Prostatic Inflammation Research Articles

Developmental stage and infection status may affect drug distribution in the prostate of rats

Prostate inflammation is often treated with drugs which are ineffective. Antibacterial agents fail to reach the prostate epithelium, and the blood-prostate barrier (BPB) may affect the drug transport process. Factors affecting drug efficacy remain unclear. Rats were categorised into groups A and B, corresponding to adulthood and puberty, respectively. Group C included the model of chronic prostate infection. Dialysates of levofloxacin and cefradine were collected from the prostate gland and jugular vein and evaluated. Pharmacokinetic analysis was conducted. The free concentrations of antimicrobials in the prostate and plasma samples of all groups peaked at 20 min, then gradually decreased. The mean AUC0-tprostate/AUC0-tplasma ratio in the levofloxacin group were 0.86, 0.53, and 0.95, and the mean values of AUC0-∞prostate/AUC0-∞plasma ratio were 0.85, 0.63, and 0.97. The corresponding values in the cefradine group were 0.67, 0.30 and 0.84, and 0.66, 0.31, and 0.85, respectively. The mean values in group B were lower than those in group A, and those in group C were higher than those in group B. The maturity of the prostate may affect the ability of the drug to cross the BPB. Infection may disrupt the BPB, affecting drug permeability.

Isoliquiritigenin reduces experimental autoimmune prostatitis by facilitating Nrf2 activation and suppressing the NLRP3 inflammasome pathway

BackgroundChronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) lead to severe irritation and impaired sperm quality in males. However, current therapeutic options often fail to achieve satisfactory effects. Consequently, the investigation of novel treatment strategies or remedies holds substantial clinical importance. As a flavonoid monomer, isoliquiritigenin (ISL) has been shown to possess anti-inflammatory activity, especially in several chronic nonspecific-inflammatory conditions. Thus, an exploration of the possible anti-inflammatory effects of ISL on CP/CPPS, a chronic aseptic inflammation of the prostate, has significant potential. MethodsAn experimental autoimmune prostatitis (EAP) model was used for the evaluation of the anti-inflammatory effects of ISL. It was found that ISL treatment could reduce the secretion and invasion of pro-inflammatory cytokines in prostate tissue. In EAP mice, ISL treatment also reduced oxidative stress (OS) and activation of the NLRP3 inflammasome. In vitro, ISL upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and inhibited NLRP3 inflammasome activation in RAW264.7 macrophages exposed to lipopolysaccharide (LPS). ResultsTreatment with ISL treatment relieved prostate inflammation and pelvic pain in EAP mice. Both in vivo and in vitro, ISL treatment activated Nrf2/HO-1 signaling, which in turn inhibited oxidative stress and activation of the NLRP3 inflammasome. Blockade of Nrf2/HO-1 signaling abolished the inhibitory effects of ISL on oxidative stress and NLRP3 inflammasome activation. ConclusionsIsoliquiritigenin reduced experimental autoimmune prostatitis by facilitating Nrf2 activation and suppressing the NLRP3 inflammasome pathway.

Effects of a proprietary mixture of extracts from Sabal serrulata fruits and Urtica dioica roots (WS®1541) on prostate hyperplasia and inflammation in rats and human cells.

Introduction: Phytotherapeutics, particularly extracts from Sabal serrulata (saw palmetto) fruit or Urtica dioica (stinging nettle) root, are popular for the treatment of male lower urinary symptoms in many countries, but their mechanism of action is poorly understood. We performed in vivo and in vitro studies to obtain deeper insight into the mechanism of action of WS®1541, a proprietary combination of a Sabal serrulata fruit and an Urtica dioica root extract (WS® 1473 and WS®1031, respectively) and its components. Methods: We used the sulpiride model of benign prostatic hyperplasia in rats and tested three doses of WS®1541 in comparison to finasteride, evaluating weight of prostate and its individual lobes as well as aspects of inflammation, oxidative stress, growth and hyperplasia. In human BPH-1 cells, we studied the effect of WS®1473, WS®1031, WS®1541 and finasteride on apoptosis, cell cycle progression and migrative capacity of the cells. Results: WS®1541 did not reduce prostate size in sulpiride treated rats but attenuated the sulpiride-induced changes in expression of most analyzed genes and of oxidized proteins and abrogated the epithelial thickening. In vitro, WS®1473 and WS®1031 showed distinct profiles of favorable effects in BPH-1 cells including anti-oxidative, anti-proliferative and pro-apoptotic effects, as well as inhibiting epithelial-mesenchymal-transition. Conclusion: This data supports a beneficial effect of the clinically used WS®1541 for the treatment of lower urinary tract symptoms associated with mild to moderate benign prostate syndrome and provides a scientific rationale for the combination of its components WS®1473 and WS®1031.

