In recent years,the role of phosphodiesterase 5(PDE5)has been highlighted in the development and progression of neurological disease.PDE5 inhibitors show significant effect of neruoprotection,which may be related with some effects such as resistance to stroke,anti-oxidation,inhibition of neuroinflammation and amelioration of cognitive deficits.Based on the domestic and overseas researches about PDE5,this review systematically summarized the neuroprotection of PDE5 and their related mechanisms.

BACKGROUND: Mesenchymal stem cell (MSC) transplantation has been gradually developed to improve the prognosis of cerebral infarction and its sequelae in clinical trials, which has been identified as effective and safe. A small sample size, however, results in the lack of evidence-based medical evidence.OBJECTIVE: To systematically review the efficacy of MSC transplantation on the prognosis of cerebral infarction. METHODS: In order to collect randomized controlled trials (RCTs) of MSC transplantation for the prognosis of cerebral infarction, we searched Cochrane Library, PubMed, Ovid, CBM, CNKI, WanFang, and VIP Data from its inception to November 2016. Articles addressing MSCs transplantation alone or with conventional drug treatment and/or rehabilitation training versus conventional drug treatment alone or with rehabilitation training were included. Two authors independently screened the literature according to the inclusion and exclusion criteria, extracted data, and assessed the risk of bias. Thereafter, qualitative description and Meta-analysis were performed. RESLUTS AND CONCLUSION: Ten RCTs involving 626 cerebral infarction patients were included in the Meta-analysis. The results showed that the MSCs group was superior to the control group with statistical significance in the daily life ability(Barthel index)[MD=20.06, 95%CI(9.95,30.18),P=0.000 1],motor function(Fugl-Meyer scale)[MD=14.60,95% CI(12.96,16.25),P<0.000 01],personal disability (functional independent measure)[MD=15.16,95%CI(9.06,21.26),P<0.000 01]and neurological deficit score(National Institute of Health stroke scale)[MD=-2.59,95% CI(-3.14,-2.05),P<0.000 01].Low fever and mild headache were reported by four included studies,and waist pain was only by one study, but these symptoms went away by themselves or after symptomatic treatment. Subgroup analysis suggested that MSCs from the bone marrow were superior to those from the umbilical cord and cord blood, but showed a greater heterogeneity. It is suggested that the MSC transplantation ameliorate the prognosis in patients with cerebral infarction, significantly improve the activities of daily living, motor function, personal disability and neurological function, with no presence of serious adverse effects. However, high-quality studies with large sample size are required for further investigation on the clinical application of MSC transplantation.

Experimentalanimalsareimportantbasisforlifescienceresearchanddevelopment.Alongwiththe continuous development of science and technology , new technology and new ideas emerging , treatment and protection of animals during experiments are important condition to ensure the scientific results accurate and reliable , so scientists have paid more attention to the issues of animal welfare and protection .This article summarizes the animal treatment and protection measures during experiments based on both own work and experience and knowledge of other scientists .

Objective To investigate the correlation between asymmetric dimethylarginine (AD-MA) and endothelial dysfunction in patients with uremia.Methods Uremic patients who did not receive hemodialysis were defined as A group (n =40) ; uremic patients who had received hemodialysis were divided into B group (n =45) ;healthy people were defined as C group (n =20) ;and chronic kidney disease (stage 2 ～ 4) patients were defined as D group (n =20).The diameter of intima-media thickness,and endothelium-dependent or independent dilation (EDD or EID) of radial artery in right forearm were detected with diasonography.The levels of ADMA were determined by high-performance liquid chromatography.Results Compared to C group,the levels of ADMA in A,B and D groups were significantly increased [C:(0.78 ±0.19) μmol/L,A:(1.51 ±0.16) μ mol/L,B:(1.13 ±0.14) μmol/L,D:(0.92 ±0.11) μmol/L; P ＜0.05].Compared to A group,the levels of ADMA were significantly decreased in B group (P ＜0.05).EDD and EID were decreased significantly in A,B and D groups compared to C group [EDD:C:(13.52±1.73)％ vs A:(7.32 ±0.54)％,B:(9.02 ±0.86)％,D:(10.13 ±1.25)％,P ＜0.05;EID:C:(14.45±1.85)％ vsA:(10.37 ±1.51)％,B:(9.54±1.39)％,D:(11.17±1.56)％,P ＜0.05].EDD in B group was significantly lower than A group (P ＜0.05).In group A,a negative correlation was found between EDD and the level of ADMA (r =-0.81,P =0.020).Conclusions ADMA level was significantly increased in uremic patients.A close correlation existed between ADMA and endothelial dysfunction of radial artery.

