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Selective type II TRK inhibitors overcome xDFG mutation mediated acquired resistance to the second-generation inhibitors selitrectinib and repotrectinib

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Acta Pharmaceutica Sinica B 2024年第2期14卷 517-532页

作者： Shuang Xiang Xiaoyun Lu International Cooperative Laboratory of Traditional Chinese Medicine Modernization and innovative drug Discovery of Chinese Ministry of Education(MOE) Guangdong Provincial Key Laboratory of New Drug Design and EvaluationGuangzhou City Key Laboratory of Precision Chemical Drug DevelopmentSchool of PharmacyJinan UniversityGuangzhou 510632China

Neurotrophic receptor kinase(NTRK) fusions are actionable oncogenic drivers of multiple pediatric and adult solid tumors,and tropomyosin receptor kinase(TRK) has been considered as an attractive therapeutic target for "pan-cancer" harboring these ***,two generations TRK inhibitors have been *** representative second-generation inhibitors selitrectinib and repotrectinib were designed to overcome clinic acquired resistance of the first-generation inhibitors larotrectinib or entrectinib resulted from solvent-front and gatekeeper on-target ***,xDFG(TRKAG667C/A/S,homologous TRKCG696C/A/S) and some double mutations still confer resistance to selitrectinib and repotrectinib,and overcoming these resistances represents a major unmet clinical *** this review,we summarize the acquired resistance mechanism of the first-and second-generation TRK inhibitors,and firstly put forward the emerging selective type Ⅱ TRK inhibitors to overcome xDFG mutations mediated ***,we concluded our perspectives on new challenges and future directions in this field.

关键词： NTRK fusions TRK kinase Clinical resistance xDFG mutations Selective type II inhibitors

Nuance of inward rectifying potassium(Kir) channel dysfunctions in neurodegenerative diseases

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Neural Regeneration Research 2024年第6期19卷 1195-1196页

作者： Benjamin Garland Linlin Ma Griffith institute for drug Discovery & School of Environment and Science Griffith University

Neurodegenerative disorders are highly prevalent and diverse in nature. Their manifestation largely depends on the cell types involved, with aberrant inflammatory episodes progressively inducing a constellation of phenotypes that are classified into specific diseases based on their neuropathological traits. The two most prevalent neurodegenerative diseases worldwide,

关键词： K-ATP CHANNELS PARKINSONS-DISEASE MODEL

Targeting calcium signaling in Alzheimer’s disease: challenges and promising therapeutic avenues

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Neural Regeneration Research 2024年第3期19卷 501-502页

作者： LinLin Song YongPei Tang Betty Yuen Kwan Law Neher’s Biophysics Laboratory for innovative drug Discovery State Key Laboratory of Quality Research in Chinese MedicineMacao University of Science and TechnologyMacao Special Administration RegionChina

The critical role of calcium dyshomeostasis in the pathogenesis of Alzheimer’s disease(AD):AD is a progressive neurodegenerative disease characterized by cognitive decline,memory impairment,and behavioral *** an estimated 50 million people being affected worldwide,the incidence of AD is constantly increasing *** hallmark of AD is the accumulation of amyloid-beta protein(Aβ)in the form of amyloid plaques and hyperphosphorylated tau protein in the form of neurofibrillary ***,increasing evidence suggests that calcium ion(Ca2+)dysregulation also plays a crucial role in the pathogenesis of AD(Calvo-Rodriguez and Bacskai,2021).As a key second messenger,Ca2+regulates a wide range of cellular processes,including the release of neurotransmitters,gene expression,and cell ***^(2+)also regulates the activity of Calcium/calmodulin-dependent protein kinase II,which is critical for synaptic plasticity,learning,and memory(Kaushik et al.,2022).Alternation in the Ca^(2+)signal is an early event in the pathogenesis of AD,which can lead to synaptic dysfunction,neuronal loss,and cognitive impairment.

关键词： Alzheimer homeostasis globally

A novel marine-derived anti-acute kidney injury agent targeting peroxiredoxin 1 and its nanodelivery strategy based on ADME optimization

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3232-3250页

作者： Ping Yu Tanwei Gu Yueyang Rao Weimin Liang Xi Zhang Huanguo Jiang Jindi Lu Jianglian She Jianmin Guo Wei Yang Yonghong Liu Yingfeng Tu Lan Tang Xuefeng Zhou Guangdong Provincial Key Laboratory of New drug Screening Guangdong-Hong Kong-Macao Joint Laboratory for New Drug ScreeningSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China CAS Key Laboratory of Tropical Marine Bio-Resources and Ecology Guangdong Key Laboratory of Marine Materia MedicaSouth China Sea Institute of OceanologyChinese Academy of SciencesGuangzhou 510301China NMPA Key Laboratory for Research and Evaluation of drug Metabolism School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China Guangdong Lewwin Pharmaceutical Research institute Co. Ltd.Guangdong Provincial Key Laboratory of Drug Non-Clinical Evaluation and ResearchGuangdong Engineering Research Center for Innovative Drug Evaluation and ResearchGuangzhou 510990China

