Acta Pharmaceutica Sinica. B最新文献_第8页

Optimized lipid nanoparticles enable effective CRISPR/Cas9-mediated gene editing in dendritic cells for enhanced immunotherapy

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.08.030

Kuirong Mao , Huizhu Tan , Xiuxiu Cong , Ji Liu , Yanbao Xin , Jialiang Wang , Meng Guan , Jiaxuan Li , Ge Zhu , Xiandi Meng , Guojiao Lin , Haorui Wang , Jing Han , Ming Wang , Yong-Guang Yang , Tianmeng Sun

{"title":"Optimized lipid nanoparticles enable effective CRISPR/Cas9-mediated gene editing in dendritic cells for enhanced immunotherapy","authors":"Kuirong Mao , Huizhu Tan , Xiuxiu Cong , Ji Liu , Yanbao Xin , Jialiang Wang , Meng Guan , Jiaxuan Li , Ge Zhu , Xiandi Meng , Guojiao Lin , Haorui Wang , Jing Han , Ming Wang , Yong-Guang Yang , Tianmeng Sun","doi":"10.1016/j.apsb.2024.08.030","DOIUrl":"10.1016/j.apsb.2024.08.030","url":null,"abstract":"<div><div>Immunotherapy has emerged as a revolutionary approach to treat immune-related diseases. Dendritic cells (DCs) play a pivotal role in orchestrating immune responses, making them an attractive target for immunotherapeutic interventions. Modulation of gene expression in DCs using genome editing techniques, such as the CRISPR-Cas system, is important for regulating DC functions. However, the precise delivery of CRISPR-based therapies to DCs has posed a significant challenge. While lipid nanoparticles (LNPs) have been extensively studied for gene editing in tumor cells, their potential application in DCs has remained relatively unexplored. This study investigates the important role of cholesterol in regulating the efficiency of BAMEA-O16B lipid-assisted nanoparticles (BLANs) as carriers of CRISPR/Cas9 for gene editing in DCs. Remarkably, BLANs with low cholesterol density exhibit exceptional mRNA uptake, improved endosomal escape, and efficient single-guide RNA release capabilities. Administration of BLAN<sub>mCas9/gPD-L1</sub> results in substantial PD-L1 gene knockout in conventional dendritic cells (cDCs), accompanied by heightened cDC1 activation, T cell stimulation, and significant suppression of tumor growth. The study underscores the pivotal role of cholesterol density within LNPs, revealing potent influence on gene editing efficacy within DCs. This strategy holds immense promise for the field of cancer immunotherapy, offering a novel avenue for treating immune-related diseases.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 642-656"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Emerging therapeutic strategies: The potential of caffeic acid-vanadium nanozymes in modulating macrophage function and reducing skin flap ischemia–reperfusion injury

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2025.01.012

Jintao Fu , Huile Gao

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Cover Story

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-01-01 DOI: 10.1016/S2211-3835(24)00509-4

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The homotherapy for heteropathy: GCGR/GLP1R pathway in fibrotic diseases

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2025.01.013

Yang Sun

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Cocrystal pleomorphism-inspired drug nanoassembly for pulmonary-endothelium targeting and pulmonary hypertension treatment

