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Chinese Journal of Cancer 2011年第3期30卷 153-162页

作者： Andrea J. McKinney Sheri L. Holmen Department of Drug and target discovery Nevada Cancer Institute

The increasing incidence and mortality associated with advanced stages of melanoma are cause for concern. Few treatment options are available for advanced melanoma and the 5-year survival rate is less than 15%. targeted therapies may revolutionize melanoma treatment by providing less toxic and more effective strategies. However, maximizing effectiveness requires further understanding of the molecular alterations that drive tumor formation, progression, and maintenance, as well as elucidating the mechanisms of resistance. Several different genetic alterations identified in human melanoma have been recapitulated in mice. This review outlines recent progress made in the development of mouse models of melanoma and summarizes what these findings reveal about the human disease. We begin with a discussion of traditional models and conclude with the recently developed RCAS/TVA somatic cell gene delivery mouse model of melanoma.

关键词：黑色素瘤小鼠模型基因传递人类疾病体细胞快速评估动物模型治疗方案

Gene regulatory network stabilized by pervasive weak repressions: micro RNA functions revealed by the May–Wigner theory

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National Science Review 2019年第6期6卷 1176-1188页

作者： Yuxin Chen Yang Shen Pei Lin Ding Tong Yixin Zhao Stefano Allesina Xu Shen Chung-I Wu School of Life Science Sun Yat-Sen University target discovery Research Boehringer Ingelheim Pharma Gmb H & Co KG Department of Biostatistics School of Public Health Yale University Department of Ecology and Evolution University of Chicago

Food web and gene regulatory networks(GRNs) are large biological networks, both of which can be analyzed using the May–Wigner theory. According to the theory, networks as large as mammalian GRNs would require dedicated gene products for stabilization. We propose that micro RNAs(mi RNAs) are those products. More than 30% of genes are repressed by mi RNAs, but most repressions are too weak to have a phenotypic consequence. The theory shows that(i) weak repressions cumulatively enhance the stability of GRNs, and(ii) broad and weak repressions confer greater stability than a few strong ones. Hence, the diffuse actions of mi RNAs in mammalian cells appear to function mainly in stabilizing GRNs. The postulated link between m RNA repression and GRN stability can be seen in a different light in yeast, which do not have mi RNAs. Yeast cells rely on non-specific RNA nucleases to strongly degrade m RNAs for GRN stability. The strategy is suited to GRNs of small and rapidly dividing yeast cells, but not the larger mammalian cells. In conclusion, the May–Wigner theory, supplanting the analysis of small motifs, provides a mathematical solution to GRN stability, thus linking mi RNAs explicitly to ’developmental canalization’.

关键词： micro RNAs network stability canalization May–Wigner theory systems biology RNA crosstalk

Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

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Neural Regeneration Research 2025年第3期20卷 725-739页

作者： Benjamin R.Helmold Angela Ahrens Zachary Fitzgerald P.Hande Ozdinler Department of Neurology Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Center for Molecular Innovation and Drug discovery Center for Developmental TherapeuticsChemistry of Life Processes InstituteNorthwestern UniversityEvanstonILUSA Mesulam Center for Cognitive Neurology and Alzheimer’s Disease Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Feinberg School of Medicine Les Turner ALS Center at Northwestern UniversityChicagoILUSA

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

关键词： ALS2 alsin amyotrophic lateral sclerosis hereditary spastic paraplegia neurodegenerative diseases personalized medicine precision medicine protein interactome protein-protein interactions SPAST spastin

Chemo-selective control of Ritter-type reaction by coordinatively unsaturated inorganic salt hydrates

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Organic Chemistry Frontiers 2022年第6期9卷 1541-1549页

作者： Huifang Lai Jiexin Xu Jin Lin Biling Su Daijun Zha Department of Medicinal Chemistry School of PharmacyFujian Medical UniversityFuzhou 350004Fujian ProvinceChina Fujian Key Laboratory of Drug target discovery and Structural and Functional Research Fujian Medical UniversityChina

The Ritter-type reaction, without relying on a pre-installed functional group, is a highly efficient tool forthe construction of amides. However, the intrinsic chemo-selectivity that determines the generation ofamides or byproducts limits the efficiency and yield of the reaction. From 68 different types of hydrates,we found that a coordinatively unsaturated inorganic salt hydrate, MgSO_(4)·2H_(2)O, controlled chemoselectivity and eliminated the shortcomings of other synthesis approaches. To rationalize the differencesin selectivity of inorganic salt hydrates, we analyzed their corresponding water content, alkalinity, anions,and cations. MgSO_(4)·2H_(2)O was used with diverse scaffolds and C–H oxygenations, which demonstratedits generality in synthetic utility. Because it is readily available and it significantly improves yield, we expectthat MgSO_(4)·2H_(2)O will have broad application for Ritter-type reactions.

