3-Hydroxy-3-methylglutaryl-CoA synthase 2 facilitates erectile dysfunction via inhibiting autophagy by enhancing the mammalian target of rapamycin pathway in type 1 diabetic mellitus rats.

BACKGROUND: The relationship between erectile dysfunction (ED) and type 1 diabetes mellitus (T1DM) is currently a hot topic of medical research. It has been reported that autophagy plays a crucial role in causing erectile dysfunction in T1DM. Recent research has shown that mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) is strongly linked to the development of T1DM. However, the specific mechanism by which it regulates the erectile function is not yet fully understood. OBJECTIVES: To investigate whether HMGCS2 affects erectile function in type 1 diabetic rats by regulating autophagy in corpus cavernosum endothelial cells (CCECs). MATERIALS AND METHODS: First, the rat model of T1DM was established. Then, the ratio of maximum penile intracavernous pressure (ICPmax) and mean arterial pressure (MAP) was detected to assess the erectile function in various groups, and the protein expression of HMGCS2, mTOR and p-mTOR was evaluated by western blot (WB) and immunohistochemistry (IHC). To explore the relationship between HMGCS2 and the mTOR signaling pathway in T1DM ED rats, we silenced the expression of HMGCS2 and activated the mTOR signaling pathway with MHY1485 in CCECs and then assessed the expression of beclin1, P62, LC3, autophagosome, endothelial nitric oxide synthase (eNOS), phosphorylation of eNOS (p-eNOS), and nitric oxide (NO) to evaluate autophagy and the erectile function by reverse transcription quantitative polymerase chain reaction and western blot. RESULTS: The study conducted on T1DM ED rats showed that the expression of HMGCS2 was significantly increased, while the autophagy was suppressed. Additionally, the mTOR signaling pathway was highly activated. In contrast, when HMGCS2 was silenced in vitro, p-mTOR/mTOR was reduced, and autophagy was improved. These effects were accompanied by the enhanced activity of eNOS. Furthermore, when HMGCS2 was silenced and the mTOR signaling pathway was simultaneously activated, the results revealed a decrease in autophagy as well as a reduction in activity of eNOS in comparison to just silencing HMGCS2 alone. DISCUSSION AND CONCLUSION: HMGCS2 upregulation in T1DM rats inhibited autophagy and eNOS activity by activating the mTOR pathway and led to a decrease in the erectile function.

Synthesis of fluorinated polycyclic dehydroaltenusin analogs through hypervalent iodine-catalyzed dearomatization.

We developed a method employing stoichiometric meta-chloroperbenzoic acid (m-CPBA) as an oxidant and hydrogen fluoride pyridine (pyr·HF) as a fluoride source with catalytic amounts of iodobenzene (PhI) for the cyclization and fluorination-dearomatization of phenols, leading to a range of fluorocyclohexa-dienones with yields of up to 94%. This reaction provides a convenient method to synthesize fluorine-containing dehydroaltenusin analogs under mild conditions, and without expensive reagents. These analogs have potential application as inhibitors of DNA polymerase.

[Corrigendum] HepaCAM inhibits cell proliferation and invasion in prostate cancer by suppressing nuclear translocation of the androgen receptor via its cytoplasmic domain.

Following the publication of the above article, an interested reader drew to the authors' attention that the western blotting data shown in Figs. 2F and 5E were strikingly similar, even though they were intended to show the results from differently performed experiments; furthermore, the migration assay images shown for the 24 h 'Blank' and 'Vector' experiments in Fig. 3C were apparently the same. The authors have consulted their original data, and realized that the errors in the presentation of these figures arose inadvertently as a consequence of selecting the wrong images for the 24 h 'Blank' experiement in Fig. 3C and the western blot for the AR / Nucleus experiment in Fig. 5E. The revised versions of Figs. 3 and 5 are shown on the next two pages. All the authors approve of the publication of this corrigendum, and the authors are grateful to the Editor of Molecular Medicine Reports for granting them the opportunity to publish this. The authors regret that these errors were included in the paper, and also apologize to the readership for any inconvenience caused. [Molecular Medicine Reports 19: 2115­2124, 2019; DOI: 10.3892/mmr.2019.9841].

Effects of various catheter fix sites on catheter-associated lower urinary tract symptoms.