Serum Prostat-Spesifik Antijen Düzeyi 2,5-10 Ng/Ml Arasındaki Erkeklerde İki Kadeh Testinin Prostat Biyopsisi ve Asemptomatik Prostat İnflamasyonu Varlığı ve Derecesiyle İlişkisinin Araştırılması

Objective: Prostate-specific antigen (PSA) is a marker used to detect prostate cancer. When high PSA values are detected, a prostate biopsy is performed considering the possibility of prostate cancer. PSA elevation is not specific to prostate cancer, but may also be caused by conditions such as benign prostatic hyperplasia (BPH), urinary tract infection, and chronic prostatitis. Prostate cancer is not detected in approximately 66% of patients undergoing a biopsy, and patients are exposed to unnecessary biopsy and biopsy complications. Chronic prostatitis is detected in approximately 40% of these biopsies. The two-glass test is based on examining urine before and after rectal examination, which is used in diagnosing chronic prostatitis. In this study, we aimed to reveal the two-glass test’s effectiveness in predicting the incidence of prostatitis and inflammation in patients with a PSA value of 2.5-10 ng/ml and who underwent prostate needle biopsy.
 
 Methods: Fifty-two male patients, aged between 50 and 78 years, with PSA values between 2.5 and 10 ng/ml, who applied to our clinic were included in the study. EPS-two-glass test and prostate biopsy were applied to all patients. EPS; is a sample obtained by removing the fluid from the urethra after a prostate massage; VB-3; shows the urine produced by taking about 10 ml of urine voided after massage. EPS and VB3 detect prostate infection. Under the microscope, ≥10 leukocytes were considered significant for prostate inflammation. According to the pathology results, the patients were divided into 3 groups; prostate cancer, BPH, and chronic prostatitis. The chronic prostatitis group was classified according to the histopathological calcification described by Nickel.
 
 Results: In this study, the ratio of chronic prostatitis was found to be 38%. VB3 positivity was found to be statistically significant in the chronic prostatitis group compared to the other groups (p = 0.028). Although there was no statistically significant difference between the prevalence of inflammation and PSA elevation, PSA was found to be higher in the multifocal inflammation subgroup than in the focal inflammation patient group.
 
 Conclusion: The relationship between chronic prostatitis and PSA elevation remains a mystery. Although no statistical relationship was found between inflammation and PSA elevation in this study, the significant correlation between chronic prostatitis and VB3 positivity reinforces the possibility of this relationship. We believe that our results will form the basis for further studies to avoid unnecessary biopsies.

Sodium butyrate alleviates experimental autoimmune prostatitis by inhibiting oxidative stress and NLRP3 inflammasome activation via the Nrf2/HO-1 pathway.

Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) leads to severe discomfort in males and loss of sperm quality. Current therapeutic options have failed to achieve satisfactory results. Sodium butyrate (NaB) plays a beneficial role in reducing inflammation, increasing antioxidant capacities, and improving organ dysfunction; additionally NaB has good safety prospects and great potential for clinical application. The purpose of the current research was to study the effect of NaB on CP/CPPS and the underlying mechanisms using a mouse model of experimental autoimmune prostatitis (EAP) mice. The EAP mouse model was successfully established by subcutaneously injecting a mixture of prostate antigen and complete Freund's adjuvant. Then, EAP mice received daily intraperitoneal injections of NaB (100, 200,or 400 mg/kg/day) for 16 days, from Days 26 to 42. We then explored anti-inflammatory potential mechanisms of NaB by studying the effects of Nrf2 inhibitor ML385 and HO-1 inhibitor zinc protoporphyrinon prostate inflammation and pelvic pain using this model. On Day 42, hematoxylin-eosin staining and dihydroethidiumstaining were used to evaluate the histological changes and oxidative stress levels of prostate tissues. Chronic pelvic pain was assessed by applying Von Frey filaments to the lower abdomen. The levels of inflammation-related cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor were detected by enzyme-linked immunosorbent assay. The regulation of Nrf2/HO-1 signaling pathway and the expression of NLRP3 inflammasome-related protein in EAP mice were detected by western blot analysis assay. Compared with the EAP group, chronic pain development, histological manifestations, and cytokine levels showed that NaB reduced the severity of EAP. NaB treatment could inhibit NLRP3 inflammasome activation. Mechanism studies showed that NaB intervention could alleviate oxidative stress in EAP mice through Nrf2/HO-1 signal pathway. Nrf2/HO-1 pathway inhibitors can inhibit NaB -mediated oxidative stress. The inhibitory effect of NaB on the activation of NLRP3 inflammasome and anti-inflammatory effect can also be blocked by Nrf2/HO-1 pathway. NaB treatment can alleviates prostatic inflammation and pelvic pain associated with EAP by inhibiting oxidative stress and NLRP3 inflammasome activation via the Nrf2/HO-1 pathway. NaB has the potential as an effective agent in the treatment of EAP.

