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The HDAC inhibitor GCJ-490A suppresses c-Met expression through IKKα and overcomes gefitinib resistance in non-small cell lung cancer

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Cancer Biology & Medicine 2022年第8期19卷 1172-1192页

作者： Ting He Yinglei Gao Yanfen Fang Yangming Zhang Shuwei Zhang Fajun Nan Jian Ding Yi Chen division of Anti-Tumor pharmacology Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of chinese Academy of Sciences Beijing 100049China State Key Laboratory of drug Research the National Center for Drug ScreeningShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China

Objective:The novel compound GCJ-490A has been discovered as a pan-histone deacetylase(HDAC)inhibitor that exerts potent inhibitory activity against HDAC1,HDAC3,and *** of the important roles of HDACs in lung cancer development and the high distribution of GCJ-490A in lung tissue,we explored the anti-tumor potency of GCJ-490A against non-small cell lung cancer(NSCLC)in vitro and in vivo in this ***:The in vitro effects of GCJ-490A alone or combined with the EGFR inhibitor gefitinib against NSCLC were measured with proliferation,apoptosis,and colony formation *** xenograft models were used to investigate the efficacy of GCJ-490A combined with gefitinib for the treatment of NSCLC in *** blot assays,luciferase reporter assays,chromatin immunoprecipitation assays,quantitative real time-PCR,immunohistochemistry,and transcription factor activity assays were used to elucidate possible ***:GCJ-490A effectively inhibited NSCLC cell proliferation and induced apoptosis in vitro and in ***,inhibition of HDAC1 and HDAC6 by GCJ-490A increased histone acetylation at the IKKαpromoter and enhanced IKKαtranscription,thus decreasing ***,this c-Met downregulation was found to be essential for the synergistic anti-tumor activity of GCJ-490A and ***:These findings highlight the promising potential of HDAC inhibitors in NSCLC treatment and provide a rational basis for the application of HDAC inhibitors in combination with EGFR inhibitors in clinical trials.

关键词： HDAC inhibitor c-Met IKKα NSCLC gefitinib

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IL-1 β genesis: the art of regulating the regulator

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Cellular & Molecular Immunology 2018年第11期15卷 998-1000页

作者： Priya Gupta Manoj K.Barthwal pharmacology division CSIR-Central Drug Research InstituteLucknow226031UPIndia

In a study published in Cellular and Molecular Immunology,Singh et *** a new mechanism of monocyte IL-1βproduction.1 It was observed that TLR-4-and TLR-2-induced IRAK-ERK pathway cross-talk with p67phox-Nox-2 for reactive oxygen species(ROS)generation,thus regulating IL-1βtranscription and processing in *** study not only establishes a direct link between IRAK and ERK,but also demonstrates the regulation of p67phox-Nox-2 by ERK for ROS and IL-1βproduction(Fig.1).This study shows that the IRAK-ERK axis can regulate both IL-βtranscription and processing through ROS.

关键词： al. Immunology Singh

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Oligodendrocyte precursor cell maturation: role of adenosine receptors

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Neural Regeneration Research 2021年第9期16卷 1686-1692页

作者： Federica Cherchi Anna Maria Pugliese Elisabetta Coppi Department of Neuroscience PsychologyDrug Research and Child Health-Neurofarba-Division of Pharmacology and ToxicologyUniversity of FlorenceFlorenceItaly

Oligodendrocyte-formed myelin sheaths allow fast synaptic transmission in the brain and their degeneration leads to demyelinating diseases such as multiple sclerosis. Remyelination requires the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes but, in chronic neurodegenerative disorders, remyelination fails due to adverse environment. Therefore, a strategy to prompt oligodendrocyte progenitor cell differentiation towards myelinating oligodendrocytes is required. The neuromodulator adenosine, and its receptors(A1, A(2A), A(2B) and A3 receptors: A1R, A(2A)R, A(2B)R and A3R), are crucial mediators in remyelination processes. It is known that A1Rs facilitate oligodendrocyte progenitor cell maturation and migration whereas the A3Rs initiates apoptosis in oligodendrocyte progenitor cells. Our group of research contributed to the field by demonstrating that A(2A)R and A(2B)R inhibit oligodendrocyte progenitor cell maturation by reducing voltage-dependent K^+ currents necessary for cell differentiation. The present review summarizes the possible role of adenosine receptor ligands as potential therapeutic targets in demyelinating pathologies such as multiple sclerosis.

