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Objective The aim of this study was to discover new CXCR4 inhibitors and build 3D interaction model between these inhibitors and CXCR4, through virtual screening the 20000 compounds in ZINC database by using new virtual screening tools of PyRx to run AutoDock Vina. Methods The study focused on the target of CXCR4, through virtual screening program of AutoDock Vina to virtual screen the compounds in ZINC database. New virtual screening tools of PyRx was used to run AutoDock Vina. The CXCR4 crystal structure (PDB ID: 3ODUJ was downloaded from PDB and modified with AutoDock Tools. Compounds' structures were downloaded from ZINC database and imported with PyRx, then processed into format of pdbqt. The post-screening compounds were imported into AutoDockTools, and the data were outputted with PyMOL. Results There were 1 000 small molecular compounds for high-throughput screening from about 20000 compounds in the library. After screening for three times, we found five highly active CXCR4 inhibitors from the 1000 small molecular compounds. Conclusion By using the tools of PyRx to run AutoDock Vina, we found five new compounds of CXCR4 inhibitors from ZINC database. [ABSTRACT FROM AUTHOR]

The robust fault-tolerant control problem of time-delay uncertain system is studied to improve the performance of fault systems. For this class of linear uncertain time-delay systems model with actuator and sensor recoverable faults, a H∞ output-feedback controller solved by a linear matrix inequality (LMI) is designed to make sure the system can work steadily using the other elements and satisfy the system index. The simulation of an attitude control closed-loop system of satellite validates that it is effective. [ABSTRACT FROM AUTHOR]

This paper investigates the integrated attitude control algorithm and steering law for agile small satellites configured with control moment gyroscope (CMG). Firstly, considering the deterioration over time of the typical pyramid-shaped CMG cluster with 4 single-gimbal CMGs, the CMG dynamic model was built. Then, based on the adaptive control theory, the integrated attitude control algorithm and steering law were designed, and the asymptotic stability of the closed-loop system was proved via Lyapunov analysis. Finally, mathematical simulation has validated the solution in a satellite closed-loop attitude control system, and the simulation shows that the solution is simple and effective for attitude maneuver control of agile small satellites. [ABSTRACT FROM AUTHOR]

An attitude tracking control algorithm was designed for the problem of attitude synchronization control during on-orbit servicing spacecraft approaching and capturing out-of-control target. The control problem of servicing spacecraft tracking out-of-control target spacecraft's attitude was converted to the relative attitude control problem by establishing the relative attitude kinematics and dynamics of servicing spacecraft with respect to out-of-control target. Considering the factor of unknown disturbances and limited control torque, and the relative attitude dynamics was expressed as two-order equation of relative attitude quaternion, utilizing the feedback linearization theory and the thought of adaptive algorithm, a nonlinear feedback control law for attitude synchronization was designed. Numerical simulations have demonstrated the effectiveness and good tracking performance of the designed control algorithm. [ABSTRACT FROM AUTHOR]

To improve the reliability of satellite system, the observer-based actuator fault diagnosis problem for satellite attitude control system was investigated. Considering the uncertainty and disturbance of the satellite attitude control system, a robust adaptive sliding mode observer was proposed. A Lyapunov function was given as the judgment condition to stabilize the observer. Then, the proposed observer was used for actuator fault reconstruction. At last, the simulation of the observer in a satellite attitude control system with actuator fault illustrates the effectiveness of the proposed approach. [ABSTRACT FROM AUTHOR]

Research on design and implementation of data interfaces in the desktop testing platform for a certain satellite was introduced in this paper. Firstly, to satisfy the engineering requirements, general structure of the platform was designed with the real-time simulator and the on-board computer as its core components, and the interfaces among various components in the platform was described. Then, topic focused on researching problems including constitution of the real-time simulator, programming on interfaces using xPC Target, sample time of the interfaces, encoding double precision floating point number for transmission through interfaces, and design of CAN bus protocol on the application layer. Finally, by analyzing results of. the testing experiment, effectiveness and practicality of the data interfaces solution were proved. [ABSTRACT FROM AUTHOR]

Abstract: The immunosuppressant drug FK506 was found to be a potent neuroprotective agent in animal models of brain ischemia. However, the mechanisms underlying the action remain to be elucidated. The delayed rectifier K+ channel has been implicated in ischemic injury and neuronal death in the brain. The aim of the present study is to investigate whether the neuroprotective action of FK506 results from blocking the K+ channel. In acutely dissociated CA1 pyramidal neurons of rat hippocampus, superfusion of FK506 (0.01–100 μM) selectively inhibited the delayed rectifier K+ current (I K) with an IC50 value of 13.2±4.9 μM. The inhibition of I K by FK506 (10 μM) had a rapid onset, and then gradually reached a steady-state level. The inhibition was voltage-dependent, became more potent when the currents were elicited by strong depolarization. Moreover, FK506 (10 μM) caused marked negative shifts of the steady-state activation and inactivation curves of I K, and accelerated its recovery from inactivation. Intracellular dialysis of FK506 (30 μM) was ineffective. The inhibition of I K by FK506 (10 μM) persisted under the low-Ca2+ conditions that blocked the basal activity of protein phosphatase 2B (calcineurin). Rapamycin did not antagonize FK506 but mimicked it. Cyclosporin A inhibited I K only at 30 and 100 μM. Taken together, the results suggest that FK506 exert a direct inhibition on the delayed rectifier K+ channel without involvement of calcineurin. [Copyright &y& Elsevier]