Effects of Prostatic Inflammation on Clinical Outcomes in Patients with Benign Prostate Hyperplasia

Background: Benign prostate hyperplasia (BPH), a non-cancerous enlargement of the prostate gland, prevalently impacts the aging male population, often disrupting the quality of life with its accompanying urinary symptoms. The intersection between BPH and prostatic inflammation has emerged as a focal point in urological research, with inflammation speculated to exacerbate BPH progression and symptoms. Understanding this relationship is pivotal in refining therapeutic approaches and improving patient outcomes. Objective: This study aimed to elucidate the effects of prostatic inflammation on the clinical outcomes of patients with BPH, focusing on symptom progression, treatment efficacy, and long-term complications. Methods: This Study Conducted at Gajju Khan Medical College Swabi, KPK, Pakistan, in the duration from January, 2023 to June, 2023. This prospective cohort study involved 126 men with BPH, categorized into two groups based on the presence (n=63) or absence (n=63) of prostatic inflammation. Data were collected over three years, with assessments including demographic information, clinical histories, and prostate examinations. Primary outcomes measured were the progression of BPH symptoms, urinary function, and prostate size. Secondary outcomes included quality of life, acute urinary retention, the need for surgical intervention, medication efficacy, and long-term complications. Statistical analyses employed included Chi-square tests, t-tests, and ANOVA, with SPSS software. Results: The group with prostatic inflammation showed significantly more severe symptom progression (p < 0.01), impaired urinary function (p < 0.01), and increased prostate size (p < 0.01) compared to the non-inflamed group. Secondary outcomes also favored the non-inflamed group with better quality of life scores (75.2 ± 5.2 vs. 78.8 ± 4.8, p < 0.01), lower rates of acute urinary retention (20.3% vs. 15.5%, p < 0.01). Conclusion: Prostatic inflammation significantly worsens the clinical outcomes of BPH, affecting symptom progression, treatment response, and the likelihood of long-term complications. These findings suggest the need for integrated therapeutic strategies that address both BPH and prostatic inflammation to optimize patient care.

(254) Extracorporeal Shock Wave Therapy Combined with Cannabidiol Reduces Prostatic Inflammation by Regulating TLR4-NFκB Signaling Pathway

Abstract Introduction Chronic prostatitis is a refractory male disease that has bothered patients and confused urologists for a long time. Recently, extracorporeal shockwave therapy (ESWT), has evolved as a promising treatment approach in several inflammatory disease. Cannabidiol (CBD) is a minor cannabinoid with reported analgesic and anti-inflammatory properties. Objective To evaluate the effect of CBD and ESWT in lipopolysaccharide(LPS)-induced prostatic inflammation \ Methods RWPE-1 cells were randomly divided into five groups: (a) RWPE-1 group (normal control), (b) LPS group (LPS-induced inflammation) and (c) CBD group (LPS-induced RWPE-1 treated with 0.1ug/ml of CBD), (d) ESWT group (LPS-induced RWPE-1 treated with ESWT), (e) CBD+ESWT group (LPS-induced RWPE-1 treated with CBD and ESWT). After administration of treatment, cells were collected for immunocytochemistry and Western blot analysis, respectively. Results CBD and ESWT improved the inflammation of LPS-induced RWPE-1 cells, with the most significant improvement in the CBD+ESWT group (p <0.01). Compared with the LPS group, CBD, ESWT decreased cyclooxygenase 2 (COX-2) expression by inhibiting the TLR4-NFκB pathway (p<0.01). Conclusions CBD and ESWT reduce inflammation by degrading COX-2 in the microenvironment through the TLR4-NFκB inhibition pathway. ESWT combined with CBD improves inflammation significantly, thus suggesting that the combination treatment may be a potential and promising therapeutic approach for prostatitis. Disclosure No.

Age-Dependent Effects of Voluntary Wheel Running Exercise on Voiding Behavior and Potential Age-Related Molecular Mechanisms in Mice.

