Alzheimer's disease (AD) is a complex neurodegenerative disorder which seriously causes the dementia in elderly people and afflicts millions of people worldwide. Drug discovery for Alzheimer's disease therapy has been a hot research area and a big challenge, in which development of acetylcholinesterase (AChE) inhibitors design was the most active and some AChE inhibitors are commercially available for AD medication already. However, practical using of commercial AChE inhibitors showed their limited usefulness and related adverse effects. Thus, it is extremely urgent to find novel AChE inhibitors with higher potency and less adverse effects. Based on the accurate crystallographic studies about AChE, strategies for multi-binding site AChE inhibitors have been formed, followed by design of the multi-target directed ligands. In this review, the structures and binding modes of commercial AChE inhibitors were briefly discussed, together with the development of AChE inhibitor design for AD therapy: from multi-binding site inhibitors to multi-target directed ligands.

OBJECTIVE:To study the protective effect of Weidean tablets on rats with stress-induced gastric ulceration. METH-ODS:Water immersion restraint stress method and empty stomach were employed to establish rat models with gastric ulceration. 60 SD rats were equally randomized into normal control group(isometric sodium chloride injection),model group(isometric sodium chloride injection),ranitidine group(0.015 g/kg),and groups of high,medium and low doses(1.70,0.87 and 0.43 g/kg)of Wei-dean tablets. General situation of stomach was observed .The gastric mucosal injury index,the NO content in serum,and the activi-ties of SOD and iNOS and the contents of MDA and PGE2 in the gastric tissue were detected for rats. Pathomorphological observa-tion of rats’gastric tissues was conducted under the microscope. RESULTS:Compared with normal control group,the rats in the model group had higher gastric mucosal injury index,lower content of NO in serum,and weaker activity of SOD,stronger activity of iNOS,higher content of MDA and PGE2,in the gastric tissue. There was statistical significance (P<0.01 or P<0.05). Dark matter,severe deformation and necrosis of gastric mucosal cells in rats were noted,as well as multiple large-area superficial ulcers. Compared with the model group,the rats in groups of high,medium and low doses of Weidean tablets had lower gastric mucosal injury index,higher content of NO in serum,and stronger activity of SOD,weaker activity of iNOS,lower content of MDA and higher content of PGE2,in the gastric tissue. There was statistical significance(P<0.01 or P<0.05). General situation of stomach and the pathomorphological condition of rats’gastric tissues were improved. CONCLUSIONS:Weidean tablets has protective ef-fect to some extent on rats with stress-induced gastric ulceration,the mechanism is related to the improvement of serum levels of anti-oxidation index in rats.

Objective To obtain the classification and characteristics of acupuncture manipulations by analyzing teacher's lifting-thrusting manipulation parameters derived from Germany-made Simi Motion 3D image analysis system using self-organizing feature map neural network (SOM). Method Thirty acupuncture teachers were selected for the study. Unilateral Quchi (LI11) was used as a point for acupuncture. A motion video of lifting-thrusting even reinforcing-reducing, reinforcing and reducing manipulations was made. The video was analyzed using Simi Motion 3D image analysis system to obtain original motion parameters at thumb tip tracking mark point. Teacher's manipulation classification parameters were analyzed using SOM. Result Acupuncture manipulation parameters showed nonnormal distribution with larger dispersion. Even reinforcing-reducing and reinforcing manipulations could be classified into four types and reducing manipulation, into five types. The characteristics of every type showed general concentration degree. Conclusion Acupuncture manipulation parameters overall showed the diversity characteristics of nonnormal distribution and are typical artificial control curve. They have the characteristic of lower concentration degree of neural network classification. Their classification is mainly based on curve shape and cycle length and related to the degree of difficulty of manipulation. This technique can be applied to the quantitative analysis of various manipulationsand the study of technical inheritance and provide reference for the standardization of acupuncture manipulation.

ObJective To observe the efficay and adverse reactions of olmesartan combined with hydrochlorothiazide on patients with primary moderate hypertension,compared with the therapy of benazapril associated with amlodipine.Methods 116 primary moderate hypertension patients were randomly divided into the treatment group and control group.Patients in treatment group were treated with olmesartan combined with hydrochlorothiazide oral administration,and control group were given benazapril combined with amlodipine oral administration,which lasted for 3 weeks.Every subject was measured blood pressure before and after the drug administration and observed adverse reaction.Cardiac hypertrophy was detected by UCG.A comparison was made in effectiveness of the drug and cardiac hypertrophy between two groups.Results There was significant difference in effectiveness of two anti-hypertension therapies,and cardiac hypertrophy in the treatment group was lighter than that in control group.Conclusion The therapy of olmesartan combined with hydrochlorothiazide was more effective than that of benazapril combined with amlodipine,also more depressed cardiac hypertrophy.