关键词： inorganic hydrate unsaturated

Reverse metabolomics as a novel strategy to annotate the human metabolome

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Chinese Journal of Natural Medicines 2024年第4期22卷 289-290页

作者： YAN Tingting NIE Liangliang HAO Haiping State Key Laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 211198China Laboratory of Metabolic Regulation and Drug target discovery School of PharmacyChina Pharmaceutical UniversityNanjing 210009China

Identifying chemical structures inhuman-derived samples presents significant challenges due to limited structural data obtained from untargeted metabolomics *** the chemical structures of molecules are closely related to the phenotypic status of human ecosystems,it becomes invaluable to devise a method for efficiently and systematically determining structures that correlate with the pathophysiological status of humans in a high-throughput approach.

关键词： Reverse metabolomics Human metabolome Combinational synthesis Bile amidates

Research progress on the pharmacological effects and chemical constituents of Pien Tze Huang and its potential Q-markers

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Chinese Journal of Natural Medicines 2023年第9期21卷 658-669页

作者： DONG Zhaomin WANG Hong WANG Guangji Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics Research Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical SciencesChina Pharmaceutical UniversityNanjing 210009China

Pien Tze Huang(PTH)was documented as an imperial prescription composed of Notoginseng Radix,Calculus Bovis,Snake Gallbladder,and *** is famous in China and Asian countries due to its excellent effects in heat clearing,detoxifying,swelling reduction,and pain *** pharmacological studies demonstrate that PTH shows excellent effects against various inflammatory diseases,liver diseases,and *** review summaries the pharmacological effects,clinical applications,and mainchemical components of *** importantly,its potential quality markers(Q-markers)were then analyzed based on the“five principles”of Q-markers under the guidance of Traditional Chinese Medicine theory,including transfer and traceability,specificity,efficacy,compatibility,and *** a result,ginsenosides Rb1,ginsenoside Rg1,ginsenoside Rd,ginsenoside Re,notoginsenoside R1,dencichine,bilirubin,biliverdin,taurocholic acid,and muscone are considered as the Q-markers of *** findings will provide guidance and assistance for the construction of a quality control system for PTH.

关键词： Pien Tze Huang(PTH) Quality marker(Q-marker) Chemical components Pharmacological effects Clinical application Qualitycontrol

Thio-ProTide strategy:A novel H_(2)S donoredrug conjugate(DDC)alleviates hepatic injury via innate lysosomal targeting

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Acta Pharmaceutica Sinica B 2024年第12期14卷 5341-5356页

作者： Haowen Jin Jie Ma Bixin Xu Sitao Xu Tianyu Hu Xin Jin Jiankun Wang Guangji Wang Le Zhen Key Laboratory of Drug Metabolism and Pharmacokinetics Research Unit of PKePD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical SciencesChina Pharmaceutical UniversityNanjing 210009China

Hydrogen sulfide(H_(2)S)is a gas signaling molecule with versatile bioactivities;however,its exploitation for disease treatment appears *** study describes the design and characteriza-tion of a novel type of H_(2)S donoredrug conjugate(DDC)based on the thio-ProTide scaffold,an evolu-tion of the ProTide strategy successfully used in drug *** new H_(2)S DDCs achieved hepatic co-delivery of H_(2)S and an anti-fibrotic drug candidate named hydronidone,which synergistically attenuated liver injury and resulted in more sufficient intracellular drug *** potent hepatoprotective ef-fects were also attributed to the H_(2)S-mediated multipronged intervention in lipid peroxidation both at the whole cellular and lysosomal *** H_(2)S accumulation and H_(2)S DDC activation were facilitated by the hydrolysis through the specific lysosomal hydrolase,representing a distinct mechanism for lysosomal targeting independent of the classical basic *** findings provided a novel pattern for the design of optimally therapeutic H_(2)S DDC and organelle-targeting functional molecules.

