The Impact of SOD3 on Prostatic Diseases: Elevated SOD3 Serves as a Novel Biomarker for the Diagnosis of Chronic Nonbacterial Prostatitis

BACKGROUND: Prostate is the most common gland for the three major diseases in male, such as chronic nonbacterial prostatitis (CNP), benign prostatic hyperplasia (BPH) and prostate cancer (PCa). However, there is lack of ideal biomarker for diagnosis with prostatic diseases, especially CNP. METHODS AND RESULTS: Extracellular superoxide dismutase (SOD3) levels in serum or expressed prostatic secretion (EPS) with CNP, and in the prostate tissues of rat CNP modules, BPH, and PCa was quantified, which showed that SOD3 was significantly increased in CNP and BPH, but decreased in PCa compared to controls. Receiver operating characteristic curve (ROC) analysis suggested that SOD3 was an efficient diagnosis biomarker discriminating CNP versus normal controls (accuracy= 0.831, 95%CI: 0.726-0.937, P＜0.001), CNP III versus CNP IV (accuracy=0.868, 95%CI: 0.716-0.940, P＜0.001). SOD3 were associated with the clinical characteristics of patients with CNP including pelvic pain, blood pressure, and lecithin/leukocyte in EPS. Multiple bioinformatic analysis showed that SOD3 mainly participated in superoxide radicals degradation, apoptotic execution phase, and mesenchymal-to-epithelial transition, etc. Furthermore, the structural features of SOD3 and the interacting proteins were evaluated by molecular docking, and hotspot analysis indicated that better affinities between SOD3 and its interacting molecules were associated with the presence of Arginine (Arg) in the binding site. CONCLUSIONS: According to the results, it can be concluded that SOD3 plays an important role in prostatic diseases, and it may potentially serve as an ideal diagnostic biomarker for CNP.

Ipertrofan Revisited—The Proposal of the Complete Stereochemistry of Mepartricin A and B

Being a methyl ester of partricin, the mepartricin complex is the active substance of a drug called Ipertrofan (Tricandil), which was proven to be useful in treatment of benign prostatic hyperplasia and chronic nonbacterial prostatitis/chronic pelvic pain syndrome. Nevertheless, no direct structural evidence on the stereochemistry of its components has been presented to date. In this contribution, we have conducted detailed, NMR-driven stereochemical studies on mepartricins A and B, aided by molecular dynamics simulations. The absolute configuration of all the stereogenic centers of mepartricin A and B was defined as 3R, 7R, 9R, 11S, 13S, 15R, 17S, 18R, 19S, 21R, 36S, 37R, and 38S, and proposed as 41R. The geometry of the heptaenic chromophore of both compounds has been established as 22E, 24E, 26E, 28Z, 30Z, 32E, and 34E. Our studies on mepartricin ultimately proved that partricins A and B are structurally identical to the previously described main components of the aureofacin complex: gedamycin and vacidin, respectively. The knowledge of the stereochemistry of this drug is a fundamental matter not only in terms of studies on its molecular mode of action, but also for potential derivatization, aiming at improvement of its pharmacological properties.

Dihydroartemisinin Ameliorates Chronic Nonbacterial Prostatitis and Epithelial Cellular Inflammation by Blocking the E2F7/HIF1α Pathway