Older men frequently develop lower urinary tract symptoms attributed to benign prostatic hyperplasia (LUTS/BPH). Risk factors for LUTS/BPH include sedentary lifestyle, anxiety/depression, obesity, and frailty, which all increase with age. Although physical exercise may reduce the progression and/or severity of LUTS/BPH, the age-related mechanisms responsible remain unknown. Voiding symptoms, body mass, and frailty were assessed after 4-weeks of voluntary wheel running in 2-month (n = 10) and 24-month (n = 8) old C57Bl/6J male mice. In addition, various social and individual behaviors were examined in these cohorts. Finally, cellular and molecular markers of inflammation and mitochondrial protein expression were assessed in prostate tissue and systemically. Despite running less (aged vs young X¯ = 12.3 vs 30.6 km/week; p = .04), aged mice had reduced voiding symptoms (X¯ = 67.3 vs 23.7; p < .0001) after 1 week of exercise, which was sustained through week 4 (X¯ = 67.3 vs 21.5; p < .0001). Exercise did not affect voiding symptoms in young mice. Exercise also increased mobility and decreased anxiety in both young and aged mice (p < .05). Exercise decreased expression of a key mitochondrial protein (PINK1; p < .05) and inflammation within the prostate (CD68; p < .05 and plasminogen activator inhibitor-1; p < .05) and in the serum (p < .05). However, a frailty index (X¯ = 0.17 vs 0.15; p = .46) and grip strength (X¯ = 1.10 vs 1.19; p = .24) were unchanged after 4 weeks of exercise in aged mice. Voluntary aerobic exercise improves voiding behavior and mobility, and decreases prostatic mitochondrial protein expression and inflammation in aged mice. This promising model could be used to evaluate molecular mechanisms of aerobic exercise as a novel lifestyle intervention for older men with LUTS/BPH.

P2X7R Modulates NEK7-NLRP3 Interaction to Exacerbate Experimental Autoimmune Prostatitis via GSDMD-mediated Prostate Epithelial Cell Pyroptosis.

Chronic prostatitis is one of the most common urologic diseases that troubles young men, with unclear etiology and ineffective treatment approach. Pyroptosis is a novel model of cell death, and its roles in chronic prostatitis are unknown. In this study, P2X7R, NEK7, and GSDMD-NT expression levels were detected in prostate tissues from benign prostate hyperplasia (BPH) patients and experiment autoimmune prostatitis (EAP) mice. P2X7R agonist, antagonist, NLRP3 inhibitor, and disulfiram were used to explore the roles of the P2X7R-NEK7-NLRP3 axis in prostate epithelial cell pyroptosis and chronic prostatitis development. We found that P2X7R, NEK7, and GSDMD-NT were highly expressed in the prostate epithelial cells of BPH patients with prostatic inflammation and EAP mice. Activation of P2X7R exacerbated prostatic inflammation and increased NLRP3 inflammasome component expressions and T helper 17 (Th17) cell proportion. Moreover, P2X7R-mediated potassium efflux promoted NEK7-NLRP3 interaction, and NLRP3 assembly and activation, which caused GSDMD-NT-mediated prostate epithelial cell pyroptosis to exacerbate EAP development. Disulfiram could effectively improve EAP by inhibiting GSDMD-NT-mediated prostate epithelial cell pyroptosis. In conclusion, the P2X7R-NEK7-NLRP3 axis could promote GSDMD-NT-mediated prostate epithelial cell pyroptosis and chronic prostatitis development, and disulfiram may be an effective drug to treat chronic prostatitis.

Trends in experimental autoimmune prostatitis: insights into pathogenesis, therapeutic strategies, and redefinition.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPSS) is a debilitating condition characterized by prostate inflammation, pain and urinary symptoms. The immune system's response to self-antigens is a contributing factor to CP/CPSS. In this review, we examine the use of experimental autoimmune prostatitis (EAP) in rodents to model salient features of autoimmune mediated CP/CPSS. By exploring etiological factors, immunological mechanisms, and emerging therapeutic strategies, our aim is to enhance our understanding of CP/CPSS pathogenesis and promote the development of strategies to test innovative interventions using the EAP pre-clinical model.

The aryl hydrocarbon receptor agonist ITE reduces inflammation and urinary dysfunction in a mouse model of autoimmune prostatitis.