关键词： adenosine receptors K^+channels oligodendrocyte differentiation oligodendrocyte progenitor cells remyelination

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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

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Acta Pharmaceutica Sinica B 2019年第2期9卷 351-368页

作者： 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 Key Laboratory of Structure-Based drug Design and Discovery of Ministry of Education Shenyang Pharmaceutical University Department of Medicinal Chemistry Shanghai Institute of Materia Medica Chinese Academy of Sciences division of Anti-tumor pharmacology State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences

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.

关键词： Fibroblast growth factor Tyrosine kinase receptor Structure-based Crystallography Selectivity Hybrid 5-Hydrosulfonyl-5Hpyrrolo[2,3-b]pyrazine Inhibitor

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Design, synthesis and biological evaluation of pyrazolo[3,4-d]pyridazinone derivatives as covalent FGFR inhibitors

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Acta Pharmaceutica Sinica B 2021年第3期11卷 781-794页

作者： Xiaowei Wu Mengdi Dai Rongrong Cui Yulan Wang Chunpu Li Xia Peng Jihui Zhao Bao Wang Yang Dai Dan Feng Tianbiao Yang Hualiang Jiang Meiyu Geng Jing Ai Mingyue Zheng Hong Liu State Key Laboratory of drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China division of Anti-Tumor pharmacology State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of chinese Academy of Sciences Beijing 100049China School of chinese Materia Medica Nanjing University of Chinese MedicineNanjing 210023China

Fibroblast growth factor receptors (FGFRs) have emerged as promising targets for anticancer *** this study,we synthesized and evaluated the biological activity of 66 pyrazolo[3,4-d]pyridazinone *** inhibition,cell proliferation,and whole blood stability assays were used to evaluate their activity on FGFR,allowing us to explore structureàactivity relationships and thus to gain understanding of the structural requirements to modulate covalent inhibitors’selectivity and *** them,compound 10h exhibited potent enzymatic activity against FGFR and remarkably inhibited proliferation of various cancer cells associated with FGFR dysregulation,and suppressed FGFR signaling pathway in cancer cells by the immunoblot ***,10h displayed highly potent antitumor efficacy (TGI Z 91.6%,at a dose of 50 mg/kg) in the FGFR1-amplified NCI-H1581 xenograft model.

关键词： Tyrosine kinase Covalent FGFR inhibitors Virtual screening Pyrazolo[3,4-d]pyridazinone Structure-activity relationships Antitumor efficacy

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Expert Consensus on the Diagnosis and Treatment of Anticancer drug-induced Interstitial Lung Disease

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Current Medical Science 2023年第1期43卷 1-12页

作者：无 Fei MA Hua-ping DAI Anticancer drug-induced Interstitial Lung Disease Diagnosis and Treatment Group China Interstitial Lung diseases Panel Chinese Medical Association-Chinese Thoracic Society and Chinese Medical Doctor Association-Chinese Association of Chest PhysiciansChina Department of Medical Oncology National Cancer CenterNational Clinical Research Center for CancerCancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 10021China Department of Pulmonary and Critical Care Medicine China-Japan Friendship HospitalNational Center for Respiratory MedicineChinese Academy of Medical SciencesBeijing 100029China

drug-induced interstitial lung disease(DILD)is the most common pulmonary adverse event of anticancer *** recent years,the incidence of anticancer DILD has gradually increased with the rapid development of novel anticancer *** to the diverse clinical manifestations and the lack of specific diagnostic criteria,DILD is difficult to diagnose and may even become fatal if not treated ***,a multidisciplinary group of experts from oncology,respiratory,imaging,pharmacology,pathology,and radiology departments in China has reached the“expert consensus on the diagnosis and treatment of anticancer DILD”after several rounds of a comprehensive *** consensus aims to improve the awareness of clinicians and provide recommendations for the early screening,diagnosis,and treatment of anticancer *** consensus also emphasizes the importance of multidisciplinary collaboration while managing DILD.

