Bioorganic & Medicinal Chemistry最新文献

{"title":"Esterase-responsive nanoparticles (ERN): A targeted approach for drug/gene delivery exploits","authors":"Ashok Kumar Madikonda ,&nbsp;Amritha Ajayakumar ,&nbsp;Sudeena Nadendla ,&nbsp;Janardhan Banothu ,&nbsp;Venkanna Muripiti","doi":"10.1016/j.bmc.2024.118001","DOIUrl":"10.1016/j.bmc.2024.118001","url":null,"abstract":"<div><div>Nanoparticles are being developed to enhance drug delivery to cancer tumors, leveraging advantages such as the enhanced permeability and retention (EPR) effect. However, traditional nanoparticles often face challenges with low specificity for cancer cells, leading to inefficient delivery and unwanted side effects. Esterase-responsive nanoparticles offer a maximum targeted approach to tumor cells because they release their therapeutic payload at the tumor site under the influence of esterase activity. This review explores the role of esterase-responsive nanoparticles in drug and gene delivery, examines esterase prodrug therapy, and discusses prostate-specific membrane antigen (PSMA) targets esterase-responsive nanoparticles in prostate cancer treatment. Additionally, we reviewed the current research progress and future potential of esterase-responsive nanoparticles in enhancing drug and gene delivery.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 118001"},"PeriodicalIF":3.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142651884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and structure-activity relationship of boronic acid bioisosteres of combretastatin A-4 as anticancer agents","authors":"Yali Kong ,&nbsp;Michael C. Edler ,&nbsp;Ernest Hamel ,&nbsp;Asa R. Britton-Jenkins ,&nbsp;Omar Gillan ,&nbsp;Susan L. Mooberry ,&nbsp;David Mu ,&nbsp;Milton L. Brown","doi":"10.1016/j.bmc.2024.117999","DOIUrl":"10.1016/j.bmc.2024.117999","url":null,"abstract":"<div><div>The boronic acid group plays an important role in drug discovery. Following our discovery of a boronic acid analog of combretastatin A-4 (CA-4), a series of analogs featuring a boronic acid group on the C phenyl ring of CA-4 was synthesized and evaluated for cytotoxicity, as well as for their ability to inhibit tubulin polymerization, inhibit the binding of [³H]colchicine to tubulin and cause depolymerization of cellular microtubules. Modifications on the C ring of CA-4, either eliminating the methoxy group or replacing the C phenyl ring with a pyridine ring, resulted in a reduced potency for inhibiting tubulin polymerization, colchicine binding and cytotoxic activities as compared to CA-4. Replacing the phenol group with a boronic acid group on the C ring of phenstatin led to a slight increase in cytotoxic potency but a decreased potency for inhibition of tubulin assembly and colchicine binding. Moreover, there was a significant decrease in activity by replacing the C phenyl ring with a pyridine ring. Our results indicate the critical importance of the methoxy group on the C ring as well as the importance of the C phenyl ring compared to a pyridine ring, despite the latter providing a nitrogen atom as a hydrogen bond donor/acceptor, which was predicted by molecular modeling to enhance interaction with the target. The decreased activities of our modified CA-4 boronic analogs may be attributed to weakened hydrogen bonding in our docking model based on the crystal structure of colchicine bound to αβ-tubulin. Notably, even though their effectiveness in inhibiting tubulin polymerization and colchicine binding and causing microtubule depolymerization in cells, the majority of these boronic acid analogs exhibited substantial cytotoxicity. This suggests that they may have additional cellular targets that contribute to their cytotoxicity, and this warrants further evaluation of these unique boronic acid compounds as potential anticancer agents.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 117999"},"PeriodicalIF":3.3,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the rhodanine universe: Design and synthesis of fluorescent rhodanine-based derivatives as anti-fibrillar and anti-oligomer agents against α-synuclein and 2N4R tau","authors":"Ahmed A. Elbatrawy ,&nbsp;Taiwo A. Ademoye ,&nbsp;Heba Alnakhala ,&nbsp;Arati Tripathi ,&nbsp;Germán Plascencia-Villa ,&nbsp;Xiongwei Zhu ,&nbsp;George Perry ,&nbsp;Ulf Dettmer ,&nbsp;Jessica S. Fortin","doi":"10.1016/j.bmc.2024.117990","DOIUrl":"10.1016/j.bmc.2024.117990","url":null,"abstract":"<div><div>Tau and α-synuclein (α-syn) are prone-to-aggregate proteins that can be responsible for pathological lesions found in the brains of Alzheimer’s disease (AD), Lewy body dementia (LBD), and Parkinson’s disease (PD) patients. The early-stage oligomers and protofibrils of tau are believed to be strongly linked to human cognitive impairment while the