European Journal of Medicinal Chemistry最新文献

{"title":"Exploring the broad-spectrum activity of carbohydrate-based Iberin analogues: from anticancer effect to antioxidant properties.","authors":"L.A. Prieto, N. Khiar-Fernandez, J.M. Calderón-Montaño, M. López-Lázaro, J. Lucía-Tamudo, J.J. Nogueira, R. León, N. Moreno, V. Valdivia, R. Recio, I. Fernandez","doi":"10.1016/j.ejmech.2025.117469","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117469","url":null,"abstract":"Iberin is a lower homolog of sulforaphane which has shown effectiveness in addressing various pathologies, including its anti-inflammatory properties, antitumor activity against various cancers, and antimicrobial effects. Building on this activity, a series of carbohydrate-based analogues of the natural isothiocyanate (ITC) iberin were synthesized, and their anticancer and antioxidant activities were evaluated. Cytotoxicity studies on three cancer cell lines using Resazurin assay<del>s</del> demonstrated significant cytotoxic activity, particularly against bladder cancer. The sulfonyl derivatives exhibited the most potent effects, with IC₅₀ values comparable to those of reference natural isothiocyanates (from 10 to 20 μM). Computational simulations support the hypothesis that carbohydrate-based ITCs can interact with STAT3’s SH2 domain in a manner similar to SFN, laying the groundwork for their potential development as STAT3-targeted anticancer agents. The antioxidant potential of these compounds was assessed by their ability to activate the Nrf2 factor, yielding CD values (concentration required to double luciferase activity compared to basal conditions) between 1.55 and 10.36 μM, without cytotoxicity at these concentrations. Notably, the phenylsulfone derivative <strong>22β</strong> displayed slightly higher or comparable antioxidant activity to that of natural isothiocyanates. Based on these findings, this phenylsulfone analogue was selected as the optimal compound due to its dual anticancer and antioxidant activities. An additional advantage of this carbohydrate-based ITC is that it is a solid compound, making it easier to handle than natural isothiocyanates, which are typically liquids.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"41 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518531","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":"LPS-Enriched Interaction Drives Spectrum Conversion in Antimicrobial Peptides: Design and Optimization of AA16 Derivatives for Targeting Gram-Negative Bacteria","authors":"Wanyang Xiao, Ruize Sun, Jietao Lou, Yanyan Xu, Xiaokun Li, Kaiyun Xin, Weijie Lu, Chenhui Sun, Tianbao Chen, Yitian Gao, Di Wu","doi":"10.1016/j.ejmech.2025.117462","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117462","url":null,"abstract":"The increasing prevalence of antibiotic-resistant Gram-negative bacteria necessitates the development of novel antimicrobial agents with targeted specificity. In this study, we designed and optimized derivatives of the antimicrobial peptide AA16, which truncated from CD14 protein α-helical region, to selectively target Gram-negative bacteria by enhancing lipopolysaccharide (LPS)-enriched interactions, thereby achieving antibacterial spectrum conversion. Starting from the parent peptide AA16 (Ac-AARIPSRILFGALRVL-Amide), we performed strategic amino acid substitutions based on structure–activity relationship analysis. This led to the identification of AA16-10R, a derivative with a specific substitution at position 10, which demonstrated significantly enhanced antibacterial activity against Gram-negative strains such as <em>Escherichia coli</em> and <em>Pseudomonas aeruginosa</em>, while maintaining low hemolytic activity. Mechanistic studies revealed that AA16-10R exhibited a strong binding affinity to LPS (<em>K</em>_d = 0.15 μM), and its interaction with LPS induced the formation of an α-helical structure. This conformational change facilitated its accumulation on the bacterial outer membrane and disrupted membrane integrity. Our innovative approach of exploiting LPS-enriched interactions successfully converted the antimicrobial spectrum of AA16 derivatives from broad-spectrum to Gram-negative-specific. This study highlights a novel strategy for the rational design of antimicrobial peptides based on specific protein–protein interactions, offering a promising avenue for targeted antimicrobial therapy against Gram-negative pathogens.