The endocrine and epigenetic impact of persistent cow milk consumption on prostate carcinogenesis

This review analyzes the potential impact of milk-induced signal transduction on the pathogenesis of prostate cancer (PCa). Articles in PubMed until November 2021 reporting on milk intake and PCa were reviewed. Epidemiological studies identified commercial cow milk consumption as a potential risk factor of PCa. The potential impact of cow milk consumption on the pathogenesis of PCa may already begin during fetal and pubertal prostate growth, critical windows with increased vulnerability. Milk is a promotor of growth and anabolism via activating insulin-like growth factor-1 (IGF-1)/phosphatidylinositol-3 kinase (PI3K)/AKT/mechanistic target of rapamycin complex 1 (mTORC1) signaling. Estrogens, major steroid hormone components of commercial milk of persistently pregnant dairy cows, activate IGF-1 and mTORC1. Milk-derived signaling synergizes with common driver mutations of the PI3K/AKT/mTORC1 signaling pathway that intersect with androgen receptor, MFG-E8, MAPK, RUNX2, MDM4, TP53, and WNT signaling, respectively. Potential exogenously induced drivers of PCa are milk-induced elevations of growth hormone, IGF-1, MFG-E8, estrogens, phytanic acid, and aflatoxins, as well as milk exosome-derived oncogenic microRNAs including miR-148a, miR-21, and miR-29b. Commercial cow milk intake, especially the consumption of pasteurized milk, which represents the closest replica of native milk, activates PI3K-AKT-mTORC1 signaling via cow milk’s endocrine and epigenetic modes of action. Vulnerable periods for adverse nutrigenomic impacts on prostate health appear to be the fetal and pubertal growth periods, potentially priming the initiation of PCa. Cow milk-mediated overactivation of PI3K-AKT-mTORC1 signaling synergizes with the most common genetic deviations in PCa, promoting PCa initiation, progression, and early recurrence.

Concentrations of canine prostate specific esterase, CPSE, at baseline are associated with the relative size of the prostate at three-year follow-up

Background Enlargement of the prostate is associated with prostatic diseases in dogs, and an estimation of prostatic size is a central part in the diagnostic workup. Ultrasonography is often the method of choice, but biomarkers constitute an alternative. Canine prostate specific esterase (CPSE) shares many characteristics with human prostate specific antigen (PSA) and is related to prostate size. In men with clinical symptoms of prostatic disease, PSA concentrations are related to prostate growth. The aims of the present follow-up study were to evaluate if the concentration of CPSE is associated with future growth of the prostate, and if analysis of a panel of 16 steroids gives further information on prostatic growth. Owners of dogs included in a previous study were 3 years later contacted for a follow-up study that included an interview and a clinical examination. The prostate was examined by ultrasonography. Serum concentrations of CPSE were measured, as was a panel of steroids. Results Of the 79 dogs included at baseline, owners of 77 dogs (97%) were reached for an interview, and 22 were available for a follow-up examination. Six of the 79 dogs had clinical signs of prostatic disease at baseline, and eight of the remaining 73 dogs (11%) developed clinical signs between baseline and follow-up, information was lacking for two dogs. Development of clinical signs was significantly more common in dogs with a relative prostate size of ≥2.5 at baseline (n = 20) than in dogs with smaller prostates (n = 51). Serum concentrations of CPSE at baseline were not associated with the change in prostatic size between baseline and follow-up. Serum concentrations of CPSE at baseline and at follow-up were positively associated with the relative prostatic size (Srel) at follow-up. Concentrations of corticosterone (P = 0.024), and the class corticosteroids (P = 0.0035) were positively associated with the difference in Srel between baseline and follow-up. Conclusions The results support the use of CPSE for estimating present and future prostatic size in dogs ≥4 years, and the clinical usefulness of prostatic size for predicting development of clinical signs of prostatic disease in the dog. The association between corticosteroids and prostate growth warrants further investigation.

Piperazine-Derived α1D/1A Antagonist 1- Benzyl-N- (3-(4- (2-Methoxyphenyl) Piperazine-1-yl) Propyl) -1H- Indole-2- Carboxamide Induces Apoptosis in Benign Prostatic Hyperplasia Independently of α1-Adrenoceptor Blocking

Previous studies have indicated that α1D/1A antagonist naftopidil (NAF) suppresses prostate growth by decreasing cell proliferation without affecting apoptosis and prostate volume in benign prostatic hyperplasia (BPH). A NAF-derived α1D/1A antagonist 1- benzyl-N-(3-(4-(2-methoxyphenyl) piperazine-1-yl) propyl)-1H-indole-2- carboxamide (HJZ-12) has been reported from our laboratory, which exhibits high subtype-selectivity to both α1D- and α1A- AR (47.9- and 19.1- fold, respectively) with respect to a1B-AR in vitro. However, no further study was conducted. In the present study, a pharmacological evaluation of HJZ-12 in BPH was performed on an estrogen/androgen-induced rat BPH model and human BPH-1 cell line. In vivo, HJZ-12 exhibited better performance than NAF in preventing the progression of rat prostatic hyperplasia by not only decreasing prostate weight and proliferation (similar to NAF) but also, shrinking prostate volume and inducing prostate apoptosis (different from NAF). In vitro, HJZ-12 exhibited significant cell viability inhibition and apoptotic induction in BPH-1 cell line, without presenting cell anti-proliferation properties. Intriguingly, the role of HJZ-12 on cell viability and apoptosis was an α1-independent action. Furthermore, RNA-Seq analysis was applied to screen out six anti-apoptotic genes (Bcl-3, B-lymphoma Mo-MLV insertion region 1 [Bmi-1], ITGA2, FGFR3, RRS1, and SGK1). Amongst them, Bmi-1 was involved in the apoptotic induction of HJZ-12 in BPH-1. Overall, HJZ-12 played a remarkable role in preventing the progression of prostatic hyperplasia through α1-independent apoptotic induction, indicating that it will be a multi-target effective candidate for BPH treatment.