关键词： ProTide prodrug Hydrogen sulfide donor Drug conjugate Cellular pharmacokinetics Liver fibrosis Lipid peroxidation Lysosomal targeting Prodrug activation

Ginkgo biloba extract protects against depression-like behavior in mice through regulating gut microbial bile acid metabolism

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Chinese Journal of Natural Medicines 2023年第10期21卷 745-758页

作者： ZHOU Junchi FAN Qilin CAI Xiaoying ZHANG Youying HOU Yuanlong CAO Shuqi LIZiguang FENG Mengzhen WANG Qingqing ZHANG Jianbing WANG Guangi ZHENG Xiao HAO Haiping State Key Laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China Laboratory of Metabolic Regulation and Drug target discovery School of PharmacyChina Pharmaceutical UniversityNanjing 210009China WanBangDe Pharmaceutical Group Co. Ltd.Wenlin 317500China

Depression is a mental disorder with high morbidity,disability and relapse *** biloba extract(GBE),a traditional Chinese medicine,has a long history of clinical application in the treatment of cerebral and mental disorders,but the key mechanism remains incompletely *** we showed that GEB exerted anti-depressant effect in mice through regulating gut microbial *** protected against unpredictable mild stress(UMS)-induced despair,anxiety-like and social avoidance behavior in mice without sufficient brain *** microbiome transplantation transmitted,while antibiotic cocktail abrogated the protective effect of *** bacterial profiling and metabolomics assay revealed a potential involvement of Parasutterella excrementihominis and the bile acid metabolite ursodeoxycholic acid(UDCA)in the effect of *** administration induced depression-like behavior in ***,these findings suggest that GBE acts on gut microbiome-modulated bile acid metabolism to alleviate stress-induced depression.

关键词： Ginkgo biloba extract Depression Gut microbiome Gut-brain axis Bile acid

Protein acylation:mechanisms,biological functions and therapeutic targets

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Signal Transduction and targeted Therapy 2023年第1期8卷 220-249页

作者： Shuang Shang Jing Liu Fang Hua CAMS Key Laboratory of Molecular Mechanism and target discovery of Metabolic Disorder and Tumorigenesis State Key Laboratory of Bioactive Substance and Function of Natural MedicinesInstitute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical College100050 BeijingP.R.China

Metabolic reprogramming is involved in the pathogenesis of not only cancers but also neurodegenerative diseases,cardiovascular diseases,and infectious *** the progress of metabonomics and proteomics,metabolites have been found to affect protein acylations through providing acyl groups or changing the activities of acyltransferases or ***,protein acylation is involved in key cellular processes relevant to physiology and diseases,such as protein stability,protein subcellular localization,enzyme activity,transcriptional activity,protein–protein interactions and protein–DNA ***,we summarize the functional diversity and mechanisms of eight kinds of nonhistone protein acylations in the physiological processes and progression of several *** also highlight the recent progress in the development of inhibitors for acyltransferase,deacylase,and acylation reader proteins for their potential applications in drug discovery.

关键词： diseases cardiovascular mechanisms

Promoting remyelination for the treatment of multiple sclerosis:opportunities and challenges

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Neuroscience Bulletin 2013年第2期29卷 144-154页

作者： Yueting Zhang Taylor B.Guo Hongtao Lu Neuroimmunology discovery Performance Unit GlaxoSmithKline Research and Development Center

Multiple sclerosis （MS） is a chronic and devastating autoimmune demyelinating disease of the central nervous system. With the increased understanding of the pathophysiology of this disease in the past two decades, many disease-modifying therapies that primarily target adaptive immunity have been shown to prevent exacerbations and new lesions in patients with relapsing-remitting MS. However, these therapies only have limited efficacy on the progression of disability. Increasing evidence has pointed to innate immunity, axonal damage and neuronal loss as important contributors to disease progression. Remyelination of denuded axons is considered an effective way to protect neurons from damage and to restore neuronal function. The identification of several key molecules and pathways controlling the differentiation of oligodendrocyte progenitor cells and myelination has yielded clues for the development of drug candidates that directly target remyelination and neuroprotection. The long-term efficacy of this strategy remains to be evaluated in clinical trials. Here, we provide an overview of current and emerging therapeutic concepts, with a focus on the opportunities and challenges for the remyelination approach to the treatment of MS.

关键词： multiple sclerosis myelination neurodegeneration oligodendrocytes disease progression disease modifying therapy drug target animal models