Insufficient therapeutic strategies for acute kidney injury(AKI)necessitate precision therapy targeting its *** study reveals the new mechanism of the marine-derived anti-AKI agent,piericidin glycoside S14,targeting peroxiredoxin 1(PRDX1).By binding to Cys83 of PRDX1 and augmenting its peroxidase activity,S14 alleviates kidney injury efficiently in Prdx1-overexpression(Prdx1-OE)***,S14 also increases PRDX1 nuclear translocation and directly activates the Nrf2/HO-1/NQO1 pathway to inhibit ROS *** to the limited druggability of S14 with low bioavailability(2.6%)and poor renal distribution,a pH-sensitive kidney-targeting dodecanaminechitosan nanoparticle system is constructed to load S14 for precise treatment of AKI.L-Serine conjugation to chitosan imparts specificity to kidney injury molecule-1(Kim-1)-overexpressed *** developed S14-nanodrug exhibits higher therapeutic efficiency by improving the in vivo behavior of S14 *** encapsulation with micelles,the AUC_(0-t),half-life time,and renal distribution of S14 increase 2.5-,1.8-,and 3.1-fold,*** main factors contributing to the improved druggability of S14 nanodrugs include the lower metabolic elimination rate and UDPglycosyltransferase(UGT)-mediated *** summary,this study identifies a new therapeutic target for the marine-derived anti-AKI agent while enhancing its ADME properties and druggability through nanotechnology,thereby driving advancements in marine drug development for AKI.

关键词： Acute kidney injury Piericidin glycoside Peroxiredoxin 1 Nanodrug Kim-1 targeted ADME Marine drug druggability

Comprehensive characterization and detection of nut allergens in bakery foods using Q-TOF mass spectrometry and bioinformatics

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Food Quality and Safety 2024年第1期8卷 145-157页

作者： Daokun Xu Haolun Huang Zhen Liu YumeiWang Qinan Liu Xing Jiang JunYang Rui Ling Nanjing institute for Food and drug Control NanjingChina State Key Laboratory of Food Science and Technology School of Food Science and TechnologyJiangnan UniversityWuxiChina Demonstration Collaborative Laboratory of Analysis and Detection Technology for Food and drug Safety Nanjing Institute for Food and Drug Control and Agilent Technologies(China)NanjingChina Collaborative Laboratory for Food Safety Nanjing Institute for Food and Drug Control and SCIEX(China)NanjingChina

Food allergy is a growing health issue worldwide and the demand for sensitive,robust and high-throughput analytical methods is *** recent years,mass spectrometry-based methods have been established for multiple food allergen *** the present study,a novel method was developed for the simultaneous detection of almond,cashew,peanut,and walnut allergens in bakery foods using liquid chromatography–mass *** unique to these four ingredients were extracted,followed by trypsin digestion,quadrupole time-of-flight(Q-TOF)mass spectrometry and bioinformatics *** raw data were processed by de-novo sequencing module plus PEAKS DB(database search)module of the PEAKS software to screen peptides specific to each nut *** thermal stability and uniqueness of these candidate peptides were further verified using triple quadrupole mass spectrometry(QQQ-MS)in multiple reaction monitoring(MRM)*** nut species was represented by four peptides,all of which were validated for label-free quantification(LFQ).Calibration curves were constructed with good linearity and correlation coefficient(r 2)greater than *** limits of detection(LODs)were determined to range from 0.11 to 0.31 mg/kg,and were compared with the reference doses proposed by Voluntary Incidental Trace Allergen Labelling(VITAL).The recoveries of the developed method in incurred bakery food matrices ranged from 72.5%to 92.1%with relative standard deviations(RSD)of<5.2%.The detection of undeclared allergens in commercial bakery food samples confirmed the presence of these *** conclusion,this method provides insight into the qualitative and quantitative detection of trace levels of nut allergens in bakery foods.

关键词： Nut allergen Q-TOF mass spectrometry peptides label-free quantitation bakery foods.

Nrf2 as a potential target for the treatment of epilepsy

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Neural Regeneration Research 2024年第9期19卷 1865-1866页

作者： Prince Kumar Singh Tawfeeq Shekh-Ahmad institute for drug Research School of PharmacyFaculty of MedicineThe Hebrew University of JerusalemJerusalemIsrael

Epilepsy is a prevalent chronic brain disorder that is characterized by a persistent predisposition to recurrently generate epileptic seizures and is often associated with cognitive and psychological *** affects approximately 65 million individuals,including both males and females of all ages worldwide,and poses a significant burden on patients,their families,and the health system(Vezzani et al.,2019).