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.11.008

Makhloufi Zoulikha , Jiahui Zou , Pei Yang , Jun Wu , Wei Wu , Kun Hao , Wei He

{"title":"Cocrystal pleomorphism-inspired drug nanoassembly for pulmonary-endothelium targeting and pulmonary hypertension treatment","authors":"Makhloufi Zoulikha , Jiahui Zou , Pei Yang , Jun Wu , Wei Wu , Kun Hao , Wei He","doi":"10.1016/j.apsb.2024.11.008","DOIUrl":"10.1016/j.apsb.2024.11.008","url":null,"abstract":"<div><div>Endothelial dysfunction is one of the early triggers of vascular remodeling during pulmonary hypertension (PH) with complex predisposing mechanisms, mainly <em>via</em> an unbalanced generation of vasoactive factors, increased expression of growth factors, prothrombotic elements, and inflammatory markers. Conventional treatment regimens are restricted to a single therapeutic pathway, which usually leads to limited clinical outcomes. Combination therapies targeting multiple cells and several signaling pathways are increasingly adopted in PH treatment. Herein, inspired by the cocrystal pleomorphism theory, we prepared rod-shaped nanococrystals of the endothelin-1 (ET-1) receptor antagonist (bosentan, BST) and the anti-inflammatory drug (andrographolide, AG) for targeting the pulmonary endothelium and alleviating PH. The 525 nm-sized co-delivery system displayed a rod-like morphology, preferentially accumulated in the pulmonary endothelium and alleviated pulmonary artery (PA) remodeling. A three-week treatment with the preparation significantly alleviated the monocrotaline (MCT)- or Sugen 5416/hypoxia (SuHx)-induced PH by reducing the pulmonary artery pressure, increasing the survival rate, improving the hemodynamics, and inhibiting vascular remodeling. Mechanistically, the nanococrystals collaboratively repaired endothelial dysfunction by suppressing the pathways of ET-1/NF-<em>κ</em>B/ICAM-1/TNF-<em>α</em>/IL-6. In conclusion, the cocrystal-based strategy offers a promising approach for constructing co-delivery systems. The developed rod-shaped nanococrystals effectively target the pulmonary endothelium and relieve experimental PH.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 557-570"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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GSFM: A genome-scale functional module transformation to represent drug efficacy for in silico drug discovery GSFM：用于表示药物疗效的基因组尺度功能模块转换，以促进硅学药物发现

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.08.017

Saisai Tian , Xuyang Liao , Wen Cao , Xinyi Wu , Zexi Chen , Jinyuan Lu , Qun Wang , Jinbo Zhang , Luonan Chen , Weidong Zhang

{"title":"GSFM: A genome-scale functional module transformation to represent drug efficacy for in silico drug discovery","authors":"Saisai Tian , Xuyang Liao , Wen Cao , Xinyi Wu , Zexi Chen , Jinyuan Lu , Qun Wang , Jinbo Zhang , Luonan Chen , Weidong Zhang","doi":"10.1016/j.apsb.2024.08.017","DOIUrl":"10.1016/j.apsb.2024.08.017","url":null,"abstract":"<div><div>Pharmacotranscriptomic profiles, which capture drug-induced changes in gene expression, offer vast potential for computational drug discovery and are widely used in modern medicine. However, current computational approaches neglected the associations within gene‒gene functional networks and unrevealed the systematic relationship between drug efficacy and the reversal effect. Here, we developed a new genome-scale functional module (GSFM) transformation framework to quantitatively evaluate drug efficacy for <em>in silico</em> drug discovery. GSFM employs four biologically interpretable quantifiers: GSFM_Up, GSFM_Down, GSFM_ssGSEA, and GSFM_TF to comprehensively evaluate the multi-dimension activities of each functional module (FM) at gene-level, pathway-level, and transcriptional regulatory network-level. Through a data transformation strategy, GSFM effectively converts noisy and potentially unreliable gene expression data into a more dependable FM active matrix, significantly outperforming other methods in terms of both robustness and accuracy. Besides, we found a positive correlation between RS<sub>GSFM</sub> and drug efficacy, suggesting that RS<sub>GSFM</sub> could serve as representative measure of drug efficacy. Furthermore, we identified WYE-354, perhexiline, and NTNCB as candidate therapeutic agents for the treatment of breast-invasive carcinoma, lung adenocarcinoma, and castration-resistant prostate cancer, respectively. The results from <em>in vitro</em> and <em>in vivo</em> experiments have validated that all identified compounds exhibit potent anti-tumor effects, providing proof-of-concept for our computational approach.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 133-150"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

YOD1 regulates microglial homeostasis by deubiquitinating MYH9 to promote the pathogenesis of Alzheimer's disease

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.11.020

Jinfeng Sun , Fan Chen , Lingyu She , Yuqing Zeng , Hao Tang , Bozhi Ye , Wenhua Zheng , Li Xiong , Liwei Li , Luyao Li , Qin Yu , Linjie Chen , Wei Wang , Guang Liang , Xia Zhao

