No bidirectional association between serum 25-hydroxyvitamin D and erectile dysfunction: Mendelian randomization and genetic association studies.

Background: The causal relationship between the level of serum 25-hydroxyvitamin D [25(OH)D] and the risk of erectile dysfunction (ED) is still unclear. Aim: We tried to determine the causal relationship between the level of serum 25(OH)D and ED risk. Methods: In this study, we used genome-wide association study data from the UK Biobank to analyse the relationship between serum 25(OH)D (as the exposure) and ED (as the outcome). Linkage disequilibrium score regression (LDSC) was used to assess the genetic correlation between 2 traits. The CAUSE (Causal Analysis using Summary Effect estimates) method and Mendelian randomization (MR) were employed to evaluate the bidirectional causal relationship. The MRlap method was utilized to assess the impact of sample overlap on the results. To assess potential heterogeneity and horizontal pleiotropy, we utilized methods such as MR-Egger, MR-PRESSO (Mendelian Randomization Pleiotropy Residual Sum and Outlier), weighted median, and others. Outcomes: The primary outcome was defined as self or physician-reported ED, or using oral ED medication, or a history of surgery related to ED. Results: The LDSC analysis did not reveal a significant genetic correlation between serum 25(OH)D and ED (rg = 0.2787, P = .3536). Additionally, the CAUSE (P value testing that the causal model is a better fit >.05) and MR analyses (odds ratio, 0.8951; 95% confidence interval, 0.7480-1.0710; P = .2260) did not support a causal relationship between 25(OH)D and ED, and our study did not detect any heterogeneity and pleiotropy. Clinical implications: This study provides evidence on whether vitamin D needs to be ingested to prevent or treat ED. Strengths and limitations: We used LDSC and MR to avoid bias. However, the population in this study was limited to European ancestry. Conclusion: No causal relationship was found between 25(OH)D and ED.

Adverse drug reactions of intravesical instillation therapy for bladder cancer: based on FDA adverse event reporting system.

BACKGROUND: Intravesical chemotherapy and immunotherapy are common adjuvant treatments for non-muscle invasive bladder cancer post-surgery. Analyzing adverse events linked to these therapies, can assist in clinical decision-making and risk assessment. STUDY DESIGN AND METHODS: Disproportionality analysis was conducted to analyze data from the Food and Drug Administration Adverse Event Reporting System database from the first quarter of 2004 to the first quarter of 2024, exploring potential positive signals between Bacillus Calmette-Guérin, mitomycin-C, epirubicin, gemcitabine, and adverse events. RESULTS: The database retrieved 2018, 140, 31, and 85 adverse event reports associated with Bacillus Calmette-Guérin, mitomycin-C, epirubicin, and gemcitabine, respectively. Adverse reactions not mentioned in the label, such as aortic aneurysm and ocular congestion, were observed in preferred term level related to Bacillus Calmette-Guérin. Mitomycin-C exhibited specificity in skin and subcutaneous tissue diseases not reflected in the package insert. Gemcitabine-induced adverse drug reactions showed signals in vascular and lymphatic diseases meeting the screening criteria of all 4 indicators, with capillary leakage syndrome being the preferred term with the highest signal intensity. CONCLUSION: This study observed new adverse event signals, providing important assistance for drug selection in adjuvant therapy for non-muscle invasive bladder cancer postoperatively.

LncRNA MALAT1 facilitates BM-MSCs differentiation into endothelial cells and ameliorates erectile dysfunction via the miR-206/CDC42/PAK1/paxillin signalling axis.

