Resveratrol used as nanotherapeutic: a promising additional therapeutic tool against hormone-sensitive, hormone-insensitive and resistant prostate cancer.

Prostate cancer is one of the most common cancers in men. Despite the development of diverse therapeutic agents for different types and stages, the progression or spread of the disease is inevitable. Another problem is the development of resistance of cancer cells to available therapeutics. Therefore, additional medicaments are urgently needed. Resveratrol is a polyphenolic phytoalexin found in numerous plants and fruits like red grapes or blueberries. Resveratrol possesses antiproliferative, anti-angiogenic and anticancer activities well proven in different types of cancer including prostate cancer. To date, it is not used clinically due to poor solubility, low bioavailability, and other limiting factors. In order to overcome these limitations, novel nanoparticle-based formulations were developed over the past years. In this review article, studies about the effect of resveratrol on prostate cancer cells are discussed focusing especially on those studies using nanotechnology. An electronic literature research was performed utilizing PubMed in August 2022. Scientific publications, which examine resveratrol using nanotechnology, are discussed. The studies clearly indicate that resveratrol-loaded nanoparticles exhibited a remarkable anti-cancer activity in various hormone-sensitive and hormone-insensitive prostate cancer cell lines including docetaxel-resistant prostate-cancer cells. The types of nanoparticles that were used varied and influenced the outcome. Additionally, the meaning of the surface functionality of the nanoparticles is emphasized. No reduction of the anti-proliferative activity of resveratrol was shown when used encapsulated. Additionally, synergistic effects of resveratrol and docetaxel were proven. Resveratrol-loaded nanoparticles, especially when combined, may represent the next generation of anticancer substances. However, further in vivo/clinical studies are necessary to confirm their clinical effectiveness.

Bee Venom Components as Therapeutic Tools against Prostate Cancer.

Prostate cancer is one of the most common cancers in men. Despite the development of a variety of therapeutic agents to treat either metastatic hormone-sensitive prostate cancer, advanced prostate cancer, or nonmetastatic/metastatic castration-resistant prostate cancer, the progression or spread of the disease often cannot be avoided. Additionally, the development of resistance of prostate cancer cells to available therapeutic agents is a well-known problem. Despite extensive and cost-intensive research over decades, curative therapy for metastatic prostate cancer is still not available. Therefore, additional therapeutic agents are still needed. The animal kingdom offers a valuable source of natural substances used for the treatment of a variety of diseases. Bee venom of the honeybee is a mixture of many components. It contains proteins acting as enzymes such as phospholipase A2, smaller proteins and peptides such as melittin and apamin, phospholipids, and physiologically active amines such as histamine, dopamine, and noradrenaline. Melittin has been shown to induce apoptosis in different cancer cell lines, including prostate cancer cell lines. It also influences cell proliferation, angiogenesis, and necrosis as well as motility, migration, metastasis, and invasion of tumour cells. Hence, it represents an interesting anticancer agent. In this review article, studies about the effect of bee venom components on prostate cancer cells are discussed. An electronic literature research was performed utilising PubMed in February 2021. All scientific publications, which examine this interesting subject, are discussed. Furthermore, the different types of application of these promising substances are outlined. The studies clearly indicate that bee venom or melittin exhibited anticancer effects in various prostate cancer cell lines and in xenografts. In most of the studies, a combination of bee venom or the modified melittin with another molecule was utilised in order to avoid side effects and, additionally, to target selectively the prostate cancer cells or the surrounding tissue. The studies showed that systemic side effects and unwanted damage to healthy tissue and organs could be minimised when the anticancer drug was not activated until binding to the cancer cells or the surrounding tissue. Different targets were used, such as the matrix metalloproteinase 2, hormone receptors expressed by prostate cancer cells, the extracellular domain of PSMA, and the fibroblast activation protein occurring in the stroma of prostate cancer cells. Another approach used loaded phosphate micelles, which were cleaved by the enzyme secretory phospholipase A2 produced by prostate cancer cells. In a totally different approach, targeted nanoparticles containing the melittin gene were used for prostate cancer gene therapy. By the targeted nonviral gene delivery, the gene encoding melittin was delivered to the prostate cancer cells without systemic side effects. This review of the scientific literature reveals totally different approaches using bee venom, melittin, modified melittin, or protoxin as anticancer agents. The toxic agents acted through several different mechanisms to produce their anti-prostate cancer effects. These mechanisms are not fully understood yet and more experimental studies are necessary to reveal the complete mode of action. Nevertheless, the researchers have conducted pioneering work. Based on these results, further experimental and clinical studies about melittin and modifications of this interesting agent deriving from nature are necessary and could possibly lead to a complementary treatment option for prostate cancer.