{"title":"YOD1 regulates microglial homeostasis by deubiquitinating MYH9 to promote the pathogenesis of Alzheimer's disease","authors":"Jinfeng Sun , Fan Chen , Lingyu She , Yuqing Zeng , Hao Tang , Bozhi Ye , Wenhua Zheng , Li Xiong , Liwei Li , Luyao Li , Qin Yu , Linjie Chen , Wei Wang , Guang Liang , Xia Zhao","doi":"10.1016/j.apsb.2024.11.020","DOIUrl":"10.1016/j.apsb.2024.11.020","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is the major form of dementia in the elderly and is closely related to the toxic effects of microglia sustained activation. In AD, sustained microglial activation triggers impaired synaptic pruning, neuroinflammation, neurotoxicity, and cognitive deficits. Accumulating evidence has demonstrated that aberrant expression of deubiquitinating enzymes is associated with regulating microglia function. Here, we use RNA sequencing to identify a deubiquitinase YOD1 as a regulator of microglial function and AD pathology. Further study showed that YOD1 knockout significantly improved the migration, phagocytosis, and inflammatory response of microglia, thereby improving the cognitive impairment of AD model mice. Through LC–MS/MS analysis combined with Co-IP, we found that Myosin heavy chain 9 (MYH9), a key regulator maintaining microglia homeostasis, is an interacting protein of YOD1. Mechanistically, YOD1 binds to MYH9 and maintains its stability by removing the K48 ubiquitin chain from MYH9, thereby mediating the microglia polarization signaling pathway to mediate microglia homeostasis. Taken together, our study reveals a specific role of microglial YOD1 in mediating microglia homeostasis and AD pathology, which provides a potential strategy for targeting microglia to treat AD.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 331-348"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Drofenine as a Kv2.1 inhibitor alleviated AD-like pathology in mice through Aβ/Kv2.1/microglial NLRP3/neuronal Tau axis

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.11.010

Jian Lu , Qian Zhou , Danyang Zhu , Hongkuan Song , Guojia Xie , Xuejian Zhao , Yujie Huang , Peng Cao , Jiaying Wang , Xu Shen

{"title":"Drofenine as a Kv2.1 inhibitor alleviated AD-like pathology in mice through Aβ/Kv2.1/microglial NLRP3/neuronal Tau axis","authors":"Jian Lu , Qian Zhou , Danyang Zhu , Hongkuan Song , Guojia Xie , Xuejian Zhao , Yujie Huang , Peng Cao , Jiaying Wang , Xu Shen","doi":"10.1016/j.apsb.2024.11.010","DOIUrl":"10.1016/j.apsb.2024.11.010","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a neurodegenerative disease with clinical hallmarks of progressive cognitive impairment. Synergistic effects of the A<em>β</em>-Tau cascade reaction are tightly implicated in AD pathology, and microglial NLRP3 inflammasome activation drives neuronal tauopathy. However, the underlying mechanism of how A<em>β</em> mediates NLRP3 inflammasome remains unclear. Herein, we determined that oligomeric A<em>β</em> (o-A<em>β</em>) bound to microglial Kv2.1 and promoted Kv2.1-dependent potassium efflux to activate NLRP3 inflammasome resulting in neuronal tauopathy by using Kv2.1 inhibitor drofenine (Dfe) as a probe. The underlying mechanism has been intensively investigated by assays with Kv2.1 knockdown <em>in vitro</em> (<em>si-Kv2.1</em>) and <em>in vivo</em> (AAV-ePHP-<em>si-Kv2.1</em>). Dfe deprived o-A<em>β</em> of its capability to promote microglial NLRP3 inflammasome activation and neuronal Tau hyperphosphorylation by inhibiting the Kv2.1/JNK/NF-<em>κ</em>B pathway while improving the cognitive impairment of 5×FAD-AD model mice. Our results have highly addressed that the Kv2.1 channel is required for o-A<em>β</em>-driven microglial NLRP3 inflammasome activation and neuronal tauopathy in AD model mice and highlighted that Dfe as a Kv2.1 inhibitor shows potential in the treatment of AD.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 371-391"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dimeric natural product panepocyclinol A inhibits STAT3 via di-covalent modification

