Prostatic Inflammation Research Articles

Hexanic Extract of Serenoa repens (Permixon®): A Review in Symptomatic Benign Prostatic Hyperplasia

The hexanic extract (HE) of Serenoa repens (Permixon®) is indicated for the symptomatic treatment of benign prostatic hyperplasia (BPH). The drug is the n-hexane lipidosterolic extract of the American dwarf palm tree (also known as saw palmetto). The anti-inflammatory activity of HE S. repens has been demonstrated in vitro, in vivo and in men with prostatic inflammation. In randomized clinical trials, the efficacy of HE S. repens was similar to that of an α-blocker in terms of improving voiding and storage symptoms, increasing urinary flow rate and reducing prostate volume in men with BPH. HE S. repens was also as effective as 5α-reductase inhibitors and/or α-blockers at improving lower urinary tract symptoms (LUTS) and quality of life (QOL) in real-world observational studies. HE S. repens was generally well tolerated, with a lesser impact on male sexual function compared with other available therapies. Thus, HE S. repens is a useful option for the treatment of symptomatic BPH.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40266-022-00924-3.

Emerging quinoline- and quinolone-based antibiotics in the light of epidemics.

Pandemics are large-scale outbreaks of infectious disease that can greatly increase morbidity and mortality all the globe. Since past 1990 till twentieth century, these infectious diseases have been major threat all over the globe associated with poor hygiene and sanitation. In light of these epidemics, researches have gained enormous rise in the developing the potential therapeutic treatment. Thus, revolutionized antibiotics have led to the near eradication of such ailments. Around 50million prescription of antibiotics written in US per year according to center for disease control and prevention (CDC) report. There is a wide range of antibiotics available which differ in their usage and their mechanism of action. Among these quinoline and quinolone class of antibiotics get attention as they show tremendous potential in fighting the epidemics. Quinoline and quinolone comprise of two rings along with substitutions at different positions which is synthetically obtained by structural modifications of quinine. Quinoline and quinolone antibiotics exhibit extensive activities approved by FDA in the treatment of the several ailments such as gastrointestinal infections, urinary tract infections, prostate inflammation, malaria, gonorrhea, skin infection, colorectal cancer, respiratory tract infections. These are active against both gram-negative and gram-positive bacteria. This basic core of quinoline and quinolone is vital due to its capability of targeting the pathogen causing disease and beneficial in treating the infectious disease. They inhibit the synthesis of nucleic acid of bacteria which results in the rupture of bacterial chromosome due to the interruption of enzymes such as DNA gyrase and topoisomerase IV. There are various quinoline and quinolone compounds that are synthetically derived by applying different synthesis approaches which show a wide range of pharmacological activities in several diseases. The most commonly used are fluoro, chloro, and hydroxychloro derivatives of quinoline and quinolone. These compounds are helpful in the treatment of numerous epidemics as a chief and combination therapy. These quinoline and quinolone pharmacophore fascinate the interest of researchers as they inhibit the entry of virus in host cell and cease its replication by blocking the host receptor glycosylation and proteolytic processing. They act as immune modulator by inhibiting autophagy and reduction of both lysosomal activity and production of cytokine. Therefore, quinoline and quinolone derivatives attain significance in area of research and treatment of various life-threatening epidemics such as SARS, Zika virus, Ebola virus, dengue, and COVID-19 (currently). In this chapter, the research and advancements of quinoline- and quinolone-based antibiotics in epidemic management are briefly discussed.

The role of prostate inflammation in the pathogenesis of urethral strictures occurring after transurethral resections

