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| 1 | Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer's disease progression显示文摘Recently,increasing evidence has suggested the association between gut dysbiosis and Alzheimer's disease(AD)progression,yet the role of gut microbiota in AD pathogenesis remains obscure.Herein,we provide a potential mechanistic link between gut microbiota dysbiosis and neuroinflammation in AD progression.Using AD mouse models,we discovered that,during AD progression,the alteration of gut microbiota composition leads to the peripheral accumulation of phenylalanine and isoleucine,which stimulates the differentiation and proliferation of pro-inflammatory T helper 1(Thl)cells.The brain-infiltrated peripheral Th1 immune cells are associated with the Ml microglia aaivation,contributing to AD-associated neuroinflammation.Importantly,the elevation of phenylalanine and isoleucine concentrations and the increase of Th1 cell frequency in the blood were also observed in two small independent cohorts of patients with mild cognitive impairment(MCI)due to AD.Furthermore,GV-971,a sodium oligomannate that has demonstrated solid and consistent cognition improvement in a phase 3 clinical trial in China,suppresses gut dysbiosis and the associated phenylalanine/isoleucine accumulation,harnesses neuroinflammation and reverses the cognition impairment.Together,our findings highlight the role of gut dysbiosis-promoted neuroinflammation in AD progression and suggest a novel strategy for AD therapy by remodelling the gut microbiota. | Xinyi Wang Guangqiang Sun Teng Feng Jing Zhang Xun Huang Tao Wang Zuoquan Xie Xingkun Chu Jun Yang Huan Wang Shuaishuai Chang Yanxue Gong Lingfei Ruan Guanqun Zhang Siyuan Yan Wen Lian Chen Du Dabing Yang Qingli Zhang Feifei Lin Jia Liu Haiyan Zhang Changrong Ge Shifu Xiao Jian Ding Meiyu Geng | 2019 | Cell Research2019，29，10： | 192 |
| 2 | Targeting ERK,an Achilles' Heel of the MAPK pathway,in cancer therapy显示文摘The mitogen-activated protein kinases(MAPK) pathway, often known as the RAS-RAFMEK-ERK signal cascade, functions to transmit upstream signals to its downstream effectors to regulate physiological process such as cell proliferation, differentiation, survival and death. As the most frequently mutated signaling pathway in human cancer, targeting the MAPK pathway has long been considered a promising strategy for cancer therapy. Substantial efforts in the past decades have led to the clinical success of BRAF and MEK inhibitors. However, the clinical benefits of these inhibitors are compromised by the frequently occurring acquired resistance due to cancer heterogeneity and genomic instability. This review briefly introduces the key protein kinases involved in this pathway as well as their activation mechanisms. We also generalize the correlations between mutations of MAPK members and human cancers, followed by a summarization of progress made on the development of small molecule MAPK kinases inhibitors. In particular, this review highlights the potential advantages of ERK inhibitors in overcoming resistance to upstream targets and proposes that targeting ERK kinase may hold a promising prospect for cancer therapy. | Feifei Liu Xiaotong Yang Meiyu Geng Min Huang | 2018 | Acta Pharmaceutica Sinica B2018，8，4： | 40 |
| 3 | Chemotherapy-induced intestinal inflammatory responses are mediated by exosome secretion of double-strand DNA via AIM2 inflammasome activation显示文摘化疗经常被知道导致严重的胃肠的道毒性,但是内在的机制仍然保持不清楚。这研究作为一个代表性的代理人认为广泛地应用的细胞毒素的代理人是 irinotecan (CPT-11 ) 并且证明治疗从说明混合物的限制剂量的肠的毒性的肠导致双海滨 DNA 的巨大的版本。明确地,通过 exosome 分泌物释放的 self-DNA 进入天生的有免疫力的房间的 cytosol 并且激活 AIM2 (在黑瘤 2 不在) inflammasome。这导致成熟 IL-1 和 IL-18 分泌物并且导致肠的 mucositis 和迟了发作的腹泻。有趣地,在 AIM2 缺乏的老鼠或由象镇静药那样的一个药理学禁止者,没有影响 CPT-11 的 anticancer 功效, AIM2 发信号的废除显著地减少导致药的腹泻的发生。这些调查结果提供化疗怎么触发引起肠的毒性的天生的有免疫力的回答的机械学的卓见,并且揭示维持反瘤效果,但是围绕联系不利煽动性的反应的新化疗政体。 | Lian, Qiaoshi Xu, Jun Yan, Shanshan Huang, Min Ding, Honghua Sun, Xiaoyu Bi, Aiwei Ding, Jian Sun, Bing Geng, Meiyu | 2017 | Cell Research2017，27，6： | 18 |
