Mendelian randomization study of urolithiasis: exploration of risk factors using human blood metabolites.

BACKGROUND: Urolithiasis is a highly prevalent global disease closely associated with metabolic factors; however, the causal relationship between blood metabolites and urolithiasis remains poorly understood. METHOD: In our study, we employed a bi-directional two-sample Mendelian randomization (MR) analysis to investigate the causal associations between urolithiasis and metabolites. The random-effects inverse-variance weighted (IVW) estimation method was utilized as the primary approach, complemented by several other estimators including MR-Egger, weighted median, colocalization and MR-PRESSO. Furthermore, the study included replication and meta-analysis. Finally, we conducted metabolic pathway analysis to elucidate potential metabolic pathways. RESULTS: After conducting multiple tests for correction, glycerol might contribute to the urolithiasis and dehydroisoandrosterone sulfate (DHEA-S) might inhibit this process. Furthermore, several blood metabolites had shown potential associations with a causal relationship. Among the protective metabolites were lipids (dehydroisoandrosterone sulfate and 1-stearoylglycerol (1-monostearin)), amino acids (isobutyrylcarnitine and 2-aminobutyrate), a keto acid (acetoacetate) and a carbohydrate (mannose). The risk metabolites included lipids (1-palmitoylglycerophosphoethanolamine, glycerol and cortisone), a carbohydrate (erythronate), a peptide (pro-hydroxy-pro) and a fatty acid (eicosenoate). In reverse MR analysis, urolithiasis demonstrated a statistically significant causal relationship with butyrylcarnitine, 3-methyl-2-oxobutyrate, scyllo-inositol, leucylleucine and leucylalanine. However, it was worth noting that none of the blood metabolites exhibited statistical significance after multiple corrections. Additionally, we identified one metabolic pathway associated with urolithiasis. CONCLUSION: The results we obtained demonstrate the causal relevance between two metabolites and urolithiasis, as well as identify one metabolic pathway potentially associated with its development. Given the high prevalence of urolithiasis, further investigations are encouraged to elucidate the mechanisms of these metabolites and explore novel therapeutic strategies.

Alcohol intake exacerbates experimental autoimmune prostatitis through gut microbiota driving cholesterol biosynthesis-mediated Th17 differentiation.

BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is very common worldwide, and alcohol consumption is a notable contributing factor. Researches have shown that gut microbiota can be influenced by alcohol consumption and is an important mediator in regulating Th17 cell immunity. However, it is still unclear the exact mechanism by which alcohol exacerbates the CP/CPPS and the role of gut microbiota in this process. METHOD: We first constructed the most-commonly used animal model for CP/CPPS, the experimental autoimmune prostatitis (EAP) model, through immunoassay. Based on this, mice were divided into EAP group and alcohol-consuming EAP group. By 16S rRNA sequencing and non-targeted metabolomics analysis, differential gut microbiota and their metabolites between the two groups were identified. Subsequently, metabolomics detection targeting cholesterols was carried out to identify the exact difference in cholesterol. Furthermore, multiple methods such as flow cytometry and immunohistochemistry were used to detect the differentiation status of Th17 cells and severity of prostatitis treated with 27-hydroxycholesterol (the differential cholesterol) and its upstream regulatory factor-sterol regulatory element-binding protein 2 (SREBP2). Lastly, fecal transplantation was conducted to preliminary study on whether alcohol intake exacerbates EAP in immune receptor mice. RESULTS: Alcohol intake increased the proportion of Th17 cells and levels of related inflammatory factors. It also led to an altered gut bacterial richness and increased gut permeability. Further metabolomic analysis showed that there were significant differences in a variety of metabolites between EAP and alcohol-fed EAP mice. Metabolic pathway enrichment analysis showed that the pathways related to cholesterol synthesis and metabolism were significantly enriched, which was subsequently confirmed by detecting the expression of metabolic enzymes. By targeting cholesterol synthesis, 27-hydroxycholesterol was significantly increased in alcohol-fed EAP mice. Subsequent mechanistic research showed that supplementation with 27-hydroxycholesterol could aggravate EAP and promote Th17 cell differentiation both in vivo and in vitro, which is regulated by SREBP2. In addition, we observed that fecal transplantation from mice with alcohol intake aggravated EAP in immunized recipient mice fed a normal diet. CONCLUSION: Our study is the first to show that alcohol intake promotes Th17 cell differentiation and exacerbates EAP through microbiota-derived cholesterol biosynthesis.

Time-dependent analysis of erectile dysfunction in kidney transplant recipients: insights from four distinct time periods.

