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Background: Coffee is a widely consumed beverage with potential benefits for various chronic diseases. Its effect on reducing erectile dysfunction (ED) risk is unclear. This Mendelian randomization (MR) study investigates the impact of coffee/caffeine consumption on ED., Methods: Two sets of coffee consumption-associated genetic variants at the genome-wide significance level were obtained from recent studies of coffee consumption. Taking into account other sources of caffeine, genetic variants associated with caffeine consumption from tea were also obtained. The inverse variance weighted (IVW) method was utilized as the primary analysis. Sensitivity analysis methods and meta-analysis methods were performed to confirm the robustness of the results, while the genetic variants associated with confounders, e.g., diabetes and hypertension, were excluded., Results: Genetically predicted coffee/caffeine consumption was unlikely to be associated with the risk of ED in the Bovijn datasets, with similar directional associations observed in the FinnGen datasets. The combined odds ratio for ED was 1.011 (95% CI 0.841-1.216, p =0.906) for coffee consumption from the genome-wide meta-analysis, 1.049 (95% CI 0.487-2.260, p =0.903) for coffee consumption from the genome-wide association study, and 1.061 (95% CI 0.682-1.651, p =0.793) for caffeine from tea., Conclusion: Using genetic data, this study found no association between coffee/caffeine consumption and the risk of ED., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xiang, Hu, Peng, Luo, Chen and Zhang.)

Accumulating evidence suggests a link between vascular endothelial growth factor (VEGF), erectile dysfunction (ED), and metabolic syndrome (Mets), possibly because VEGF can alter the physiological pathways involved in the regulation of endothelial cell proliferation. This study aimed to investigate the genetic susceptibility of VEGF 2578C>A polymorphism to the development of ED and Mets. Collected data included five-item International Index of Erectile Function (IIEF-5), components of Mets, and VEGF 2578C>A polymorphism. A total of 596 subjects from Kaohsiung with a mean age of 55.5 years were enrolled, data collection was done at our hospital. Individuals carrying the VEGF 2578 A allele (CA+AA genotypes) demonstrated a higher prevalence of ED compared to those with the CC genotype, with an adjusted odds ratio (OR) of 1.582 (95% confidence interval [95% CI] = 1.123-2.227, p value = 0.009) in multivariate binary regression analysis. Similarly, individuals carrying the VEGF 2578 A allele showed a higher prevalence of Mets compared to those with the CC genotype, with an adjusted OR of 2.461 (95% CI = 1.491-4.064, p value < 0.001). Furthermore, A allele carriers had significantly lower IIEF-5 scores and a higher number of Mets components compared to those with the C allele ( P value < 0.001, respectively). In conclusion, VEGF 2578 A allele carriers are at a greater risk of both Mets and ED, suggesting that the VEGF 2578C>A polymorphism may serve as a common genetic susceptibility factor in the development of both disorders. Further research is warranted to evaluate the mechanisms underlying this association., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: In this study, we aimed to explore the potential association between COVID-19 infection, hospitalization, severe COVID-19, and erection dysfunction (ED) using the two-sample Mendelian randomization (MR) method., Methods: Data pertaining to COVID-19 were extracted from the latest version of the COVID-19 Host Genetics Initiative genome-wide association study (GWAS) meta-analyses (Round 7, April 2022), and outcome data were obtained from the Open GWAS database. We applied various MR analysis methods, including the inverse variance weighted method, weighted median method, and MR-Egger regression., Results: Our investigation revealed a negative causal association between COVID-19 hospitalization and ED (total testosterone levels: beta = -0.026; 95% confidence interval: -0.049 to -0.001). However, no evidence supported causal relationships between COVID-19 infection, hospitalization for COVID-19, or severe COVID-19 and other ED risk factors., Conclusion: The results of this comprehensive MR analysis suggest a negative causal link between COVID-19 hospitalization and total testosterone levels. Nonetheless, COVID-19 (comprising infection, hospitalization, and severe illness) may not directly correlate with an increased risk of ED. These findings imply that COVID-19 may exert a distinct impact on ED through indirect pathways., Competing Interests: Declaration of conflicting interestThe authors declare that there is no conflict of interest.

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., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Erectile dysfunction (ED) incidence is higher in patients with obstructive sleep apnea (OSA). Studies have suggested that ED and OSA may activate similar pathways; however, few have investigated the links between their underlying genotypic profiles. Therefore, we conducted an in-silico analysis to test whether ED and OSA share genetic variants of risk and to identify any molecular, cellular and biological interactions between them. Two gene lists were manually curated through a literature review based on a PUBMED search, which resulted in one gene list associated with ED (total of 205 genes) and the other with OSA (total of 2622 genes). Between those gene sets, 35 were common for both lists (Fisher exact test, p-value = 0.027). The Protein-protein interaction (PPI) analysis using the intersect list as input showed that 3 of them had direct interactions (LPL, DGKB and PLCB1). In addition, the biological function of the genes contained in the intersect list suggested that pathways related to lipid metabolism and the neuromuscular junction were commonly found in the genetic basis of ED and OSA. From the shared genes between both conditions, the biological pathways highlighted in this study may serve as preliminary findings for future functional investigations on OSA and ED association., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: This study aims to investigate the causal relationship between erectile dysfunction (ED) and psychological states including worry, tension, insomnia, sensitivity to environmental stress and adversity (SESA)., Method: This study the used two-sample bi-directional Mendelian randomization (MR) method. The study data was obtained from a pooled dataset of genome-wide association studies (GWAS). The bi-directional MR analysis was performed using inverse variance weighting, weighted median method, and MR-Egger regression analysis to assess the causality between ED and psychological states including worry, tension, insomnia, SESA in terms of odd ratios (OR). The study tested for heterogeneity using the Cochran Q method and for multiple validity using the MR-Egger and MR-PRESSO methods., Results: In forward MR analysis correlating worry, tension, insomnia, and SESA as exposures, no causal relationship was found between worry or tension and ED (p < 0.05). However, insomnia (p = 0.001, OR = 3.441, 95%CI = 1.593-7.435) and SESA (p = 0.004, OR = 1.804, 95%CI = 1.203-2.701) were found to have a significant causal effect on ED risk. The reverse MR analysis with ED as the exposure did not show any significant correlation (all p > 0.05)., Conclusion: Individuals with insomnia and SESA are at higher risk for developing ED. Clinical evaluation should be more thorough for these individuals. Insomnia can be treated simultaneously with psychological counseling to reduce the risk of ED. In addition, there is no evidence to suggest that worry and tension increase the risk of ED., (© 2023 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

The mechanisms of adenosine and specific adenosine receptor subtypes in promoting penile rehabilitation remain unclear. Single-cell RNA sequencing of human corpus cavernosum,  adenosine deaminase (ADA) and adenosine receptors knock-out mice (ADA -/- , A1 -/- , A2a -/- , A2b -/- , and A3 -/- ), and primary corpus cavernosum smooth muscle cells are used to determine receptor subtypes responsible for adenosine-induced erection. Three rat models are established to characterize refractory erectile dysfunction (ED): age-related ED, bilateral cavernous nerve crush related ED (BCNC), and diabetes mellitus-induced ED. In single-cell RNA sequencing data, the corpus cavernosum of ED patients show a decrease in adenosine A1, A2a and A2b receptors. In vivo, A2b receptor knock-out abolishes adenosine-induced erection but not that of A1, A2a, or A3 receptor. Under hypoxic conditions in vitro, activating the A2b receptor increases HIF-1α and decreases PDE5 expression. In refractory ED models, activating the A2b receptor with Bay 60-6583 improves erectile function and down-regulates HIF-1α and TGF-β. Administering Dipyridamole (40 mg Kg -1 ) to BCNC rats improve penile adenosine levels and erectile function. Our study reveals that the A2b receptor mediates adenosine-induced penile erection. Activating the A2b receptor promotes penile rehabilitation of refractory ED by alleviating hypoxia and fibrosis., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Erectile dysfunction (ED) seriously affects men's normal life, and obstructive sleep apnoea (OSA) has been diagnosed as a causative factor. Currently, exosomes secreted by adipose mesenchymal stem cells (ADSC) have been used in the non-clinical experimental treatment of ED disease with prominent efficacy due to the advantages of high stability and no immune exclusion., Methods: In this study, chronic intermittent hypoxia (CIH) exposure was used to induce ED-corresponding phenotypes in Sprague Dawley (SD) rats as well as in cavernous smooth muscle cells (CCSMCs). ED symptoms were treated using exosomes secreted by ADSCs overexpressing circPIP5K1C (EXO-circ) injected into the rat corpus cavernosum., Results: EXO-circ has the effect of ameliorating ED induced by CIH exposure in rats, the mechanism of which is to promote the expression of the downstream target gene SMURF1 after adsorption of miR-153-3p through the sponge so that SMURF1 and PFKFB3 occur protein-protein binding and ubiquitination degradation of PFKFB3 appears to inhibit the occurrence of spongiotic smooth muscle cells glycolysis, and to restore the function of the smooth muscle., Conclusions: These findings show that EXO-circ have a promising therapeutic potential in OSA-induced ED., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., (© 2024. The Author(s).)

