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南方医科大学学报 2012年第8期32卷 1082-1087页

作者：周志刚朱美华梁中锟陈振瑞贺微李长征谭万龙姜世勃刘叔文周烨周辰广州医学院第二附属医院儿科广东广州510260 南方医科大学南方医院南方医科大学药学院南方医科大学中医药学院复旦大学上海医学院分子病毒学教育部//卫生部重点实验室上海200032 南方医科大学基因工程研究所广东广州510515 香港Dgen生物技术有限公司香港999077

目的构建系统性红斑狼疮(SLE)儿童个体特异性哺乳动物细胞表面展示的全长人抗体基因库。方法采集SLE确诊患儿外周血,分离外周血淋巴细胞,提取外周血淋巴细胞总RNA,用RT-PCR扩增全长Kappa轻链(LCκ)和重链可变区(VH)基因、构建抗体轻链... 详细信息

目的构建系统性红斑狼疮(SLE)儿童个体特异性哺乳动物细胞表面展示的全长人抗体基因库。方法采集SLE确诊患儿外周血,分离外周血淋巴细胞,提取外周血淋巴细胞总RNA,用RT-PCR扩增全长Kappa轻链(LCκ)和重链可变区(VH)基因、构建抗体轻链基因库和抗体重链基因库,将抗体基因库转染293T细胞,流式细胞仪分析抗体在293T细胞表面的表达。结果以0.8μg总RNA为模板,用6套引物成功扩增全长Kappa轻链和重链可变区基因,插入表达载体,构建获得的重链基因库容量为9.4×104,轻链基因库容量为8.4×104。随机挑选的10个重链克隆有8个含有正确的阅读框架,编码8个不同的氨基酸序列,10个轻链克隆7个含有正确的阅读框架,编码7个不同的氨基酸序列。流式细胞仪分析挑选的单克隆和抗体基因库,均检测到全长抗体在293T细胞表面的表达,理论上抗体库中可表达的抗体多样性可以达到109。结论以0.8μg总RNA为模板,通过RT-PCR扩增,成功构建SLE儿童特异性全长人抗体基因库,并在293T细胞表面成功展示SLE儿童个体抗体库中的全长抗体,为进一步研究SLE儿童自身抗体的特点及自身抗体在SLE发病机制中的作用及临床应用打下良好基础。

关键词：系统性红斑狼疮儿童哺乳动物细胞表面展示全长人源抗体库

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Amelioration of Lipid Abnormalities by α-Lipoic acid Through Antioxidative and Anti-Inflammatory Effects

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OBESITY 2011年第8期19卷 1647-1653页

作者： Zhang, Yongyan Han, Ping Wu, Na he, Bing Lu, Yan Li, shuwen Liu, Yang Zhao, Sheng Liu, Letong Li, Yan China Med Univ Shengjing Hosp Dept Endocrinol Shenyang Peoples R China

Recent data have revealed that oxidative products and inflammatory mediators are increased in the insulin-resistant states of obesity and type 2 diabetes mellitus (T2DM). Obese patients with impaired glucose tolerance (IGT) are at high risk for developing T2DM and have high incidence of dyslipidemia. alpha-Lipoic acid (ALA) is a potent antioxidant with insulin sensitizing activity. However, it is not clear whether ALA is effective on lipid parameters in humans. This study has investigated 22 obese subjects with IGT (obese-IGT), 13 of whom underwent 2-week ALA treatment, 600 mg intravenously once daily. Before and after the treatment, euglycemic-hyperinsulinemic clamps were used to measure insulin sensitivity. Meanwhile, plasma lipids, oxidative products, and chronic inflammatory markers were measured. After treatment of ALA in obese-IGT patients, insulin sensitivity was improved, insulin sensitivity index (ISI) impressively enhanced by 41%. Plasma levels of free fatty acids (FFAs), triglyceride (TG), total cholesterol (T-Chol), low density lipoprotein-cholesterol (LDL-Chol), small dense LDL-Chol (sd-LDL), oxidized LDL-Chol (ox-LDL-Chol), very low density lipoprotein-cholesterol (VLDL-Chol) were all significantly decreased (P < 0.01). At the same time, both plasma oxidative products (malondialdehyde (MDA), 8-iso-prostaglandin) and inflammatory markers (tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6)) were remarkably decreased (P < 0.01), while adiponectin was increased (P < 0.01). There are significant negative correlations between ISI and plasma FFAs, sd-LDL-Chol, ox-LDL-Chol, MDA, 8-iso-prostaglandin, TNF-alpha, and IL-6, and positive correlations with HDL-Chol and adiponectin in obese-IGT patients. The results indicate that short-term treatment with ALA can improve insulin sensitivity and plasma lipid profile possibly through amelioration of oxidative stress and chronic inflammatory reaction in obese patients with IGT.

