ABSTRACT
Benign prostatic hypertrophy (BPH) is a serious medical condition among elderly male population. BPH pathogenesis has been linked to inflammation, cellular proliferation, oxidative stress and apoptosis. Diacerein (DIA) is a FDA approved anthraquinone drug that is used to treat joint diseases such as osteoarthritis. DIA has been studied for its potent anti-inflammatory and antioxidant effects, yet its role in managing BPH has not been investigated. In this study, DIA administration for two weeks at 50 mg/kg in testosterone-induced BPH rats significantly reduced prostate weight and index. Moreover, prostatic biochemical and structural features in BPH rats were significantly improved upon DIA treatment. Mechanistically, DIA treatment associated prostatic anti-hyperplastic effects were linked to downregulation of Nrf-2/HO-1 axis, downregulation of inflammatory TNF-a, IL-1ß, IL-6, downregulation of the cell proliferative marker PCNA and upregulation of caspase-3 levels. In addition, DIA treatment upregulated prostatic antioxidant GSH, the enzymatic SOD and CAT activities and reduced prostatic lipid peroxidation levels. Altogether, the present study provides evidence that DIA treatment might limit BPH progression via its potent anti-oxidant, anti-inflammatory, anti-proliferative and apoptosis inducing effects.
Subject(s)
Anthraquinones/pharmacology , Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Prostatic Hyperplasia/drug therapy , Prostatitis/drug therapy , Animals , Anthraquinones/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Antioxidants/therapeutic use , Apoptosis/drug effects , Apoptosis/immunology , Cell Proliferation/drug effects , Disease Models, Animal , Humans , Male , Oxidative Stress/drug effects , Oxidative Stress/immunology , Prostate/drug effects , Prostate/immunology , Prostate/pathology , Prostatic Hyperplasia/chemically induced , Prostatic Hyperplasia/immunology , Prostatic Hyperplasia/pathology , Prostatitis/immunology , Prostatitis/pathology , Rats , Testosterone/administration & dosage , Testosterone/toxicityABSTRACT
BACKGROUND: The prostate is susceptible to changes in androgen levels, which can play an important role in the development of Benign Prostatic Hyperplasia (BPH). Natural compounds have beneficial properties for organisms and can be an important therapeutic strategy in the treatment of diseases. ß-Caryophyllene (BCP) is a phytocannabinoid present in several medicinal and food plants species and has shown beneficial effects in different organs. However, little is known about its effects on the prostate. The present study seeks to evaluate the effects of exposure to BCP on the morphophysiology of the ventral prostate of adult gerbils supplemented with testosterone. METHODS: Animals were distributed into four groups (n = 8/group): Intact control (C); ß-Caryophyllene (BCP): ß-Caryophyllene (50 mg/kg/day); Testosterone (T): animals received subcutaneous injections of Testosterone Cypionate (3 mg/Kg), on alternate days, for one month and were euthanized 30 days supplementation ended; Testosterone and ß-Caryophyllene (TBCP): animals were exposed to testosterone cypionate (3 mg/Kg) to induce hyperplastic alterations followed by daily BCP (50 mg/kg). Morphological, biometric, immunohistochemical, and serological analyses were performed. RESULTS: Proliferative disorders and inflammatory foci were present in the ventral prostate of all experimental groups. An increase in the multiplicity of benign intraepithelial neoplasm and subepithelial inflammatory foci was observed in T group. The incidence of intraluminal inflammatory foci and microinvasive carcinoma was verified only in the T group. Cellular rearrangement and tissue remodeling occurred in the prostate of groups exposed to phytocannabinoids. A reduction was observed in the frequency of PHH3 and Cox2 markers in the prostatic epithelium of TBCP in comparison with T. A decrease in F4/80 and CD163 positive macrophages were also observed in the prostatic stroma of the TBCP group in comparison with T. The results suggest that BCP had favorable effects on BPH, reducing the proliferation and frequency of some inflammatory cells. CONCLUSION: BCP impacts the tissue remodeling process in the premalignant prostate environment and that the use of this phytocannabinoid can have a promising effect in the handling of BPH.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Cell Proliferation/drug effects , Polycyclic Sesquiterpenes/administration & dosage , Prostate/drug effects , Prostatic Hyperplasia/chemically induced , Prostatic Hyperplasia/drug therapy , Animals , Cell Proliferation/physiology , Gerbillinae , Injections, Subcutaneous , Male , Prostate/pathology , Prostatic Hyperplasia/pathology , Testosterone/administration & dosage , Testosterone/analogs & derivatives , Testosterone/toxicity , Treatment OutcomeABSTRACT
Cadmium (Cd) is a heavy metal that is widely present in modern industrial production. It is a known, highly toxic environmental endocrine disruptor. Long-term exposure to Cd can cause varying degrees of damage to the liver, kidney, and reproductive system of organisms, especially the male reproductive system. This study aimed to explore the mechanism of Cd toxicity in the male reproductive system during puberty. Eighteen healthy 6-week-old male Sprague-Dawley rats were randomly divided into three groups (control group, low-dose group, and high-dose group) according to their body weight, with six in each group. Cd (0, 1, and 3 mg/kg/day) was given by gavage for 28 consecutive days. The results showed that Cd exposure to each dose group caused a decrease in the testicular organ coefficient and sperm count, compared with the control group. Cd exposure resulted in significant changes in testicular morphology in the 3 mg/kg/day Cd group. In the 1 and 3 mg/kg/day Cd groups, serum testosterone decreased and apoptosis of testicular cells increased significantly (p < 0.05). In addition, compared with the control group, the activity of glutathione peroxidase and superoxide dismutase in each Cd exposure dose group decreased, but the content of malondialdehyde in the high-dose, 3 mg/kg/day Cd treatment group significantly increased (p < 0.05). Although Cd exposure caused an increase in the messenger RNA (mRNA) levels of Bcl-2, Caspase-3 and Caspase-9 in the testicular tissues (p < 0.05), Bcl-2 expression was unchanged (p > 0.05). The expression level of Akt mRNA in testicular tissue of rats in the high-dose 3 mg/kg/day Cd group was increased (p < 0.05). Our data suggest that Cd affected testosterone levels, and apoptosis was observed in spermatids.