ObjectiveTo make an extensive evaluation about the effects of histopathological findings acquired from the resection materials of patients who underwent transurethral resection of prostate (TUR-P) due to benign prostate hyperplasia (BPH) on postoperative urethral stricture formation. Materials and methodsAmong patients who had TUR-P due to BPH and were followed up for minimum 6 months, 51 patients detected to have urethral stricture based on endoscopic imaging were included in the urethral stricture group (Group 1) and 52 patients without urethral stricture were included in the control group (Group 2). The relation between histopathological findings of TURP materials and postoperative stricture occurrence was investigated. ResultsNo difference in age, prostate volume, operation time and postoperative catheterization time was detected among the groups (p=0.86, p=0.13, p=0.06, p=0.32, respectively). Average time until the urethral stricture diagnosis in the group with urethral stricture was measured as 57.9±27.2 days. In our study, inflammation intensity in peri-urethral, stromal and periglandular areas and intraglandular destruction ratios were higher in urethral stricture group (Group 1) (p=0.048, p=0.3, p=0.03, p=0.01, respectively). Again, it was detected that neutrophil, plasmocyte and eosinophil cell ratios were higher in peri-urethral, stromal and periglandular areas and lymphocyte values were lower compared to the control group. ConclusionAcquired data has shown that acute inflammatory attacks may be related to urethral stricture with a mostly chronic inflammation background in the prostate. During histopathological examination of prostate tissue acquired through TURP, especially high peri-urethral neutrophil, plasmocyte and eosinophil cell ratios and intra-glandular destruction ratios are important for predicting postoperative urethral stricture occurrences.

Health inequity drives disease biology to create disparities in prostate cancer outcomes.

Prostate cancer exerts a greater toll on African American men than on White men of European descent (hereafter referred to as European American men): the disparity in incidence and mortality is greater than that of any other common cancer. The disproportionate impact of prostate cancer on Black men has been attributed to the genetics of African ancestry, to diet and lifestyle risk factors, and to unequal access to quality health care. In this Review, all of these influences are considered in the context of the evolving understanding that chronic or recurrent inflammatory processes drive prostatic carcinogenesis. Studies of inherited susceptibility highlight the contributions of genes involved in prostate cell and tissue repair (BRCA1/2, ATM) and regeneration (HOXB13 and MYC). Social determinants of health appear to accentuate these genetic influences by fueling prostate inflammation and associated cell and genome damage. Molecular characterization of the prostate cancers that arise in Black versus White men further implicates this inflammatory microenvironment in disease behavior. Yet, when Black and White men with similar grade and stage of prostate cancer are treated equally, they exhibit equivalent outcomes. The central role of prostate inflammation in prostate cancer development and progression augments the impact of the social determinants of health on disease pathogenesis. And, when coupled with poorer access to high-quality treatment, these inequities result in a disparate burden of prostate cancer on African American men.

The Translational Role of Animal Models for Estrogen-Related Functional Bladder Outlet Obstruction and Prostatic Inflammation.

The prevalence of LUTS and prostatic diseases increases with age both in humans and companion animals, suggesting that a common underlying cause of these conditions may be age-associated alterations in the balance of sex hormones. The symptoms are present with different and variable micturition dysfunctions and can be assigned to different clinical conditions including bladder outlet obstruction (BOO). LUTS may also be linked to chronic non-bacterial prostatitis/chronic pelvic pain syndrome (CP/CPPS), but the relationship between these conditions is unknown. This review summarizes the preclinical data that supports a role for excessive estrogen action in the development of obstructive voiding and nonbacterial prostatic inflammation. Preclinical studies that are emphasized in this review have unequivocally indicated that estrogens can induce functional and structural changes resembling those seen in human diseases. Recognizing excessive estrogen action as a possible hormonal basis for the effects observed at multiple sites in the LUT may inspire the development of innovative treatment options for human and animal patients with LUTS associated with functional BOO and CP/CPPS.

Prostate luminal progenitor cells: from mouse to human, from health to disease.

Stem and progenitor cells of the adult prostate epithelium have historically been believed to reside mainly or exclusively within the basal cell compartment and to possess basal-like phenotypic characteristics. Within the past decade, evidence of the existence of luminal epithelial cells exhibiting stem/progenitor properties has been obtained by lineage tracing and by functional characterization of sorted luminal-like cells. In 2020, the boom of single-cell transcriptomics led to increasingly exhaustive profiling of putative mouse luminal progenitor cells and, importantly, to the identification of cognate cells in the human prostate. The enrichment of luminal progenitor cells in genetically modified mouse models of prostate inflammation, benign prostate hypertrophy and prostate cancer, and the intrinsic castration tolerance of these cells, suggest their potential role in prostate pathogenesis and in resistance to androgen deprivation therapy. This Review bridges different approaches that have been used in the field to characterize luminal progenitor cells, including the unification of multiple identifiers employed to define these cells (names and markers). It also provides an overview of the intrinsic functional properties of luminal progenitor cells, and addresses their relevance in mouse and human prostate pathophysiology.

