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Introduction: Intravesical prostatic protrusion (IPP) has been reported to be associated with bladder outlet obstruction and is the main cause of lower urinary tract symptoms (LUTS) during the development of benign prostatic hyperplasia (BPH). However, the molecular mechanism of IPP remains unclear. Methods: Clinical data analysis was performed to analyze the association between IPP and long-term complications in patients with BPH. RNA sequencing was performed on prostate tissues (IPP or not). Stromal cells were obtained from IPP-derived primary cultures to explore the molecular mechanism of IPP formation. Cell proliferation was evaluated by a CCK-8 assay. Multiple proteins in the signaling pathway were assessed using Western blot. Results: First, we confirmed that IPP is a prognostic factor for long-term complications in patients with BPH. Then, we observed that FGF7 was upregulated in both IPP tissues and IPP primary stromal cells through immunohistochemistry, Western blot, and quantitative real-time PCR. Furthermore, FGF7 was significantly upregulated in high IPP-grade prostate tissues. The coculture experiments showed that the downregulation of FGF7 in IPP-derived stromal cells inhibited the proliferation and migration of the prostate epithelial cells. Additionally, FGF7 was bound to FGFR2 to induce the epithelial-mesenchymal transition process through binding to FGFR2. RNA sequencing analysis also revealed the activation of the MAPK/ERK1/2 signaling pathway. The MAPK/ERK1/2 was downregulated by a specific inhibitor affecting the FGF7 stimulation in vitro. Conclusions: Our data reveal a novel amplification effect, i.e., stromal cell-derived FGF7 promotes epithelial cell proliferation and stromal cell phenotype, ultimately inducing IPP formation. Targeting FGF7 can significantly reduce epithelial to stromal transition and provide a potential therapeutic target for BPH progression. [ABSTRACT FROM AUTHOR]

Objective: The aim of the present study was to observe the effect of the stroma proportion in hyperplasia nodules on the clinical symptoms of benign prostatic hyperplasia (BPH) patients and to identify the different genes and pathways in prostatic hyperplasia nodules between patients with epithelial-dominated hyperplasia (EDH) and stromal-dominated hyperplasia (SDH) nodules. Methods: Sixty-seven BPH patient samples underwent transurethral resection of the prostate (TURP) were collected and retrospectively analyzed. The differences in clinical parameters between the EDH and SDH groups were investigated. Collagen fiber percentage was assessed, and the correlation with clinical parameters was evaluated. mRNA sequencing in hyperplasia nodules of 8 BPH patients was performed, and differentially expressed genes (DEGs) between the EDH and SDH groups were screened. These DEGs were analyzed using GO, KEGG and PPI analysis. Results: The results showed the IPSS was significantly higher in the SDH group than in the EDH group (p < 0.01). The collagen fiber percentage of BPH nodules was higher in the SDH group than in the EDH group (p < 0.05), and the collagen fiber percentage was positively correlated with the IPSS (r = 0.4058, p = 0.0007). A total of 172 DEGs were obtained, including 63 up-regulated genes and 109 down-regulated genes. GO and KEGG pathway enrichment analyses showed DEGs were mainly enriched in extracellular matrix structural constituents. The top 10 hub genes were associated to the components of extracellular matrix and fibrosis. Conclusion: These results suggested that the symptoms of BPH patients with SDH nodules may be associated with prostate fibrosis and fibrosis may be a significant contributing factor in BPH/LUTS patients with SDH nodules. [ABSTRACT FROM AUTHOR]

