Background/Objectives: Diabetes mellitus-induced erectile dysfunction (DMED) is characterized by severe endothelial and smooth-muscle dysfunction and reduced responsiveness to conventional therapy. Guanxinning tablet (GXN), a traditional Chinese medicine compound containing Salvia miltiorrhiza (Danshen) and Ligusticum stratum (Chuanxiong), has vascular-protective and anti-oxidative properties, but its effect on DMED remains unclear. This study evaluated whether GXN improves erectile function in a streptozotocin (STZ)-induced type 1 diabetic rat model and explored the possible involvement of PI3K/Akt/FOXO1 signaling. Methods: STZ-induced diabetic rats with ED were treated with GXN. Artery pressure (AP) and intracavernous pressure (ICP) were measured to evaluate erectile dysfunction. Western blots, immunohistochemistry, immunofluorescence, biochemical assays, TUNEL staining, RNA-seq, and in vitro HCMEC assays were performed to evaluate erectile effector cell function, oxidative stress, fibrosis, apoptosis, and PI3K/Akt/FOXO1-associated changes. Results: GXN improved erectile function in DMED rats and was associated with improved endothelial and smooth-muscle-related markers, reduced oxidative stress, attenuated fibrosis, and decreased apoptosis. RNA-seq and protein validation suggested that GXN treatment was associated with activation of PI3K/Akt/FOXO1-related signaling. In HCMECs, LY294002 (a PI3K inhibitor) partially reversed the GXN-associated improvement in cell viability and apoptosis-related markers. Conclusions: GXN ameliorated erectile dysfunction and tissue injury in STZ-induced type 1 diabetic rats, which were associated with PI3K/Akt/FOXO1 signaling. These findings support the potential of GXN as a traditional Chinese medicine compound for treating DMED.

To investigate the relationship between android-to-gynoid fat ratio (A/G ratio) and stress urinary incontinence (SUI) in US adult women. The study employed data from the National Health and Nutrition Examination Survey (NHANES) database, encompassing the 2005–2006 and 2011–2018 cycles. We utilized multivariable-adjusted logistic regression models to examine the independent effect of the A/G ratio on SUI. Additionally, refined subgroup analyses were conducted to assess the impact of effect modifiers, along with sophisticated smooth curve fitting methods to delve into the potential non-linear relationship between the A/G ratio and SUI. Of the 6779 women participants with an average age of 40.812, 2565 (37.8

Castration-resistant prostate cancer (CRPC) has been a major cause of tumor-associated death among men worldwide. The discovery of novel therapeutic medicines for CRPC remains imperative. Atractylenolide I (ATR-I), a prominent bioactive component from Atractylodes macrocephala, exhibits powerful anticancer potentials in various malignancies. Nevertheless, the ATR-I’s activity on CRPC has not been reported. An enzalutamide-resistant (EnzR) cell line was successfully constructed. CCK-8, EdU, wound healing, Transwell assays, flow cytometry, and xenograft tumor models were applied to investigate the antitumor activity of ATR-I against CRPC. The changes in the gene expression profiles after ATR-I treatment were analyzed using RNA sequencing. ATR-I suppressed the proliferative and migratory abilities of AR+ and AR− CRPC cells, while triggering cell cycle arrest and apoptosis. ATR-I also exerted anti-cancer activity on EnzR cell lines. Intriguingly, a combination of ATR-I with enzalutamide synergistically induced more apoptosis of tumor cells. RNA-sequencing identified kinesin family member 15 (KIF15) as a potential target of ATR-I. KIF15 was up-regulated in prostate cancer (PCa), and its higher level was associated with poorer clinical outcomes. Further investigation showed that ATR-I mediated ubiquitin-proteasomal degradation of AR/AR-V7 through targeting KIF15, resulting in CRPC repression. Finally, our in vivo experiment verified that ATR-I alone or in combination with enzalutamide retarded the growth of EnzR xenograft tumors. These findings identified ATR-I as a promising therapeutic drug for overcoming enzalutamide resistance in CRPC patients and increased our understanding about its antitumor mechanisms.