Objective To investigate the pathomorphology effects of memantine on organs in neonatal rats.Methods Sixty-eight neonatal rats were randomly divided into 7 groups:5 groups by different doses memantine intraperitoneally and the controls by water intraperitoneally.The pathomorphology changes of organs were observed in all dead neonatal rats promptly after administration of memantine and in all survived rats after 7 days recover.Results 1.The ratio of organ weight and body weight in dead neonatal rats were higher than those of controls.2.The result of pathomorphology indicated that neurodegeneration and necrosis in the brain,the liver congestion and cell degeneration.The other organs had not distinct changes.3.The pathologic changes and mortality rate of neonatal rats were positively correlated with the dosage of memantine.Conclusion Memantine will affect liver and brain of neonatal rats.

Objective To investigate the lipid hepatoprotective effect of silibinin on high fat diet-induced nonalcoholic fatty liver (NAFL) rat model and provide a theoretical basis for the treatment of silibinin on NAFL.Methods The NAFL rat model was established by administration of high fat emulsion and high fat diet.Rats in control group was treated with saline and normal diet.The model rats were randomly divided into model group,simvastatin (positive drug,1.8 mg/kg) group,Silibinin groups with low,middle and high doses (18.9,37.8 and 75.6 mg/kg).From the fifth week,NAFLrats were treated with different drugsonce a day for eight weeks.All rats were anaesthetized after final administration,Livertissues were weighed for the calculation of hepatic coefficient The hepatic morphology was observed through HE staining.Serum was obtained from abdominal aortic blood for detection of triglyceride separation (TG),total cholesterol (TC),high density lipoprotein (HDL),low-density lipoprotein (LDL),aspartate aminotransferase (AST),and alanine aminotransferase (ALT) levels.Results After eight-week treatment,compared with model group,middle and high doses of silibinin could significantly improve the hepatic steatosis.The levels of hepatic coefficient,serum TC,TG,AST and ALT in rats treated with individual dose of Silibinin were significantly decreased (P ＜ 0.05,0.01).Particularly,high dose of silibinin significantly reduced LDL level whereas elevated HDL level in serum (P ＜ 0.01).Conclusion Silibinin has a therapeutic effect on nonalcoholic fatty liver rats,and possible mechanism is related to lipid-lowering and hepatic protection.

Objective:To study the functional connectivity (FC) and metabolic effective connectivity (MEC) patterns of the default mode network (DMN) in healthy male adults based on a novel hybrid PET/MR system.Methods:Fifteen healthy male adults with median age of 29 years were recruited locally in Xi′an from January to May 2019. All subjects went through PET/MR scan to get the whole brain 18F-fluorodeoxyglucose (FDG) PET, resting-state functional MRI (fMRI) and magnetization prepared rapid gradient echo (MPRAGE) T 1 weighted imaging data. CONN18b and statistical parametric mapping (SPM) 12 softwares were used to analyze data. The voxel-wise FC and FDG metabolic data were extracted within 4 sub-networks of DMN, which included medial prefrontal cortex (MPFC), posterior cingulate cortex (PCC) and bilateral lateral parietal (LP). The FC and MEC between 4 sub-networks were calculated based on merged resting-state fMRI and metabolic data, and analyzed by one-sample t test separately, with Bonferroni correction. Results:FC pathways were all significant within 4 sub-networks of DMN ( t values: 6.00-7.71, all P<0.008, Bonferroni corrected). Meanwhile, there were significant bi-directional MEC between MPFC and PCC(MPFC to PCC: t=10.03; PCC to MPFC: t=3.73, both P<0.004, Bonferroni corrected), as well as between bilateral LP (LP_L to LP_R: t=5.28; LP_R to LP_L: t=4.76, both P<0.004, Bonferroni corrected). There were significant uni-directional MEC from both MPFC and PCC to bilateral LP ( t values: 3.44-6.93, all P<0.004, Bonferroni corrected). Conclusions:Special FC and MEC patterns exist within DMN. The closely interrelated MPFC and PCC play more important roles in DMN, and they may mediate LP jointly. The novel integrated PET/MR system will bring new perspective on the organization of brain networks, which may deepen the comprehensive understanding of DMN.