The sterile inflammation (SI) of the urinary tract is a common problem requiring serious consideration after prostatectomy. This study mainly focuses on the role of the reactive oxygen species–NLR family, pyrin domain‐containing 3 (ROS–NLRP3) signaling pathway in SI after thulium laser resection of the prostate (TmLRP). Urinary cytokines were determined in patients who received TmLRP, and heat shock protein 70 (HSP70) was detected in the resected tissues. The involvement of ROS signaling in HSP70‐induced inflammation was explored in THP‐1 cells with or without N‐acetyl‐ l‐cysteine (NAC) pretreatment. The function of NLRP3 and Caspase‐1 was determined by Western blot analysis, enzyme‐linked immunosorbent assay (ELISA), and polymerase chain reaction. These phenomena and mechanisms were verified by the beagle models that received TmLRP. Clinical urine samples after TmLRP showed high expression of inflammatory factors and peaked 3–5 days after surgery. The high expression of HSP70 in the resected tissues was observed. After HSP70 stimulation, the expression of ROS, NLRP3, Caspase‐1, and interleukin‐18 (IL‐18) increased significantly and could be reduced by ROS inhibitor NAC. The expression of IL‐1β and IL‐18 could be inhibited by NLRP3 or Caspase‐1 inhibitors. In beagle models that received TmLRP, HSP70, NLRP3, Caspase‐1, IL‐1β, and IL‐18 were highly expressed in the wound tissue or urine, and could also be reduced by NAC pretreatment. Activation of the ROS–NLRP3 signaling pathway induces SI in the wound after prostatectomy. Inhibition of this pathway may be effective for clinical prevention and treatment of SI and related complications after prostatectomy. [ABSTRACT FROM AUTHOR]

Benign prostatic hyperplasia (BPH) is a common disease in elderly men, and transurethral laser prostatectomy (TULP) has been widely used in the clinic to remove bladder outlet obstruction caused by BPH. Previous animal models for wound repair after prostatectomy have many limitations, and there have been no previous reports of a mouse model of TULP. Therefore, this study aimed to establish a novel mouse model of TULP. Twelve healthy adult Kunming (KM) mice received transurethral laser vaporization prostatectomy with a 200-μm thulium laser. The mice were sacrificed, and wound specimens from the prostatic urethra and bladder neck were harvested at 1 day, 3 days, 5 days, and 7 days after surgery. Hematoxylin-eosin (HE) and immunohistochemistry were applied to confirm the establishment of the mouse TULP model. One day after the surgery, urothelium expressing uroplakin (UPK) was absent in the urethral wound site, and a large number of necrotic tissues were found in the wound site. There was no UPK-positive urothelium in the wound 3 days after surgery. At 5 days after surgery, monolayer urothelium expressing UPK was found in the wound site, indicating that the re-epithelization of the wound had been completed. On the 7th day after surgery, there were multiple layers of urothelium with UPK expression, indicating that the repair was completed. It is feasible to establish a mouse TULP model by using a microcystoscope system and a 200-μm thulium laser. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) secrete various cytokines with angiogenic and neuroprotective effects. This study aimed to assess the effects of human umbilical cord Wharton's jelly-derived MSCs (hWJ-MSCs) on diabetes-related intracavernosal pressure (ICP) impairment in rats. hWJ-MSCs were isolated from human umbilical cord Wharton's jelly and transplanted into the corpus cavernosum of streptozotocin (STZ)-induced diabetic rats by unilateral injection. The erectile function was evaluated at 4 weeks, as well as the expression levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), endothelial nitric oxide synthase (eNOS), and insulin-like growth factor 1 (IGF1). STZ-induced diabetic rats showed impaired ICP, which was significantly improved by hWJ-MSC treatment. VEGF, eNOS, IGF1, and bFGF expression levels were higher in hWJ-MSC injection sites than those in control ones in STZ-induced diabetic rats. These results suggest that hWJ-MSC transplantation might improve diabetic erectile dysfunction through increased production of paracrine growth factors, highlighting a novel potential therapeutic option for erectile dysfunction. [ABSTRACT FROM AUTHOR]

