Causality investigation among gut microbiota, immune cells, and prostate diseases: a Mendelian randomization study.

Background: The gut microbiota has been demonstrated to have a significant role in the pathogenesis and progression of a variety of diseases, including prostate cancer, prostatitis, and benign prostatic hyperplasia. Potential links between prostate diseases, immune cells and the gut microbiota have not been adequately investigated. Methods: MR studies were conducted to estimate the effects of instrumental variables obtained from genome-wide association studies (GWASs) of 196 gut microbial taxa and 731 immune cells on the risk of prostate diseases. The primary method for analysing causal relationships was inverse variance-weighted (IVW) analysis, and the MR results were validated through various sensitivity analyses. Results: MR analysis revealed that 28 gut microbiome taxa and 75 immune cell types were significantly associated with prostate diseases. Furthermore, reverse MR analysis did not support a causal relationship between prostate diseases and the intestinal microbiota or immune cells. Finally, the results of the mediation analysis indicated that Secreting Treg % CD4 Treg, Activated & resting Treg % CD4 Treg, and Mo MDSC AC inhibited the role of the class Mollicutes in reducing the risk of PCa. In prostatitis, CD8+ T cells on EM CD8br hinder the increased risk associated with the genus Eubacterium nodatum group. Interestingly, in BPH, CD28- CD25++CD8br AC and CD16-CD56 on HLA DR+ NK promoted the role of the genus Dorea in reducing the risk of BPH. Conclusion: This study highlights the complex relationships among the gut microbiota, immune cells and prostate diseases. The involvement of the gut microbiota in regulating immune cells to impact prostate diseases could provide novel methods and concepts for its therapy and management.

[Changes in seminal plasma composition and corresponding sperm quality in patients with chronic prostatitis / chronic pelvic pain syndrome: Progress in studies].

Prostatitis is one of the three most common prostate diseases in men, the other two being prostatic hyperplasia and prostate cancer, and about 50% of men worldwide have been attacked by prostatitis during their lives. The incidence of infertility is significantly higher in patients with chronic prostatitis / chronic pelvic pain syndrome (CP/CPPS) than in those without it, which is mainly attributed to the changed semen composition of the CP/CPPS patients. Using the key words chronic prostatitis, chronic pelvic pain syndrome, sperm, semen, and seminal plasma, we searched PubMed and Medical Lines online for originals, review articles, clinical trials, case reports and associated citations on humans and animals published up to 2024. We comprehensively reviewed the previous studies and investigations relating chronic prostatitis, seminal plasma change and sperm quality, and discussed the impact of the change of semen composition on sperm quality.

Unraveling CCL20's role by regulating Th17 cell chemotaxis in experimental autoimmune prostatitis.

Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS), a prevalent urological ailment, exerts a profound influence upon the well-being of the males. Autoimmunity driven by Th17 cells has been postulated as a potential factor in CP/CPPS pathogenesis. Nonetheless, elucidating the precise mechanisms governing Th17 cell recruitment to the prostate, triggering inflammation, remained an urgent inquiry. This study illuminated that CCL20 played a pivotal role in attracting Th17 cells to the prostate, thereby contributing to prostatitis development. Furthermore, it identified prostate stromal cells and immune cells as likely sources of CCL20. Additionally, this research unveiled that IL-17A, released by Th17 cells, could stimulate macrophages to produce CCL20 through the NF-κB/MAPK/PI3K pathway. The interplay between IL-17A and CCL20 establishes a positive feedback loop, which might serve as a critical mechanism underpinning the development of chronic prostatitis, thus adding complexity to its treatment challenges.

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

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

Contrast-enhanced and conventional ultrasound images of renal wounds after partial nephrectomy.