The existing research on the association between apolipoproteins (Apos) and erectile dysfunction (ED) primarily relies on observational studies and does not distinguish between organic and psychogenic causes when diagnosing ED. It is difficult to believe that Apos play a role in psychogenic ED. To address these issues, our study explored the causal relationship between lipoproteins and ED using Mendelian randomization (MR) analysis and differentiate between organic and psychogenic ED through the use of nocturnal penile tumescence and rigidity (NPTR) monitoring. Multivariate MR analysis revealed significant causal associations between high-density lipoprotein (HDL), Apo A1, and Apo B/A1 with ED (OR and 95% CI were 0.33 (0.14-0.78), 3.58 (1.52-8.43), and 0.30 (0.13-0.66)). we conducted statistical and analytical analyses on the data of 212 patients using multivariate analyses and receiver operating characteristic (ROC) curves. Patients with organic ED had significantly lower levels of HDL, Apo A1 and Apo A1/B, whereas patients with organic ED had considerably higher levels of Apo B and low-density lipoprotein (LDL). The diagnostic value of Apos in predicting the risk of organic ED was evaluated using ROC curves. The results indicated that Apo A1 and Apo A1/B demonstrated good predictive value. HDL, Apo A1, and Apo A1/B have been identified as risk factors for ED in our study. Furthermore, our research highlights the significance of Apo A1 and Apo A1/Apo B in the development of organic ED and suggests their potential use as indicators to assess the risks associated with organic ED., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Yan, Li, Pan, Wang, Xu, Zhou and Liu.)

Background: Previous research has underscored the correlation between Alzheimer's disease (AD) and erectile dysfunction (ED). However, due to inherent limitations of observational studies, the causative relationship remains inconclusive., Methods: Utilizing publicly available data from genome-wide association studies (GWAS) summary statistics, this study probed the potential causal association between AD and ED using univariate Mendelian randomization (MR). Further, the multivariable MR assessed the confounding effects of six cardiovascular diseases (CVDs). The primary approach employed was inverse variance weighted (IVW), supplemented by three additional methods. A series of sensitivity analyses were conducted to ensure the robustness of the results., Results: In the forward MR analysis, the IVW method revealed causal evidence of genetically predicted AD being a risk factor for ED (OR = 1.077, 95% CI 1.007∼1.152, P = 0.031). Reverse analysis did not demonstrate any causal evidence linking ED to AD (OR = 1.018, 95% CI 0.974∼1.063, P = 0.430). Multivariable MR analysis showed that after adjusting for coronary heart disease (OR = 1.082, 95% CI 0.009∼1.160, P = 0.027), myocardial infarction (OR = 1.085, 95% CI 1.012∼1.163, P = 0.022), atrial fibrillation (OR = 1.076, 95% CI 1.002∼1.154, P = 0.043), heart failure (OR = 1.103, 95% CI 1.024∼1.188, P = 0.010), ischemic stroke (OR = 1.079, 95% CI 1.009∼1.154, P = 0.027), hypertension (OR = 1.092, 95% CI 1.011∼1.180, P = 0.025), and all models (OR = 1.115, 95% CI 1.024∼1.214, P = 0.012), the causal association between AD and ED persisted. Sensitivity analyses confirmed the absence of pleiotropy, heterogeneity, and outliers, validating the robustness of our results (P > 0.05)., Conclusions: This MR study consistently evidences a causal effect of genetically predicted AD on the risk of ED, independent of certain CVDs, yet offers no evidence for a reverse effect from ED., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Liao, Lou. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Erectile dysfunction (ED) affects a significant proportion of men aged 40-70 and is caused by cavernous tissue dysfunction. Presently, the most common treatment for ED is phosphodiesterase 5 inhibitors; however, this is less effective in patients with severe vascular disease such as diabetic ED. Therefore, there is a need for development of new treatment, which requires a better understanding of the cavernous microenvironment and cell-cell communications under diabetic condition. Pericytes are vital in penile erection; however, their dysfunction due to diabetes remains unclear. In this study, we performed single-cell RNA sequencing to understand the cellular landscape of cavernous tissues and cell type-specific transcriptional changes in diabetic ED. We found a decreased expression of genes associated with collagen or extracellular matrix organization and angiogenesis in diabetic fibroblasts, chondrocytes, myofibroblasts, valve-related lymphatic endothelial cells, and pericytes. Moreover, the newly identified pericyte-specific marker, Limb Bud-Heart (Lbh) , in mouse and human cavernous tissues, clearly distinguishing pericytes from smooth muscle cells. Cell-cell interaction analysis revealed that pericytes are involved in angiogenesis, adhesion, and migration by communicating with other cell types in the corpus cavernosum; however, these interactions were highly reduced under diabetic conditions. Lbh expression is low in diabetic pericytes, and overexpression of LBH prevents erectile function by regulating neurovascular regeneration. Furthermore, the LBH-interacting proteins (Crystallin Alpha B and Vimentin) were identified in mouse cavernous pericytes through LC-MS/MS analysis, indicating that their interactions were critical for maintaining pericyte function. Thus, our study reveals novel targets and insights into the pathogenesis of ED in patients with diabetes., Competing Interests: SB, GY, JO, JS, JR No competing interests declared, JP Reviewing editor, eLife, (© 2023, Bae, Yin, Ock et al.)

