Structure-Based Design and Synthesis of C-1- and C-4-Modified Analogs of Zanamivir as Neuraminidase Inhibitors

Feng, Enguang,Shin, Woo-Jin,Zhu, Xuelian,Li, Jian,Ye, Deju,Wang, Jiang,Zheng, Mingyue,Zuo, Jian-Ping,No, Kyoung Tai,Liu, Xian,Zhu, Weiliang,Tang, Wei,Seong, Baik-Lin,Jiang, Hualiang,Liu, Hong American Chemical Society 2013 Journal of medicinal chemistry Vol.56 No.3

<P>In order to exploit the 430-cavity in the active sites of neuraminidases, 22 zanamivir analogs with C-1 and C-4 modification were synthesized, and their inhibitory activities against both group-1 (H5N1, H1N1) and group-2 neuraminidases (H3N2) were determined. Compound <B>9f</B> exerts the most potency, with IC<SUB>50</SUB> value of 0.013, 0.001, and 0.09 μM against H3N2, H5N1, and H1N1, which is similar to that of zanamivir (H3N2 IC<SUB>50</SUB> = 0.0014 μM, H5N1 IC<SUB>50</SUB> = 0.012 μM, H1N1 IC<SUB>50</SUB> = 0.001 μM). Pharmacokinetic studies of compound <B>9f</B> in rats showed a much longer plasma half-life (<I>t</I><SUB>1/2</SUB>) than that of zanamivir following administration (po dose). Molecular modeling provided information about the binding model between the new inhibitors and neuraminidase, with the elongated groups at the C-1-position being projected toward the 430-loop region. This study may represent a novel starting point for the future development of improved antiflu agents.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2013/jmcmar.2013.56.issue-3/jm3009713/production/images/medium/jm-2012-009713_0009.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jm3009713'>ACS Electronic Supporting Info</A></P>

Identification and Functional Analysis of Differentially Expressed Genes Related to Metastatic Osteosarcoma

Niu, Feng,Zhao, Song,Xu, Chang-Yan,Chen, Lin,Ye, Long,Bi, Gui-Bin,Tian, Gang,Gong, Ping,Nie, Tian-Hong Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.24

Background: To explore the molecular mechanisms of metastatic osteosarcoma (OS) by using the microarray expression profiles of metastatic and non-metastatic OS samples. Materials and Methods: The gene expression profile GSE37552 was downloaded from Gene Expression Omnibus database, including 2 human metastatic OS cell line models and 2 two non-metastatic OS cell line models. The differentially expressed genes (DEGs) were identified by Multtest package in R language. In addition, functional enrichment analysis of the DEGs was performed by WebGestalt, and the protein-protein interaction (PPI) networks were constructed by Hitpredict, then the signal pathways of the genes involved in the networks were performed by Kyoto Encyclopaedia of Genes and Genomes (KEGG) automatic annotation server (KAAS). Results: A total of 237 genes were classified as DEGs in metastatic OS. The most significant up- and down-regulated genes were A2M (alpha-2-macroglobulin) and BCAN (brevican). The DEGs were significantly related to the response to hormone stimulus, and the PPI network of A2M contained IL1B (interleukin), LRP1 (low-density lipoprotein receptor-related protein 1) and PDGF (platelet-derived growth factor). Furthermore, the MAPK signaling pathway and focal adhesion were significantly enriched. Conclusions: A2M and its interactive proteins, such as IL1B, LRP1 and PDGF may be candidate target molecules to monitor, diagnose and treat metastatic OS. The response to hormone stimulus, MAPK signaling pathway and focal adhesion may play important roles in metastatic OS.