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"4 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518530","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":"Structure-based Design of Novel 2,4,5-Trisubstituted Pyrimidine Derivatives as Potent HIV-1 NNRTIs by Exploiting the Tolerant Regions in NNTRIs Binding Pocket","authors":"Zhenzhen Zhou, Minghui Xie, Zongji Zhuo, Yalin Wang, Fabao Zhao, Sining Tao, Zhening Liang, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Dongwei Kang, Xinyong Liu","doi":"10.1016/j.ejmech.2025.117464","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117464","url":null,"abstract":"To promote the development of the new generation of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel 2,4,5-trisubstituted pyrimidine derivatives targeting the “tolerant region I” and “tolerant region II” of NNRTI binding pocket (NNIBP) were designed through multi-site binding strategy. Among them, <strong>13a</strong> was demonstrated with an improved potency against wild-type (WT) and a panel of mutant HIV-1 strains with EC₅₀ values ranging from 0.0062-0.25 <em>μ</em>M, being superior to that of efavirenz (EFV, EC₅₀ = 0.0080-0.37 <em>μ</em>M). In addition, <strong>13a</strong> was proved to have low cytotoxicity (CC₅₀ = 160.7 <em>μ</em>M) and high SI values (SI = 25254). Further HIV-1 RT inhibition assay demonstrated that <strong>13a</strong> is a classical NNRTI with an IC₅₀ value of 0.41 <em>μ</em>M. Molecular docking and molecular dynamics simulations results illustrated its binding mode with HIV-1 RT. Overall, these enchanting results illuminated the potential of <strong>13a</strong> as a promising lead for the development of the new generation HIV-1 NNRTIs drugs.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"13 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518532","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":"Conjugation with the XJB Peptide Enhanced Neuroprotective Effect of Honokiol via SIRT3 Modulation","authors":"Guoliang Liu, Tao Zhang, Shunmeng Qian, Xiaoshuang Zhang, Hongxiang Lou, Peihong Fan","doi":"10.1016/j.ejmech.2025.117460","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117460","url":null,"abstract":"Mitochondria play a crucial role in cellular processes such as growth, differentiation, and energy conversion. Dysfunctional mitochondria have been implicated in Alzheimer’s disease (AD), making mitochondrial improvement a promising therapeutic approach. SIRT3, a mitochondrial deacetylase, modulates mitochondrial function by deacetylating associated proteins. This study aimed to enhance the activity of honokiol, a natural SIRT3 modulator, and improve mitochondrial function for neuroprotective activity, using mitochondria targeting strategy. We synthesized mitochondrial targeting peptide conjugates using XJB as a carrier and found that honokiol conjugates exhibited lower toxicity and higher activity on neuronal injury models <em>in vitro</em> and i<em>n vivo (</em>Zebrafish model) at lower concentrations compared to honokiol. The neuroprotective mechanism may involve the activation of cellular autophagy-related pathways, promotion of SIRT3 pathway activation, and up-regulation of mitochondrial fusion-associated protein Mfn-1 expression under damaged conditions. This study offers a promising approach for developing anti-Alzheimer's disease (AD) natural product derivatives based on SIRT3 regulation.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"129 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507385","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":"Discovery of a Potent and in Vivo Anti-inflammatory Efficacious, P2Y14R Antagonist with a Novel Benzisoxazoles Scaffold by DNA-Encoded Chemical Library Technology","authors":"ZhiYi Wei, Bingqian Han, Longhua Yang, Jiannan Zhao, Takashi Nakai, Suyi Chen, Yongfang Yao, Chuanjun Song, Yongtao Duan","doi":"10.1016/j.ejmech.2025.117451","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117451","url":null,"abstract":"P2Y₁₄R is activated by UDP (uridine diphosphate) and UDP glucose and associated with the development of many inflammatory diseases. P2Y₁₄R antagonists are expected to be a new choice for the treatment of inflammatory diseases. A DNA-encoded chemical library (DEL) of 4 billion molecules was screened, leading to the identification of compound A, a novel benzisoxazole scaffold-based P2Y₁₄ antagonist with an IC₅₀ value of 23.60 nM. Binding mode analysis and SPR analysis (KD = 7.26 μM) demonstrated that Compound A bind strongly to P2Y₁₄R. ‌Molecular dynamics simulations and binding free energy calculations were performed to analyze the binding mode of Compound A with P2Y₁₄R. And in the LPS-induced acute lung injury mice, after treatment with Compound <strong>A,</strong> the degree of lung injury was greatly reduced, the infiltration of immune cells was decreased, the level of inflammatory factors IL-6, TNF-α and IL-β were considerably decreased. Compound A exhibited good P2Y₁₄R antagonist activity, demonstrated efficacy both <em>in vitro</em> and <em>in vivo</em>, possessed favorable druggability, and featured a novel benzisoxazole scaffold with potential for further optimization, providing a new strategy for developing subsequent P2Y14 antagonists.