Low-intensity pulsed ultrasound (LIPUS) is a promising therapy that has been increasingly explored in basic research and clinical applications. LIPUS is an appealing therapeutic option as it is a noninvasive treatment that has many advantages, including no risk of infection or tissue damage and no known adverse reactions. LIPUS has been shown to have many benefits including promotion of tissue healing, angiogenesis, and tissue regeneration; inhibition of inflammation and pain relief; and stimulation of cell proliferation and differentiation. The biophysical mechanisms of LIPUS remain unclear and the studies are ongoing. In recent years, more and more research has focused on the relationship between LIPUS and stem/progenitor cells. A comprehensive search of the PubMed and Embase databases to July 2020 was performed. LIPUS has many effects on stem cells. Studies show that LIPUS can stimulate stem cells in vitro; promote stem cell proliferation, differentiation, and migration; maintain stem cell activity; alleviate the problems of insufficient seed cell source, differentiation, and maturation; and circumvent the low efficiency of stem cell transplantation. The mechanisms involved in the effects of LIPUS are not fully understood, but the effects demonstrated in studies thus far have been favorable. Much additional research is needed before LIPUS can progress from basic science research to large-scale clinical dissemination and application. [ABSTRACT FROM AUTHOR]

To improve the diagnostic efficiency of prostate cancer (PCa) and reduce unnecessary biopsies, we defined and analyzed the diagnostic efficiency of peripheral zone prostate-specific antigen (PSA) density (PZ-PSAD). Patients who underwent systematic 12-core prostate biopsies in Shanghai General Hospital (Shanghai, China) between January 2012 and January 2018 were retrospectively identified (n = 529). Another group of patients with benign prostatic hyperplasia (n = 100) were randomly preselected to obtain the PSA density of the non-PCa cohort (N-PSAD). Prostate volumes and transition zone volumes were measured using multiparameter magnetic resonance imaging (mpMRI) and were combined with PSA and N-PSAD to obtain the PZ-PSAD from a specific algorithm. Receiver operating characteristic (ROC) curve analysis was used to assess the PCa detection efficiency in patients stratified by PSA level, and the area under the ROC curve (AUC) of PZ-PSAD was higher than that of PSA, PSA density (PSAD), and transition zone PSA density (TZ-PSAD). PZ-PSAD could amend the diagnosis for more than half of the patients with inaccurate transrectal ultrasonography (TRUS) and mpMRI results. When TRUS and mpMRI findings were ambiguous to predict PCa (PIRADS score ≤3), PZ-PSAD could increase the positive rate of biopsy from 21.7% to 54.7%, and help 63.8% (150/235) of patients avoid unnecessary prostate biopsy. In patients whose PSA was 4.0–10.0 ng ml−1, 10.1–20.0 ng ml−1, and >20.0 ng ml−1, the ideal PZ-PSAD cut-off value for predicting clinically significant PCa was 0.019 ng ml−2, 0.297 ng ml−2, and 1.180 ng ml−2, respectively (sensitivity >90%). Compared with PSA, PSAD, and TZ-PSAD, the efficiency of PZ-PSAD for predicting PCa is the highest, leading to fewer missed diagnoses and unnecessary biopsies. [ABSTRACT FROM AUTHOR]