Purpose: Lipid parameters have been shown to have significant predictive value for cardiovascular disease, but few studies have evaluated their correlation with erectile dysfunction (ED) in young men., Methods: The case-control study encompassed 186 young ED patients (ages 20-40) and 186 healthy controls. Lipid parameters, including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), TC/HDL ratio, TG/HDL ratio, and LDL-C/HDL-C ratio, were assessed in all participants. The International Index of Erectile Function (IIEF-5) scores were collected for all participants to evaluate erectile status. Multivariate logistic regression analysis was utilized to appraise the association of lipid-related parameters with ED. Single-nucleotide polymorphisms (SNPs) significantly correlated with lipid parameters (TC, TG, LDL-C, HDL-C) were selected from genome-wide association studies (GWAS) as instrumental variables (IV) (P < 5.0 × 10 -8 ). Summary data for ED was gathered from a GWAS with a sample size of (n = 17,353 cases/28,210 controls). The inverse variance weighted (IVW) method was employed as the primary mendelian randomization (MR) analysis method to assess causal effects. Causal estimates were represented as odds ratios (OR) with 95% confidence intervals (CI)., Results: Results from the case-control study revealed that, when compared with the control group, levels of LDL-C, TG, UA, LDL-C/HDL-C, TG/HDL-C, and TC/HDL-C in the ED group were significantly elevated (P < 0.01), while HDL-C was significantly decreased (P < 0.01) in the ED group. Multivariate logistic regression analysis indicated LDL-C/HDL-C as a risk factor for both the incidence and severity of ED (P < 0.001). Two-sample MR analysis demonstrated no significant causal correlation between lipid parameters-LDL-C (OR, 0.98, 95% CI, 0.88-1.08, P = 0.616), HDL-C (OR, 1.07, 95% CI: 0.96-1.19, P = 0.249), TC (OR, 1.07, 95% CI, 0.96-1.18, P = 0.208), TG (OR, 0.98, 95% CI, 0.80-1.13, P = 0.579) -and an increased risk of ED (all P > 0.05)., Conclusions: The case-control analysis ascertained a significant association between LDL-C, HDL-C, LDL-C/HDL-C, and ED and its severity. However, results from the MR study do not support a causal role of lipid parameters in ED., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Erectile dysfunction (ED), defined as the inability to achieve or maintain a penile erection sufficient to satisfy sexual behavior, is prevalent worldwide., Aim: Using previous research, bioinformatics, and experimental confirmation, we aimed to discover genes that contribute to ED through regulating hypoxia in corpus cavernosum smooth muscle cells (CCSMCs)., Methods: We used the Gene Expression Omnibus to acquire the sequencing data of the corpus cavernosum transcriptome for diabetic ED and nerve injury type ED rats. We intersected the common differentially expressed genes. Further verification was performed using single cell sequencing. Real-time quantitative polymerase chain reaction and immunofluorescence were used to investigate whether the differentially expressed genes are found in the corpus cavernosum. We used induced hypoxia to assess cell viability changes, and we developed a lentivirus overexpressing Cldn4 for in vitro and in vivo experiments to measure changes in JNK signaling, fibrosis, hypoxia, and erectile function., Outcomes: Our results indicate that targeting the JNK pathway and decreasing local hypoxia may be better options for therapeutic intervention to improve erectile function., Results: We identified Cldn4 and found its expression increased in the corpora cavernosa of the 2 datasets. In addition, we found that hypoxia can increase the expression of Cldn4, activate the JNK signaling pathway, and exacerbate fibrosis in CCSMCs. Cldn4 overexpression in CCSMCs activated the JNK signaling pathway and increased fibrotic protein expression. Last, rat corpus cavernosum overexpressing Cldn4 activated the JNK signaling pathway, increased local fibrosis, and impaired erectile function., Clinical Implications: Through bioinformatics and in vitro and in vivo experiments, we found that Cldn4 has a negative effect on ED, and targeting Cldn4 may provide new ideas for ED treatment., Strengths and Limitations: Although we have identified Cldn4 as a potential target for ED treatment, we have only conducted preliminary validation on CCMSCs, and we still need to further validate in other cell lines., Conclusion: CCSMC hypoxia leads to increased Cldn4, in both nerve injury and diabetic ED rat models, and promotes fibrosis by activating the JNK signaling pathway., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society of Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The interaction between intestinal microbiota and erectile dysfunction (ED) is less investigated. This study was performed to explore the association between intestinal microbiota and ED., Methods: In this two-sample Mendelian randomization (MR) study, genetic variants of gut microbiota were obtained from MiBioGen consortium containing 18,340 individuals. Six methods including inverse variance weighting (IVW), MR-Egger, weighted median, maximum likelihood, MR robust adjusted profile score, and MR pleiotropy residual sum and outlier were used to investigate the causal links between intestinal microbiota and ED. Furthermore, reverse MR analysis was performed to exclude the causal impact of ED on gut microbiota., Results: As revealed by the IVW estimator, the risks of ED were raised by genetically proxied Lachnospiraceae (OR: 1.27), Lachnospiraceae NC2004 group (OR: 1.17), Oscillibacter (OR: 1.20), Senegalimassilia (OR: 1.32) (All P < 0.05) and Tyzzerella-3 (OR: 1.14, P < 0.05). It was observed that Ruminococcaceae UCG013 exerted protective effect against ED (OR: 0.77, P < 0.05). These results were consistent with other estimators in sensitivity analyses. In reverse MR analyses, genetic liability to ED did not alter the abundances of Lachnospiraceae, Lachnospiraceae NC2004 group, Oscillibacter, Senegalimassilia, Tyzzerella-3, and Ruminococcaceae UCG013 (All P > 0.05). No heterogeneity and pleiotropy were detected by Cochran's Q-test, MR-Egger, and global test (All P > 0.05)., Conclusions: This study provided novel evidence that genetically proxied Lachnospiraceae, Lachnospiraceae NC2004 group, Oscillibacter, Senegalimassilia, Tyzzerella-3, and Ruminococcaceae UCG013 had potentially causal effects on ED. Further studies are needed to clarify the biological mechanisms linking intestinal microbiota to ED., (© 2023 American Society of Andrology and European Academy of Andrology.)

Objective: We aimed to explore the association between the leucocyte telomere length (LTL) and erectile dysfunction (ED) among a nationally representative sample of US adults., Design: Secondary population-based study., Setting: The National Health and Nutrition Examination Survey (NHANES) (2001-2002)., Participants: A total of 1694 male participants were extracted from the NHANES database for 2001-2002., Primary and Secondary Outcome Measures: The primary focus of the study was to determine the association between the LTL and ED, using multivariate logistic regression and restricted cubic spline models for examination. The secondary outcome measures involved conducting stratified subgroup analyses to exclude interactions of different variables with the LTL., Results: Participants with ED had shorter LTLs than those without ED (p<0.05). After adjusting for confounding factors, compared with the reference lowest LTL quartile, the ORs and 95% CIs for the second, third and fourth LTL quartiles were (OR 1.51; 95% CI 1.01 to 2.26), (OR 1.79; 95% CI 1.24 to 2.58) and (OR 1.25; 95% CI 0.74 to 2.11), respectively. In addition, restricted cubic splines showed an inverted J-curve relationship between the LTL and ED. At an LTL of 1.037, the curve showed an inflection point. The ORs (95% CI) of ED on the left and right sides of the inflection point were (OR 1.99; 95% CI 0.39 to 10.20; p=0.385) and (OR 0.17; 95% CI 0.03 to 0.90; p=0.039)., Conclusion: Our results demonstrated an inverted J-curve relationship between the LTL and ED. When the LTL was ≥1.037, the incidence of ED decreased with increasing LTL., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Noonan syndrome (NS) is a genetic disorder characterized by multiple congenital defects caused by mutations in the RAS/mitogen-activated protein kinase pathway. Male fertility has been reported to be impaired in NS, but only a few studies have focused on fertility status in NS patients and underlying mechanisms are still incompletely understood. We describe the case of a 35-year-old man who underwent an andrological evaluation due to erectile dysfunction and severe oligospermia. A syndromic facial appearance and reduced testis size were present on clinical examination. Hormonal evaluation showed normal total testosterone level, high FSH level, and low-normal AMH and inhibin B, compatible with primary Sertoli cell dysfunction. Genetic analysis demonstrated the pathogenetic heterozygous variant c.742G>A, p.(Gly248Arg) of the LZTR1 gene (NM&#95;006767.3). This case report provides increased knowledge on primary gonadal dysfunction in men with NS and enriches the clinical spectrum of NS from a rare variant in the novel gene LZTR1 ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Orsolini, Pignata, Baldinotti, Romano, Tonacchera and Canale.)

Objectives: Inflammatory cytokines (ICs) play an important role in erectile dysfunction (ED). Previous studies have demonstrated that most ED patients have high levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8). The causality between 41 ICs and ED is investigated using the Mendelian randomization (MR) approach., Methods: Single nucleotide polymorphisms (SNPs) exposure data of 41 ICs came from a genome-wide association study (GWAS) of 8293 subjects. At the same time, the FINNGEN R9 database provided the ED outcome data containing 2205 ED patients and 164104 controls. MR-Egger (ME), inverse variance weighting (IVW), and weighted median (WM) were applied to conduct the MR study and IVW was taken as the main criterion., Results: From a genetic perspective, the increase of interferon-inducible protein-10 (IP-10) level significantly increased the risk of ED (P=0.043, odds ratio (OR)=1.269, 95% confidence interval (95%CI): 1.007-1.600), while the increase of interleukin-1 receptor antagonist (IL-1RA) markedly decreased the risk of ED (P=0.037, OR=0.768, 95%CI: 0.600-0.984). Meanwhile, IP-10 (p=0.099) and IL-1RA (p=0.135) failed to demonstrate causality in reverse MR analysis., Conclusions: Changes in ICs levels will significantly affect the risk of ED, especially IP-10 as a risk component for ED and IL-1RA as a protective component for ED. In the future, we can achieve targeted treatment and prevention of ED by intervening with specific inflammatory factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Qin, Yi, Xie, Liang, Zhu, Yang and Zhang.)

Plentiful studies have clarified miRNAs take on a key role in the sexual dysfunction of diabetic rats. This study aimed to figure out microRNA (miR)-503-5p/SYDE2 axis' latent mechanisms in streptozotocin-induced diabetic rat sexual dysfunction. A model of erectile dysfunction (ED) in diabetic rats was established by injecting streptozotocin. MiR-503-5p and SYDE2 in ED rats were altered by injection of miR-503-5p mimic or si/oe-SYDE2. The targeting link between miR-503-5p and SYDE2 was testified. ICP/MAP value was tested by pressure sensor; Penile capillary abundance was assessed; Penile cGMP and AGEs were detected; penile smooth muscle cell apoptosis was assessed; MiR-503-5p and SYDE2 were tested. In streptozotocin-induced ED rats, miR-503-5p was reduced and SYDE2 was elevated. Elevating miR-503-5p or silencing of SYDE2 can enhance penile erection rate, ICP/MAP value, capillary abundance, and cGMP but reduce AGEs and penile smooth muscle cell apoptosis rate in ED rats. Strengthening SYDE2 with elevating miR-503-5p turned around the accelerating effect of elevated miR-503-5p on penile erection in ED rats. SYDE2 was a downstream target gene of miR-503-5p. MiR-503-5p protects streptozotocin-induced sexual dysfunction in diabetic rats by targeting SYDE2.

