Plasma proteome analysis implicates novel proteins as potential therapeutic targets for chronic kidney disease: A proteome-wide association study.

Chronic kidney disease (CKD) is prevalent globally with limited therapeutic drugs available. To systemically identify novel proteins involved in the pathogenesis of CKD and possible therapeutic targets, we integrated human plasma proteomes with the genome-wide association studies (GWASs) of CKD, estimated glomerular filtration rate (eGFR) and blood urea nitrogen (BUN) to perform proteome-wide association study (PWAS), Mendelian Randomization and Bayesian colocalization analyses. The single-cell RNA sequencing data of healthy human and mouse kidneys were analyzed to explore the cell-type specificity of identified genes. Functional enrichment analysis was conducted to investigate the involved signaling pathways. The PWAS identified 22 plasma proteins significantly associated with CKD. Of them, the significant associations of three proteins (INHBC, LMAN2, and SNUPN) were replicated in the GWASs of eGFR, and BUN. Mendelian Randomization analyses showed that INHBC and SNUPN were causally associated with CKD, eGFR, and BUN. The Bayesian colocalization analysis identified shared causal variants for INHBC in CKD, eGFR, and BUN (all PP4 > 0.75). The single-cell RNA sequencing revealed that the INHBC gene was sparsely scattered within the kidney cells. This proteomic study revealed that INHBC, LMAN2, and SNUPN may be involved in the pathogenesis of CKD, which represent novel therapeutic targets and warrant further exploration in future research.

Targeting Adenosine A2b Receptor Promotes Penile Rehabilitation of Refractory Erectile Dysfunction.

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-ß. 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.

The Role of Autophagy in Erectile Dysfunction.

Autophagy is a conservative lysosome-dependent material catabolic pathway, and exists in all eukaryotic cells. Autophagy controls cell quality and survival by eliminating intracellular dysfunction substances, and plays an important role in various pathophysiology processes. Erectile dysfunction (ED) is a common male disease. It is resulted from a variety of causes and pathologies, such as diabetes, hypertension, hyperlipidemia, aging, spinal cord injury, or cavernous nerve injury caused by radical prostatectomy, and others. In the past decade, autophagy has begun to be investigated in ED. Subsequently, an increasing number of studies have revealed the regulation of autophagy contributes to the recovery of ED, and which is mainly involved in improving endothelial function, smooth muscle cell apoptosis, penile fibrosis, and corpus cavernosum nerve injury. Therefore, in this review, we aim to summarize the possible role of autophagy in ED from a cellular perspective, and we look forward to providing a new idea for the pathogenesis investigation and clinical treatment of ED in the future.

Insights into modifiable risk factors of erectile dysfunction, a wide-angled Mendelian Randomization study.

INTRODUCTION: The causal association between modifiable risk factors and erectile dysfunction (ED) remains unclear, which hinders the early identification and intervention of patients with ED. The present study aimed to clarify the causal association between 42 predominant risk factors and ED. METHODS: Univariate Mendelian Randomization (MR), multivariate MR, and mediation MR analyses were used to investigate the causal association between 42 modifiable risk factors and ED. Combined results were pooled from two independent ED genome-wide association studies to verify the findings. RESULTS: Genetically predicted body mass index (BMI), waist circumference, trunk fat mass, whole body fat mass, poor overall health rating, type 2 diabetes, basal metabolic rate, adiponectin, cigarette consumption, insomnia, snoring, hypertension, stroke, ischemic stroke, coronary heart disease, myocardial infarction, heart failure, and major depressive disorder were found to increase the risk of ED (all P < 0.05). Additionally, genetic liability to higher body fat percentage and alcohol consumption were suggestively associated with an increased risk of ED (P < 0.05 and adjusted P > 0.05). Genetic predisposition to higher sex hormone-binding globulin (SHBG) levels could decrease the risk of ED (P < 0.05). No significant association was detected between lipid levels and ED. Multivariate MR identified type 2 diabetes, basal metabolic rate, cigarette consumption, hypertension, and coronary heart disease as risk factors for ED. The combined results confirmed that waist circumference, whole body fat mass, poor overall health rating, type 2 diabetes, basal metabolic rate, adiponectin, cigarette consumption, snoring, hypertension, ischemic stroke, coronary heart disease, myocardial infarction, heart failure, and major depressive disorder could increase the risk of ED (all P < 0.05), while higher SHBG decreased the risk of ED (P = 0.004). There were suggestive significances of BMI, insomnia, and stroke on ED (P < 0.05 and adjusted P > 0.05). CONCLUSION: This comprehensive MR study supported the causal role of obesity, type 2 diabetes, basal metabolic rate, poor self-health rating, cigarette and alcohol consumption, insomnia and snoring, depression, hypertension, stroke, ischemic stroke, coronary heart disease, myocardial infarction, heart failure, SHBG, and adiponectin in the onset and development of ED.