关键词： drug-induced interstitial lung disease anticancer drug diagnosis treatment

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Enhanced digestion inhibition and mucus penetration of F127-modified self-nanoemulsions for improved oral delivery

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Asian Journal of Pharmaceutical Sciences 2018年第4期13卷 326-335页

作者： Wenyi Song Yuting Yang Miaorong Yu Quanlei Zhu Mohammadali Soleimani Damaneh Haijun Zhong Yong Gan Department of Pharmacy Medical College of Nanchang University Shanghai Institute of Materia Medica Chinese Academy of Sciences University of chinese Academy of Sciences division of Anti-tumor pharmacology State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of Sciences

Self-nanoemulsifying systems(SNEs) have excellent ability to improve the solubility ofpoorly water-soluble drugs(PWSD). However, SNEs are likely to be degraded in gastroin-testinal(GIT) when their surface is recognized by lipase/co-lipase enzyme complex, result-ing in rapid release and precipitation of encapsulated drugs. The precipitates are then cap-tured and removed by intestinal mucus, reducing the delivery efficacy of SNEs. Herein, theamphiphilic polymer Pluronic? F127 was incorporated into long and short-chain triglyc-erides(LCT, SCT) based SNEs to diminish the recognition and therefore minimized theirdegradation by enzymes and clearance by mucus. The SNEs were characterized in termsof particle size, zeta potential and stability. Ex vivo multiple particles tracking studies wereperformed by adding particle solution into fresh rat mucus. Cellular uptake of SNEs wereconducted by using E12 cells, the absorption and distribution in small intestine were alsostudied after oral administration in male Sprague-Dawley(SD) rats. The in vitro digestionrate of SNEs were found to be in following order SCT-SNE > SCT-F127-SNE > LCT-SNE > LCT-F127-SNE. Moreover, the LCT-F127-SNE was found to be most effective in enhancing cellularuptake, resulting in 3.5-fold, 2.1-fold and 1.7-fold higher than that of SCT-SNE, LCT-SNE andSCT-F127-SNE, respectively. After incubating the SNE with E12 cells, the LCT-F127-SNE ex-hibited the highest amount regarding both mucus penetration and cellular uptake, with anuptake amount number(via bicinchoninic acid(BCA) analysis) of 3.5-fold, 2.1-fold and 1.7-fold higher than that of SCT-SNE, LCT-SNE and SCT-F127-SNE, respectively. The in vivo results revealed that orally administered LCT-F127-SNE could significantly increase the bioavailability of Cyclosporine A(CsA), which was approximately 2.43-fold, 1.33-fold and 1.80-fold higher than that of SCT-SNE, SCT-F127-SNE and LCT-SNE, respectively. We address in this work that F127-modified SNEs have potentia

关键词： Self-nanoemulsifying system(SNEs) Oral absorption Enzymatic degradation Mucus penetration Pluronic^(■) F127

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Advances in ethnopharmacology,phytochemistry and pharmacology of Erigerontis Herba and its chinese medicine prescriptions

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Traditional Medicine Research 2025年第1期10卷 44-61页

作者： Yang Zhou Yuan-Yan Huang Ding-Yue Shang Ying Chen Meng Tian Cheng-Yu Jin Xin Lu Bing-Chun Yan Han-Qing Pang Institute of Translational Medicine School of MedicineYangzhou UniversityYangzhou 225009China Jiangsu Key Laboratory of Integrated Traditional chinese and Western Medicine for Prevention and Treatment of Senile diseases Yangzhou UniversityYangzhou 225009China School of Medicine Nanjing University of Chinese MedicineNanjing 210023China State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources Guangxi Normal UniversityGuiling 541004China.

Erigerontis Herba(EH),the dried whole plant of Erigeron breviscapus,is well-known for circulating blood,activating meridians to alleviate pain,expelling wind,and clearing away *** has been extensively utilized in southern China for the treatment of stroke hemiplegia,chest stuffiness and pains,rheumatic arthralgia,headache,and *** review focuses on the botany,ethnopharmacology,phytochemistry,pharmacology and toxicity of EH and its related prescriptions to offer new insights for prospective research of *** information about EH was retrieved from ancient records and books,PubMed,China National Knowledge Infrastructure,chinese Pharmacopoeia,Web of Science,Doctoral and Master’s Theses,and various electronic *** is a member of Compositae family and is mainly grown in southern *** chinese medicine records that EH has the effects of circulating blood and removing blood stasis,expelling wind,and removing cold,as well as relieving rigidity of muscle and relieving *** now,nearly 200 ingredients have been characterized from EH,including flavonoids,caffeoyls,aromatic acids,coumarins,pentacyclic terpenoids,volatile oil and other *** extracts,EH related prescriptions(Dengzhan Xixin injection,Dengzhan Shengmai capsules,etc.)or compounds(scutellarin,scutellarein,etc.)possessed obvious therapeutic effects of ischemic stroke,cerebral hemorrhage,myocardial infarction,Alzheimer’s disease,diabetes and its complications,gastric cancer,bone,and joint degenerative ***,the major active compound of EH,has been used as a quality *** no obvious toxicity of EH has been *** to its traditional applications,ethnopharmacology,phytochemistry,pharmacology,and toxicity,EH was applied as a valuable herb for clinical application in food and medicine *** several compounds have been shown to possess diverse biological activities,the underlying mechanisms of their actions remain *** fully exploi