Botulinum toxin therapy in children with neurogenic detrusor overactivity.

Special birth defects and neurological diseases can cause neurogenic detrusor overactivity (NDO). First-line pharmacotherapy is the antimuscarinic therapy, which can be limited by side effects or non-effectiveness. Therefore, pharmacological treatment of NDO in children includes off-label use of intravesical injections of botulinum toxin type A (BTA). In this review article, various clinical studies in which BTA was used for the treatment of NDO of different etiologies in children are discussed, including studies about children with acquired NDO. An electronic literature search was performed using PubMed, and studies published prior to March 2019 are reported. BTA injections are a clinically and urodynamically effective and safe treatment for NDO in children. The treatment is also important in protecting the upper urinary tract from damage and improving concomitant bowel dysfunctions. Fibrotic, acontractile bladders with poor bladder compliance and/or a very small initial bladder capacity and/or the presence of an open bladder neck all contributed to poor responses. A combined injection into the detrusor and external urethral sphincter may improve the clinical outcome in the detrusor-sphincter dyssynergia. New application methods are promising, such as the electromotive drug administration, to avoid general anesthesia. Furthermore, the minimal clinically effective dosage, inclusion criteria, and prognostic factors remain to be established.

Is testosterone important in LUT function in men and women? ICI-RS 2015.

AIM: This review article is a collaborative report based upon the Authors' presentations and Group discussion on the role of testosterone (T) in the male and female lower urinary tract (LUT) which took place at the 6th International Consultation on Incontinence Research Society's (ICI-RS) annual meeting, in Bristol, UK (September 8-10, 2015). METHODS: It comprises overviews and opinions on both the current state of knowledge of the role of T in LUT function and dysfunction in both sexes. RESULTS: Results from animal studies suggest that T treatment may be beneficial for disorders of the LUT in women including urinary incontinence and pelvic organ prolapse. The need for clinical studies to evaluate the effect of T treatment in peri- and post-menopausal women, taking into account the type of applied androgen, the application form, timing and dosage, is especially emphasized. In males, findings on the impact of T on the male external urethral sphincter underscores that there is still much to learn about its role in male LUT physiology. The important topic of the use of T therapy in the treatment of enuresis in the young, both sexes, is also discussed. The importance of understanding the steroidogenic pathways linking T with estradiol is discussed as being of paramount importance in researching the unique actions of T in the LUT. CONCLUSION: The overall conclusion is that further research into the role of T in LUT function and dysfunction across genders and age groups (young to old) is extremely important. Neurourol. Urodynam. 36:859-862, 2017. © 2017 Wiley Periodicals, Inc.

Psychological and Physical Environmental Factors in the Development of Incontinence in Adults and Children: A Comprehensive Review.

The aim of this review was to identify etiological environmental factors related to incontinence in children and adults. A variety of etiological environmental factors for the development of incontinence were identified. In children, these encompass stressful life events and trauma, family dysfunction, parental psychopathology, school-related stressors, toilet or "potty" training, fluid consumption habits, housing conditions, and the availability of toilets. In adults, physical exercise, obesity, working conditions, fluid intake, and the availability of toilets play a role. Intervening variables such as hormonal variations due to work shifts have also been identified as influencing the likelihood of incontinence. Current research suggests that environmental factors influence the development of incontinence in children and adults. The interactions between biological factors, the immediate environment, and intervening variables need to be explored in greater detail. Practical solutions to reduce barriers to adequate fluid intake and healthy toileting habits should be implemented in school and work settings.

