Acta Pharmaceutica Sinica. B最新文献_第2页

Phenotypic plasticity and secretory heterogeneity in subpopulations derived from single cancer cell

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-05-01 DOI: 10.1016/j.apsb.2025.02.039

Zhun Lin , Siping Liang , Zhe Pu , Zhengyu Zou , Luxuan He , Christopher J. Lyon , Yuanqing Zhang , Tony Y. Hu , Minhao Wu

{"title":"Phenotypic plasticity and secretory heterogeneity in subpopulations derived from single cancer cell","authors":"Zhun Lin , Siping Liang , Zhe Pu , Zhengyu Zou , Luxuan He , Christopher J. Lyon , Yuanqing Zhang , Tony Y. Hu , Minhao Wu","doi":"10.1016/j.apsb.2025.02.039","DOIUrl":"10.1016/j.apsb.2025.02.039","url":null,"abstract":"<div><div>Single-cell analysis of phenotypic plasticity could improve the development of more effective therapeutics. Still, the development of tools to measure single-cell heterogeneity has lagged due to difficulties in manipulating and culturing single cells. Here, we describe a single-cell culture and phenotyping platform that employs a starburst microfluidic network and automatic liquid handling system to capture single cells for long-term culture and multi-dimensional analysis and quantify their clonal properties <em>via</em> their surface biomarker and secreted cytokine/growth factor profiles. Studies performed on this platform found that cells derived from single-cell cultures maintained phenotypic equilibria similar to their parental populations. Single-cell cultures exposed to chemotherapeutic drugs stochastically disrupted this balance to favor stem-like cells. They had enhanced expression of mRNAs and secreted factors associated with cell signaling, survival, and differentiation. This single-cell analysis approach can be extended to analyze more complex phenotypes and screen responses to therapeutic targets.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 5","pages":"Pages 2723-2735"},"PeriodicalIF":14.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CDH17-targeting CAR-NK cells synergize with CD47 blockade for potent suppression of gastrointestinal cancers

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-05-01 DOI: 10.1016/j.apsb.2025.03.039

Liuhai Zheng , Youbing Ding , Xiaolong Xu , Huifang Wang , Guangwei Shi , Yang Li , Yuanqiao He , Yue Gong , Xiaodong Zhang , Jinxi Wei , Zhiyu Dong , Jiexuan Li , Shanchao Zhao , Rui Hou , Wei Zhang , Jigang Wang , Zhijie Li

{"title":"CDH17-targeting CAR-NK cells synergize with CD47 blockade for potent suppression of gastrointestinal cancers","authors":"Liuhai Zheng , Youbing Ding , Xiaolong Xu , Huifang Wang , Guangwei Shi , Yang Li , Yuanqiao He , Yue Gong , Xiaodong Zhang , Jinxi Wei , Zhiyu Dong , Jiexuan Li , Shanchao Zhao , Rui Hou , Wei Zhang , Jigang Wang , Zhijie Li","doi":"10.1016/j.apsb.2025.03.039","DOIUrl":"10.1016/j.apsb.2025.03.039","url":null,"abstract":"<div><div>Gastrointestinal (GI) cancers are a leading cause of cancer morbidity and mortality worldwide. Despite advances in treatment, cancer relapse remains a significant challenge, necessitating novel therapeutic strategies. In this study, we engineered nanobody-based chimeric antigen receptor (CAR) natural killer (NK) cells targeting cadherin 17 (CDH17) for the treatment of GI tumors. In addition, to enhance the efficacy of CAR-NK cells, we also incorporated CV1, a CD47–SIRP<em>α</em> axis inhibitor, to evaluate the anti-tumor effect of this combination. We found that CDH17-CAR-NK cells effectively eliminated GI cancers cells in a CDH17-dependent manner. CDH17-CAR-NK cells also exhibit potent <em>in vivo</em> anti-tumor effects in cancer cell-derived xenograft and patient-derived xenograft mouse models. Additionally, the anti-tumor activity of CDH17-CAR-NK cells is synergistically enhanced by CD47–signal regulatory protein <em>α</em> (SIRP<em>α</em>) axis inhibitor CV1, likely through augmented macrophages activation and an increase in M1-phenotype macrophages in the tumor microenvironment. Collectively, our findings suggest that CDH17-targeting CAR-NK cells are a promising strategy for GI cancers. The combination of CDH17-CAR-NK cells with CV1 emerges as a potential combinatorial approach to overcome the limitations of CAR-NK therapy. Further investigations are warranted to speed up the clinical translation of these findings.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 5","pages":"Pages 2559-2574"},"PeriodicalIF":14.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhaled non-viral delivery systems for RNA therapeutics

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-05-01 DOI: 10.1016/j.apsb.2025.03.033