Subject(s)
Cadmium/toxicity , Reproduction/drug effects , Spermatozoa/drug effects , Testis/drug effects , Testosterone/toxicity , Animals , Apoptosis/drug effects , Caspases/analysis , Caspases/metabolism , Genes, bcl-2/drug effects , Male , RNA, Messenger/analysis , RNA, Messenger/metabolism , Random Allocation , Rats , Rats, Sprague-Dawley , Testosterone/bloodABSTRACT
Supraphysiological doses of anabolic-androgenic steroids (AAS) may cause long-term functional abnormalities, particularly in the heart and liver, which may only represent the later-stage of the cumulative damage caused by dysfunctional organelles. We investigated whether mid-term supraphysiological doses of Testosterone and Nandrolone impair mitochondrial Ca2+ and membrane potential (ΔΨm) dynamics, and redox machinery in the heart and liver of mice. CF1 albino mice were treated daily with 15â¯mg/kg of Nandrolone (ND) or Testosterone (T), or oil (vehicle) for 19â¯days. Preparations enriched in mitochondria from the heart or liver were used to perform assays of Ca2+ influx/efflux, ΔΨm, and H2O2 production. ND significantly impaired mitochondrial Ca2+ influx in the heart, and ΔΨm in both organs. ND and T increased H2O2 levels in the heart and liver relative to controls. Also, ND increased oxidative damage to lipids and proteins (TBARS and carbonyls) in the heart, and both AAS decreased glutathione peroxidase activity in the heart and liver. In summary, supraphysiological doses of ND, and in a lesser extend T, impaired mitochondrial Ca2+ influx and ΔΨm, and redox homeostasis being early mechanistic substrates for inducing heart and liver tissue damage.
Subject(s)
Anabolic Agents/toxicity , Heart/physiopathology , Liver/pathology , Mitochondria/pathology , Nandrolone/toxicity , Testosterone/toxicity , Androgens/pharmacology , Animals , Heart/drug effects , Liver/drug effects , Male , Mice , Mitochondria/drug effects , Oxidation-ReductionABSTRACT
Despite of physiological and toxicological relevance, the potential of androgens to influence fish lipid metabolism remains poorly explored. Here, brown trout primary hepatocytes were exposed to six concentrations (1 nM to 100 µM) of dihydrotestosterone (DHT) and testosterone (T), to assess changes in the mRNA levels of genes covering diverse lipid metabolic pathways. Acsl1, essential for fatty acid activation, was up-regulated by T and DHT, whereas the lipogenic enzymes FAS and ACC were up-regulated by the highest (100 µM) concentration of T and DHT, respectively. ApoA1, the major component of high-density lipoprotein (HDL), was down-regulated by both androgens. PPARγ, linked to adipogenesis and peroxisomal ß-oxidation, was down-regulated by T and DHT, while Acox1-3I, rate-limiting in peroxisomal ß-oxidation, was down-regulated by T. Fabp1, StAR and LPL were not altered. Our findings suggest that androgens may impact on lipid transport, adipogenesis and fatty acid ß-oxidation and promote lipogenesis in fish liver.