We conducted the present study to assess the correlation of the prostatic anatomical parameters, especially the ratio of peripheral zone thickness and transitional zone thickness, with clinical and uroflowmetry characteristics suggestive of benign prostate hyperplasia (BPH). A total of 468 consecutive patients with a detailed medical history were identified. All patients were evaluated by scoring subjective symptoms with the International Prostate Symptom Score (IPSS) and quality of life (QoL). The prostatic anatomical parameters were measured using transrectal ultrasonography, and postvoid residual urine and maximum flow rate (Qmax) values were also determined. Pearson's correlation analysis revealed that both total prostate volume (TPV; r = 0.160, P < 0.001) and transitional zone volume (TZV; r = 0.104, P = 0.016) increased with patients' age; however, no correlations were observed of TPV, TZV, transitional zone index (TZI), and transitional zone thickness (TZT) with IPSS or QoL (all P >0.05). Peripheral to transitional zone index (PTI) was found negatively correlated with total IPSS (r = −0.113, P = 0.024), storage IPSS (r = −0.103, P = 0.041), and voiding IPSS (r = −0.123, P = 0.014). As regards the uroflowmetry characteristics, PTI (r = 0.157, P = 0.007) was indicated to be positively correlated with Qmaxand negatively correlated with TZI (r = −0.119, P = 0.042) and TZT (r = −0.118, P = 0.045), but not correlated with TPV, TZV, or peripheral zone thickness (PZT) (all P > 0.05). Postvoid residual urine (PVR) had not correlated with all the prostatic anatomical variables (all P > 0.05). This is the first study that formally proposed the concept of PTI, which is an easy-to-measure prostate anatomical parameter which significantly correlates with total IPSS, storage IPSS, voiding IPSS, and Qmax, suggesting that PTI would be useful in evaluating and managing men with lower urinary tract symptoms (LUTS)/BPH. However, well-designed studies are mandatory to verify the clinical utility of PTI. [ABSTRACT FROM AUTHOR]

Erectile dysfunction attributable to testosterone deficiency is less common in young males, and the effect of estradiol on erectile function in eugonadal young males is unclear. We analyzed data from 195 male participants, including 143 eugonadal patients with erectile dysfunction and 52 healthy men. To distinguish psychogenic and organic erectile dysfunction, penile rigidity was measured using the nocturnal penile tumescence rigidity test. Serum levels of sexual hormones were quantified by electrochemiluminescence, and penile vascular status was assessed by penile color Doppler ultrasound. Both serum estradiol levels and the ratio of estradiol to testosterone were higher in patients with organic erectile dysfunction than in patients with psychogenic erectile dysfunction or healthy controls. Organic erectile dysfunction was negatively associated with estradiol levels and the ratio of estradiol to testosterone, and estradiol was the only significant risk factor for organic erectile dysfunction (odds ratio: 1.094; 95% confidence interval: 1.042–1.149, P = 0.000). Moreover, serum estradiol levels were negatively correlated with penile rigidity. Serum estradiol levels were higher and penile rigidity was lower in patients with venous erectile dysfunction than in patients with nonvascular erectile dysfunction. We conclude that elevated serum estradiol levels may impair erectile function and may be involved in the pathogenesis of organic erectile dysfunction in eugonadal young men. [ABSTRACT FROM AUTHOR]

The androgen receptor (AR) pathway is critical for prostate cancer carcinogenesis and development; however, after 18‐24 months of AR blocking therapy, patients invariably progress to castration‐resistant prostate cancer (CRPC), which remains an urgent problem to be solved. Therefore, finding key molecules that interact with AR as novel strategies to treat prostate cancer and even CRPC is desperately needed. In the current study, we focused on the regulation of RNA‐binding proteins (RBPs) associated with AR and determined that the mRNA and protein levels of AR were highly correlated with Musashi2 (MSI2) levels. MSI2 was upregulated in prostate cancer specimens and significantly correlated with advanced tumor grades. Downregulation of MSI2 in both androgen sensitive and insensitive prostate cancer cells inhibited tumor formation in vivo and decreased cell growth in vitro, which could be reversed by AR overexpression. Mechanistically, MSI2 directly bound to the 3′‐untranslated region (UTR) of AR mRNA to increase its stability and, thus, enhanced its transcriptional activity. Our findings illustrate a previously unknown regulatory mechanism in prostate cancer cell proliferation regulated by the MSI2‐AR axis and provide novel evidence towards a strategy against prostate cancer. [ABSTRACT FROM AUTHOR]

