A physiologically-based pharmacokinetic model adequately predicted the human pharmacokinetic profiles of ZSP1601, a novel pan-phosphodiesterase inhibitor / 药学学报

ZSP1601, a novel pan-phosphodiesterase inhibitor is in development for the treatment of nonalcoholic steatohepatitis. A physiologically-based pharmacokinetic (PBPK) model was developed to predict the pharmacokinetics of ZSP1601 in human. The PBPK model following intravenous and oral dose of ZSP1601 in rats and dogs was firstly built using preclinical in vitro and in vivo data. The PBPK model in human was then built based on models in animal. The in vitro-in vivo extrapolation (IVIVE) method and some allometric scaling methods were used to predict the clearance in human, respectively. The PBPK models using IVIVE and allometry of unbound CL plus the rule of exponents methods predicted the pharmacokinetics of ZSP1601 in healthy Chinese subjects successfully. The predicted parameters Cmax and AUC following single oral dose administration were within 0.5-2 folds of the observed data. The model was optimized and the final model was used to predict the pharmacokinetics of ZSP1601 in North European Caucasian, Geriatrics, Obese and Morbidly Obese, respectively. Animal studies were approved by the Animal Management and Use Committee of Suzhou AppTec Inc., and the approved No. is SZ20140916.

Efficacy and safety of Ahmed glaucoma valve implantation with lens extraction in neovascular glaucoma with cataract / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM:To assess the efficacy of Ahmed glaucoma valve implantation combined with lens extraction for neovascular glaucoma(NVG)with cataract.<p>METHODS: A retrospective comparative study was designed. 93 patients with NVG were enrolled. All patients received preoperative anti-vascular endothelial growth factor(VEGF)injections, 41 eyes underwent Ahmed glaucoma valve(AGV)implantation only, and 52 eyes underwent AGV implantation and lens extraction by phacoemusification. The best corrected visual acuities(BCVA), intraocular pressure(IOP), and surgical complications were evaluated.<p>RESULTS: Postoperative visual acuity was improved in 16 eyes(39%), decreased in 14 eyes(34%), unchanged in 11 eyes(27%)in group 2, and 15 eyes(29%)improved,24 eyes(46%)decreased, 13 eyes(25%)unchanged in group 1 respectively(<i>P</i>>0.05). The group 2 demonstrated an 51% complete and 22% qualified success rate and 27% failure rate, and the 44% complete and 25% qualified success rate and 31% failure rate in group 1(<i>P</i>>0.05). Among the complications, fibrous exudation(56%)was the first, hyphema(46%)came second in group 2, while shallow anterior chamber(35%)was the most, fibrous exudations(31%)and anterior chamber hyphema(25%)followed in the group 1. And no tube extrusion serious complication had occurred in both groups(<i>P</i><0.05). No significant differences in postoperative complications were observed between the groups(<i>P</i>>0.05).<p>CONCLUSION: For NVG with cataract, AGV implantation with lens extraction is a priority for reduction of IOP and improvement of visual acuity.

Mandibular torus variation of Chinese ancient population / 解剖学报

Objective To present the performance of mandibular torus of Chinese in the Holocene, to analyze the age variation and the intercrowd variation of the mandibular torus and to explore related reasons. Methods Image comparison and combination description of the mandibular torus with seeds of the specified size, such as peanuts, soybeans, pumpkin seeds, etc,and compare them in different eras,genders,and locations. Results The result showed that the male's mandibular torus was distinctively stronger than that of the female. It was larger in the Neolithic Age than in the Bronze and Iron Age and the size decreased further as human beings moved into the modern era. Iri comparison of mandibular torus in different locations, Jiangjialiang was the largest, Xinjiang was the second, and Tuchengzi and Lamadong were the smallest. Conclusion During the Holocene period, the degree of bulging of the mandibular torus is reduced from time to time, and the difference in the performance of the mandibular torus may be closely related to the difference in mastication pressure caused by food differences.

