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Multimodal Blood-Based Biomarker Panel Reveals Altered Lysosomal Ionic Content in Alzheimer's Disease. 多模式血液生物标志物显示阿尔茨海默病溶酶体离子含量改变
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2025-01-17 Epub Date: 2024-12-19 DOI: 10.1021/acschembio.4c00602
Senthilkumar Deivasigamani, Shareefa Thekkan, Hernando M Vergara, Owen Conolly, Mali Cosden, Thienlong Phan, Sean Smith, Jacob Marcus, Jason Uslaner, Dhivya Venkat, Robert E Drolet, Yamuna Krishnan, Souvik Modi
{"title":"Multimodal Blood-Based Biomarker Panel Reveals Altered Lysosomal Ionic Content in Alzheimer's Disease.","authors":"Senthilkumar Deivasigamani, Shareefa Thekkan, Hernando M Vergara, Owen Conolly, Mali Cosden, Thienlong Phan, Sean Smith, Jacob Marcus, Jason Uslaner, Dhivya Venkat, Robert E Drolet, Yamuna Krishnan, Souvik Modi","doi":"10.1021/acschembio.4c00602","DOIUrl":"10.1021/acschembio.4c00602","url":null,"abstract":"<p><p>Lysosomal storage disorders (LSDs) and adult neurodegenerative disorders like Alzheimer's disease (AD) share various clinical and pathophysiological features. LSDs are characterized by impaired lysosomal activity caused by mutations in key proteins and enzymes. While lysosomal dysfunction is also linked to AD pathogenesis, its precise role in disease onset or progression remains unclear. Lysosomal ionic homeostasis is recognized as a key feature of many LSDs, but it has not been clinically linked with AD pathology. Thus, investigating whether this regulation is disrupted in AD is important, as it could lead to new therapeutic targets and biomarkers for this multifactorial disease. Here, using two-ion mapping (2-IM) technology, we quantitatively profiled lysosomal pH and Ca<sup>2+</sup> in blood-derived monocytes from AD patients and age-matched controls and correlated lysosome ionicity with age and key markers of AD pathology, namely, amyloid deposits, tauopathy, neurodegeneration, and inflammation. Together, the data show that the ionic milieu of lysosomes is dysregulated in monocytes of AD patients and correlates with key plasma biomarkers of AD. Using a machine learning model based on the above parameters, we describe a proof-of-concept combinatorial biomarker platform that accurately distinguishes between patients with AD and control participants with an area under the curve of >96%. Our study introduces a convenient, noninvasive platform with the potential to diagnose Alzheimer's disease based on fluid, cellular, and molecular biomarkers. Further, these findings highlight the potential for investigating therapeutic mechanisms capable of restoring lysosome ionic homeostasis to ameliorate AD.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"137-152"},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Introducing Our Authors. 介绍作者。
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2025-01-17 DOI: 10.1021/acschembio.4c00846
Jen Wagner
{"title":"Introducing Our Authors.","authors":"Jen Wagner","doi":"10.1021/acschembio.4c00846","DOIUrl":"https://doi.org/10.1021/acschembio.4c00846","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 1","pages":"1-2"},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142995976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Recognition of Noncanonical RNA Base Pairs Using Triplex-Forming Peptide Nucleic Acids. 利用三聚体形成肽核酸识别非规范RNA碱基对。
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2025-01-17 Epub Date: 2024-12-22 DOI: 10.1021/acschembio.4c00662
Sara Farshineh Saei, Vladislavs Baskevics, Martins Katkevics, Eriks Rozners
{"title":"Recognition of Noncanonical RNA Base Pairs Using Triplex-Forming Peptide Nucleic Acids.","authors":"Sara Farshineh Saei, Vladislavs Baskevics, Martins Katkevics, Eriks Rozners","doi":"10.1021/acschembio.4c00662","DOIUrl":"10.1021/acschembio.4c00662","url":null,"abstract":"<p><p>Noncanonical base pairs play an important role in enabling the structural and functional complexity of RNA. Molecular recognition of such motifs is challenging because of their diversity, significant deviation from the Watson-Crick structures, and dynamic behavior, resulting in alternative conformations of similar stability. Triplex-forming peptide nucleic acids (PNAs) have emerged