Subject(s)
Dihydrotestosterone/metabolism , Testosterone/metabolism , Trout/physiology , Water Pollutants, Chemical/metabolism , Androgens/metabolism , Androgens/toxicity , Animals , Dihydrotestosterone/toxicity , Fatty Acid-Binding Proteins , Fatty Acids/metabolism , Hepatocytes/metabolism , Hepatocytes/physiology , Lipid Metabolism , Lipogenesis , Liver/metabolism , PPAR gamma/metabolism , Testosterone/toxicity , Trout/metabolism , Water Pollutants, Chemical/toxicityABSTRACT
Androgens are relevant in order to achieve a normal growth and maturation of the follicle and oocyte, since both excess and absence of androgens may affect the correct ovarian function. The current study analyzes the impact of neonatal androgenization in the first ovulation and oocyte maturation in response to exogenous gonadotrophin stimulation. Neonatal rats were daily treated with testosterone, dihydrotestosterone, or vehicle during follicle assembly period (days 1 to 5). At juvenile period, rats were stimulated sequentially with PMSG and hCG. Ovulation, ovarian histology, hormonal milieu, morphological characteristics of meiotic spindle, and in vitro fertilization rate in oocytes were analyzed. Our data shows that oocytes from androgenized rats displayed a major proportion of aberrant spindles and altered meiotic advance that control animals. These alterations were accompanied with an increase in both fertilization rate and aberrant embryos after 48 h of culture. Our findings showed a direct impact of neonatal androgens on oocyte development; their effects may be recognized at adulthood, supporting the idea of a programming effect exerted by neonatal androgens. These results could be relevant to explain the low fertility rate seen in polycystic ovary syndrome patients after in vitro fertilization procedures.
Subject(s)
Androgens/toxicity , Dihydrotestosterone/toxicity , Oocytes/drug effects , Oocytes/growth & development , Testosterone/toxicity , Virilism/chemically induced , Animals , Animals, Newborn , Coculture Techniques , Female , Male , Oocytes/pathology , Ovary/drug effects , Ovary/pathology , Ovulation/drug effects , Ovulation/physiology , Pregnancy , Rats , Rats, Wistar , Virilism/pathologyABSTRACT
This study quantitatively evaluated the effects of pyrethroid pesticides on the testis of male rats. An extensive literature search for relevant studies was conducted on PubMed, Web of Science, Excerpta Medica Database, the Chinese National Knowledge Infrastructure, and Chinese Biomedical Literature Database. Pooled standard mean difference with corresponding 95% confidence interval was calculated via the random-effects model. I 2 was used to evaluate heterogeneity among studies. A total of 19 studies were included for analysis in our study. Results indicated that the sperm count of rats exposed to fenvalerate was lower than that of rats in control groups. The sperm count, sperm motility, and testosterone level of rats exposed to cypermethrin and deltamethrin were lower than those of rats in control groups. Moreover, the sperm morphology of rats exposed to these pyrethroid pesticides was abnormal compared with that of rats in control groups. The present meta-analysis indicates that pyrethroid pesticides decrease rat sperm count, sperm motility, and testosterone level and cause abnormal rat sperm morphology. Therefore, pyrethroid pesticides can damage the testis of male rats.
Subject(s)
Insecticides/toxicity , Pyrethrins/toxicity , Testis/drug effects , Animals , Male , Rats , Spermatozoa/drug effects , Testosterone/toxicityABSTRACT
The aim of this study was to evaluate whether high levels of exogenous testosterone (T) interfere in prostate morphogenesis. Pregnant females were exposed to subcutaneous injections of T cypionate (500 µg/animal) at gestational days 20 and 22. Male and female pups were euthanized at postnatal days 1 and 15. 15-day-old males had only fibroblast growth factor 10 (FGF10) immunostaining and nuclear form factor altered by the treatment, whereas treated females (T1 and T15) had almost all analyzed parameters changed. T1 females showed an increased anogenital distance (AGD), whereas T15 females had both AGD and ovary weight increased. T1 females had a higher number of epithelial buds emerging from the urethral and vaginal epithelium. We observed ectopic prostatic tissue surrounding the vagina in both T1 and T15 females. Moreover, the ectopic acini of T15 females showed delayed luminal formation, and there was a thickening of the periacinar smooth muscle layer (SML). Finally, FGF10 immunostaining intensity decreased in both T15 male and female prostates. Indeed, Sonic hedgehog (Shh) was upregulated in T15 female prostates, whereas no difference was observed between the male groups. These data showed that exogenous T changed the nuclear morphology of prostate epithelial cells in both males and females. Surprisingly, smooth muscle hyperplasia was also observed in the ectopic female prostate. Moreover, T downregulated FGF10 in both male and female prostates. Interestingly, the results suggest that FGF10 downregulation is mediated by the upregulation of Shh in females. In conclusion, exogenous T disrupts prostate development, particularly, affecting, the female.
