Benign prostatic hyperplasia nodules in patients treated with celecoxib and/or finasteride have reduced levels of NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, a mitochondrial protein essential for efficient function of the electron transport chain.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a condition generally associated with advanced age in men that can be accompanied by bothersome lower urinary tract symptoms (LUTS) including intermittency, weak stream, straining, urgency, frequency, and incomplete bladder voiding. Pharmacotherapies for LUTS/BPH include alpha-blockers, which relax prostatic and urethral smooth muscle and 5ɑ-reductase inhibitors such as finasteride, which can block conversion of testosterone to dihydrotestosterone thereby reducing prostate volume. Celecoxib is a cyclooxygenase-2 inhibitor that reduces inflammation and has shown some promise in reducing prostatic inflammation and alleviating LUTS for some men with histological BPH. However, finasteride and celecoxib can reduce mitochondrial function in some contexts, potentially impacting their efficacy for alleviating BPH-associated LUTS. METHODS: To determine the impact of these pharmacotherapies on mitochondrial function in prostate tissues, we performed immunostaining of mitochondrial Complex I (CI) protein NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 (NDUFS3) and inflammatory cells on BPH specimens from patients naïve to treatment, or who were treated with celecoxib and/or finasteride for 28 days, as well as prostate tissues from male mice treated with celecoxib or vehicle control for 28 days. Quantification and statistical correlation analyses of immunostaining were performed. RESULTS: NDUFS3 immunostaining was decreased in BPH compared to normal adjacent prostate. Patients treated with celecoxib and/or finasteride had significantly decreased NDUFS3 in both BPH and normal tissues, and no change in inflammatory cell infiltration compared to untreated patients. Mice treated with celecoxib also displayed a significant decrease in NDUFS3 immunostaining and no change in inflammatory cell infiltration. CONCLUSIONS: These findings suggest that celecoxib and/or finasteride are associated with an overall decrease in NDUFS3 levels in prostate tissues but do not impact the presence of inflammatory cells, suggesting a decline in mitochondrial CI function in the absence of enhanced inflammation. Given that BPH has recently been associated with increased prostatic mitochondrial dysfunction, celecoxib and/or finasteride may exacerbate existing mitochondrial dysfunction in some BPH patients thereby potentially limiting their overall efficacy in providing metabolic stability and symptom relief.

Using a Multi-pronged Behavioral Intervention to Standardize Antibiotic Prophylaxis at the Time of Foley Catheter Removal After Radical Prostatectomy.

OBJECTIVE: To identify antibiotic prescribing patterns at the time of foley catheter removal after radical prostatectomy and implement a multi-pronged behavioral intervention to standardize antibiotic use. METHODS: This was a single-institution study examining the prescribing of antibiotics at the time of foley catheter removal after radical prostatectomy. Pre-intervention data were collected retrospectively to establish baselines for antibiotic prescribing, patient characteristics, and urinary tract infection rates. A single dose of an oral antibiotic taken at the time of foley catheter removal was recommended as the standard antibiotic protocol. A multi-pronged behavioral intervention was used to encourage compliance with our protocol. Adherence to the protocol, quantity of antibiotics prescribed, and rate of urinary tract infection were recorded prospectively. Durability of the intervention was evaluated during a post-intervention phase. RESULTS: A total of 416 patients and 6 surgeons were included in the study. Accordance with the standardized antibiotic protocol was 59% in the pre-intervention phase and 91% in the intervention phase (P = .03). No patients in the intervention or post-intervention phase were prescribed more than one dose of an antibiotic. The rate of urinary tract infection did not differ across the study phases. CONCLUSION: Implementation of a multi-pronged behavioral intervention resulted in a high rate of surgeon compliance with a standardized antibiotic protocol. This led to a significant reduction in antibiotic use with no change in the rate of urinary tract infection after foley catheter removal after radical prostatectomy.

Utilizing a Questionnaire to Implement a Risk-based Antibiotic Prophylaxis Protocol for Transrectal Prostate Biopsy.

OBJECTIVE: To develop and evaluate a risk-based antibiotic prophylaxis protocol for patients undergoing transrectal prostate biopsy. METHODS: We created a risk-based protocol for antibiotic prophylaxis before transrectal prostate biopsy. Patients were screened for infection risk-factors with a self-administered questionnaire. The protocol was implemented from January 1, 2020 to March 31, 2020. We compared patient risk-factors, antibiotic regimens, and 30-day infection rates for patients undergoing transrectal prostate biopsies during the intervention and for a 3-month period before the intervention. RESULTS: There were 116 prostate biopsies in the preintervention group and 104 in the intervention group. Although there was no significant difference in the number of high-risk patients between the 2 groups (48% vs 55%; P = .33), the percentage of patients treated with augmented prophylaxis decreased from 74% to 45% (P = 0.03). The duration of antibiotic administration and the median number of doses prescribed also decreased significantly. Despite significant decreases in antibiotic use, there were no differences in infection rates (5% vs 5%; P = .90) or sepsis rates (1% vs 2%; P = .60). CONCLUSION: We developed a risk-based protocol for prophylactic antibiotics before prostate biopsy. The protocol was associated with less antibiotic use but did not lead to an increase in infectious complications.

Increased COX-1 expression in benign prostate epithelial cells is triggered by mitochondrial dysfunction.