Songorine, a diterpenoid alkaloid isolated from the genus Aconitum, was recently found to enhance the excitatory synaptic transmission in rat hippocampus. The mechanism underlying the effects was examined in the present study. The alkaloid at 0.1–300 μM inhibited the specific binding of [3H]muscimol to Triton-treated synaptic membranes of rat brain in a concentration-dependent manner (IC50=7.06 μM; 95% confidence limits: 3.28–10.84 μM). Scatchard analysis and Lineweaver–Burk double reciprocal plot of [3H]muscimol saturation binding data indicate a non-competitive inhibition of the alkaloid on the γ-aminobutyric acidA (GABAA) receptor. In acutely dissociated rat hippocampal neurons the alkaloid did not elicit current response, but markedly inhibited the GABA-induced inward current (IC50=19.6 μM). The results suggest that songorine is a novel non-competitive antagonist at the GABAA receptor in rat brain. [Copyright &y& Elsevier]

Polarity establishment is one of the key factors affecting early embryonic development. Polarity establishment begins with myosin phosphorylation in the 8-cell embryo, and phosphorylation activates actin leading to its initiation of contractility. Subsequently, actin undergoes reorganization to form an apical domain rich in microvilli on the non-contacting surface of each blastomere, and form the actomyosin ring that marks the maturation of the apical domain in conjunction with polar protein complexes and others. From the process of polarity establishment, it can be seen that the formation of the apical domain is influenced by actin-related proteins and polar protein complexes. Some zygote genome activation (ZGA) and lineage-specific genes also regulate polarity establishment. Polarity establishment underlies the first cell lineage differentiation during early embryonic development. It regulates lineage segregation and morphogenesis by affecting asymmetric cell division, asymmetric localization of lineage differentiation factors, and activity of the Hippo signaling pathway. In this review, we systematically summarize the mechanisms of early embryonic polarity establishment and its impact on lineage differentiation in mammals, and discuss the shortcomings of the currently available studies in terms of regulatory mechanisms and species, thereby providing clues and systematic perspectives for elucidating early embryonic polarity establishment.

Objective: To explore the potential action mechanism of Huotu Jiji Pellets (HJP) in the treatment of erectile dysfunction (ED) based on network pharmacology and molecular docking., Methods: We identified the main effective compounds and active molecular targets of HJP from the database of Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Integrative Pharmacology-Based Research Platform of Traditional Chinese Medicine (TCMIP) and the therapeutic target genes of ED from the databases of Genecards. Then we obtained the common targets of HJP and ED using the Venny software, constructed a protein-protein interaction (PPI) network of HJP acting on ED, and screened out the core targets with the Cytoscape software. Lastly we performed GO functional enrichment and KEGG pathway enrichment analyses of the core targets followed by molecular docking of HJP and the core targets using Chem3D and AutoDock Tools and QuickVina-W software., Results: A total of 64 effective compounds, 822 drug-related targets, 1 783 disease-related targets and 320 common targets were obtained in this study. PPI network analysis showed that the core targets of HJP for ED included ESR1, HSP90AA1, SRC, and STAT3. GO functional enrichment analysis indicated the involvement of the core targets in such biological processes as response to xenobiotic stimulus, positive regulation of kinase activity, and positive regulation of MAPK cascade. KEGG pathway enrichment analysis suggested that PI3K-Akt, apoptosis, MAPK, HIF-1, VEGF, autophagy and other signaling pathways may be related to the mechanism of HJP acting on ED. Molecular docking prediction exhibited a good docking activity of the key active molecules of HJP with the core targets., Conclusion: This study showed that HJP acted on ED through multi-components, multi-targets and multi-pathways, which has provided some evidence and reference for the clinical treatment and subsequent studies of the disease.

Objective: To explor the potential mechanisms of ferroptosis involvement in non-obstructive azoospermia based on bioinformatics and machine learning methods., Methods: To obtain disease-related datasets and ferroptosis-related genes, we utilized the GEO database and FerrDb database, respectively. Using the R software, the disease dataset was subjected to normalization, differential analysis, and GO and KEGG enrichment analysis. The differentially expressed genes from the disease dataset were then intersected with the ferroptosis-related genes to identify common genes. Core genes were selected using three machine learning algorithms, namely LASSO, SVM-RFE, and random forest. Further analysis included exploring immune infiltration correlation, predicting target drugs, and conducting molecular docking simulations., Results: The differential analysis of the GSE45885 dataset yielded 1751 differentially expressed genes, while the GSE145467 dataset yielded 4358 differentially expressed genes. The intersection of these two gene sets resulted in a disease-related gene set consisting of 508 genes. Taking the intersection of the disease-related gene set and the ferroptosis-related gene set, we obtained 17 disease-related ferroptosis genes. After machine learning-based screening, three core genes were identified: GPX4, HSF1, and KLHDC3., Conclusion: The mechanism underlying the involvement of ferroptosis in non-obstructive azoospermia may be linked to the downregulation of GPX4, HSF1, and KLHDC3 expression. This finding provides a basis for subsequent in-depth mechanistic and therapeutic studies.