OBJECTIVETo investigate the lead exposure, its effects, and the relationships between biomarkers of susceptibility in the workers with low-level occupational lead exposure, and to explore its sensitivity and practical value to evaluate the health hazard.

METHODSThe concentrations of lead fume and lead dust in workplaces of a lead acid storage battery enterprise in Jiangsu Province, China, were measured by occupational health monitoring method. The blood samples of 233 workers with occupational lead exposure and 76 non-occupational lead exposure were collected to measure the blood lead (Pb-B) level using graphite furnace atomic absorption spectrometry (GFAAS), the zinc Protoporphyrin (ZPP) level with blood fluorescence assay, and the delta-aminolevulinic acid dehydratase (ALAD) concentration by a spectrophotometer, and to determine the gene polymorphism of ALAD with TaqMan real-time polymerase chain reaction. At the same time, their urine samples were collected to measure urine lead (Pb-U) concentration with GFAAS and delta-aminolevulinic acid (ALA-U) concentration with a spectrophotometer. The correlations between the above indices were analyzed by multiple linear regression method.

RESULTSThe concentration of lead fume in 18 testing sites and the concentration of lead dust in 30 testing sites were 0.002-0.019 mg/m3 and 0.004-0.013 mg/m3, respectively. Pb-B level was positively correlated with Pb-U concentration (r=0.62, P<0.01) and ZPP level (r=0.47, P<0.01) and was negatively correlated with ALAD concentration (r=-0.77, P<0.01) in 233 workers with occupational lead exposure. Among 233 workers, 218 (93.6%) had ≤70 µg/L Pb-U, and 15 (6.9%) had ≥400≥g/L Pb-B. Pb-B level was not correlated with ZPP level as Pb-B level was <190 µg/L (r=0.18, P=0.068 ), while Pb-B level was positively correlated with ZPP level as Pb-B level was ≥190 µg/L (r=0.36, P<0.01). Pb-U concentration was positively correlated with ALA-U concentration (r=0.49, P<0.01) and ZPP level (r=0.47, P<0.01). ZPP level was negatively correlated with ALAD concentration (r=-0. 19, P<0.01), and was positively correlated with ALA-U concentration (r=0.27, P<0.01). ALAD concentration was not correlated with ALA-U concentration (r =-0. 11, P>0.05). And in 233 workers with occupational lead exposure, there were no significant differences in Pb-B level, ZPP level, and ALAD activity between the workers with ALAD1-2 genotype and the workers with ALAD1-1 genotype (P>0.05). In 76 workers with non-occupational lead exposure, there was no significant difference in Pb-B level between the workers with ALAD1-2 genotype and the workers with ALAD1-1 genotype (P >0.05). The workers with ALAD1-2 genotype had a significantly lower ALAD activity, and a significantly higher ZPP level compared with those ALAD1-1 genotype (P<0.01).

CONCLUSIONIn the workers with low-level occupational lead exposure, ZPP level is positively correlated with Pb-B level when Pb-B level was ≥190 µ/L. ALAD could be used as an effect biomarker of low Pb-B level. ALAD gene polymorphism shows different effects on the Pb-B level and the toxic effects between the workers with occupational lead exposure and the workers with non-occupational lead exposure.

Aminolevulinic Acid ; blood ; Biomarkers ; blood ; China ; Electric Power Supplies ; Genotype ; Humans ; Lead ; blood ; Linear Models ; Occupational Exposure ; Polymorphism, Genetic ; Porphobilinogen Synthase ; blood ; genetics ; Protoporphyrins ; blood