BACKGROUND AND INTENTION: Erectile dysfunction (ED) is an underappreciated clinical condition in men. This study aims to compare the dynamic changes in the distribution of ED among male kidney transplant recipients (mKTRs) in four epochs: end-stage renal disease period (ESRDp), early post-transplant period (EPTP), pre-COVID-19, and post-COVID-19. METHODS: General information was gathered through interviews, follow-ups, and medical records. The International Index of Erectile Function Questionnaire-5 was used to assess erectile function. The Mann-Whitney U test and chi-square test were used to analyze differences in ED strength. Univariate and logistic regression analyses were conducted to identify risk factors for ED. RESULTS: The database contains 230 mKTRs. In the ESRDp, 17.0% had normal erectile function, 53.5% had mild ED, 18.3% had moderate ED, and 11.3% had severe ED. In the EPTP, the distribution was 38.2% normal, 42.6% mild, 10.8% moderate, and 8.2% severe. In the pre-COVID-19 period, it was 34.3%, 47.3%, 10.4%, and 7.8%, and in the post-COVID-19 period, it was 23.0%, 45.6%, 21.3%, and 10.0%. Overall, erectile function improved after kidney transplant (KT). However, post-COVID-19, the proportion of erectile function significantly decreased compared to EPTP and pre-COVID-19 periods. Risk factors for post-pandemic ED included degree, Generalized Anxiexy Disorder-7, kidney donor type, postoperative time, hypertension and hemoglobin concentration. CONCLUSION: KT improves erectile function in mKTRs within 5 years, but post-SARS-CoV-2 viral infection, ED worsens due to altered risk factors. These findings inform future research for comprehensive ED prevention and management strategies in this population.

Single-cell analysis revealing the metabolic landscape of prostate cancer.

ABSTRACT: Tumor metabolic reprogramming is a hallmark of cancer development, and targeting metabolic vulnerabilities has been proven to be an effective approach for castration-resistant prostate cancer (CRPC) treatment. Nevertheless, treatment failure inevitably occurs, largely due to cellular heterogeneity, which cannot be deciphered by traditional bulk sequencing techniques. By employing computational pipelines for single-cell RNA sequencing, we demonstrated that epithelial cells within the prostate are more metabolically active and plastic than stromal cells. Moreover, we identified that neuroendocrine (NE) cells tend to have high metabolic rates, which might explain the high demand for nutrients and energy exhibited by neuroendocrine prostate cancer (NEPC), one of the most lethal variants of prostate cancer (PCa). Additionally, we demonstrated through computational and experimental approaches that variation in mitochondrial activity is the greatest contributor to metabolic heterogeneity among both tumor cells and nontumor cells. These results establish a detailed metabolic landscape of PCa, highlight a potential mechanism of disease progression, and emphasize the importance of future studies on tumor heterogeneity and the tumor microenvironment from a metabolic perspective.

Is There a Two-Way Risk between Decreased Testosterone Levels and the Progression and Prognosis of Chronic Kidney Disease? A Cohort Study Based on the National Health and Nutrition Examination Survey Database.

PURPOSE: The causal relationship between the incidence and prognosis of chronic kidney disease (CKD) and serum testosterone levels in patients is not yet fully understood. This study aims to use the National Health and Nutrition Examination Survey (NHANES), a large-scale nationally representative sample, to investigate the relationship between CKD and testosterone. MATERIALS AND METHODS: This study included six NHANES cycles for linear regression analysis, verified by multiple imputation methods. Stratified analysis and subgroup analysis were used to demonstrate the stability of CKD's effect on testosterone. Furthermore, we used Kaplan-Meier plots and log-rank tests to evaluate differences in survival rates between CKD male patients with low and normal levels of testosterone. RESULTS: From a total of 71,163 subjects, the cohort selected 28,663 eligible participants. Results showed that CKD patients had testosterone levels 28.423 ng/mL (24.762, 32.083) lower than non-CKD patients. The results of multiple imputations (ß=27.700, 95% confidence interval: 23.427, 31.974) were consistent with those of linear regression analysis, and the numerical match was good. Stratified regression analysis, and subgroup analysis results showed that CKD had a significant impact on testosterone at different dimensions. Kaplan-Meier plots showed significantly reduced survival rates in low testosterone CKD male patients (p<0.0001). CONCLUSIONS: The results of this big data analysis suggest that there may be a two-way risk between low levels of testosterone and CKD. The testosterone levels of CKD patients were significantly lower than those of the non-CKD population, and CKD patients with low testosterone levels had poorer prognoses. These results suggest that correcting testosterone levels in a timely manner can have preventive and therapeutic effects on the progression of CKD.