunction group. The hub OSRGs-related miRNAs participated in smooth muscle cell proliferation. Besides, miR-125a-3p (p = 0.034) and miR-138-2-3p (p = 0.012) were validated as promising oxidative stress-related miRNA biomarkers. Our findings revealed the genetic alternations of oxidative stress in diabetic erectile dysfunction. These results will be instructive to explore the molecular landscape and the potential treatment for diabetic erectile dysfunction.

Metabolic Understanding of the Genetic Dysregulation in the Tumor Microenvironment of Kidney Renal Clear Cell Carcinoma.

The metabolic dysregulation is a hallmark of cancers including KIRC, specifically caused by alterations in metabolic genes. Currently, a lack of consensus exists between metabolic signatures in the tumor microenvironment. Here, in this study, we observed the significant correlations of differentially expressed metabolic genes (DEmGs) between KIRC and the related normal samples. Briefly, we collected sets of metabolic genes through RNA-seq data of KIRC and normal tissues from TCGA, followed by the identification of KIRC-related DEmGs. Next, patients were classified into three clusters, and using WGCNA, we identified metabolic genes involved in the survival among different clusters. Furthermore, we investigated survival and clinical parameters along with immune infiltration in the clusters. At the same time, we constructed and validated a prediction model based on these DEmGs. These analyses revealed that the patients having high expression of DEmGs showed poor survival, while infiltration of less-immune cells was associated with the metastasis of KIRC. In the end, we identified NUDT1 as a hub gene as it showed significantly high expression in KIRC samples as well as associated with the survival and prognosis of the patients. Further analysis revealed the oncogenic role of NUDT1 in 786-O and ACHN cells. Thus, we conclude that NUDT1 could be a potential diagnostic and prognostic marker for KIRC.

Circular RNA Plasmacytoma Variant Translocation 1 (CircPVT1) knockdown ameliorates hypoxia-induced bladder fibrosis by regulating the miR-203/Suppressor of Cytokine Signaling 3 (SOCS3) signaling axis.

The effects of circular RNAs (circRNAs) on bladder outlet obstruction (BOO)-induced hypertrophy and fibrogenesis in rats and hypoxia-induced bladder smooth muscle cell (BSMC) fibrosis remain unclear. This study aimed to determine the regulatory role of circRNAs in the phenotypic changes in BSMCs in BOO-induced rats.circRNAmicroarray and real-time PCR were used to explore differentiated expressed circRNAs. Bioinformatics analyses and dual-luciferase reporter were performed to identify the targets for circRNA PVT1 (circPVT1). BOO was performed to establish a bladder fibrosis animal model. The circPVT1 and suppressor of cytokine signaling 3 (SOCS3) expression levels were upregulated (p = 0.0061 and 0.0328, respectively), whereas the microRNA-203a (miR-203) level was downregulated in rats with bladder remodeling (p=0.0085). Bioinformatics analyses and dual-luciferase reporter assay results confirmed that circPVT1 sponges miR-203 and that the latter targets the 3'-untranslated region of SOCS3. Additionally, circPVT1 knockdown alleviated BOO-induced bladder hypertrophy and fibrogenesis. Furthermore, hypoxia was induced in BSMCs to establish a cell model of bladder fibrosis. Hypoxia induction in BSMCs resulted in upregulated circPVT1 and SOCS3 levels (p = 0.0052) and downregulated miR-203 levels. Transfection with circPVT1 and SOCS3 shRNA ameliorated hypoxia-induced transforming growth factor-ß (TGF-ß1), TGFßR1, α-smooth muscle actin, fibrotic growth factor, extracellular matrix subtypes, BSMC proliferation, and apoptosis-associated cell injury, whereas co-transfection with miR-203 inhibitor counteracted the effect of circPVT1 shRNA on these phenotypes.These findings revealed a novel circRNA regulator of BOO-associated bladder wall remodeling and hypoxia-induced phenotypic changes in BMSCs by targeting the miR-203-SOCS3 signaling axis.