Effects of testosterone replacement on serotonin levels in the prostate and plasma in a murine model of hypogonadism

Benign prostate hyperplasia is a dysfunctional disease with an elevated prevalence. Despite the accepted impact of aging and testosterone (TES) in its pathophysiology, its aetiology remains unknown. Recent studies described that serotonin (5-HT) inhibits benign prostate growth through the modulation of the androgen receptor, in the presence of TES. Accordingly, this work aimed to determine the impact of castration and TES replacement in plasmatic and prostatic 5-HT regulation. C57BL/6 mice were submitted to surgical castration and divided into three groups, continually exposed to either vehicle or different TES doses for 14 days. Plasmatic 5-HT concentration was measured before and after castration, and after TES reintroduction. Finally, total prostatic weight and intra-prostatic 5-HT were determined in the different groups. Our results demonstrate that mice prostate exhibits high 5-HT tissue levels and that intra-prostatic total 5-HT was independent of castration or TES reintroduction, in all studied groups. Also, 5-HT plasmatic concentration significantly increased after castration and then normalized after TES administration. Our findings revealed that mice prostate has a high 5-HT content and that total prostatic 5-HT levels do not depend on androgens’ action. On the other hand, castration induced a significant increase in plasmatic 5-HT concentration, raising the hypothesis that androgens might be regulating the production of extra-prostatic 5-HT.

The relationship between glucose homeostasis status and prostate size in aging Chinese males with benign prostatic hyperplasia

Purpose Increasing evidence shows that many metabolic factors are involved in the progression of benign prostatic hyperplasia (BPH). We aimed to assess the relationship between the status of glucose homeostasis and prostate size in aging Chinese males undergoing transurethral resection of the prostate (TURP) for BPH. Methods A total of 1006 medical records of BPH patients undergoing TURP were reviewed. Prostate size was measured by transrectal ultrasound. Annual total prostate (TP) and transitional zone (TZ) growth rates were calculated. According to the American Diabetes Association criteria, the patients were categorized as normoglycemic, prediabetic, or diabetic. Levels of glucose homeostasis and other variables were considered independent variables in an effort to evaluate any potential correlations using non-adjusted and multivariate-adjusted regression models. Results A total of 659 individuals were included in the study. BPH patients < 70 years old and ≥ 70 years old in the normoglycemic group had a stable prostate growth rate. The change in prostate size in those younger than 70 years, however, was faster in the prediabetic and diabetic group. Further analysis revealed that abnormal glucose homeostasis was positively correlated with prostate size. In those younger than 70 years, compared with the normal glucose group, the adjusted odds ratio (OR) for TP and TZ enlargement in the prediabetic group was 2.27 (95%CI 1.29–4.00) and 3.19 (95%CI 1.78–5.72), respectively, and the adjusted ORs were 4.74 (95%CI 2.18–10.30) and 6.16 (95%CI 2.70–14.06), respectively, for men with diabetes. However there was no significant difference among men aged ≥ 70 years. Conclusions Among patients undergoing TURP, the prostate volume and growth rate were affected by different status of glucose homeostasis. Hyperglycemia may play an important role in prostate growth.

The Yin Yang Role of Nitric Oxide in Prostate Cancer

Nitric oxide (NO) is a ubiquitous signaling molecule in the human body with well-known roles in many different processes and organ systems. In cancer, the two-concentrations hypothesis of NO has dictated that low levels of NO are cancer promoting, while high levels of NO are protective against cancer. Although prostate cancer is a hormonally driven malignancy, research has been shifting away from androgen-responsive epithelial cells and evolving to focus on NO therapies, the tumor microenvironment (TME), and inflammation. NO is reported to be able to inhibit activity of the androgen receptor. This may prevent prostate growth, but low levels of NO could conversely select for castration-resistant prostate cells, creating an aggressive cancer phenotype. At high levels, nitrosative stress created from NO overproduction can be protective against prostate neoplasia. In this review, we discuss development and possibilities of NO-based therapies for prostate cancer.

Evaluation of ayurvedic therapy in management of Benign Prostatic Hyperplasia

Benign Prostatic Hyperplasia (BPH) is a common condition that affects 50% of men in their 50 th decade. There have been many advances in the treatment of this condition, which aim to improve the patient’s quality of life.1 Although there is no cure for BPH, but there are many useful options for treating the problem. Treatment focuses on prostate growth, which is the cause of BPH symptoms. Once prostate growth starts, it often continues unless treatment starts. The prostate grows in two different ways-in one type of growth, cell multiply around the urethra and squeeze it whereas in the second type of growth is middle lobe prostate growth in which cell grow into the urethra and the bladder outlet area. This type of prostate growth typically requires surgery. The first line of care for treating BPH is often medication.2 Efficacy of Vasti therapy an Ayurvedic therapeutic procedure was studied in 75 patients of Benign Prostatic Hyperplasia (BPH). The treatment was given for 21 days, and then the effect was assessed clinically and objectively. Objective observations include determination of size (weight) of prostate and residual urine in the urinary bladder by ultrasonography, estimation of blood urea, serum creatinine and routine, microscopic and microbiological study of urine was also done. After the therapy in 70.67% of 75 patients, the size of the prostate was found regressed, and in 82.14% of 56 patients, the residual urine volume was decreased along with other objective and subjective improvement.