No abstract

The dysregulation of androgen receptor ( AR ) signaling is a critical event in the progression of prostate cancer (PCa) and hormone therapy consisting of androgen deprivation (ADT) or AR inhibition is therefore used to treat advanced cases. It is known that N-cadherin becomes upregulated following ADT and can directly induce PCa transformation to the castration-resistant stage (CRPC). However, the relationship between AR and N-cadherin is unclear and may promote better understanding of CRPC pathogenesis and progression. Here, we demonstrate a new axis of N-cadherin/c-Jun/N-myc downstream regulated gene 1 ( NDRG1 ) that N-cadherin promotes c-Jun expression and suppresses NDRG1 to promote invasion and migration of PCa cells through epithelial to mesenchymal transition (EMT). Targeting N-cadherin in combination with enzalutamide (ENZ) treatment synergistically suppressed PC3 cell proliferation in vivo and in vitro . Further studies showed that compared to lower Gleason score (GS) (GS < 7) cases, high GS (GS > 7) cases exhibited elevated N-cadherin expression and reduced NDRG1 expression, corroborating our in vitro observations. We further demonstrate that c-Jun, AR, and DNA methyltransferase-1 ( DNMT1 ) form a complex in the 12-O-tetradecanoyl phorbol-13-acetate (TPA) response elements (TREs) region of the NDRG1 promoter, which suppresses NDRG1 transcription through DNA hypermethylation. In conclusion, we demonstrate an underlying mechanism for how N-cadherin collaborates with AR and NDRG1 to promote CRPC progression. Controlling N-cadherin/c-Jun/NDRG1 axis may help to overcome resistance to commonly used hormone therapy to improve long-term patient outcomes.

ObjectiveTo examine the association of kidney stones with new-onset hypertension, diabetes and obesity. Participants and MethodsThis prospective cohort study included participants in the Qingdao Port Cardiovascular Health Study who were aged ≥18 years and had abdominal ultrasonography results in 2013 that were negative for kidney stones. Multivariable Cox regression models with time-dependent covariates were used to estimate the effects of new-onset hypertension, diabetes and obesity on the incidence of kidney stones. ResultsThere were 9667 participants without kidney stones in 2013 (mean age 46.2 years; 75.6% men). During a mean (range) follow-up of 33.5 (6-42) months, 676 (7.0%) incident cases of kidney stones were identified. Kidney stones were more frequent among those who had new-onset of a metabolic factor vs those who did not (hypertension: 7.7 vs 6.0%; diabetes: 8.4 vs 6.6%; obesity: 7.4 vs 6.8%). Adjusted Cox models identified that increased risk of kidney stones was associated with new-onset hypertension (adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.25-2.27), newonset diabetes (HR 1.78, 95% CI 1.07-2.96), and new-onset obesity (HR 1.78, 95% CI 1.15-2.74). ConclusionsNew-onset of hypertension, diabetes and obesity were all strongly associated with an increased risk of kidney stones in this prospective cohort study. Results suggest that a substantial proportion of kidney stones are potentially preventable by appropriate control of these metabolic risk factors.Abbreviations: HR, hazard ratio; MetS, metabolic syndrome; BMI, body mass index.

Background: Icariside II (ICAII) is a flavonoid isolated from herb Epimedium that has been shown to improve erectile function in rats. However, ICAII's underlying mechanism remains unclear.Methods: Type 2 diabetes mellitus erectile dysfunction (T2DMED) rats were induced by single intraperitoneal injection of 25 mg/kg streptozotocin (STZ) and fed a high-fat, high-sugar, and high-calorie diet for 8 weeks. In the control and T2DMED groups, rats were administered with normal saline; in the metformin (MET) group, rats were administered with MET at 0.2 g/kg/day; and in the ICAII + MET group, rats were administered with ICA II at 10 mg/kg/day and MET for 0.2 g/kg/day. The deposition of advanced glycation end products (AGEs), expression of receptor for AGEs (RAGEs), reactive oxygen species (ROS), and superoxide dismutase (SOD) activity, and corpus cavernosum smooth muscle cells (CCSMCs) mitochondrial autophagy were measured. We also evaluated the expression of LC3-

Introduction: Type 2 diabetes mellitus erectile dysfunction (T2DMED) is one of the common complications of type 2 diabetes mellitus (T2DM). Icariside II (ICA II), a flavonoid derived from Epimedium, has been shown to improve erectile function in T2DMED rats. Aim: To investigate the effect of ICA II and metformin (MET) on penile erectile function, mitochondrial autophagy, glucose-lipid metabolism in rats with T2DMED. Methods: In the control and T2DMED groups, rats were administered normal saline. In the MET group, rats were administered MET for 0.2 g/kg/day. In the ICA IIþMET group, rats were administered ICA II for 10 mg/kg/day and MET for 0.2 g/kg/day. Results: The number of mating rats, number of erectile rats, erection rate, erection frequency, intracorneal pressure, and intracorneal pressure/mean arterial pressure in the ICA IIþMET group and control group were significantly higher than corresponding values in than T2DMED group. The absolute values of fasting plasma glucose, glycated haemoglobin in the ICA IIþMET group, MET group, and control group were significantly lower than in the T2DMED group. The advanced glycation end product (AGE) values in the ICA IIþMET group and the MET group were lower than in the T2DMED group. The receptors for the AGE values and angiotensin II values in the ICA IIþMET group were lower than in the T2DMED and MET groups. The highdensity lipoprotein values, testosterone values, nitric oxide synthase activity, and cyclic guanosine monophosphate content in the ICA IIþMET and control groups were higher than in the T2DMED group. The lowdensity lipoprotein values, triglyceride values, estradiol values, and total cholesterol values in the ICA IIþMET and control groups were lower than in the T2DMED group. Conclusion: ICA II could increase erectile function and smooth muscle cell/collagen fibril proportions, decreased mitochondrial autophagy, and AGE concentrations and improve lipid metabolism, nitric oxide synthase activity, cyclic guanosine monophosphate content, testosterone, estradiol, and Ang II in rat with T2DMED. Zhang J, Li S, Zhang S, et al.