Joseph-Frédéric-Benoît Charrière - How to Explain His Success as One of the Most Famous Surgical Instrument Makers Regarding His Life from Childhood to Death.

INTRODUCTION: We use the name 'Charrière' every day as a unit of measurement. This article explains his success as one of the most famous instrument makers who ever lived. MATERIALS AND METHODS: A review of the literature was completed using PubMed. Additionally, material of historical sources like the museum of Bulle was used. RESULTS: Joseph-Frédéric-Benoît Charrière was born in Switzerland in 1803. At the age of 13, he moved to Paris and learned the profession of a cutler. In 1820, he took over the workshop of his teacher Vincent. Dupuytren was one of the most important people in Charrière's professional life. Charrière specialized in the fabrication of surgical instruments of such high quality that he was very sought after by famous surgeons. In 1837, Charrière went to Sheffield, England, to learn more about working with metals and alloys. In 1851, he was inducted into the Legion of Honour. Charrière died in 1876 in Paris. CONCLUSIONS: The patronage of Dupuytren was a very important supporting factor in Charrière's professional life, but mainly his great courage, the willingness to learn from others, his creativity and technical fantasy and his curiosity and broad interest in a lot of different fields explain his unmatched professional success.

Do we manage incontinence in children and adults with special needs adequately? ICI-RS 2014.

AIMS: To review studies on the associations of incontinence and special needs in children and adults and to outline future directions in research and clinical care. MATERIALS AND METHODS: A review of literature was conducted. Open questions and future directions were discussed during the ICI-RS meeting in 2014. RESULTS: Special needs comprise a wide variety of conditions and disabilities. Individuals with special needs carry a greater risk for all types of incontinence. There is a high tendency for incontinence to persist from childhood into adulthood. Many people do not receive adequate medical care for their incontinence. CONCLUSIONS: More detailed research is needed, especially in the adult population with special needs. Assessment and treatment of incontinence should be offered routinely to all those with special needs.

Inhibitory effects of the ATP-sensitive potassium channel openers cromakalim, pinacidil and minoxidil on the carbachol-response curve in porcine detrusor muscle.

AIMS: ATP-sensitive potassium channels represent promising drug targets for treating specific bladder diseases. The inhibitory effects of ATP-selective potassium channel openers (PCOs) on the carbachol-response curve in porcine detrusor muscle were examined. MATERIALS AND METHODS: Each of the three substances used in the study represent one prototype of a different class of PCO: cromakalim belongs to the benzopyran series, pinacidil is a cyanoguanidine derivative, and minoxidil represents a pyrimidine derivative. The porcine detrusor muscle represents one of the best models for human detrusor. Experiments were conducted on muscle strips of porcine detrusor muscle suspended in a tissue bath. Concentration-response curves of carbachol were constructed after pretreatment with cromakalim at 10(-7), 10(-6) and 10(-5) M, and with pinacidil and minoxidil at 10(-6), 10(-5.5) and 10(-5) M, respectively. Each muscle strip was only used to examine one concentration of one substance. RESULTS: Cromakalim had the greatest inhibitory effect, significantly suppressing the carbachol-response curve at 10(-6) and 10(-5) M. Pinacidil showed a significant inhibitory effect at 10(-5.5) and 10(-5) M, which was smaller than that of cromakalim. Minoxidil did not significantly inhibit the contractions at all examined concentrations. CONCLUSIONS: The examined ATP-sensitive PCOs belonging to the benzopyrans and cyanoguanidines significantly suppressed detrusor contractions. The development of derivatives of these prototypes could open new possibilities for the pharmacological treatment of selected bladder diseases.