Genetically proxied intestinal microbiota and risk of erectile dysfunction.

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.

Cascading effects of hypobaric hypoxia on the testis: insights from a single-cell RNA sequencing analysis.

Most mammals tolerate exposure to hypobaric hypoxia poorly as it may affect multiple regulatory mechanisms and inhibit cell proliferation, promote apoptosis, limit tissue vascularization, and disrupt the acid-base equilibrium. Here, we quantified the functional state of germ cell development and demonstrated the interaction between the germ and somatic cells via single-cell RNA sequencing (scRNA-seq). The present study elucidated the regulatory effects of hypobaric hypoxia exposure on germ cell formation and sperm differentiation by applying enrichment analysis to genomic regions. Hypobaric hypoxia downregulates the genes controlling granule secretion and organic matter biosynthesis, upregulates tektin 1 (TEKT1) and kinesin family member 2C (KIF2C), and downregulates 60S ribosomal protein 11 (RPL11) and cilia- and flagella-associated protein 206 (CFAP206). Our research indicated that prosaposin-G protein-coupled receptor 37 (PSAP-GPR37) ligands mediate the damage to supporting cells caused by hypobaric hypoxic exposure. The present work revealed that hypoxia injures peritubular myoid (PTM) cells and spermatocytes in the S phase. It also showed that elongating spermatids promote maturation toward the G2 phase and increase their functional reserve for sperm-egg binding. The results of this study provide a theoretical basis for future investigations on prophylactic and therapeutic approaches toward protecting the reproductive system against the harmful effects of hypobaric hypoxic exposure.

Genetic Insights into Intestinal Microbiota and Risk of Infertility: A Mendelian Randomization Study.

BACKGROUND: The interaction between intestinal microbiota and infertility is less researched. This study was performed to investigate the causal association between gut microbiota and infertility. METHODS: In this two-sample Mendelian randomization (MR) study, genetic variants of intestinal microbiota were obtained from the MiBioGen consortium, which included 18,340 individuals. Inverse variance weighting (IVW), MR-Egger, weighted median, maximum likelihood, MR Robust adjusted profile score, MR Pleiotropy residual sum, and outlier (MR-PRESSO) methods were used to explore the causal links between intestinal microbiota and infertility. The MR-Egger intercept term and the global test from the MR-PRESSO estimator were used to assess the horizontal pleiotropy. The Cochran Q test was applied to evaluate the heterogeneity of instrumental variables (IVs). RESULTS: As indicated by the IVW estimator, significantly protective effects of the Family XIII AD3011 group (OR = 0.87) and Ruminococcaceae NK4A214 group (OR = 0.85) were identified for female fertility, while Betaproteobacteria (OR = 1.18), Burkholderiales (OR = 1.18), Candidatus Soleaferrea (OR = 1.12), and Lentisphaerae (OR = 1.11) showed adverse effects on female fertility. Meanwhile, Bacteroidaceae (OR = 0.57), Bacteroides (OR = 0.57), and Ruminococcaceae NK4A214 group (OR = 0.61) revealed protective effects on male fertility, and a causal association between Anaerotruncus (OR = 1.81) and male infertility was detected. The effect sizes and directions remained consistent in the other five methods except for Candidatus Soleaferrea. No heterogeneity or pleiotropy were identified by Cochran's Q test, MR-Egger, and global test (all p > 0.05). CONCLUSIONS: This two-sample MR study revealed that genetically proxied intestinal microbiota had potentially causal effects on infertility. In all, the Ruminococcaceae NK4A214 group displayed protective effects against both male and female infertility. Further investigations are needed to establish the biological mechanisms linking gut microbiota and infertility.

Obesity, metabolic dysfunction, and risk of kidney stone disease: a national cross-sectional study.

BACKGROUND: This study aimed to investigate the association between different metabolic syndrome-body mass index (MetS-BMI) phenotypes and the risk of kidney stones. MATERIALS AND METHODS: Participants aged 20-80 years from six consecutive cycles of the NHANES 2007-2018 were included in this study. According to their MetS status and BMI, the included participants were allocated into six mutually exclusive groups: metabolically healthy normal weight (MHN)/overweight (MHOW)/obesity (MHO) and metabolically unhealthy normal weight (MUN)/overweight (MUOW)/obesity (MUO). To explore the association between MetS-BMI phenotypes and the risk of kidney stones, binary logistic regression was used to determine the odds ratios (ORs). RESULTS: A total of 13,589 participants were included. It was revealed that all the phenotypes with obesity displayed higher risks of kidney stones (OR = 1.38, p < 0.01 for MHO & OR = 1.80, p < 0.001 for MUO, in the fully adjusted model). The risk increased significantly when metabolic dysfunction coexisted with overweight and obesity (OR = 1.39, p < 0.05 for MUOW & OR = 1.80, p < 0.001 for MUO, in the fully adjusted model). Of note, the ORs for the MUO and MUOW groups were higher than those for the MHO and MHOW groups, respectively. CONCLUSIONS: Obesity and unhealthy metabolic status can jointly increase the risk of kidney stones. Assessing the metabolic status of all individuals may be beneficial for preventing kidney stones.