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ChemInform Abstract: Discovery of a Spiroindane Based Compound as a Potent, Selective, Orally Bioavailable Melanocortin Subtype‐4 Receptor Agonist.

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ChemInform 2010年第35期41卷

作者： shuwen he et al. et al. Dep. Med. Chem. Merck Res. Lab. Rahway NJ 07065 USA

Design, multi‐step synthesis, and properties of diastereoisomeric spiroindanes of type (I) are reported.

关键词： pyridine derivatives spirocyclic compounds indan derivatives receptor binding activity

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狼疮性肾炎合并颅内静脉窦血栓一例

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中华肾病研究电子杂志 2012年第2期1卷 44-45页

作者：何芳刘述文魏日胞汤力林淑董燕陈香美解放军总医院肾脏病科全军肾脏病研究所肾脏疾病国家重点实验室北京100853

系统性红斑狼疮（systemic lupus erythematosus，SLE）是以全身免疫异常导致多器官受累为特征的疾病，主要见于育龄期女性，约80％的患者合并肾脏损害，10％～40％的患者抗磷脂抗体试验阳性。现将我院及时诊断、成功治疗的1例狼疮性肾... 详细信息

系统性红斑狼疮（systemic lupus erythematosus，SLE）是以全身免疫异常导致多器官受累为特征的疾病，主要见于育龄期女性，约80％的患者合并肾脏损害，10％～40％的患者抗磷脂抗体试验阳性。现将我院及时诊断、成功治疗的1例狼疮性肾炎合并颅内静脉窦血栓患者报道如下。

关键词：颅内静脉窦血栓狼疮性肾炎 erythematosus 系统性红斑狼疮 lupus 多器官受累育龄期女性免疫异常

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ChemInform Abstract: Highly Diastereoselective Asymmetric Thio-Claisen Rearrangements.

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ChemInform 2010年第15期31卷

作者： shuwen he Sergey A. Kozmin Viresh H. Rawal Dep. Chem. Univ. Chicago Chicago IL 60637 USA

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, p... 详细信息

关键词： stereochemistry (general, optical resolution) alkylation, arylation, dealkylation, dearylation, C-acylation, olefination pyrrole derivatives

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Synthesis and SAR of heterocyclic carboxylic acid isosteres based on 2-biarylethylimidazole as bombesin receptor subtype-3 (BRS-3) agonists for the treatment of obesity

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BIOORGANIC & MEDICINAL CheMISTRY LETTERS 2010年第9期20卷 2912-2915页

作者： Hadden, Mark Goodman, Allan Guo, Cheng Guzzo, Peter R. henderson, Alan J. Pattamana, Kevin Ruenz, Megan Sargent, Bruce J. Swenson, Brian Yet, Larry Liu, Jian he, shuwen Sebhat, Iyassu K. Lin, Linus S. Tamvakopoulos, Constantin Peng, Qianping Kan, Yanqing Palyha, Oksana Kelly, Theresa M. Guan, Xiao-Ming Metzger, Joseph M. Reitman, Marc L. Nargund, Ravi P. AMRI Albany NY 12212 USA Merck Res Labs Dept Med Chem Rahway NJ 07065 USA Merck Res Labs Dept Metab Disorders Rahway NJ 07065 USA Merck Res Labs Dept Pharmacol Rahway NJ 07065 USA Merck Res Labs Dept Drug Metab Rahway NJ 07065 USA