Curcumin induces apoptosis by PTEN/PI3K/AKT pathway in EC109 cells / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To study the molecular mechanism of curcumin in human esophageal carcinoma cell line (EC109).</p><p><b>METHODS</b>EC109 cells were cultivated in vitro. When 80%-90% confluence was reached, they were treated with curcumin in different concentrations (15-120 µmol/L). The effects on cell proliferation were examined by CCK-8 colorimetry. The ultrastructure of EC109 cells were detected with transmission electron microscope(TEM). The cells apoptosis was observed with laser confocal microscope(LCM) by AnnexinV-FITC/PI double staining. The proteins level of PTEN, AKT, GSK3β and Caspase 3 were tested by flow cytometry(FCM) .</p><p><b>RESULTS</b>CCK-8 test showed that curcumin could inhibit the proliferation of EC109 cells in a time- and concentration-dependent manner. TEM and LCM examinations indicated that curcumin could make EC109 cells apoptosis. The data of FCM showed that curcumin could increase the expression of PTEN, GSK3β and Caspase 3, decreased the expression of AKT.</p><p><b>CONCLUSION</b>The effects of curcumin on inhibiting proliferation and promoting apoptosis of EC109 cells were related with increased expression of PTEN and inhibition of PI3K/AKT signaling pathway.</p>

Effect of matrine on Fas, VEGF, and activities of telomerase of MCF-7 cells / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To study the effect of matrine on Fas, VEGF, and activities of telomerase of MCF-7 cells.</p><p><b>METHODS</b>In vitro cultured human breast cancer MCF-7 cells were randomly divided into the experimental group and the control group. The matrine solution was added in cells of the experimental group. Equal volume of culture medium was added in cells of the control group or the negative control group. Zedoary Turmeric Oil, the telomerase inhibitor was added in cells of the positive control group. Morphological changes were observed under an inverted microscope. The telomerase activity was detected by TRAP-ELISA. Expressions of Fas and VEGF protein were detected by immunocytochemical assay.</p><p><b>RESULTS</b>Matrine obviously inhibited the growth and induced apoptosis of breast cancer cells. MCF-7 cells were treated by matrine of different concentrations at 24, 48, and 72 h, the telomerase activity gradually decreased along with increased matrine concentration and prolonged action time, showing dose-effect and time-effect positive relations. Matrine could up-regulate Fas protein expression and downregulate VEGF protein expression of MCF-7 cells.</p><p><b>CONCLUSION</b>Matrine showed obvious effect in inhibiting the growth of MCF-7 cells and promoting the apoptosis, which might be achieved by up-regulating the expression of Fas protein, inhibiting telomerase activity induced apoptosis of breast cancer cells, down-regulating the expression of VEGF protein, and inhibiting the tumor vascular formation.</p>

Effects of transforming growth factor-β2 on human Tenon fibroblasts transformation and scarring after glaucoma filtration surgery / 中华实验眼科杂志

Background Research showed that transforming growth factor-β2 (TGF-β2) promotes scar formation.But its mechanism in scarring after glaucoma filtration surgery is worthy of studying.Objective This study was to investigate the effect of TGF-β2 on myofibroblast transition of human Tenon fibroblasts (HTFs) and scarring after glaucoma filtration surgery.Methods Tenon capsular tissue was obtained from 3 patients with strabismus during the surgery and was incubated in DMEM with 10％ fetal bovine serum (FBS).The cells were collected and passaged in the free-serum medium for 24 hours,and then 1,2,5,10,20 μg/L TGF-β2 was added into the medium respectively,to induce the transformation of HTFs,and 2 μg/L or 5 μg/L TGF-β2 was used to treat the HTFs for 6,24,48 and 72 hours.The control group was not treated with TGF-β2.The expressions of α-smooth muscle actin (α-SMA) and phosphorylation of the signaling proteins (pSmad2) in HTFs were detected by Western blot assay.The expressions of α-SMA and F-actin were located by cell immunofluorescine technique under the confocal immunofluorescence microscopy.Cell contractility was determined by collagen gel contraction assays.This study was approved by Ethic Committee of Institute of Surgery Research of Daping Hospital,and informed consent was obtained from each patient or custodian initial of the study.Results The expression of α-SMA protein in the HTFs was increased significantly after the treatment of TGF-β2 in comparison with the control group and reached a peak at 24-48 hours.The α-SMA expression was gradually weakened in the 10 μg/L TGF-β2 groups.Little of α-SMA and F-actin were expressed in the control group.However,strong staining for α-SMA and F-actin were observed in the 1,2 and 5 μg/L TGF-β2 groups and then the staining weakened at the concentration of 10 μg/L.In addition,pSmad2 showed a stronger expression in the 2 μg/L TGF-β2 group than that in the PBS group and FBS group,with the strongest expression in 30 minutes through 2 hours.The untreated gel contracted (78.00±3.13)％ from its initial size,and contraction in the 1,2,5,10 μg/L TGF-β2 group were (63.88±1.78)％,(20.69±0.65)％,(19.49-±0.54)％,(16.24±0.84) ％,respectively,TGF-β2 increased HTFs contraction significantly (Fgroup =859.400,P =0.000).Conclusions TGF-β2 can induce transdifferentiation of Tenon fibroblast into myofibroblast and increase cell contractility,with a concentration-dependent and time-dependent pattern to an extent.It may be the mechanism of scar formation after glaucoma filter surgery.