In vitro effects of the cyclooxygenase inhibitor indomethacin and of the phospholipase-C inhibitor U-73122 on carbachol-induced contractions of porcine detrusor muscle.

Prostaglandin synthetase inhibitors belong to one substance class additionally used in the treatment of bladder dysfunctions associated with involuntary bladder contractions. However, the mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs) on the detrusor muscle is not clear. In this study, it was examined in vitro whether the NSAID indomethacin exhibited an inhibitory effect on carbachol-induced contractions of the porcine detrusor muscle. Additionally, the inhibitory effect of the phospholipase-C inhibitor U-73122 on carbachol-induced contractions of the porcine detrusor muscle was investigated. Experiments were performed on the muscle strips of the porcine detrusor muscle suspended in a tissue bath. Effects of indomethacin at 10(-6) and 10(-5) M on the maximum carbachol-induced contraction and on the carbachol-response curve were investigated. Additionally, the inhibitory influence of U-73122 at a concentration of 10(-5.5) M on the carbachol-response curve was investigated. Pretreatment with indomethacin at both concentrations did not result in a significant reduction in the maximum contraction compared with the control. In the experiments in which carbachol concentration-response curves were generated, indomethacin exhibited at both concentrations a very small but significant change at carbachol concentrations of 10(-8) and 10(-7.5) M. In the experiments with U-73122, a significant change was found in the concentration-response curve of carbachol at all concentrations of carbachol from 10(-6.5) to 10(-4) M. The mean maximum carbachol-induced contraction was 141.8 +/- 6.8% after incubation with U-73122 and 166.0 +/- 6.4% in the control group (P < 0.05). Indomethacin did not inhibit the carbachol-induced contractions of the porcine detrusor muscle. The cyclooxygenase does not play a significant role in the carbachol-induced bladder contraction of the porcine detrusor muscle. The inhibitory action of the phospholipase-C inhibitor U-73122 on the carbachol-induced contraction was significant, but small. The results point to an inferior role of this pathway.

Inhibitory effects of different ATP-sensitive potassium channel openers on electrically generated and carbachol-induced contractions of porcine and human detrusor muscle.

The inhibitory effects of different potassium channel openers (PCOs) on electrically generated and carbachol-induced contractions of porcine and human detrusor muscle were examined. PCOs could be an interesting substance class for treatment of detrusor overactivity. Experiments were performed on muscle strips suspended in a tissue bath. Human tissue originated from patients who underwent total cystectomy. The concentration-relaxation curves of the first-generation PCOs cromakalim and pinacidil and the untypical PCO minoxidil were performed using carbachol-precontracted detrusor muscle strips of pigs and humans. Additionally, the inhibitory effects of cromakalim, pinacidil and minoxidil on electrically generated contractions of porcine detrusor muscle were examined. Furthermore, the inhibitory effect of the second-generation, bladder-selective PCO ZM 226600 on electrically generated contractions of the human detrusor muscle was determined. Frequency-response curves were performed before and after incubation with one PCO used in two different concentrations. In humans, cromakalim and pinacidil led to a maximum decrease of 73.5 and 68.4% and showed mean pD2 values of 6.65 and 5.5, respectively. In pigs, cromakalim and pinacidil led to a maximum decrease of 90.6 and 93.6% and showed mean pD2 values of 6.39 and 5.01, respectively. Minoxidil did not significantly decrease the precontraction at the highest used concentration in both species. Cromakalim exhibited the biggest inhibitory effect being significant at 10(-5) and 10(-6) M. Pinacidil showed only a significant inhibitory effect at 10(-5) M which was smaller than that of cromakalim. At 3 x 10(-6) M only a very small effect occurred at 1 Hz. Minoxidil did not inhibit the contractions at both examined concentrations except for a very small effect at 1 Hz. In humans, ZM 226600 exhibited at 10(-6) and 10(-5) M a significant inhibitory effect. At 10(-7) M it was only significant at one frequency.

Relaxation of human detrusor muscle by selective beta-2 and beta-3 agonists and endogenous catecholamines.