toxic α-syn oligomers are associated with behavioral motor deficits. Therefore, concurrent targeting of both proteinaceous aggregates and oligomers are very challenging. Herein, rhodanine-based compounds were designed and synthesized to target the fibrils and oligomers of tau and α-syn proteins. In particular, the indole-containing rhodanines <strong>5l</strong> and <strong>5r</strong> displayed significantly high anti-aggregation activity towards α-syn fibrils by reducing of the thioflavin-T (ThT) fluorescence to less than 5 %. Moreover, <strong>5r</strong> showed a remarkable decrease in the fluorescence of thioflavin-S (ThS) when incubated with the non-phosphorylated tau 0N4R and 2N4R, as well as the hyperphosphorylated tau isoform 1N4R. Transmission electron microscopy (TEM) analyses validated the powerful anti-fibrillar activity of <strong>5l</strong> and <strong>5r</strong> towards both protein aggregates. In addition, both <strong>5l</strong> and <strong>5r</strong> highly suppressed 0N4R tau and α-syn oligomer formation using the photo-induced cross-linking of unmodified protein (PICUP) assay. The fluorescence emission intensity of <strong>5l</strong> was quenched to almost half in the presence of both protein fibrils at 510 nm. <strong>5r</strong> showed a similar fluorescence response upon binding to 2N4R fibrils while no quenching effect was observed with α-syn aggregates. <em>Ex vivo</em> disaggregation assay using extracted human A<em>β</em> plaques was employed to confirm the ability of <strong>5l</strong> and <strong>5r</strong> to disaggregate the dense fibrils. Both inhibitors reduced the A<em>β</em> fibrils isolated from AD brains. <strong>5l</strong> and <strong>5r</strong> failed to show activity toward the cell-based α-syn inclusion formation. However, another indolyl derivative <strong>5j</strong> prevented the α-syn inclusion at 5 µM. Collectively, the indolyl-rhodanine scaffold could act as a building block for further structural optimization to obtain dual targeting disease-modifying candidates for AD, LBD, and PD.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 117990"},"PeriodicalIF":3.3,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of the synergy between sulindac and NO expands the application of NSAIDs in cardiac complications","authors":"Wen Zhou ,&nbsp;Ping Jiang ,&nbsp;Chunping Wang ,&nbsp;Shaohua Gou","doi":"10.1016/j.bmc.2024.117991","DOIUrl":"10.1016/j.bmc.2024.117991","url":null,"abstract":"<div><div>Cardiac inflammation, a pathological cornerstone in cardiac dysfunction, triggers diastolic impairment, leading to profound myocardial hypoxia. This hypoxic state serves as a potent stimulus for the amplification of inflammatory mediator release, ultimately limiting the therapeutic potential of monotherapies. To address this challenge, compounds that integrate non-steroidal anti-inflammatory drugs (NSAIDs) with nitric oxide (NO) donors was synthesized. The <em>in vitro</em> screening unveiled the remarkable anti-hypoxic inflammatory injury activity of a sulindac derivative, despite its suboptimal COX-2 inhibition when comparing with other NSAIDs derivatives. This revelation propelled us to delve deeper into the intricate synergistic relationship between sulindac and NO. Employing two-way ANOVA and high-throughput screening technique, we incontrovertibly confirmed their synergism. Further, the underlying mechanism was unmasked through the detection of signal molecule release levels and western blot analysis. In a definitive step, we evaluated the therapeutic effects of sulindac and its derivatives <em>in vivo</em>, leveraging a rat model that recapitulates cardiac inflammation coupled with hypoxia. Our findings herald a promising drug candidate and establish a foundation for the expanded utilization of NSAIDs in the intricate landscape of cardiovascular diseases.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 117991"},"PeriodicalIF":3.3,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sulfonamide-derivatized galactosides selectively target an unexplored binding site in the galectin-9N-terminal domain","authors":"Mukul Mahanti ,&nbsp;Sofi Gummesson ,&nbsp;Anders Sundin ,&nbsp;Hakon Leffler ,&nbsp;Fredrik Zetterberg ,&nbsp;Ulf J Nilsson","doi":"10.1016/j.bmc.2024.117989","DOIUrl":"10.1016/j.bmc.2024.117989","url":null,"abstract":"<div><div>Four directional and positional variants of sulfonamide-derivatized galactopyranosides were synthesized and evaluated against human galectin-1, -3, -4C (C-terminal), -7, -8N (N-terminal), -8C (C-terminal), -9N (N-terminal), and -9C (C-terminal), which revealed that one of the sulfonamide positions and directionalities (methyl 3-{4-[2-(phenylsulfonylamino)-phenyl]-triazolyl}-3-deoxy-α-<span>d</span>-galactopyranosides) bound with 6–15 fold higher affinity than the corresponding phenyltriazole (lacking the phenylsulfonamide moiety) for galectin-9N. Molecular dynamic simulations suggested that inhibitor adopted a conformation that is complementary to the galectin-9N binding site and where the sulfonamide moiety protrudes into an unexplored and non-conserved binding site perpendicular to and below the A–B subsite to interact with a His61 N<img>H proton. This resulted in the discovery of galectin-9N inhibitors with unprecedented selectivity over other galectins, thus constituting valuable tools for studies of the biological functions of galectin-9.