Prostate inflammation is linked to lower urinary tract dysfunction and is a key factor in chronic prostatitis/chronic pelvic pain syndrome. Autoimmunity was recently identified as a driver of prostate inflammation. Agonists of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, have been used to suppress autoimmunity in mouse models of colitis, rhinitis, and dermatitis, but whether AHR agonists suppress prostate autoimmunity has not been examined. Here, we test whether ITE (2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester), an AHR agonist, suppresses inflammation, allodynia, and urinary dysfunction in a mouse model of experimental autoimmune prostatitis (EAP). C57BL/6J adult male mice were immunized with rat prostate antigen to induce EAP or TiterMax Gold® adjuvant (uninflamed control). Mice were also treated with ITE (10 mg/kg/day IP) or DMSO (vehicle, 5 mg/kg/day IP) for 6 days. Using the Nanostring nCounter Inflammation Panel, we evaluated the impact of EAP and ITE on prostatic RNA abundance. We validated EAP and ITE-mediated changes in a subset of RNAs by RT-PCR and RNAScope in situ RNA detection. EAP appeared to heighten histological inflammation in the dorsal prostate, induced tactile allodynia, and appeared to increase the frequency of non-voiding bladder contractions. ITE mitigated some actions of EAP. EAP changed abundance of 40 inflammation-related RNAs, while ITE changed abundance of 28 inflammation-related RNAs. We identified a cluster of RNAs for which ITE protected against EAP-induced changes in the abundance of H2-Ab1, S100a8, and S100a9. ITE also increased the abundance of the AHR-responsive Cyp1a1 RNA. These findings support the hypothesis that ITE activates the AHR in the prostate and reduces autoimmune-mediated prostatitis in mice.

Growth Patterns of Prostate Cancers Undetected by Prostate 3T Multiparametric MRI.

The multiparametric magnetic resonance imaging (mpMRI)-ultrasound (US) fusion targeted biopsy (TB) is a useful diagnostic device for men with suspected prostate cancer (PC) and can increase the detection rate for clinically significant PCs (csPC). However, few studies have shown pathological findings of undetectable csPCs on the prostate mpMRI. This study investigated the growth patterns of csPC undetected in prostate mpMRI. The study enrolled 248 patients with suspected PCs and ≥PI-RADS 2 lesions, who then underwent mpMRI-US fusion TB and nearly prostate-mapping systematic biopsies (SB). A total 248 biopsies included 404 regions of interest in TB and 2976 mapping-regions in SB. The detection rates of csPC, defined as PC grade group (GG) ≥2, were 42% in TB and 44% in SB, and the highest detection rate was 50%, using both TB and SB. Approximately 79% of PI-RADS 3/4/5 with any PC showed csPC. A total 201 PI-RADS 3/4/5 lesions showed benign prostatic hyperplasia, lymphocytic prostatitis, or fibromuscular stroma only in the core tissues. Notably, 22 csPCs detected in SB but undetected in prostate mpMRI preferentially showed a pattern of mixed well-formed and fused PC glands. The other patterns including cribriform glands and poorly formed glands with intracytoplasmic vacuoles were also seen. Approximately 85% of the 22 csPCs showed tumor volume less than 50% of core tissues. Changes in prostatic stroma amounts, inflammation severity, tumor volume and growth patterns of PC glands affected the detectability of prostate mpMRI.

4-Octyl itaconate alleviates experimental autoimmune prostatitis by inhibiting the NLRP3 inflammasome-induced pyroptosis through activating Nrf2/HO-1 pathway.

Chronic prostatitis demonstrates a prevalence rate of nearly 5%-10% among young and middle-aged individuals, significantly affecting their daily lives. Researchers have obtained significant outcomes investigating the anti-inflammatory properties of itaconic acid (IA) and its derivative, 4-Octyl itaconate (4-OI), against diverse chronic inflammatory disorders, such as osteoarthritis and airway inflammation. Nevertheless, whether IA can also exert anti-inflammatory effects in chronic prostatitis requires extensive research and validation. Human prostate tissues obtained through transurethral prostate resection (TURP) from individuals were divided into three groups based on different levels of inflammation using hematoxylin and eosin staining (H&E). Subsequently, immunohistochemistry (IHC) was employed to detect the expression of immune-responsive gene 1 (IRG-1) in these different groups. The animal experiment of this study induced experimental autoimmune prostatitis (EAP) in nonobese diabetic mice through intradermal prostate antigen injection and complete Freund's adjuvant. Then, the experimental group received intraperitoneal injections of different doses of 4-OI, while the control group received injections of saline. Western blot (WB), H&E staining, and TUNEL staining helped analyze the prostate tissues, while enzyme-linked immunosorbent assay (ELISA) helped evaluate serum inflammatory factors. Reactive oxygen species, superoxide dismutase (SOD), and malondialdehyde (MDA) were assessed for oxidative stress across experimental groups. IHC analysis of human prostate tissue depicts that IRG-1 expression enhances as prostate inflammation worsens, highlighting the critical role of IA in human prostatitis. The application of 4-OI increased Nrf2/HO-1 expression while inhibited NLRP3 expression following the WB results, and its application resulted in a decrease in cell pyroptosis in prostate tissue, demonstrated by the results of TUNEL staining. Administering a Nrf2 inhibitor ML385 1 h before intraperitoneal injection of 50 mg/kg 4-OI reversed the previous conclusion, further confirming the above conclusion from another perspective. Meanwhile, the ELISA results of serum inflammatory factors (IL-1β, IL-6, and TNF-α), as well as the measurements of oxidative stress markers MDA and SOD, further confirmed the specific anti-inflammatory effects of 4-OI in EAP. The present study indicates that 4-OI can alleviates EAP by inhibiting the NLRP3 inflammasome-induced pyroptosis through activating Nrf2/HO-1 pathway, which may facilitate a novel approach toward prostatitis treatment.