The present study aimed to compare the effects of various catheter fix sites on catheter-associated lower urinary tract symptoms (CALUTS) in 450 patients who underwent surgical removal of upper urinary calculi 24 h earlier. All patients had 16 French Foley catheters inserted and the balloons were filled. In group A, the catheters were fixed on the top one-third of the thigh. In group B, the catheters were fixed on the abdominal wall. Patients in whom the catheters were neither fixed on the thigh nor abdominal wall were designated as controls. There were 150 patients in each group. CALUTS, such as frequency, urgency, burning during micturition, odynuria, bladder pain and other symptoms, including urethral discharge, a red and swollen external urethral orifice, catheter traction or blockage and catheter-associated discomfort were recorded. Patients in group A compared with the control group had a significantly lower incidence of frequency, urgency, odynuria, urethral discharge, catheter traction and catheter-associated discomfort (P<0.05). Patients in group B were observed to have a significantly lower incidence of urgency, urethral discharge, catheter traction and catheter-associated discomfort compared with the control group (P<0.05), but a higher incidence of odynuria, urethral pain, urethral discharge and a red and swollen external urethral orifice compared with group A (P<0.05). An additional catheter fixation site for bedridden patients was necessary and an additional fix site on the thigh was preferred to the abdominal wall, which may further reduce catheter-associated lower urinary tract symptoms.

Synthesis of Antitricyclic Morpholine Derivatives through Iodine(III)-Mediated Intramolecular Umpolung Cycloaddition of Olefins.

A (diacetoxyiodo)benzene-mediated intramolecular cycloaddition of olefins to construct tricyclic morpholines is presented. A series of substituted tricyclic morpholines were obtained in one-step simple operation under mild conditions, and the NMR studies were employed to see the interaction of reactants. The studies on stereochemistry showed that transformation of Z-alkene was inhibited, which is interpreted by density functional theory calculations on Z- and E-transition state models, and only E-alkene resulted in an anticycloaddition product, which is testified by a single-crystal X-ray diffraction analysis.

Synthesis of Polycyclic Cyclohexadienone through Alkoxy-Oxylactonization and Dearomatization of 3'-Hydroxy-[1,1'-biphenyl]-2-carboxylic Acids Promoted by Hypervalent Iodine.

Alkox-oxylactonization and dearomatization of 3'-hydroxy-[1,1'-biphenyl]-2-carboxylic acid simultaneously promoted by hypervalent iodine have been developed using stoichiometric PhI(OAc)2 or a catalytic amount of chiral aryl-λ3-iodane generated in situ. This reaction provides a concise method to synthesize diverse polycyclic cyclohexadienones as potential inhibitors of DNA polymerase under mild reaction conditions.

HepaCAM inhibits cell proliferation and invasion in prostate cancer by suppressing nuclear translocation of the androgen receptor via its cytoplasmic domain.

Hepatocyte cell adhesion molecule (HepaCAM) is a tumour suppressor. However, the mechanism of HepaCAM function in prostate cancer (PCa) remains unknown. In the present study, HepaCAM, androgen receptor (AR) and Ran were analysed in 46 PCa tissue samples using immunohistochemistry. Subsequently, the influence of HepaCAM and its cytoplasmic domain on cell proliferation, migration, and invasion, and associated proteins was examined using MTT, wound healing, Transwell and western blotting assays, respectively. Furthermore, nuclear translocation of AR and Ran was analysed using immunofluorescence and Western blot assays. The results demonstrated that HepaCAM expression was reduced in PCa, and there was an association between downregulation of HepaCAM and changes in the distribution of AR and Ran. Furthermore, HepaCAM, specifically the cytoplasmic domain, was involved in cell proliferation, migration and invasion. Nuclear translocation of AR was dependent on HepaCAM and its cytoplasmic domain. Additionally, HepaCAM suppression of the nuclear translocation of AR occurred via Ran. The results suggest that HepaCAM and its cytoplasmic domain suppress the nuclear translocation of AR via Ran in PCa. The cytoplasmic domain of HepaCAM may serve as a novel target for therapy in PCa.

A Three-Gene Classifier Associated With MicroRNA-Mediated Regulation Predicts Prostate Cancer Recurrence After Radical Prostatectomy.