Heterogeneous nuclear ribonucleoprotein M (HnRNPM) is a key splicing factor involved in various biological processes, including the epithelial‒mesenchymal transition and cancer development. Alternative splicing is widely involved in the process of spermatogenesis. However, the function of hnRNPM as a splicing factor during spermatogenesis remains unknown. The expression of hnRNPM in germ cells at different stages was detected by polymerase chain reaction, western blotting, a single-cell database, and chromosome spreading assays. Conditional hnRNPM knockout mice were generated to observe the development of testes and germ cells in male mice. Histological staining, immunofluorescence staining and transmission electron microscopy were used to observe the abnormal development of sperm from conditional hnRNPM-deficient mice. Coimmunoprecipitation and mass spectrometry analyses revealed the proteins that interact with hnRNPM. RNA sequencing was performed to analyse the different alternative splicing events in the testes of control and hnRNPM-deficient mice. In this study, we revealed that hnRNPM is highly expressed in spermatocytes and round spermatids, with the exception of XY bodies and metaphase. Therefore, we generated a germ cell-specific hnRNPM conditional knockout mouse model to investigate the role of hnRNPM in spermatogenesis. A lack of hnRNPM led to male infertility under natural conditions. Male hnRNPM-deficient mice presented lower numbers of sperm, lower motility, significantly more malformed sperm and even tailless sperm. Moreover, we found that hnRNPM interacted with PTBP1 to collectively regulate the process of spermatogenesis. In addition, we found that hnRNPM deficiency caused 1617 different alternative splicing events, and we detected abnormal exon skipping events in Cep152, Cyld, Inpp4b and Cd59b. Together, our results suggest that hnRNPM regulates the alternative splicing of mRNAs during spermatogenesis by recruiting PTBP1 and is required for male mouse fertility.

Diabetes mellitus (DM) is a chronic metabolic disease that often leads to vascular endothelial injury and peripheral neuropathy. Erectile dysfunction (ED), a common condition in andrology, is frequently associated with DM. The incidence of diabetes mellitus-induced ED (DMED) is second only to the cardiovascular complications of diabetes. Compared to other types of ED, DMED presents with more severe symptoms, rapid progression, and notable resistance to phosphodiesterase type 5 inhibitors (PDE5is). Various forms of programmed cell death (PCD)—including apoptosis, autophagy, pyroptosis, and ferroptosis—play pivotal roles in the pathogenesis of DMED. An exacerbation of DMED is linked to critical irritants like advanced glycation end-products (AGEs) and reactive oxygen species (ROS) in the corpus cavernosum tissue. These irritants can spark anomalous activations of diverse PCDs, which damage primary corpus cavernosum cells like cavernous nerve cells, endothelial cells, and myocytes, leading to ED. Hence, we reviewed current knowledge on the mechanisms and therapeutic potential of targeting PCDs in DMED, aiming to advance strategies for enhancing erectile function.

Benign prostatic hyperplasia (BPH) is a common proliferative disease in older males. PuleanPian, containing rape pollen (RP), is a certified BPH medicine, but its main active compound and mechanism are unknown. This study aims to identify the main active compound of RP for the treatment of BPH. BPH rat models were induced with estradiol/testosterone (E2/T) and treated with RP or its alcohol extract (ALRP). RNA-seq and metabolomics were conducted, and RP compounds were identified via liquid chromatography-mass spectrometry (LC-MS). In vitro experiments used BPH-1 and RWPE-1 cells. E2/T induced BPH symptoms, alleviated by RP and ALRP treatment. RP possibly acts through phosphatidylinositol-3-kinase (PI3K)/AKT pathways, promoting autophagy. LC-MS identified five main RP compounds, with sinigrin implicated in BPH treatment via the PI3K/AKT(AKT Serine/Threonine Kinase 1)/mammalian target of rapamycin (mTOR) axis. Sinigrin may be the active compound in RP for BPH treatment, acting through the PI3K/AKT/mTOR axis.