CAV1 and KRT5 are potential targets for prostate cancer.

Prostate cancer is the most common malignant tumor of male urogenital system that occurs in prostate epithelium. However, relationship between CAV1 and KRT5 and prostate cancer remains unclear. The prostate cancer datasets GSE114740 and GSE200879 were downloaded from Gene Expression Omnibus generated by GPL11154 and GPL32170. De-batch processing was performed, differentially expressed genes (DEGs) were screened, and weighted gene co-expression network analysis. The construction and analysis of protein-protein interaction network, functional enrichment analysis, gene set enrichment analysis. Gene expression heat map was drawn and immune infiltration analysis was performed. Comparative toxicogenomics database analysis were performed to find the disease most related to core gene. In addition, the cell experiment was performed to verify the role of CAV1 and KRT5 by western blot. Divided into 4 groups: control, prostate cancer, prostate cancer-over expression, and prostate cancer- knock out. TargetScan screened miRNAs that regulated central DEGs; 770 DEGs were identified. According to Gene Ontology analysis, they were mainly concentrated in actin binding and G protein coupled receptor binding. In Kyoto Encyclopedia of Gene and Genome analysis, they were mainly concentrated in PI3K-Akt signal pathway, MAPK signal pathway, and ErbB signal pathway. The intersection of enrichment terms of differentially expressed genes and GOKEGG enrichment terms was mainly concentrated in ErbB signaling pathway and MAPK signaling pathway. Three important modules were generated. The protein-protein interaction network obtained 8 core genes (CAV1, BDNF, TGFB3, FGFR1, PRKCA, DLG4, SNAI2, KRT5). Heat map of gene expression showed that core genes (CAV1, TGFB3, FGFR1, SNAI2, KRT5) are highly expressed in prostate cancer tissues and low in normal tissues. Comparative toxicogenomics database analysis showed that core genes (CAV1, TGFB3, FGFR1, SNAI2, KRT5) were associated with prostate tumor, cancer, tumor metastasis, necrosis, and inflammation. CAV1 and KRT5 are up-regulated in prostate cancer. CAV1 and KRT5 are highly expressed in prostate cancer. The higher expression of CAV1 and KRT5, the worse prognosis.

YAP1 Recognizes Inflammatory and Mechanical Cues to Exacerbate Benign Prostatic Hyperplasia via Promoting Cell Survival and Fibrosis.

Chronic prostatic inflammation promotes cell survival and fibrosis, leading to benign prostatic hyperplasia (BPH) with aggravated urinary symptoms. It is investigated whether yes-associated protein 1 (YAP1), an organ size controller and mechanical transductor, is implicated in inflammation-induced BPH. The correlation between YAP1 expression and fibrosis in human and rat BPH specimens is analyzed. Furthermore, the effects of YAP1 activation on prostatic cell survival and fibrosis, as well as the underlying mechanism, are also studied. As a result, total and nuclear YAP1 expression, along with downstream genes are significantly upregulated in inflammation-associated human and rat specimens. There is a significant positive correlation between YAP1 expression and the severity of fibrosis or clinical performance. YAP1 silencing suppresses cell survival by decreasing cell proliferation and increasing apoptosis, and alleviates fibrosis by reversing epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) deposition in prostatic BPH-1 and WPMY-1 cells. Mechanistically, inflammatory stimulus and rigid matrix stiffness synergistically activate the RhoA/ROCK1 pathway to provoke cytoskeleton remodeling, thereby promoting YAP1 activation to exacerbate BPH development. Overall, inflammation-triggered mechanical stiffness reinforcement activates the RhoA/ROCK1/F-actin/YAP1 axis, thereby promoting prostatic cell survival and fibrosis to accelerate BPH progression.