Hypoxia-induced circular RNA has_circRNA_403658 promotes bladder cancer cell growth through activation of LDHA.

Bladder cancer (BC) is one of the most common cancers in male patients, and the leading cause of cancer-related death in men. Hypoxia plays a critical role in carcinoma biology, including in bladder cancer. However, whether circular RNAs are associated with hypoxia-mediated progression of bladder cancer remain unknown. In this study, our aim was to investigate the role of circular RNA on the hypoxic adaptive response in bladder cancer. Here, we identified a hypoxia-inducible circular RNA, has-circRNA-403658 that contributes to bladder cancer progression. Has-circRNA-403658 is spliced from its host gene, ZNF292, through back-splicing between the 1st and 4th exon. We demonstrated that has-circRNA-403658 was an important circRNA that upregulated in bladder cancer cells under hypoxia, and higher has-circRNA-403658 levels were associated with poorer survival outcome. Silencing has-circRNA-403658 in bladder cancer cells inhibited cell growth and induced cell apoptosis. In addition, has-circRNA-403658 was induced by HIF1α and silencing has-circRNA-403658 inhibited LDHA-mediated aerobic glycolysis, inhibiting bladder cancer cell growth. Thus, our results suggest that has-circRNA-403658 may function as a novel therapeutic target in human bladder cancer.

Comparison of desmopressin, alarm, desmopressin plus alarm, and desmopressin plus anticholinergic agents in the management of paediatric monosymptomatic nocturnal enuresis: a network meta-analysis.

OBJECTIVE: To assess the efficacy of desmopressin, alarm, desmopressin plus alarm, and desmopressin plus anticholinergic agent (AA) therapy in the management of paediatric monosymptomatic nocturnal enuresis (MNE) using a network meta-analysis. MATERIALS AND METHODS: We searched the electronic databases PubMed, Cochrane Library, EMBASE and Web of Science from inception to 1 March 2018. Randomized controlled trials (RCTs) that compared desmopressin, alarm, desmopressin plus alarm, and desmopressin plus AAs were identified. The network meta-analysis was conducted with software R 3.3.2 and STATA 14.0. RESULTS: Eighteen RCTs with a total of 1 649 participants were included. The meta-analysis results showed that complete response (CR) and success rates with desmopressin plus AAs were higher than with desmopressin or alarm monotherapy. Success rates for desmopressin plus alarm therapy were higher than for alarm monotherapy. No obvious difference was observed between desmopressin plus AAs and desmopressin plus alarm therapy with regard to CR rate and success rate. The relapse rate with alarm monotherapy was much lower than with desmopressin monotherapy. Adverse events seemed to be infrequently and tolerable for all treatments. The ranking probability results were as follows: desmopressin plus AA ranked first for the outcomes of CR and success, desmopressin plus alarm therapy ranked first for mean number of wet nights per week, and alarm therapy had the lowest relapse rate. CONCLUSIONS: The network meta-analysis showed that desmopressin had similar efficacy to alarm therapy but a higher relapse rate. Desmopressin plus AA therapy was associated with better efficacy than and a similar relapse rate to desmopressin monotherapy. Desmopressin plus alarm therapy was similar to both desmopressin and alarm monotherapy in efficacy. All treatments, including desmopressin plus AAwere associated with tolerable adverse events; however, additional high-quality studies are needed for further evaluation of these treatments.

A Functional Comparison of Treatment of Intrinsic Sphincter Deficiency with Muscle-Derived and Adipose Tissue-Derived Stem Cells.