Subject(s)
Epithelium/metabolism , Fibroblast Growth Factor 10/biosynthesis , Hedgehog Proteins/biosynthesis , Muscle, Smooth/metabolism , Prenatal Exposure Delayed Effects/metabolism , Prostate/metabolism , Testosterone/toxicity , Animals , Animals, Newborn , Epithelium/drug effects , Epithelium/pathology , Female , Fibroblast Growth Factor 10/genetics , Gene Expression Regulation, Developmental , Gerbillinae , Hedgehog Proteins/genetics , Male , Muscle, Smooth/cytology , Muscle, Smooth/drug effects , Pregnancy , Prenatal Exposure Delayed Effects/chemically induced , Prostate/drug effects , Prostate/pathologyABSTRACT
AIM: To investigate the possible modulatory effect of febuxostat in testosterone-induced benign prostatic hyperplasia (BPH) in rats with emphasis on xanthine oxidase (XO)/Janus Kinases (JAK)/signal transducer and activator of transcription (STAT) axis. MAIN METHODS: Male Wistar rats were treated with testosterone with/out febuxostat. Effect of febuxostat on BPH was assessed at the structural level by histopathology and determination of prostate weight/index. Cyclin D1 protein expression was assessed immunohistochemically and the ratio of Bax/Bcl-2 mRNA expression was determined by real time polymerase chain reaction analysis (RT-PCR). Besides, uric acid serum level was determined colorimetrically. Prostatic XO activity, as well as oxidative stress and inflammatory markers were evaluated. Additionally, western blot analysis was performed for determination of JAK-1 and phosphorylated form of STAT-3 expression in tissues. KEY FINDINGS: Results revealed that febuxostat inhibited the increase in prostatic weight and index compared to testosterone-treated group. Additionally, febuxostat ameliorated testosterone-induced histopathological changes, prevented the rise in cyclin D1 expression and enhanced Bax/Bcl2 ratio. Febuxostat suppressed testosterone induced- increase in XO activity in prostates and serum level of uric acid. Moreover, it regulated oxidative stress markers including; malondialdehyde (MDA), superoxide dismutase (SOD) activity and glutathione (GSH) content. Also, it inhibited the increase in prostate contents of interleukin-6 (IL-6), interleukin-1ß (IL-1 ß), tumor necrosis factor (TNF-α) and nuclear factor (NF-κB). Interestingly, febuxostat markedly reduced JAK-1 and subsequent phosphorylation of STAT-3 protein expression. SIGNIFICANCE: Febuxostat ameliorates testosterone-induced BPH via suppressing XO/JAK/STAT axis. This may help to re-purpose the use of XO inhibitors.
Subject(s)
Febuxostat/pharmacology , Gene Expression Regulation, Neoplastic/genetics , Gout Suppressants/pharmacology , Janus Kinase 1/metabolism , Prostatic Hyperplasia/drug therapy , STAT3 Transcription Factor/metabolism , Testosterone/toxicity , Androgens/toxicity , Animals , Janus Kinase 1/genetics , Male , Prostatic Hyperplasia/chemically induced , Prostatic Hyperplasia/metabolism , Prostatic Hyperplasia/pathology , Rats , Rats, Wistar , STAT3 Transcription Factor/geneticsABSTRACT
Estrogenic effects triggered by androgens have been previously shown in a few studies. Aromatization and direct binding to estrogen receptors (ERs) are the most proposed mechanisms. For example, previously, a modulation of vitellogenin A (VtgA) by testosterone (T), an aromatizable androgen, was reported in brown trout primary hepatocytes. The effect was reversed by an ER antagonist. In this study, using the same model the disruption caused by T and by the non-aromatizable androgen - dihydrotestosterone (DHT), was assessed in selected estrogenic targets. Hepatocytes were exposed (96 h) to six concentrations of each androgen. The estrogenic targets were VtgA, ERα, ERß1 and two zona pellucida genes, ZP2.5 and ZP3a.2. The aromatase CYP19a1 gene and the androgen receptor (AR) were also included. Modulation of estrogenic targets was studied by quantitative real-time PCR and immunohistochemistry, using an HScore system. VtgA and ERα were up-regulated by DHT (1, 10, 100 µM) and T (10, 100 µM). In contrast, ERß1 was down-regulated by DHT (10, 100 µM), and T (100 µM). ZP2.5 mRNA levels were increased by DHT and T (1, 10, 100 µM), while ZP3a.2 was up-regulated by DHT (100 µM) and T (10, 100 µM). Positive correlations were found between VtgA and ERα mRNA levels and ZPs and ERα, after exposure to both androgens. The mRNA levels of CYP19a1 were not changed, while AR expression tended to increase after micromolar DHT exposures. HScores for Vtg and ZPs corroborated the molecular findings. Both androgens triggered estrogen signaling through direct binding to ERs, most probably ERα.