OBJECTIVES: To observe the features of conventional ultrasound (US) and contrast-enhanced ultrasound (CEUS) images of renal wounds after minimally-invasive partial nephrectomy (MIPN) and evaluate their severity using these two modalities. METHODS: This prospective, observational study included 120 patients who underwent MIPN from April to December 2019 in our hospital. The postoperative US images were evaluated and classified, and contrast extravasation characteristics of CEUS were recorded. The correlation between the classification system and perioperative factors was analyzed. RESULTS: Eighty-five patients underwent US and CEUS after MIPN. Conventional US images were classified into three grades according to the surface morphology of renal wounds and overall shape of the kidney around the incision. Univariable and multivariable analyses indicated that the N component of the R.E.N.A.L. score and the resection range were preoperative and intraoperative factors, respectively, related to the US image grades (UIGs). A deep location and expanded excision contributed to an increased UIG. The extravasation rate increased with the UIG (Spearman correlation rho=0.247, P=0.022), and a higher UIG prolonged the length of extravasation. The depth of the tumor and resection range were related to the UIG. CONCLUSIONS: US and CEUS were feasible and repeatable methods that reflect the morphologic changes of renal wounds after MIPN and may be useful for evaluating their severity.

The role of glutamine metabolism in castration-resistant prostate cancer.

Reprogramming of metabolism is a hallmark of tumors, which has been explored for therapeutic purposes. Prostate cancer (PCa), particularly advanced and therapy-resistant PCa, displays unique metabolic properties. Targeting metabolic vulnerabilities in PCa may benefit patients who have exhausted currently available treatment options and improve clinical outcomes. Among the many nutrients, glutamine has been shown to play a central role in the metabolic reprogramming of advanced PCa. In addition to amino acid metabolism, glutamine is also widely involved in the synthesis of other macromolecules and biomasses. Targeting glutamine metabolic network by maximally inhibiting glutamine utilization in tumor cells may significantly add to treatment options for many patients. This review summarizes the metabolic landscape of PCa, with a particular focus on recent studies of how glutamine metabolism alterations affect therapeutic resistance and disease progression of PCa, and suggests novel therapeutic strategies.

Treatment and surveillance for non-muscle-invasive bladder cancer: a clinical practice guideline (2021 edition).

Non-muscle invasive bladder cancer (NMIBC) is a major type of bladder cancer with a high incidence worldwide, resulting in a great disease burden. Treatment and surveillance are the most important part of NIMBC management. In 2018, we issued "Treatment and surveillance for non-muscle-invasive bladder cancer in China: an evidence-based clinical practice guideline". Since then, various studies on the treatment and surveillance of NMIBC have been published. There is a need to incorporate these materials and also to take into account the relatively limited medical resources in primary medical institutions in China. Developing a version of guideline which takes these two issues into account to promote the management of NMIBC is therefore indicated. We formed a working group of clinical experts and methodologists. Through questionnaire investigation of clinicians including primary medical institutions, 24 clinically concerned issues, involving transurethral resection of bladder tumor (TURBT), intravesical chemotherapy and intravesical immunotherapy of NMIBC, and follow-up and surveillance of the NMIBC patients, were determined for this guideline. Researches and recommendations on the management of NMIBC in databases, guideline development professional societies and monographs were referred to, and the European Association of Urology was used to assess the certainty of generated recommendations. Finally, we issued 29 statements, among which 22 were strong recommendations, and 7 were weak recommendations. These recommendations cover the topics of TURBT, postoperative chemotherapy after TURBT, Bacillus Calmette-Guérin (BCG) immunotherapy after TURBT, combination treatment of BCG and chemotherapy after TURBT, treatment of carcinoma in situ, radical cystectomy, treatment of NMIBC recurrence, and follow-up and surveillance. We hope these recommendations can help promote the treatment and surveillance of NMIBC in China, especially for the primary medical institutions.

IL-17 exacerbates experimental autoimmune prostatitis via CXCL1/CXCL2-mediated neutrophil infiltration.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a poorly understood disease. Accumulating evidence suggests that autoimmune dysfunction is involved in the development of CP/CPPS. Interleukin-17 (IL-17) is associated with the occurrence and development of several chronic autoimmune inflammatory diseases. However, the molecular mechanisms underlying the role of IL-17 in CP/CPPS are not clear. We confirmed that IL-17 was increased in the prostate tissues of experimental autoimmune prostatitis (EAP) mice. Corresponding to the increase of IL-17, neutrophil infiltration and the levels of CXCL1 and CXCL2 (CXC chemokine ligands 1 and 2) were also increased in the prostate of EAP. Treatment of EAP mice with an IL-17-neutralizing monoclonal antibody (mAb) decreased the number of infiltrated neutrophils and CXCL1 and CXCL2 levels. Depletion of neutrophils using anti-Ly6G antibodies ameliorated the inflammatory changes and hyperalgesia caused by EAP. Fucoidan, a could potent inhibitor of neutrophil migration, also ameliorate the manifestations of EAP. Our findings suggested that IL-17 promoted the production of CXCL1 and CXCL2, which triggered neutrophil chemotaxis to prostate tissues. Fucoidan might be a potential drug for the treatment of EAP via the effective inhibition of neutrophil infiltration.