Mutations in AP22.65 Accelerate Flowering in Arabidopsis thaliana

Ji Hong Xing,Feng Ru Wang,Jiao Jia,Jing Zhang,Li Li,Zhan Chen,Qiao Yun Weng,Ping Yang,Ye Zhang,Bin Zhao,He Long Si,Jin Gao Dong,Jian Min Han 한국식물학회 2013 Journal of Plant Biology Vol.56 No.1

Identification of the gene(s) responsible for floweringtime in Arabidopsis has significant implications. We used theT-DNA insertion library of Arabidopsis thaliana to screen anearly-flowering mutant that exhibits accelerated floweringunder short-day conditions. AP22.65, a novel flowering-timegene in that species, was isolated and identified via genomewalkingand bioinformatics analysis. The flowering time ofAP22.65-complementing plants was similar to that of theCol-0 wild type (WT). Conversely, its overexpression delayedflowering. Consistent with this phenotype, expression ofAP22.65 was decreased in the ap22.65-1 mutant, recoveredin AP22.65-complementing plants, and increased in AP22.65-overexpressing plants. Compared with the WT, expressionlevels of critical genes in different flowering pathways, i.e.,SPY, FLC, GI, CO, FT, and LFY, were down-regulated inloss-of-function mutants. Expression of AP22.65 was distributedin flowers, siliques, rosette leaves, and whole seedlings. Therefore, this gene may be a negative regulator of Arabidopsisflowering.

Purification and Cloning of an Extracellular Serine Protease from the Nematode-Trapping Fungus Monacrosporium cystosporium

( Jin Kui Yang ),( Feng Ping Ye ),( Qi Li Mi ),( Song Qing Tang ),( Juan Li ),( Ke Qin Zhang ) 한국미생물 · 생명공학회 2008 Journal of microbiology and biotechnology Vol.18 No.5

Expression of the Pokemon Proto-oncogene in Nasopharyngeal Carcinoma Cell Lines and Tissues

Jiao, Wei,Liu, Fei,Tang, Feng-Zhu,Lan, Jiao,Xiao, Rui-Ping,Chen, Xing-Zhou,Ye, Hui-Lan,Cai, Yong-Lin Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.11

To study the differentiated expression of the proto-oncogene Pokemon in nasopharyngeal carcinoma (NPC) cell lines and tissues, mRNA and protein expression levels of CNE1, CNE2, CNE3 and C666-1 were detected separately by reverse transcription polymerase chain reaction (RT-PCR), real-time PCR and Western-blotting. The immortalized nasopharyngeal epithelial cell line NP69 was used as a control. The Pokemon protein expression level in biopsy specimens from chronic rhinitis patients and undifferentiated non keratinizing NPC patients was determined by Western-blotting and arranged from high to low: C666-1>CNE1>CNE2> CNE3>NP69. The Pokemon mRNA expression level was also arranged from high to low: CNE1>CNE2>NP69>C666-1>CNE3. Pokemon expression of NP69 and C666-1 obviously varied from mRNA to protein. The Pokemon protein level of NPC biopsy specimens was obviously higher than in chronic rhinitis. The data suggest that high Pokemon protein expression is closely associated with undifferentiated non-keratinizing NPC and may provide useful information for NPC molecular target therapy.

Changing patterns of Serum CEA and CA199 for Evaluating the Response to First-line Chemotherapy in Patients with Advanced Gastric Adenocarcinoma

He, Bo,Zhang, Hui-Qing,Xiong, Shu-Ping,Lu, Shan,Wan, Yi-Ye,Song, Rong-Feng Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.8

Background: This study was designed to investigate the value of CEA and CA199 in predicting the treatment response to palliative chemotherapy for advanced gastric cancer. Materials and Methods: We studied 189 patients with advanced gastric cancer who received first-line chemotherapy, measured the serum CEA and CA199 levels, used RECIST1.1 as the gold standard and analyzed the value of CEA and CA199 levels changes in predicting the treatment efficacy of chemotherapy. Results: Among the 189 patients, 80 and 94 cases had increases of baseline CEA (${\geq}5ng/ml$) and CA199 levels (${\geq}27U/ml$), respectively. After two cycles of chemotherapy, 42.9% patients showed partial remission, 33.3% stable disease, and 23.8% progressive disease. The area under the ROC curve (AUC) for CEA and CA199 reduction in predicting effective chemotherapy were 0.828 (95%CI 0.740-0.916) and 0.897 (95%CI 0.832-0.961). The AUCs for CEA and CA199 increase in predicting progression after chemotherapy were 0.923 (95%CI 0.865-0.980) and 0.896 (95%CI 0.834-0.959), respectively. Patients who exhibited a CEA decline ${\geq}24%$ and a CA199 decline ${\geq}29%$ had significantly longer PFS (log rank p=0.001, p<0.001). With the exception of patients who presented with abnormal levels after chemotherapy, changes of CEA and CA199 levels had limited value for evaluating the chemotherapy efficacy in patients with normal baseline tumor markers. Conclusions: Changes in serum CEA and CA199 levels can accurately predict the efficacy of first-line chemotherapy in advanced gastric cancer. Patients with levels decreasing beyond the optimal critical values after chemotherapy have longer PFS.