Astaxanthin alleviates chronic prostatitis/chronic pelvic pain syndrome by increasing colonization of Akkermansia muciniphila in the intestine

BackgroundAstaxanthin (AST) is a natural compound with anti-inflammatory/immunomodulatory properties that has been found to have probiotic properties. However, the role and mechanism of AST in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) are still not fully understood. PurposeThe aim of this study was to evaluate the effect of AST on CP/CPPS and elucidate the mediating role of the gut microbiota. Materials and methodsAn experimental autoimmune prostatitis (EAP) mouse model was utilized to test the potential role of AST on CP/CPPS. Antibiotic cocktail (ABX) treatment and fecal microbiota transplantation (FMT) were used to elucidate the gut microbiota-mediated effects on AST. In addition, 16S rRNA gene sequencing and qRT-PCR analyses were used to analyze changes in the gut microbiota of EAP mice and CP/CPPS patients. Finally, the mechanism by which AST exerts a protective effect on CP/CPPS was explored by untargeted metabolomics and gut barrier function assays. ResultsOral administration of AST reduced prostate inflammation scores, alleviated tactile sensitization of the pelvic region in EAP mice, reduced CD4+ T cell and CD68+ macrophage infiltration in the prostatic interstitium, and inhibited the up-regulation of systemic and localized pain/pro-inflammatory mediators in the prostate. After ABX, the protective effect of AST against CP/CPPS was attenuated, whereas colonization with fecal bacteria from AST-treated EAP mice alleviated CP/CPPS. 16S rRNA gene sequencing and qRT-PCR analyses showed that Akkermansia muciniphila in the feces of EAP mice and CP/CPPS patients showed a trend toward a decrease, which was associated with poor progression of CP/CPPS. In contrast, oral administration of AST increased the relative abundance of A. muciniphila, and oral supplementation with A. muciniphila also alleviated inflammation and pain in EAP mice. Finally, we demonstrated that both AST and A. muciniphila interventions increased serum levels of SCFAs acetate, up-regulated expression of colonic tight junction markers, and decreased serum lipopolysaccharide levels in EAP mice. ConclusionOur results showed that AST improved CP/CPPS by up-regulating A. muciniphila, which provides new potentially effective strategies and ideas for CP/CPPS management.

Inflammation in Prostate Cancer: Exploring the Promising Role of Phenolic Compounds as an Innovative Therapeutic Approach.

Prostate cancer (PCa) remains a significant global health concern, being a major cause of cancer morbidity and mortality worldwide. Furthermore, profound understanding of the disease is needed. Prostate inflammation caused by external or genetic factors is a central player in prostate carcinogenesis. However, the mechanisms underlying inflammation-driven PCa remain poorly understood. This review dissects the diagnosis methods for PCa and the pathophysiological mechanisms underlying the disease, clarifying the dynamic interplay between inflammation and leukocytes in promoting tumour development and spread. It provides updates on recent advances in elucidating and treating prostate carcinogenesis, and opens new insights for the use of bioactive compounds in PCa. Polyphenols, with their noteworthy antioxidant and anti-inflammatory properties, along with their synergistic potential when combined with conventional treatments, offer promising prospects for innovative therapeutic strategies. Evidence from the use of polyphenols and polyphenol-based nanoparticles in PCa revealed their positive effects in controlling tumour growth, proliferation, and metastasis. By consolidating the diverse features of PCa research, this review aims to contribute to increased understanding of the disease and stimulate further research into the role of polyphenols and polyphenol-based nanoparticles in its management.