Objective To explore the protection of valsartan combined with simvastatin on kidney in early diabetic nephropathy rats. Methods Diabetic nephropathy rats model were induced by streptozocin (STZ) ,the experimental rats were randomly divided into 5 groups: control (group C), diabetic nephropathy (group D) ,diabetes treated with valsartan (group X) ,diabetes treated with simvastatin (group Z) ,and diabetes treated with combined valsartan and simvastatin ( group L). Blood glucose (BG), HbA1c, blood cholesterol ( TC), trigalloylglycerol ( TG ), blood ureanitrogen ( BUN ), serum creatinine (SCr) , urinary albumin excretion rate (UAER) were measured, and the podocyte ultrastructure was observed by transmission electronic microscopy. Results The levels of BG, HbA1c,TC,TG and UAER in group D increased significantly compared togroup C(BG:[20.3 ±3.2]mmol/L vs [6.1 -±0. 4]mmol/L;HbA1c:[7.18 ±0.47]% vs [3.37 ±0. 15]% ;TC: [2. 69 ±0. 35] mmol/L vs [1.28 ±0. 24] mmol/L;TG: [3.09 ±0. 37] mmol/L vs [1.18 ±0. 25]mmol/L) (P ＜ 0. 05 ). Creatinine clearance rates (Ccr) in group D ( [0. 89 ± 0. 19] ml/min ) decreased significantly compared to group C( [1.27 ±0. 33] ml/min) ,as well as group X,Z and L( Ps ＜ 0. 05 ). UAER in group D was significantly higher than that in group C ( [19. 87 ±3. 85] μg/24 h vs [3. 67 ± 1.01] μg/24 h) (P ＜ 0. 05 ), as well as group X, Z and L ( P ＜ 0. 05 ), and the improvement in group L was particularly significant ( P ＜ 0. 05 ). The projections of podocyte in group D severely syncretized, there were slightly improvement in group X, Z and L compared to group D, and the improvement in group L was remarkable. Conclusion The treatment with valsartan, simvastatin and their combination will effectively protect the kidney in early diabetic nephropathy rats,and the effect of using the combination therapy is much better.

Background The proliferation and migration of vascular endothelial cells is a primary link during angiogenesis.Studies showed that heat shock protein B6 (HspB6) promotes the secretion of multiple angiogenesis-related factors and therefore leads to neovascularization.Understanding the effects of neutralizing HspB6 antibody on the biological behavior of human choroidal vascular endothelial cells has an important significance in the target treatment of choroidal neovacularization diseases.Objective This study was to address the role and mechanism of neutralizing HspB6 antibody in tube formation of human choroidal vascular endothelial cells.Methods Human choroidal vascular endothelial cell line was normally cultured and harvested for total RNA extraction.Expressions of HspB6 mRNA and protein in human choroidal vascular endothelial cells were detected by reverse transcription PCR (RT-PCR) and flow cytometry (FCM).The cells were seeded on 96-well plate covered with matrigel at the density of 2×104/hole.Then the neutralizing HspB6 antibody at the concentration of 100 μg/Land 500 μg/L was added into the medium respectively,and the control cells were set without the addition of HspB6 antibody.The number of capillary tubes was calculated 12 hours after culture by three-dimensional matrigel assay.In addition,0,50,100,500 μg/L of neutralizing HspB6 antibody were added into the cell medium separately for 24hours,cell counting kit-8 (CCK-8) method was employed to assay the inhibitory rate(IR) of the cells.Transwell test was used to count the cell number across chamber membrane for the evaluation of migration ability of the cells.The apoptosis of the cells was assayed by FCM.Results Both HspB6 mRNA and protein were expressed on human choroidal vascular endothelial cells.The number of capillary tube formation of human choroidal vascular endothelial cells was (67.25±5.75),(60.39±6.41) and (39.76±10.73) /field in the 0,100 and 500 μg/L neutralizing HspB6 antibody groups,with significant difference among them (F =10.210,P =0.012),and the tube number was significantly less in the 500 μg/L neutralizing HspB6 antibody group compared with 0 μg/L neutralizing HspB6 group (P =0.005).The IR of neutralizing HspB6 antibody to the cellular proliferation and migration was enhanced with the increases of concentration and time lapse(Fconcentration =7.485,P =0.002 ; Ftime =16.684,P =0.001).The number of the cells through Transwell chamber membrane was 14.0 ± 2.5,11.1 ± 0.8,6.6 ± 0.1,6.7 ± 0.2 in the 0,50,100,500 μg/L neutralizing HspB6 antibody group respectively,and that in the 100 μg/L and 500 μg/L neutralizing HspB6 antibody group was lessened in comparison with the 0 μg/L neutralizing HspB6 antibody group(both at P=0.000).The apoptosis rate of the cells was (22.73 ± 2.53)％ in the neutralizing HspB6 antibody group,which was significantly lower than (13.33±2.08) ％ of the control group (t=4.967,P=0.008).Conclusions Neutralizing HspB6 antibody inhibits capillary tube formation of human choroidal endothelial cells in vitro in dose-and timedependent manner,probably through suppressing the proliferation and migration and promoting the apoptosis of choroidal endothelial cells.