BACKGROUND: Erectile dysfunction (ED) is a common male sexual dysfunction, with an increasing incidence, and the current treatment is often ineffective. METHODS: Vascular endothelial growth factor (VEGFA) was used to treat bone marrow-derived mesenchymal stem cells (BM-MSCs), and their cell migration rates were determined by Transwell assays. The expression of the von Willebrand Factor (vWF)VE-cadherin, and endothelial nitric oxide synthase(eNOS) endothelial markers was determined by qRT‒PCR and Western blot analyses. The MALAT1-induced differentiation of BM-MCs to ECs via the CDC42/PAK1/paxillin pathway was explored by transfecting VEGFA-induced BM-MSC with si-MALAT1 and overexpressing CDC42 and PAK1. The binding capacity between CDC42, PAK1, and paxillin in VEGFA-treated and non-VEGFA-treated BM-MSCs was examined by protein immunoprecipitation. MiR-206 was overexpressed in VEGFA-induced BM-MSC, and the binding sites of MALAT1, miR-206, and CDC42 were identified using a luciferase assay. Sixty male Sprague‒Dawley rats were divided into six groups (n = 10/group). DMED modelling was demonstrated by APO experiments and was assessed by measuring blood glucose levels. Erectile function was assessed by measuring the intracavernosa pressure (ICP) and mean arterial pressure (MAP). Penile erectile tissue was analysed by qRT‒PCR, Western blot analysis, and immunohistochemical staining. RESULTS: MALAT1 under VEGFA treatment conditions regulates the differentiation of BM-MSCs into ECs by modulating the CDC42/PAK1/paxillin axis. In vitro experiments demonstrated that interference with CDC42 and MALAT1 expression inhibited the differentiation of BM-MSCs to ECs. CDC42 binds to PAK1, and PAK1 binds to paxillin. In addition, CDC42 in the VEGFA group had a greater ability to bind to PAK1, whereas PAK1 in the VEGFA group had a greater ability to bind to paxillin. Overexpression of miR-206 in VEGFA-induced BM-MSCs demonstrated that MALAT1 competes with the CDC42 3'-UTR for binding to miR-206, which in turn is involved in the differentiation of BM-MSCs to ECs. Compared to the DMED model group, the ICP/MAP ratio was significantly greater in the three BM-MSCs treatment groups. CONCLUSIONS: MALAT1 facilitates BM-MSC differentiation into ECs by regulating the miR-206/CDC42/PAK1/paxillin axis to improve ED. The present findings revealed the vital role of MALAT1 in the repair of BM-MSCs for erectile function and provided new mechanistic insights into the BM-MSC-mediated repair of DMED.

Regulatory role of BNP in the spinal center of rats with nonbacterial prostatitis.

BACKGROUND: A growing body of evidence has shown that activating spinal cord glial cells (typically astrocytes and microglial cells) is closely related to hyperpathia and persistent pain. OBJECTIVE: To investigate the expression of GFAP and CR3/CD11b in cornu dorsale medullae spinalis of rats with nonbacterial prostatitis, to explore the therapeutic efficacy and action mechanism of intrathecal injection of BNP alleviating chronic neuropathic pain. METHODS: Eighteen male SPF SD rats were randomly divided into sham operation control group, nonbacterial prostatitis group (NBP) and intrathecal injection BNP group, the NBP model was established by intraprostatic injection of CFA, and the spinal cord of L6-S1 segment was extracted seven days after intrathecal injection of BNP; The expression of GFAP and CR3/CD11b in dorsal horn of spinal cord were detected by immunofluorescence and Western blot. RESULTS: The cumulative optical density values of GFAP and CR3/CD11b immunofluorescence assay in the NBP group were higher than those in the sham operation group, with statistical significance (p⁢ï⁢»â¢ 0.01); The expression of GFAP and CR3/CD11b in intrathecal injection BNP group were lower than those in NBP group, the differences were statistically significant (p⁢ï⁢»â¢ 0.01). Western blot results showed that the expression of GFAP and CR3/CD11B in NBP group were higher than those in sham operation group, with statistical significance (p⁢ï⁢»â¢ 0.05). The expression of GFAP and CR3/CD11B in intrathecal injection BNP group were lower than those in NBP group, the differences were statistically significant (p⁢ï⁢»â¢ 0.05). CONCLUSION: Intrathecal injection of BNP can down-regulate the expressions of GFAP and CR3/CD11b in L6-S1 spinal cord of NBP rat model and to further inhibit chronic pain caused by NBP.

