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New developments in small molecular compounds for anti-hepatitis C virus(HCV) therapy

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Journal of zhejiang university-Science B(Biomedicine & Biotechnology) 2012年第1期13卷 56-82页

作者： Jing TONG1,2,You-wei WANG2,Yuan-an LU1,2(1Department of Public Health Sciences,university of Hawaii,Honolulu,Hawaii 96822,USA)(2Key Laboratory of Combinatorial Biosynthesis and Drug Discovery,Ministry of Education,institute of Traditional Chinese medicine & Natural Products,school of Pharmaceutical Sciences,Wuhan university,Wuhan 430071,china) Department of Public Health Sciences University of Hawaii Honolulu Hawaii 96822 USA

Infection with hepatitis C virus （HCV） affects approximately 170 million people worldwide. However, no vaccine or immunoglobulin is currently available for the prevention of HCV infection. The standard of care （SOC） involving pegylated interferon-（] （PEG-IFN a） plus ribavirin （RBV） for 48 weeks results in a sustained virologic re- sponse in less than 50% of patients with chronic hepatitis C genotype 1, the most prevalent type of HCV in North America and Europe. Recently, reliable in vitro culture systems have been developed for accelerating antiviral therapy research, and many new specifically targeted antiviral therapies for hepatitis C （STAT-C） and treatment strategies are being evaluated in clinical trials. These new antiviral agents are expected to improve present treatment significantly and may potentially shorten treatment duration. The aim of this review is to summarize the current developments in new anti-HCV drugs.

关键词： Hepatitis C virus (HCV) Clinical trial Small molecular compounds Review

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Sexual contact decreases contextual fear and prevents impairment of hip-pocampal long-term potentiation via dopamine D1/D5 receptors

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Sexual contact decreases contextual fear and prevents impair...

中国神经科学学会第四次会员代表大会暨第七届全国学术会议

作者： Hua-yi BAI~1,Na LIU~3,Lin XU~2,Jian-hong LUO~1 1 institute of Neuroscience,zhejiang university school of medicine,hangzhou 310058,china 2 Laboratory of Learning and Memory,Kunming institute of Zoology,The Chinese Academy of Sciences,Kunming 650223,china 3 College of Veterinary medicine,Yangzhou university,Yangzhou 225009,china

＜正＞Hippocampal long-term potentiation（LTP） is believed to be the mechanism underlying certain types of memory, which is exquisitely sensitive to *** the present study,we introduced a na＆iuml;ve female rat to a stressed male rat that just experienced contextual fear conditioning,for 24 hours in home cage where they showed sexual behaviors. Remarkably,these male rats exhibited much lower contextual fear than those without female rats,and their impaired LTP of the field excitatory postsynaptic potentials in hippocampal CA1 was *** marked contrast,when we introduced a na＆iuml;ve male rat to a stressed male rat that was trained in contextual fear conditioning,the male rats still showed high levels of contextual fear and the impaired *** addition,the effects of female both on behavior and electrophysiology were prevented by the dopamine D1/D5 receptor antagonist SCH *** novel findings suggest that heterosexual contact decreases contextual fear and prevents the impairment of hippocampal LTP,thereby providing potential explanation why heterosexual contacts modulate mood and promote work efficacy in humans.

关键词： Sexual contact Contextual fear conditioning Long-term potentiation Dopamine D1/D5 receptor SCH23390

传染性法氏囊病病毒多聚蛋白基因在家蚕中的表达

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生物工程学报 2002年第4期18卷 472-476页

作者：卢觅佳李建荣王莹飞金勇丰于涟浙江大学动物预防医学研究所浙江大学生物化学研究所杭州310029

将传染性法氏囊病病毒 (IBDV)细胞致弱株 (JD1株 )的基因组A节段基因重组于家蚕杆状病毒转移载体pAcHLT C中 ,获得的重组转移载体pAcHLT C A与线性化病毒Bm BacPAK6DNA共转染家蚕培养细胞 ,获得重组病毒BacPAK A。DIG标记的DNA点杂交证... 详细信息