Subject(s)
Androgens/toxicity , Dihydrotestosterone/toxicity , Estrogens/metabolism , Hepatocytes/drug effects , Testosterone/toxicity , Trout/metabolism , Water Pollutants, Chemical/toxicity , Androgens/metabolism , Animals , Cells, Cultured , Dihydrotestosterone/metabolism , Estrogen Receptor alpha/genetics , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/genetics , Estrogen Receptor beta/metabolism , Estrogens/genetics , Gene Expression/drug effects , Hepatocytes/metabolism , Male , Primary Cell Culture , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Testosterone/metabolism , Vitellogenins/genetics , Vitellogenins/metabolism , Water Pollutants, Chemical/metabolismABSTRACT
Ascending bacterial pyelonephritis, a form of urinary tract infection (UTI) that can result in hospitalization, sepsis, and other complications, occurs in ~250,000 US patients annually; uropathogenic Escherichia coli (UPEC) cause a large majority of these infections. Although UTIs are primarily a disease of women, acute pyelonephritis in males is associated with increased mortality and morbidity, including renal scarring, and end-stage renal disease. Preclinical models of UTI have only recently allowed investigation of sex and sex-hormone effects on pathogenesis. We previously demonstrated that renal scarring after experimental UPEC pyelonephritis is augmented by androgen exposure; testosterone exposure increases both the severity of pyelonephritis and the degree of renal scarring in both male and female mice. Activin A is an important driver of scarring in non-infectious renal injury, as well as a mediator of macrophage polarization. In this work, we investigated how androgen exposure influences immune cell recruitment to the UPEC-infected kidney and how cell-specific activin A production affects post-pyelonephritic scar formation. Compared with vehicle-treated females, androgenized mice exhibited reduced bacterial clearance from the kidney, despite robust myeloid cell recruitment that continued to increase as infection progressed. Infected kidneys from androgenized mice harbored more alternatively activated (M2) macrophages than vehicle-treated mice, reflecting an earlier shift from a pro-inflammatory (M1) phenotype. Androgen exposure also led to a sharp increase in activin A-producing myeloid cells in the infected kidney, as well as decreased levels of follistatin (which normally antagonizes activin action). As a result, infection in androgenized mice featured prolonged polarization of macrophages toward a pro-fibrotic M2a phenotype, accompanied by an increase in M2a-associated cytokines. These data indicate that androgen enhancement of UTI severity and resulting scar formation is related to augmented local activin A production and corresponding promotion of M2a macrophage polarization.
Subject(s)
Activins/metabolism , Androgens/toxicity , Escherichia coli Infections/metabolism , Kidney/drug effects , Macrophages/drug effects , Pyelonephritis/metabolism , Testosterone/analogs & derivatives , Urinary Tract Infections/metabolism , Animals , Bacterial Load , Cytokines/metabolism , Escherichia coli Infections/microbiology , Escherichia coli Infections/pathology , Female , Fibrosis , Host-Pathogen Interactions , Inflammation Mediators/metabolism , Kidney/metabolism , Kidney/microbiology , Kidney/pathology , Macrophages/metabolism , Macrophages/microbiology , Mice, Inbred C57BL , Mice, Transgenic , Phenotype , Pyelonephritis/microbiology , Pyelonephritis/pathology , Testosterone/toxicity , Urinary Tract Infections/microbiology , Urinary Tract Infections/pathology , Uropathogenic Escherichia coli/pathogenicityABSTRACT
The imbalance of testosterone to estradiol ratio has been related to the development of prostate diseases. Although rat models of prostate diseases induced by endocrine-disrupting chemicals (EDCs) and/or hormone exposure are commonly used to analyze gene expression profiles in the prostate, most studies utilize a single endpoint. In this study, microarray analysis was used for gene expression profiling in rat prostate tissue after exposure to EDCs and sex hormones over multiple time points (prepubertal through adulthood). We used dorsolateral prostate tissues from Sprague-Dawley rats (male offspring) and postnatally administered estradiol benzoate (EB) on postnatal days (PNDs) 1, 3, and 5, followed by treatment with additional hormones [estradiol (E) and testosterone (T)] on PNDs 90-200, as described by Ho et al. Microarray analysis was performed for gene expression profiling in the dorsolateral prostate, and the results were validated via qRT-PCR. The genes in cytokine-cytokine receptor interaction, cell adhesion molecules, and chemokines were upregulated in the EB+T+E group on PNDs 145 and 200. Moreover, early-stage downregulation of anti-inflammatory gene: bone morphogenetic protein 7 gene was observed. These findings suggest that exposure to EB, T, and E activates multiple pathways and simultaneously downregulates anti-inflammatory genes. Interestingly, these genes are reportedly expressed in prostate cancer tissues/cell lines. Further studies are required to elucidate the mechanism, including analyses using human prostate tissues.
Subject(s)
Endocrine Disruptors/toxicity , Estradiol/analogs & derivatives , Estradiol/toxicity , Gene Expression Profiling/methods , Gene Expression , Prostate/metabolism , Puberty , Testosterone/toxicity , Transcriptome , Age Factors , Animals , Bone Morphogenetic Protein 7/genetics , Bone Morphogenetic Protein 7/metabolism , Cell Adhesion Molecules/genetics , Cell Adhesion Molecules/metabolism , Chemokines/genetics , Chemokines/metabolism , Endocrine Disruptors/adverse effects , Estradiol/adverse effects , Inflammation/genetics , Male , Microarray Analysis , Rats, Sprague-Dawley , Receptors, Cytokine/genetics , Receptors, Cytokine/metabolism , Testosterone/adverse effectsABSTRACT
BPH is a disease prevalent among elderly men that is characterized by abnormal proliferation of prostatic epithelial and stromal tissues. No effective treatment exists for BPH owing to lack of a clear understanding of its molecular etiology. Although several studies have reported therapeutic effects of baicalin against numerous diseases, including prostate cancer, its beneficial effects on BPH have not yet been explored. The present study investigated the therapeutic effects of baicalin on the development of BPH and its mechanism of action. We established a testosterone-treated BPH animal model and DHT-stimulated prostate cell lines, including RWPE-1 and WPMY-1. Administration of baicalin ameliorated the pathological prostate enlargement, suppressed the production of DHT, and inhibited the activity of 5α- reductase Type II in the animal model. BC exerted these effects via its anti-proliferative effects by restoring the Bax/Bcl-2 ratio, activating caspase-3 and caspase-8, and inducing the phosphorylation of AMPK. In vitro studies using DHT-stimulated prostate cells demonstrated an up-regulation of BPH-related and proliferation markers, whereas baicalin clearly reduced the overexpression of AR, PSA, PCNA, and Bcl-2. These results suggested that baicalin could suppress androgen-dependent development of BPH both in vivo and in vitro by inducing apoptosis.