OBJECTIVES: The goal of this study was to identify potent relaxant agents of the human detrusor muscle. Therefore, the relaxant effects of different selective beta (beta)-adrenoceptor agonists were examined. Also, the relaxant effects of the endogenous catecholamines were investigated to functionally characterize the beta-adrenoceptor subtype mainly responsible for adrenergic-mediated relaxation in the detrusor muscle of humans. METHODS: Experiments were performed on muscle strips of human detrusor suspended in a tissue bath. The tissue originated from patients who had undergone total cystectomy. The selective beta3-agonists BRL 37344, ZD 7114, and CGP 12177, the selective beta2-agonists terbutaline and clenbuterol, and the nonselective beta-agonist isoprenaline were investigated. Concentration-relaxation curves of the catecholamines were performed to determine the rank order of potency. RESULTS: The maximal relaxation induced by BRL 37344, ZD 7114, and CGP 12177 was 36%, 39%, and 37%, respectively. The corresponding pD2 values were 6.73, 4.82, and 6.09, respectively. Terbutaline and clenbuterol induced a maximal relaxation of 48% and 27%, and their pD2 value was 4.97 and 5.34, respectively. Isoprenaline, adrenaline, and noradrenaline induced a maximal relaxation of 72%, 58%, and 79%, respectively. The corresponding pD2 values were 6.18, 6.16, and 6.09, respectively. Because their differences were not significant, no rank order of potency was determined. CONCLUSIONS: Beta-adrenergic agonists are potent relaxant agents of the human detrusor muscle in vitro. Both beta2 and beta3-adrenoceptors contribute to adrenergic-mediated relaxation. Our results point to a slightly greater role for the beta3-receptor in human detrusor muscle.

Correlation between motor function and lower urinary tract dysfunction in patients with infantile cerebral palsy.

AIMS: The aim of this study was to evaluate urodynamic findings in patients with infantile cerebral palsy (CP) and to correlate the findings with impaired motor function. METHODS: We conducted a videourodynamic investigation on a highly select group of 29 patients (3-53 years). Motor function was assessed in each patient by the Gross Motor Function Classification System for CP (GMFCS). With this system, motor function is divided into five levels: patients in Level I have the most independent motor function and patients in Level V the least. The patients were divided into Group 1 (23 symptomatic patients with recurrent urinary tract infection or urinary incontinence) and Group 2 (6 asymptomatic patients). RESULTS: In Group 1, 21 patients (91%) had reduced compliance (0.6-16.4 ml/cmH(2)O) and 16 patients (70%) had increased DLPP (>40 cmH(2)O). Detrusor overactivity and pelvic floor overactivity were found in all 23 patients. In Group 2, two patients (33%) had reduced compliance (0.7 and 5.8 ml/cmH(2)O) and four (67%) had increased DLPP (>40 cm H(2)O). Detrusor overactivity and pelvic floor overactivity were observed in five patients (83%). Symptomatic patients showed higher GMFCS levels than asymptomatic patients. In the group of asymptomatic patients, there was no one classified as Levels IV or V, while there were no symptomatic patients classified as Level I. CONCLUSIONS: We conclude that urinary symptoms and pathological urodynamic findings increase along with the degree of motor function impairment shown by the GMFCS. Pathologic urodynamic findings can be found in both symptomatic and in asymptomatic patients.

Inhibitory effects of L- and T-type calcium antagonists on contractions of human detrusor muscle.