OBJECTIVE To explore potential proarrhythmic effect and underlying mechanism of azithromycin (AZM) and Shengmai injection (SM) used clinically.METHODS ① In vivo guinea pig ECG recordings were made to analyze effects of jugular intravenous(iv) injection of AZM [38.2 mg· kg-1,one time (clinically relevant dose,CRD)],or SM (4.6 mL· kg-1,one time CRD) or their combination.②In vitro ECG recordings were made to analyze effects of AZM,SM or AZM + SM on ECG in isolated hearts of guinea pigs.AZM [one,five and ten times (clinically relevant concentrations,CRC)] was perfused in this order:41.5 →207.5 → 415 mg· L-1 and SM (one,five and ten times CRC) in this order:5 →25 →50 mL· L-1.Also,AZM (41.5 mg· L-1,one time CRC) +SM (5 mL· L-1,one time CRC) was perfused to isolated hearts of guinea pigs.③ Enzymatically isolated cardiomyocytes from guinea pig left ventricles were perfused in this order:AZM 41.5 mg· L-1 →AZM 41.5 mg· L-1+SM 5 mL· L-1 for action potential,L-type Ca2+ and Na+ current recordings,respectively.RESULTS ① Neither AZM 38.2 mg· kg-1,nor SM 4.6 mL· kg-1 significantly changed the in vivo ECG.However,AZM 38.2 mg· kg-1 +SM 4.6 mL · kg-1 significantly reduced heart rate (P＜0.05) and prolonged the P-R (P＜0.05) and QRS (P＜0.05) intervals.②AZM 41.5,207.5 and 415 mg· L-1 reduced heart rate (P＜0.05) and prolonged the P-R (P＜0.05) and QRS (P＜0.05) intervals in a concentration-dependent manner.AZM 415 mg·L-1 also prolonged QTc (P＜0.05) interval.SM 5,25 and 50 mL· L-1 reduced heart rate (P＜0.05) and prolonged the P-R interval (P＜0.05) in a concentration-dependent manner.SM had no effect on QRS or QTc intervals.Washout partially recovered the above changes.Moreover,AZM 41.5 mg· L-1 + SM 5 mg·L-1 significantly reduced heart rate (P＜0.05) and prolonged the P-R (P＜0.05) and QRS intervals.③ AZM 41.5 mg·L-1 did not significantly change the action potential amplitude (APA),action potential durations at 50％ (APD50) and 90％ (APD90) repolarization levels,or L-type Ca2+ and Na+ currents.However,AZM+SM 5 mg· L-1 significantly reduced APA (P＜0.05),shortened APD50 (P＜0.05) and APD90 (P＜0.05) and inhibited the L-type Ca2+ (P＜0.05) and Na+ (P＜0.05) currents.CONCLUSION AZM and SM has potential prorrhythmic risks.The combined use might cause higher risk of arrhythmia.The underlying mechanism for proarrhythmia is mediated by inhibition of the L-type Ca2+ and Na+ currents.