Clinical practice guideline for transurethral plasmakinetic resection of prostate for benign prostatic hyperplasia (2021 Edition).

Benign prostatic hyperplasia (BPH) is highly prevalent among older men, impacting on their quality of life, sexual function, and genitourinary health, and has become an important global burden of disease. Transurethral plasmakinetic resection of prostate (TUPKP) is one of the foremost surgical procedures for the treatment of BPH. It has become well established in clinical practice with good efficacy and safety. In 2018, we issued the guideline "2018 Standard Edition". However much new direct evidence has now emerged and this may change some of previous recommendations. The time is ripe to develop new evidence-based guidelines, so we formed a working group of clinical experts and methodologists. The steering group members posed 31 questions relevant to the management of TUPKP for BPH covering the following areas: questions relevant to the perioperative period (preoperative, intraoperative, and postoperative) of TUPKP in the treatment of BPH, postoperative complications and the level of surgeons' surgical skill. We searched the literature for direct evidence on the management of TUPKP for BPH, and assessed its certainty generated recommendations using the grade criteria by the European Association of Urology. Recommendations were either strong or weak, or in the form of an ungraded consensus-based statement. Finally, we issued 36 statements. Among them, 23 carried strong recommendations, and 13 carried weak recommendations for the stated procedure. They covered questions relevant to the aforementioned three areas. The preoperative period for TUPKP in the treatment of BPH included indications and contraindications for TUPKP, precautions for preoperative preparation in patients with renal impairment and urinary tract infection due to urinary retention, and preoperative prophylactic use of antibiotics. Questions relevant to the intraoperative period incorporated surgical operation techniques and prevention and management of bladder explosion. The application to different populations incorporating the efficacy and safety of TUPKP in the treatment of normal volume (< 80 ml) and large-volume (≥ 80 ml) BPH compared with transurethral urethral resection prostate, transurethral plasmakinetic enucleation of prostate and open prostatectomy; the efficacy and safety of TUPKP in high-risk populations and among people taking anticoagulant (antithrombotic) drugs. Questions relevant to the postoperative period incorporated the time and speed of flushing, the time indwelling catheters are needed, principles of postoperative therapeutic use of antibiotics, follow-up time and follow-up content. Questions related to complications incorporated types of complications and their incidence, postoperative leukocyturia, the treatment measures for the perforation and extravasation of the capsule, transurethral resection syndrome, postoperative bleeding, urinary catheter blockage, bladder spasm, overactive bladder, urinary incontinence, urethral stricture, rectal injury during surgery, postoperative erectile dysfunction and retrograde ejaculation. Final questions were related to surgeons' skills when performing TUPKP for the treatment of BPH. We hope these recommendations can help support healthcare workers caring for patients having TUPKP for the treatment of BPH.

The long noncoding RNA glycoLINC assembles a lower glycolytic metabolon to promote glycolysis.

Non-covalent complexes of glycolytic enzymes, called metabolons, were postulated in the 1970s, but the concept has been controversial. Here we show that a c-Myc-responsive long noncoding RNA (lncRNA) that we call glycoLINC (gLINC) acts as a backbone for metabolon formation between all four glycolytic payoff phase enzymes (PGK1, PGAM1, ENO1, and PKM2) along with lactate dehydrogenase A (LDHA). The gLINC metabolon enhances glycolytic flux, increases ATP production, and enables cell survival under serine deprivation. Furthermore, gLINC overexpression in cancer cells promotes xenograft growth in mice fed a diet deprived of serine, suggesting that cancer cells employ gLINC during metabolic reprogramming. We propose that gLINC makes a functional contribution to cancer cell adaptation and provide the first example of a lncRNA-facilitated metabolon.