Cloning and characterization of a novel gene with alternative splicing in murine mesenchymal stem cell Line C3H/10T1/2 by gene trap screening

( Ming Ke Wang ),( Hui Qin Sun ),( Fan Jiang ),( Jing Han ),( Feng Ye ),( Tao Wang ),( Yong Ping Su ),( Zhong Min Zou ) 생화학분자생물학회 (구 한국생화학분자생물학회) 2010 BMB Reports Vol.43 No.12

A novel gene, designated mgt-6, containing four splicing variants, was isolated from a gene trap clone library of C3H/10T1/ 2 cells transfected with retroviral promoterless gene-trap vector, ROSAFARY. The transcript variants were differentially expressed in murine tissues and cell lines and differentially responded to diverse stimuli including TGF-β1 and mitogen-activated protein kinase (MAPK) inhibitors. The mgt-6 gene encoded a protein of 37 or 11 amino acid residuals with cytoplasmic distribution. However, when C3H/10T1/2 cells were treated with 5-azacytidine, the protein translocated into cell nucleus as indicated by fused LacZ or C-terminally tagged EGFP. Our preliminary results suggest that further study on the role of mgt-6 gene in cell transformation and differentiation may be of significance. [BMB reports 2010; 43(12): 789-794]

Antitumor Activity of Chloroquine in Combination with Cisplatin in Human Gastric Cancer Xenografts

Zhang, Hui-Qing,Fang, Nian,Liu, Xiao-Mei,Xiong, Shu-Ping,Liao, Yu-Qian,Jin, Wen-Jian,Song, Rong-Feng,Wan, Yi-Ye Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.9

Purpose: To investigate the antitumor activity and mechanism of chloroquine (CQ) in combination with cisplatin (DDP) in nude mice xenografted with gastric cancer SGC7901 cells. Materials and Methods: 35 cases of gastric cancer patients with malignant ascites were enrolled and intraperitoneal cisplatin injection was performed. Ascites were collected before and 5 days after perfusion for assessment of autophagy levels in cancer cells. In addition, 24 tumor-bearing mice were randomly divided into control, DDP, CQ and CQ + DDP groups. Results: In 54.3% (19/35) of patients the treatment was therapeutically effective (OR), 5 days after peritoneal chemotherapy, 13 patients had the decreased ascites Beclin-1 mRNA levels. In 16 patients who had NR, only 2 cases had decreased Beclin-1 (P=0.001). Compared with the control group, the xenograft growth in nude mice in the DDP group was low, and the inhibition rate was 47.6%. In combination with chloroquine, the inhibition rate increased to 84.7% (P<0.01). The LC3-II/I ratio, and Beclin1 and MDR1/P-gp expression were decreased, while caspase 3 protein levels increased (P<0.05). Conclusions: Antitumor ability of cisplatin was associated with autophagy activity and chloroquine can enhance chemosensitivity to cisplatin in gastric cancer xenografts nude mice.