Postoperative cognitive dysfunction (POCD) is a kind of serious neurologic complications and dexmedetomidine has a certain effect on POCD. However, functional mechanism of dexmedetomidine on POCD still remains unclear, so the research mainly studied the effect of dexmedetomidine on cognitive function and protein expression in hippocampus and prefrontal cortex cerebrospinal fluid after extracorporeal circulation operation in aged rats. We Found that, compared with POCD group, the cognitive function was improved in POCD + Dex group. We speculate that dexmedetomidine could improve the cognitive function after extracorporeal circulation operation in aged rats and Aβ, p-Tau, and PSD95 protein might have contributed to this favorable outcome.

<b><i>Background:</i></b> Benign prostatic hyperplasia (BPH) is a common chronic progressive disease resulting in urinary obstruction in aging men. It comes to more and more patients with massive BPH with the aging of society and extension of life expectancy. <b><i>Objective:</i></b> The aim of the study was to compare the clinical efficacy, safety, and complications between transurethral bipolar plasmakinetic enucleation of the prostate (PKEP) and transurethral resection of the prostate (TURP) in the treatment of massive BPH. <b><i>Design and Setting:</i></b> Patients with BPH were divided into the PKEP group and the TURP group randomly. Intraoperative blood loss (BL), operation time (OT), resected tissue weight (RTW), gland resection ratio (GRR), postoperative indwelling ureter time (IUT), bladder fistula time (BFT) and hospital stay time (HST), preoperative and postoperative serum sodium concentration (SSC), hemoglobin concentration (HGB), prostate weight (PW), postvoid residual (PVR), maximum urinary flow rate (<i>Q</i>_max), international prostate symptom score (IPSS), quality of life (QOL), International Index of Erectile Function (IIEF), and other complications were analyzed and compared respectively. <b><i>Results:</i></b> There was no statistical difference in preoperative IPSS, preoperative QOL score, preoperative PVR, preoperative <i>Q</i>_max, postoperative QOL score, postoperative PVR, postoperative <i>Q</i>_max, IPSS difference value (DV), <i>Q</i>_max DV, and PVR DV between the PKEP group and the TURP group (<i>p</i> &#x3e; 0.05). OT, BL, IUT, BFT, HST, and postoperative IPSS in the PKEP group were significantly lower than that in the TURP group (<i>p</i> &#x3c; 0.01). RTW and GRR in the PKEP group were significantly higher than that in the TURP group (<i>p</i> &#x3c; 0.01). QOL DV in the PKEP group was higher than that in the TURP group (<i>p</i> &#x3c; 0.05). There was statistical difference in SSC DV between the PKEP group and the TURP group (<i>p</i> &#x3c; 0.05). There was significant statistical difference in postoperative PW, postoperative HGB, PW DV, and HGB DV between the PKEP group and the TURP group (<i>p</i> &#x3c; 0.01). There was significant statistical difference in IPSS, QOL, PVR, and <i>Q</i>_max between postoperative value and preoperative value in both groups (<i>p</i> &#x3c; 0.01). The incidence of transurethral resection syndrome, obturator nerve reflex, transient urinary incontinence, and retrograde ejaculation between the PKEP group and the TURP group has no statistical difference (<i>p</i> &#x3e; 0.05). Capsule perforation, blood transfusion, secondary hemorrhage, bladder neck contracture, and urethral stricture in the PKEP group were lower than that in the TURP group (<i>p</i> &#x3c; 0.05). Bladder spasm in the PKEP group was significantly lower than that in the TURP group (<i>p</i> &#x3c; 0.01). There was no statistical difference in preoperative and postoperative IIEF-5, effective erectile frequency, telotism average tension, sustainable telotism average time, and sexual dissatisfaction between the PKEP group and the TURP group (<i>p</i> &#x3e; 0.05). <b><i>Conclusions:</i></b> PKEP and TURP have similar clinical efficacy in the treatment of massive BPH. PKEP has advantages in shorter OT, less BL, more GRR, and fewer complications, but the long-term therapeutic effect of PKEP needs further follow-up.

Summary Introduction Myocardial ischemia/reperfusion injury (myocardial I/R injury) has a high disability rate and mortality. Novel treatments for myocardial I/R injury are necessary. Aim In order to explore the protective effect of hydromorphine on myocardial I/R injury, we illuminate the underlying mechanism of the protective effect. Results Hydromorphine significantly reduced myocardial infarct size (IFN/AAR), CKMB (Creatine Kinase MB) and TN‐T (Troponin T) release, and improved cardiac function compared with I/R group. However, these advantageous effects were partly suppressed in the presence of hydromorphine. Myocardial I/R injury significantly decreased the phosphorylation of Akt and eNOS, and down‐regulated total nitric oxide and nitrotyrosine content, while these inhibitory effects were partly abolished by hydromorphine. Conversely, the activated effects of hydromorphine on the phosphorylation of Akt and eNOS, and NO release were totally reversed by LY294002, which, used individually, show the same influence on reperfusion injury. Conclusions These findings suggest that hydromorphine postconditioning may protect isolated rat heart against reperfusion injury via activating P13K/Akt/eNOS signaling.