Predictive nomograms for risk and prognostic factors in metastatic bladder cancer: a population-based study.

Background: Given the poor prognosis of patients with metastatic bladder cancer (MBC), the development of an effective diagnostic and prognostic model is significant in cancer management and for guidance in clinical practice. Methods: We acquired data of 23,180 bladder cancer patients from Surveillance Epidemiology and End Results (SEER) database registered from 2010 to 2019. The optimal cut-off value for patient age and tumor size was determined by x-tile software. Independent risk factors for MBC were identified by univariate and multivariate logistic regression analyses and prognosis factors were identified by univariate and multivariate cox regression analyses, and risk and prognostic nomograms were constructed. The accuracy of the nomograms was verified by receiver operating characteristic (ROC) curves, calibration curves, and its clinical utility was determined by decision curve analysis (DCA) curves and clinical impact curves (CIC). Kaplan-Meier (K-M) survival curves further confirmed the clinical validity of the prognostic model. Results: Through logistic regression analyses, we derived that age, histological type, tumor size, T stage, and N stage were independent risk factors for metastasis in bladder cancer patients. By cox regression analyses, age, chemotherapy, histological type, bone, lung and liver metastases were identified as risk factors influencing prognosis of MBC patients. Area under the curve (AUC) of the risk nomogram was 0.80, the AUC values of 1/2/3 years were 0.74/0.71/0.71 in the training group and 0.81/0.77/0.77 in the validation group. Based on calibration curves, DCA curves, CIC and K-M curves, the nomograms were validated with excellent predictive performance and clinical utility for MBC. Conclusions: The nomograms we constructed have perfect predictive accuracy and clinical practicality for MBC patients, enabling clinicians to provide treatment advice and clinical guidance to patients.

Primary testicular neuroendocrine tumor with liver lymph node metastasis: A case report and review of the literature.

BACKGROUND: Primary testicular neuroendocrine tumors (TNETs) are sporadic, accounting for only 0.23% of all testicular tumors. Few cases have been reported in the literature, and no uniform treatment protocol exists. We report a case of a primary TNET with liver lymph node metastasis diagnosed at the age of 24 years and discuss its clinicopathological features, diagnosis, differential diagnosis, treatment, and prognosis. CASE SUMMARY: We report the case of a 24-year-old patient with a primary TNET with liver lymph node metastasis. The patient was found to have a right testicular swelling of about 3 cm × 4 cm in size with unclear borders and no testicular pressure pain seven years ago without any examination or treatment. One month ago, an ultrasound examination was performed for persistent enlargement of the right testis, which showed an occupying lesion of the right testis approximately 110 mm × 102 mm × 82 mm in size. Magnetic resonance imaging scan of the testis (plain scan) showed that the right testis was an occupying lesion with inhomogeneous density and mixed signal, the boundary was still clear, and the possibility of seminoma was considered; chest X-ray and computed tomography did not show any apparent abnormalities. The patient underwent radical orchiectomy, and the pathological examination suggested a right TNET with a typical carcinoid tumor histological type. One month after the surgery, the patient received nine cycles of lanreotide chemotherapy at a dose of 90 mg/mo without adverse effects. No distant lymph node or other organ metastases were detected at follow-up. He is in good physical condition and attends regular follow-up visits. CONCLUSION: Neuroendocrine tumors are rare in clinical practice, and the diagnosis mainly relies on the characteristics of microscopic tumor cells and immunohistochemical features. Treatment involves radical orchiectomy. If it is accompanied by distant lymph node metastasis and the metastatic lesion can be resected, it should be surgically removed; if it cannot be resected, growth inhibitor analog octreotide or lanreotide chemotherapy can be administered to obtain good results, with close postoperative follow-up to prevent recurrence and metastasis.

LncRNA MALAT1 facilitates BM-MSCs differentiation into endothelial cells via targeting miR-206/VEGFA axis.