Phosphodiesterase type-5 inhibitors (PDE5is) are used for the treatment of erectile dysfunction (ED) and have potential cardioprotective effects. The impacts of PDE5is on cardiovascular parameters, which may be associated with the occurrence and progression of subclinical cardiovascular diseases, remain uncertain. In this study, we evaluated the effects of PDE5is on vascular parameters. Randomized controlled trials (RCTs) that compared the effects of PDE5is and placebo on vascular parameters and were published from 1998 to 2022 were identified from PubMed, Scopus and Web of Science. Mean differences (MDs) with 95

ABSTRACT:Erectile dysfunction (ED) is prevalent among men, but its relationship with dietary habits is uncertain. The aim of our study was to assess whether dietary patterns enhance erectile function by reviewing the literature published before August 1, 2022, via PubMed, Web of Science, and EMBASE databases. The data compiled included author details; publication dates, countries, treatments, patient numbers, ages, follow-ups, and clinical trial outcomes, such as ED cases, odds ratios (ORs), confidence intervals (CIs), and International Index of Erectile Function-5 (IIEF-5) scores with means and standard deviations. An analysis of 14 studies with 27 389 participants revealed that plant-based diets (OR = 0.71, 95% CI: 0.66-0.75; P < 0.00001), low-fat diets (OR = 0.27, 95% CI: 0.13-0.53; P = 0.0002), and alternative diets such as intermittent fasting and organic diets (OR = 0.54, 95% CI: 0.36-0.80; P = 0.002) significantly reduced ED risk. High-protein low-fat diets (hazard ratio [HR] = 1.38, 95% CI: 1.12-1.64; P < 0.00001) and high-carb low-fat diets (HR = 0.79, 95% CI: 0.55-1.04; P < 0.00001) improved IIEF-5 scores. Combined diet and exercise interventions decreased the likelihood of ED (OR = 0.49, 95% CI: 0.28-0.85; P = 0.01) and increased the IIEF-5 score (OR = 3.40, 95% CI: 1.69-5.11; P < 0.0001). Diets abundant in fruits and vegetables (OR = 0.97, 95% CI: 0.96-0.98; P < 0.00001) and nuts (OR = 0.54, 95% CI: 0.37-0.80; P = 0.002) were also correlated with lower ED risk. Our meta-analysis underscores a strong dietary-ED association, suggesting that low-fat/Mediterranean diets rich in produce and nuts could benefit ED management.

Abstract Background The efficacy of surgical treatment for benign prostatic hyperplasia (BPH) patients with detrusor underactivity (DU) remains controversial. Methods To summarize relevant evidence, three databases (PubMed, Embase, and Web of Science) were searched from database inception to May 1, 2023. Transurethral surgical treatment modalities include transurethral prostatectomy (TURP), photoselective vaporization of the prostate (PVP), and transurethral incision of the prostate (TUIP). The efficacy of the transurethral surgical treatment was assessed according to maximal flow rate on uroflowmetry (Qmax), International Prostate Symptom Score (IPSS), postvoid residual (PVR), quality of life (QoL), voided volume, bladder contractility index (BCI) and maximal detrusor pressure at maximal flow rate (PdetQmax). Pooled mean differences (MDs) were used as summary statistics for comparison. The quality of enrolled studies was evaluated by using the Newcastle–Ottawa Scale. Sensitivity analysis and funnel plots were applied to assess possible biases. Results In this study, 10 studies with a total of 1142 patients enrolled. In BPH patients with DU, within half a year, significant improvements in Qmax (pooled MD, 4.79; 95% CI, 2.43–7.16; P < 0.05), IPSS(pooled MD, − 14.29; 95%CI, − 16.67–11.90; P < 0.05), QoL (pooled MD, − 1.57; 95% CI, − 2.37–0.78; P < 0.05), voided volume (pooled MD, 62.19; 95% CI, 17.91–106.48; P < 0.05), BCI (pooled MD, 23.59; 95% CI, 8.15–39.04; P < 0.05), and PdetQmax (pooled MD, 28.62; 95% CI, 6.72–50.52; P < 0.05) were observed after surgery. In addition, after more than 1 year, significant improvements were observed in Qmax (pooled MD, 6.75; 95%CI, 4.35–9.15; P < 0.05), IPSS(pooled MD, − 13.76; 95%CI, − 15.17–12.35; P < 0.05), PVR (pooled MD, − 179.78; 95%CI, − 185.12–174.44; P < 0.05), QoL (pooled MD, − 2.61; 95%CI, − 3.12–2.09; P < 0.05), and PdetQmax (pooled MD, 27.94; 95%CI, 11.70–44.19; P < 0.05). Compared with DU patients who did not receive surgery, DU patients who received surgery showed better improvement in PVR (pooled MD, 137.00; 95%CI, 6.90–267.10; P < 0.05) and PdetQmax (pooled MD, − 8.00; 95%CI, − 14.68–1.32; P < 0.05). Conclusions Our meta-analysis results showed that transurethral surgery can improve the symptoms of BPH patients with DU. Surgery also showed advantages over pharmacological treatment for BPH patients with DU. Systematic review registration PROSPERO CRD42023415188.