Objective To study the expression of selenoprotein genes in human immunodeficiency virus(HIV)infection and its mother-to-child transmission,so as to provide a theoretical basis for the prevention,diagnosis,and treatment of acquired immunodeficiency syndrome.Methods The dataset GSE4124 was downloaded from the Gene Expression Omnibus(GEO).Two groups of HIV-positive mothers( n =25)and HIV-negative mothers( n =20)were designed.HIV-positive mothers included a subset of transmitter(TR)mothers( n =11)and non-transmitter(NTR)mothers( n =14).Then, t -test was carried out to compare the expression levels of selenoprotein genes between the four groups(HIV-positive vs. HIV-negative,NTR vs. HIV-negative,TR vs. HIV-negative,TR vs. NTR).Univariate and multivariate Logistic regression were adopted to analyze the effects of differentially expressed genes on HIV infection and mother-to-child transmission.R software was used to establish a nomogram prediction model and evaluate the model performance.Results Compared with the HIV-negative group,HIV-positive,NTR,and TR groups had 8,5 and 8 down-regulated selenoprotein genes,respectively.Compared with the NTR group,the TR group had 4 down-regulated selenoprotein genes.Univariate Logistic regression analysis showed that abnormally high expression of GPX1,GPX3,GPX4,TXNRD1,TXNRD3,and SEPHS2 affected HIV infection and had no effect on mother-to-child transmission.The multivariate Logistic regression analysis showed that the abnormally high expression of TXNRD3( OR =0.032,95% CI =0.002-0.607, P =0.022)was positively correlated with HIV infection.As for the nomogram prediction model,the area under the receiver-operating characteristic curve for 1-year survival of HIV-infected patients was 0.840(95% CI =0.690-1.000),and that for 3-year survival of HIV-infected patients was 0.870(95% CI =0.730-1.000).Conclusions Multiple selenoprotein genes with down-regulated expression levels were involved in the regulation of HIV infection and mother-to-child transmission.The abnormal high expression of TXNRD3 was positively correlated with HIV infection.The findings provide new ideas for the prevention,diagnosis,and treatment of acquired immunodeficiency syndrome.

Background: COVID-19 is a global pandemic. Currently, the predominant strain is SARS-CoV-2 Omicron subvariant BA.2 in many countries. Understanding its infection characteristics can facilitate clinical management., Objectives: This study aimed to characterize the clinical, laboratory, and high-resolution computed tomography (HRCT) findings in patients with mild or moderate infection from SARS-CoV-2 Omicron subvariant BA.2., Methods: We performed a retrospective study on patients infected with SARS-CoV-2 Omicron subvariant BA.2 between April 4th and April 17th, 2022. The clinical characteristics, laboratory features, and HRCT images were reviewed., Results: A total of 805 patients were included (411 males and 394 females, median age 33 years old). The infection was mild, moderate, severe, and asymptomatic in 490 (60.9%), 37 (4.6%), 0 (0.0%), and 278 (34.5%) patients, respectively. Notably, 186 (23.1%), 96 (11.9%), 265 (32.9%), 11 (3.4%), 7 (0.9%), and 398 (49.4%) patients had fever, cough, throat discomfort, stuffy or runny nose, fatigue, and no complaint, respectively. Furthermore, 162 (20.1%), 332 (41.2%), and 289 (35.9%) patients had decreased white blood cell counts, reduced lymphocytes, and elevated C-reactive protein levels, respectively. HRCT revealed pneumonia in 53 (6.6%) patients. The majority of the lung involvements were ground-glass opacity (50, 94.3%) mostly in the subpleural area. The grade of lung injury was mainly mild (90.6%). Short-term follow-ups showed that most patients with pneumonia recovered., Conclusion: Most patients with mild or moderate infection from SARS-CoV-2 Omicron subvariant BA.2 were adults, with fever and upper respiratory symptoms as the main clinical presentations. Lower respiratory infection was mild, with ground-glass opacity in the subpleural area as the main finding., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: To observe the clinical effect of Simiaotongzhuo Decoction (SMTZD) on the symptoms of type III prostatitis with damp-heat stagnation syndrome., Methods: Using the randomized control method, we divided 140 cases of type III prostatitis with damp-heat stagnation syndrome into two groups and treated them orally with SMTZD at 200 ml per time bid (n = 65) and Tamsulosin Hydrochloride Sustained Release Capsules (THSRC) at 0.2 mg per time qd (n = 75), both for 6 weeks. Before and after medication, we recorded the counts of white blood cells (WBC) and lecithin bodies in the prostatic fluid, NIH-CPSI scores and traditional Chinese medicine syndrome (TCMS) scores, and compared them between the two groups of patients., Results: Compared with the baseline, the WBC count and NIH-CPSI scores were decreased and the number of lecithin bodies increased in both the SMTZD (NIH-CPSI score: ［18±6.47］ vs ［9±5.02］) and THSRC groups after medication, with statistically significant difference only in the former group (P<0.05), the TCMS scores were significantly reduced in both the SMTZD (［21.97±5.12］ vs ［6.4±4.88］, P<0.05) and the THSRC group (［20.73±4.97］ vs ［11.33±5.93］, P<0.05), even more significantly in the former. No statistically significant difference was observed in the incidence of adverse reactions between the SMTZD and THSRC groups (9.2% vs 9.3%, P>0.05), and all the adverse reactions were mild., Conclusion: Simiaotongzhuo Decoction is safe and effective for the treatment of type III prostatitis with damp-heat stagnation syndrome, which can reduce the WBC count in the prostatic fluid, increase the number of lecithin bodies and improve the NIH-CPSI and TCMS scores of the patient.

Objective To investigate the expression regulation of autophagy-related genes(ATG)and the mechanism of autophagy in rheumatoid arthritis(RA).Methods The differentially expressed genes(DEG)of RA were identified from GSE55235 and GSE55457,on the basis of which the differentially expressed autophagy-related genes(DE-ATG)were selected from the Human Autophagy Database.STRING 11.0 and GeneMANIA were used to establish protein-protein interaction networks.Further,the transcription factor-gene-miRNA co-expression network was established via NetworkAnalyst and Cytoscape.Finally,receiver operating characteristic(ROC)curve and DrugBank were employed to evaluate the efficacy of the predicted biomarkers and the performance of drugs targeting DE-ATG.GraphPad Prism 8.2.1 and R 4.0.3 were used for statistical analysis and graphics.Results A total of 485 DEG were enriched in signaling pathways such as T cell activation,hormone regulation,osteoclast differentiation,RA,and chemokines.Eleven DE-ATG regulated the expression of RUNX1,TP53,SOX2,and hsa-mir-155-5p in synovial tissues of RA patients and were involved in the response to environmental factors such as 2,3,7,8-tetrachlorodibenzodioxin and silicon dioxide.The ROC curve analysis identified the DE-ATG with good sensitivity and specificity,such as MYC,MAPK8,CDKN1A,and TNFSF10,which can be used to distinguish certain phenotypes and serve as novel biomarkers for RA.Conclusions In RA,down-regulated DE-ATG expression may promote apoptosis and lysis of chondrocytes.The identified novel biomarkers provides new ideas and methods for diagnosing and treating RA.The establishment of transcription factor-miRNA-gene co-expression network provides direct evidence for dissecting synovial inflammation and articular cartilage destruction.