[Omics molecular subtyping, prognostic prediction and individualized treatment of prostate cancer: Advances in studies].

Prostate cancer (PCa) is a most common malignancy in males. It has a greater heterogeneity than other cancers, which poses a real challenge to the clinical diagnosis, classification and prognostic monitoring. At present, high-, medium- and low-risk PCa patients are classified mainly by Gleason scores and the PSA level, which, however, fail to reveal the diverse molecular heterogeneity and precisely distinguish the molecular subtypes of PCa. With the development of high-throughput sequencing, more and more studies on the molecular classification of the malignancy have paved the theoretical ground for the early diagnosis, efficacy prediction and individualized treatment of PCa. This study reviews the molecular classification, prognosis prediction and individualized treatment of PCa to date, hoping to contribute to the development of the precise treatment of PCa.

[Prevalence of and associated factors for prostate calcification in ≥40-year-old males with benign prostatic enlargement].

OBJECTIVE: To investigate the prevalence of and risk factors for prostate calcification (PCal) in ≥40 years old males with benign prostatic enlargement (BPE) found in health checkup. METHODS: We retrospectively analyzed the data on 671 ≥40-year-old men found with BPE in health checkup and investigated the prevalence of and risk factors for PCal in BPE males aged ≥40 years by univariate and multivariate analyses. RESULTS: Among 1 582 men aged ≥40 years undergoing health checkup, 671 were found with BPE and 274 (17.3%) with both BPE and PCal. The incidence rate of PCal was 40.8% (274/671) in the BPE patients, which was increased with age (trend χ2 = 5.289, P = 0.021), with statistically significant differences in different age groups (χ2 = 9.243, P = 0.026). Significant differences were also observed in age, height, estimated glomerular filtration rate (eGFR), urine pH level and the number of cases of uneven prostatic echoes between the BPE patients with and those without PCal (P < 0.05). Logistic regression analysis showed that age (OR = 1.027, 95% CI: 1.010－1.044), urine pH (OR = 1.446, 95% CI: 1.148－1.823) and uneven prostatic echoes (OR = 2.150, 95% CI: 1.108－4.174) were the associated factors for PCal in BPE patients aged ≥40 years. CONCLUSION: The incidence rate of PCal is high and increased with age in BPE patients aged ≥40 years, and age, urine pH and uneven prostatic echoes are associated factors for PCal in this cohort.

[Modified urethral reconstruction with lingual mucosa for complicated anterior urethral stricture].

OBJECTIVE: To investigate the efficiency and complications of modified urethral reconstruction with lingual mucosa in the treatment of complicated anterior urethral stricture (CAUS). METHODS: We retrospectively studied the clinical data on 10 cases of CAUS treated by modified urethral reconstruction with lingual mucosa from December 2017 to June 2019 concerning the age of the patients and the causes, location and length of urethral stricture. We statistically analyzed the pre- and post-operative maximum urine flow rate (Qmax), scores on Mental Status Scale in Non-psychiatric Settings (MSSNS) and quality of life (QOL) scores and observed post-operative complications such as abnormal taste, tongue numbness, urinary tract infection, urethral diverticulum, and urethral stricture. RESULTS: Compared with the baseline, Qmax was significantly improved and the MSSNS and QOL scores dramatically decreased at 3, 6 and 12 months after surgery (P < 0.01). Paraurethral infection developed in 1 case postoperatively, which was cured after dressing change, external urethral orifice stenosis occurred in another, which was improved after regular urethral orifice expansion, and mild tongue numbness was found in 2 cases at 1 month but gradually restored to abnormal. Urethrography showed no urethral diverticulum before catheter removal. CONCLUSIONS: Lingual mucosa is an ideal alternative material for urethral reconstruction in the treatment of CAUS, and lateral lingual mucosa can be easily obtained. Modified urethral reconstruction by embedding lingual mucosa in the dorsal base of the urethra, with the advantages of definite effectiveness and few postoperative complications, is worthy of clinical application.

Identifying the role of apolipoprotein A-I in prostate cancer.