Objective: The effect of hypolipidemic drugs on male erectile function is still controversial. This Mendelian randomization (MR) study aimed to explore the potential impact of lipid-lowering drug targets on ED., Methods: We collected seven genetic variants encoding lipid-lowering drug targets (LDLR, HMGCR, NPC1L1, PCSK9, APOB, APOC3 and LPL) from published genome-wide association study (GWAS) statistics, and performed drug target MR analysis. The risk of ED was defined as the primary outcome, sex hormone levels and other diseases as the secondary outcomes. Mediation analyses were performed to explore potential mediating factors., Results: The results showed that LDLR, LPL agonists and APOC3 inhibitors were significantly associated with a reduced risk of ED occurrence. APOB inhibitors were associated with an increased risk of ED occurrence. In terms of sex hormone levels, LDLR and LPL agonists were significantly associated with increased TT levels, and HMGCR was associated with decreased TT and BT levels significantly. In terms of male-related disease, MR results showed that LDLR agonists and PCSK9 inhibitors were significantly associated with an elevated risk of PH; HMGCR, NPC1L1 inhibitors were associated with a reduced risk of PCa; and LDLR agonists were significantly associated with a reduced risk of AS and MI; in addition, HMGCR inhibitors were associated with a reduced risk of PCa., Conclusion: After performing drug-targeted MR analysis, we found that that there was a causal relationship between lipid-lowering drug targets and ED. APOC3, APOB, LDLR and LPL may be new candidate drug targets for the treatment of ED., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Su, Wang, Luo, Tang and Wang.)

This study aimed to evaluate the causal effects of inflammatory bowel disease (IBD) and erectile dysfunction (ED) using Mendelian randomization (MR). All datasets were obtained from the public genome-wide association study database. In the exposure group, 12,882 IBD patients and 21,770 controls were included. A total of 1154 ED patients and 94,024 controls were included in the outcome group. Two-sample MR was conducted to estimate the causal effect of IBD on ED. Furthermore, Crohn's disease (CD) and ulcerative colitis (UC) were exposure factors in subgroup analyses. Weighted median, MR-egger, Inverse-variant weighted (IVW), weighted mode, and simple mode methods were used in MR analysis. Horizontal pleiotropy test, heterogeneity test, and leave-one-out method were utilized to evaluate the sensitivity and stability of results. After analysis, 62, 52, and 36 single nucleotide polymorphisms (SNPs) that IBD-ED, CD-ED, and UC-ED were included, respectively. The incidence of ED was increased by IBD (IVW: OR = 1.110, 95% CI = 1.017-1.211, P = 0.019; P-heterogeneity > 0.05) and, in addition, ED was affected by CD (IVW: OR = 1.085, 95% CI = 1.015-1.160, P = 0.016; P-heterogeneity > 0.05). However, there was no causal effect of UC on ED (IVW: OR = 1.018, 95% CI = 0.917-1.129, P = 0.743; P-heterogeneity < 0.05). All SNPs showed no significant horizontal pleiotropy (P > 0.05). These results indicate that IBD and CD can cause ED; However, UC did not cause ED. Additional research was required to determine causality and potential mechanisms further., (© 2024. The Author(s).)

Background: Aspirin, as one of the most commonly used drugs, possesses a broad spectrum of therapeutic applications. Presently, the potential association between aspirin usage and the risk elevation of erectile dysfunction (ED) remains inconclusive. The objective of this study employing two-sample Mendelian randomization (MR) was to clarify the causal impact of aspirin use on the risk of ED., Methods: This study incorporated two sets of Genome-Wide Association Study (GWAS) summary statistics, one for aspirin use (46,946 cases and 286,635 controls) and another for ED (6,175 cases and 217,630 controls) in individuals of European ancestry. The inverse-variance weighted (IVW) method was employed as the primary approach, supplemented by MR-Egger, weighted median, weighted mode, and simple mode to estimate the causal effect of aspirin usage on the risk of ED development. To assess pleiotropy, the MR-PRESSO global test and MR-Egger regression were used. Cochran's Q test was adopted to check heterogeneity, and the leave-one-out analysis was performed to confirm the robustness and reliability of the results., Results: The causal association between genetically inferred aspirin use and ED was found by using inverse variance weighted (OR = 20.896, 95% confidence interval = 2.077-2.102E+2, P = 0.010). The sensitivity analysis showed that no pleiotropy and heterogeneity was observed. Furthermore, the leave-one-out analysis demonstrated that the findings were not significantly affected by any instrumental variables., Conclusion: The results of this study highlighted the significance of aspirin use as a predisposing factor for ED and provided further evidence supporting the causal association between aspirin utilization and ED within European populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Peng, Deng, Li and Wu.)

Purpose: Sexual dysfunctions are often experienced by male patients with acromegaly, due to a combination of hypogonadism and other comorbidities, but are a scarcely investigated complication. Erectile dysfunction is also closely related to cardiovascular diseases through endothelial dysfunction. Therefore, this project aimed to assess the prevalence of erectile dysfunction in a population of acromegalic men and evaluate its association with cardio-metabolic disorders, also exploring associations with androgen and estrogen receptor gene polymorphisms., Methods: Sexually active men aged 18-65 with previous diagnosis of acromegaly were recruited. Clinical and laboratory data were retrospectively collected. Each patient also provided a blood sample for AR and ERβ gene polymorphisms analyses and filled out the IIEF-15 questionnaire., Results: Twenty men with previous diagnosis of acromegaly (mean age 48.4 ± 10.0 years) were recruited. 13/20 subjects (65%) had erectile dysfunction, but only four had a concurrent biochemical hypogonadism, with no significant correlation with IIEF-15 scores. Total testosterone negatively correlated with sexual intercourse satisfaction domain (ρ = - 0.595; p = 0.019) and general satisfaction domain (ρ = - 0.651; p = 0.009). IGF-1 levels negatively correlated with biochemical hypogonadism (ρ = - 0.585; p = 0.028). The number of CAG and CA repeats in AR and ERβ receptors genes was not significantly associated with IIEF-15 scores or with GH/IGF-1 levels, but a negative correlation between CA repeats and the presence of cardiomyopathy (ρ = - 0.846; p = 0.002) was present., Conclusions: Men with acromegaly have a high prevalence of erectile dysfunction, but it does not appear to be correlated with treatments, testosterone levels and AR/ER-beta signaling. Nonetheless, a shorter CA polymorphic trait (ERbeta) is associated with the presence of cardiomyopathy. If confirmed, these data may suggest an association between an incorrect hormonal balance and increased cardiovascular risk in acromegaly subjects., (© 2023. The Author(s).)

Genetic risk factors have been shown to contribute to the development of sexual dysfunction. However, the role of methylenetetrahydrofolate reductase ( MTHFR ) gene variants in the risk of erectile dysfunction (ED) remains unclear. In this study, we recruited 1254 participants who underwent ED assessed by the International Index of Erectile Function-5. The MTHFR c.677C>T variant was also measured by fluorescence polymerase chain reaction (PCR). No significant difference in the genotypic frequency of the MTHFR C677T polymorphism (CC, CT, and TT) was observed between men from the ED and non-ED groups. In addition, on binary logistic regression analysis, both crude and adjusted models showed that the risk of ED was not significantly associated with the C677T polymorphism. Interestingly, a significantly higher frequency of the 677TT polymorphism was found in severe and moderate ED (P = 0.02). The positive correlation between the MTHFR 677TT polymorphism and severe ED was confirmed by logistic regression analysis, even after adjusting for potential confounders (odds ratio [OR] = 2.46, 95% confidence interval [CI] 1.15-5.50, P = 0.02). These findings suggest a positive correlation between the MTHFR 677TT polymorphism and the risk of severe ED. Identification of MTHFR gene polymorphisms may provide complementary information for ED patients during routine clinical diagnosis., (Copyright © 2023 Copyright: © The Author(s)(2023).)