Vitamin D3 improved erectile function recovery by regulating autophagy and apoptosis in a rat model of cavernous nerve injury.

Vitamin D3 is an important element in improving erectile function. However, the mechanisms of vitamin D3 remain unknown. Thus, we explored the effect of vitamin D3 on erectile function recovery after nerve injury in a rat model and investigated its possible molecular mechanisms. Eighteen male Sprague-Dawley rats were used in this study. The rats were randomly divided into three groups: the control, bilateral cavernous nerve crush (BCNC), and BCNC + vitamin D3 groups. BCNC model was established in rats by surgery. The intracavernosal pressure and the ratio of intracavernosal pressure to mean arterial pressure were utilized to evaluate erectile function. Masson trichrome staining, immunohistochemistry, terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling and western blot analysis were performed on penile tissues to elucidate the molecular mechanism. The results indicated that vitamin D3 alleviated hypoxia and suppressed the fibrosis signalling pathway by upregulating the expression of eNOS (p = 0.001), nNOS (p = 0.018) and α-SMA (p = 0.025) and downregulating the expression of HIF-1α (p = 0.048) and TGF-ß1 (p = 0.034) in BCNC rats. Vitamin D3 promoted erectile function restoration by enhancing the autophagy process through decreases in the p-mTOR/mTOR ratio (p = 0.02) and p62 (p = 0.001) expression and increases in Beclin1 expression (p = 0.001) and the LC3B/LC3A ratio (p = 0.041). Vitamin D3 application improved erectile function rehabilitation by suppressing the apoptotic process through decreases in the expression of Bax (p = 0.002) and caspase-3 (p = 0.046) and an increase in the expression of Bcl2 (p = 0.004). Therefore, We concluded that vitamin D3 improved the erectile function recovery in BCNC rats by alleviating hypoxia and fibrosis, enhancing autophagy and inhibiting apoptosis in the corpus cavernosum.

Antifibrotic Effects of Tetrahedral Framework Nucleic Acids by Inhibiting Macrophage Polarization and Macrophage-Myofibroblast Transition in Bladder Remodeling.

Bladder outlet obstruction (BOO) is a prevalent condition arising from urethral stricture, posterior urethral valves, and benign prostatic hyperplasia. Long-term obstruction can lead to bladder remodeling, which is characterized by inflammatory cell infiltration, detrusor hypertrophy, and fibrosis. Until now, there are no efficacious therapeutic options for BOO-induced remodeling. Tetrahedral framework nucleic acids (tFNAs) are a type of novel 3D DNA nanomaterials that possess excellent antifibrotic effects. Here, to determine the treatment effects of tFNAs on BOO-induced remodeling is aimed. Four single-strand DNAs are self-assembled to form tetrahedral framework DNA nanostructures, and the antifibrotic effects of tFNAs are investigated in an in vivo BOO animal model and an in vitro transforming growth factor beta1 (TGF-ß1)-induced fibrosis model. The results demonstrated that tFNAs could ameliorate BOO-induced bladder fibrosis and dysfunction by inhibiting M2 macrophage polarization and the macrophage-myofibroblast transition (MMT) process. Furthermore, tFNAs regulate M2 polarization and the MMT process by deactivating the signal transducer and activator of transcription (Stat) and TGF-ß1/small mothers against decapentaplegic (Smad) pathways, respectively. This is the first study to reveal that tFNAs might be a promising nanomaterial for the treatment of BOO-induced remodeling.

Applications of artificial intelligence in the diagnosis and prediction of erectile dysfunction: a narrative review.

Despite the high prevalence of erectile dysfunction, patients are reluctant to seek medical advice, which leads to low diagnostic rates in clinical practice. Artificial intelligence has been widely applied in the diagnosis of many diseases and may alleviate the situation. However, the applications of artificial intelligence in erectile dysfunction have not been reviewed to date. Therefore, the assistance from artificial intelligence needs to be summarized. In this review, 418 publications before January 10, 2021, regarding artificial intelligence applications in diagnosing and predicting erectile dysfunction, were retrieved from five databases, including PubMed, EMBASE, the Cochrane Library, and two Chinese databases (WANFANG and CNKI). In addition, the reference lists of the included studies or relevant reviews were checked to avoid bias. Finally, 30 articles were reviewed to summarize the current status, merits, and limitations of applying artificial intelligence in diagnosing and predicting erectile dysfunction. The results showed that artificial intelligence contributed to developing novel diagnostic questionnaires, equipment, expert systems, classifiers by images and predictive models. However, most of the included studies were not subjected to external validations, resulting in doubt on the generalizability. In the future, more rigorously designed studies with high-quality datasets for erectile dysfunction are required.