BACKGROUND AND OBJECTIVE: After radical prostatectomy (RP), prostate cancer (PCa) patients may experience biochemical recurrence (BCR) and clinical recurrence, which remains a dominant issue in PCa treatment. The purpose of this study was to identify a protein-coding gene classifier associated with microRNA (miRNA)-mediated regulation to provide a comprehensive prognostic index to predict PCa recurrence after RP. METHODS: Candidate classifiers were constructed using two machine-learning algorithms (a least absolute shrinkage and selector operation [LASSO]-based classifier and a decision tree-based classifier) based on a discovery cohort (n = 156) from The Cancer Genome Atlas (TCGA) database. After selecting the LASSO-based classifier based on the prediction accuracy, both an internal validation cohort (n = 333) and an external validation cohort (n = 100) were used to examined the classifier using survival analysis, time-dependent receiver operating characteristic (ROC) curve analysis, and univariate and multivariate Cox proportional hazards regression analyses. Functional enrichment analysis of co-expressed genes was carried out to explore the underlying moleculer mechanisms of the genes included in the classifier. RESULTS: We constructed a three-gene classifier that included FAM72B, GNE, and TRIM46, and we identified four upstream prognostic miRNAs (hsa-miR-133a-3p, hsa-miR-222-3p, hsa-miR-1301-3p, and hsa-miR-30c-2-3p). The classifier exhibited a remarkable ability (area under the curve [AUC] = 0.927) to distinguish PCa patients with high and low Gleason scores in the discovery cohort. Furthermore, it was significantly associated with clinical recurrence (p < 0.0001, log rank statistic = 20.7, AUC = 0.733) and could serve as an independent prognostic factor of recurrence-free survival (hazard ratio: 1.708, 95% CI: 1.180-2.472, p < 0.001). Additionally, it was a predictor of BCR according to BCR-free survival analysis (p = 0.0338, log rank statistic = 4.51). CONCLUSIONS: The three-gene classifier associated with miRNA-mediated regulation may serve as a novel prognostic biomarker for PCa patients after RP.

Copper-Catalyzed Oxidative Difunctionalization of Terminal Unactivated Alkenes.

The copper(II)-promoted free-radical oxidative difunctionalization of terminal alkenes to access ketoazides by utilizing molecular oxygen has been reported. A series of styrene derivatives have been evaluated and were found to be compatible to give the desired difunctionalized products in moderate to good yields. The role of molecular oxygen both as an oxidant and oxygen atom source in this catalytic transformation has been unquestionably demonstrated by 18O-labeling studies and a radical mechanistic pathway involving the oxidative formation of azidyl radicals is also designed. This environment-friendly catalytic oxidative protocol can transform aldehyde to nitrile.

Application of nephrostomy tubes with balloon after percutaneous nephrolithotomy: A randomized controlled clinical trial.

OBJECTIVE: To evaluate the effect of nephrostomy tubing with balloon on postoperative hemorrhage after percutaneous nephrolithotomy. METHODS: A total of 284 patients with upper urinary calculi were enrolled for blocked randomization with 71 blocks and block length of 4. The experimental group consisted of 143 patients receiving 14-Fr silicone tubing with balloon, and the control group consisted of 141 patients receiving 14-Fr silicone tubing without balloon. One patient in the control group developed intraoperative bleeding as a result of calyceal laceration, and was reassigned to the experimental group receiving nephrostomy tubing with balloon. RESULTS: Postoperative drop in hemoglobin level at 3 days was significantly less in the experimental group (3.31 ± 2.85 g/L) compared with the control group (5.14 ± 3.43 g/L) (P < 0.001). The duration of gross hematuria, defined by urine with visible light or bright red color (2.73 ± 1.59 days vs. 3.55 ± 2.09 days, P < 0.001), and the incidence of postoperative extravasation (22/143 vs. 38/141, P < 0.05) for patients in the experimental group (implanted with 14-Fr silicone tubing with balloon) were significantly lower compared with the control group. CONCLUSION: Use of indwelling nephrostomy tubes with balloon after percutaneous nephrolithotomy can reduce blood loss. Further consideration for more widespread adoption of this type of tubing to limit perioperative bleeding complications is warranted.

Expression of aquaporins in prostate and seminal vesicles of diabetic rats.