The ubiquitination is crucial for controlling cellular homeostasis and protein modification, in which ubiquitin-conjugating enzyme (E2) acts as the central player in the ubiquitination system. Ubiquitin-conjugating enzymes, which have special domains that catalyse substrates, have sequence discrepancies and modulate various pathophysiological processes in different cells of multiple organisms. E2s take part in the mitosis of primordial germ cells, meiosis of spermatocytes and the formation of mature haploid spermatids to maintain normal male fertility. In this review, we summarize the various types of E2s and their functions during distinct stages of spermatogenesis.

PURPOSE:Erectile dysfunction (ED) is associated with several vascular disorders, but the associations between ED and vascular parameters are still unclear. MATERIALS AND METHODS:We analyzed and synthesized a comprehensive range of studies from PubMed, Web of Science, and Scopus regarding the associations between ED and the following measures: ankle-brachial index (ABI), pulse wave velocity (PWV), intima-media thickness (IMT), nitrate-mediated dilation (NMD), flow-mediated dilation (FMD), augmentation index (AI), endothelial progenitor cells (EPCs) and other vascular parameters. Subgroup analysis was conducted according to specific types of parameters. Study quality was assessed by using the Newcastle-Ottawa Scale. Sensitivity analysis was conducted to confirm the robustness of the pooled results. RESULTS:Fifty-seven studies with 7,312 individuals were included. Twenty-eight studies were considered to be high-quality. ED patients had a 0.11 mm higher IMT (95% confidence interval [CI]: 0.07, 0.15), a 2.86% lower FMD (95% CI: -3.56, -2.17), a 2.34% lower NMD (95% CI: -3.37, -1.31), a 2.83% higher AI (95% CI: 0.02, 5.63), a 1.11 m/s higher PWV (95% CI: 0.01, 2.21), and a 0.72% lower percentage of EPCs (95% CI: -1.19, -0.24) compared to those without ED. However, ABI was similar between ED patients and non-ED individuals. According to sensitivity analysis, the pooled results were robust. CONCLUSIONS:Our study confirmed the associations between ED and several vascular parameters and highlighted the importance of prevention and management of vascular and endothelial dysfunction in ED patients.

Background Psychological stress and its two stress response systems, the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS), are closely related to psychogenic erectile dysfunction (pED). However, the analyses of perceived stress and stress systems in pED patients need to be more in-depth, especially the interactions between them. Methods Our study included 75 patients with pEDs and 75 healthy men. The International Index of Erectile Function-5 (IIEF-5) and the 10-item Perceived Stress Scale (PSS-10) were used for assessing the severity of ED and perceived stress. All participants collected saliva samples on three consecutive days at eight specific times with strict reference to the time of morning awakening for measuring cortisol parameters and wore electrocardiography for 24 h to derive heart rate variability (HRV). Results The PSS-10 scores of pED patients were significantly higher than the control group (p<0.001). Although PSS-10 and IIEF-5 scores were negatively correlated in pED patients, there was no statistical significance between them (r=−0.049, p=0.677). Compared with the control group, the HRV parameters of pED patients were significantly increased in LF/HF ratio (p=0.014) but significantly decreased in LF, HF, and pNN50 (p<0.001). However, the two groups had no statistically significant differences in cortisol variables (all p>0.05). The interaction between sympathovagal modulation (HF, rMSSD) and cortisol awakening response (CAR AUCi) explained significantly greater variance in perceived stress than either stress system alone. Higher parasympathetic activity combined with a higher cortisol awakening response was associated with greater perceived stress. Conclusion Our results suggested that the interrelation between ANS and HPA axis activity might enhance our comprehension of how stress affected the physical and mental health of pED patients.