Tissue S100/calgranulin expression and blood neutrophil-to-lymphocyte ratio (NLR) in prostatic disorders in dogs

BackgroundProstatic carcinoma (PCA) is a rare but severe condition in dogs that is similar to the androgen-independent form of PCA in men. In contrast to humans, PCA is difficult to diagnose in dogs as reliable biomarkers, available for PCA screening in human medicine, are currently lacking in small animal oncology. Calprotectin (S100A8/A9) and S100A12 are Ca2+-binding proteins of the innate immune system with promising potential to distinguish malignant from benign urogenital tract conditions, similar to the blood neutrophil-to-lymphocyte-ratio (NLR). However, both have not yet been extensively investigated in dogs with PCA. Thus, this study aimed to evaluate the expression of the S100/calgranulins (calprotectin, S100A12, and their ratio [Cal-ratio]) in prostatic biopsies from nine dogs with PCA and compare them to those in dogs with benign prostatic lesions (eight dogs with prostatitis and ten dogs with benign prostatic hyperplasia [BPH]) as well as five healthy controls. In addition, blood NLRs were investigated in twelve dogs with PCA and 22 dogs with benign prostatic conditions.ResultsTissue S100A8/A9+ cell counts did not differ significantly between tissue from PCA and prostatitis cases (P = 0.0659) but were significantly higher in dogs with prostatitis than BPH (P = 0.0013) or controls (P = 0.0033). S100A12+ cell counts were significantly lower in PCA tissues than in prostatitis tissue (P = 0.0458) but did not differ compared to BPH tissue (P = 0.6499) or tissue from controls (P = 0.0622). Cal-ratios did not differ significantly among the groups but were highest in prostatitis tissues and significantly higher in those dogs with poor prostatitis outcomes than in patients that were still alive at the end of the study (P = 0.0455). Blood NLR strongly correlated with prostatic tissue S100A8/A9+ cell counts in dogs with PCA (ρ = 0.81, P = 0.0499) but did not differ among the disease groups of dogs.ConclusionsThis study suggests that the S100/calgranulins play a role in malignant (PCA) and benign (prostatic inflammation) prostatic conditions and supports previous results in lower urinary tract conditions in dogs. These molecules might be linked to the inflammatory environment with potential effects on the inflammasome. The blood NLR does not appear to aid in distinguishing prostatic conditions in dogs. Further investigation of the S100/calgranulin pathways and their role in modulation of tumor development, progression, and metastasis in PCA is warranted.

Acute, subchronic toxicity and genotoxicity studies of JointAlive, a traditional Chinese medicine formulation for knee osteoarthritis.

In vivo and in vitro toxicity tests of JointAlive® were studied in animal models to support the safe use of JointAlive® as a drug for knee osteoarthritis treatment. The acute toxicity study in Sprague Dawley (SD) rats was conducted at a 20 g/kg bw/day dose of JointAlive®. For 13-week subchronic toxicity tests, SD rats were orally dosed daily with 0.5, 1.5 and 5 g/kg bw/day of JointAlive®. To assess the potential genotoxicity, Ames test, cellular chromosome aberration and mouse micronucleus test in vivo were carried out. Based on a lack of notable findings other than histopathology finding of co-incidental prostate inflammation at the high dose, the "No Observed Adverse Effect Level (NOAEL)" of JointAlive® was concluded as 5 g/kg bw/day in males and females. Results also indicated that JointAlive® has no risk of genotoxicity. General toxicity and genotoxicity studies empirically demonstrated that JointAlive® poses a low risk of potential health risks, providing safety supports for the application of JointAlive® as a potential drug candidate to treat knee osteoarthritis.

Electroacupuncture stimulating Zhongji (CV3), Guanyuan (CV4), and bilateral Dahe (KI12) attenuates inflammation in rats with chronic nonbacterial prostatitis induced by estradiol through inhibiting toll-like receptor 4 pathway.

To investigate the anti-inflammatory effect of electroacupuncture (EA) on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), also known as chronic nonbacterial prostatitis (CNP), and explore its underlying mechanism. A CNP rat was established by surgical castration combined with 17-β estradiol injection in male Sprague-Dawley rats for thirty consecutive days. The CNP rats received EA treatment once a day for eight days. Chronic pelvic pain was evaluated by mechanical withdrawal threshold measurement. The histological change was assessed by hematoxylin-eosin staining. The inflammatory cytokines in prostates were determined by enzyme-linked immunosorbent assays. The expressions of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), inhibitors of kappa-B alpha (IκBα), and nuclear factor-kappa B (NF-κB) were detected by Western blotting. The nuclear translocation of NF-κB and the location of TLR4 were observed with immunofluorescence staining. The results showed that EA decreased the prostate index, upregulated the mechanical withdrawal threshold, restored the histomorphology of the prostate, reduced the inflammatory factor levels, inhibited NF-κB p65 nuclear translocation, and downregulated the expression levels of critical proteins involved in the TLR4/NF-κB signaling pathway in prostates. Our findings suggested that EA could relieve pelvic pain and attenuate prostatic inflammation in estradiol-induced CNP rats. The underlying mechanism may be related to the inhibition of the TLR4/NF-κB signaling pathway.