Subject(s)
Apoptosis/drug effects , Enzyme Inhibitors/pharmacology , Flavonoids/pharmacology , Prostate-Specific Antigen/drug effects , Prostate/drug effects , Prostatic Hyperplasia/metabolism , Receptors, Androgen/drug effects , 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/drug effects , Androgens/toxicity , Animals , Cell Line , Cell Proliferation/drug effects , Dihydrotestosterone/metabolism , Dihydrotestosterone/toxicity , Disease Models, Animal , Humans , Male , Proliferating Cell Nuclear Antigen/drug effects , Prostate/metabolism , Prostate/pathology , Prostate-Specific Antigen/metabolism , Prostatic Hyperplasia/chemically induced , Prostatic Hyperplasia/pathology , Proto-Oncogene Proteins c-bcl-2/drug effects , Proto-Oncogene Proteins c-bcl-2/metabolism , Rats , Receptors, Androgen/metabolism , Testosterone/toxicityABSTRACT
Benign prostatic hyperplasia (BPH) is considered a normal part of the aging process in men, and is characterized by an imbalance between cell proliferation and apoptosis. Our study aimed to investigate the potential protective role of silymarin (SIL) against testosterone-induced BPH in rats and to elucidate the molecular mechanisms underlying SIL pro-apoptotic and anti-proliferative effects. Forty adult male Wistar rats were divided equally into four groups: control group, BPH group (3 mg/kg testosterone propionate, s.c. for 14 days, SIL group (50 mg/kg SIL, orally, once daily concomitantly with 3 mg/kg testosterone propionate s.c.) and inhibitor group (50 mg/kg SIL orally concomitantly with 3 mg/kg testosterone, s.c. and 0.5 mg/rat Z-VAD-FMK, i.p.). Silymarin induced caspase-dependent apoptosis in BPH as SIL significantly reduced prostatic Bcl-2 protein and increased Bax protein concentration. Also, SIL down-regulated survivin (Inhibitor of apoptosis protein (IAPs) gene expression in rat prostate assisting mainly caspase-dependent pathway. Silymarin significantly decreased cytochrome-c cytosolic concentration and increased caspase 3 activity compared to BPH group. Silymarin significantly increased the content of p27/kip1 (Cyclin dependent kinase inhibitor (CDKIs) promoting cell cycle arrest. The histological features of BPH such as hypertrophy, papillary projections formation, improved in SIL group. Silymarin showed a significant anti-proliferative and pro-apoptotic role in BPH and accordingly it could be effectively and safely used as a treatment tool in cases of BPH or prostatic disorders.
Subject(s)
Antioxidants/pharmacology , Apoptosis/drug effects , Prostatic Hyperplasia/pathology , Silymarin/pharmacology , Animals , Male , Prostate/drug effects , Prostate/pathology , Prostatic Hyperplasia/chemically induced , Rats , Rats, Wistar , Testosterone/toxicityABSTRACT
Benign prostatic hyperplasia (BPH) is a pathology characterised by an increase in prostate size associated with low urinary tract symptoms. Finasteride (F), a 5a-reductase inhibitor, is the standard treatment for BPH reducing prostate weight but also sexual desire. The Peruvian plant known as Red Maca (RM) (Lepidium meyenii) inhibits BPH in rats and mice. The aim of the study was to assess the inflammatory effect of RM and finasteride in rats with testosterone enanthate (TE)-induced BPH. Thirty rats were divided into 5 groups: Control, TE (50 mg/rat), TE + F (0.6 mg/kg), and two groups of TE + RM 40/80 (40 or 80 mg). After treatments, tumour necrosis factor alpha (TNFa), interleukin 4 (IL4) and interferon gamma (INFg) as well as testosterone and oestradiol were evaluated and inflammatory cells (neutrophils, mast cells and lymphocytes) in prostate were quantified. Red Maca and finasteride treatments decreased inflammatory cells counts in prostate, inhibiting TNFa by different pathways. Finasteride increased IL4 whereas Red Maca increased INFg. In conclusion, data suggest that finasteride acts on Th2 response by increasing IL4 in prostate, while Red Maca acts on Th1 response mediated by INFg.