Although localized prostate cancer (PCa) can be cured by prostatectomy and radiotherapy, the development of effective therapeutic approaches for advanced prostate cancer, including castration-resistant PCa (CRPC) and neuroendocrine PCa (NEPC), is lagging far behind. Identifying a novel prognostic and diagnostic biomarker for early diagnosis and intervention is an urgent clinical need. Here, we report that apolipoprotein A-I (ApoA-I), the major component of high-density lipoprotein (HDL), is upregulated in PCa based on both bioinformatics and experimental evidence. The fact that advanced PCa shows strong ApoA-I expression reflects its potential role in driving therapeutic resistance and disease progression by reprogramming the lipid metabolic network of tumor cells. Molecularly, ApoA-I is regulated by MYC, a frequently amplified oncogene in late-stage PCa. Altogether, our findings have revealed a novel indicator to predict prognosis and recurrence, which would benefit patients who are prone to progress to metastasis or even NEPC, which is the lethal subtype of PCa.

Circular RNA circANKS1B acts as a sponge for miR-152-3p and promotes prostate cancer progression by upregulating TGF-α expression.

BACKGROUND: A growing number of studies indicate that circular RNAs (circRNAs) play critical roles in human diseases, and show great potential as biomarkers and therapeutic targets. This study aimed to investigate the expression and function of circANKS1B in prostate cancer (PC). METHODS: The expression of circANKS1B and miR-152-3p was analyzed by real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Cell migration and invasion were measured using a transwell assay. The interaction between circANKS1B and miR-152-3p was confirmed by a dual-luciferase reporter gene assay. Rescue experiments were conducted to determine whether circANKS1B regulated the invasion of PC cells via the circANKS1B-miR-152-3p-TGF-α pathway. RESULTS: The expression of circANKS1B was markedly upregulated in both PC cells and tissues. Moreover, high circANKS1B expression was associated with poor prognosis in PC patients. Dual-luciferase reporter assay indicated that circANKS1B directly bound to miR-152-3p. Furthermore, circANKS1B negatively regulated miR-152-3p expression. Knockdown of circANKS1B markedly suppressed cell migration and invasion and TGF-α expression in PC cells, whereas the effects of circANKS1B silencing were reversed by miR-152-3p deficiency. In addition, the impact of miR-152-3p silencing on invasion of circANKS1B-deficient PC cells was also abrogated by TGF-α deficiency. Overall, circANKS1B acts as a sponge for miR-152-3p to promote PC progression by upregulating TGF-α expression. CONCLUSION: Our findings reveal that circANKS1B may be a potential prognostic biomarker and therapeutic target for PC.

[Transurethral 180 W front-firing GreenLight laser vaporization of the prostate for the treatment of benign prostatic hyperplasia].

OBJECTIVE: To evaluate the clinical effect and safety of transurethral 180 W front-firing GreenLight laser vaporization of the prostate (PVP) in the treatment of benign prostatic hyperplasia (BPH). METHODS: A total of 61 BPH patients underwent 180W front-firing GreenLight laser PVP (n = 30, the PVP group) or transurethral plasmakinetic resection of the prostate (n = 31, the control group) from March to December 2019. We collected the pre-, intra- and post-operative clinical data and compared them between the two groups of patients. RESULTS: Operations were successfully completed in all the cases with no blood transfusion or serious complications. Compared with the controls, the patients of the PVP group showed remarkably less intra-operative blood loss (ï¼»62.3 ± 15.9ï¼½ vs ï¼»48.8 ± 9.6ï¼½ ml, P < 0.05), shorter operation time (ï¼»75.0 ± 9.9ï¼½ vs ï¼»57.5 ± 19.0ï¼½ min, P < 0.05), postoperative bladder lavage time (ï¼»64.4 ± 10.5ï¼½ vs ï¼»25.2 ± 11.5ï¼½ h, P < 0.05), catheter-indwelling time (ï¼»5.1 ± 0.5ï¼½ vs ï¼»2.5 ± 0.5ï¼½ d, P < 0.05) and hospitalization time (ï¼»7.3 ± 1.7ï¼½ vs ï¼»4.1 ± 0.6ï¼½ d, P < 0.05), and a lower incidence of postoperative hematuria (12.9% ï¼»4/31ï¼½ vs 0% ï¼»0/30ï¼½, P < 0.05). No statistically significant differences, however, were found between the two groups in the incidence rates of capsular perforation, transurethral resection syndrome (TURS), urinary incontinence, urethral stricture and post-extubation urinary retention. Significant improvement was observed in IPSS, QOL, Qmax and PVR in both groups post-operatively (P < 0.05). CONCLUSIONS: Compared with transurethral plasmakinetic resection of the prostate, 180W front-firing GreenLight laser PVP, with the advantages of less bleeding, shorter catheter-indwelling time and faster recovery, is safer and more effective for the treatment of BPH, with no need for drug withdrawal for those taking anticoagulants, and especially applicable to the elderly and high-risk patients.