Objective To establish small-for-size (SFS) graft injury models in miniature pigs with high standardization, reproducibility and similarity to clinical situation. Methods Ba-Ma miniature pigs were introduced in this study and orthotopic liver transplantations (OLTs) were performed in 12 pigs with 30% liver volume allogeneil grafts (small portion of right paramedian lobe, right lateral lobe and caudate lobe) without veno-venous bypass. The profiles of intra-operational hemodynamics and metabolism were investigated. Animals were observed for 7 days with daily serum biochemistry and coagulation function exam. The survival rate related to operation itself and the SFS grafts were respectively calculated as well as the graft regenerative ratio at post-operational day (POD) 7. Results Graft weight as a percentage of the recipient's native liver weight (GW/RLW) and the total body weight (GW/BW) were (28. 63±4. 42)% and (0. 73±0.06)%. The mean operation time, anhepatic phase, and the time of blockage of infra-hepatic IVC were (191. 7±14. 2) min, (28. 3±3. 6) min, and (45. 0±5. 8) min. The survival rate related to the operation itself and the SFS graft were 83. 33% (10/12) and 40% (4/10), and the graft regenerative ratio at POD7 was (278. 06±42. 95) %. Contrast to the remarkable increase of heart rate and serum potassium during anhepatic phase, the mean arterial pressure, central venous pressure, rectal temperature, PH value and buffer excess had a significant decrease (P<0.01) with a gradual recovery after reperfusioa Serum ALT, AST, PT, Cr, and TB were significantly increased with a peak level at POD1 for the former 4 and POD2 for TB, and then began to decrease and favorably recovered at POD7, but TB, PT, and AST levels were still high when compared to those of prereperfusion (P<0. 05). Conclusion This model of OLT performed with 30% liver volume graft without veno-venous bypass was an ideal large animal model for series studies related to SFS graft injury.

OBJECTIVE:To explore the effect of Compound pueraria tablets on the kidney tissues of diabetic nephropathy rats. METHODS:High sugar and lipid diet combined with intraperitoneal injection of streptozotocin were used to establish the model of diabetic nephropathy (DN). Normal control group was established. Model rats were randomly divided into model control group, positive control group(Irbesartan tablet),Compound pueraria tablets low-dose,medium-dose and high-dose [0.102,0.203,0.406 g/(kg·d)] groups(n were 8-10). The corresponding drugs were given,and fasting blood glucose(FBG)and 24 h urinary protein (Upro) were collected at 1st,14th,28th,42nd,56th day after treatment. SCr,BUN,TC,TG and KI were detected,and renal pathology was observed after the last dose. RESULTS:Compared with normal group,FBG of those groups were all increased after modeling,and 24 h Upro of them were all increased after 28th day (P<0.05 or P<0.01). Compared with model control group, FBG of Compound pueraria tablets medium-dose and high-dose groups were all decreased since 42nd day (P<0.05 or P<0.01), and 24 h Upro of Compound pueraria tablets groups were all decreased since 28th day(P<0.05 or P<0.01);BUN,TC,TG and KI of Compound pueraria tablets in medium-dose and high-dose groups were all decreased significantly,and SCr of 3 dose groups were all increased (P<0.05 or P<0.01). The morphological structure of renal cells was improved significantly in drug treatment groups. CONCLUSIONS:Compound pueraria tablets can correct lipid metabolism disorder,reduce Upro and improve renal func-tion,indicating certain protective effect on the kidney tissues of diabetic nephropathy rats.

OBJECTIVE:To study the effect of Compound pueraria tablets on osteoporosis model rats induced by retinoic acid. METHODS:The osteoporosis model was induced by intragastric administration of retinoic acid solution for 15 days;normal group was established. After modeling,the rats were randomly divided into model control group,Xianling gubao capsule [0.32 g/(kg·d)] positive control group,Compound pueraria tablets low-dose and high-dose [0.24,0.4 g/(kg·d)] groups (n=8). After 6 weeks of ig,the serum sample was collected to determine the levels of serum calcium(s-Ca),serum phosphorus(s-P),ALP and bone gla protein (BGP);bone density instrument was used to detect the contents of bone mineral density (BMD),bone mineral content (BMC),bone image area (BIA) and muscle content (MC);the results of compact bone substance scanning were observed. RE-SULTS:Compared with normal group,the levels of s-Ca,BMD,BMC and MC in rats were decreased in model control group, while the level of BGP was increased(P<0.05 or P<0.01). Compared with model control group,related index and compact bone substance scanning of Compound pueraria tablets groups were all improved;the levels of s-Ca,s-P,ALP,BMD and MC were in-creased in Compound pueraria tablets high-dose group,while the level of BGP was decreased;the levels of BMD and MC were in-creased significantly in Compound pueraria tablets low-dose group(P<0.05 or P<0.01). CONCLUSIONS:Compound pueraria tab-lets can improve the osteoporosis induced by retinoic acid in rats.

