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A Few Specialized Issues That Should Be Focused on Anti-HIV Drug Evaluation In Vitro

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Virologica Sinica 2010年第4期25卷 301-306页

作者： Dao-min ZHUANG jing-yun li State Key Laboratory of Pathogen and Biosecurity Institute of Microbiology and Epidemiology Academy of Military Medical Science Beijing 100071 China

Since the introduction of antiretroviral therapy (ART), the lifespan and quality of life of patients infected with HIV have been significantly improved. But treatment efficacy was compromised eventually by the development of resistance to antiretroviral drugs, and more new anti-HIV drugs with lower toxicity and higher activity were needed. Based on the experience and lessons learned from the treatment in the developed countries, US FDA suggested that more pharmacodynamical researches should be considered ahead of the clinical trials. To facilitate the anti-HIV drug research and development, we reviewed a few specialized issues that should be focused on drug evaluations in vitro, including: 1) Mechanism of action studies, demonstrating the candidate drug's efficacy to specifically inhibit viral replication or a virus-specific function and confirm the drug target. 2) Drug resistance studies, selecting the drug-resistant variants in vitro and determining the activities inhibiting HIV isolates resistant to approved antiretroviral drugs of the same class. 3) Antiviral activity in vitro in the presence of serum proteins, ascertaining whether an investigational product is significantly bound by serum proteins. 4) Combination activity analysis, evaluating in vitro antiviral activity of an investigational product in two-drug combinations with other drugs approved.

关键词： Human immunodeficiency virus Drug evaluation Drug resistance

Chronic stress causes protein kinase C epsilon-aldehyde dehydrogenase 2 signaling pathway perturbation in the rat hippocampus and prefrontal cortex,but not in the myocardium

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Neural Regeneration Research 2018年第7期13卷 1225-1230页

作者： Wen-Yuan Zhang Ke-Yi Wang yun-jing li Ying-Ran li Rong-Zhi Lu Department of Pharmacy Zhongshan Hospital of Sun Yat-sen University Department of Magnetic Resonance Imaging Zhongshan Hospital of Sun Yat-sen University

Chronic stress is strongly associated with the occurrence and development of depression and cardiovascular *** can induce altered mitochondrial function and activation of apoptosis in the cardio-cerebral ***,it is unknown whether the protein kinase C ε（PKCε）-aldehyde dehydrogenase 2（ALDH2） pathway is altered under chronic stress,and this study sought to address this question.A rat model of depression was established using a chronic unpredictable mild stress（CUMS） *** experiencing CUMS for 4 weeks,the sucrose preference test and the forced swim test verified depressive-like *** linked immunosorbent assays showed that ALDH2 activity was decreased in the rat hippocampus and prefrontal cortex,but was not altered in the *** blot assays demonstrated reduced levels of ALDH2 and PKCε,but increased levels of 4-hydroxy-2-nonenal（4 HNE） ***-3 expression did not obviously alter,but active forms of caspase-3 were increased in the hippocampus and prefrontal *** the myocardium,expression of ALDH2,PKCε and 4 HNE adducts did not remarkably alter;while caspase-3 expression was reduced and the active forms of caspase-3 were ***＇s correlation test demonstrated that expression of 4 HNE adducts was positively correlated with levels of the active forms of caspase-3 in the hippocampus and prefrontal cortex,but not in the *** conclusion,chronic stress can damage the PKCε-ALDH2 signaling pathway in the hippocampus and prefrontal cortex,but not in the ***,4 HNE is associated with active forms of caspase-3 in the hippocampus and prefrontal cortex.

关键词： nerve regeneration stress depression protein kinase C ε aldehyde dehydrogenase 2 4-hydroxy-2-nonenal apoptosis hippocampus prefrontal cortex myocardium neural regeneration

Synthesis of cerium oxalate hydrate by precipitation technique under external magnetic field

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Rare Metals 2023年第3期42卷 1028-1035页

作者： Jian-Bo Yu Zhi-Gang Yang Zhi-Hao Wang Ting-Sheng Tu Zhen-Qiang Zhang jing-yun li yun-Bo Zhong Zhong-Ming Ren State Key Laboratory of Advanced Special Steels School of Material Science and EngineeringShanghai UniversityShanghai 200072China School of Material Science and Engineering Shijiazhuang Tiedao UniversityShijiazhuang 050043China

Cerium oxalate hydrate particles were synthesized by precipitation technique under external magnetic field with respective intensities of 0,0.1,0.3,and 0.6 *** particle morphologies were investigated by scanning electron microscopy(SEM)and transmission electron microscope(TEM).Results show that external magnetic field has a great influence on the growth behavior of cerium oxalate hydrate ***-like and plate-like cerium oxalate hydrate particles with smaller size are formed without the applying of external magnetic ***,the extremely big rod-like particles with the average size of 12.47μm were prepared under external magnetic field of 0.6 *** increasing magnetic field intensity makes the grain grow *** analysis supports the presence of 8.5 H_(2)O molecules associated with cerium ***,the growth mechanism of cerium oxalate hydrate under external magnetic field was briefly discussed.