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 117989"},"PeriodicalIF":3.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ringing medicinal chemistry: The importance of 3-membered rings in drug discovery","authors":"Sahani Sandalima Uthumange ,&nbsp;Angie Jun Hui Liew ,&nbsp;Xavier Wezen Chee ,&nbsp;Keng Yoon Yeong","doi":"10.1016/j.bmc.2024.117980","DOIUrl":"10.1016/j.bmc.2024.117980","url":null,"abstract":"<div><div>Scaffold-based drug design has become increasingly prominent in the pharmaceutical field due to the systematic and effective approach through which it facilitates the development of novel drugs. The identification of key scaffolds provides medicinal chemists with a fundamental framework for subsequent research. With mounting evidence suggesting that increased aromaticity could impede the chances of developmental success for oral drug candidates, there is an imperative need for a more thorough exploration of alternative ring systems to mitigate attrition risks. The unique characteristics exhibited by three-membered rings have led to their application in medicinal chemistry. This review explores the use of cyclopropane-, aziridine-, thiirane-, and epoxide-containing compounds in drug discovery, focusing on their roles in approved medicines and drug candidates. Specifically, the importance of the three-membered ring systems in rending biological activity for each drug molecule was highlighted. The undeniable therapeutic value and intriguing features presented by these compounds suggest significant pharmacological potential, providing justification for their incorporation into the design of novel drug candidates.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 117980"},"PeriodicalIF":3.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and biological evaluation of novel TMPRSS2-PROTACs with florosubstituted 4-guanidino-N-phenylbenzamide derivative ligands","authors":"Hao Yang ,&nbsp;Haoran Xu ,&nbsp;Xinxin Lin ,&nbsp;Zengxuan Cai ,&nbsp;Yong Xia ,&nbsp;Yu Wang ,&nbsp;Zejie Chen ,&nbsp;Koutian Zhang ,&nbsp;Yanling Wu ,&nbsp;Jianwei Wang ,&nbsp;Annoor Awadasseid ,&nbsp;Wen Zhang","doi":"10.1016/j.bmc.2024.117982","DOIUrl":"10.1016/j.bmc.2024.117982","url":null,"abstract":"<div><div>Transmembrane Serine Protease 2 (TMPRSS2) plays a critical role in tumorigenesis and progression, making its degradation a promising therapeutic strategy. In this study, we designed and synthesized TMPRSS2-PROTACs, including <strong>VPOT64</strong> and <strong>VPOT76</strong>, based on camostat. Both compounds exhibited superior inhibitory effects on HT-29 colorectal and Calu-3 lung cancer cells compared to paclitaxel. Notably, <strong>VPOT76</strong> effectively degraded TMPRSS2, significantly inhibiting the proliferation of TMPRSS2-positive HT-29 cells and inducing apoptosis with an IC₅₀ of 0.39 ± 0.01 μM. Flow cytometry analysis demonstrated that <strong>VPOT76</strong> increased early apoptotic cells in a dose-dependent manner and caused G2 phase arrest at 0.8 μM. Colony formation assays showed that <strong>VPOT76</strong> inhibited HT-29 colony formation, even at low concentrations, further confirming its anti-proliferative effect. Additionally, wound healing assays indicated that <strong>VPOT76</strong> reduced the migration of HT-29 cells after 48 h, suggesting its potential to impair tumor cell invasion and metastasis. These findings highlight the multifaceted anticancer activities of <strong>VPOT76</strong>, including apoptosis induction, cell cycle arrest, colony formation inhibition, and migration suppression. Overall, this study establishes <strong>VPOT76</strong> as a potent TMPRSS2-degrading PROTAC with strong therapeutic potential, laying the groundwork for further development of TMPRSS2-targeting treatments for colorectal and other cancers.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 117982"},"PeriodicalIF":3.