Background and purpose: Castration-resistant prostate cancer (CRPC) has been a major cause of tumor-associated death among men worldwide. The discovery of novel therapeutic approaches for CRPC remains imperative. Atractylenolide I (ATR-I), a prominent bioactive component from Atractylodes macrocephala, exhibits powerful anticancer potentials in various malignancies. Nevertheless, the ATR-I’s activity on CRPC and its underlying mechanism has not been reported. Experimental approach: An enzalutamide-resistant (EnzR) cell line was successfully constructed. The pharmacological effects of ATR-I were assessed in vitro and in vivo. The changes in the gene expression profiles after ATR-I treatment were analyzed using RNA sequencing (RNA-seq). Key results: ATR-I suppressed the proliferative and migratory abilities of CRPC cells, while triggering cell cycle arrest and apoptosis. In constructed EnzR cells, ATR-I also inhibited their proliferation and promoted apoptosis. Intriguingly, a combination of ATR-I with enzalutamide synergistically induced more apoptosis of EnzR cells. Mechanistically, RNA-seq results identified kinesin family member 15 (KIF15) as a potential target of ATR-I. KIF15 was up-regulated in prostate cancer (PCa), and its higher level was associated with poorer clinical outcomes. Further investigation showed that ATR-I inhibited the expression of KIF15 mRNA and protein, thus mediating ubiquitin-proteasomal degradation of AR/AR-V7. Finally, our in vivo experiment verified that ATR-I alone or in combination with enzalutamide retarded the growth of EnzR xenograft tumors. Conclusion and implications: This study elucidated the antitumor mechanism of ATR-I against CRPC. Notably, ATR-I may be a promising therapeutic drug for CPRC patients and enhance the response to enzalutamide in EnzR patients.

Background: Ginsenosides, phenolic compounds, and polysaccharides are the bioactive constituents of Panax ginseng Meyer. Compound K (CK) is a secondary ginsenoside with better bioavailability. It is also a promising anticancer agent. Purpose: We aimed to evaluate the effect of CK on prostate cancer (PCa) and its potential mechanisms. Study design: The proliferation, migration and cell cycle of PCa cells after CK treatment were assessed in various PCa cell lines. Docetaxel was used as a positive control drug. Unlike other published studies, the potential mechanisms of CK (50 mu M) were investigated by an unbiased global transcriptome sequencing in the current study. Methods: Key CK related genes (CRGs) with prognostic significance were identified and verified by bioinformatic methods using data from the TCGA dataset and GSE21034 dataset. The role of CDK1 in the effect of CK treatment on PCa cells was investigated by overexpression of CDK1. Results: CK inhibited the proliferation and migration of PCa cells at concentrations (less than 25 mu M) without obvious cytotoxicity. Five key CRGs with prognostic significance were identified, including CCNA2, CCNB2, CCNE2, CDK1, and PKMYT1, which are involved in cell cycle pathways. CK inhibited the expression of these 5 genes and the cell cycle of PCa cells. According to the results of bioinformatic analysis, the expression of the five key CRGs was strongly associated with poor prognosis and advanced pathological stage and grade of PCa. In addition, CK could restore androgen sensitivity in castration-resistant PCa cells, probably by inhibiting the expression of CDK1. After CDK1 overexpression, the inhibition of proliferation and migration of PCa cells by CK was decreased. The inhibition on the phosphorylation of AKT by CK was also reduced. Conclusion: CK can inhibit PCa cells, and the mechanisms may be associated with the inhibition of cell cycle pathways through CDK1. CK is also a potential clinical anticancer agent for treating PCa.