关键词： Cerium oxalate hydrate Precipitation technique Magnetic field Grain Growth

Synthesis and Anti-HIV Activity of Trisubstituted (3′R, 4′R)-3′,4′- Di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) Analogs

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Chinese Chemical Letters 2005年第10期16卷 1297-1300页

作者： Chun Hong ZHAO Ting ZHOU Lan XIE jing yun li Zuo Yi BAO Zhao Wen LOU Kuo Hsiung LEE Beijing Institute of Pharmacology ＆ Toxicology Beijing 100850 Department of Chemistry Hubei University Wuhan Hubei 430062 Beijing Institute of Microbiology ＆ Epidemiology Beijing 100850 School of Pharmacy University of North Carolina at Chapel HillNC 27599 USA

To further explore the potential of DCK analogs as anti-HIV drug candidates, ten new tri-substituted （3＇R,4＇R）-3＇,4＇-di-O-（S）-camphanoyl-（＋）-cis-khellactone （DCK） derivatives （4-13） were designed, synth... 详细信息

关键词： anti-HIV agent DCK analogs synthesis.

Indinavir Resistance Evolution in One Human Immunodeficiency Virus Type 1 Infected Patient Revealed by Single-Genome Amplification

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Virologica Sinica 2010年第5期25卷 316-328页

作者： Qing-mao GENG Han-ping li Zuo-yi BAO Yong-jian liU Dao-min ZHUANG lin li Si-yang liU jing-yun li State Key Laboratory of Pathogen and Biosecurity Beijing Institute of Microbiology and Epidemiology Beijing100071 China

Human Immunodeficiency Virus Type 1 exists in vivo as quasispecies, and one of the genome's characteristics is its diversity. During the antiretroviral therapy, drug resistance is the main obstacle to effective viral prevention. Understanding the molecular evolution process is fundamental to analyze the mechanism of drug resistance and develop a strategy to minimize resistance. Objective: The molecular evolution of drug resistance of one patient who had received reverse transcriptase inhibitors for a long time and had treatment which replaced Nevirapine with Indinavir was analyzed, with the aim of observing the drug resistance evolution pathway. Methods: The patient, XLF, was followed-up for six successive times. The viral populations were amplified and sequenced by single-genome amplification. All the sequences were submitted to the Stanford HIV Drug Resistance Database for the analysis of genotypic drug resistance. Results: 149 entire protease and 171 entire reverse transcriptase sequences were obtained from these samples, and all sequences were identified as subtype B. Before the patient received Indinavir, the viral population only had some polymorphisms in the protease sequences. After the patient began Indinavir treatment, the variants carrying polymorphisms declined while variants carrying the secondary mutation G73S gained the advantage. As therapy was prolonged, G73S was combined with M46I/L90M to form a resistance pattern M46I/G73S/L90M, which then became the dominant population. 97.9% of variants had the M46I/G73S/L90M pattern at XLF6. During the emergence of protease inhibitors resistance, reverse transcriptase inhibitors resistance maintained high levels. Conclusion: Indinavirresistance evolution was observed by single-genome amplification. During the course of changing the regimen to incorporate Indinavir, the G73S mutation occurred and was combined with M46I/L90M.

关键词： Single-Genome Amplification Indinavir Resistance Evolution M46I/G73S/L90M Mutation Pattern

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Virologica Sinica 2012年第3期27卷 165-171页

作者： Zheng Wang Tian-yi li jing-yun li li-li Chen Yong-jian liu Han-ping li Zuo-yi Bao Xiao-lin Wang Dao-min Zhuang Si-yang liu lin li Department of AIDS Research State Key Laboratory of Pathogen and BiosecurityBeo'ing Institute of Microbiology and EpidemiologyBeijing 100071China Urumqi General Hospital of Lanzhou Military Area Command Urumqi 830000China

Neutralizing antibodies are considered to be an important protective parameter used in HIV-1 vaccine evaluation. However, the exact role that neutralizing antibodies plays in controlling the disease progression of HIV-1 infected peoples is still undetermined. In this paper, we compared the protective function of the neutralizing antibody response in the plasma from LTNP and TP against clade B and clade C pseudoviruses. No difference in the neutralizing activities between the plasma from LTNP and TP was found, which was consistent with the most recent reports. In addition, no correlations between the titer or breadth and CD4+ or viral load in HIV-1 infected individuals were found. The protective roles played by neutralizing antibodies in controlling disease progression of HIV-1 infected people need to be considered in a new viewpoint.