Ethnomedicinal Studies, Chemical Composition, and Antibacterial Activity of the Mammea americana L. Bark in the Municipality of Cértegui, Chocó, Colombia.

Mammea americana L. is a plant with diverse medicinal uses in the municipality of Cértegui, Chocó, Colombia. This research characterized the ethnomedicinal, chemical, and antibacterial activities of the bark of Mammea americana. Through interviews and semistructured surveys with the community, its ethnomedicinal uses were determined. Compounds present in the bark extract were identified and quantified by gas chromatography-coupled to mass spectrometry (GC-MS), and a qualitative analysis was performed by preliminary phytochemistry. Antibacterial activity and minimum inhibitory concentration (MIC) were carried out by agar diffusion and dilution methods, respectively, using ethanolic and aqueous extracts. Ethnomedical data showed that the bark is used to treat 14 conditions, the most representative being gallstones, prostate inflammation, and malaria. Preliminary phytochemical analyses showed the existence of several secondary metabolites such as tannins, alkaloids, flavonoids, triterpenes and/or steroids, quinones, and saponins. A total of 29 compounds were identified; the most abundant were ethyl 5-oxo-4-(p-toluidine)-2,5-dihydro-3-furancarboxylate, phenol, 4,4′,4″-ethylidynetris, nerolidol, 19-hydroxy-13-epimanoyl oxide, α-elemene, and δ-cadinene. The results showed remarkable antibacterial activity of the ethanolic extract (20 mg/ml) against Staphylococcus aureus (22.6 mm) and Escherichia coli (19.6 mm) and of the crude water extract (20 mg/ml) against Staphylococcus aureus (18.5 mm) and Escherichia coli (12.4 mm). The strongest MIC was for the ethanolic extract with values of 0.357 and 0.897 mg/ml against S. aureus and E. coli strains, respectively, while in the aqueous extract, S. aureus (3.99 mg/ml) and E. coli (4.3 mg/ml) were recorded. It is assumed that the compounds identified in this study could be responsible for the antibacterial activity of the species, as well as the relationship of the identified compounds and metabolites with the ethnomedical uses given by the community, providing a scientific and traditional basis for its different traditional medical uses.

Poor Kidney Function and the risk of Prostate Cancer among Aged Men in Kogi East, Kogi State, Nigeria

Prostate Specific Antigen (PSA) is a protein that is produced by cells in the male prostate gland. An increase in PSA levels is associated with prostate inflammation, prostate cancer, and benign prostatic hypertrophy. This work provides information on the values of Kidney function indices and PSA in apparently normal ageing men residing within the Eastern zone of Kogi State, Nigeria. The subjects were divided into different groups based on their age range. There was a gradual increased in PSA and serum urea as the age increases.
 Keyword: Kidney, Prostate cancer, Prostate Specific Antigen, Blood Urea Nitrogen and Creatinine

Protective effect of the association of curcumin with piperine on prostatic lesions: New perspectives on BPA-induced carcinogenesis

Bisphenol A (BPA) is a chemical agent which can exert detrimental effects on the male reproductive system, especially the prostate gland. In this study we described the efficacy of the dietary agent curcumin, alone or combined with piperine, to suppress the impact of BPA on the prostate. Adult gerbils were divided into nine experimental groups (n = 7 each group), regarding control (water and oil), exposed to BPA (50 μg/kg/day in water) or curcumin (100 mg/kg) and/or piperine (20 mg/kg). To evaluate the effects of the phytotherapic agents, the other groups received oral doses every two days, BPA plus curcumin (BCm), piperine (BP), and curcumin + piperine (BCmP). BPA promoted prostatic inflammation and morphological lesions in ventral and dorsolateral prostate lobes, associated with an increase in androgen receptor-positive cells and nuclear atypia, mainly in the ventral lobe. Curcumin and piperine helped to minimize these effects. BPA plus piperine or curcumin showed a reduction in nuclear atypical phenotype, indicating a beneficial effect of phytochemicals. Thus, these phytochemicals minimize the deleterious action of BPA in prostatic lobes, especially when administered in association. The protective action of curcumin and piperine consumption is associated with weight loss, anti-inflammatory potential, and control of prostate epithelial cell homeostasis.