This study investigated the effect of muscle-derived stem cells (MDSCs) and adipose tissue-derived stem cells (ADSCs) in the treatment of stress urinary incontinence (SUI) and their differences in a rat model. MDSCs and ADSC were isolated from rats (n = 10), examined for their properties, and labeled with enhanced green fluorescent protein (EGFP) and ß-galactosidase (ß-gal) gene. Rats received bladder-neck and transurethral sphincter injection of EGFP-labeled MDSCs and ß-gal gene-labeled ADSC and injection of D-Hanks as a control (n = 24 each group). At 0, 15, 30, and 60 days after cells injection, urinary voiding function was assessed by urine dynamics detector. The rats were killed to harvest their urethras for tracking of MDSCs and ADSC. Western blotting and quantitative real-time reverse transcription PCR (qRT-PCR) was performed to detect smooth muscle contents. Urodynamic test showed that MDSCs and ADSC improved the function of urination in rats with intrinsic sphincter deficiency (ISD), and effect of MDSCs-treatment was more pronounced. In addition, histologic analysis showed that the MDSCs and ADSC-treated groups had significantly higher myosin and α-smooth muscle actin (α-SMA) content than the control group. Compared with ADSC-treated groups, the MDSCs-treated groups in myosin and α-SMA content showed the tendency of increase. In summary, MDSCs and ADSCs have obvious effects in the treatment and/or prevention of ISD and transplantation of MDSCs is more effective than ADSC. © 2018 IUBMB Life, 70(10):976-984, 2018.

The effect of a gene associated with retinoid-interferon-induced mortality 19 (GRIM-19) on STAT3-induced gene expression in renal carcinoma.

This study aimed to investigate the exact regulatory mechanisms of retinoid-interferon-induced mortality 19 (GRIM-19) in renal carcinoma. Tumour tissue samples from patients with renal carcinoma (n = 30, there were seven cases of Stage I, eight cases of Stage II, eight cases of Stage III, seven cases of Stage IV) and control subjects were selected from adjacent normal tissue (n = 10). Real-time quantitative PCR and western blotting were used to assess the level of GRIM-19, signal transducer and activator of transcription-3 (STAT3) and its downstream molecules. CD31 was detected by immunohistochemistry. The MTT assay was used to measure cell proliferation. The amount of apoptosis cells was analysed by Flow cytometry. The results showed that expression of GRIM-19 was decreased in renal carcinoma. However, in tumour tissue, STAT3 and its downstream signalling molecules showed the higher expression compared with control. Overexpression of GRIM-19, inhibited tumour growth apoptosis by mediating activators of STAT3 signal. In addition, interferon-ß and all-trans-retinoic acid inhibited the renal carcinoma cell growth and induced apoptosis, and effect of drug combinations was particularly evident. In conclusion, GRIM-19 expression is associated with hyperactivation of STAT3-induced gene expression in renal carcinoma.

Urine flow acceleration is superior to Qmax in diagnosing BOO in patients with BPH.

We performed a retrospective, case-control study to evaluate whether the urine flow acceleration (UFA, mL/s(2)) is superior to maximum uroflow (Qmax, mL/s) in diagnosing bladder outlet obstruction (BOO) in patients with benign prostatic hyperplasia (BPH). In this study, a total of 50 men with BPH (age: 58±12.5 years) and 50 controls (age: 59±13.0 years) were included. A pressure-flow study was used to determine the presence of BOO according to the recommendations of Incontinence Control Society (ICS). The results showed that the UFA and Qmax in BPH group were much lower than those in the control group [(2.05±0.85) vs. (4.60±1.25) mL/s(2) and (8.50±1.05) vs. (13.00±3.35) mL/s] (P<0.001). According to the criteria (UFA<2.05 mL/s(2), Qmax<10 mL/s), the sensitivity and specificity of UFA vs. Qmax in diagnosing BOO were 88%, 75% vs. 81%, 63%. UFA vs. Omax, when compared with the results of P-Q chart (the kappa values in corresponding analysis), was 0.55 vs. 0.35. The prostate volume, post void residual and detrusor pressure at Qmax between the two groups were 28.6±9.8 vs. 24.2±7.6 mL, 60.4±1.4 vs. 21.3±2.5 mL and 56.6±8.3 vs. 21.7±6.1 cmH2O, respectively (P<0.05). It was concluded that the UFA is a useful urodynamic parameter, and is superior to Qmax in diagnosing BOO in patients with BPH.