关键词： HIV-1 Long term non-progressor (LTNP) Typical progressor (TP) Neutralization activity

An Improved Strategy for Efficient Expression and Purification of Soluble HIV-1 Tat Protein in ***

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Virologica Sinica 2009年第6期24卷 518-528页

作者： Shi-meng ZHANG Rong FAN Tian-yi YANG Yi SUN jing-yun li Qin-zhi XU Ping-kun ZHOU The Department of Radiation Toxicology and Oncology Beijing Institute of Radiation Medicine Beijing100850 China Institute of Microbiology and Epidemiology Beijing 100071 China

Although the endogenous function of Tat has been elucidated in the past twenty years, the study of its exogenous activity has been hampered due to the difficulty of large scale preparation of the active Tat protein. To express the full-length Tat protein in ***, the tat gene was cloned from an HIV infected patient by overlapping PCR. Rare codon usage analysis showed that rare *** codons, especially consecutive rare codons for Arg, account for 14% (14 of 101) rare *** codons in the tat gene. The expression of the HIV-1 tat gene was verified to be very poor in strain BL21 (DE3) due to the abundance of rare codons; however, tat gene expression was found to be very efficient in the host strain of Rosetta-gami B (DE3), which was supplemented with six rare tRNAs for Arg, Leu, Ile and Pro. Subsequent purification revealed that the proteins are soluble and unusually, the tagged Tat can form dimers independent of cystine disulfide bonds. The purity, integrity and molecular weight of the Tat protein were demonstrated by MALDI-TOF mass spectrometry. Reporter gene activating assay was further confirmed by investigating the transactivation activity of the recombinant Tat protein. Our improved strategy for efficient high level expression and purification of soluble Tat protein has paved the way to fully investigate its exogenous function.

关键词： HIV tat gene E.coli Protein expression Codon usage

HIV-1 Vif Protein Mediates the Degradation of APOBEC3G in Fission Yeast When Over-expressed Using Codon Optimization

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Virologica Sinica 2008年第4期23卷 255-264页

作者： lin li jing-yun li Hong-shuai SUI Richard Y. Zhao Yong-jian liU Zuo-yi BAO Si-yang liU Dao-min ZHUANG AIDS Research Department State Key Laboratory of Pathogen and Biosecurity Beijing Institute of Microbiology and Epidemiology Being 100071 China Department of Pathology Department of Microbiology- Immunology Institute of Human Virology University of Maryland 10 South Pine Street MSTF7OOA Baltimore MD 21201 USA

Interaction between the HIV-1 Vif protein and the cellular host APOBEC3G protein is a promising target for inhibition of HIV-1 replication. Considering that human cells are a very complicated environment for the study of protein interactions, the goal of this study was to check whether fission yeast could be used as a model cell for studying the Vif-APOBEC3G interaction. Vif and APOBEC3G were expressed in fusion with GFP protein in the S. pombe SP223 strain. Subcellular localizations of Vif and APOBEC3G were observed with fluorescent microscopy. Codon optimization was used to over express the Vif protein in S. pombe cells. The degradation of APOBEC3G mediated by Vif was tested through expressing Vif and GFP-APOBEC3G proteins in the same cell. Western Blot analysis was used to measure the corresponding protein levels under different experimental conditions. The results showed that the Vif protein was predominantly localized in the nucleus of S. pombe cells, APOBEC3G was localized in the cytoplasm and concentrated at punctate bodies that were often in close proximity to the nucleus but were not necessarily restricted from other regions in the cytoplasm. Vif protein expression levels were increased significantly by using codon optimization and APOBEC3G was degraded when Vif was over-expressed in the same S. pombe cells. These results indicate that fission yeast is a good model for studying the interaction between the Vif and APOBEC3G proteins.

关键词： HIV Vif protein APOBEC3G Fission yeast (Schizosaccharomyces pombe)

Infection Route Analysis of Ventilator Associated Pneumonia

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国际感染病学（电子版） 2012年第4期1卷 211-215页

作者： Wei Guo Jie Zhang jing-yun li Yue Ma Sheng-hui Cui Department of Respiratory Diseases Beijing Tiantan HospitalCapital Medical University National Center for Surveillance of Antimicrobial Resistance the State Food and Drug Administration

Objective A prospective study was conducted in a tertiary care center to identify the risk factors of ventilator associated pneumonia(VAP) through phenotypic and molecular biological methods. Methods The patients who were mechanically ventilated in the respiratory intensive care unit(RICU) and the neurological internal intensive care unit(NICU) were enrolled in our study, and samples were collected from the lower respiratory tract, oropharynx and stomach. Other samples, including the environmental air, swabs of nurses' hands, subglottic secretion and ventilator circuit, were also collected. Microorganisms in the collected samples were recovered and identified at species level by biochemical detection. Genetic relationship of dominant species was further characterized by pulsed field gel electrophoresis(PFGE). Results Out of 48 enrolled patients, 22 cases developed VAP and bacterial cultures were recovered from the lower respiratory tract samples of 14 cases. The average hospitalization time with VAP was significantly longer than that of patients without VAP(P lia were dominant. It was more likely that subglottic secretion and gastric juice samples contained the same isolates as recovered in the lower respiratory tract by PFGE analysis. Conclusions Mechanical ventilation in RICU and NICU was a high risk factor for VAP development. Special emphasis of VAP prophylaxis should be paid on subglottic secretion and gastric juice reflux.

关键词： Ventilator Pneumonia Pulsed field gel electrophoresis Molecular epidemiology