as excellent ligands for the recognition of Watson-Crick base-paired double helical RNA. The present study extends the recognition potential of PNA to RNA helices having noncanonical GoU, AoC, and tandem GoA/AoG base pairs. The purines of the noncanonical base pairs formed M<sup>+</sup>·GoU, T·AoC, M<sup>+</sup>·GoA, and T·AoG Hoogsteen triples of similar or slightly reduced stability compared to the canonical M<sup>+</sup>·G-C and T·A-U triples. Recognition of pyrimidines was more challenging. While the P·CoA triple was only slightly less stable than P·C-G, the E nucleobase did not form a stable triple with U of the UoG wobble pair. Molecular dynamics simulations suggested the formation of expected Hoogsteen hydrogen bonds for all of the stable triples. Collectively, these results expand the scope of triple helical recognition to noncanonical structures and sequence motifs common in biologically relevant RNAs.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"179-185"},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Revealing NOD1-Activating Gram-Positive Gut Microbiota via in Vivo Labeling with a meso-Diaminopimelic Acid Probe. 通过中二氨基戊酸探针在体内标记揭示nod1激活的革兰氏阳性肠道微生物群。
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2025-01-17 Epub Date: 2025-01-02 DOI: 10.1021/acschembio.4c00629
Huibin Lin, Xinying Zheng, Liyuan Lin, Chaoyong Yang, Wei Wang
{"title":"Revealing NOD1-Activating Gram-Positive Gut Microbiota via in Vivo Labeling with a meso-Diaminopimelic Acid Probe.","authors":"Huibin Lin, Xinying Zheng, Liyuan Lin, Chaoyong Yang, Wei Wang","doi":"10.1021/acschembio.4c00629","DOIUrl":"10.1021/acschembio.4c00629","url":null,"abstract":"<p><p>As an important receptor in a host's immune and metabolic systems, NOD1 is usually activated by Gram-negative bacteria having <i>meso</i>-diaminopimelic acid (<i>m</i>-DAP) in their peptidoglycan (PGN). But some atypical Gram-positive bacteria also contain <i>m</i>-DAP in their PGN, giving them the potential to activate NOD1. The prevalence of <i>m</i>-DAP-type Gram-positive bacteria in the gut, however, remains largely unknown. Here, we report a stem-peptide-based <i>m</i>-DAP-containing tetrapeptide probe for labeling and identifying <i>m</i>-DAP-type Gram-positive microbiota. The probe was synthesized via a five-step convergent approach and demonstrated moderate selectivity toward <i>m</i>-DAP-type bacteria <i>in vitro</i>. <i>In vivo</i> labeling revealed that ∼13.7% of the mouse gut microbiota (mostly Gram-positive) was selectively labeled. We then identified <i>Oscillibacter</i> and several other Gram-positive genera in this population, most of which were previously unknown <i>m</i>-DAP-type bacteria. The following functional assay showed that <i>Oscillibacter</i>'s PGN could indeed activate NOD1, suggesting an overlooked NOD1-activating role for these Gram-positive bacteria. These findings deepen our understanding of the structural diversity of gut microbes and their interactions with the host's immune system.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"62-68"},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Exploring the Impact of Amidation Status in Meso-Diaminopimelic-Acid-Containing Disaccharide Peptidoglycan Fragments on Host Innate Immune Activation. 探讨含中二氨基戊酸双糖肽聚糖片段酰胺化状态对宿主先天免疫激活的影响。
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2025-01-17 Epub Date: 2025-01-03 DOI: 10.1021/acschembio.4c00700
Yaquan Liang, Christopher Adamson, Shiliu Feng, Yuan Qiao
{"title":"Exploring the Impact of Amidation Status in <i>Meso</i>-Diaminopimelic-Acid-Containing Disaccharide Peptidoglycan Fragments on Host Innate Immune Activation.","authors":"Yaquan Liang, Christopher Adamson, Shiliu Feng, Yuan Qiao","doi":"10.1021/acschembio.4c00700","DOIUrl":"10.1021/acschembio.4c00700","url":null,"abstract":"<p><p>Bacterial peptidoglycan, the essential cell surface polymer that protects bacterial integrity, also serves as the molecular pattern recognized by the host's innate immune system. Although the minimal motifs of bacterial peptidoglycan fragments (PGNs) that activate mammalian NOD1 and NOD2 sensors are well-known and often represented by small canonical ligands, the immunostimulatory effects of natural