European Journal of Medicinal Chemistry最新文献

{"title":"Identification of a new small Rho GTPase inhibitor effective in glioblastoma human cells","authors":"Angela Parise ,&nbsp;Ivana Manini ,&nbsp;Enrico Pobega ,&nbsp;Sonia Covaceuszach ,&nbsp;Luca Secco ,&nbsp;Federica Simonelli ,&nbsp;Serena Mastantuono ,&nbsp;Carla di Loreto ,&nbsp;Alessio Pizzignach ,&nbsp;Miran Skrap ,&nbsp;Marco Vindigni ,&nbsp;Riccardo Sgarra ,&nbsp;Guidalberto Manfioletti ,&nbsp;Daniela Cesselli ,&nbsp;Alessandra Magistrato","doi":"10.1016/j.ejmech.2025.117704","DOIUrl":"10.1016/j.ejmech.2025.117704","url":null,"abstract":"<div><div>Glioblastoma (GBM) is the most common and lethal primary brain tumour. The prognosis for GBM patients remains poor due to rapid tumour recurrence and resistance to conventional treatments. Small Rho GTPase proteins, which regulate cell shape and motility, are critical for GBM aggressive growth and infiltration into the surrounding brain parenchyma. Hence, small-molecule inhibitors targeting them represent an appealing opportunity to hinder the infiltration behaviour of GBM.</div><div>Here, a synergistic experimental and computational approach allowed us to identify an inhibitor that reduces migration in patient-derived GBM cell lines. Computational and <em>in vitro</em> functional assays reveal that this compound inhibits Rho GTPases function by targeting multiple allosteric sites thereby enhancing flexibility of key functional regions and hindering their interaction with protein regulators. Our research unveiled a novel hit molecule targeting Rho GTPases with significant potential to improve the treatment of GBM and other highly aggressive tumours.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117704"},"PeriodicalIF":6.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143885403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N-Terminal random curl-tandam α-helical peptide 7W: A potent antibacterial and anti-inflammatory dual-effect agent through tryptophan substitution","authors":"Jietao Lou ,&nbsp;Xinyi Wu ,&nbsp;Wenwen Ji ,&nbsp;Jiaye Yu ,&nbsp;Yanyan Xu ,&nbsp;Wanyang Xiao ,&nbsp;Weijie Lu ,&nbsp;Kaiyun Xin ,&nbsp;Tianbao Chen ,&nbsp;Qidong Tang ,&nbsp;Guang Liang ,&nbsp;Yitian Gao ,&nbsp;Di Wu","doi":"10.1016/j.ejmech.2025.117686","DOIUrl":"10.1016/j.ejmech.2025.117686","url":null,"abstract":"<div><div>This study investigates the impact of tryptophan substitution on the properties of the Medisin family peptide MS-PT. By substituting hydrophobic amino acids in MS-PT1 with tryptophan, a series of derivative peptides were synthesized. Among them, the 7W peptide stood out with its unique N-terminal random curl and α-helix structure. In vitro, 7W effectively inhibited the secretion of pro-inflammatory cytokines like IL-6 and TNF-α in LPS-induced Membrane-Proximal Macrophages (MPMs) by blocking the MAPK/NF-κB signaling pathway. It also exhibited stronger antimicrobial activity against Gram-positive bacteria compared to the parent peptide MS-PT1, with good safety as indicated by a low hemolysis rate. In vivo, in the CLP-induced sepsis mouse model, 7W alleviated lung and liver injury, suppressed the expression of inflammatory factors in serum and tissues, and had a relatively long plasma half-life of 46.8 h. Mechanistically, 7W interacted preferentially with bacterial mimic membranes and LPS, and its anti-inflammatory effect might be mediated by binding to TLR4. These findings not only clarify the role of tryptophan substitution in modulating peptide properties but also offer a new strategy for the development of multifunctional antimicrobial peptides, suggesting that 7W has great potential as a therapeutic agent for sepsis and other inflammatory diseases.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117686"},"PeriodicalIF":6.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143885405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent advances in degraders engaging lysosomal pathways and related nanomedicine","authors":"Runxin Lu ,&nbsp;Xiaofeng Ni ,&nbsp;Sha Diao ,&nbsp;Yong Wu ,&nbsp;Lingli Zhang","doi":"10.1016/j.ejmech.2025.117701","DOIUrl":"10.1016/j.ejmech.2025.117701","url":null,"abstract":"<div><div>The advent of targeted protein degradation (TPD) strategies presents unparalleled opportunities for innovating and expediting the development of new drugs. As the most mature TPD technology to date, proteolysis targeting chimeras (PROTACs) reliant on the ubiquitin proteasome system (UPS) have successfully transitioned from the laboratory to phase III clinical trials after nearly two decades of development. In recent years, the