Relationship between single nucleotide polymorphisms and its haplotype of X-ray repair cross complementing group 1 and susceptibility of pancreatic carcinoma / 中华肿瘤杂志

<p><b>OBJECTIVE</b>The aim of this study was to evaluate the effects of XRCCl gene polymorphisms and its haplotype on the susceptibility of pancreatic carcinoma.</p><p><b>METHODS</b>Peripheral blood DNA was extracted from 210 pancreatic carcinoma patients and 213 control subjects. SNaPshot technique was used for genotyping seven SNP sites of the XRCCl gene (rs3213403, rs25487, rs1799782, rs731420, rs1001581, rs12611088, and rs3213282). Logistic regression model was performed to analyze the relationship of different genotypes or haplotype and the susceptibility of pancreatic carcinoma.</p><p><b>RESULTS</b>The frequency for allele A at site rs25487 in the case group was significantly higher than that in the control group (P < 0.05). The frequency of GG, GA and AA genotype between the case group and control group had statistically significant differences (P < 0.05). Compared with GG genotype, the risk of pancreatic carcinoma in the subjects carrying mutated allele A (GA+AA) was increased by 0.648 times (P < 0.05). Among them the pancreatic carcinoma risk of individuals carrying A allele was increased by 0.552 times compared with the individuals carrying G allele. The frequency of allele and genotype at site rs1799782 in the case group and control group had a significant difference (P < 0.05). Compared with the CC genotype, the risk of pancreatic carcinoma in the subjects carrying mutated allele T (CT+TT) was increased by 0.683 times. Among them the pancreatic carcinoma risk of individuals carrying T allele was increased by 0.549 times compared with the individuals carrying C allele. Significant differences were observed in linkage disequilibrium between any two of the seven SNPs (P < 0.05), the frequency of H4-AGCCCGC, H6-GGCCCGG or H7-AGCCTAG haplotypes was significantly lower in the case group than that in the control group (P < 0.05).</p><p><b>CONCLUSIONS</b>The single nucleotide polymorphisms of rs25487 and rs1799782 for XRCC1 gene may be correlated with the occurrence of pancreatic carcinoma. The haplotypes of H4-AGCCCGC, H6-GGCCCGG and H7-AGCCTAG might be a potential genetic protective factor for the occurrence of pancreatic carcinoma.</p>

Effects of deguelin on the proliferation and apoptosis of human esophageal cancer cell Ec-109: an experimental research / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To observe the effects of deguelin on the apoptosis and proliferation of human esophageal cancer cell Ec-109, and to explore its possible mechanisms.</p><p><b>METHODS</b>Human esophageal cancer cells Ec-109 were in vitro cultured. They were divided into the blank control group, and 5, 10, 20, and 40 nmol/L deguelin groups. The inhibition on the proliferation was detected at 24, 48, and 72 h using CCK-8 assay. The early apoptosis rate at 24 h was detected by flow cytometry. The expressions of apoptosis-related proteins Bcl-2 and Bax were detected at 24 and 48 h respectively.</p><p><b>RESULTS</b>Compared with the blank control group at the same point, the growth inhibition rate in all deguelin groups increased at 24, 48, and 72 h, showing statistical difference (P <0.05). The early apoptosis rate was 4.37% +/- 0.35%, 6.71% +/-0.14%, 15.62% +/- 0.21%, and 19.78% +/- 0.15% in 5, 10, 20, and 40 nmol/L deguelin groups, respectively, showing statistical difference when compared with that of the blank control group (1.10% +/- 0.08%, P < 0.05). Compared with the blank control group, Bcl-2 protein expression obviously decreased, and Bax protein expression obviously increased in 10, 20, and 40 nmol/L deguelin groups, showing statistical difference (P <0.05). The aforesaid indices were in time- and dose-dependent manners.</p><p><b>CONCLUSION</b>Deguelin showed obvious effects on inhibiting the proliferation of Ec-109 cells and promoting their apoptosis, which was correlated with up-regulating Bax protein expression and down-regulating Bcl-2 protein expression.</p>