Natural polybrominated diphenyl ethers, often isolated from marine sponges, have been reported to possess various biological activities, such as antibacterial, antioxidant and antidiabetic effects. Via a high throughput screening of our marine natural product library, the polybrominated diphenyl ether 3 was found to display a KCNQ potassium channel activation effect. To obtain more compound 3 related natural products and their derivatives for further bioactivity study, a diversity-oriented synthesis was conducted, leading to the successful synthesis of five polybrominated diphenyl ether natural products (1-4, 6) and 30 new derivatives. Compound 3 was found to preferentially potentiate KCNQ1 potassium channel, whereas 17h relatively activated KCNQ2 potassium channel. The structure-activity relationship was analyzed assisted by molecular docking and 17h was further conducted for its agonistic mechanism study on KCNQ2 channel. This research work may give an insight for the discovery of marine polybrominated diphenyl ether derived new drug leads., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Major depressive disorder is characterized by not only monoamine neurotransmitters deficiencies but also persistent neuroinflammation. The complement system is an attractive therapeutic target for various inflammation-related diseases due to its early activation in inflammatory processes., Results: In the present study, the dynamic alteration of complement C3 and its receptor C3aR during the occurrence of depression and the mechanism of astrocyte-microglia IL-1R/C3/C3aR on synaptic pruning were investigated. The proteomic analysis firstly showed that chronic stress caused an elevation of C3. GO analysis indicated that complement system-mediated synaptic pruning signaling was involved in depression. The dynamic observation indicated that C3/C3aR was activated in the early onset and throughout the course of depression induced by lipopolysaccharide (LPS) and chronic stress. In contrast, C3aR blockade inhibited the hyperactivation of microglial APT2/DHHC7 palmitoylation cycle, which mediated the translocation of STAT3 and the expression of proinflammatory cytokines. Meanwhile, C3aR blockade also attenuated the synaptic pruning and enhanced the synaptogenesis in the prefrontal cortex of mice. Moreover, the blockade of IL-1R/NF-κB signaling pathway reduced the release of C3 from astrocyte., Conclusions: The current study demonstrates that astrocyte-microglia IL-1R/C3/C3aR activation causes the abnormal synaptic pruning in depression, and suggests that the activation of complement C3/C3aR may be particularly helpful in predicting the onset stage of depression., (© 2022. The Author(s).)

Ethnopharmacological relevance Paeonia lactiflora is a famous Traditional Chinese medicine widely used for immunological regulation. Paeoniflorin, the main component of Paeonia lactiflora, exerts neuroprotective and antidepressant-like effects in rodents., Aim of the Study: Fibroblast growth factor 2 (FGF-2) is essentially required in the central nervous system as it acts as both a neurotrophic factor and an anti-inflammatory factor participating in the regulation of proliferation, differentiation and apoptosis of neurons in the brain. However, it is unclear whether paeoniflorin could exert antidepressant effects via regulating FGF-2., Materials and Methods: In the present study, the effects of paeoniflorin were evaluated in depressive mice induced by the endotoxin lipopolysaccharide (LPS) injection., Results: The results showed that paeoniflorin markedly increased sucrose preference and reduced immobility time in LPS mice, indicating antidepressant effects. Consistent with the results from molecular docking showing paeoniflorin antagonizes TLR4, NF-κB and NLRP3, the biochemical analysis also indicated paeoniflorin inhibited TLR4/NF-κB/NLRP3 signaling, decreased proinflammatory cytokine levels and microglial activation in the hippocampus of LPS induced mice. In addition, the levels of neuronal FGF-2 and the density of dendritic spine were improved by paeoniflorin. More importantly, the FGFR1 inhibitor SU5402 prevented the antidepressant effects of paeoniflorin and blocked the neuroinflammatory and neurogenic regulatory effects of paeoniflorin, indicating that FGF-2/FGFR1 activation was required for the effects of paeoniflorin., Conclusion: Taken together, the results demonstrate that paeoniflorin exhibits neuroprotective and antidepressant effects in mice, which may be mediated by activating neuronal FGF-2/FGFR1 signaling via the inhibition of microglial activation in the hippocampus., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Chalcomoracin (CMR) is a kind of Diels-Alder adduct extracted from the mulberry leaves. Recent studies showed that CMR has a broad spectrum of anticancer activities and induces paraptosis in breast cancer and prostate cancer cells. In this study, we investigated the effects of CMR against human non-small cell lung cancer cells and the underlying mechanisms. We found that CMR dose-dependently inhibited the proliferation of human lung cancer H460, A549 and PC-9 cells. Furthermore, exposure to low and median doses of CMR induced paraptosis but not apoptosis, which was presented as the formation of extensive cytoplasmic vacuolation with increased expression of endoplasmic reticulum stress markers, Bip and Chop, as well as activation of MAPK pathway in the lung cancer cells. Knockdown of Bip with siRNA not only reduced the cell-killing effect of CMR, but also decreased the percentage of cytoplasmic vacuoles in H460 cells. Moreover, CMR also increased the sensitivity of lung cancer cells to radiotherapy through enhanced endoplasmic reticulum stress. In lung cancer H460 cell xenograft nude mice, combined treatment of CMR and radiation caused greatly enhanced tumor growth inhibition with upregulation of endoplasmic reticulum stress proteins and activation of pErk in xenograft tumor tissue. These data demonstrate that the anticancer activity and radiosensitization effect of CMR result from inducing paraptosis, suggesting that CMR could be considered as a potential anticancer agent and radiation sensitizer in the future cancer therapeutics.