Osteopontin Deficiency Ameliorates Prostatic Fibrosis and Inflammation.

Fibrogenic and inflammatory processes in the prostate are linked to the development of lower urinary tract symptoms (LUTS) in men. Our previous studies identified that osteopontin (OPN), a pro-fibrotic cytokine, is abundant in the prostate of men with LUTS, and its secretion is stimulated by inflammatory cytokines potentially to drive fibrosis. This study investigates whether the lack of OPN ameliorates inflammation and fibrosis in the mouse prostate. We instilled uropathogenic E. coli (UTI89) or saline (control) transurethrally to C57BL/6J (WT) or Spp1tm1Blh/J (OPN-KO) mice and collected the prostates one or 8 weeks later. We found that OPN mRNA and protein expression were significantly induced by E. coli-instillation in the dorsal prostate (DP) after one week in WT mice. Deficiency in OPN expression led to decreased inflammation and fibrosis and the prevention of urinary dysfunction after 8 weeks. RNAseq analysis identified that E. coli-instilled WT mice expressed increased levels of inflammatory and fibrotic marker RNAs compared to OPN-KO mice including Col3a1, Dpt, Lum and Mmp3 which were confirmed by RNAscope. Our results indicate that OPN is induced by inflammation and prolongs the inflammatory state; genetic blockade of OPN accelerates recovery after inflammation, including a resolution of prostate fibrosis.

Icariin ameliorates metabolic syndrome-induced benign prostatic hyperplasia in rats

Metabolic syndrome (MetS) is an immense health issue that causes serious complications in aging males including BPH. Icariin (ICA) is a flavonol glycoside that exerts a plethora of pharmacological effects. The present investigation tested the potential of ICA to ameliorate benign prostatic hyperplasia (BPH) induced by MetS in rats. Animals were allocated to 5 groups in which the first and second groups were kept on water and regular food pellets. MetS was induced in the third, fourth, and fifth groups by keeping the animals on high fructose and salt diets for twelve consecutive weeks. These groups were given vehicle, ICA (25 mg/kg), and ICA (50 mg/kg), respectively. MetS was confirmed by an increase in rats' weight, accumulation of visceral fat, insulin resistance, and dyslipidemia. This was accompanied by manifestation of BPH including increased prostate weight, prostate index, and histopathological alterations. Treating the animals with both doses of ICA significantly ameliorated the increase in weight and index of the prostate as well as altered prostate histopathology. In addition, ICA significantly decreased cyclin D1 expression, upregulated Bax, and downregulated Bcl2 mRNA expression. ICA prevented lipid peroxidation, reduced glutathione depletion, and catalase exhaustion, which further lowered markers of prostate inflammation such as interleukin-6 and tumor necrosis factor-α. Moreover, ICA prevented the decrease in prostate content of phosphorylated 5'-adenosine monophosphate (AMP)-activated protein kinase (pAMPK). In conclusion, ICA protects against MetS-induced BPH. This is due to its antiproliferative, proapoptotic, antioxidant, and anti-inflammatory activities as well as the activation of AMPK.

Effect of thermophilic bacterium HB27 manganese superoxide dismutase in a rat model of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).