BACKGROUND: Prostatic inflammation is closely linked to the development and progression of benign prostatic hyperplasia (BPH). Clinical studies of non-steroidal anti-inflammatory drugs, which inhibit cyclooxygenase-2 (COX-2), targeting prostate inflammation patients with symptomatic BPH have demonstrated conflicting results, with some studies demonstrating symptom improvement and others showing no impact. Thus, understanding the role of the cyclooxygenases in BPH and prostatic inflammation is important. METHODS: The expression of COX-1 was analyzed in a cohort of donors and BPH patients by immunohistochemistry and compared to previously determined characteristics for this same cohort. The impact of mitochondrial dysfunction on COX-1 and COX-2 was determined in experiments treating human benign prostate epithelial cell lines BPH-1 and RWPE-1 with rotenone and MitoQ. RWPE-1 cells were transfected with small interfering RNA specific to complex 1 gene NDUFS3. RESULTS: COX-1 expression was increased in the epithelial cells of BPH specimens compared to young healthy organ donor and normal prostate adjacent to BPH and frequently co-occurred with COX-2 alteration in BPH patients. COX-1 immunostaining was associated with the presence of CD8+ cytotoxic T-cells, but was not associated with age, prostate size, COX-2 or the presence of CD4+, CD20+ or CD68+ inflammatory cells. In cell line studies, COX protein levels were elevated following treatment with inhibitors of mitochondrial function. MitoQ significantly decreased mitochondrial membrane potential in RWPE-1 cells. Knockdown of NDUFS3 stimulated COX-1 expression. CONCLUSION: Our findings suggest COX-1 is elevated in BPH epithelial cells and is associated with increased presence of CD8+ cytotoxic T-cells. COX-1 can be induced in benign prostate epithelial cells in response to mitochondrial complex I inhibition, and knockdown of the complex 1 protein NDUFS3. COX-1 and mitochondrial dysfunction may play more of a role than previously recognized in the development of age-related benign prostatic disease.

Claudin-1 down-regulation in the prostate is associated with aging and increased infiltration of inflammatory cells in BPH.

INTRODUCTION AND OBJECTIVE: Benign prostatic hyperplasia (BPH) is an age-related disease that is frequently associated with chronic prostatic inflammation. In previous studies, we detected the presence of PSA protein in the stroma of BPH nodules and down-regulation of junction proteins E-cadherin and claudin-1. Transmission electron microscopy (TEM) imaging showed a decrease in tight junctions suggesting the luminal epithelial barrier in BPH tissues may be compromised. Recent in vitro studies showed that stimulation of benign prostate epithelial cell lines with TGF-ß1 induced a decrease in claudin-1 expression suggesting that inflammation might be associated with alterations in the prostate epithelial barrier. This study explored the potential associations between aging and loss of junction proteins and the presence of inflammatory cells in prostate tissue specimens from young healthy donors and aged BPH patients. METHODS: Immunostaining of serial prostate sections from 13 BPH patients and five healthy young donors was performed for claudin-1, CD4, CD8, CD20 and CD68. H-Scores and the number of inflammatory cells were calculated for the same area in donor, normal adjacent prostate (NAP) to and BPH specimens. Quantification and statistical correlation analyses were performed. RESULTS: Claudin-1 immunostaining was inversely associated with increasing age, and inflammation in prostate specimens. B-cell infiltration increased with age and BPH was associated with an increased infiltration of T-cells and macrophages compared to NAP. CONCLUSIONS: These findings suggest that aging is associated with down-regulation of claudin-1 and claudin-1 is further decreased in BPH. Claudin-1 down-regulation was associated with increased infiltration of inflammatory cells in both NAP and BPH tissues. Claudin-1 down-regulation in the aging prostate could contribute to increased prostatic inflammation, subsequently contributing to BPH pathogenesis.

E-cadherin expression is inversely correlated with aging and inflammation in the prostate.

INTRODUCTION AND OBJECTIVE: Benign prostatic hyperplasia (BPH) is a prostatic disease that is significantly associated with aging. However, it is not well understood how aging contributes to BPH pathogenesis. Several factors associated with an increased risk of BPH are also associated with increasing age, including chronic inflammation and declining epithelial barrier function. Thus, this study explored the potential associations between aging, loss of adherens junction protein E-cadherin and the presence of inflammatory mediators in prostate tissue specimens from healthy young donor and BPH patients. METHODS: Serial prostate sections from a cohort of five donors aged 15-26 years and 13 BPH patients aged 50-77 years were immunostained with E-cadherin, COX-2, CD4, CD8, CD20 and CD68. E-cadherin and COX-2 H-Scores and the number of inflammatory cells were calculated for the same area in donor, normal adjacent prostate to BPH (NAP) and BPH specimens. Quantification and statistical correlation analyses were performed for comparisons between groups. RESULTS: E-cadherin was decreased in aged NAP tissues and in BPH compared to young donor tissue. E-cadherin was inversely correlated with age and infiltration of inflammatory cells in NAP compared to young healthy donor prostate. Stromal COX-2 was positively correlated with age and inflammation. E-cadherin was further down-regulated in BPH, while COX-2 H-Scores were not significantly altered in BPH compared to NAP. CONCLUSIONS: These findings suggest that aging is associated with down-regulation of E-cadherin and up-regulation of stromal COX-2 immunostaining in the prostate. E-cadherin immunostaining was inversely associated with age and inflammation, while stromal COX-2 immunostaining was positively associated with age and inflammation in the prostate. These findings suggest that the prostate epithelial barrier is altered and inflammation is increased with age in the prostate. These changes are further exacerbated in BPH, and may be involved in BPH pathogenesis.