| 4 | Chromopeptide A, a highly cytotoxic depsipeptide from the marine sediment-derived bacterium Chromobacterium sp. HS-13-94显示文摘A bicyclic depsipeptide, chromopeptide A(1), was isolated from a deep-sea-derived bacterium Chromobacterium sp. HS-13-94. Its structure was determined by extensive spectroscopic analysis and by comparison with a related known compound. The absolute configuration of chromopeptide A was established by X-ray diffraction analysis employing graphite monochromated Mo K_α radiation(λ ? 0.71073 ?) with small Flack parameter 0.03. Chromopeptide A suppressed the proliferation of HL-60, K-562, and Ramos cells with average IC_(50) values of 7.7, 7.0, and 16.5 nmol/L, respectively. | Zhenfang Zhou Xin Wang Hui Zhang Jingya Sun Linghui Zheng Hongchun Liu Jidong Wang Aijun Shen Meiyu Geng Yuewei Guo | 2015 | Acta Pharmaceutica Sinica B2015，5，1： | 6 |
| 5 | Targeting sphingosine-1-phosphate signaling for cancer therapy显示文摘Sphingosine-1-phosphate(S1P) is a potent pleotropic bioactive lipid mediator involved in immune cell trafficking, cell survival,cell proliferation, cell migration, angiogenesis and many other cellular processes. S1 P either activates S1 P receptors(S1PR1-5) through 'inside-out signaling' or acts directly on intracellular targets to regulate various cellular processes. In the past two decades, much progress has been made in exploring S1 P signaling and its pathogenic roles in diseases as well as in developing modulators of S1 P signaling, including S1 P agonists, S1 P antagonists and sphingosine kinase(SphK) inhibitors.Ceramide and S1 P have been defined as reciprocal regulators of cell fate, and S1 P signaling has been shown to be crucial for the pathogenesis of various diseases, including autoimmune diseases, inflammation and cancer; therefore, targeting S1 P signaling may curtail the process of pathogenesis and serve as a potential therapeutic target for the treatment of these diseases. In this review, we describe recent advances in our understanding of S1 P signaling in cancer development(particularly in inflammationassociated cancer) as well as in innate and adaptive immunity, and we also discuss modulators of S1 P signaling in cancer treatment. | Zuoquan Xie Hong Liu Meiyu Geng | 2017 | Science China(Life Sciences)2017，60，6： | 5 |
| 6 | Alzheimer’s disease hypothesis and related therapies显示文摘Alzheimer’s disease(AD)is a progressive neurodegenerative disorder and the most common cause for dementia.There are many hypotheses about AD,including abnormal deposit of amyloidβ(Aβ)protein in the extracellular spaces of neurons,formation of twisted fibers of tau proteins inside neurons,cholinergic neuron damage,inflammation,oxidative stress,etc.,and many anti-AD drugs based on these hypotheses have been developed.In this review,we will discuss the existing and emerging hypothesis and related therapies. | Xiaoguang Du Xinyi Wang Meiyu Geng | 2018 | Translational Neurodegeneration2018，7，1： | 4 |
| 7 | Tetrahydroisoquinolines as novel histone deacetylase inhibitors for treatment of cancer显示文摘Histone acetylation is a critical process in the regulation of chromatin structure and gene expression.Histone deacetylases(HDACs)remove the acetyl group,leading to chromatin condensation and transcriptional repression.HDAC inhibitors are considered a new class of anticancer agents and have been shown to alter gene transcription and exert antitumor effects.This paper describes our work on the structural determination and structure-activity relationship(SAR)optimization of tetrahydroisoquinoline compounds as HDAC inhibitors.These compounds were tested for their ability to inhibit HDAC 1,3,6 and for their ability to inhibit the proliferation of a panel of cancer cell lines.Among these,compound 82 showed the greatest inhibitory activity toward HDAC 1,3,6 and strongly inhibited growth of the cancer cell lines,with results clearly superior to those of the reference compound,vorinostat(SAHA).Compound 82 increased the acetylation of histones H3,H4 and tubulin in a concentration-dependent manner,suggesting that it is a broad inhibitor of HDACs. | Danqi Chen Aijun Shen Guanghua Fang Hongchun Liu Minmin Zhang Shuai Tang Bing Xiong Lanping Ma Meiyu Geng Jingkang Shen | 2016 | Acta Pharmaceutica Sinica B2016，6，1： | 4 |
| 8 | Effect of acidic oligosaccharide sugar chain on scopolamine-induced memory impairment in rats and its related mechanisms显示文摘 | Ying Fan Jinfeng Hu Jing Li Zhao Yang Xianliang Xin Jia Wang Jian Ding Meiyu Geng | 2006 | 中国生物学文摘2006，20，3： | 2 |