Subject(s)
Lepidium/chemistry , Plant Extracts/pharmacology , Prostate/drug effects , Prostatic Hyperplasia/drug therapy , Signal Transduction/drug effects , 5-alpha Reductase Inhibitors/pharmacology , 5-alpha Reductase Inhibitors/therapeutic use , Animals , Disease Models, Animal , Finasteride/pharmacology , Finasteride/therapeutic use , Humans , Interferon-gamma/metabolism , Interleukin-4/metabolism , Male , Plant Extracts/therapeutic use , Prostate/cytology , Prostate/immunology , Prostate/pathology , Prostatic Hyperplasia/chemically induced , Prostatic Hyperplasia/immunology , Prostatic Hyperplasia/pathology , Rats , Signal Transduction/immunology , Testosterone/analogs & derivatives , Testosterone/toxicity , Th1 Cells/drug effects , Th1 Cells/immunology , Th1 Cells/metabolism , Th2 Cells/drug effects , Th2 Cells/immunology , Th2 Cells/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND: Prostatic hyperplasia (PH) is one of the most important disorders in intact dogs. In this study, we aimed to induce PH experimentally using the combination of testosterone and estrogen and evaluate important factors associated with this disease. RESULTS: The results showed that in the induction group, prostate volume and prostate specific antigen (PSA) concentration increased significantly on day 21 onwards compared to those of the control group. Canine prostatic specific esterase (CPSE) and dihydrotestosterone (DHT) concentrations increased significantly on day 42 onwards while the testosterone levels increased on day 63. In addition, prostatic acid phosphatase (PAP) concentration did not change significantly in the control and induction groups. Biochemistry profiles and hematologic factors were measured for monitoring the function of liver and kidney, and there were no adverse effects following the induction of PH. CONCLUSIONS: It seems that testosterone and estrogen administration led to prostatic hyperplasia during 2 months. Investigating the size of the prostate, accompanied by prostate markers including CPSE, PSA, DHT, and testosterone, is helpful for the PH diagnosis. However, further studies should be carried out on PAP.
Subject(s)
Dog Diseases/chemically induced , Estrogens/toxicity , Prostate-Specific Antigen/blood , Prostatic Hyperplasia/veterinary , Testosterone/toxicity , Animals , Biomarkers/blood , Dihydrotestosterone/blood , Dog Diseases/blood , Dogs , Esterases/blood , Male , Prostatic Hyperplasia/blood , Prostatic Hyperplasia/chemically inducedABSTRACT
The effect of Rhodiola sachalinensis Boriss extract irradiated with 50 kGy gamma rays (HKC) on benign prostatic hyperplasia (BPH) was investigated. Seven-week-old male SD rats received a subcutaneous injection of 20 mg/kg of testosterone propionate (TP) to induce BPH. Then, the testosterone only group received testosterone, the testosterone + finasteride group received testosterone and finasteride (5 mg/kg), the testosterone + HKC group received testosterone and HKC extract (500 mg/kg). Prostate weight and the dihydrotestosterone (DHT) levels in serum or prostate tissue were determined. The mRNA expressions of 5-alpha reductase (AR) in prostate tissue were also measured. Compared to the control group, prostate weight was significantly improved in the TP group and decreased in the HKC and finasteride-treated groups. Furthermore, the mRNA expression of 5-AR in the prostate was significantly reduced in the HKC and finasteride-treated groups. Similarly, the expression levels of α-smooth muscle actin (α-SMA) and cytokeratin, which are associated with prostatic enlargement in the HKC and finasteride groups, were much lower than in the TP group. HKC treatment showed similar efficacy to finasteride treatment on rats with testosterone-induced BPH. HKC may be explored as a potential new drug for BPH treatment.
Subject(s)
Cholestenone 5 alpha-Reductase/metabolism , Gamma Rays , Plant Extracts/chemistry , Plant Extracts/therapeutic use , Prostatic Hyperplasia/drug therapy , Rhodiola/chemistry , Testosterone/metabolism , Testosterone/toxicity , Animals , Cholestenone 5 alpha-Reductase/genetics , Male , Prostatic Hyperplasia/blood , Rats , Rats, Sprague-Dawley , Testosterone/bloodABSTRACT
The preventive effects of purple rice crude ethanolic extract (PRE) were firstly investigated on testosterone-induced benign prostatic hyperplasia (BPH) in castrated rats. As compared to vehicle-treated rats, lower prostate weights were found in the BPH rats that received PRE 1 g/kg bw. In addition, the PRE treatment down-regulated the androgen receptor (AR) expression in the dorsolateral prostate of those rats. In human prostate cancer cell line, LNCaP, PRE could reduce the cell growth, down-regulate the expression of AR and suppress prostate-specific antigen (PSA) secretion. Moreover, PRE also inhibited an activity of 5α-reductase from rat liver microsomes and the mutagenicity of Salmonella Typhimurium induced by standard mutagen. These results demonstrate that PRE altered testosterone-induced BPH in rats and retarded prostate cancer cell growth by modulating AR expression. It is therefore recommended that further investigation is undertaken into the chemopreventive potential of PRE in androgen-AR mediated diseases. PRACTICAL APPLICATIONS: This study revealed the mechanisms of purple rice extract on testosterone-induced rat benign prostatic hyperplasia. Such information, purple rice components show promise as an effective chemopreventive agent for prostatic hyperplasia prevention by alternating the influence of testosterone through its receptor. Thus, purple rice might be developed as food supplement for reduction of prostatic hyperplasia or cancer in elder men.