gradually emerging degraders engaging lysosomal pathways have further broadened the range of degradation mechanisms and substantially increased the diversity of potential targets and indications, ushering in a new era for the TPD field. Despite their significant advantages, the limited permeability, adverse pharmacokinetic properties, and off-target side effects caused by non-specific distribution still pose significant challenges to the clinical translation of these degraders. Currently, researchers are exploring the use of nanotechnology to surmount these obstacles and have achieved notable progress. This paper systematically summarizes the fundamental design principles, research status, challenges and future prospects of degraders engaging lysosomal pathways, and highlights the efforts and latest advances in related nanomedicine to optimize these degraders. The aim of this review is to deepen our comprehension of this emerging field and offer guidance for future exploration, development, and further utilization of new TPD techniques.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117701"},"PeriodicalIF":6.0,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143885406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"D-(+)-Biotinylated squaraine dyes: A journey from synthetic conception, photophysical and -chemical characterization, to the exploration of their photoantitumoral action mechanisms","authors":"Eurico Lima ,&nbsp;Octávio Ferreira ,&nbsp;Renato E. Boto ,&nbsp;José R. Fernandes ,&nbsp;Paulo Almeida ,&nbsp;Samuel M. Silvestre ,&nbsp;Adriana O. Santos ,&nbsp;Lucinda V. Reis","doi":"10.1016/j.ejmech.2025.117699","DOIUrl":"10.1016/j.ejmech.2025.117699","url":null,"abstract":"<div><div>Biotin is primarily taken up by cells through sodium-dependent multivitamin transporter, which is highly expressed in aggressive cancer cell lines, often at levels surpassing those of the folate receptor. This makes biotin an attractive ligand for tumor-targeted drug delivery. Building on this rationale, this study presents a series of six <em>D</em>-(+)-biotin-conjugated squaraine dyes derived from benzothiazole, indolenine, and benz[e]indole, with <em>N</em>-ethyl and <em>N</em>-hexyl chains. These compounds were thoroughly characterized in terms of their photophysical and photochemical properties, revealing strong absorption in the so-called “phototherapeutic window”, notable fluorescence, especially the benzothiazole derivatives, aqueous stability, particularly the indolenine-based dyes, and moderate to high photostability. Computational studies further indicated a strong binding affinity to human serum albumin and avidin proteins. All dyes exhibited photodynamic activity, with indolenine derivatives showing remarkable tumor selectivity and benz[<em>e</em>]indole analogs evidencing superior photocytotoxicity. The most promising compounds preferentially accumulated in mitochondria, and both singlet oxygen and other reactive oxygen species were found to play a role in their photobiological effects. Additionally, they were non-genotoxic in the absence of irradiation, and apoptosis was the primary mechanism of cell death upon light activation. This was evidenced by preserved cytoplasmic membrane integrity, nuclear fragmentation, and caspase-3/7 activation, reinforcing the safety and potential of these compounds as phototherapeutic agents. Although cellular uptake <em>via</em> the sodium-dependent multivitamin transporter was not established, and diffusion is expected to be the predominant mechanism, the high predicted avidin-binding affinity of these dyes opens exciting new avenues for photodynamic therapy-combined strategies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"293 ","pages":"Article 117699"},"PeriodicalIF":6.0,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143885404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and Biological evaluation of novel macrocyclic derivatives as potent ATP-citrate lyase inhibitors","authors":"Yongjun Zang ,&nbsp;Maoying Shi ,&nbsp;Luyang Tai ,&nbsp;Yuanyang Hu ,&nbsp;Yu Wang ,&nbsp;Runan Zheng ,&nbsp;Zhiqi Feng ,&nbsp;Haoliang Yuan ,&nbsp;Xiaoan Wen ,&nbsp;Liang Dai","doi":"10.1016/j.ejmech.2025.117684","DOIUrl":"10.1016/j.ejmech.2025.117684","url":null,"abstract":"<div><div>ATP-citrate lyase (ACLY) is a key lipogenic enzyme involved in the synthesis of fatty acid and cholesterol, which converts cytosolic citrate to acetyl-CoA, a starting material for <em>de novo</em> lipogenesis. ACLY inhibitor is considered as potential therapeutic strategy for dyslipidemia and related diseases. In this study, we reported a series of novel macrocyclic derivatives as ACLY inhibitors, among them, compound <strong>55</strong> exhibited potent ACLY inhibitory activity (IC₅₀ = 8.3 nM) and high binding affinity to ACLY. Notably, compound <strong>55</strong> demonstrated good pharmacokinetic profiles and potent in vivo hypolipidemic effect. Collectively, compound <strong>55</strong> deserved further development to provide potential candidate for treatment of hyperlipidemia and related diseases.