INTRODUCTION: Aquaporins (AQPs) are membrane proteins that facilitate the movement of water and many small solutes across biological membranes. Seminal fluid is primarily produced by prostate and seminal vesicles, and its production may potentially be mediated by many mechanisms related to transudation of fluid. Epidemiological data suggest that semen volume in diabetic men is significantly less than in nondiabetic men. AIM: To investigate the change in volume of secretions of the prostate and seminal vesicles in diabetic rats and its association with the expression of AQPs 1-4. METHODS: Twenty male Sprague Dawley rats were randomly divided among 4- and 6-week diabetic groups and 4- and 6-week control groups. Prostate and seminal vesicle secretions were collected and measured, and levels of expression of AQPs 1-4 were determined by immunohistochemical study and Western blot. MAIN OUTCOME MEASURES: The levels of expression of AQPs 1-4 were determined in the prostate and seminal vesicles of diabetic rats by Western blot and immunohistochemical study. RESULTS: Plasma glucose was significantly higher in diabetic model groups than in controls (P < 0.05). The weights of secretions of the prostate and seminal vesicles were significantly lower in diabetic model groups (P < 0.05). The levels of expression of AQPs 1 and 4 in seminal vesicles were significantly lower in diabetic model groups (P < 0.05). There was no difference in the level of expression of AQP3 in seminal vesicles among the groups. The levels of expression of AQPs 1, 3, and 4 in prostate were significantly lower in diabetic model groups (P < 0.05). AQP2 was not detectable in the prostate or seminal vesicles of any of the groups. CONCLUSIONS: Decreased weight of prostate secretions in diabetic rats may be partly due to decreased levels of AQPs 1, 3, and 4 in prostatic tissue. Decreased weight of seminal vesicle secretions in diabetic rats may be partly due to decreased levels of AQP1 and AQP4 in seminal vesicles. There is no relationship between the expression of AQPs 1-4 and the duration of disease.

[Expression of heme oxygenase 2 in the corpus cavernosum of castrated rats].

OBJECTIVE: To determine the expressions of HO-2 and eNOS in the corpus cavernosum of castrated rats and investigate the correlation of HO-2 and eNOS with erectile dysfunction. METHODS: Forty SD rats of 10 weeks were equally divided into 3 castrated groups (4, 8 and 12 weeks respectively after removal of bilateral testes) and a sham operation control group. All the rats were detected for serum testosterone (T), intracavernosal pressure (ICP) and mean arterial blood pressure (MAP) 2, 8 and 12 weeks after the surgery, the content of HO-2 analyzed by Western blot and the expressions of eNOS and HO-2 determined by immunohistochemistry. RESULTS: Testosterone level and ICP/MAP ratio were markedly decreased after the castration (P < 0.05). The HO-2 expression was detected in the corpus cavernosum of all but the 12-week castrated rats, and the area under the curve was (341.50 +/- 99.70) in the 4-week castrated group, significantly less than in the 8-week (705.00 +/- 152. 74) and the control group (876 +/- 443. 36) (P < 0. 05), with no obvious difference between the latter two. eNOS was found mainly in the vascular endothelial cells of the corpus cavernosum, significantly less in the castrated (123.94 +/- 30. 23) than in the control group (421.21 +/- 125. 12). CONCLUSION: Androgens might mediate the penile erectile function through HO-2 and eNOS in the corpus cavernosum of rats.

[Expression of Rho-kinase and heme oxygenase in the corpus cavernosum of spontaneous hypertensive rats].

OBJECTIVE: To investigate the expression of Rho-kinase and heme oxygenase and the interaction among NOS/NO, HO/CO and RhoA/Rho-kinase in the corpus cavernosum of spontaneous hypertensive rats (SHRs). METHODS: A series of electric stimuli were applied to the corpus cavernosum nerves of 7 SHRs, the changes of ICP/MAP observed continuously and the expressions of ROCK2, HO-2 and eNOS analyzed by Western blot and immunohistochemistry. Another 7 WKY rats were taken as controls. RESULTS: Compared with the controls, ICP/MAP did not rise obviously (P < 0.05), HO-2 dropped sharply (P = 0.006) and the expression of the ROCK2 protein was elevated markedly (P = 0.017) in the SHRs. Immunohistochemistry showed HO-2 to be distributed in the smooth muscle cells and nervous cells of the corpus cavernosum, and eNOS mainly in the vascular endothelial cells. The expressions of HO-2 and eNOS were obviously reduced in the SHRs. CONCLUSION: NOS/NO, HO/CO and RhoA/Rho-kinase are related with erectile dysfunction in SHRs and may interact on one another.