The expression of nicotinamide phosphoribosyl transferase and vascular endothelial growth factor-A in gastric carcinoma and their clinical significance / 中华外科杂志

<p><b>OBJECTIVES</b>To study the expression of nicotinamide phosphoribosyl transferase (Nampt) and vascular endothelial growth factor-A (VEGF-A) in gastric carcinoma and investigate their correlations to clinicopathologic features and prognostic significance.</p><p><b>METHODS</b>The proteins of Nampt and VEGF-A in 68 specimens of gastric carcinoma and 59 specimens normal gastric tissue were detected by immunohistochemistry during January 2000 to December 2004, and the 68 patients were followed up.</p><p><b>RESULTS</b>Nampt protein was detected in the cytoplasm of both tissues, and Nampt in gastric carcinoma (13 ± 5) were significantly higher than that in normal gastric tissue (6 ± 3) (t = 7.46, P < 0.01). The expression of Nampt was correlated to invasive depth (F = 4.693, P = 0.034), lymph node metastasis (F = 4.027, P = 0.049), clinical TNM stage (F = 9.979, P = 0.002), but not to gender, age, tumor location, tumor size, differentiation (P > 0.05). The expression of Nampt is correlated with survival of patients that underwent surgical resection for gastric cancer. The survival rate of patients in negative of Nampt was very higher than that of the positive patients, and its co-expression with VEGF-A showed a trend towards poorer survival. The positive correlation was found between the expression of Nampt and VEGF-A in gastric carcinoma (r = 0.293, P = 0.015).</p><p><b>CONCLUSIONS</b>The expression of Nampt is positively correlated to that of VEGF-A in gastric carcinoma. The correlation between the expression of Nampt and VEGF-A in gastric carcinoma plays an important role cooperatively in carcinogenesis, development and metastasis of gastric carcinoma.</p>

Gamma-globin synthesis in K562 cells induced with Tortois plastron, Astragali, Salviae miltiorrhizae and Codonopsis pilosulae / 中国实验血液学杂志

This study was purposed to investigate the effects of tortois plastron, astragali, salviae miltiorrhizae and codonopsis pilosulae on gamma-globin gene synthesis in K562 cells in vitro. Benzidine staining was used to clarify the dose-and time-dependent effects of tortois plastron, astragali, salviae miltiorrhizae and codonopsis pilosulae on hemoglobin synthesis in K562 cells and Western blotting was performed to determine the level of hemoglobin F (alpha(2)gamma(2)). The results indicated that the K562 cells treated with 4 kinds of traditional Chinese medicine had different stain rates of benzidine for: 23.5% (tortois plastron), 19.8% (astragali), 15.8% (salviae miltiorrhizae) and 14.5% (codonopsis pilosulae) at 6 days after the treatment. Western blot indicated that synthesis of HbF increased. It is concluded that tortois plastron, astragali, salviae miltiorrhizae and codonopsis pilosulae enhance globins-gamma synthesis level and increase hemoglobin F level in K562 cells, the effect of which resembles that of sodium butyrate.

Role and significance of extrahepatic control of hepatic vein and inferior vena cava in difficult hepatectomies for patients with liver tumors / 中华外科杂志

<p><b>OBJECTIVE</b>To explore the role of extrahepatic control on blood flow of hepatic vein and inferior vena cava in hepatectomy, and observe its effect on minimizing hemorrhage.</p><p><b>METHODS</b>From 2001 to April 2003, 33 patients who had liver tumors involving segment IV, VII, VIII or half liver underwent major hepatectomies that required exposure of the inferior vena cava and main trunks of hepatic veins, during which the major hepatic veins and inferior vena cava were isolated and taped to control blood flow when necessary.</p><p><b>RESULTS</b>In 33 attempts, 32 were successful and all tumors were resected successfully. The placement of occlusion tape was unsuccessful in 1 case. 7 cases did not need blood transfusion during operation. The amount of blood transfusion for other cases were form 0 to 1 600 ml. there was no operative mortality.</p><p><b>CONCLUSIONS</b>Appropriate control of main truck of hepatic vein and inferior vena cava is effective in reducing blood loss during hepatectomies. It is also very helpful for performing difficult hepatectomies.</p>