Subject(s)
Androgen Receptor Antagonists/pharmacology , Oryza/chemistry , Plant Extracts/pharmacology , Prostatic Hyperplasia/chemically induced , Prostatic Neoplasms/drug therapy , Receptors, Androgen/metabolism , Testosterone/toxicity , Androgen Receptor Antagonists/chemistry , Animals , Cholestenone 5 alpha-Reductase/metabolism , Dose-Response Relationship, Drug , Humans , Male , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Plant Extracts/chemistry , Prostatic Hyperplasia/drug therapy , Rats, WistarABSTRACT
BACKGROUND: Finding a medical treatment which can combat cell proliferation and relax smooth muscles in canine benign prostatic hyperplasia (BPH) appears to be imperative. AIMS: This study aimed to evaluate the oxidative stress and inflammatory proteins following the treatment of dogs induced for BPH with an anti-proliferative agent called tadalafil. MATERIALS AND METHODS: Twenty-five adult intact male dogs were randomly designated into five groups (n = 5): Control group was not induced for BPH and not treated with tadalafil; dogs induced for BPH by testosterone enanthate and estradiol benzoate and treated with tadalafil (5 mg/day P.O.); dogs which received tadalafil (5 mg/day P.O.); dogs induced for BPH and treated with castration; and dogs induced for BPH. Oxidative stress factors (glutathione peroxidase [GPX], superoxide dismutase [SOD], catalase) and inflammatory proteins (haptoglobin, serum amyloid A [SAA], malondialdehyde [MDA]) were measured in the blood serum for four sequential weeks. RESULTS: Glutathione peroxidase and SOD serum levels declined in dogs in the BPH-induced group compared to those in the control group. Those levels diminished in BPH-induced castrated and tadalafil-treated groups. The changes in the GPX and SOD serum concentrations were not significant between the BPH-induced castrated group and BPH-induced tadalafil-treated group. Moreover, MDA concentration increased slightly in groups with BPH and groups which were castrated. Generally, however, there were no significant differences in the MDA serum concentrations between other groups. Haptoglobin and SAA concentrations increased in BPH-castrated group. Also, the differences in haptoglobin and SAA were not significant between the groups. CONCLUSION: Tadalafil could not control oxidative stress and inflammatory mediators which happened during BPH in dogs.
Subject(s)
Dog Diseases/chemically induced , Inflammation/metabolism , Oxidative Stress/drug effects , Prostatic Hyperplasia/veterinary , Tadalafil/therapeutic use , Androgens/administration & dosage , Androgens/toxicity , Animals , Contraceptive Agents, Hormonal/administration & dosage , Contraceptive Agents, Hormonal/toxicity , Dog Diseases/drug therapy , Dogs , Estradiol/administration & dosage , Estradiol/analogs & derivatives , Estradiol/toxicity , Gene Expression Regulation/drug effects , Inflammation/drug therapy , Male , Phosphodiesterase 5 Inhibitors/therapeutic use , Testosterone/administration & dosage , Testosterone/analogs & derivatives , Testosterone/toxicityABSTRACT
BACKGROUND: Annona muricata is used in traditional African medicine to manage urinary obstruction. In this study, we hypothesized that hexane fraction of Annona muricata (HFAM) seeds will ameliorate testosterone propionate (Tp)-induced benign prostatic hyperplasia (BPh). METHODS: Castrated rats were assigned into six groups: non-castrated control, castrated control, castrated rats that received Tp (BPh group), [BPh+HFAM], [BPh+HFAM + finasteride], [BPh + finasteride]. RESULTS: The BPh rats had 3.8 and 3.9 folds increases in prostatic and organo-somatic weight, while treatment with HFAM alone and [HFAM + finasteride] decreased prostatic weight by 22% and 34%, respectively. BPh increased the activities of serum and prostatic total acid phosphatase by 95% and 121%; and activities of serum and prostatic alkaline phosphatase by 54% and 281%, respectively. Serum and prostatic lipid peroxidation were increased by 44% and 82%, respectively, in BPh rats with a concomitant decrease in prostatic superoxide dismutase by 73%. In BPh rats, serum and prostatic myeloperoxidase increased by 4.0 and 2.0 folds, while serum nitric oxide increased by 2.4 folds, respectively. Strong expression of inducible nitric oxide synthase, Bcl2, beta-catenin, androgen and estrogen receptors were observed in BPh rats. Importantly, treatment with HFAM or finasteride (or combination) attenuated prostatic weight, inflammatory and antioxidant indices in BPh rats. CONCLUSION: HFAM may serve as novel therapeutic agent against BPh.