Objective: Chronic nonbacterial prostatitis (CNP) has remained one of the most prevalent urological diseases, particularly in older men. Dihydroartemisinin (DHA) has been identified as a semi-synthetic derivative of artemisinin that exhibits broad protective effects. However, the role of DHA in inhibiting CNP inflammation and prostatic epithelial cell proliferation remains largely unknown. Materials and Methods: CNP mice model was induced by carrageenan and Haemotoxylin Eosin (HE) ,immunofluorescence and immunochemistry staining were used to confirm CNP and E2F7 expression. Human prostatic epithelial cells (HPECs) and RWPE-1 was induced by lipopolysaccharide (LPS) to mimic CNP model in vitro. Real-time quantitative PCR and Western blot were used to detect proliferation and inflammatory genes expression. Cell proliferation was determined using MTT assay.Results: DHA significantly alleviated the rough epithelium and inhibited multilamellar cell formation in the prostatic gland cavity and prostatic index induced by carrageenan. In addition, DHA decreased the expression of TNF-α and IL-6 inflammatory factors in prostatitis tissues and in LPS-induced epithelial cells. Upregulation of transcription factor E2F7, which expression was inhibited by DHA, was found in CNP tissues, human BPH tissues and LPS-induced epithelial cells inflammatory response. Mechanically, we found that depletion of E2F7 by shRNA inhibited epithelial cell proliferation and LPS-induced inflammation while DHA further enhance these effects. Furthermore, HIF1α was transcriptional regulated by E2F7 and involved in E2F7-inhibited CNP and cellular inflammatory response. Interestingly, we found that inhibition of HIF1α blocks E2F7-induced cell inflammatory response but does not obstruct E2F7-promoted cell growth.Conclusion: The results revealed that DHA inhibits the CNP and inflammation by blocking the E2F7/HIF1α pathway. Our findings provide new evidence for the mechanism of DHA and its key role in CNP, which may provide an alternative solution for the prevention and treatment of CNP.

Evaluation of Effectiveness of Immunomodulatory Therapy in Combined Treatment of Patients with Chronic Nonbacterial Prostatitis

Among men of working age, chronic prostatitis is the most common urological disease, and its inherent symptoms are a common reason for seeking urological care. To date, there is no single universal successful therapy for chronic prostatitis. Therefore, it justifies the further search for new methods of treatment of patients with this pathology. The objective: the aim of the study was to evaluate the effectiveness of immunomodulatory therapy in treatment of patients with chronic nonbacterial prostatitis with inflammatory chronic pelvic pain syndrome (CP/CPPS (NIH IIIA)). Materials and methods. Under observation there were 78 patients with chronic nonbacterial prostatitis, with inflammatory chronic pelvic pain syndrome (NIH IIIA), with a disease duration of more than 2 years and low effectiveness of treatment on the background of standard therapy. All patients received standard therapy according to the clinical protocol. Some patients (group 58-II) on the background of standard therapy were additionally prescribed Overin (cridanimod sodium salt 250 mg/2 ml in 1 amp.) From the pharmaceutical company “Geolik Pharm Marketing Group” 2 ml intramuscularly once a day every 48 h, 10 injections, followed by a comparative evaluation of clinical results relative to the control group of patients (group 20 – I) who received only standard therapy, immediately after treatment and 6 months after treatment. Results. It was found that the use of standard therapy, Overin, in patients with chronic nonbacterial prostatitis with inflammatory chronic pelvic pain syndrome (CP/CPPS – NIHIII A), contributed to a longer and lasting clinical effect, in contrast to the results in the group of patients who received only standard therapy. According to the assessment of the general condition (S+QoL) in group I of patients after treatment and 6 months after the standard course of treatment, the indicator improved by 38.5 and 30.9 %, respectively (p<0.05). Whereas in group II of patients, the score (S+QoL) after treatment after 6 months was 52.8 % and 49.1 % lower than before treatment (p<0.05). Overin has also been shown to be more effective in terms of the severity of the inflammatory process according to the results of prostate secretion microscopy. Lack of inflammatory activity in the prostate, in the presence of less than 10 leukocytes in the field of view at microscopy of its secretion in patients of group I after treatment was observed in 55 %, after 6 months in 45 % of patients, respectively in group II was in 77.3 % after treatment and in 75 % of patients 6 months after treatment. A more visible positive dynamics of immune status in the second group of patients was obtained. Namely, after treatment, there was a probable increase in IFN-γ in the blood by 29.9 % and a decrease in IL-6 by 2.7 times (in ejaculate by 3.2) while maintaining the visible dynamics compared to input data before treatment after 6 months (p<0.05). Whereas in the blood of patients of group I IFN-γ increased after treatment by only 5.5 % and IL-6 decreased by 24.0 % (ejaculate by 22.9 %). The level of sІgA in the ejaculate of patients of group I after treatment increased by 15.7 %, while in group II by 30.2 % (p<0.05). After 6 months, the studied indicators of immune status in the blood and ejaculate of patients of group I, visibly did not differ from the data in this group before treatment (p>0.05). Conclusions. The use of Overin on the background of standard therapy in patients with inflammatory form of CP/CPPS, contributes to a stable and long-lasting clinical effect, which is confirmed by the dynamics of the obtained clinical and laboratory data.