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"28 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518534","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":"Synthesis, anti-allergic rhinitis evaluation and mechanism investigation of novel 1,2,4-triazole-enamides as CB1 R antagonist","authors":"Lu Wang, Yan Geng, Lifang Liu, Jun Wang, Jiaxin Chen, Yunying Li, Jingbo Wang, Liyan Song, Kexin Sun, Yajie Yan, Shiqing Zhou, Dan Tian, Ran Lin, Hongliang Yao","doi":"10.1016/j.ejmech.2025.117461","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117461","url":null,"abstract":"Allergic rhinitis (AR) is a non-infectious inflammatory disease and affects nearly half of the world's population currently, thus becoming a global health problem. In our study, a series of 1,2,4-triazole enamides were designed and used to evaluate the anti-inflammatory activity of AR. We found that compound <strong>11g</strong> could significantly reduce the increased expression of interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in Raw264.7 cells induced by lipopolysaccharides (LPS), and inhibit the expression of inflammation through MAPK pathway and NF-κB pathway by influencing the expression of cannabinoid-1 receptor (CB1 R). In the AR mice model, <strong>11g</strong> can significantly reduce the number of inflammatory cells in Nasal lavage fluids (NLF), showing a good effect on the treatment of AR. This study provides a new and effective candidate for treatment of AR.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"13 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518533","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":"Structure–Activity Relationship Analysis of Meta-Substituted N-Cyclopropylmethyl-Nornepenthones with Mixed KOR/MOR Activities","authors":"Siyuan Tang, Shuyang Hu, Linghui Kong, Jiangwen Gui, Ying Zhang, Zi-Han Liu, Denggao Zhang, An-An Liu, Xiao Liu, Chuyuan Hu, Yingjie Lan, Xiaoning Liu, Zixiang Li, Panwen Liu, Shaoliang Duan, Lijing Feng, Zeyi Du, Min Liu, Qiong Xie, Jinggen Liu, Wei Li","doi":"10.1016/j.ejmech.2025.117449","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117449","url":null,"abstract":"Substance Use Disorder (SUD) remains a significant global challenge, with current treatment options offering limited efficacy. Agonists targeting the kappa opioid receptor (KOR), especially those with additional mu opioid receptor (MOR) antagonistic activity, have shown promise in addressing SUD. In this study, a series of <em>meta-</em>substituted <em>N</em>-cyclopropylmethyl-nornepenthone derivatives were designed and synthesized, and their biological activities were assessed, leading to the identification of a KOR/MOR dual modulator, compound <strong>10a</strong>. Unlike its <em>para-</em> positional isomer <strong>SLL-1062</strong>, where KOR activity is completely abolished, compound <strong>10a</strong> displayed a single-digit nanomolar affinity for KOR, while its binding profiles for MOR and delta opioid receptor (DOR) were comparable to those of <strong>SLL-1062</strong>. Functional assays <em>in vitro</em> confirmed that compound <strong>10a</strong> exhibited agonistic activity at KOR and antagonistic activity at MOR. The molecular basis for the introduction of a KOR component into compound <strong>10a</strong> was further elucidated. Although compound <strong>10a</strong> did not produce apparent antinociception <em>in vivo</em>, it effectively blocked morphine-induced antinociception and intestinal motility inhibition in rodent models. This study provides valuable insights into the development of MOR/KOR dual modulators and presents new lead compounds for potential treatments for SUD.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"10 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143496058","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":"Research progress and perspectives of dual-target inhibitors","authors":"Xiaojing Pang, Wen Xu, Jing Liang, Yang Liu, Hua Li, Lixia Chen","doi":"10.1016/j.ejmech.2025.117453","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117453","url":null,"abstract":"The occurrence and development of diseases are complex, and single-target drugs that affect only a single target or pathway often fail to achieve the expected therapeutic effect. The simultaneous effect on two key targets could not only increase patient tolerance but also accelerate disease remission. Dual-target inhibitors have already been studied the most intensively in the development of dual-target drugs. This article briefly introduces the function of drug therapy targets, and mainly summarizes the design strategies and research progress of dual-target inhibitors in neurodegenerative diseases, infectious diseases, metabolic diseases and cardiovascular diseases.