Cheng Huang , Hongjian Li , Xing Duan , Peidong Zhang , Shaolong Qi , Jianshi Du , Xiangrong Song , Aiping Tong , Guocan Yu

{"title":"Inhaled non-viral delivery systems for RNA therapeutics","authors":"Cheng Huang , Hongjian Li , Xing Duan , Peidong Zhang , Shaolong Qi , Jianshi Du , Xiangrong Song , Aiping Tong , Guocan Yu","doi":"10.1016/j.apsb.2025.03.033","DOIUrl":"10.1016/j.apsb.2025.03.033","url":null,"abstract":"<div><div>RNA-based gene therapy has been widely used for various diseases, and extensive studies have proved that suitable delivery routes greatly help the development of RNA therapeutics. Identifying a safe and effective delivery system is key to realizing RNA therapeutics’ clinical translation. Inhalation is a non-invasive pulmonary delivery modality that can enhance the retention of therapeutic agents in the lungs with negligible toxicity, thereby improving patient compliance. Inhaled RNA therapeutics are increasingly becoming an area of focus for researchers; however, only several clinical trials have explored inhaled delivery of RNA for pulmonary diseases. This review presents an overview of recent advances in inhaled delivery systems for RNA therapeutics, including viral and nonviral systems, highlighting state of the art regarding inhalation in the messenger RNA (mRNA) field. We also summarize the applications of mRNA inhalants in infectious and other lung diseases. Simultaneously, the research progresses on small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), and different types of RNA are also discussed to provide new strategies for developing RNA inhalation therapy. Finally, we clarify the challenges inhaled RNA-based therapeutics face before their widespread adoption and provide insights to help advance this exciting field to the bedside.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 5","pages":"Pages 2402-2430"},"PeriodicalIF":14.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Editorial of virtual special issue: The development of antiviral drug discovery

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-05-01 DOI: 10.1016/j.apsb.2025.03.013

Shaoqing Du , Xueping Hu , Xinyong Liu , Peng Zhan

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Structural insights into the binding modes of lanreotide and pasireotide with somatostatin receptor 1

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-05-01 DOI: 10.1016/j.apsb.2025.03.043

Zicheng Zeng , Qiwen Liao , Shiyi Gan , Xinyu Li , Tiantian Xiong , Lezhi Xu , Dan Li , Yunlu Jiang , Jing Chen , Richard Ye , Yang Du , Thiansze Wong

{"title":"Structural insights into the binding modes of lanreotide and pasireotide with somatostatin receptor 1","authors":"Zicheng Zeng , Qiwen Liao , Shiyi Gan , Xinyu Li , Tiantian Xiong , Lezhi Xu , Dan Li , Yunlu Jiang , Jing Chen , Richard Ye , Yang Du , Thiansze Wong","doi":"10.1016/j.apsb.2025.03.043","DOIUrl":"10.1016/j.apsb.2025.03.043","url":null,"abstract":"<div><div>Somatostatin receptor 1 (SSTR1) is a crucial therapeutic target for various neuroendocrine and oncological disorders. Current SSTR1-targeted treatments, including the first-generation somatostatin analog lanreotide (Lan) and the second-generation analog pasireotide (Pas), show promise but encounter challenges related to selectivity and efficacy. This study presents high-resolution cryo-electron microscopy structures of SSTR1 complexed with Lan or Pas, revealing the distinct mechanisms of ligand-binding and activation. These structures illustrate unique conformational changes in the SSTR1 orthosteric pocket induced by each ligand, which are critical for receptor activation and ligand selectivity. Combined with the biochemical assays and molecular dynamics simulations, our results provide a comparative analysis of binding characteristics within the SSTR family, highlighting subtle differences in SSTR1 activation by Lan and Pas. These insights pave the way for designing next-generation therapies with enhanced efficacy and reduced side effects through improved receptor subtype selectivity.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 5","pages":"Pages 2468-2479"},"PeriodicalIF":14.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Author correction to “Sphingosine-1-phosphate, a novel TREM2 ligand, promotes microglial phagocytosis to protect against ischemic brain injury” [Acta Pharm Sin B 12 (2022) 1885–1898] 作者更正“鞘氨醇-1-磷酸，一种新的TREM2配体，促进小胶质细胞吞噬以保护缺血性脑损伤”[Acta Pharm Sin B 12 (2022) 1885-1898]

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-05-01 DOI: 10.1016/j.apsb.2025.02.032

Tengfei Xue , Juan Ji , Yuqin Sun , Xinxin Huang , Zhenyu Cai , Jin Yang , Wei Guo , Ruobing Guo , Hong Cheng , Xiulan Sun

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Cover Story

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-05-01 DOI: 10.1016/S2211-3835(25)00262-X

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NAT10 inhibition alleviates astrocyte autophagy by impeding ac4C acetylation of Timp1 mRNA in ischemic stroke