将传染性法氏囊病病毒 (IBDV)细胞致弱株 (JD1株 )的基因组A节段基因重组于家蚕杆状病毒转移载体pAcHLT C中 ,获得的重组转移载体pAcHLT C A与线性化病毒Bm BacPAK6DNA共转染家蚕培养细胞 ,获得重组病毒BacPAK A。DIG标记的DNA点杂交证实重组病毒基因组中含有A节段基因 ,重组病毒感染家蚕 5龄幼虫进行表达 ,ELISA和Westernblotting等结果表明多聚蛋白基因在蚕体内得到了表达 ,表达产物具有免疫反应性 ,表达量在感染后 5～ 6d达到最高。家蚕生物反应器表达IBDV多聚蛋白具有我国的资源优势 ,为今后研制低成本、实用化的IBDV基因工程疫苗打下基础。

关键词：传染性法氏囊病病毒多聚蛋白基因家蚕表达

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Different mutations of p53 in plateau rodents reflect diverse hypoxia adaptation patterns

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Different mutations of p53 in plateau rodents reflect divers...

中国生理学会第23届全国会员代表大会暨生理学学术大会

作者： Yang ZHAO~1,Xue-Qun CHEN~(1,*),Xiao-Cheng CHEN~2,Ji-Zeng DU~(1,*) 1 Lab of Neurobiology and Physiology,institute of Neuroscience,school of medicine,zhejiang university,hangzhou,310058, china 2 Northwest Plateau institute of Biology,the Chinese Academy of Sciences,Xining,810001,china

＜正＞Myospalax baileyi and Microtus oeconomus are native rodents living at Qinghai-Tibet plateau in china. Myospalax baileyi lives in burrows underground at altitude of about 3200 m for its whole life cycle,enduring hypoxia and a～28 fold higher carbon dioxide condition;whereas Microtus oeconomus resides in meadows above 3 000 m on the Qinghai-Tibet plateau,suffering a different content of hypoxia due to the smaller depth of its caves. Given the variation of their habitats,the two species accommodated various mechanisms to adapt to hypoxia and/ or high carbon *** tumor suppressor p53 has been considered as a "master gene" of diversity,as it can be modified during evolution to provide multiple *** we show that even in both plateau rodents,variation of habitats confers different transactivation patterns of p53 *** p53 of Myospalax baileyi and Microtus oeconomus were cloned and *** code region of Myospalax p53 is 1179 bp and codes for a 392-aminoacid protein,showing identities of 85%,83%,80%and 95%in comparative to human,rat,mouse and Spalax in Israel *** p53 is 1176 bp and codes for a 391-amino-acid protein,showing identities of 82%, 83%,78%,88%and 88%in comparative to human,rat,mouse,Spalax in Israel and Myospalax respectively. Multiple alignment analysis revealed that,compared with other mammals,three residues within the DNA-binding domain（DBD） of Myospalax p53 and two residues of Microtus p53 mutated during *** dual-luciferase assay,we compared the transactivation of Myospalax,Microtus,human and a series of site-directed mutated p53 to its target *** with human p53,wild-type Myospalax p53 has a higher transactivation to pro-apoptotic target genes Apaf1 and IGFBP3（P＜0.001）,while transactivation of wild-type Microtus p53 to IGFBP3 is significantly lower than that of human p53（P＜0.001）.Humanization of each mutated site of Myospalax p53 using sitedirected mutagenesis decreased the increment of its

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Effect of genetic variation of human cytochrome P450 oxidoreductase on the metabolic activation of aflatoxin B1

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Effect of genetic variation of human cytochrome P450 oxidore...