The inhibitory and relaxant effects of the L-type calcium antagonists nifedipine, nimodipine, verapamil and diltiazem, and of the T-type calcium antagonist mibefradil, on contractions of isolated human detrusor muscle were investigated. The tissue was obtained from 10 patients undergoing cystectomy due to bladder cancer. Effects of the calcium antagonists at different concentrations on the concentration-response curves for carbachol were investigated. Furthermore, concentration-relaxation curves were performed using potassium-precontracted muscle strips. All L-type calcium antagonists suppressed the mean concentration-response curve of carbachol significantly at a concentration of 10(-6) M. Mibefradil up to 10(-5) M did not significantly suppress it. Nifedipine significantly reduced the carbachol-induced maximum contraction to 75% and 44%, verapamil to 75% and 67% of the appropriate control value at concentrations of 10(-7) and 10(-6) M, respectively. Diltiazem reduced it insignificantly to 96% and 71% at the above-mentioned concentrations. The concentration-relaxation experiments revealed following pD2-values and maximum relaxations of nifedipine, nimodipine, verapamil and diltiazem, respectively: 6.23, 6.37, 5.66, 5.81 and 85%, 83%, 82%, 90%. Maximum relaxations and pD2-values were not significantly different from each other. The lowest concentration, for which a significant effect compared to control in Student;s t-test was found, amounted to 10(-10) M, 10(-9) M, 10(-7) M, 10(-6.5) M and 10(-4) M for nimodipine, nifedipine, diltiazem, verapamil and mibefradil, respectively. L-type calcium antagonists are very potent relaxant agents of the human detrusor muscle in vitro.

Inhibitory effects of various L-type and T-type calcium antagonists on electrically generated, potassium-induced and carbachol-induced contractions of porcine detrusor muscle.

The inhibitory effects of different calcium antagonists on contractions of isolated porcine detrusor muscle were investigated. Suppression of the maximum potassium-induced contraction and electrically generated contractions by nifedipine, verapamil and diltiazem were investigated. Furthermore, concentration-response curves of carbachol after pretreatment with the L-type antagonists nifedipine, verapamil, diltiazem, nimodipine and the T-type antagonist mibefradil at different concentrations were performed. Nifedipine significantly reduced the potassium-induced maximum contraction to 89, 60, 21, 8 and 4% (10(-9)-10(-5) M). Verapamil and diltiazem significantly reduced it to 64, 30 and 5% (10(-7)-10(-5) M) or 79, 27, 7 and 1% (10(-7)-10(-4) M), respectively. Nifedipine, verapamil and diltiazem significantly reduced the electrically generated contraction to 55, 36, 34 and 25% (10(-7)-10(-4) M), 71, 32 and 2% (10(-6)-10(-4) M), 96, 78, 38 and 5% (10(-7)-10(-4) M), respectively. pD2 values of nifedipine, verapamil and diltiazem amounted to 7.07, 5.56 and 5.40 and differed significantly. After pretreatment with nifedipine at 10(-6) M, the concentration-response curve of carbachol was nearly suppressed. The effects of nimodipine, verapamil and diltiazem were smaller. Mibefradil caused only at 10(-5) M a significant reduction. All investigated L-type calcium antagonists were strong inhibitors of the examined contractions. Nifedipine showed the biggest inhibitory effect.

Intraluminal tumour thrombus of a mixed non-seminomatous germ cell tumour of testis within the inferior vena cava.

BACKGROUND: Intracaval tumour thrombus developed per continuitatem from a primary testicular tumour is rare. CASE REPORT: A patient with metastatic mixed non-seminomatous germ cell tumour of the testis extending into the inferior vena cava (IVC) is presented. He belonged to the intermediate-risk group according to the IGCCCG (International Germ Cell Cancer Collaborative Group) classification. The 26-year-old man underwent right inguinal orchiectomy. Computed tomography revealed the tumour thrombus as filling defect in the IVC extending nearly to the right renal vein. Duplex sonography detected a partial thrombosis of the IVC. Combination chemotherapy led to regression of pulmonal metastases and the intraluminal tumour thrombus. 5 months later, retroperitoneal lymphadenectomy was performed and the intraluminal thrombus was extracted by cavotomy. The thrombus originated from the ostium of the right testicularis vein in the IVC. Histological examination revealed no vital tumour tissue. CONCLUSION: In patients with testicular cancer information about pathological processes of the IVC is important for therapeutic management. Testicular tumours seldom extend up the IVC.