Geissoschizine methyl ether (GM) is an indole alkaloid isolated from Uncaria rhynchophyll (UR) that has been used for the treatment of epilepsy in traditional Chinese medicine. An early study in a glutamate-induced mouse seizure model demonstrated that GM was one of the active ingredients of UR. In this study, electrophysiological technique was used to explore the mechanism underlying the antiepileptic activity of GM. We first showed that GM (1-30 μmol/L) dose-dependently suppressed the spontaneous firing and prolonged the action potential duration in cultured mouse and rat hippocampal neurons. Given the pivotal roles of ion channels in regulating neuronal excitability, we then examined the effects of GM on both voltage-gated and ligand-gated channels in rat hippocampal neurons. We found that GM is an inhibitor of multiple neuronal channels: GM potently inhibited the voltage-gated sodium (Na V ), calcium (Ca V ), and delayed rectifier potassium (I K ) currents, and the ligand-gated nicotinic acetylcholine (nACh) currents with IC 50 values in the range of 1.3-13.3 μmol/L. In contrast, GM had little effect on the voltage-gated transient outward potassium currents (I A ) and four types of ligand-gated channels (γ-amino butyric acid (GABA), N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainite (AMPA/KA receptors)). The in vivo antiepileptic activity of GM was validated in two electricity-induced seizure models. In the maximal electroshock (MES)-induced mouse seizure model, oral administration of GM (50-100 mg/kg) dose-dependently suppressed generalized tonic-clonic seizures. In 6-Hz-induced mouse seizure model, oral administration of GM (100 mg/kg) reduced treatment-resistant seizures. Thus, we conclude that GM is a promising antiepileptic candidate that inhibits multiple neuronal channels.

We compared the predictive ability of the 2014 and 2005 Gleason grading systems in 568 patients initially diagnosed with metastatic prostate cancer (PCa). Outcomes included the duration of castration-resistant prostate cancer-free survival (CFS) and overall survival (OS). Univariate analyses and log-rank tests were used to identify prognosis indicators and assess univariable differences in CFS and OS in Gleason score (GS) groups. Cox proportional hazards and area under the curves of receiver operator characteristics methods were used to evaluate the predictive efficacy of the 2005 and 2014 ISUP grading systems. Univariate analyses showed that the 2005 and 2014 grading systems were prognosticators for CFS and OS; both systems could distinguish the clinical outcome of patients with GS 6, GS 7, and GS 8-10. Using the 2014 criteria, no statistical differences in patient survival were observed between GS 3 + 4 and GS 4 + 3 or GS 8 and GS 9-10. The predictive ability of the 2014 and 2005 grading systems was comparable for CFS and OS (P = 0.321). However, the 2014 grading system did not exhibit superior predictive efficacy in patients initially diagnosed with PCa and bone metastasis; trials using larger cohorts are required to confirm its predictive value. To the best of our knowledge, ours is the first study to compare the 2005 and 2014 grading systems in initially diagnosed PCa with bone metastasis. At present, we recommend that both systems should be used to predict the prognosis of patients with metastatic PCa.

Objectives: To investigate gene rearrangement and protein expression of ETS related gene ( ERG ) in prostate cancer of Chinese patients and its correlation with clinicopathological characteristics and prognosis., Methods: This study collected 482 cases of prostatic adenocarcinomas diagnosed by prostate biopsy in West China Hospital of Sichuan University from 2009 to 2014. Fluorescence in situ hybridization (FISH) and immuno-histochemical staining (IHC) were performed to access the ERG rearrangement and protein expression respectively. Relationship between ERG rearrangement and protein expression was assessed by Spearman rank order correlation. The correlations of ERG rearrangement and protein expression with clinicopathological variables and prognosis were further analyzed., Results: ERG rearrangement was detected in 87 (18.0 %) cases, of which 45 (51.7%) was translocation and 42 (48.3%) was deletion. ERG protein expression was detected in 74 (15.4%) cases. Follow-up data was obtained in 368 cases. ERG rearrangement and protein expression had no correlations to age, Gleason score and pre-operation PSA level ( P >0.05), but ERG protein level was decreased in metastatic cases or castration resistant prostate cancer (CRPC) cases ( P <0.05) . Kaplan-Meier curve showed both gene rearrangement and protein expression of ERG had no prognostic significance., Conclusions: ERG rearrangement, as well as ERG protein expression, could not serve as an independent prognostic biomarker.