We investigated the therapeutic effects of superoxide dismutase (SOD) from thermophilic bacterium HB27 on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and its underlying mechanisms. A Sprague–Dawley rat model of CP/CPPS was prepared and then administered saline or Thermus thermophilic (Tt)-SOD intragastrically for 4 weeks. Prostate inflammation and fibrosis were analyzed by hematoxylin and eosin staining, and Masson staining. Alanine transaminase (ALT), aspartate transaminase (AST), serum creatinine (CR), and blood urea nitrogen (BUN) levels were assayed for all animals. Enzyme-linked immunosorbent assays (ELISA) were performed to analyze serum cytokine concentrations and tissue levels of malondialdehyde, nitric oxide, SOD, catalase, and glutathione peroxidase. Reactive oxygen species levels were detected using dichlorofluorescein diacetate. The messenger ribonucleic acid (mRNA) expression of tissue cytokines was analyzed by reverse transcription polymerase chain reaction (RT-PCR), and infiltrating inflammatory cells were examined using immunohistochemistry. Nuclear factor-κB (NF-κB) P65, P38, and inhibitor of nuclear factor-κBα (I-κBα) protein levels were determined using western blot. Tt-SOD significantly improved histopathological changes in CP/CPPS, reduced inflammatory cell infiltration and fibrosis, increased pain threshold, and reduced the prostate index. Tt-SOD treatment showed no significant effect on ALT, AST, CR, or BUN levels. Furthermore, Tt-SOD reduced inflammatory cytokine expression in prostate tissue and increased antioxidant capacity. This anti-inflammatory activity correlated with decreases in the abundance of cluster of differentiation 3 (CD3), cluster of differentiation 45 (CD45), and macrophage inflammatory protein 1α (MIP1α) cells. Tt-SOD alleviated inflammation and oxidative stress by reducing NF-κB P65 and P38 protein levels and increasing I-κBα protein levels. These findings support Tt-SOD as a potential drug for CP/CPPS.

Flavonoids derived from Anemarrhenae Rhizoma ameliorate inflammation of benign prostatic hyperplasia via modulating COX/LOX pathways

Ethnopharmacological relevanceFlavonoids are the main components of the traditional Chinese medicine Anemarrhenae Rhizoma (dried rhizome of Anemarrhena asphodeloides Bge.), which has been reported to possess activity against inflammation and tumor. Aim of studyRegulation of the arachidonic acid (AA) cascade through cyclooxygenase (COX) and lipoxygenase (LOX) represent the two major pathways to treat inflammatory of benign prostatic hyperplasia (BPH). In this study, Anemarrhenae Rhizoma flavonoids and its main compounds (mangiferin, neomangiferin and isomangiferin) were investigated for effects on AA metabolism. MethodsUltra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was used to monitor AA metabolites in BPH rats and in PC-3 cells. COX-2 and 5-LOX protein and mRNA levels were measured by Western blot and qPCR, respectively, along with histopathological assessment of prostate tissues. ResultsTreatment with flavonoids significantly ameliorated BPH-associated prostate inflammation and inhibited the expression of COX-2 and 5-LOX at the protein and mRNA levels. Quantitative metabolomic analysis of blood plasma showed flavonoids treatment decreased AA levels and its metabolites associated with the COX and LOX pathways. Further exploration of the flavonoid compounds mangiferin, neomangiferin and isomangiferin showed they inhibited AA metabolism to varying degrees in PC-3 cell cultures. ConclusionAnemarrhenae Rhizoma flavonoids act to inhibit BPH-related inflammation in vivo and in vitro by targeting AA metabolism and interfering with COX and LOX pathways. The identification of mangiferin, neomangiferin and isomangiferin as anti-inflammatory components suggests flavonoids interventions represent a promising therapeutic approach for BPH.

Impairment of autophagy may represent the molecular mechanism behind the relationship between obesity and inflammation in patients with BPH and LUTS.

Aim of this study was to evaluate the roles of inflammation and autophagy in obese patients with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). We analyzed 150 surgical specimens from patients underwent transurethral resection of the prostate (TURP) for LUTS/BPH (Median age 70.3±8.1 years, median BMI 25.7±4.0 kg/m2 and median PSA 6.0±5.4 ng/mL). All surgical specimens were investigated for the presence inflammatory infiltrates, according to the standardized classification of chronic prostatitis of the National Institute of Health. The inflammatory score (IS Score) was calculated. High IS score was defined as ≥7. Each sample was stained for anti-LC3B (cell signaling) and for anti-P62/SQSTM1 (MBL) according to manufacturer's suggestions and scored as follow: 0 (no dots); 1 (detectable dots in 5-25% of cells); 2 (readily detectable dots in 25-75% of cells); 3 (dots in >75% of cells). High percentage of p62 or LC3B was defined as >25%, whereas low percentage of p62 or LC3B was defined as <25% of cells with dots. Overall 74/150 (49.3%) patients were overweight or obese (BMI >25 kg/m2). Obese patients presented a higher inflammatory score. Obese/overweight patients presented a lower percentage of LC3B (58/74; 78.4%) and higher of p62 (49/74; 66.2%) compared to those of normal weight, which it means a deactivated autophagy (P<0.05). At multivariate analysis LC3B (OR=0.22; CI: 0.069-0.70; P=0.01) percentage and BMI (OR=1.118; CI: 1.001-1.250; P=0.04) were independent risk factors of prostatic inflammation (IS≥7). Here we confirm the association between obesity and prostatic inflammatory infiltrates and present the first evidence of autophagy deregulation in obese patients with LUTS/BPH. Further studies should better investigate this relationship and provide new possible therapeutic targets.