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery and biological evaluation of cholic acid derivatives as potent TGR5 positive allosteric modulators","authors":"Yan Li ,&nbsp;Jingjing Sun ,&nbsp;Xiao Wang,&nbsp;Zhijie Luo,&nbsp;Xuemei Shao,&nbsp;Yingxiu Li,&nbsp;Qirong Cao,&nbsp;Shuai Zhao,&nbsp;Mingcheng Qian,&nbsp;Xin Chen","doi":"10.1016/j.bmc.2023.117418","DOIUrl":"https://doi.org/10.1016/j.bmc.2023.117418","url":null,"abstract":"<div><p>In this study, twenty-two novel cholic acid (CA) derivatives were designed and synthesized as potential Takeda G protein-coupled receptor 5 (TGR5) positive allosteric modulators (PAMs) using structure-based drug design (SBDD). GloSensor cAMP accumulation assay was employed to assess the functional activity and allosteric mechanism of final compounds. Biological results showed that all target compounds were able to activate the TGR5 in the cAMP formation assay. Remarkably, compound <strong>B1</strong>, selective methylation of 7-OH in CA, exhibited 5-fold higher activity for TGR5 compared to that of CA. Moreover, <strong>B1</strong> positively modulate the functional activity of chenodeoxycholic acid (CDCA) in TGR5, indicating that <strong>B1</strong> is a TGR5 PAM. On the other hand, 12-carbonyl derivative <strong>A1</strong> displayed 7-fold higher potency for TGR5 relative to CA. Unexpectedly, compound <strong>A1</strong> exhibited the same positive allosteric effect as <strong>B1</strong>, suggesting that <strong>A1</strong> is a TGR5 PAM as well. Molecular modeling study revealed that 12-carbonyl in <strong>A1</strong> and 12-OH in <strong>B1</strong> formed H-bolds with the key amino acid Thr131, which are significant for TGR5 allosteric property. Taken together, we found two potent TGR5 PAMs <strong>A1</strong> and <strong>B1</strong> through SBDD, which could be used as lead compounds to further study TGR5 allosteric functionality.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"92 ","pages":"Article 117418"},"PeriodicalIF":3.5,"publicationDate":"2023-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"3462528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glycogen synthase kinase-3: A potential target for diabetes","authors":"Divya M. Teli,&nbsp;Anuradha K. Gajjar","doi":"10.1016/j.bmc.2023.117406","DOIUrl":"https://doi.org/10.1016/j.bmc.2023.117406","url":null,"abstract":"<div><p><span>Elevated circulating glucose level<span><span> due to β-cell dysfunction has been a key marker of Type-II diabetes. Glycogen synthase kinase-3 (GSK-3) has been recognized as an enzyme involved in the control of </span>glycogen metabolism. Consequently, inhibitors of GSK-3 have been explored for anti-diabetic effects </span></span><em>in vitro</em><span><span> and in animal models<span><span>. Further, the mechanisms governing the regulation of this enzyme have been elucidated by means of a combination of structural and cellular biological investigations. This review article examines the structural analysis of GSK-3 as well as molecular modeling<span><span> reports from numerous researchers in the context of the design and development of GSK-3 inhibitors. This article centers on the signaling pathway of GSK-3 relevant to its potential as a target for diabetes and discusses advancements till date on different </span>molecular modification approaches used by researchers in the development of novel GSK-3 inhibitors as potential therapeutics for the </span></span>treatment of </span></span>Type II diabetes.</span></p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"92 ","pages":"Article 117406"},"PeriodicalIF":3.5,"publicationDate":"2023-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"3462529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteolytic polymer: polyacrylamides functionalized with amino acids cleave bovine and human serum albumins","authors":"Takahiko Matsushita ,&nbsp;Hinako Yamochi ,&nbsp;Shinzo Omiya ,&nbsp;Tetsuo Koyama ,&nbsp;Ken Hatano ,&nbsp;Koji Matsuoka","doi":"10.1016/j.bmc.2023.117422","DOIUrl":"https://doi.org/10.1016/j.bmc.2023.117422","url":null,"abstract":"<div><p>Polyacrylamides with various compositions of serine, aspartic acid, and histidine, which are the amino acids involved in the catalytic triad of natural serine protease chymotrypsin, were synthesized and their protein cleavage activity was investigated. SDS-PAGE analysis showed that some of the synthesized ternary copolymers showed cleavage activity against bovine and human serum albumins. Polyacrylamides incorporating a single type of amino acid were also able to cleave the protein substrates. These homopolymers exhibited unique cleavage profiles and pH and temperature sensitivities that differed from those of α-chymotrypsin. The results indicate the potential of polymers functionalized with amino acids as proteolytic artificial enzymes.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"92 ","pages":"Article 117422"},"PeriodicalIF":3.5,"publicationDate":"2023-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"2823622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}