Bone marrow-derived mesenchymal stem cells (BM-MSCs) implantation shows a repair effect on erectile function in diabetes mellitus-induced erectile dysfunction (DMED) due to its differentiative capacity into endothelial cells (ECs) that contributes to endothelial repair. This study was designed to explore the functional role and mechanism of long noncoding RNA (lncRNA)-metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in BM-MSCs-mediated DMED repairing. The DMED rat model was established and the erectile function was evaluated by calculating the intracavernous pressure (ICP)/mean arterial pressure (MAP) ratio in the DMED models with or without BM-MSCs implantation. The differentiation of BM-MSCs toward ECs was assessed by measuring the expression of EC-specific genes. RNA pull-down and luciferase reporter assay were performed to explore the interaction between miR-206 and MALAT1 or VEGFA. BM-MSCs implantation improved the erectile function of DMED rats and increased MALAT1 expression. MALAT1 was time-dependently upregulated during the VEGF-induced BM-MSCs differentiation into ECs. Mechanistically, MALAT1 acted as a sponge of miR-206 to upregulate VEGFA expression, thereby promoting the differentiation of BM-MSCs into ECs. Moreover, MALAT1 silencing in vivo impaired the repairing effect of BM-MSCs on erectile dysfunction. Collectively, MALAT1 facilitates BM-MSCs differentiation into ECs via regulating miR-206/VEGFA axis.

Down-regulation of lncRNA MEG3 promotes endothelial differentiation of bone marrow derived mesenchymal stem cells in repairing erectile dysfunction.

AIMS: In the treatment of diabetes mellitus associated erectile dysfunction (DMED), the intracavernous and periprostatic implantations of bone marrow derived mesenchymal stem cells (BM-MSCs) represent the new therapeutic approaches with great applied prospect. However, the specific mechanisms of BM-MSCs protecting erectile function remain largely unknown. MATERIALS AND METHODS: The DMED rats were induced and the erectile function was assessed in the models with or without BM-MSCs implantation using intracavernous pressure (ICP)/mean arterial pressure (MAP) ratio. The differentiation of BM-MSCs toward endothelial cells (ECs) was induced by exogenous vascular endothelial growth factor (VEGF) in vitro. RNA pull-down and RIP assays were performed to explore the interaction between MEG3 and FOXM1 protein. KEY FINDINGS: Intracavernous implantation of BM-MSCs effectively improved the erectile function of DMED rats, which was accompanied by a significant decrease in the expression of MEG3 in the corpus cavernosum tissues. Also, our study revealed that MEG3 expression was significantly down-regulated during the endothelial differentiation of BM-MSCs in vitro. The down-regulation of MEG3 was further confirmed to be conducive to the differentiation of BM-MSCs toward ECs. More importantly, MEG3 promoted the degradation of FOXM1 protein via facilitating FOXM1 ubiquitination, thereby decreasing VEGF expression, which ultimately regulated the endothelial differentiation of BM-MSCs. SIGNIFICANCE: Taken together, our findings presented the vital role of MEG3 in the repairing processes of BM-MSCs for erectile function and provided new mechanistic insights into the BM-MSCs-mediated DMED repairing.

The Effect of microRNA-328 antagomir on erectile dysfunction in streptozotocin-induced diabetic rats.

The study aimed at exploring the effect of microRNA-328 (miR-328) antagomir on erectile dysfunction (ED) in streptozotocin (STZ)-induced diabetic rats. A total of 120 male Sprague-Dawley (SD) rats were selected for this study. Fifteen rats were assigned as the diabetic control group and 75 out of the remaining rats (105 diabetic rat models) were divided into five groups with 15 rats in each group: diabetic ED, diabetic ED+negative control (NC), diabetic ED+miR-328 antagomir, diabetic ED+sildenafil and diabetic ED+miR-328 antagomir+sildenafil groups. The cGMP/AGEs production levels were measured using enzyme-linked immunosorbent assay (ELISA) test. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were conducted for testing the expression level of miR-328, transcription and protein levels of endothelial nitric oxide synthase (eNOS) and dickkopf-3 (DKK3). The diabetic ED+miR-328 antagomir group had better erectile function, lower cGMP production level, transcription and protein levels of eNOS and DKK3 but higher AGEs production level than the diabetic control group. The diabetic control group showed higher cGMP production level transcription and protein levels of eNOS and DKK3 and lower production levels of AGEs and miR-328 than the diabetic ED and diabetic ED+NC groups. Our results indicated that miR-328 antagomir could improve ED in STZ-induced diabetic rats by regulating cGMP and AGEs.