PGNs, which are structurally more complex and potentially can simultaneously activate both the NOD1 and NOD2 signaling pathways in hosts, have not been comprehensively investigated. In particular, many bacteria incorporate additional structural modifications in peptidoglycans to evade host immune surveillance, resulting in diverse structural variations among natural PGNs that may influence their biological effects in hosts. The focus of this study is on the amidation status of γ-d-glutamic acid and <i>meso</i>-diaminopimelic acid (mDAP) at the second and third positions of stem peptides in peptidoglycan, which represent key structural features that vary across different bacterial species. With four synthetic mDAP-containing disaccharide PGNs of different amidation states, we systematically investigated their structure-activity relationship in stimulating host innate immune responses <i>in vitro</i>. Our findings revealed that the amidation of disaccharide PGNs has distinct effects on NOD1 and NOD2 induction, along with their differential immunostimulatory activities in macrophage cells. Additionally, we found that, like the canonical NOD2 ligand, natural PGNs confer immune tolerance to LPS, and amidation states do not affect this outcome. Overall, our work highlights the potential immunological implications of these differentially amidated mDAP-type disaccharide PGNs in host-microbe crosstalk.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"69-76"},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142918802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Dual-Performing Vinyltetrazine for Rapid, Selective Bioconjugation and Functionalization of Cysteine Proteins. 双效乙烯基四嗪用于半胱氨酸蛋白的快速、选择性生物偶联和功能化。
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2025-01-17 Epub Date: 2024-12-21 DOI: 10.1021/acschembio.4c00610
Mengyang Chang, Hang Xu, Yue Dong, Giri Gnawali, Fangchao Bi, Wei Wang
{"title":"Dual-Performing Vinyltetrazine for Rapid, Selective Bioconjugation and Functionalization of Cysteine Proteins.","authors":"Mengyang Chang, Hang Xu, Yue Dong, Giri Gnawali, Fangchao Bi, Wei Wang","doi":"10.1021/acschembio.4c00610","DOIUrl":"10.1021/acschembio.4c00610","url":null,"abstract":"<p><p>Although methods for Cys-specific bioconjugation and functionalization of proteins have been developed and widely utilized in biomolecule engineering and therapeutic development, reagents for this purpose are generally designed to accomplish bioconjugation only. Consequently, additional clickable groups must be attached to these reagents to accomplish functionalization. Herein, we describe a new, simple, dual-performing bioconjugation-functionalization reagent, VMeTz, which possesses an electron-withdrawing tetrazine (Tz) substituted vinyl (V) moiety to serve as both a Michael receptor for selective conjugation with Cys and a site for click with TCO derivatives to introduce functionality. Critically, VMeTz contains a methyl group that prevents the formation of multiple Tz-containing Cys-adducts. Reactions of VMeTz with Cys-containing peptides and proteins both in vitro and in live cells produce single stable Michael adducts with high selectivity. Moreover, the Cys-VMeTz peptide and protein conjugates undergo facile click reactions with TCO-functionalized reagents for labeling and protein profiling. Furthermore, VMeTz selectively activates and delivers the TCO-caged toxic substances Dox and PROTAC ARV-771 to cancer cells to produce therapeutic effects that are comparable to those of the parent drugs. Collectively, the studies demonstrate that VMeTz is a useful reagent for therapeutically significant Cys-specific protein bioconjugation and functionalization.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"153-161"},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Strategic Acyl Carrier Protein Engineering Enables Functional Type II Polyketide Synthase Reconstitution In Vitro. 战略性酰基载体蛋白工程实现功能性II型聚酮合成酶的体外重组。
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2025-01-17 Epub Date: 2025-01-02 DOI: 10.1021/acschembio.4c00678
Kevin Li, Yae In Cho, Mai Anh Tran, Christoph Wiedemann, Shuaibing Zhang, Rebecca S Koweek, Ngọc Khánh Hoàng, Grayson S Hamrick, Margaret A Bowen, Bashkim Kokona, Pierre Stallforth, Joris Beld, Ute A Hellmich, Louise K Charkoudian