Objective: To investigate the expressions of sphingosine-1-phosphate receptors 1-3 (S1P1- 3) in the corpus cavernosum of castrated male rats and its relationship with the NOS/NO/cGMP and RhoA/Rho kinase signaling pathways., Methods: We equally randomized 18 eight-week-old healthy male SD rats into a sham-operation control, a castration, and a testosterone replacement (TR) group and harvested the bilateral testes and epididymides from the rats in the latter two groups, followed by 4 weeks of subcutaneous injection of testosterone propionate at 3 mg per kilogram of the body weight per day for those in the TR group and that of plant oil for those in the control and castration groups. At the age of 12 weeks, we measured the serum testosterone (T) level and maximum intracavernous pressure/mean arterial pressure (ICPmax/MAP) of the animals and determined the expressions of SlP1-3, eNOS, P-eNOS, ROCK1, and ROCK2 in the corpus cavernosum by Western blot and immunohistochemistry., Results: The serum T level was significantly decreased in the rats of the castration group as compared with those of the control and TR groups ([0.41 ± 0.04] vs [16.01 ± 1.02] and [15.84 ± 1.32] nmol/L, P < 0.01), with no statistically significant difference between the latter two groups. The ICPmax/MAP at 0 V, 3 V, and 5 V electric stimulation was remarkably lower in the rats of the castration group (0.088 ± 0.014, 0.323 ± 0.014, and 0.432 ± 0.012) than in those of the control group (0.155 ± 0.011, 0.711 ± 0. 010, and 0.819 ± 0.024) and TR group (0.153 ± 0.012, 0.696 ± 0.017, and 0.763 ± 0.027) (P < 0.01), with no significant difference between the latter two groups. With GAPDH as internal control, the animals of the castration group showed markedly reduced expressions of S1P1 ([49.99 ± 3.39]%), eNOS ([46.82 ± 3.81]%) , and P-eNOS ([45.42 ± 4.35]%) in comparison with those in the control group ([72.57 ± 3.06], [89.76 ± 3.98], and [82.53 ± 8.92] and TR group ([71.77 ± 4.43], [87.19 ± 4.23], and [79.82 ± 7.38]%) (P < 0.01) , while the expressions of S1P2, S1P3, ROCK1, and ROCK2 were significantly upregulated in the castration group ([82.35 ± 4.13], [61.03 ± 5.14], [74.50 ± 4.02], and [69.83 ± 5.75]%) as compared with those in the control group ([41.67 ± 1.68], [31.66 ± 2.67], [35.69 ± 5.56], and [39.85 ± 7.17]%) and TR group ([42.80 ± 3.87], [32.25 ± 4.22], 38.06 ± 5.21], and [42.36 ± 4.44]%) (P < 0.01)., Conclusion: Androgen deficiency induces significant reduction of ICPmax/ MAP in male rats, which is possibly associated with the decline of S1P1 in the corpus cavernosum, inhibition of the eNOS/NO/cGMP signaling pathway, increased expressions of S1P2 and S1P3, and activation of the RhoA/Rho kinase signaling pathway.

Renal cell carcinoma (RCC) is common genitourinary malignancy in human, 30-40% of patients with RCC would be diagnosed with metastatic RCC (mRCC). Even in the era of targeted therapy, patients with mRCC would inevitably progress due to drug resistance. Herein, exploration of the mechanisms of resistance is noteworthy to study. In the present study, we firstly reported the expression profile of SOX9 in renal carcinoma cells and tissues, and found that its expression was significantly associated with Fuhrman grading. Dual luciferase analysis confirmed that Raf/MEK/ERK pathway could directly be regulated by SOX9, and sequential experiments demonstrated that, renal carcinoma cells could sensitize to Sorafenib/Sunitinib through Raf/MEK/ERK signaling pathway inhibition regulated by SOX9 down-regulation. In a small cases with mRCC treated with Sorafenib/Sunitinib (n=38), comparative analysis showed that patients with SOX9 (-) had much better therapeutic response to TKIs than those with SOX9 (+) (PD: 9.1% vs. 56.2%, P=0.002, DCR: 90.9% vs. 43.8%, P=0.002). Based on these findings, we concluded that, SOX9 was firstly described to be highly expressed in renal cell carcinoma, and its expression was involved in TKIs drug resistance through activation of Raf/MEK/ERK pathway. In vitro, patients with SOX9 (-) was related to better response to TKIs treatment than those with SOX9 (+). SOX9 could be expected to be a promising biomarker predicting TKIs response and even expected to be another novel target in the treatment of mRCC.

Objective: To investigate the expression of proapoptosis protein BNIP3 in clear cell renal cell carcinoma (ccRCC) and its clinical significance., Methods: The RCC tumor tissue samples from 30 pathologically diagnosed ccRCC and their adjacent pericarcinous tissues were adopted to detect the mRNA and protein expressions of BNIP3, von Hippel-Lindau (VHL), hypoxia inducible factor (HIF)-1alpha and vascular enothelial growth factor (VEGF) by real-time quantitative PCR (real-time PCR) and Western blot. The correlations of these genes expressions with clinicopathologic features were analyzed., Results: The expression levels of BNIP3 and VHL were lower in ccRCC tissues than those in pericarcinous tissues (P < 0.05), but the mRNA expression levels of HiF-1alpha and VEGF were higher in ccRCC tissues than those in pericarcinous tissues (P < 0.05). The lower level expression of BNIP3 in ccRCC was not related with any clinicopathologic features. No significant correlation was observed between the BNIP3 mRNA and protein level with the expressions of VHL, HIF-1alpha and VEGF., Conclusion: In ccRCC, the expression of BNIP3 is decreased, which not correlated with the expression levels of VHL, HIF-1alpha and VEGF.

Objective: To determine the expression of Bcl2 related protein A1(Bfl-1) mRNA in prostate cancer cell lines and tissues, and to explore the functions of Bfl-1 in prostate adenocarcinoma., Methods: RT-PCR, real-time quantitative PCR (Q-PCR)and in situ hybridization (ISH) were used to detect the expression of Bfl-1 mRNA in prostate cancer cell lines, tissues and benign prostate hyperplasia (BPH) tissue samples. The relationship between Bfl-1 expression and clinicopathological parameters was analyzed. Antisense oligonucleotides (ASONs) were used to interfere the expression of Bfl-1 and its effects on prostate cancer cells. MTT was used to detect the survival, morphologic changes of prostate cancer cells was observed by inverted microscope., Results: Bfl-1 mRNA, detected by RT-PCR, Q-PCR and ISH, was overexpressed in the androgen-independent prostate cancer cell lines PC-3 and DU145, but not detectable in the androgen-dependent prostate cancer cell line LNCaP and BPH tissue samples (P < 0.05). Significantly higher Bfl-1 mRNA levels were observed in higher stage and metastatic prostate cancer cases than those without metastasis or of low stage. ASONs targeting Bfl-1 significantly inhibited androgen-independent prostate cancer cell growth (P < 0.05), cell was rounding off or fragmentation., Conclusion: Bfl-1 is involved in maintaining the hormone-independent prostate cancer cell growth. Bfl-1 may become a new therapeutic target in advanced prostate cancer.