[Causes of and risk factors for failure in catheter removal after transurethral resection of the prostate].

OBJECTIVE: To find the causes of the failure in the first catheter removal (CR) after transurethral resection of the prostate (TURP) and the related risk factors. METHODS: We collected the clinical data on 285 BPH patients treated by TURP from June 2015 to May 2018. We divided the cases into a successful CR (SCR) and a failed CR (FCR) group and investigated the risk factors for the first CR after TURP by multivariate logistic regression analysis. RESULTS: CR was successfully performed in 246 and failed in 39 of the 285 cases. In the FCR group, post-CR urinary retention occurred in 15 cases immediately after, severe urinary tract irritation in 13, massive gross hematuria in 7 and urinary incontinence in 4 within 1 month. Multivariate logistic regression analysis showed that the independent risk factors for CR failure included IPSS (OR = 5.106, P = 0.013), preoperative urinary tract infection (OR = 3.835, P = 0.041), prostate volume (OR = 4.160, P = 0.011) and catheter compression time (OR = 4.051, P = 0.017). CONCLUSIONS: The common causes of the failure in catheter removal after TURP included early postoperative urinary retention, urinary infection, secondary hematuria and urinary incontinence.

Effect of Eriocalyxin B on prostatic inflammation and pelvic pain in a mouse model of experimental autoimmune prostatitis.

BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common disease in males. Eriocalyxin B (EriB), a natural diterpenoid purified from Isodon eriocalyx var. laxiflora, was previously reported to have antitumor effects via multiple immune-related pathways. In this study, we investigated the effect of EriB on CP/CPPS using a mouse model of experimental autoimmune prostatitis (EAP) and explored its potential mechanisms. METHODS: The EAP model was established in nonobese diabetic mice by intradermal injecting a mixture of prostate antigens and Complete Freund's Adjuvant on days 0 and 28. Then, EAP mice received daily intraperitoneal injections of EriB (5 or 10 mg/kg/d) for 14 days, from days 28 to 42 (EAP+EriB5 or EAP+EriB10 groups). The histopathological appearance of the prostate tissues was evaluated. Chronic pelvic pain development was assessed by cutaneous allodynia. Inflammatory cytokines were measured by enzyme-linked immunosorbent assay tests. We then explored anti-inflammatory potential mechanisms of EriB by studying the effects of PI3K inhibitor wortmannin (EAP+EriB10+Wort group) and NF-κB inhibitor SC75741 (EAP+EriB10+SC group) on prostate inflammation and pelvic pain using this model. RESULTS: Histological analyses revealed significant prostate inflammation in EAP mice compared with control mice. Significantly increased pelvic pain was detected in EAP mice (P < .05). Compared with the EAP+Veh group, chronic pain development, histological appearance, and cytokine levels demonstrated that EriB could alleviate the severity of EAP in a dose-dependent manner though upregulation of the PI3K/Akt/mTOR pathway and downregulation of the NF-κB pathway. Further mechanism research demonstrated that the PI3K/AKT/mTOR pathway could be blocked by wortmannin, but was not affected by SC75741. In addition, the NF-κB pathway could be further inhibited by SC75741 compared with the EAP+EriB10+Veh group. However, wortmannin could reactivate the NF-κB pathway, indicating that the PI3K/AKT/mTOR pathway negatively regulates the NF-κB pathway during EriB treatment. CONCLUSIONS: The results of the present study suggested that EriB could alleviate the severity of prostatic inflammation and pelvic pain in an EAP mouse model. These findings may broaden the value of EriB as a promising candidate for the treatment of CP/CPPS.