This study compared the diagnostic efficacy of transrectal ultrasound (TRUS)-guided prostate biopsy (TRBx) and transperineal prostate biopsy (TPBx) in patients with suspected prostate cancer (PCa). We enrolled 2962 men who underwent transrectal (n = 1216) or transperineal (n = 1746) systematic 12-core prostate biopsy. Clinical data including age, prostate-specific antigen (PSA) level, and prostate volume (PV) were recorded. To minimize confounding, we performed propensity score-matching analysis. We measured and compared PCa detection rates between TRBx and TPBx, which were stratified by clinical characteristics and Gleason scores. The effects of clinical characteristics on PCa detection rate were assessed by logistic regression. For all patients, TPBx detected a higher proportion of clinically significant PCa (P < 0.001). Logistic regression analyses illustrated that PV had a smaller impact on PCa detection rate of TPBx compared with TRBx. Propensity score-matching analysis showed that the detection rates in TRBx were higher than those in TPBx for patients aged >– 80 years (80.4% vs 56.5%, P = 0.004) and with PSA level 20.1–100.0 ng ml−1 (80.8% vs 69.1%, P = 0.040). In conclusion, TPBx was associated with a higher detection rate of clinically significant PCa than TRBx was; however, because of the high detection rate at certain ages and PSA levels, biopsy approaches should be optimized according to patents' clinical characteristics. [ABSTRACT FROM AUTHOR]

Quaking homolog (QKI) is a member of the RNA‐binding signal transduction and activator of proteins family. Previous studies showed that QKI possesses the tumour suppressor activity in human cancers by interacting with the 3'‐untraslated region (3'‐UTR) of various gene transcripts via the STAR domain. This study first assessed the association of QKI‐6 expression with clinicopathological and survival data from bladder cancer patients and then investigated the underlying molecular mechanisms. Bladder cancer tissues (n = 223) were subjected to immunohistochemistry, and tumour cell lines and nude mice were used for different in vitro and in vivo assays following QKI‐6 overexpression or knockdown. QKI‐6 down‐regulation was associated with advanced tumour TNM stages and poor patient overall survival. QKI‐6 overexpression inhibited bladder cancer cell growth and invasion capacity, but induced tumour cell apoptosis and cell cycle arrest. Furthermore, ectopic expression of QKI‐6 reduced tumour xenograft growth and expression of proliferation markers, Ki67 and PCNA. However, knockdown of QKI‐6 expression had opposite effects in vitro and in vivo. QKI‐6 inhibited expression of E2 transcription factor 3 (E2F3) by directly binding to the E2F3 3'‐UTR, whereas E2F3 induced QKI‐6 transcription by binding to the QKI‐6 promoter in negative feedback mechanism. QKI‐6 expression also suppressed activity and expression of nuclear factor‐κB (NF‐κB) signalling proteins in vitro, implying a novel multilevel regulatory network downstream of QKI‐6. In conclusion, QKI‐6 down‐regulation contributes to bladder cancer development and progression. [ABSTRACT FROM AUTHOR]