第九届全国药物和化学异物代谢学术会议

作者： LI Dan-xi~1,GUO Yu~2,CHEN Shu-qing~(1*),HONG Jun-yan~(1,3) 1 College of Pharmaceutical Science,zhejiang university,hangzhou,zhejiang,china 2 Basic Medical school/Department of Pharmacology,Wuhan university,Hubei,china 3 school of Public Health/Environmental and Occupational Hea lth Sciences institute,university of medicine and Dentistry of New Jersey,Piscataway,NJ 08854,USA

Cytochrome P450(CYP) enzymes play a critical role in the metabolic activation of environmental carcinogens. NADPH-cytochrome P450 oxidoreductase(POR),a flavoprotein transferring electrons from NADPH to CYP enzymes, is required for the catalytic function of all microsomal CYP ***,naturally occruing POR missense variants have been discovered in human ***,their functional significance in CYP-mediated carcinogen activation is not *** aim of this study was to determine the effect of POR genetic variation on cytotoxicity induced by aflatoxin B1(AFB1),a mycotoxin and a potent carcinogen in human and *** previous work demonstrated that human CYP2A13 is highly efficient in the metabolic activation of AFB1(He et al.,2006).In this study,we established Flp-In CHO cells co-expressing human CYP2A13 and human wild-type or variant POR *** there was no significant difference in AFB1-induced cytotoxicity between the cells co-expressing wild-type human POR and the POR variants M263V and A503V,the cytotoxicity was decreased in the cells co-expressing the POR variants A287P,Y459H and *** results demonstrate that POR genetic variation can affect CYP2A13-catalyzed AFB1 activation and suggest that individuals carrying the functional variant POR alleles may have different susceptibility to AFB1 exprosure.

关键词： POR Genetic variation CYP2A13 AFB1 cytotoxicity

Interleukin-2 inhibits NMDA receptor-mediated currents directly and may differentially affect subtypes

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Interleukin-2 inhibits NMDA receptor-mediated currents direc...

浙江省生理科学会2006年学术年会

作者： Yi Shen, Li-Jun Zhu, Shuang-Shuang Liu, Su-Ya Zhou, Jian-Hong Luo Department of Neurobiology, institute for Neuroscience, zhejiang university school of medicine, hangzhou, 310058, china These authors contributed equally to this work.

Using whole-cell patch-clamp recordings, this study investigated the effects of interleukin-2 (IL-2) on N-methyl-D-aspartate (NMDA) receptor-mediated currents (INMDA) in rat cultured hippocampal neurons and human embr... 详细信息

关键词： rat interleukin-2 NMDA receptors hippocampal neuron Whole-cell patch clamp

FEN-1基因对细胞周期和遗传稳定性的影响

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生物化学与生物物理学报 2001年第3期33卷 309-314页

作者：石斌山余应年蔡朱男沈炳辉浙江大学医学院病理生理教研室!杭州310031 City of Hope National Medical Center and Beckman Research institute!Duart CA910103000USA

结构特异性核酸酶FEN 1在DNA复制和修复 ,以及维持细胞遗传稳定性方面都起着重要作用。采用RT PCR方法 ,证实了FEN 1基因阻断细胞 (FL FEN 1-)通过FEN 1反义mRNA片段的表达 ,阻断了FEN 1基因。应用流式细胞仪对FL FEN 1-细胞进行细胞周... 详细信息

结构特异性核酸酶FEN 1在DNA复制和修复 ,以及维持细胞遗传稳定性方面都起着重要作用。采用RT PCR方法 ,证实了FEN 1基因阻断细胞 (FL FEN 1-)通过FEN 1反义mRNA片段的表达 ,阻断了FEN 1基因。应用流式细胞仪对FL FEN 1-细胞进行细胞周期分析 ,发现FL FEN 1-细胞进入S期DNA合成的过程被延缓 ,并发生了G1期的阻滞。在由穿梭质粒 pZ189介导的突变试验中 ,质粒在FL FEN 1-细胞中复制后 ,其SupFtRNA基因的自发突变频率为 19.1× 10 4 ,而对照细胞FL和FL M细胞分别为 2 .9× 10 4 和 3.0× 10 4 ,但FL FEN 1-细胞经甲基硝基亚硝基胍 (MNNG)诱发后的非定标突变频率与对照细胞并无明显差异 ,这表明由FEN 1阻断造成的突变频率升高与细胞在受低浓度MNNG攻击后发生的非定标突变可能通过不同的途径形成。FL FEN 1-细胞对MNNG的敏感性高于对照细胞

关键词： FEN-1 细胞周期遗传不稳定性非定标突变 MNNG敏感性

Genetic variations of cytochrome P450 oxidoreductase:A potential biomarker to predict anticancer prodrug response

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Genetic variations of cytochrome P450 oxidoreductase:A poten...