Molecular identification and expression patterns of carboxylesterase genes based on transcriptome analysis of the common cutworm, Spodoptera litura (Lepidoptera: Noctuidae)

Ya Nan Zhang,Jin-Bu Li,Peng He,Liang Sun,Zhao-Qun Li,Li-Ping Fang,Zhan-Feng Ye,Dao-Gui Deng,Xiu-Yun Zhu 한국응용곤충학회 2016 Journal of Asia-Pacific Entomology Vol.19 No.4

Carboxylesterases (CXEs) belong to a family of metabolic enzymes that are widely distributed in insects and other organisms and can rapidly degrade the components of sex pheromones and plant volatiles with an acetate functional group. The common cutworm, Spodoptera litura, is an important agricultural pest around the world, causing vast economic losses every year. The female sex pheromones of S. litura comprise four acetates, Z9, E11-14:OAc; Z9, E12-14:OAc; Z9-14:OAc; and E11-14:OAc, but the degradation mechanisms of these components are not well understood. By analysing previously obtained transcriptomic data of the sex pheromone glands,we identified a total of 24 putative CXE genes in S. litura. Gene expression patterns and phylogenetic analysis revealed 5 genes with antennae-specific or biased expression, and clusteredwith genes showed involvement in the degradation of sex pheromones or other detoxification in other insects. SlitCXE10was expressed specifically in the antennae of both sexes, and SlitCXE14, 17, 19, and 21 had high antenna biased expression. Interestingly, RT-PCR and qPCR tests indicated that SlitCXE24 had significantly higher expression in PG than in other tissue, and that it could be a potential candidate gene for sex pheromone degradation in PG. This study is the first to provide solid background information for the further elucidation of sex pheromone degradation, and ultimately provides potential targets for the disruption of sexual communication in S. litura for new pest management.

Clinicopathologic Characteristics and Prognoses for Multicentric Occurrence and Intrahepatic Metastasis in Synchronous Multinodular Hepatocellular Carcinoma Patients

Li, Shi-Lai,Su, Ming,Peng, Tao,Xiao, Kai-Yin,Shang, Li-Ming,Xu, Bang-Hao,Su, Zhi-Xiong,Ye, Xin-Ping,Peng, Ning,Qin, Quan-Lin,Chen, De-Feng,Chen, Jie,Li, Le-Qun Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.1

Background: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and the outcomes for patients are still poor. It is important to determine the original type of synchronous multinodular HCC for preoperative assessment and the choice of treatment therapy as well as for the prediction of prognosis after treatment. Aims: To analyze clinicopathologic characteristics and prognoses in patients with multicentric occurrence (MO) and intrahepatic metastasis (IM) of synchronous multinodular hepatocellular carcinoma (HCC). Methods: The study group comprised 42 multinodular HCC patients with a total of 112 nodules. The control group comprised 20 HCC patients with 16 single nodular HCC cases and 4 HCC cases with a portal vein tumor emboli. The mitochondrial DNA (mtDNA) D-loop region was sequenced, and the patients of the study group were categorized as MO or IM based on the sequence variations. Univariate and multivariate analyses were used to determine the important clinicopathologic characteristics in the two groups. Results: In the study group, 20 cases were categorized as MO, and 22 as IM, whereas all 20 cases in the control group were characterized as IM. Several factors significantly differed between the IM and MO patients, including hepatitis B e antigen (HBeAg), cumulative tumor size, tumor nodule location, cirrhosis, portal vein and/or microvascular tumor embolus and the histological grade of the primary nodule. Multivariate analysis further demonstrated that cirrhosis and portal vein and/or microvascular tumor thrombus were independent factors differentiating between IM and MO patients. The tumor-free survival time of the MO subjects was significantly longer than that of the IM subjects ($25.7{\pm}4.8$ months vs. $8.9{\pm}3.1$ months, p=0.017). Similarly, the overall survival time of the MO subjects was longer ($31.6{\pm}5.3$ months vs. $15.4{\pm}3.4$ months, p=0.024). The multivariate analysis further demonstrated that the original type (p=0.035) and Child-Pugh grade (p<0.001) were independent predictors of tumor-free survival time. Cirrhosis (p=0.011), original type (p=0.034) and Child-Pugh grade (p<0.001) were independent predictors of overall survival time. Conclusions: HBeAg, cumulative tumor size, tumor nodule location, cirrhosis, portal vein and/or microvascular tumor embolus and histological grade of the primary nodule are important factors for differentiating IM and MO. MO HCC patients might have a favorable outcome compared with IM patients.