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Spinal cord injury regenerative therapy development:integration of design of experiments

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Neural Regeneration research 2025年第9期20卷 2571-2573页

作者： Yuji Okano Hideyuki Okano Yoshitaka Kase Division of CNS Regeneration and drug discovery International Center for Brain Science(ICBS)Fujita Health UniversityKutsukake-ChoToyoake-ShiAichiJapan Department of Extended Intelligence for Medicine The Ishii-Ishibashi LaboratoryKeio University School of MedicineShinanomachiShinjuku-KuTokyoJapan Keio University Regenerative Medicine research center Kawasaki-kuKawasaki-shiJapan

Spinal cord injury(SCI)can cause motor and sensory paralysis,and autonomic nervous system disorders including malfunction of urination and defecation,thereby significantly impairing the quality of *** continue to explo re new stem cell strategies for the treatment of paralysis by transpla nting human induced pluripotent stem cell-derived neural ste m/progenitor cells(hiPSCNS/PCs)into spinal cord injured tissues.

关键词： Spinal paralysis injury

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

STING agonist-boosted mRNA immunization via intelligent design of nanovaccines for enhancing cancer immunotherapy

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National Science Review 2023年第10期10卷 123-138页

作者： Lei Zhou Wenzhe Yi Zehong Zhang Xiaoting Shan Zitong Zhao Xiangshi Sun Jue Wang Hao Wang Hualiang Jiang Mingyue Zheng Dangge Wang Yaping Li State Key Laboratory of drug research & center of Pharmaceutics Shanghai Institute of Materia MedicaChinese Academy of Sciences China State Institute of Pharmaceutical Industry Univerisity of Chinese Academy of Sciences drug discovery and Design center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Precision research center for Refractory Diseases Shanghai General HospitalShanghai Jiao Tong University School of Medicine Shandong Laboratory of Yantai drug discovery Bohai Rim Advanced Research Institute for Drug Discovery

Messenger RNA(mRNA) vaccine is revolutionizing the methodology of immunization in ***,mRNA immunization is drastically limited by multistage biological barriers including poor lymphatic transport,rapid clearance,catalytic hydrolysis,insufficient cellular entry and endosome ***,we design a mRNA nanovaccine based on intelligent design to overcome these *** efficient nanovaccines are carried out with machine learning techniques from datasets of various nanocarriers,ensuring successful delivery of mRNA antigen and cyclic guanosine monophosphate-adenosine monophosphate(cGAMP) to *** activates stimulator of interferon genes(STING),promotes mRNA-encoded antigen presentation and boosts antitumour immunity in vivo,thus inhibiting tumour growth and ensuring long-term survival of tumour-bearing *** work provides a feasible and safe strategy to facilitate STING agonist-synergized mRNA immunization,with great translational potential for enhancing cancer immunotherapy.

关键词： vaccine mRNA STING cancer immunotherapy nanoparticles

Structure-based drug design of a novel family of chalcones as PPARα agonists:virtual screening,synthesis,and biological activities in vitro

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Acta Pharmacologica Sinica 2007年第12期28卷 2040-2052页

作者： Xiang-hua LI~(2,3),Han-jun ZOU~(2,3),An-hui WU~2,Yang-liang YE~2,Jian-hua SHEN~(2,4)~2 drug discovery and Design center,State Key Laboratory of drug research,Shanghai Institute of Materia Medica,Chinese Academy ofSciences,Shanghai 201203,China drug discovery and Design center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China

Aim:To design and synthesize a novel class of peroxisome proliferator-activatedreceptors (PPAR)α agonists,which is obtained by the combination of the classi-cal fibrate"head group",a linker with appropriate length and a ***:Thirty seven compounds were designed and identified employing the virtualscreening *** compounds were then selected for synthesis and bioas-say according to the virtual screening results,structural similarity,and ***:Six new compounds (4b and 4d-h) were synthesized *** were found to be potent PPARα agonists,compound 4 h being themost prominent with a 50% effective concentration value of 0.06 μmol/***:This study provides a promising novel family of chalcones with a potentialhypolipidemic effect.

关键词： peroxisome proliferator-activated receptors drug design virtual screening

Highly Aromatic Norditerpenoid Heterodimers and Monomers from Trigonostemon fragilis

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Engineering 2024年第7期38卷 144-154页

作者： Jun-Su Zhou Long Cheng Yuan Gao Zhan-Peng Ge Bin Zhou Jing-Ya Li Jin-Xin Zhao Jian-Min Yue State Key Laboratory of drug research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Shandong Laboratory of Yantai drug discovery Bohai Rim Advanced Research Institute for Drug DiscoveryYantai 264117China