Inflammation induced by lipopolysaccharide advanced androgen receptor expression and epithelial-mesenchymal transition progress in prostatitis and prostate cancer.

BackgroundTo explore the mechanism of prostatic inflammation on prostate cancer (PCa) by comparing the changes of prostate epithelial cells and PCa cells in an inflammatory environment.MethodsFirst, immunohistochemistry (IHC) was used to compare the level of expression of TNF-α, IL-1β, IL-6, and TGF-β between benign prostatic hyperplasia (BPH), prostatitis, and PCa. Then primary prostate epithelial cells were sampled from patients who were suspected of PCa and had histological prostatitis (HP) confirmed by pathological biopsy. Lipopolysaccharide (LPS) or BAY11-7082 were used to investigate the change of androgen receptor (AR) and AR-mediated transcription, epithelial-mesenchymal transition (EMT) in primary prostate epithelial cells, and lymph node carcinoma of the prostate (LNCap) cells.ResultsTNF-α, IL-1β, IL-6, and TGF-β were significantly increased in HP and PCa compared with those in BPH patients. The proliferation of primary prostate epithelial cells and LNCap cells got the inflection point at LPS 10 µg/mL. In an inflammatory environment with 10 µg/mL LPS, both primary prostate epithelial cell and LNCap cell viability increased, and AR, AR-mediated transcription, and EMT processes were significantly increased. Inhibitors of NF-κB with 10 nM BAY11-7082 decreased AR, AR-mediated transcription, and EMT processes.ConclusionsNF-κB regulates AR expression and EMT in prostatitis and PCa, and NF-κB inhibitors may have potential therapeutic value.

Identification of prostate cancer using multiparametric MR imaging characteristics of prostate tissues referenced to whole mount histopathology

In this study, the objective was to characterize the MR signatures of the various benign prostate tissues and to differentiate them from cancer. Data was from seventy prostate cancer patients who underwent multiparametric MRI (mpMRI) and subsequent prostatectomy. The scans included T2-weighted imaging (T2W), diffusion weighted imaging, dynamic contrast-enhanced MRI (DCE MRI), and MR spectroscopic imaging. Histopathology tissue information was translated to MRI images. The mpMRI parameters were characterized separately per zone and by tissue type. The tissues were ordered according to trends in tissue parameter means. The peripheral zone tissue order was cystic atrophy, high grade prostatic intraepithelial neoplasia (HGPIN), normal, atrophy, inflammation, and cancer. Decreasing values for tissue order were exhibited by ADC (1.8 10−3 mm2/s to 1.2 10−3 mm2/s) and T2W intensity (3447 to 2576). Increasing values occurred for DCE MRI peak (143% to 157%), DCE MRI slope (101%/min to 169%/min), fractional anisotropy (FA) (0.16 to 0.19), choline (7.2 to 12.2), and choline / citrate (0.3 to 0.9). The transition zone tissue order was cystic atrophy, mixed benign prostatic hyperplasia (BPH), normal, atrophy, inflammation, stroma, anterior fibromuscular stroma, and cancer. Decreasing values occurred for ADC (1.6 10−3 mm2/s to 1.1 10−3 mm2/s) and T2W intensity (2863 to 2001). Increasing values occurred for DCE MRI peak (143% to 150%), DCE MRI slope (101%/min to 137%/min), FA (0.18 to 0.25), choline (7.9 to 11.7), and choline / citrate (0.3 to 0.7). Logistic regression was used to create parameter model fits to differentiate cancer from benign prostate tissues. The fits achieved AUCs ≥0.91. This study quantified the mpMRI characteristics of benign prostate tissues and demonstrated the capability of mpMRI to discriminate among benign as well as cancer tissues, potentially aiding future discrimination of cancer from benign confounders.