| 9 | Discovery of a series of dimethoxybenzene FGFR inhibitors with 5H-pyrrolo[2,3-b]pyrazine scaffold: structure–activity relationship, crystal structural characterization and in vivo study显示文摘Genomic alterations are commonly found in the signaling pathways of fibroblast growth factor receptors(FGFRs). Although there is no selective FGFR inhibitors in market, several promising inhibitors have been investigated in clinical trials, and showed encouraging efficacies in patients. By designing a hybrid between the FGFR-selectivity-enhancing motif dimethoxybenzene group and our previously identified novel scaffold, we discovered a new series of potent FGFR inhibitors, with the best one showing sub-nanomolar enzymatic activity. After several round of optimization and with the solved crystal structure, detailed structure–activity relationship was elaborated. Together with in vitro metabolic stability tests and in vivo pharmacokinetic profiling, a representative compound(35) was selected and tested in xenograft mouse model, and the result demonstrated that inhibitor 35 was effective against tumors with FGFR genetic alterations, exhibiting potential for further development. | Peng Wei Bo Liu Ruifeng Wang Yinglei Gao Lanlan Li Yuchi Ma Zhiwei Qian Yuelei Chen Maosheng Cheng Meiyu Geng Jingkang Shen Dongmei Zhao Jing Ai Bing Xiong | 2019 | Acta Pharmaceutica Sinica B2019，9，2： | 2 |
| 10 | The potential molecular targets of marine sulfated poly-mannuroguluronate interfering HIV-1 entry显示文摘 | Geng Meiyu Li Fuchuan Xin Xianliang | 2003 | Antiviral Research2003，59，： | 1 |
| 11 | Sulfated polymannuroguluronate, a novel anti-acquired immune deficiency syndrome (AIDS) drug candidate, targeting CD4 in lymphocytes显示文摘 | Benchun Miao Meiyu Geng Jing Li Fuchuan Li Haixia Chen Huashi Guan Jian Ding | 2004 | Biochemical Pharmacology2004，，4： | 1 |
| 12 | Effects of D-Polymannuronic Sulfate on Serum Nitric oxid Levels and Plasma Endothelin-1 and AngiotensinⅡ Contents in Renovascular Hypertensive Rats (Series Ⅲ)显示文摘 | Zhu Haibo Geng Meiyu Guan Huashi | 2001 | JOURNAL OF OCEAN UNIVERSITY OF QINGDAO2001，31，2： | 1 |
| 13 | Antihypertensive effect of Dpolymannuronic sulfate and its related mechanisms in renovascular hypertensive rats显示文摘 | ZI-IU Haibo GENG Meiyu GUAN Huashi | 2000 | Acta Pharmacologica Sinica2000，21，8： | 1 |
| 14 | Sulfated polymannuroguluronate, a novel anti - acquired immune deficiency syndrome (AIDS) drug candidate, targeting CD4 in lymphocytes 显示文摘 | Benchun Miao Meiyu Geng Jing Li | 2004 | Biochemical Pharmacology2004，68，4： | 1 |
| 15 | Pharmacokinetics,distribution,and excretion of sodium oligomannate,a recently approved anti-Alzheimer's disease drug in China显示文摘The National Medical Products Administration has authorized sodium oligomannate for treating mild-to-moderate Alzheimer’s disease.In this study,an LC-MS/MS method was developed and validated to quantitate sodium oligomannate in different biomatrices.The plasma pharmacokinetics,tissue distribution,and excretion of sodium oligomannate in Sprague-Dawley rats and beagle dogs were systematically investigated.Despite its complicated structural composition,the absorption,distribution,metabolism,and excretion profiles of the oligosaccharides in sodium oligomannate of different sizes and terminal derivatives were indiscriminate.Sodium oligomannate mainly crossed the gastrointestinal epithelium through paracellular transport following oral administration,with very low oral bioavailability in rats(0.6%-1.6%)and dogs(4.5%-9.3%).Absorbed sodium oligomannate mainly resided in circulating body fluids in free form with minimal distribution into erythrocytes and major tissues.Sodium oligomannate could penetrate the blood-cerebrospinal fluid(CSF)barrier of rats,showing a constant area under the concentration-time curve ratio(CSF/plasma)of approximately 5%.The cumulative urinary excretion of sodium oligomannate was commensurate with its oral bioavailability,supporting that excretion was predominantly renal,whereas no obvious biliary secretion was observed following a single oral dose to bile duct-cannulated rats.Moreover,only 33.7%(male)and 26.3%(female)of the oral dose were recovered in the rat excreta within 96 h following a single oral administration,suggesting that the intestinal flora may have ingested a portion of unabsorbed sodium oligomannate as a nutrient. | Jiaojiao Lu Qiongqun Pan Jieqiang Zhou Yan Weng Kaili Chen Lv Shi Guanxiu Zhu Chunlin Chen Liang Li Meiyu Geng Zhenqing Zhang | 2022 | Journal of Pharmaceutical Analysis2022，12，1： | 1 |