BackgroundProstate cancer (PCa) is an age-associated malignancy with high morbidity and mortality rate, posing a severe threat to public health. Cellular senescence, a specialized cell cycle arrest form, results in the secretion of various inflammatory mediators. In recent studies, senescence has shown an essential role in tumorigenesis and tumor development, yet the extensive effects of senescence in PCa have not been systematically investigated. Here, we aimed to develop a feasible senescence-associated prognosis model for early identification and appropriate management in patients with PCa.MethodThe RNA sequence results and clinical information available from The Cancer Genome Atlas (TCGA) and a list of experimentally validated senescence-related genes (SRGs) from the CellAge database were first obtained. Then, a senescence-risk signature related with prognosis was constructed using univariate Cox and LASSO regression analysis. We calculated the risk score of each patient and divided them into high-risk and low-risk groups in terms of the median value. Furthermore, two datasets (GSE70770 and GSE46602) were used to assess the effects of the risk model. A nomogram was built by integrating the risk score and clinical characteristics, which was further verified using ROC curves and calibrations. Finally, we compared the differences in the tumor microenvironment (TME) landscape, drug susceptibility, and the functional enrichment among the different risk groups.ResultsWe established a unique prognostic signature in PCa patients based on eight SRGs, including CENPA, ADCK5, FOXM1, TFAP4, MAPK, LGALS3, BAG3, and NOX4, and validated well prognosis-predictive power in independent datasets. The risk model was associated with age and TNM staging, and the calibration chart presented a high consistency in nomogram prediction. Additionally, the prognostic signature could serve as an independent prediction factor due to its high accuracy. Notably, we found that the risk score was positively associated with tumor mutation burden (TMB) and immune checkpoint, whereas negatively correlated with tumor immune dysfunction and exclusion (TIDE), suggesting that these patients with risk scores were more sensitive to immunotherapy. Drug susceptibility analysis revealed differences in the responses to general drugs (docetaxel, cyclophosphamide, 5-Fluorouracil, cisplatin, paclitaxel, and vincristine) were yielded between the two risk groups.ConclusionIdentifying the SRG-score signature may become a promising method for predicting the prognosis of patients with PCa and tailoring appropriate treatment strategies.

Background and purpose: Castration-resistant prostate cancer (CRPC) has been a major cause of tumor-associated death among men worldwide. The discovery of novel therapeutic approaches for CRPC remains imperative. Atractylenolide I (ATR-I), a prominent bioactive component from Atractylodes macrocephala, exhibits powerful anticancer potentials in various malignancies. Nevertheless, the ATR-I’s activity on CRPC and its underlying mechanism has not been reported. Experimental approach: An enzalutamide-resistant (EnzR) cell line was successfully constructed. The pharmacological effects of ATR-I were assessed in vitro and in vivo. The changes in the gene expression profiles after ATR-I treatment were analyzed using RNA sequencing (RNA-seq). Key results: ATR-I suppressed the proliferative and migratory abilities of CRPC cells, while triggering cell cycle arrest and apoptosis. In constructed EnzR cells, ATR-I also inhibited their proliferation and promoted apoptosis. Intriguingly, a combination of ATR-I with enzalutamide synergistically induced more apoptosis of EnzR cells. Mechanistically, RNA-seq results identified kinesin family member 15 (KIF15) as a potential target of ATR-I. KIF15 was up-regulated in prostate cancer (PCa), and its higher level was associated with poorer clinical outcomes. Further investigation showed that ATR-I inhibited the expression of KIF15 mRNA and protein, thus mediating ubiquitin-proteasomal degradation of AR/AR-V7. Finally, our in vivo experiment verified that ATR-I alone or in combination with enzalutamide retarded the growth of EnzR xenograft tumors. Conclusion and implications: This study elucidated the antitumor mechanism of ATR-I against CRPC. Notably, ATR-I may be a promising therapeutic drug for CPRC patients and enhance the response to enzalutamide in EnzR patients.