SAR around non-peptidic potent bombesin receptor subtype-3 (BRS-3) agonist lead 2 is presented. Attempts to replace the carboxylic acid with heterocyclic isosteres to improve oral bioavailability and brain penetration... 详细信息

关键词： BRS-3 Obesity Acid isosteres

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Spiroindane based amides as potent and selective MC4R agonists for the treatment of obesity

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BIOORGANIC & MEDICINAL CheMISTRY LETTERS 2010年第15期20卷 4399-4405页

作者： he, shuwen Ye, Zhixiong Dobbelaar, Peter H. Sebhat, Iyassu K. Guo, Liangqin Liu, Jian Jian, Tianying Lai, Yingjie Franklin, Christopher L. Bakshi, Raman K. Dellureficio, James P. Hong, Qingmei Weinberg, David H. MacNeil, Tanya Tang, Rui Strack, Alison M. Tamvakopoulos, Constantin Peng, Qianping Miller, Randy R. Stearns, Ralph A. Chen, Howard Y. Chen, Airu S. Fong, Tung M. Wyvratt, Matthew J., Jr. Nargund, Ravi P. Merck Res Labs Dept Med Chem Rahway NJ 07065 USA Merck Res Labs Dept Metab Disorders Rahway NJ 07065 USA Merck Res Labs Dept Pharmacol Rahway NJ 07065 USA Merck Res Labs Dept Drug Metab Rahway NJ 07065 USA

We report a series of potent and selective MC4R agonists based on spiroindane amide privileged structures for potential treatments of obesity. Among the synthetic methods used, Method C allows rapid synthesis of the analogs. The series of compounds can afford high potency on MC4R as well as good rodent pharmacokinetic profiles. Compound 1r (MK-0489) demonstrates MC4R mediated reduction of food intake and body weight in mouse models. Compound 1r is efficacious in 14-day diet-induced obese (DIO) rat models. (C) 2010 Elsevier Ltd. All rights reserved.

关键词： Spiroindane Amide Privileged structure Melanocortin subtype-4 receptor MC4R Agonist MK-0489 Obesity

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Discovery of potent, selective, and orally bioavailable 3H-spiro[isobenzofuran-1,4′-piperidine] based melanocortin subtype-4 receptor agonists

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BIOORGANIC & MEDICINAL CheMISTRY LETTERS 2010年第16期20卷 4895-4900页

作者： Guo, Liangqin Ye, Zhixiong Liu, Jian he, shuwen Bakshi, Raman K. Sebhat, Iyassu K. Dobbelaar, Peter H. Hong, Qingmei Jian, Tianying Dellureficio, James P. Tsou, Nancy N. Ball, Richard G. Weinberg, David H. MacNeil, Tanya Tang, Rui Tamvakopoulos, Constantin Peng, Qianping Chen, Howard Y. Chen, Airu S. Martin, William J. MacIntyre, D. Euan Strack, Alison M. Fong, Tung M. Wyvratt, Matthew J. Nargund, Ravi P. Merck Res Labs Dept Med Chem Rahway NJ 07065 USA Merck Res Labs Dept Pharmacol Rahway NJ 07065 USA Merck Res Labs Dept Obes Res Rahway NJ 07065 USA Merck Res Labs Dept Drug Metab & Pharmacokinet Rahway NJ 07065 USA

Design, synthesis, and SAR of a series of 3H-spiro[isobenzofuran-1,4'-piperidine] based compounds as potent, selective and orally bioavailable melanocortin subtype-4 receptor (MC4R) agonists are disclosed. (c) 201... 详细信息