{"title":"Strategic Acyl Carrier Protein Engineering Enables Functional Type II Polyketide Synthase Reconstitution In Vitro.","authors":"Kevin Li, Yae In Cho, Mai Anh Tran, Christoph Wiedemann, Shuaibing Zhang, Rebecca S Koweek, Ngọc Khánh Hoàng, Grayson S Hamrick, Margaret A Bowen, Bashkim Kokona, Pierre Stallforth, Joris Beld, Ute A Hellmich, Louise K Charkoudian","doi":"10.1021/acschembio.4c00678","DOIUrl":"10.1021/acschembio.4c00678","url":null,"abstract":"<p><p>Microbial polyketides represent a structurally diverse class of secondary metabolites with medicinally relevant properties. Aromatic polyketides are produced by type II polyketide synthase (PKS) systems, each minimally composed of a ketosynthase-chain length factor (KS-CLF) and a phosphopantetheinylated acyl carrier protein (<i>holo</i>-ACP). Although type II PKSs are found throughout the bacterial kingdom, and despite their importance to strategic bioengineering, type II PKSs have not been well-studied <i>in vitro</i>. In cases where the KS-CLF can be accessed via <i>E. coli</i> heterologous expression, often the cognate ACPs are not activatable by the broad specificity <i>Bacillus subtilis</i> surfactin-producing phosphopantetheinyl transferase (PPTase) Sfp and, conversely, in systems where the ACP can be activated by Sfp, the corresponding KS-CLF is typically not readily obtained. Here, we report the high-yield heterologous expression of both cyanobacterial <i>Gloeocapsa</i> sp. PCC 7428 minimal type II PKS (gloPKS) components in <i>E. coli</i>, which allowed us to study this minimal type II PKS <i>in vitro</i>. Initially, neither the cognate PPTase nor Sfp converted gloACP to its active <i>holo</i> state. However, by examining sequence differences between Sfp-compatible and -incompatible ACPs, we identified two conserved residues in gloACP that, when mutated, enabled high-yield phosphopantetheinylation of gloACP by Sfp. Using analogous mutations, other previously Sfp-incompatible type II PKS ACPs from different bacterial phyla were also rendered activatable by Sfp. This demonstrates the generalizability of our approach and breaks down a longstanding barrier to type II PKS studies and the exploration of complex biosynthetic pathways.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"197-207"},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142918804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A Small-Molecule Inhibitor of Gut Bacterial Urease Protects the Host from Liver Injury. 肠道细菌脲酶小分子抑制剂保护宿主免受肝损伤。
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2025-01-17 Epub Date: 2025-01-08 DOI: 10.1021/acschembio.3c00556
Khyle C Richards-Corke, Yindi Jiang, Vladimir Yeliseyev, Yancong Zhang, Eric A Franzosa, Zhipeng A Wang, Maheeshi Yapa Abeywardana, Phillip A Cole, Curtis Huttenhower, Lynn Bry, Emily P Balskus
{"title":"A Small-Molecule Inhibitor of Gut Bacterial Urease Protects the Host from Liver Injury.","authors":"Khyle C Richards-Corke, Yindi Jiang, Vladimir Yeliseyev, Yancong Zhang, Eric A Franzosa, Zhipeng A Wang, Maheeshi Yapa Abeywardana, Phillip A Cole, Curtis Huttenhower, Lynn Bry, Emily P Balskus","doi":"10.1021/acschembio.3c00556","DOIUrl":"10.1021/acschembio.3c00556","url":null,"abstract":"<p><p>Hyperammonemia is characterized by the accumulation of ammonia within the bloodstream upon liver injury. Left untreated, hyperammonemia contributes to conditions such as hepatic encephalopathy that have high rates of patient morbidity and mortality. Previous studies have identified gut bacterial urease, an enzyme that converts urea into ammonia, as a major contributor to systemic ammonia levels. Here, we demonstrate use of benurestat, a clinical candidate used against ureolytic organisms in encrusted uropathy, to inhibit urease activity in gut bacteria. Benurestat inhibits ammonia production by urease-encoding gut bacteria and is effective against individual microbes and complex gut microbiota. When administered to conventional mice with liver injury induced by thioacetamide exposure, benurestat reduced gut and serum ammonia levels and rescued 100% of mice from lethal acute liver injury. Overall, this study provides an important proof-of-concept for modulating host ammonia levels and microbiota-driven risks for hyperammonemia with gut microbiota-targeted small-molecule inhibitors.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"48-55"},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Mapping the FGF2 Interactome Identifies a Functional Proteoglycan Coreceptor. 定位FGF2相互作用组鉴定功能性蛋白聚糖辅助受体。