Therapeutic Effects of 25-Hydroxyvitamin D on the Pathological Process of Benign Prostatic Hyperplasia: An In Vitro Evidence.

The pathogenesis of benign prostatic hyperplasia (BPH) is extremely complicated which involving the multiple signaling pathways. The deficiency of vitamin D is an important risk factor for BPH, and exogenous vitamin D is effective for the treatment of BPH. In this study, we provided in vitro mechanical evidence of vitamin D as a treatment for BPH using BPH-1, WPMY-1, and PBMC cells. We found that 25-hydroxyvitamin D (25-OH D) level is decreased in BPH and closely correlated with age, prostate volume, maximum flow, international prostate symptom score, and prostate-specific antigen of the BPH patients. We further revealed that 25-OH D ameliorated TGF-β1 induces epithelial-mesenchymal transition (EMT) of BPH-1 cells and proliferation of WPMY-1 cells via blocking TGF-β signaling. Moreover, 25-OH D was able to block NF-κB signaling in PBMCs of BPH patients and STAT3 signaling in BPH cells to relieve inflammation. 25-OH D also protects BPH cells from inflammatory cytokines selected by PBMCs. Finally, we uncovered that 25-OH D alleviated prostate cell oxidative stress by triggering Nrf2 signaling. In conclusion, our data verified that 25-OH D regulated multiple singling pathways to restrain prostate cell EMT, proliferation, inflammation, and oxidative stress. Our study provides in vitro mechanical evidence to support clinical use of vitamin D as a treatment for BPH.

Therapeutic effects of nerve growth factor-targeting therapy on bladder overactivity in rats with prostatic inflammation.

The present study examined the effect of liposomes conjugated with antisense oligonucleotide of nerve growth factor (NGF-OND) on local overexpression of NGF and bladder overactivity using rats with prostatic inflammation (PI). Male Sprague-Dawley rats were divided into three groups: (1) Control group; intact rats, (2) PI-NS group; rats with PI and intravesical instillation of normal saline (NS), (3) PI-OND group; rats with PI and intravesical instillation of NGF-OND. On Day 0, PI was induced by intraprostatic 5%-formalin injection. On Day 14, NGF-OND or NS was instilled directly into the bladder after laparotomy. On Day 28, therapeutic effects of NGF-OND were evaluated by awake cystometry and histological analysis as well as reverse-transcription polymerase chain reaction measurements of messenger RNA (mRNA) levels of NGF in the bladder and prostate, inflammatory markers in the prostate, C-fiber afferent markers, and an A-type K+ channel α-subunit (Kv 1.4) in L6-S1 dorsal root ganglia (DRG). Intravesical NFG-OND treatment reduced PI-induced overexpression of NGF in both bladder and prostate, and reduced PI-induced bladder overactivity evident as longer intercontraction intervals in association with reductions of TRPV1 and TRPA1 mRNA expression levels in DRG. mRNA expression of Kv1.4 in DRG was reduced after PI, but improved in the PI-OND group. These results indicate that NGF locally expressed in the bladder is an important mediator inducing bladder overactivity with upregulation of C-fiber afferent markers and downregulation of an A-type K+ channel subunit in DRG following PI, and that liposome-based, local NGF-targeting therapy could be effective for not only bladder overactivity and afferent sensitization, but also PI. Thus, local blockade of NGF in the bladder could be a therapeutic modality for male LUTS due to BPH with PI.

Mast cell function in prostate inflammation, fibrosis, and smooth muscle cell dysfunction.