It has been well known that smoking alters the property and functionality of a wide range of immune cells including dendritic cells (DCs). However, a great deal of effort in the past has been mainly devoted to dissect the effect of smoking on pulmonary DCs, while its exact impact on circulating DCs remains to be fully addressed. Therefore, in the present report we particularly examined the impact of smoking on the number and subset of DCs in the peripheral blood by multi-parametric flow cytometry analysis. A significant increase for peripheral blood mononuclear cells (PBMCs) was noted in the smoking subjects. Subsequent studies revealed that the percentage for plasmacytoid DCs (pDCs) and total DCs in PBMCs was significantly higher in the smoking subjects as compared with that of control subjects, while the percentage for myeloid DCs (mDCs) did not differ between two groups. It was also found that the absolute number for total DCs, mDCs and pDCs were significantly higher in the smoking subjects than that of control subject. However, the mDC/pDC ratio was significantly reduced, suggesting that smoking impairs the balance of DC subsets. Given that pDCs are in favor of tolerogenic function, our data support that smoking could induce the production of pDCs to manifest immunosuppressive properties in the chronic smokers.

Objective: To study the expressions of proapoptosis protein BNIP3 and its correlation with HIF-1alpha and VEGF in clear cell renal cell carcinoma (ccRCC)., Methods: The expression levels of BNIP3, HIF-1alpha and VEGF were examined by two-step immunohistochemical staining with tissue chip technique in 104 cases of ccRCC and in 48 cases of normal renal tissues. The correlation of BNIP3 expression with HIF-1alpha and VEGF was analyzed., Result: The positive expression rates of BNIP3, HIF-1alpha and VEGF were 36.5%, 61.5%, and 69.2% in ccRCC, while were 12.5%, 8.3%, and 12.5% in paracancerous normal renal tissue, respectively. The expression of both HIF-1alpha and VEGF were not significantly increased in BNIP3 positive tumors in comparison with BNIP3 negative counterpart (P > 0.05), but there was a significant correlation between HIF-1alpha and VEGF (P < 0.05)., Conclusion: The lower expression level of BNIP3 is not coincident with the high level of HIF-1alpha and VEGF in clear cell renal cell carcinoma.

Objective: To evaluate the effect of interferon-alpha (IFN-alpha) on locally advanced clear cell renal cell carcinoma (ccRCC) after radical nephrectomy in terms of tumor progression free survival (PFS) and overall survival (OS)., Methods: 176 cases with locally advanced ccRCC were followed up in West China Hospital from 1999 to 2007. All patients were divided into two groups according to whether treated with IFN-alpha as adjuvant therapy. PFS and OS were analyzed with Kaplan-Meier method and Cox regression model., Results: Median follow-up was 48 months, 53 cases of disease progressed, and 37 were dead. Mortality rate within treatment and observed groups were 44.3% and 18.6%, respectively (P < 0.001). There were significant differences between the two groups in PFS [(59.12 +/- 5.04) months vs. (81.42 +/- 5.84) months, P = 0.005] and OS [(74.66 +/- 4.77) months vs. (85.18 +/- 4.92) months, P = 0.031]. Cox regression model demonstrated that IFN-alpha, as adjuvant therapy after surgery, was an independent negative risk factor for the prognosis of locally advanced clear cell renal cell carcinoma., Conclusion: IFN-alpha was ineffective in locally advanced ccRCC after radical nephrectomy in terms of PFS and OS, and there is no evidence that IFN-alpha could be considered as adjuvant therapeutic drug.

Objective: To compare the clinical features of severe hand foot and mouth disease between enterovirus (EV) 71 and other EV to find specific diagnosis index of EV71 severe hand foot and mouth disease., Methods: Case definition were adopted from national guideline of hand foot and mouth disease diagnose (Version 2010). Clinical data of severe hand foot and mouth disease came from case history and contents of questionnaire would include the ones between the time of onset and diagnoses being made. EV and EV71, Cox A16 nucleic acid tested were by RT-PCR in stool samples. Clinical features of severe hand foot and mouth disease between EV71 and other EV were compare., Results: There appeared statistical differences between neurologic symptoms such as tremor, myoclonic jerk, listlessness, convulsion and white blood cell counts in CSF (P < 0.05). Results from the step Fisher discriminant analysis showed only tremor and white blood cell had an increase in CSF, with statistically significant differences. The discriminant equation of EV71 was Y = 3.059X(1) + 3.83X(5) - 2.742 and the equation of other EV was Y = 1.634X(1) + 1.623X(5) - 1.693. The specificity of EV71 was 91% and the specificity of other EV was 40%., Conclusion: The increase of clinical features of tremor and white blood cell in CSF could be used as diagnosis index of severe EV71.