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.10.001

Li Li , Yuezhou Wang , Yiqiu Wang , Xiaoyang Li , Qihong Deng , Fei Gao , Wenhua Lian , Yunzhan Li , Fu Gui , Yanling Wei , Su-Jie Zhu , Cai-Hong Yun , Lei Zhang , Zhiyu Hu , Qingyan Xu , Xiaobing Wu , Lanfen Chen , Dawang Zhou , Jianming Zhang , Fei Xia , Xianming Deng

{"title":"Dimeric natural product panepocyclinol A inhibits STAT3 via di-covalent modification","authors":"Li Li , Yuezhou Wang , Yiqiu Wang , Xiaoyang Li , Qihong Deng , Fei Gao , Wenhua Lian , Yunzhan Li , Fu Gui , Yanling Wei , Su-Jie Zhu , Cai-Hong Yun , Lei Zhang , Zhiyu Hu , Qingyan Xu , Xiaobing Wu , Lanfen Chen , Dawang Zhou , Jianming Zhang , Fei Xia , Xianming Deng","doi":"10.1016/j.apsb.2024.10.001","DOIUrl":"10.1016/j.apsb.2024.10.001","url":null,"abstract":"<div><div>Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma <em>in vitro</em> and <em>in vivo,</em> especially those with constitutively activated STAT3 or STAT3<sup>Y640F</sup>. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 409-423"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of a novel AhR–CYP1A1 axis activator for mitigating inflammatory diseases using an in situ functional imaging assay

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.09.014

Feng Zhang , Bei Zhao , Yufan Fan , Lanhui Qin , Jinhui Shi , Lin Chen , Leizhi Xu , Xudong Jin , Mengru Sun , Hongping Deng , Hairong Zeng , Zhangping Xiao , Xin Yang , Guangbo Ge

{"title":"Discovery of a novel AhR–CYP1A1 axis activator for mitigating inflammatory diseases using an in situ functional imaging assay","authors":"Feng Zhang , Bei Zhao , Yufan Fan , Lanhui Qin , Jinhui Shi , Lin Chen , Leizhi Xu , Xudong Jin , Mengru Sun , Hongping Deng , Hairong Zeng , Zhangping Xiao , Xin Yang , Guangbo Ge","doi":"10.1016/j.apsb.2024.09.014","DOIUrl":"10.1016/j.apsb.2024.09.014","url":null,"abstract":"<div><div>The aryl hydrocarbon receptor (AhR) plays a crucial role in regulating many physiological processes. Activating the AhR–CYP1A1 axis has emerged as a novel therapeutic strategy against various inflammatory diseases. Here, a practical <em>in situ</em> cell-based fluorometric assay was constructed to screen AhR-CYP1A1 axis modulators, <em>via</em> functional sensing of CYP1A1 activities in live cells. Firstly, a cell-permeable, isoform-specific enzyme-activable fluorogenic substrate for CYP1A1 was rationally constructed for <em>in-situ</em> visualizing the dynamic changes of CYP1A1 function in living systems, which was subsequently used for discovering the efficacious modulators of the AhR–CYP1A1 axis. Following screening of a compound library, <strong>LAC-7</strong> was identified as an efficacious activator of the AhR–CYP1A1 axis, which dose-dependently up-regulated the expression levels of both CYP1A1 and AhR in multiple cell lines. <strong>LAC-7</strong> also suppressed macrophage M1 polarization and reduced the levels of inflammatory factors in LPS-induced bone marrow-derived macrophages. Animal tests showed that <strong>LAC-7</strong> could significantly mitigate DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice, and markedly reduced the levels of multiple inflammatory factors. Collectively, an optimized fluorometric cell-based assay was devised for <em>in situ</em> functional imaging of CYP1A1 activities in living systems, which strongly facilitated the discovery of efficacious modulators of the AhR–CYP1A1 axis as novel anti-inflammatory agents.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 508-525"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0