| 16 | Sulfated polymannuroguluronate, a novel anti-acquired immune deficiency syndrome (AIDS) drug candidate, targeting CD44 in lymphocytes 显示文摘 | Miao BC Meiyu Geng MY Li J | 2004 | Biochemical Pharmacology2004，68，4： | 1 |
| 17 | Exploiting histone deacetylases for cancer therapy: from hematological malignancies to solid tumors显示文摘Perturbations of the epigenomic landscape,as defined by genome-wide localization of histone post-translational modifications,DNA methylations and chromatin regulatory proteins,have been increasingly appreciated as a common feature of cancer.While epigenetic changes were previously argued as merely a consequence of the cancerous state,recent evidence collectively points to a perception that altered epigenetic states may play a causal role in cancer development(Brien et al.,2016).In fact,cancer | Min Huang Meiyu Geng | 2017 | Science China(Life Sciences)2017，60，1： | 1 |
| 18 | Glucose Transporter 1, Distribution in the Brain and in Neural Disorders: Its Relationship With Transport of Neuroactive Drugs Through the Blood-Brain Barrier显示文摘 | Guo Xiuli Geng Meiyu Du Guanhua | 2005 | Biochemical Genetics2005，，3： | 1 |
| 19 | China's reform of the regulatory system for medical products and its impact显示文摘On 9 August 2015, the State Council of the People’s Republic of China issued ‘The Opinions on Reforming Review and Approval Process for Drugs and Medical Devices’(GUOFA[2015] No. 44). This important policy document not only provides the guideline for creating a more scientific and efficient regulatory process for drugs and medical devices, but also initiates the reform of the administration system for medical products in China. In October 2017, the general office of the Communist Party of China Central Committee and the general office. | Ruilin Song Guowei Sang Meiyu Geng Hualiang Jiang | 2019 | National Science Review2019，6，1： | 0 |
| 20 | SYK-mediated epithelial cell state is associated with response to c-Met inhibitors in c-Met-overexpressing lung cancer显示文摘Genomic MET amplification and exon 14 skipping are currently clinically recognized biomarkers for stratifying subsets of non-small cell lung cancer(NSCLC)patients according to the predicted response to c-Met inhibitors(c-Metis),yet the overall clinical benefit of this strategy is quite limited.Notably,c-Met protein overexpression,which occurs in approximately 20–25%of NSCLC patients,has not yet been clearly defined as a clinically useful biomarker.An optimized strategy for accurately classifying patients with c-Met overexpression for decision-making regarding c-Meti treatment is lacking.Herein,we found that SYK regulates the plasticity of cells in an epithelial state and is associated with their sensitivity to c-Metis both in vitro and in vivo in PDX models with c-Met overexpression regardless of MET gene status.Furthermore,TGF-β1 treatment resulted in SYK transcriptional downregulation,increased Sp1-mediated transcription of FRA1,and restored the mesenchymal state,which conferred resistance to c-Metis.Clinically,a subpopulation of NSCLC patients with c-Met overexpression coupled with SYK overexpression exhibited a high response rate of 73.3%and longer progression-free survival with c-Meti treatment than other patients.SYK negativity coupled with TGF-β1 positivity conferred de novo and acquired resistance.In summary,SYK regulates cell plasticity toward a therapy-sensitive epithelial cell state.Furthermore,our findings showed that SYK overexpression can aid in precisely stratifying NSCLC patients with c-Met overexpression regardless of MET alterations and expand the population predicted to benefit from c-Met-targeted therapy. | Ji Zhou Xu-Chao Zhang Shan Xue Mengdi Dai Yueliang Wang Xia Peng Jianjiao Chen Xinyi Wang Yanyan Shen Hui Qin Bi Chen Yu Zheng Xiwen Gao Zuoquan Xie Jian Ding Handong Jiang Yi-Long Wu Meiyu Geng Jing Ai | 2023 | Signal Transduction and Targeted Therapy2023，8，6： | 0 |
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