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117684"},"PeriodicalIF":6.0,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143877877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Refinement of imidazo[2,1-a]pyrimidines in pursuit of potential drug candidates against group 2 influenza A viruses","authors":"Malaika D. Argade ,&nbsp;Varada Anirudhan ,&nbsp;Sean P. Bradley ,&nbsp;Łukasz Tomorowicz ,&nbsp;Ryan Bott ,&nbsp;Boopathi Sownthirarajan ,&nbsp;Christian A. Zielinski ,&nbsp;John P. Sloan ,&nbsp;Dejan S. Nikolic ,&nbsp;Arsen M. Gaisin ,&nbsp;Terry W. Moore ,&nbsp;Balaji Manicassamy ,&nbsp;Norton P. Peet ,&nbsp;Lijun Rong ,&nbsp;Irina N. Gaisina","doi":"10.1016/j.ejmech.2025.117679","DOIUrl":"10.1016/j.ejmech.2025.117679","url":null,"abstract":"<div><div>We discovered a series of imidazo[1,2-<em>a</em>]pyrimidines as potent, group 2 selective inhibitors of influenza A viruses (IAVs) that target the hemagglutinin-mediated viral entry process. Preliminary hit-to-lead optimization efforts afforded promising IAV inhibitors with improved activity against infectious H7N7 and H3N2 viruses. We now report a more comprehensive cycle of structure-activity relationship studies and optimization of metabolic stability, and overall druglike properties of this series of imidazo[1,2-<em>a</em>]pyrimidines, which allowed in the identification of two lead compounds that show promise as preclinical candidates. Compounds <strong>10</strong> and <strong>12</strong> inhibited pseudotyped H7N1 with EC₅₀ values of 0.09 and 0.47 μM, respectively. They were among the most potent compounds in the viral replication assay when tested against infectious H3N2 IAV, and they also demonstrated remarkable activity against avian influenza viruses; these data designated these imidazo[1,2-<em>a</em>]pyrimidines as potent broad-spectrum group 2 IAV inhibitors. Compounds <strong>10</strong> and <strong>12</strong> exhibit dissimilar but desirable drug metabolism and pharmacokinetics (DMPK) profiles, and therefore they offer different options for specific and effective patient treatment.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117679"},"PeriodicalIF":6.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the correlation of linker structure and antimicrobial activities of pyridinium-based cationic biocides: Aromatic versus aliphatic architectures","authors":"Nikita A. Frolov ,&nbsp;Mary A. Seferyan ,&nbsp;Elena V. Detusheva ,&nbsp;Evgeniya A. Saverina ,&nbsp;Elizabeth Son ,&nbsp;Radmir N. Akchurin ,&nbsp;Alena S. Kartseva ,&nbsp;Victoria V. Firstova ,&nbsp;Anatoly N. Vereshchagin","doi":"10.1016/j.ejmech.2025.117673","DOIUrl":"10.1016/j.ejmech.2025.117673","url":null,"abstract":"<div><div>Cationic biocides, particularly quaternary ammonium compounds (QACs), play a vital role in controlling microbial infections across various industries, healthcare facilities and households. As their widespread use increased drastically in the last few years due to COVID-19, there is growing concern about the development of resistance among microorganisms exposed to cationic biocides. It is crucial to recognize this threat in advance and respond by modifying and replacing the old generation of commercial biocides. Reported here is the pyridinium-based bis-QACs tuning via combination of two simple synthesis approaches to achieve novel biocide's architectures with mixed linkers. The obtained compounds were subjected to a broad bioactivity assay against a panel of 26 microbial pathogens, including multi-resistant bacterial ESKAPEE strains, fungi and biofilms. Novel hit-compounds showed improved antibacterial and antibiofilm action, rapid bacterial eradication within 15–30 min of exposure and 4.5-fold lower hemotoxicity, as well as lower potential for the development of bacterial resistance compared to commercial lead antiseptic octenidine. Highlighted findings and insights will serve as a good basis for further studies of bis-QACs as highly effective biocides.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117673"},"PeriodicalIF":6.