Background: The causal relationship between obesity-related anthropometric indicators/body composition and erectile dysfunction has not been established in previous observational studies., Method: We screened single nucleotide polymorphisms significantly associated with exposure from genome-wide association studies as instrumental variables (p < 5.0 × 10 -8 ). The summary statistics for erectile dysfunction were collected from a genome-wide association study with a sample size of 223,805. Exposure and outcome populations included are of European ancestry. We used univariate and multivariate Mendelian randomization (i) to investigate the causal relationship between genetically predicted obesity-related anthropometric indicators/body composition and erectile dysfunction and (ii) to examine the mediating role of coronary artery disease. Mendelian randomization analysis was conducted using an inverse variance weighted method. A series of sensitivity analyses validated the results of the Mendelian randomization analysis. Causal estimates are expressed as odds ratios with 95% confidence intervals., Results: Obesity-related anthropometric indicators/body composition were associated with an increased risk of erectile dysfunction in univariate Mendelian randomization analyses. For the 1-SD increase in body mass index, the odds ratio was 1.841 (95% confidence interval: 1.049-1.355, p = 0.006). For the 1-SD increase in waist circumference and hip circumference, the odds ratios were 1.275 (95% confidence interval: 1.101-1.478, p = 0.001) and 1.156 (95% confidence interval: 1.015-1.317, p = 0.009), respectively. The odds ratio for the 1-SD increase in whole body fat mass was 1.221 (95% confidence interval: 1.047-1.388, p = 0.002). For the 1-SD increase in leg fat percentage (left and right), the odds ratios were 1.256 (95% confidence interval: 1.006-1.567, p = 0.044) and 1.285 (95% confidence interval: 1.027-1.608, p = 0.028), respectively. For the 1-SD increase in leg fat mass (left and right), the odds ratios were 1.308 (95% confidence interval: 1.108-1.544, p = 0.001) and 1.290 (95% confidence interval: 1.091-1.524, p = 0.003), respectively. For the 1-SD increase in arm fat mass (left and right), the odds ratios were 1.269 (95% confidence interval: 1.113-1.447, p < 0.001) and 1.254, respectively. Multivariate Mendelian randomization analysis showed that after adjusting for coronary artery disease, some genetic predispositions to obesity-related anthropometric indicators and body composition were still associated with an increased risk of erectile dysfunction. Significant associations were found for waist circumference-erectile dysfunction (odds ratio: 1.218, 95% confidence interval: 1.036-1.432), leg fat percentage (left)-erectile dysfunction (odds ratio: 1.245, 95% confidence interval: 1.035-1.497), leg fat mass (left)-erectile dysfunction (odds ratio: 1.264, 95% confidence interval: 1.051-1.521), arm fat mass (right)-erectile dysfunction (odds ratio: 1.186, 95% confidence interval: 1.024-1.373), and arm fat mass (left)-erectile dysfunction (odds ratio: 1.17, 95% confidence interval: 1.018-1.360). Meanwhile, coronary artery disease mediated the effects of fat on erectile dysfunction, and the proportion of coronary artery disease-mediated cases ranged from 10% to 22%., Conclusion: There is a potential causal relationship between obesity-related anthropometric indicators/body composition and erectile dysfunction. Higher waist circumference, leg fat percentage, and arm fat mass may increase the risk of erectile dysfunction, and coronary artery disease partly mediates this overall effect. Understanding the causal relationship between obesity and erectile dysfunction and the mediating role of coronary artery disease may provide more information for erectile dysfunction intervention and prevention strategies., (© 2023 American Society of Andrology and European Academy of Andrology.)

Objective: Studies have found that gut microbiota may be associated with the development of erectile dysfunction (ED); however, the exact link between the two remains unclear. This study aimed to elucidate the relationship between the gut microbiota and the risk of ED from a genetic perspective., Methods: We investigated the relationship between the gut microflora and ED using two-sample Mendelian randomization. GWAS-pooled data for ED were obtained from 223805 participants in Europe. GWAS summary data for ED were obtained from 223805 subjects in Europe and that for the gut microbiota were obtained from 18340 participants in 24 cohorts. We used the inverse-variance weighted (IVW) estimator as the primary method for the preliminary analysis, and the MR-Egger, weighted median (WM), simple model, and weighted model as secondary methods. We used Cochrane's Q-test, to detect heterogeneity, MREgger to detect pleiotropy, and the leave-one-out method to test the stability of the MR results. Ultimately, we genetically predicted a causal relationship between 211 gut microbiota and ED., Results: A total of 2818 SNPs associated with gut microflora were screened in the ED correlation analysis based on the assumption of instrumental variables. The results of MR analysis showed a causal relationship between the six gut microbes and ED occurrence. The results of the fixed effects IVW method revealed five gut microflora, including Lachnospiraceae (OR, 1.265; P = 0.008), Lachnospiraceae NC2004 group (OR, 1.188; P = 0.019), Oscillibacter (OR, 1.200; P = 0.015), Senegalimassilia (OR, 1.355; P = 0.002), Tyzzerella3 (OR, 1.133; P = 0.022), to be negatively associated with ED. In addition, the IVW method revealed Ruminococcaceae UCG-013 (OR, 0.827; P = 0.049) to be positively associated with ED. Quality control results showed no heterogeneity or horizontal pleiotropy in the MR analysis (P > 0.05)., Conclusions: Six gut microbes were genetically associated with ED; of which, Ruminococcaceae UCG-013 was causally associated with a reduced risk of ED development. Our findings provide a new direction for research on the prevention and treatment of ED; however, the mechanisms and details require further investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Su, Long, Luo, Jiang, Zheng, Wang and Tang.)

Lipid metabolism plays a key role in erectile dysfunction. Our purpose was to evaluate the influence of lipid-lowering drugs on erectile dysfunction employing a two-sample Mendelian randomization (MR) study. Genetic instruments were employed to represent the exposure of lipid-lowering drugs. Inverse variance-weighted MR (IVWMR) was employed to calculate the estimation of effects. IVW-MR analysis showed that the positive relationship between the expression of HMGCR and the risk of erectile dysfunction (odds ratio [OR] = 1.27, 95% confidence interval [CI] 1.03-1.57; p = 0.028). No significant relationship was detected between NPC1L1, PSK9 expression and erectile dysfunction. This MR study suggested that HMGCR inhibitors are a more desirable treatment modality for patients with ED., (© 2023. The Author(s).)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yuan, Chen, Sun, Cui, Wei, Li and Meng.)

Background: Diabetes mellitus erectile dysfunction (DMED) is one of common complications of diabetes. We aimed to investigate the potential efficacy of methyl protodioscin (MPD) in DMED and explored the underlying mechanism., Methods: Diabetic mice were induced by streptozotocin, while vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) were stimulated with high glucose. MPD was administrated in vitro and in vivo to verify its efficacy on DMED. The interaction of c-Myc and AKAP12 was determined by luciferase reporter assay and chromatin immunoprecipitation assay., Results: c-Myc and AKAP12 were upregulated in penile tissues in DMED mice. In high glucose-stimulated VSMCs or VECs, MPD intervention enhanced cell viability, inhibited apoptosis, decreased c-Myc and AKAP12, as well as elevated p-eNOS Ser1177 . MPD-induced apoptosis inhibition, AKAP12 reduction and p-eNOS Ser1177 elevation were reversed by AKAP12 overexpression. c-Myc functioned as a positive regulator of AKAP12. Overexpression of c-Myc reversed the effects induced by MPD in vitro, which was neutralized by AKAP12 silencing. MPD ameliorated erectile function in diabetic mice via inhibiting AKAP12., Conclusions: MPD improved erectile dysfunction in streptozotocin-caused diabetic mice by regulating c-Myc/AKAP12 pathway, indicating that MPD could be developed as a promising natural agent for the treatment of DMED., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

DMED is a common complication of diabetes, for which new treatment methods are urgently required. Focused on DMED, the pharmacological mechanism of simvastatin (Sim) was probed. A model of DMED was made in rats with streptozotocin and orally medicated with Sim. Lentiviral vectors that interfere with miR-9-5p or PDCD4 were injected, and the erectile function, histopathology of cavernous tissue, and α-SMA expression were evaluated. Cavernous smooth muscle cells (CMSCs) obtained from DMED rats were treated with Sim and transfected with the plasmid vector that interferes with miR-9-5p or PDCD4 to observe cell viability and apoptosis. The binding relationship between miR-9-5p and PDCD4 was checked. After 8-week treatment with Sim, erectile function was improved and the corpus cavernosum injury was alleviated. Upregulating miR-9-5p or downregulating PDCD4 further improved erectile function and cavernous injury in rats. miR-9-5p targeted regulation of PDCD4. In vitro cell experiment results showed that Sim induced proliferation and reduced apoptosis of CSMCs by enhancing miR-9-5p-targeted regulating PDCD4 in vitro. Sim attenuates DMED in rats via miR-9-5p/PDCD4.