关键词： Erigeron breviscapus traditional applications ethnopharmacology phytochemistry pharmacology

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Tetrandrine inhibits migration and invasion of rheumatoid arthritis fibroblast-like synoviocytes through down-regulating the expressions of Rac1, Cdc42, and Rho A GTPases and activation of the PI3K/Akt and JNK signaling pathways

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chinese Journal of Natural Medicines 2015年第11期13卷 831-841页

作者： LV Qi ZHU Xian-Yang XIA Yu-Feng DAI Yue WEI Zhi-Feng Jiangsu Key Laboratory of drug Discovery for Metabolic diseases Department of Pharmacology of Chinese Materia MedicaChina Pharmaceutical University

Tetrandrine （Tet）, the main active constituent of Stephania tetrandra root, has been demonstrated to alleviate adjuvant-induced arthritis in rats. The present study was designed to investigate the effects of Tet on the migration and invasion of rheumatoid arthritis fibroblast-like synovioeytes （RA-FLS） and explore the underlying mechanisms. By using cultures of primary FLS isolated from synoviums of RA patients and cell line MH7A, Tet （0.3, 1 μmol L-1） was proven to significantly impede migration and invasion of RA-FLS, but not cell proliferation. Tet also greatly reduced the activation and expressions of matrix degrading enzymes MMP-2/9, the expression of F-actin and the activation of FAK, which controlled the morphologic changes in migration process of FLS. To identify the key signaling pathways by which Tet exerts anti-migration effect, the specific inhibitors of multiple signaling pathways LY294002, Triciribine, SP600125, U0126, SB203580, and PDTC （against PI3K, Akt, JNK, ERK, p38 MAPK and NF-kB-p65, respectively） were used. Among them, LY294002, Triciribine, and SP600125 were shown to obviously inhibit the migration of MH7A cells. Consistently, Tet was able to down-regulate the activation of Akt and JNK as demonstrated by Western blotting assay. Moreover, Tet could reduce the expressions of migration-related proteins Rho GTPases Rac 1, Cdc42, and RhoA in MH7A cells. In conclusion, Tet can impede the migration and invasion of RA-FLS, which provides a plausible explanation for its protective effect on RA. The underlying mechanisms involve the reduction of the expressions of Racl, Cdc42, and RhoA, inhibition of the activation of Akt and JNK, and subsequent down-regulation of activation and/or expressions of MMP-2/9, F-actin, and FAK.

关键词： Tetrandrine Rheumatoid arthritis Fibroblast-like synoviocytes Migration Invasion

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Design,synthesis and biological evaluation of acylhydrazone derivatives as PI3K inhibitors

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chinese Chemical Letters 2015年第1期26卷 118-120页

作者： Guo-Rui Gao Jia-Li Liu De-Sheng Mei Jian Ding Ling-Hua Meng Wen-Hu Duan School of Pharmacy East China University of Science & Technology division of Anti-tumor pharmacology State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of Sciences Department of Medicinal Chemistry Shanghai Institute of Materia MedicaChinese Academy of Sciences

Since the PI3K signaling pathway is the most commonly activated in human cancers,inhibition of PI3K is a promising approach to cancer *** this study,a series of 2-methyl-5-nitrobenzeneacylhydrazones were designed and *** the new derivatives were tested by p110α enzymatic and Rh30 cellular *** enzyme selectivity profiling proved that 6e and 7 were potential selective PI3K inhibitors.

关键词： PI3K Inhibitor Aclhydrazone

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