Objectives: 5α‐reductase inhibitor (5‐ARI) is a commonly used medicine in the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Our study mainly focuses on the mechanism of BPH development after 5ARI treatment. Materials and Methods: Prostate specimens from patients were collected. Insulin‐like growth factor 1 (IGF‐1), Beclin‐1, LC3 levels, was analysed by immunohistochemistry. The role IGF‐1 on autophagic flux in prostate epithelial cells was studied. Additionally, effect of autophagy on recombinant grafts consisting of prostate stromal and epithelial cells in nude mice was investigated. Results: We demonstrated that IGF‐1 expression is down‐regulated in prostate fibroblasts after long‐term 5‐ARI application. A decrease in IGF‐1 levels was found to activate autophagic flux through the mTOR pathway in prostate epithelial cells, while the inhibition of IGF‐1 receptor function induced autophagy in prostate epithelial cells. In addition, we revealed that blocking autophagic flux initiation can reduce the volume of recombinant grafts in vivo. Finally, our findings suggest that long‐term 5‐ARI application reduces IGF‐1 secretion by prostatic stromal cells, thereby inducing autophagy of prostatic epithelial cells, which is one of the mechanisms underlying BPH pathogenesis and progression. Conclusions: Focusing on the autophagy induced by low levels of IGF‐1 in prostatic epithelial cells, after elucidating AR signalling impairment of prostate stromal cells, might provide a novel strategy for the treatment and prevention of BPH development. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Benign prostatic hyperplasia (BPH) patients experience complications after surgery. We studied oxidative stress scavenging by porous Se@SiO 2 nanospheres in prostatic urethra wound healing after transurethral resection of the prostate (TURP). Beagle dogs were randomly distributed into two groups after establishing TURP models. Wound recovery and oxidative stress levels were evaluated. Re-epithelialization and the macrophage distribution at the wound site were assessed by histology. The mechanism by which porous Se@SiO 2 nanospheres regulated macrophage polarization was investigated by qRT-PCR, western blotting, flow cytometry, immunofluorescence and dual luciferase reporter gene assays. Our results demonstrated that Porous Se@SiO 2 nanosphere-coated catheters advance re-epithelization of the prostatic urethra, accelerating wound healing in beagle dogs after TURP, and improve the antioxidant capacity to inhibit oxidative stress and induced an M2 phenotype transition of macrophages at the wound. By restraining the function of reactive oxygen species (ROS), porous Se@SiO 2 nanospheres downregulated Ikk, IκB and p65 phosphorylation to block the downstream NF-κB pathway in macrophages in vitro. Since activation of NF-κB signaling cascades drives macrophage polarization, porous Se@SiO 2 nanospheres promoted macrophage phenotype conversion from M1 to M2. Our findings suggest that porous Se@SiO 2 nanosphere-coated catheters promote postoperative wound recovery in the prostatic urethra by promoting macrophage polarization toward the M2 phenotype through suppression of the ROS-NF-κB pathway, attenuating the inflammatory response. Statement of Significance The inability to effectively control post-operative inflammatory responses after surgical treatment of benign prostatic hyperplasia (BPH) remains a challenge to researchers and surgeons, as it can lead to indirect cell death and ultimately delay wound healing. Macrophages at the wound site work as pivotal regulators of local inflammatory response. Here, we designed and produced a new type of catheter with a coating of porous Se@SiO 2 nanosphere and demonstrated its role in promoting prostatic urethra wound repair by shifting macrophage polarization toward the anti-inflammatory M2 phenotype via suppressing ROS-NF-κB pathway. These results indicate that the use of porous Se@SiO 2 nanosphere-coated catheter may provide a therapeutic strategy for postoperative complications during prostatic urethra wound healing to improve patient quality of life. [ABSTRACT FROM AUTHOR]

Abstract We previously demonstrated that maternal exposure to di-n-butyl phthalate (DBP) resulted in renal fibrosis in male offspring; however, the underlying mechanism governing this effect has not been thoroughly elucidated to date. We hypothesized that DBP exposure induces TGF-β expression and abnormal activation of epithelial-mesenchymal transition (EMT) in fibrotic kidneys. Pregnant rats received DBP orally at a dose of 850 mg/kg BW/day during gestational days 14–18. In the DBP-exposed group, immunohistochemistry (IHC) staining showed increased expression of TGF-β1 and EMT markers. In rat kidney tubular epithelial cells (NRK52E), ROS production increased expression levels of TGF-β1 and subsequently contributed to the induction of Snail1-mediated EMT. Notably, DBP exposure also promoted autophagy that downregulated TGF-β1. Taken together, our findings suggest that maternal exposure to DBP promotes EMT in tubular epithelial cells via upregulation of TGF-β1. Highlights • Maternal exposure to DBP promoted TGF-β1 expression in kidney. • Autophagy regulated expression of TGF-β1 induced by DBP in renal tubular cells. • TGF-β signaling regulation contributed to DBP-induced EMT. [ABSTRACT FROM AUTHOR]