B Cell Lymphoma-2-Modified Bone Marrow-Derived Mesenchymal Stem Cells Transplantation for the Treatment of Diabetes Mellitus-Induced Erectile Dysfunction in a Rat Model.

OBJECTIVE: The study aimed to explore the effects of B cell lymphoma-2 (Bcl-2)-modified bone marrow-derived mesenchymal stem cells (BMSCs) transplantation for the treatment of diabetes mellitus-induced erectile dysfunction (DMED) in a rat model. METHODS: The DMED rat model was successfully established. Thirty-six DMED rats were assigned into the Bcl-2-BMSCs, null-BMSCs, BMSCs and phosphate buffered saline (PBS) groups. Meanwhile, 9 normal rats injected with PBS were taken as the normal control group. RESULTS: In the Bcl-2-BMSCs group, the average times of erection, rate of erection, peak intra-cavernous pressure (ICP) and peak ICP/mean arterial pressure were higher than those in the null-BMSCs, BMSCs and PBS groups, but were lower than those in the normal control group. In the Bcl-2-BMSCs group, capillary vessels and Bcl-2 mRNA and protein expressions were similar to those in the normal control group, while they were higher than those in other groups. CONCLUSION: These findings indicate that Bcl-2-modified BMSC transplantation could improve erectile function in DMED rats.

Comparative proteomic profiling identifies potential prognostic factors for human clear cell renal cell carcinoma.

The identification of markers for disease diagnostic, prognostic, or predictive purposes will have a great effect in improving patient management. Proteomic­based approaches for biomarker discovery are promising strategies used in cancer research. In this study, we performed quantitative proteomic analysis on four patients including clear cell renal cell carcinoma (ccRCC) and paired adjacent non­cancerous renal tissues using label­free quantitative proteomics and liquid chromatography­tandem mass spectrometry (LC­MS/MS) to identify differentially expressed proteins. Among 3,061 identified non­redundant proteins, we found that 210 proteins were differentially expressed (83 overexpressed and 127 underexpressed) in ccRCC tissue when compared with normal kidney tissues. Two most significantly dysregulated proteins (PCK1 and SNRPF) were chosen to be confirmed by western blotting. Pathway analysis of 210 differentially expressed proteins showed that dysregulated proteins are related to many cancer­related biological processes such as oxidative phosphorylation, glycolysis and amino acid synthetic pathways. Online survival analysis indicated the prognostic value of these dysregulated proteins. In conclusion, we identified some potential diagnostic biomarkers for ccRCC and an in­depth understanding of their involved biological pathways may help pave the way to discover new therapeutic strategies for ccRCC.

Identification of pathology from diesel exhaust particles in the bladder in a rat model by aspiration of particles from the pharynx.

To determine whether diesel exhaust particles (DEPs) could be a toxic agent to the bladder, rats were exposed to different concentrations of DEPs for one month or three months. When the rats were sacrificed, morphologic changes of the urothelium were investigated. The antioxidase activity and the levels of lipid peroxidation in the bladder were assayed. In the three-month group, DEPs at doses of 21.03 µg/µl insulted the structural integrity of surface glycosaminoglycans, widened the gap between urothelial cells, increased levels of lipid peroxidation, and decreased antioxidase activities in the urinary bladder (p<0.05). Furthermore, DEPs at a dose of 5.61 µg/µl decreased glutathione, catalase, and glutathione peroxidase activities (p<0.05). These results led to the conclusion that DEPs were a toxic agent in the bladder. The toxic effects might be attributed to oxidative damage mediated by pro-oxidant/antioxidant imbalance or excessive free radicals.