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and biological evaluation of novel CDK4/6 and BRD4 dual inhibitors for treatment of KRAS-mutant NSCLC","authors":"Xiaojie Tong,&nbsp;Tong Shen,&nbsp;Song Li,&nbsp;Liqiang Wu","doi":"10.1016/j.ejmech.2025.117685","DOIUrl":"10.1016/j.ejmech.2025.117685","url":null,"abstract":"<div><div>CDK4/6 is the candidate therapeutic target for KRAS-mutant NSCLC. However, its frequent primary and acquired resistance limits its potential clinical application. Recently it had been shown that BRD4 up-regulation induced conferred resistance of KRAS-mutant NSCLC cells to CDK4/6 inhibitor, and BRD4 inhibitor synergized with CDK4/6 inhibitor induced senescence in KRAS-mutant NSCLC tumors and cells, meanwhile, the combined therapy extended survival of the KRAS-mutant NSCLC mouse model. Thus, a series of CDK4/6 and BRD4 dual inhibitors were prepared to target KRAS-mutant NSCLC. Among these compounds, <strong>PJ2</strong> exhibited potent antiproliferative effects against KRAS-mutant NSCLC cells NCI–H358 (IC₅₀ = 0.34 ± 0.01 μM) and A549 (IC₅₀ = 0.31 ± 0.04 μM), and had excellent inhibitory effects on CDK4, CDK6, BRD4(BD1) and BRD4(BD2), and IC₅₀ values were 168.75 ± 46.32 nM, 292.45 ± 11.67 nM, 23.17 ± 3.61 nM and 3.12 ± 0.15 nM, respectively. Mechanism research indicated that <strong>PJ2</strong> induced cell cycle arrest, senescence and apoptosis through ROS-mediated DNA damage. Furthermore, <strong>PJ2</strong> could effectively suppress the migration and invasion of NCI–H358 cells. These results proved that developing potent CDK4/6 and BRD4 dual inhibitors was a promising strategy for the KRAS-mutant NSCLC therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117685"},"PeriodicalIF":6.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Virtual screening and fragment growth strategy for developing near-infrared fluorescent probes to detect Aβ in Alzheimer's disease model","authors":"Guanyu Xu ,&nbsp;Can Zhou ,&nbsp;Geng Su ,&nbsp;Zeying Liang ,&nbsp;Jianyu Wu ,&nbsp;Tiantian Tang ,&nbsp;Yuemin Bian ,&nbsp;Jian Cai ,&nbsp;Yi Zou ,&nbsp;Jian Yang","doi":"10.1016/j.ejmech.2025.117695","DOIUrl":"10.1016/j.ejmech.2025.117695","url":null,"abstract":"<div><div>Amyloid fibrils are well-established biomarkers of Alzheimer's disease (AD), and the development of novel near-infrared fluorescent (NIRF) probes for early detection of <em>β</em>-amyloid can help differentiate AD from other neurodegenerative conditions. In this study, we report the discovery of an effective NIRF probe, <strong>probe 6</strong>–<strong>4</strong>, through a combined approach of virtual screening and fragment growth. <strong>Probe 6</strong>–<strong>4</strong> binds strongly to A<em>β</em> oligomers and aggregates, showing robust fluorescent properties with an emission maximum near 650 nm when bound to A<em>β</em> aggregates and oligomers. It exhibits high sensitivity, with a nearly 100-fold increase in fluorescence intensity, and strong affinity (<em>K</em>_d = 9.4 nM for oligomers and 12.5 nM for aggregates). <em>In vivo</em> and <em>ex-vivo</em> NIRF imaging studies further demonstrated that <strong>probe 6</strong>–<strong>4</strong> can distinguish AD transgenic model mice from wild-type controls. Overall, <strong>probe 6</strong>–<strong>4</strong> proves to be a potent and efficient tool for detecting A<em>β</em> aggregates and oligomers in the brain, validating the effectiveness of combining virtual screening and fragment growth in developing NIRF probes for AD research.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117695"},"PeriodicalIF":6.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Annual review of EGFR inhibitors in 2024","authors":"Chao Gao ,&nbsp;Wanning Wang ,&nbsp;Tong Liu ,&nbsp;Xingyu Li ,&nbsp;Yongbo Yu ,&nbsp;Jianhui Wu","doi":"10.1016/j.ejmech.2025.117677","DOIUrl":"10.1016/j.ejmech.2025.117677","url":null,"abstract":"<div><div>Epidermal growth factor receptor (EGFR) inhibitors play a crucial role in the treatment of EGFR mutation-driven cancers, such as non-small cell lung cancer (NSCLC). In 2024, significant breakthroughs were made in new drug development, resistance mechanisms, and combination therapy strategies. This review summarizes the key studies published in 2024, with a focus on the design strategies, structure-activity relationships (SAR), mechanisms of action, and both in vitro and in vivo activities of EGFR inhibitors. The aim is to provide new research perspectives and theoretical foundations for developing highly effective and selective inhibitors targeting diverse EGFR mutations.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117677"},"PeriodicalIF":6.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}