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2025-01-17 Epub Date: 2024-12-20 DOI: 10.1021/acschembio.4c00475
Meg Critcher, Jia Meng Pang, Mia L Huang
{"title":"Mapping the FGF2 Interactome Identifies a Functional Proteoglycan Coreceptor.","authors":"Meg Critcher, Jia Meng Pang, Mia L Huang","doi":"10.1021/acschembio.4c00475","DOIUrl":"10.1021/acschembio.4c00475","url":null,"abstract":"<p><p>Fibroblast growth factor 2 (FGF2) is a multipotent growth factor and signaling protein that exhibits broad functions across multiple cell types. These functions are often initiated by binding to growth factor receptors and fine-tuned by glycosaminoglycan (GAG)-modified proteins called proteoglycans. The various outputs of FGF2 signaling and functions arise from a dynamic and cell type-specific set of binding partners. However, the interactome of FGF2 has yet to be comprehensively determined. Moreover, the identity of the proteoglycan proteins carrying GAG chains is often overlooked and remains unknown in most cell contexts. Here, we perform peroxidase-catalyzed live cell proximity labeling using an engineered APEX2-FGF2 fusion protein to map the interactome of FGF2. Across two cell lines with established and distinct FGF2-driven functions, we greatly expand upon the known FGF2 interactome, identifying >600 new putative FGF2 interactors. Notably, our results demonstrate a key role for the GAG binding capacity of FGF2 in modulating its interactome.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"105-116"},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
High-Throughput Computer Screen Aids Discovery of Methotrexate as miR-20b Inhibitor to Suppress Nonsmall Cell Lung Cancer Progression. 高通量计算机筛选有助于发现甲氨蝶呤作为miR-20b抑制剂抑制非小细胞肺癌进展。
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2025-01-17 Epub Date: 2024-12-30 DOI: 10.1021/acschembio.4c00706
Xiaorui Shi, Chong Hu, Liangli Fan, Bin Guo, Jingyu Zhang, Chu Tang, Fu Wang
{"title":"High-Throughput Computer Screen Aids Discovery of Methotrexate as miR-20b Inhibitor to Suppress Nonsmall Cell Lung Cancer Progression.","authors":"Xiaorui Shi, Chong Hu, Liangli Fan, Bin Guo, Jingyu Zhang, Chu Tang, Fu Wang","doi":"10.1021/acschembio.4c00706","DOIUrl":"10.1021/acschembio.4c00706","url":null,"abstract":"<p><p>MicroRNAs (miRNAs) play a significant role in tumor progression, and regulating miRNA expression with small molecules may offer a new approach to cancer therapy. Among them, miRNA-20b has been found to be dysregulated in several cancers, including nonsmall cell lung cancer (NSCLC). Herein, an in silico high-throughput computer screen was conducted to identify small molecules that downregulate miR-20b using the three-dimensional structure of the Dicer binding site on pre-miR-20b. Among 1058 small molecule compounds, Methotrexate (MTX), was discovered to be a potential miR-20b-specific inhibitor, which has been found to suppress miR-20b by specifically blocking Dicer processing in p53 wild-type A549 NSCLC cells but not in H1299 cells with p53 depletion. MTX effectively inhibited the proliferation, survival, migration, and invasion of A549 cells in a dose-dependent manner. Furthermore, the treatment of MTX up-regulated the expression of miR-20b target genes PTEN, STAT3, and HIF1α. Notably, MTX also significantly inhibited tumor growth in a mouse xenograft tumor model of NSCLC, with no observed tissue toxicity. Our findings indicate that MTX may have a novel role as an established drug in p53 wild-type NSCLC tumor therapy by down-regulating miR-20b expression. These findings are expected to provide preclinical evidence for miR-20b-targeting NSCLC therapeutic strategies.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"208-218"},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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