Intraurethral inoculation of mice with uropathogenic Escherichia coli (CP1) results in prostate inflammation, fibrosis, and urinary dysfunction, recapitulating some but not all of the pathognomonic clinical features associated with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). In both patients with LUTS and CP1-infected mice, we observed increased numbers and activation of mast cells and elevated levels of prostate fibrosis. Therapeutic inhibition of mast cells using a combination of a mast cell stabilizer, cromolyn sodium, and the histamine 1 receptor antagonist cetirizine di-hydrochloride in the mouse model resulted in reduced mast cell activation in the prostate and significant alleviation of urinary dysfunction. Treated mice showed reduced prostate fibrosis, less infiltration of immune cells, and decreased inflammation. In addition, as opposed to symptomatic CP1-infected mice, treated mice showed reduced myosin light chain-2 phosphorylation, a marker of prostate smooth muscle contraction. These results show that mast cells play a critical role in the pathophysiology of urinary dysfunction and may be an important therapeutic target for men with BPH/LUTS.NEW & NOTEWORTHY LUTS-associated benign prostatic hyperplasia is derived from a combination of immune activation, extracellular matrix remodeling, hyperplasia, and smooth muscle cell contraction in prostates of men. Using a mouse model, we describe the importance of mast cells in regulating these multiple facets involved in the pathophysiology of LUTS. Mast cell inhibition alleviates both pathology and urinary dysfunction in this model, suggesting the potential for mast cell inhibition as a therapeutic that prevents and reverses pathology and associated symptomology.

SUVmax/ADC Ratio as a Molecular Imaging Biomarker for Diagnosis of Biopsy-Naïve Primary Prostate Cancer.

Background:Gallium-68-prostate-specific membrane antigen (68Ga-PSMA) positron emission tomography/computed tomography (PET/CT) has recently been shown to be very high accuracy in biopsy-naïve prostate cancer (PCa) detection and can potentially improve the low specificity noted with diffusion-weighted magnetic resonance imaging (DW-MRI), especially in instances of prostate inflammation. We aimed to compare the diagnostic accuracy of DW-MRI and PSMA PET/CT using apparent diffusion coefficient (ADC) and maximum standardized uptake (SUVmax) values in the diagnosis of PCa.Patients and Methods:A retrospective study comparing and analyzing the diagnostic accuracy of prebiopsy DW-MRI and 68Ga-PSMA PET/CTs done in patients with suspected PCa (raised prostate specific antigen [PSA] and/or positive digital rectal examination) from January 2019 to December 2020. The standard of reference was transrectal ultrasound-guided biopsies.Results:Sixty-seven patients were included in the study, mean age: 70 years (range 49–84), mean PSA: 23.2 ng/ml (range 2.97–45.6). Biopsy was positive for PCa in 56% (n = 38) and negative in 43% (n = 29). Of the benign results, benign hyperplasia was noted in 75% (n = 22) and prostatitis in 25% (n = 7). Of the PCa, 55% (n = 21) of were high International Society of Urological Pathology (ISUP) grade (4–5) and 45% (n = 17) low/intermediate ISUP grade (1–3). Overall the sensitivity/specificity/Accuracy for prediction of PCa of MRI using prostate imaging and reporting data system version 2 criteria and PSMA PET/CT using PCa molecular imaging standardized evaluation criteria was 92.1%/65.5%/80.5% and 76.3%/96.5%/85.1% respectively. Mean apparent diffusion co-efficient (mean ADC) value of benign lesions and PCa was 1.135 × 10-3 mm2/s and 0.723 × 10-3 mm2/s, respectively (P = 0.00001). Mean SUVmax and ADC of benign and PCa lesions was 4.01 and 16.4 (P = 0.000246). Mean SUVmax/ADC ratio of benign and malignant lesions was 3.8 × 103 versus 25.21 × 103 (P < 0.000026). Inverse correlation was noted between ADC and SUVmax values (R = −0.609), inverse correlation noted between ADC and Gleason's score (R = −0.198), and positive correlation of SUVmax and SUVmax/ADC with Gleason's score (R = 0.438 and R = 0.448). Receiver operating characteristic curve analysis revealed a SUVmax cutoff 6.03 (sensitivity/specificity - 76%/90%, area under the curve (AUC) - 0.935, Youden index (YI) - 0.66), ADC cutoff of 0.817 × 10−3 mm2/s (sensitivity/specificity – 79%/86%, AUC – 0.890, YI - 0.65), and SUVmax/ADC ratio cutoff of 7.43 × 103 (sensitivity/specificity – 87%/98%, AUC - 0.966, YI - 0.85) for PCa diagnosis.Conclusion:For diagnosis of biopsy-naïve PCas, the combination of diffusion-weighted MRI and PSMA PET/CT (i.e., SUVmax/ADC ratio) shows better diagnostic accuracy than either used alone and the combination of PET and MRI is especially useful when distinguishing cancer from prostatitis.