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"23 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507422","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":"Rationally designed peptides inhibit the formation of α-synuclein fibrils and oligomers","authors":"Tariq T. Ali ,&nbsp;Madiha Merghani ,&nbsp;Mohammed Al-Azzani ,&nbsp;Luisa Maria Gatzemeier ,&nbsp;Michael Hoppert ,&nbsp;Dora Kaloyanova ,&nbsp;Tiago F. Outeiro ,&nbsp;Piotr Neumann ,&nbsp;Blagovesta Popova ,&nbsp;Gerhard H. Braus","doi":"10.1016/j.ejmech.2025.117452","DOIUrl":"10.1016/j.ejmech.2025.117452","url":null,"abstract":"<div><div>Parkinson's Disease (PD) is characterized by the pathological aggregation of α-synuclein (αSyn) into oligomers and amyloid fibrils, making αSyn aggregation a key target for drug development. Peptides have gained recent attention as potential agents to inhibit aggregation. Two previously identified peptide inhibitors, discovered through large-scale yeast screening, were used as templates for <em>in silico</em> mutagenesis aimed at designing novel peptides with improved efficacy in inhibiting αSyn aggregation and cytotoxicity. The newly designed peptides underwent <em>in silico</em> docking analysis, and the most promising candidates were tested <em>in vitro</em> and in cellular models. Peptides T02 and T05 emerged as the most effective inhibitors, with T02 binding αSyn monomers and T05 targeting lower-order oligomers. Both peptides reduce αSyn fibril and oligomer formation <em>in vitro</em> and significantly suppress αSyn aggregation and cytotoxicity in yeast and human H4 cells. These novel peptides represent antagonists of αSyn aggregation with promising potential for therapeutic intervention for PD.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117452"},"PeriodicalIF":6.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and in vitro evaluation of radioiodine labeled hypoxia-targeted drugs containing 2-nitroimidazole and benzenesulfonamide groups","authors":"Weiqi Liu,&nbsp;Taiwei Chu","doi":"10.1016/j.ejmech.2025.117443","DOIUrl":"10.1016/j.ejmech.2025.117443","url":null,"abstract":"<div><div>Designing new radiolabeled hypoxia-targeted drugs is of great help in the diagnosis of tumors. Hypoxia-targeted drugs with dual bioactive groups can enhance hypoxia selectivity, strengthen the binding of drugs to targets, and improve diagnostic accuracy compared with traditional hypoxia-targeted drugs containing only one nitroimidazole group. In this study, a series of novel radioiodine labeled tyrosine derivatives containing 2-nitroimidazole and benzenesulfonamide groups were synthesized and <em>in vitro</em> evaluated. In the uptake experiments of S180 cells that didn't express carbonic anhydrase IX (CAIX), the compound [¹³¹I]-3-(3-iodo-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-2-(2-(2-nitro-1<em>H</em>-imidazole-1-yl)acetamido)-<em>N</em>-(2-(2-nitro-1<em>H</em>-imidazole-1-yl)ethyl)propenamide (^{<strong>131</strong>}<strong>I-Tyr-05</strong>) containing two 2-nitroimidazole groups was modified from phenolic hydroxyl to methoxy to 2-(2-methoxyethoxy)ethoxy, gradually achieving improved membrane permeability and enhanced hydrophilicity. Compared with other compounds with similar structures but containing only one 2-nitroimidazole, it had higher hypoxic selectivity. In the uptake experiment of HeLa cells that expressed CAIX, [¹³¹I]-<em>N</em>-(3-(3-iodo-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-1-((2-(2-nitro-1<em>H</em>-imidazole-1-yl)ethyl)amino)-1-oxopropan-2-yl)-4-sulfamoylbenzamide (^{<strong>131</strong>}<strong>I-Tyr-06</strong>), which contained both 2-nitroimidazole and benzenesulfonamide group, achieved enhanced hypoxic uptake and selectivity through the combination of two targeting groups. The S180 cell blocking experiments of ^{<strong>131</strong>}<strong>I-Tyr-05</strong> and ^{<strong>131</strong>}<strong>I-Tyr-06</strong> showed that the benzenesulfonamide group of the compounds didn't inhibit cellular uptake, and inhibition of cytochrome P450 (CYP450) enzyme had no effect on cellular uptake. <em>In silico</em> ADMET evaluation showed that <strong>I-Tyr-05</strong> and <strong>I-Tyr-06</strong> possessed acceptable physicochemical and ADMET properties. In conclusion, this work demonstrated the advantages of hypoxia-targeted drugs containing dual bioactive groups compared to a single group, and also found it was a feasible approach to design new dual-targeted drugs by combining 2-nitroimidazole and benzenesulfonamide groups.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117443"},"PeriodicalIF":6.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486368","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}