CaMK4-dependent phosphorylation of Akt/mTOR underlies Th17 excessive activation in experimental autoimmune prostatitis.

Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) is a complicated syndrome characterized by genitourinary pain in the absence of bacterial infection. Th17 cell-driven autoimmunity has been proposed as a cause of CP/CPPS. However, the factors that promote Th17-driven autoimmunity in experimental autoimmune prostatitis (EAP) and the molecular mechanisms are still largely unknown. Here, we showed that Th17 cells were excessively activated, and blockade of IL-17A could effectively ameliorate various symptoms in EAP. Furthermore, we revealed that calcium/calmodulin-dependent kinase Ⅳ (CaMK4), especially Thr196 p-CaMK4 was increased in the Th17 cells of the EAP group, which were activated by intracellular cytosolic Ca2+ . Pharmacologic and genetic inhibition of CaMK4 decreased the proportion of Th17 cells, and the protein and mRNA level of IL-17A, IL-22, and RORγt. The phosphorylation of CaMK4 was dependent on the increase in intracellular cytosolic Ca2+ concentration in Th17 cells. A mechanistic study demonstrated that inhibition of CaMK4 reduced IL-17A production by decreasing the phosphorylation of Akt-mTOR, which was well accepted to positively regulate Th17 differentiation. Collectively, our results demonstrated that Ca2+ -CaMK4-Akt/mTOR-IL-17A axis inhibition may serve as a promising therapeutic strategy for CP/CPPS.

Effect of alcohol on chronic pelvic pain and prostatic inflammation in a mouse model of experimental autoimmune prostatitis.

BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent disease of the urogenital system. Alcohol has been reported to be closely related to CP/CPPS. Thus, we intended to verify the role of alcohol in CP/CPPS and determine the underlying mechanism. METHODS: We induced experimental autoimmune prostatitis (EAP) mouse model by intradermally injecting a mixture of prostate antigens (PAgs) and complete Freund's adjuvant on days 0 and 28. Mice were treated with alcohol (control-alcohol and EAP-alcohol groups) or vehicle (control-vehicle, and EAP-vehicle groups) from day 32 to 42. Forty-two days after PAg injection, the pathological appearance of the prostate tissues was evaluated, and histological analyses of the prostate were performed. Chronic pelvic pain was assessed by applying von Frey filaments to the lower abdomen. Proinflammatory cytokines were detected by enzyme-linked immunosorbent assay tests. Then, we explored the effects of the NLRP3 inhibitor MCC950 on chronic pelvic pain and prostatic inflammation in this model. RESULTS: Histological analyses showed diffuse inflammation in the stromal tissues that were characterized by severe infiltration of neutrophils and mononuclear cells in mice in the EAP-alcohol group compared with EAP-vehicle group. Chronic pain tests showed that the response frequency was significantly increased using a von Frey filament at forces of 0.4, 1.0, and 4.0 g in EAP-alcohol group compared with EAP-vehicle (P < .05). The levels of proinflammatory cytokines, including interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL-17, and IL-1ß were all significantly elevated in EAP-alcohol group compared with the EAP-vehicle group (P < .05). However, between the control-alcohol and control-vehicle groups, chronic pain tests, histological assays, and cytokine determinations showed no differences. Furthermore, our results demonstrated that MCC950 could decrease the expression level of NLRP3 inflammasome-related proteins including NLRP3, ASC, and caspase-1. The chronic pain tests, histological assays, and cytokine determinations showed that MCC950 could attenuate the chronic pain and prostatic inflammation through the inhibition of the NLRP3 inflammasome. CONCLUSIONS: This study indicated that alcohol could aggravate the severity of prostatic inflammation in EAP model though activating the NLRP3 inflammasome. Furthermore, the role of MCC950 in inhibiting NLRP3 inflammasome and decreasing IL-1ß secretion to alleviate EAP severity may show that it is a promising therapeutic agent for CP/CPPS.