Four new norditerpenoid heterodimers with different dimerization patterns-namely,trigofragiloids A-C(denoted as compounds 1-3)and(+)-and(-)-trigofragiloid D(compound 4)-and three new phenanthrenone norditerpenoids-namely,trigofragiloids E-G(compounds 5-7)-were isolated from Trigonostemon *** 1 and 2 feature a novel heterodimeric carbon skeleton formed by the conjugation of a tetra-norditerpenoid and an ennea-norditerpenoid;they have been identified as class 2 atropisomers by means of quantum chemical *** 3 is an unprecedented phenylpropanoid-norditerpenoid adduct with a new dimerization ***(+)-and(-)-4 are the first example of S-shaped 1,4-dioxane-fused norditerpenoid *** by the structure elucidation of compound 4,two co-occurring analogues,actephilol A and epiactephilol A,were structurally revised as a pair of geometrical isomers and were identified as two pairs of enantiomers,(+)-and(-)-8 and(+)-and(-)-9,*** structures were characterized using a combined ***,compound 7 exhibits remarkable adenosine triphosphate-citrate lyase(ACLY)inhibition with a halfmaximal inhibition concentration(IC50)value of(0.46±0.11)lmol·L^(-1),as active as the positive control BMS-303141,and a molecular docking study offers deep insight into the interaction between compound 7 and ACLY.

关键词： Norditerpenoid heterodimer Trigonostemon fragilis Euphorbiaceae Trigofragiloid Structural revision Adenosine triphosphate-citrate lyase(ACLY) inhibitory activity

The disruption of protein-protein interactions with co-chaperones and client substrates as a strategy towards Hsp90 inhibition

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Acta Pharmaceutica Sinica B 2021年第6期11卷 1446-1468页

作者： Michael A.Serwetnyk Brian S.J.Blagg Department of Chemistry and Biochemistry Warren Family Research Center for Drug Discovery and DevelopmentUniversity of Notre DameIN 46556USA

The 90-kilo Dalton(kD) heat shock protein(Hsp90) is a ubiquitous,ATP-dependent molecular chaperone whose primary function is to ensure the proper folding of several hundred client protein *** many of these clients are overexpressed or become mutated during cancer progression,Hsp90 inhibition has been pursued as a potential strategy for cancer as one can target multiple oncoproteins and signaling pathways *** first discovered Hsp90 inhibitors,geldanamycin and radicicol,function by competitively binding to Hsp90’s N-terminal binding site and inhibiting its ATPase ***,most of these N-terminal inhibitors exhibited detrimental activities during clinical evaluation due to induction of the pro-survival heat shock response as well as poor selectivity amongst the four ***,alternative approaches to Hsp90 inhibition have been pursued and include C-terminal inhibition,isoform-selective inhibition,and the disruption of Hsp90 protein-protein *** the Hsp90 protein folding cycle requires the assembly of Hsp90 into a large heteroprotein complex,along with various co-chaperones and immunophilins,the development of small molecules that prevent assembly of the complex offers an alternative method of Hsp90 inhibition.

关键词： Hsp90 Protein-protein interactions Disruptors Natural products Small molecules Peptidomimetics

Grignard Addition to Quinoxalinium Salt: Synthesis of 1, 2-Dihydro-quinoxaline and 1, 2, 3, 4-Tetrahydroquinoxaline Derivatives

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Chinese Chemical Letters 2006年第2期17卷 165-168页

作者： Lian You ZHENG Xu BAI The center for Combinatorial Chemistry and drug discovery Jilin University Changchun 130012

Grignard additions to a quinoxalinium salt were studied. Depending on the ratio of the reagents and reaction temperature, 1, 2, 3, 4-tetrahydroquinoxaline and 1, 2-dihydroquinoxaline derivatives could be resulted sele... 详细信息

关键词： Grignard addition quinoxalinium salt dihydroquinoxaline tetrahydroquinoxaline.

One-pot synthesis of 2-(1-acyloxypentyl)benzoic acids

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Chinese Chemical Letters 2008年第8期19卷 915-917页

作者： Zhen Li Min Yi Hua Zhang Yi Sheng Lai Si Xun Peng center of drug discovery China Pharmaceutical University Nanjing 210009 China

A one-pot synthesis of 2-（1-acyloxypcntyl） benzoic acids by trapping the carboxylatc/alkoxide dianion with acylating reagents following Grignard addition with n-BuMgBr to 2-formylbcnzoic acid was described. Compared... 详细信息

关键词： One-pot synthesis 3-n-Butyl-1(3H)-isobcnzofuranone 2-(1-Hydroxypcntyl)benzoic acid 2-(1-Acyloxypcntyl)-benzoic acids

Synthesis and biological evaluation of tetrahydroisoquinoline derivatives as potential multidrug resistance reversal agents in cancer

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Chinese Chemical Letters 2008年第2期19卷 169-171页

作者： Yu Li Hui Bin Zhang Wen Long Huang Xia Zhen Yun Man Li center of drug discovery China Pharmaceutical University Nanjing 210009 China

Tetrahydroisoquinoline derivatives were synthesized and their multidrug resistance reversal activities were evaluated in vitro. The results showed that some of the synthetic compounds had higher multidrug resistance ... 详细信息

关键词： Tetrahydroisoquinoline derivatives Synthesis Mulfidrug resistance (MDR) Peptoids