Purpose: Erectile dysfunction (ED) often appears concomitantly with cardiovascular diseases (CVDs). However, the causal relationship between ED and CVDs is still unclear. This study aimed to investigate the causal effects between CVDs and ED using bidirectional Mendelian randomization (MR)., Methods: ED data (6175 cases and 217,630 controls) were obtained from the IEU OpenGWAS project. Seven types of CVDs were acquired in our study, including stroke (Sample size = 440,328), myocardial infection (Sample size = 184,305), coronary heart disease (Sample size = 86,995), hypertension (Sample size = 36,683), heart failure (Sample size = 208,178), atrial fibrillation (Sample size = 1,030,836), and coronary artery disease (Sample size = 141,217). Inverse variance weighted (IVW) was selected as the primary method for MR analysis., Results: IVW results indicated that stroke (OR = 1.14, 95% CI = 1.02-1.29, P = 0.025), coronary artery disease (OR = 1.09, 95% CI = 1.02-1.16, P = 0.013), coronary heart disease (OR = 1.07, 95% CI = 1.01-1.13, P = 0.017), myocardial infection (OR = 1.09, 95% CI = 1.02-1.17, P = 0.011), and atrial fibrillation (OR = 1.06, 95% CI = 1.00-1.12, P = 0.04) were causally associated with ED. The reverse MR analysis suggested that ED did not influence the prevalence of CVDs., Conclusion: These findings highlighted CVDs as causal risk factors for ED, but ED did not directly result in the development of CVDs. Regular monitoring of the erectile function of individuals with CVDs, along with implementing appropriate preventive measures, might help reduce the incidence of ED and enhance the sexual well-being of patients with CVDs., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Aims: There are no clear conclusions as to whether heart failure (HF) and coronary heart disease (CAD) increase the risk of erectile dysfunction (ED).In our study, we used Mendelian randomization (MR) analysis to discover a causal relationship between HF, CAD and ED., Methods: Single nucleotide polymorphisms (SNPs) associated with HF, CAD and ED were obtained from the MRC IEU Open Genome-Wide Association Study (GWAS) database.After a series of screenings, the remaining SNPs were selected as instrumental variables (IVs) for HF and CAD for MR analysis to assess the relationship between genetically predicted HF or CAD and the pathogenesis of ED.Among them, we used the random-effects inverse variance weighted (IVW) method as the primary analysis method.Finally, Cochran's q-test, funnel plots, MR-Egger regression, Leave-one-out method and MR-PRESSO were used for sensitivity analysis., Results: In the IVW method, there was no significant causal relationship between genetically predicted HF and CAD and the incidence of ED.(HF: OR = 1.17, 95% CI 0.99-1.39; p = 0.074;CAD: OR = 1.08, 95% CI 0.99-1.17, p = 0.068)。The results of sensitivity analyses supported our conclusion that no horizontal pleiotropism was found., Conclusion: This study did not find a causal relationship between HF or CAD and ED in European populations, which requires further in-depth research., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The association between cardiovascular diseases (CVD), including ischemic stroke (IS), heart failure (HF), myocardial infarction (MI), and coronary heart disease (CHD), and erectile dysfunction (ED) remains unclear from observational studies., Objectives: We explored the potential bidirectional association between CVD and ED by Mendelian randomization (MR)., Methods: Data from genome-wide association studies for CVD in individuals with European ancestry were obtained from several databases, with 1,711,875-977,323 participants, while that for ED included 223,805 participants. We conducted univariate MR (UVMR), inverse variance-weighting (IVW), weighted median, MR-Egger, and multivariate MR (MVMR) analyses to explore the bidirectional causal effects between CVD and ED., Results: UVMR indicated that IS (odds ratios [OR] = 1.34, 95% confidence interval [CI]: 1.08-1.21, P = 0.007), HF (OR = 1.36, 95% CI 1.07-1.74, P = 0.013), and CHD (OR = 1.15, 95% CI 1.09-1.18, P = 0.022) were associated with ED. By MVMR, IS estimates remained significant after accounting for combining single nucleotide polymorphisms from CVDs (OR = 1.42, 95%CI: 1.13-1.79, P = 0.002). Moreover, the effect of a genetic susceptibility to IS on ED was not mediated by type 2 diabetes or triglycerides; that of HF was not mediated by type 2 diabetes, and that of CHD was not mediated by body mass index. Bidirectional analyses showed that genetic susceptibility to ED did not confer any increased CVD risk., Conclusions: Our results, based on MR, indicated that genetic susceptibility to IS, HF, and CHD was causally associated with ED. These findings can inform prevention and intervention strategies for ED in IS, HF, and CHD patients., (© 2023 American Society of Andrology and European Academy of Andrology.)

Objective：The purpose of this study was to explore the causal relationship between nonalcoholic fatty liver disease (NAFLD) and the risk of erectile dysfunction (ED) by using two-sample Mendelian randomization (MR) analysis., Methods: Single nucleotide polymorphisms (SNPs) were screened as instrumental variables (IVs) using the public genome-wide association study summary data set (GWAS). Univariate MR, bidirectional MR and multivariate MR methods were used to analyze the causal relationship between NAFLD and ED., Results: IVW results showed that NAFLD was not associated with ED (OR=0.991 2, 95%CI: 0.955 2－1.0286, P=0.640 6). The results of reverse MR showed that there was no correlation between ED and NAFLD (OR=1.181 5, 95%CI: 0.820 8－1.7007, P=0.369 5). Multivariate MR results showed that there was still no causal relationship between the two diseases after adjusting for confounding factors., Conclusion: The results showed that there was no causal relationship between NAFLD and the risk of ED.

Phosphodiesterase type 5 inhibitors (PDE5is) constitute the primary therapeutic option for treating erectile dysfunction (ED). Nevertheless, a substantial proportion of patients, approximately 30%, do not respond to PDE5i treatment. Therefore, new treatment methods are needed. In this study, we identified a pathway that contributes to male erectile function. We show that mechano-regulated YAP/TAZ signaling in smooth muscle cells (SMCs) upregulates adrenomedullin transcription, which relaxed the SMCs to maintain erection. Using single-nucleus RNA sequencing, we investigated how penile erection stretches the SMCs, inducing YAP/TAZ activity. Subsequently, we demonstrate that YAP/TAZ plays a role in erectile function and penile rehabilitation, using genetic lesions and various animal models. This mechanism relies on direct transcriptional regulation of adrenomedullin by YAP/TAZ, which in turn modulates penile smooth muscle contraction. Importantly, conventional PDE5i, which targets NO-cGMP signaling, does not promote erectile function in YAP/TAZ-deficient ED model mice. In contrast, by activating the YAP/TAZ-adrenomedullin cascade, mechanostimulation improves erectile function in PDE5i nonrespondent ED model rats and mice. Furthermore, using clinical retrospective observational data, we found that mechanostimulation significantly promotes erectile function in patients irrespective of PDE5i use. Our studies lay the groundwork for exploring the mechano-YAP/TAZ-adrenomedullin axis as a potential target in the treatment of ED., (© 2023. The Author(s).)

Sleep has attracted extensive attention due to its significance in health. However, its association with erectile dysfunction (ED) is insufficiently investigated. To investigate the potential causal links between sleep traits (insomnia, sleep duration, and chronotype) and ED, this study was performed. The single-nucleotide polymorphisms (SNPs) associated with insomnia, sleep duration, and chronotype were retrieved from previous genome-wide association studies (GWAS). A conventional two-sample Mendelian randomization (MR) was used to estimate the causal links between sleep traits and ED. The summary statistics of ED were from individuals of European ancestry (6175 cases vs 217 630 controls). As shown by the random effect inverse-variance-weighting (IVW) estimator, genetically predicted insomnia was causally associated with a 1.15-fold risk of ED (95% confidence interval: 1.07-1.23, P < 0.001). Sleep duration and morningness were not causally associated with ED, as indicated by the IVW (all P > 0.05). These findings were consistent with the results of sensitivity analyses. Based on genetic data, this study provides causal evidence that genetically predicted insomnia increases the risk of ED, whereas sleep duration and chronotype do not., Competing Interests: None

Background and Aims: There are currently no clear conclusions about whether major depression (MD) and bipolar disorder (BD) increase the risk of erectile dysfunction (ED). In our study, we used a Mendelian randomization (MR) analysis to discover the causal associations between MD, BD and ED., Methods: We got single-nucleotide polymorphisms (SNPs) related to MD, BD and ED from the MRC IEU Open genome-wide association study (GWAS) datasets. After a series of selection, SNPs left were selected as instrumental variables (IVs) of MD and BD for the following MR test to evaluate the relationship of genetically predicted MD or BD with the incidence of ED. Among them, we used the random-effects inverse-variance weighted (IVW) method as the main analysis. Finally, sensitivity analyses were further performed using Cochran's Q test, funnel plots, MR-Egger regression, Leave-one-out method and MR- pleiotropy residual sum and outlier (PRESSO)., Results: Genetically-predicted MD was causally related to the incidence of ED in the IVW methods (odds ratio (OR), 1.53; 95% confidence interval (CI), 1.19-1.96; p = 0.001), while no causal impact of BD on the risk of ED (OR = 0.95, 95% CI 0.87-1.04; p = 0.306). The results of sensitivity analyses supported our conclusion, and no directional pleiotropy were found., Conclusion: The findings of this research found evidence of a causal relationship between MD and ED. However, we did not find a causal relationship between BD and ED in European populations., (© 2023. The Author(s).)