第九届全国药物和化学异物代谢学术会议

作者： LI Dan-xi~1,GUO Yu~2,CHEN Shu-qing~(1*),HONG Jun-yan~(1,3) 1 College of Pharmaceutical Science,zhejiang university,hangzhou,zhejiang,china 2 Basic Medical school/Department of Pharmacology,Wuhan university,Hubei,china 3 school of Public Health/Environmental and Occupational Health Sciences institute, university of medicine and Dentistry of New Jersey,Piscataway,NJ 08854,USA

Identification of genetic biomarkers that can predict efficacy and toxicity of chemotherapeutic drugs is a critical step in the development of personalized *** P450 oxidoreductase(POR) plays an important role in the metabolic activation of some common anticancer prodrugs that are the substrates of either POR or cytochrome P450(CYP) *** existence of POR genetic variations in human subjects has been recently demonstrated. However,the functional significance of these POR variants in metabolizing anticancer prodrugs is largely unknown. Previously,we demonstrated that mitomycin C(MMC)-induced toxicity was significantly decreased in the cells stably expressing several POR variants(Wang et al,2007).The present work extended our study to a total of 28 reported missense POR *** them,the Y459H and L565P variants were found to have a total loss of capability in activating MMC,while the R316W,H628P and V631I variants showed a decreased POR *** POR is known to be critical in supporting all microsomal CYP-mediated drug metabolism,we also examined the effect of POR genetic variation on CYP2B6-mediated activation of cyclophosphamide(CPA).Preliminary results showed that CPA-induced cytotoxicity was significantly decreased in the cells co-expressing CYP2B6 and the POR variants Y181D,A287P,and *** results indicate that functional POR genetic variations can affect POR-involved metabolic activation of anticancer prodrugs and may serve as a predictive biomarker for therapeutic response in relevant cancer treatment.

关键词： POR anticancer drugs CYP2B6 MMC CPA

Cell-specific Regulation of APOBEC3F by Interferons

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Acta Biochimica et Biophysica Sinica 2007年第4期39卷 297-304页

作者： Songcheng YING~1# Xuzhao ZHANG~1# Phuong Thi Nguyen SARKIS~2# Rongzhen XU~1 Xiaofang YU~(1,2*) 1 Second Affiliated Hospital,Cancer institute,school of medicine,zhejiang university,hangzhou 310009,china 2 Department of Molecular Microbiology and Immunology,Johns Hopkins BIoomberg school of Public Health,Baltimore.Maryland 21205,USA SecondAffiliatedHospital CancerInstituteSchoolofMedicineZhejiangUniversityHangzhou310009China DepartmentofMolecularMicrobiologyandImmunology JohnsHopkinsBloombergSchoolofPublicHealthBaltimoreMaryland21205USA

Human cytidine deaminase APOBEC3F（A3F）has broad anti-viral activity against hepatitis Bvirus and retroviruses including human immunodeficiency virus type ***,its regulation in viralnatural target cells such CD4+T lymphocytes,macrophages,and primary liver cells has not been *** we showed that A3F was up-regulated by interferon（IFN）-α in primary hepatocytes andmultiple liver cell lines as well as *** the IFN-α signaling pathway was active in Tlymphoid cells and induction of other IFN stimulated genes such as PKR was detected,A3F and APOBEC3G（A3G）were not induced by IFN-α in these ***,additional factors other than known IFN-stimulatedgenes also regulated IFN-α-induced A3F expression distinctly.A3F and A3G expression levels in primaryhepatocytes,especially after IFN-α stimulation,were comparable to those in CD4~ T lymphocytes in *** variations of A3F and A3G expression in primary hepatocytes from various subjectswere *** variations in A3F and/or A3G regulation and expression might influence the clinicaloutcomes of hepatitis B infection.

关键词： APOBEC3F interferon human immunodeficiency virus type 1 hepatitis B virus cytidine deaminase