The association between heavy metal exposure and erectile dysfunction in the United States.

Literature regarding the impacts of heavy metal exposure on erectile dysfunction (ED) is scarce. We aimed to evaluate the correlation between 10 urinary metals and ED in a large, nationally representative adult male sample. The dataset was extracted from the National Health and Nutrition Examination Survey (NHANES) during the period of 2001-2002 and 2003-2004. Weighted proportions and multivariable logistic regression analysis adjusted for confounding variables were utilized to determine the relationship between metal exposure and ED. Weighted quantile sum (WQS) regression was utilized to evaluate the impact of a mixture of urinary metals on ED. A total of 1328 participants were included in our study. In multivariable logistic regression analysis, cobalt (Co) and antimony (Sb) were positively associated with ED (odds ratio [OR]: 1.36, 95% confidence interval [CI]: 1.10-1.73, P = 0.020; and OR: 1.41, 95% CI: 1.12-1.77, P = 0.018, respectively) after full adjustment. Men in tertile 4 for Co (OR: 1.49, 95% CI: 1.02-2.41, P for trend = 0.012) and Sb (OR: 1.53, 95% CI: 1.08-2.40, P for trend = 0.041) had significantly higher odds of ED than those in tertile 1. Furthermore, the WQS index was significantly linked with increased odds of ED after full adjustment (OR: 1.31, 95% CI: 1.04-1.72, P < 0.05). Our study expanded on previous literature indicating the possible role of heavy metal exposure in the etiology of ED. The evaluation of heavy metal exposure should be included in the risk assessment of ED.

Genetically predicted insomnia causally increases the risk of erectile dysfunction.

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.

Serum uric acid as a risk factor for rejection after deceased donor kidney transplantation: A mono-institutional analysis of paired kidneys.

Background: Deceased donor kidney transplantation (DDKT) is a major therapeutic option for patients with end-stage renal diseases. Although medical techniques improved in recent years, acute or chronic rejection after DDKT is not uncommon and often results in poor graft survival. Therefore, the determination of risk factors is very important to stratify patients and to improve outcomes. This study aims to evaluate the risk factors for treated rejection (TR) of patients after DDKT. Methods: Clinical data of deceased donors and corresponding recipients were retrospectively collected. The primary outcome was TR defined as the treatment for rejection within 24 months after DDKT. Univariate comparisons of baseline characteristics were performed with Chi-square test, t-test, and Mann-Whitney U test. Logistic regression was constructed to analyze potential risk factors. Receiver operating characteristic (ROC) curve and Jordan index were generated to determine the optimal cutoff value. The association between continuous variables and TR was examined and visualized by using restricted cubic spline (RCS) models. Results: Data of 123 deceased donors and 246 recipients were obtained and analyzed. The median age was 41 (4-62) years for recipients and 39 (1-65) years for donors. The recipients who died or suffered graft loss during the follow-up period were 8 (3.3%) and 12 (4.9%), respectively. After univariate analysis and subsequent multivariate analysis, the preoperative serum uric acid (OR, 2.242; 95% CI, 1.037-4.844; P = 0.040), platelet (OR, 2.163; 95% CI, 1.073-4.361, P = 0.031), absolute neutrophil count (OR, 2.183; 95% CI, 1.025-4.649; P = 0.043), and HLA-DQ mismatch (OR, 2.102; 95% CI, 1.093-4.043; P = 0.026) showed statistical significance. RCS models showed that patients with higher levels of uric acid had increased risk of TR. Conclusions: Serum uric acid and other three indicators were found to be the independent risk factors for TR, which may contribute to stratify patients and develop personalized regimen in perioperative period.

Short Sleep Duration and Erectile Dysfunction: A Review of the Literature.

The meaning of sleep has puzzled people for millennia. In modern society, short sleep duration is becoming a global problem. It has been established that short sleep duration can increase the risk of several diseases, such as cardiovascular and metabolic diseases. Currently, a growing body of research has revealed a possible link between sleep disorders and erectile dysfunction (ED). However, the mechanisms linking short sleep duration and ED are largely unknown. Thus, we provide a review of clinical trials and animal studies. In this review, we propose putative pathways connecting short sleep duration and ED, including neuroendocrine pathways and molecular mechanisms, aiming to pave the way for future research. Meanwhile, the assessment and improvement of sleep quality should be recommended in the diagnosis and treatment of ED patients.