Background: The mechanism of high-fat diet (HFD)-induced decrease in erectile function has not been elucidated, and in previous studies, spectrin alpha, erythrocytic 1 (SPTA1) is a cytoskeletal protein that regulates cellular function, which belongs to a family of proteins that can affect cell and tissue growth and development by regulating YAP, an effector on the Hippo signaling pathway, but its particular role has not been elucidated., Objective: To explore the role of SPTA1 in the abnormality of erectile function induced by HFD., Methods: We analyzed the penile tissues of mice on normal diet and HFD by transcriptomics and screened for differentially expressed genes, further identified closely related target genes in rat penile tissues, and verified target gene expression in in vitro construction of high-glucose (HG)-treated corpus cavernosum endothelial cells (CCECs) and corpus cavernosum smooth muscle cells (CCSMCs) models. The distribution of target genes in various cell populations in penile tissues was retrieved by single-cell sequencing Male Health Atlas database. Moreover, interfering with target genes was further applied to explore the mechanisms involved in erectile function decline., Results: Transcriptomic analysis screened out down-regulated differential gene SPTA1; Western blot and immunohistochemistry results showed that SPTA1 expression significantly decreased in the penile tissues of Sprague-Dawley (SD) rats in the HFD group. Immunofluorescence staining showed a positive expression of CD31 and VWF in CCECs and a positive expression of α-SMA in CCSMCs. The expression level of SPTA1 protein significantly decreased in the HG group of CCECs and CCSMCs. The expression of SPTA1 mRNA significantly decreased in CCSMCs while significantly increased in CCECs. SPTA1 may have various expression patterns and biological functions in different cell populations. Real-time quantitative PCR results showed that the siSPTA1 transfected in CCSMCs had a significant interference effect compared with the control siNC. Transfection of siSPTA1 into CCSMCs resulted in the significant down-regulation of mRNA and protein expression of eNOS, and significant up-regulation of YAP, Caspase-1, GSDMD, GSDMD-N IL-18, and IL-1β protein expression levels. The expression level of CCSMCs contractile-type protein α-SMA was significantly down-regulated., Conclusions: The down-regulation of SPTA1 in SD rats fed with HFD may induce cell pyroptosis and lead to the decrease of erectile function by activating the Hippo pathway; these findings may provide new therapeutic targets for improving erectile function., (© 2022 American Society of Andrology and European Academy of Andrology.)

Background: The prevalence of age-associated erectile dysfunction (ED) increases pronouncedly with age. However, the cellular composition and transcriptomic changes of aging penile corpus cavernosum remain largely unclear., Methods: Herein, we performed single cell sequencing penile corpus cavernosum from five young with normal erectile response and five old rats with ED., Results: Clustering analysis identified 19 cell types, such as fibroblasts, myofibroblasts and immune cells. We next revealed their transcriptomic alterations and investigated novel subpopulations of major cell types. Among them, fibroblasts possessed the largest cell number and showed apparent heterogeneity. By performing single-cell entropy analysis on fibroblasts, we observed the age-associated decrease of entropy, and aged fibroblasts were found to adopt senescent secretory phenotype, as evidenced by the high expression of genes associated with the senescence-associated secretory phenotype (SASP). Finally, we constructed a comprehensive intercellular communication network and highlighted key mediators of crosstalk between fibroblasts and other cell types., Conclusions: We plotted a cellular atlas of aging cells within penile corpus cavernosum, especially fibroblasts. Our work will deepen the understanding of the heterogeneity among certain cell types within aged penile corpus cavernosum, which will generate positive effects on the future treatment of age-associated ED., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Coronavirus disease 19 (COVID-19) and erectile dysfunction (ED) have been linked in some observational research, but the causality of this association in the European population is uncertain. Therefore, the research intended to investigate the causality of susceptibility to COVID-19 on ED. We used Mendelian randomization (MR) analysis for this research. The subjects were from two genome-wide association studies (GWAS) of the European population, including COVID-19 (14,134 cases and 1,284,876 controls) and ED (6175 cases and 217,630 controls). We utilized the inverse variance-weighted (IVW) to evaluate the causality of COVID-19 genetic susceptibility on ED. Heterogeneity and pleiotropy were determined using the Cochran's Q test and MR-Egger regression. The robustness of the findings was verified using the Leave-one-out method. We obtained six single nucleotide polymorphisms (SNPs) as COVID-19 genetic instrumental variables (IVs), and there was no significant pleiotropy, heterogeneity or bias in these IVs. MR analysis revealed the causality of genetic susceptibility to COVID-19 on elevated risk of ED (OR IVW  = 1.235, 95% CI: 1.044-1.462, p < 0.05). The present study suggested the causality of genetic susceptibility to COVID-19 on elevated ED risk among the European population. Therefore, in order to decrease the ED risk, the European population ought to positively prevent COVID-19., (© 2022 Wiley-VCH GmbH.)

Erectile dysfunction (ED) is a common male sexual dysfunction disease, and it was predicted that the number of ED patients worldwide will reach 322 million by 2025. However, the pathogenesis of ED is complex and the current treatment options are still limited, so it is urgent to explore new treatment strategies. Recent studies have shown that microRNAs (miRNAs) play an important role in ED, and these single-stranded non-coding small RNA molecules are involved in key pathophysiological processes in the occurrence and development of ED. Therefore, miRNAs have remarkable potential as therapeutic targets in ED. Here, this review introduces the physiological basis of erectile function and the pathophysiological changes in ED and summarizes the current knowledge on the expression, biological functions, and molecular mechanisms of miRNAs in ED, especially the potential of miRNA-targeted therapies to improve ED. This review will provide a comprehensive view of the role of miRNAs in the pathogenesis of ED and the potential value of miRNAs in the treatment of ED., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Song, Wang, Liu, Xu, Sun and Liu.)

Aged-related erectile dysfunction (A-ED) is generally regarded as degeneration of penile erectile tissue due to age, male hormone deficiency and concomitant cardiovascular disease. Current pathological studies of A-ED are still limited. In this study, aged rats were divided into AE group (aged rats with ED) and YN group (young normal rats) for evaluating the roles of miRNA-200a and RhoA/ROCK signalling pathway in A-ED. Apo-morphine test, ICP measurement and pathological results were compared between these two groups. After transfection of miRNA-200a into Corpus cavernosum smooth muscle cells (CCSMCs), the expression of miRNA-200a, RhoA, ROCK1 and ROCK2 in the AE group were significantly increased. Additionally, miRNA-200a, RhoA, ROCK1 and ROCK2 were upregulated at a high level after transfecting the miRNA-200a mimics. Therefore, we speculated that miRNA-200a is a positive regulator, which may inhibit the growth of CCSMCs by activating the Rho/ROCK pathway in vitro., (© 2022 Wiley-VCH GmbH.)

The corpus cavernosum is the most important structure for penile erection, and its dysfunction causes many physiological and psychological problems. However, its cellular heterogeneity and signalling networks at the molecular level are poorly understood because of limited access to samples. Here, we profile 64,993 human cavernosal single-cell transcriptomes from three males with normal erection and five organic erectile dysfunction patients. Cell communication analysis reveals that cavernosal fibroblasts are central to the paracrine signalling network and regulate microenvironmental homeostasis. Combining with immunohistochemical staining, we reveal the cellular heterogeneity and describe a detailed spatial distribution map for each fibroblast, smooth muscle and endothelial subcluster in the corpus cavernosum. Furthermore, comparative analysis and related functional experiments identify candidate regulatory signalling pathways in the pathological process. Our study provides an insight into the human corpus cavernosum microenvironment and a reference for potential erectile dysfunction therapies., (© 2022. The Author(s).)