关键词： Melanocortin subtype-4 receptor MC4R agonists Obesity Oral bioavailability Food intake Spiro isobenzofuran

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Four-way ligation for construction of a mammalian cell-based full-length antibody display library

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生物化学与生物物理学报（英文版） 2011年第3期43卷 232-238页

作者： Ivan Zhou Wanlong Tan Shibo Jiang Chen Zhou Zhe-Huan Zhang Chang-Zheng Li Zhen-Rui Chen Wei he Ye Zhou shuwen Liu Shuguang Wu Yuanping Zhou Antiviral Research Center School of Pharmaceutical Science Southern Medical University Guangzhou 510515 China Nanfang Hospital Southern Medical University Guangzhou 510515 China Antiviral Research Center School of Pharmaceutical Science Southern Medical University Guangzhou 510515 China Lindsley F. Kimball Research Institute New York Blood Center New York NY 10065 USA Antiviral Research Center School of Pharmaceutical Science Southern Medical University Guangzhou 510515 China Dgen Biotech Limited Hong Kong China Institute of Genetic Engineering Southern Medical University Guangzhou 510515 China

A unique four-way ligation strategy was developed for rapid construction of a full-length antibody library.A mammalian expression vector was constructed that contained dual mammalian expression cassettes and sequences recognized by the unique restriction enzymes BsmBI, BstXI, and SfiI, Both full-length light-chain and variable domain of heavy-chain genes were inserted into the vector in one step by four-way ligation, and fulllength bivalent antibodies were displayed on mammalian cell surfaces. Using this strategy, only 2 weeks were required to successfully construct high-quality, full-length human antibody libraries.

关键词： four-way ligation library construction antibody library antibody display mammalian display

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Regulation of Energy Homeostasis by Bombesin Receptor Subtype-3: Selective Receptor Agonists for the Treatment of Obesity

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CELL METABOLISM 2010年第2期11卷 101-112页

作者： Guan, Xiao-Ming Chen, Howard Dobbelaar, Peter H. Dong, Yan Fong, Tung M. Gagen, Karen Gorski, Judith he, shuwen Howard, Andrew D. Jian, Tianying Jiang, Michael Kan, Yanqing Kelly, Theresa M. Kosinski, Jennifer Lin, Linus S. Liu, Jian Marsh, Donald J. Metzger, Joseph M. Miller, Randy Nargund, Ravi P. Palyha, Oksana Shearman, Lauren Shen, Zhu Stearns, Ralph Strack, Alison M. Stribling, Sloan Tang, Yui Sing Wang, Sheng-Ping White, Amanda Yu, Hong Reitman, Marc L. Merck Res Labs Rahway NJ 07065 USA

Bombesin receptor subtype 3 (BRS-3) is a G protein coupled receptor whose natural ligand is unknown. We developed potent, selective agonist (Bag-1, Bag-2) and antagonist (Bantag-1) ligands to explore BRS-3 function. BRS-3-binding sites were identified in the hypothalamus, caudal brainstem, and several midbrain nuclei that harbor monoaminergic cell bodies. Antagonist administration increased food intake and body weight, whereas agonists increased metabolic rate and reduced food intake and body weight. Prolonged high levels of receptor occupancy increased weight loss, suggesting a lack of tachyphylaxis. BRS-3 agonist effectiveness was absent in Brs3(-/Y) (BRS-3 null) mice but was maintained in Npy(-/-)Agrp(-/-), Mc4r(-/-), Cnr1(-/-), and Lepr(db/db) mice. In addition, Brs3(-/Y) mice lost weight upon treatment with either a MC4R agonist or a CB1R inverse agonist. These results demonstrate that BRS-3 has a role in energy homeostasis that complements several well-known pathways and that BRS-3 agonists represent a potential approach to the treatment of obesity.

关键词： HUMDISEASE MOLNEURO

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