Objective To explore the effect of calreticulin (CRT) on cell proliferation and invasion of human hepatocellular carcinoma cell line SMMC-7721 and HepG2.Methods SMMC-7721 and HepG2 cells were transfected with small interfering RNA (siRNA).The transfection rate was detected by immunoflurescence and western blot.The cell proliferation,invasion and apoptosis of SMMC-7721 and HepG2 cells were determined by using cell counting kit-8 (CCK-8) assays,transwell assays and flow cytometry,respectively.The p-Akt and Akt levels were detected by western blot.Results The growth inhibition rate in the siRNA experimental group of SMMC-7721 and HepG2 cells for 24,36 and 48 h were (41.0 ±2.2) ％,(46.5 ±1.6)％,(59.7 ±2.2)％ and (36.8 ±2.7)％,(47.3 ± 1.8)％,(61.5 ±3.2)％,respectively.The apoptosis rate after down-regulating the expression of CRT in SMMC-7721 and HepG2 cells for 36h were (45.2 ± 9.1) ％ and (48.9 ± 8.0) ％,respectively.Compared with the blank group and the negative control group,the growth inhibition rate in the siRNA experimental group was lower (P ＜0.05),but the apoptosis rate was significantly higher (P ＜ 0.05).Transwell experiments confirmed that the numbers of invaded SMMC-7721 and HepG2 cells in the blank group and the negative control group and siRNA experimental group were (96.8±7.3),(95.6±5.4),(34.0±4.2) and (124.0 ±9.9),(121.6 ±7.0),(70.4±9.5),respectively,indicating that cell invasion in the siRNA experimental group was significantly suppressed (P ＜ 0.05).The expression of p-Akt was decreased (P ＜ 0.05) after down-regulating the expression of CRT for 36h.Conclusion CRT gene silencing by siRNA can inhibit the SMMC-7721 and HepG2 cell proliferation and invasion,but increase the cell apoptosis by regulating PI3K/Akt signal pathway.

Objective To investigate the predictive value of IL-9 cytokines in the patients with acute respiratory distress syndrome (ARDS).Methods According to Berlin definition of ARDS published in 2012,data of 28 patients with ARDS and another 22 healthy subjects as control were collected for prospective study from June,2013 to July,2014.Of them,there were 23 patients with severe pneumonia,1 patient with acute mercury poisoning,2 patients with severe acute pancreatitis,2 patients with acute paraquat poisoning.The survivors of ARDS patients were followed up.The ARDS patients were divided into moderate group (n =18) and severe group (n =10) as per the severity of the disease diagnosed at the first day after admission.And the ARDS patients were also divided into non-survival group (n =15) and survival group (n =13) according to the ARDS patients survived for 28 days.Three mLs of peripheral venous blood were collected in the early morning from fasted ARDS patients on the first and the third day after diagnosis of ARDS confirmed,and those of healthy subjects were collected on the first day after admission.The IL-9 cytokine level of peripheral venous blood detected by using enzyme linked immunosorbent assay (ELISA).The comparisons of levels of IL-9 cytokine were carried out between ARDS group and control group on the first day after diagnosis of ARDS established,between moderate group and severe group on the first day and the third day,and between survival group and non-survival group.The receiver operating characteristic (ROC) curve was used to evaluate the performance of IL-9 as a prognostic indicator in the early stage of ARDS.Data were analyzed by using SPSS 19.0 software.Results On the first day after diagnosis of ARDS,there were no statistically significant differences in age,APACHE Ⅱ score,procalcitonin (PCT),C-reactive protein (CRP),white blood cell count,lactate,and albumin between survival group and non-survival group (P ＞ 0.05).PH value in non-survival group was significantly lower than that in survival group (P＜0.05).IL-9 cytokine level of peripheral venous serum in ARDS group was significantly higher than that in healthy control group (P ＜ 0.05).There were no statistically significant differences in IL-9 level of peripheral venous serum both between moderate group and severe group and between survival group and non-survival group (P ＞ 0.05).On the third day,IL-9 level in severe group was significantly higher than that in moderate group (P ＜ 0.05),and that in survival group was significantly lower than that in non-survival group (P ＜ 0.05).The ROC of IL-9 at the first day for predicting mortality had all area under curve (AUC) to be 0.579 (95％ CI 0.361-0.798,P ＞ 0.05).The ROC of IL-9 on the third day for predicting mortality had AUC of 0.769 (95％ CI 0.592-0.947,P ＜ 0.05).When the cut-off value of IL-9 for the death followed up for 28 day' s was 2.88 pg/mL,the sensitivity was 86.7％,and the specificity was 61.5％.Conclusions IL-9 levels of in patients with ARDS were significantly higher,and IL-9 level can be helpful for the assessment of ARDS severity in the early stage,and for prognosis as well.