Background: The key regulatory roles of long non-coding RNAs (lncRNAs) in age-related erectile dysfunction (A-ED) are unknown., Aim: This study aimed to identify putative lncRNAs that regulate age-related erectile dysfunction via transcriptome analyses, and to predict their specific regulatory routes via bioinformatics methods., Methods: 22 geriatric male SD rats were divided into age-related erectile dysfunction (A-ED) and negative control (NC) groups after evaluations of intracavernous pressure (ICP). By comparative analysis of transcriptomes of cavernosal tissues from both groups, we identified differentially expressed lncRNAs, miRNAs, and mRNAs. Seven differentially expressed lncRNAs were selected and further verified by quantitative real-time polymerase chain reactions (RT-qPCR). The construction of the lncRNA-miRNA-mRNA network, the Gene Ontology (GO) term enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed in Cytoscape., Results: From comparative transcriptome analyses of A-ED and NC groups, 69, 29, and 364 differentially expressed lncRNAs, miRNAs, and mRNAs were identified respectively. Differentially expressed lncRNAs were culled to seven, which were all verified by qPCR. Three of these lncRNAs (ENSRNOT00000090050, ENSRNOT00000076482, and ENSRNOT00000029245) were used to build regulatory networks, of which only ENSRNOT00000029245 was successful. Moreover, GO and KEGG analyses demonstrated that these lncRNAs possibly regulated muscle myosin complex, muscle cell cellular homeostasis, and ultimately erectile function in rats through PI3K-Akt, fluid shear stress, and atherosclerosis pathways., Conclusion: Our study identified differentially expressed lncRNAs, miRNAs, and mRNAs through comparisons of transcriptomes of geriatric rats. An identified lncRNA verified by qPCR, was used to construct a lncRNA-miRNA-mRNA regulatory network. LncRNA ENSRNOT00000029245 possibly regulated downstream mRNAs through this regulatory network, leading to apoptosis in the cavernous tissue, fibrosis, and endothelial dysfunction, which ultimately caused ED. These findings provide seminal insights into the molecular biology of aging-related ED, which could spur the development of effective therapeutics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhou, Cong, Yao, Zhou, Luan, Zhang, Zhang, Ren, Zhang, Meng and Song.)

Erectile dysfunction (ED), a complication of diabetes mellitus (DM), affects 50-75% of men with diabetes. Fibroblast growth factor 21 (FGF21) is a liver-derived metabolic regulator which plays a role in insulin-independent glucose uptake in adipocytes. We designed a clinical study and an animal experiment to investigate the relationship between FGF21 and DM-induced ED. The clinical study enrolled 93 participants aged > 18 years (61 patients with type 2 DM and 32 healthy controls) from Taian City Central Hospital (TCCH) in Shandong Province, China, amongst whom the association between serum FGF21 and diabetic ED was analyzed. To further validate this association, we developed animal model of diabetic ED using Sprague-Dawley (SD) rats. Serum FGF21 concentration and FGF21 mRNA expression in penile samples of the rats were determined with Western blotting and quantitative real-time PCR. Among the 93 participants, the level of serum FGF21 was negatively correlated with the IIEF-5 score ( r = -0.74, P < 0.001). The analysis on the performance of FGF21 for ED diagnosis showed that the area under the receiver operating characteristic (ROC) curve was 0.875 (95% confidence interval [CI]: 0.803 to 0.946). In the animal experiment, the levels of serum FGF21, 2 -Δ Δ Ct values of FGF21 mRNA expression, and relative levels of FGF21 in penile samples were higher in the ED group compared to the DM and control groups. Our findings demonstrated an association between the FGF21 level and diabetic ED, indicating the potential of this cytokine in predicting diabetic ED., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Zhang, Lyu, Gu, Zhang, Liu, Zheng, Guo, Zhang and Hou.)

Background: The association between snoring and erectile dysfunction (ED) is inconsistent in multiple observational studies. To clarify the causal association of snoring on ED, we performed this two-sample Mendelian randomization study., Materials and Methods: The single nucleotide polymorphisms (SNPs) associated with snoring were retrieved from the UK biobank cohort with 314,449 participants (117,812 cases and 196,637 controls). The summary statistics of ED were obtained from the European ancestry with 223,805 subjects (6,175 cases and 217,630 controls). Single-variable Mendelian randomization (MR) and multivariable MR were used to assess the causal relationship between snoring and ED., Results: Snoring increases the risk of ED (Odds ratio [OR] = 3.45, 95% confidence interval [CI] = 1.68 - 7.09, P < 0.001) in the inverse variance weighting estimator. In sensitivity analyses, the ORs for the weighted median, MR robust adjusted profile score, and MR Pleiotropy Residual Sum and Outlier approach, MR-Egger, and maximum likelihood method are 5.70 (95% CI = 1.19 - 27.21, P < 0.05), 3.14 (95% CI = 1.01 - 9.72, P < 0.05), 3.11 (95% CI = 1.63 - 5.91, P < 0.01), 1.23 (95% CI = 0.01 - 679.73, P > 0.05), and 3.59 (95% CI = 1.07 - 12.00, P < 0.05), respectively. No heterogeneity and pleiotropy are observed ( P for MR-Egger intercept = 0.748; P for global test = 0.997; P for Cochran's Q statistics > 0.05). After adjusting for total cholesterol, triglyceride, low-density lipoprotein, and cigarette consumption, the ORs for ED are 5.75 (95% CI = 1.80 - 18.34, P < 0.01), 4.16 (95% CI = 1.10 - 15.81, P < 0.05), 5.50 (95% CI = 1.62 - 18.69, P < 0.01), and 2.74 (95% CI = 1.06 - 7.10, P < 0.05), respectively., Conclusion: This study provides genetic evidence supporting the causal role of snoring in ED., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xiong, Zhong, Zhang, Wang, Zhang, Wu, Qin and Yuan.)

Objective: Most men suffering from depression have different degrees of erectile dysfunction (ED), but the relationship between depression and ED is not clear. This study explored the effect of depression on erectile function in rats and the underlying mechanism., Methods: The potential targets and key signaling pathways of depression and ED were predicted through bioinformatics analysis, and a depression rat model was established by inducing chronic restraint stress. Pathological changes in rat penis tissue were studied by hematoxylin and eosin staining. The serum dopamine level was quantified by an enzyme-linked immunosorbent assay. The expression of related proteins and mRNA was detected by western blotting and real-time quantitative reverse transcription-polymerase chain reaction., Results: Hematoxylin and eosin staining showed pathological damage in the penile tissue of the model group rats. The serum dopamine level, dopamine receptor D2 (DRD2) and solute carrier family 6 member 3 (SLC6A3) protein levels in penile tissue, and DRD2 and SLC6A3 mRNA levels were lower in the model group than in the control group., Conclusion: The decrease in erectile function in the depression rat model was related to dysfunction of the dopamine system and dopaminergic synapse signaling pathway.

Purpose: To assess the diverse cell populations of human corpus cavernosum in patients with severe erectile dysfunction (ED) at the single-cell level., Methods: Penile tissues collected from three patients were subjected to single-cell RNA sequencing using the BD Rhapsody™ platform. Common bioinformatics tools were used to analyze cellular heterogeneity and gene expression profiles from generated raw data, including the packages Seurat, Monocle, and CellPhoneDB., Results: Disease-related heterogeneity of cell types was determined in the cavernous tissue such as endothelial cells (ECs), smooth muscle cells, fibroblasts, and immune cells. Reclustering analysis of ECs identified an arteriole ECs subcluster and another one with gene signatures of fibroblasts. The proportion of fibroblasts was higher than the other cell populations and had the most significant cellular heterogeneity, in which a distinct subcluster co-expressed endothelial markers. The transition trajectory of differentiation from smooth muscle cells into fibroblasts was depicted using the pseudotime analysis, suggesting that the expansion of corpus cavernosum is possibly compromised as a result of fibrosis. Cell-cell communications among ECs, smooth muscle cells, fibroblasts, and macrophages were robust, which indicated that inflammation may also have a crucial role in the development of ED., Conclusions: Our study has demonstrated a comprehensive single-cell atlas of cellular components in human corpus cavernosum of ED, providing in-depth insights into the pathogenesis. Future research is warranted to explore disease-specific alterations for individualized treatment of ED., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fang, Tan, Song, Gu, Pan, Yang, Song, Yuan, Peng, Zhang, Xin, Li and Guan.)