关键词： epilepsy Nrf2

Reductive lipid nanoparticles loaded with vinorelbine inhibit chemotherapy-induced invasion of cancer cells by modulating ENPP2

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Nano Research 2024年第4期17卷 2886-2898页

作者： Xiaoqi Zhao Xuemeng Guo Mei Pang Weigen Qiu Zhenyu Luo Qing Lin Yichao Lu Hang Yin Sijie Wang Huihui Liu Junlei Zhang Lihua Luo Jian You College of Pharmaceutical Sciences Zhejiang University866 Yuhangtang RoadHangzhou 310058China Hangzhou institute of innovative Medicine Zhejiang UniversityHangzhou 310058China

Cancer is a predominant culprit behind worldwide death and accounts for up to 10 million deaths every *** is the primary therapeutic method employed for cancer in clinical settings and is essential in controlling tumor *** the advances in this field,tumor invasion and metastasis during treatment remain a significant cause of treatment ***,the underlying mechanisms involving such a disappointing phenomenon are still not fully ***(VNB)extends the lifespan of many cancer patients in the clinic as an emerging chemotherapy drug approved by Food and drug Administration(FDA).However,VNB-induced tumor metastasis is still an intractable problem,which may be closely related to the abnormal oxidative stress generated during VNB-mediated ***,the study aims to construct a reductive nanosystem loaded with VNB,called VNB-VNP,to improve cancer cure rates and reduce tumor *** the reductive component vitamin E,VNB-VNP can effectively reduce oxidative stress and significantly outperform free VNB in preventing tumor *** transcriptome analysis shows that VNB-VNP can alleviate the over-expression of ectonucleotide pyrophosphatase/phosphodiesterase 2(ENPP2),which may be the main reason why VNB-VNP can inhibit tumor invasion and ***,the research designs a new platform for VNB treatment,which demonstrates promising efficacy in inhibiting neoplastic progression and identifies a new mechanism associated with VNB-induced tumor metastasis,which may offer several valuable references for enhancing chemotherapy efficacy in clinical anti-tumor therapy.

关键词： chemotherapy vinorelbine tumor Invasion lysophosphatidic acid ectonucleotide pyrophosphatase/phosphodiesterase 2(ENPP2)

Development of SV2A Ligands for Epilepsy Treatment:A Review of Levetiracetam,Brivaracetam,and Padsevonil

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Neuroscience Bulletin 2024年第5期40卷 594-608页

作者： Peng-Peng Wu Bi-Rong Cao Fu-Yun Tian Zhao-Bing Gao Center for Neurological and Psychiatric Research and drug Discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai201203China University of Chinese Academy of Sciences Beijing100049China Zhongshan institute for drug Discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesZhongshan528400China

Epilepsy is a common neurological disorder that is primarily treated with antiseizure medications(ASMs).Although dozens of ASMs are available in the clinic,approximately 30%of epileptic patients have medically refractory seizures;other limitations in most traditional ASMs include poor tolerability and drug-drug ***,there is an urgent need to develop alternative ***(LEV)is a first-line ASM that is well tolerated,has promising efficacy,and has little drug-drug *** it is widely accepted that LEV acts through a unique therapeutic target synaptic vesicle protein(SV)2A,the molecular basis of its action remains *** so,the next-generation SV2A ligands against epilepsy based on the structure of LEV have achieved clinical *** review highlights the research and development(R&D)process of LEV and its analogs,brivaracetam and padsevonil,to provide ideas and experience for the R&D of novel ASMs.

关键词： Levetiracetam Epilepsy Antiseizure medications Synaptic vesicle protein 2A Brivaracetam Padsevonil

Performance assessment of prefabricated vertical drains in mitigating soil reliquefaction subjected to repeated seismic events using shaking table experiments

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Frontiers of Structural and Civil Engineering 2024年第3期18卷 411-427页

作者： Gowtham PADMANABHAN Ganesh Kumar SHANMUGAM Department of Earthquake Engineering Indian Institute of Technology RoorkeeUttarakhand 247667India Geotechnical Engineering Division CSIR-Central Building Research institute Academy of Scientific and Innovative Research(AcSIR)Uttarakhand 247667India

The use of prefabricated vertical drains(PVD)in liquefiable deposits is gaining attention due to enhanced ***,investigations on PVD in mitigating re-liquefaction during repeated shaking events are not *** study performed a series of shaking table experiments on untreated and PVD-treated specimens prepared with 40%and 60%relative *** sinusoidal loading was applied with an incremental peak acceleration of 0.1g,0.2g,0.3g,and 0.4g,at 5 Hz shaking frequency with 40 s *** performance of treated ground was evaluated based on the generation and dissipation of excess pore water pressure(EPWP),induced sand densification,subsidence,and cyclic stress *** addition,the strain accumulated in fresh and exhumed PVD was investigated using geotextile tensile testing apparatus aided with digital image *** evidence of pore pressure was reported up to 0.2g peak acceleration for 40%and 60%relative density *** continuous occurrence of soil densification and drainage medium restrained and delayed the generation of EPWP and expedited the dissipation *** study demonstrates PVD can mitigate re-liquefaction,without suffering from deterioration,when subjected to medium to high intense repeated shaking events.

关键词： prefabricated vertical drains drainage re-liquefaction shaking table digital image correlation