BACKGROUND:The discovery of androgen receptor (AR) having transrepression effects completes the circle of its functionalities as a typical transcription factor, which intrinsically bears dual functions of activation and repression linked to co-factor competition and redistribution. Indeed, AR dual functions are exemplified by locus-wide regulation of the oncogenic 8q24-MYC region. METHODS:RT-qPCR assay and public RNA-profiling datasets were used to assess MYC transcription in androgen-sensitive cell lines. Public ChIP-seq and RNA-Seq datasets were computed to evaluate AR-MYC direct and indirect signatures. Gene sets in typical MYC and AR pathways were monitored to validate their cross-talks. Bio-informatics and chromosome conformation capture (3C) assay were performed in the AR gene locus to examine androgen-elicited distal regulation. Finally, co-factor re-distribution were globally tracked between AR and MYC binding sites. RESULTS:In this report, we found MYC responded negatively to androgen with hypersensitivity, rivaling AR natural functions as an innate androgen effector. Furthermore, both direct and indirect AR and MYC transcriptional programs were actively in equilibration. With established androgen-mediated versus MYC-mediated gene subsets, we validated AR and MYC pathways were both bidirectional and extensively entangled. In addition, we determined that the AR gene locus resembled the MYC gene region and both loci were androgen-repressed via epigenetics and chromatin architectural alterations. Significantly, transcriptional factor profiling along the prostate cancer (PCa) genome exposed that PCa transcriptomes were dynamically equilibrated between AR-binding site and MYC-binding site. CONCLUSION:Together, our findings stratified AR-MYC interactions that are extensively wired and intricately organized to compensate for essential PCa transcriptional programs and neutralize excessive signaling.

Background Androgen receptor (AR) activation and repression dual-functionality only became known recently and still remains intriguing in prostate cancer (PCa). MYC is a prominent oncogene that functionally entangles with AR signaling in PCa. Further exploration of AR regulatory mechanisms on MYC gene transcription bears clinical and translation significance. Methods Bioinformatics analysis of PCa cell line and clinical RNA-Seq and ChIP-Seq (chromatin immunoprecipitation-sequencing) datasets to anchor interactions of AR and MYC transcriptional networks. ChIP-qPCR and 3C (chromosome conformation capture) analyses to probe MYC distal regulation by AR binding sites (ABSs). CRISPR/Cas9-mediated genome-editing to specify functions of ABS within the 8q24-MYC locus on androgen-mediated MYC transcription. Global FoxA1 and HoxB13 distribution profiling to advance AR transcriptional mechanisms. Results Here we recognize AR bi-directional transcription mechanisms by exploiting the prominent 8q24-MYC locus conferring androgen hyper-sensitivity. At ~ 25 Kb downstream of the MYC gene, we identified an undefined ABS, P10. By chromatin analyses, we validated androgen-dependent spatial interaction between P10 and MYC-Promoter (MYC-Pro) and temporal epigenetic repression of these MYC-proximal elements. We next designed a CRISPR/Cas9-mediated double genomic knock-out (KO) strategy to show that P10-KO slightly lessened androgen-elicited MYC transrepression in LNCaP-AR cells. In similar genomic editing assays, androgen-mediated MYC repression became slightly deepened upon KO of P11, an ABS in the PVT1 gene locus highly enriched in AR-binding motifs and peaks. We also investigated multiple ABSs in the established PCAT1 super-enhancer that distally interacts with MYC-Pro for transactivation, with each KO pool consistently shown to relieve androgen-elicited MYC repression. In the end, we systemically assessed androgen effects in the 8q24-MYC locus and along PCa genome to generalize H3K27ac and BRD4 re-distribution from pioneer factors (FoxA1 and HoxB13) to AR sites. Conclusion Together, we reconciled these observations by unifying AR dual-functions that are mechanistically coupled to and equilibrated by co-factor redistribution. Graphical Abstract

目的 探讨尿液中23种金属浓度与精液质量参数的关联性.方法 招募394名育龄男性,收集精液和尿液样本,使用电感耦合等离子体质谱联用仪(inductively coupled plasma-mass spectrometry,ICP-MS)检测尿液中23种金属浓度,对每种尿液金属浓度四分位数分组(0.05).结论 尿液中锌和铅浓度与精子前向运动活力、精子总活力和精子存活率呈负相关,尿液中锑浓度与精子正常形态率呈负相关.