Objective: To investigate the urodynamic changes in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) and nocturnal polyuria., Methods: From Sept. 2002 to Jun. 2008, 23 patients with nocturnal polyuria were diagnosed as having OSAHS by polysomnography (PSG). The number and output of nocturia, the osmotic pressure and the excretion of Na(+) were recorded during both the PSG night and CPAP titrating night. Plasma levels of brain natriuretic peptide (BNP) and atrial natriuretic peptides (ANP) were also measured at 11PM in the 2 nights and 7AM in the next mornings. Urodynamic studies including urine flow, bladder pressure during filling, pressure-flow study during voiding and urethral pressure were carried out in these patients. Urodynamic studies were performed again after treatment with CPAP for 3 months., Results: PSG showed that the patients with nocturnal polyuria had moderate to severe OSAHS, in which the apnea-hypopnea index (AHI) being 48 ± 15 events per hour. The number of nocturnal voiding during the PSG night was more than that during the CPAP titrating night. During the PSG night, the output of nocturia, the nocturia excretion of Na(+), ANP levels (at 7am in the next morning after PSG night) increased and the osmotic pressure of nocturia decreased. CPAP therapy could reverse these abnormalities. The main characteristics of urodynamics in these patients included weak detrusor contraction, hypoesthesia in filling cystometry, and decreased bladder compliance, and detrusor external sphincter dyssynergia. After 3 months of CPAP treatment, both the motility of the detrusor of bladder and the bladder compliance improved., Conclusions: CPAP therapy can effectively reverse the nocturnal polyuria in OSAHS patients. In OSAHS patients, the features of nocturia, including the changes of output, osmotic pressure and the excretion of Na(+), may be related to the secretion of high-level of ANP. During the course of chronic progressively OSAHS pathophysiology, detrusor function of bladder may be damaged. CPAP therapy could decrease the nocturnal excretion of ANP, and improve the motility of the detrusor of bladder.

Aim: N,No-[oxybis(2,1-ethanediyloxy-2,1-ethanediyl)]bis(4-methyl)- benzenesulfonamide (OMBSA) is a hit compound with potent voltage-gated K+ (Kv) channel-blocking activities that was found while searching the MDL Available Chemicals Directory with a virtual screening approach. In the present study, the blocking actions of OMBSA on Kv channels and relevant mechanisms were characterized., Methods: Whole-cell voltage-clamp recording was made in acutely dissociated hippocampal CA1 pyramidal neurons of newborn rats., Results: Superfusion of OMBSA reversibly inhibited both the delayed rectifier (I(K)) and fast transient K+ currents (I(A)) with IC50 values of 2.1+/-1.1 micromol/L and 27.8+/-1.5 micromol/L, respectively. The inhibition was voltage independent. OMBSA markedly accelerated the decay time course of IK, without a significant effect on that of I(A). OMBSA did not change the activation, steady-state inactivation of IK, and its recovery from inactivation, but the compound caused a significant hyperpolarizing shift of the voltage dependence of the steady-state inactivation of I(A) and slowed down its recovery from inactivation. Intracellular dialysis of OMBSA had no effect on both I(K) and I(A)., Conclusion: The results demonstrate that OMBSA blocks both I(K) and I(A) through binding to the outer mouth of the channel pore, as predicted by the molecular docking model used in the virtual screening. In addition, the compound differentially moderates the inactivation kinetics of the K+ channels through allosteric mechanisms.

Objective: To compare the acute effects of oxygen therapy and nasal continuous positive airway pressure (nCPAP) therapy on Cheyne-Stokes respiration (CSR) in patients with stable chronic congestive heart failure (CHF)., Methods: Prior to the study, all patients had an echocardiogram performed to measure the left ventricular ejection fraction (LVEF). In addition, all patients had an initial sleep study to identify the presence of CSR. Those patients identified as having CSR were randomized to a night on 2 L/min oxygen therapy, a night on 4 L/min oxygen therapy (by nasal cannula) and another night on nCPAP therapy [mean pressure (9.1 +/- 1.1) cm H2O]., Results: Twenty-six patients stable CHF, with a mean age of 64.1 +/- 6.8, and a mean LVEF of (27.1 +/- 5.8)%, were studied, of whom 14 (53.8%) had CSR during their initial sleep study. The 14 patients had an average apnea-hypopnea index (AHI) of 34.9 +/- 8.2 events per hour, an average apnea-hypopnea length of (20.6 +/- 3.2) s, mean cycle length (74.8 +/- 21.3) s, circulation time (25.6 +/- 4.4) s, the lowest oxygen saturation during the night (76.2 +/- 4.7)%, the periods of time with a oxygen saturation of < 90% of total sleep time (20.9 +/- 8.6)%. When compared with baseline measurements, both oxygen therapy (2 L/min or 4 L/min) and nCPAP therapy significantly decreased the AHI, with 4 L/min oxygen therapy and nCPAP therapy producing the better results, with no significant difference between these two therapies. All three forms of treatment significantly increased the lowest oxygen saturation during the night to a similar extent. The mean percent time the oxygen saturation was < 90% also improved with all interventions, with 4 L/min O(2) producing the best results. In addition, 2 L/min or 4 L/min oxygen therapy and nCPAP produced similar improvements in total sleep time and sleep efficiency. When compared with baseline measurements, the apnea-hypopnea length, cycle length, and circulation time did not significantly change with either oxygen therapy or nasal CPAP therapy., Conclusion: CSR occurs frequently in patients with stable CHF. Both higher concentration oxygen and nCPAP can be used as therapeutic strategies in CHF patients with CSR.

Aim: To examine the effect of BmTx3B, a novel short-chain peptide isolated from the venom of Asian scorpion Buthus martensi Karsch, on voltage-gated potassium channels., Methods: Two types of voltage-dependent potassium currents were recorded from dissociated hippocampal neurons of neonatal rat in whole-cell voltage-clamp mode, and separated based upon their kinetic properties., Results: BmTx3B (10-100 micromol/L) selectively inhibited the delayed rectifier potassium current (I(K)), without affecting the fast transient potassium current (I(A)). The inhibition of the peptide on I(K) was reversible, concentration-dependent and voltage-independent. BmTx3B did not affect the steady-state activation and inactivation kinetics of the current., Conclusion: The short-chain scorpion peptide BmTx3B selectively blocked the delayed rectifier potassium channel.