Posible differential diagnosis of various chronic nonbacterial prostatites

Background: The purpose of the study was to diagnose possible chronic nonbacterial prostatitis (CNP) and chronic pelvic pain syndrome (CPPS) among patients, as well as differentiate between the inflammatory (category IIIA) or non-inflammatory (category IIIB) types in selecting and optimizing differential drug treatment of this category of patients. Material and methods: The study was conducted on 43 patients diagnosed with CNP/CPPS. The control group included 10 healthy men. Both the production of nitric oxides (NO) by phagocytes, as well as prostate secretion and ejaculate were determined according to the procedure described by Metelyskaya B.A., which was modified by Gudumac V, et al. Results: There was a 39.0% (p <0. 05) decrease in NO production by induced NO-synthase (iNOS), determined in the blood of 11 patients (from the main group – 2) with CNP/CPPS and a 115% (p <0.05) increase was determined in 32 patients (from the main group 1) if compared to the same indices in the control group. The prostatic secretion and ejaculate showed a higher macrophage iNOS activity by 80% (p <0.05) and 75% (p <0.05) if compared to the same parameters from the control group. The iNOS activity in prostatic fluid and split-ejaculate fractions from the main group – 2 did not differ from that of the control group. Conclusions: The assessment of NO production, prostate secretion and ejaculate allows to somewhat establish the main diagnosis of CNP and category III types (A – inflammatory and B – non-inflammatory prostatitis), which will significantly contribute to the optimization and selection of an appropriate differential treatment based on the drug action mechanisms

The impact of SOD3 on prostatic diseases: elevated SOD3 is a novel biomarker for the diagnosis of chronic nonbacterial prostatiti

Prostate is the most common gland for the three major diseases in men, such as chronic nonbacterial prostatitis (CNP), benign prostatic hyperplasia (BPH) and prostate cancer (PCa). However, there is lack of ideal biomarker for diagnosis with prostatic diseases. This prospective study quantified extracellular superoxide dismutase (SOD3) levels in serum or expressed prostatic secretion (EPS) with CNP, and in the prostatic tissues with BPH or PCa, to evaluate SOD3 as possible surrogate markers for diagnosis and treatment efficacy. The diagnostic ability of SOD3 with CNP was estimated by ROC analysis. The potential function of SOD3 in prostatic disoders was further investigated via bioinformatic analysis. As a result, SOD3 was significantly increased in CNP and BPH, but dereased in PCa compared to controls. SOD3 was significantly elevated in patients with CNP III (6.491643 ± 1.592292, P༜0.001), CNP IV (8.617879 ± 1.535176, P༜0.001) compared to normal controls (4.705892 ± 1.484917), discriminating CNP versus normal controls (accuracy = 0.831, 95%CI: 0.726–0.937, P༜0.001), CNP III versus CNP IV (accuracy = 0.868, 95%CI: 0.716–0.940, P༜0.001). Furthermore, SOD3 in serum were associated with clinical characteristics of patients with CNP including plevic pain, blood pressure and lecithin/leukocyte in EPS. Functionally, SOD3 mainly interacted with CP, DSG2, RBP4, and CFP via spercific amino acid residue, and participated in the signal pathway of superoxide radicals degradation and apoptotic execution phase. Our findings suggested that SOD3 and its interactors might play an important role in prostatic diseases, and SOD3 could be an ideal diagnostic marker and therapeutic target for CNP.