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-05-01 DOI: 10.1016/j.apsb.2025.03.042

Li Yang , Xiaotong Li , Yaxuan Zhao , Hao Chen , Can Wang , Angrong Wu , Xintong Guo , Yue Huang , Qihui Wang , Lingyun Hao , Xiaowen Li , Ying Ji , Jin Ban , Guangtian Wang , Junli Cao , Zhiqiang Pan

{"title":"NAT10 inhibition alleviates astrocyte autophagy by impeding ac4C acetylation of Timp1 mRNA in ischemic stroke","authors":"Li Yang , Xiaotong Li , Yaxuan Zhao , Hao Chen , Can Wang , Angrong Wu , Xintong Guo , Yue Huang , Qihui Wang , Lingyun Hao , Xiaowen Li , Ying Ji , Jin Ban , Guangtian Wang , Junli Cao , Zhiqiang Pan","doi":"10.1016/j.apsb.2025.03.042","DOIUrl":"10.1016/j.apsb.2025.03.042","url":null,"abstract":"<div><div>Although a single nucleotide polymorphism for <em>N</em>-acetyltransferase 10 (NAT10) has been identified in patients with early-onset stroke, the role of NAT10 in ischemic injury and the related underlying mechanisms remains elusive. Here, we provide evidence that NAT10, the only known RNA <em>N</em>4-acetylcytidine (ac4C) modification “writer”, is increased in the damaged cortex of patients with acute ischemic stroke and the peri-infarct cortex of mice subjected to photothrombotic (PT) stroke. Pharmacological inhibition of NAT10 with remodelin on Days 3–7 post-stroke or astrocytic depletion of NAT10 <em>via</em> targeted virus attenuates ischemia-induced infarction and improves functional recovery in PT mice. Mechanistically, NAT10 enhances ac4C acetylation of the inflammatory cytokine tissue inhibitor of metalloproteinase 1 (<em>Timp1</em>) mRNA transcript, which increases TIMP1 expression and results in the accumulation of microtubule-associated protein 1 light chain 3 (LC3) and progression of astrocyte autophagy. These findings demonstrate that NAT10 regulates astrocyte autophagy by targeting <em>Timp1</em> ac4C after stroke. This study highlights the critical role of ac4C in the regulation of astrocyte autophagy and proposes a promising strategy to improve post-stroke outcomes <em>via</em> NAT10 inhibition.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 5","pages":"Pages 2575-2592"},"PeriodicalIF":14.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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SMAD4 depletion enhances NHEJ by regulating BRCA1 expression through ARIH1 in pancreatic cancer

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-05-01 DOI: 10.1016/j.apsb.2025.03.035

Yiran Song , Yazhi He , Tianyu Yu , Yang Wang , Liwei An , Yang Shi , Yingqun Zhou , Junyi Ju , Feng Wang

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First ATG101-recruiting small molecule degrader for selective CDK9 degradation via autophagy–lysosome pathway

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-05-01 DOI: 10.1016/j.apsb.2025.03.047

Ye Zhong , Jing Xu , Huiying Cao , Jie Gao , Shaoyue Ding , Zhaohui Ren , Huali Yang , Yili Sun , Maosheng Cheng , Jia Li , Yang Liu

{"title":"First ATG101-recruiting small molecule degrader for selective CDK9 degradation via autophagy–lysosome pathway","authors":"Ye Zhong , Jing Xu , Huiying Cao , Jie Gao , Shaoyue Ding , Zhaohui Ren , Huali Yang , Yili Sun , Maosheng Cheng , Jia Li , Yang Liu","doi":"10.1016/j.apsb.2025.03.047","DOIUrl":"10.1016/j.apsb.2025.03.047","url":null,"abstract":"<div><div>Cyclin-dependent kinase 9 (CDK9) is a member of the transcription CDK subfamily and plays a role in transcriptional regulation. Selective CDK9 degraders possess potent clinical advantages over reversible CDK9 inhibitors. Herein, we report the first ATG101-recruiting selective CDK9 degrader, <strong>AZ-9</strong>, based on the hydrophobic tag kinesin degradation technology. <strong>AZ-9</strong> showed significant degradation effects and selectivity toward other homologous cell cycle CDKs <em>in vitro</em> and <em>in vivo</em>, which could also affect downstream related phenotypes. Mechanism research revealed that <strong>AZ-9</strong> recruits ATG101 to initiate the autophagy–lysosome pathway, and forms autophagosomes through the recruitment of LC3, which then fuses with lysosomes to degrade CDK9 and the partner protein Cyclin T1. These dates validated the existence of non-proteasomal degradation pathway of hydrophobic driven protein degradation strategy for the first time, which might provide research ideas for chemical induction intervention on other types of pathogenic proteins.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 5","pages":"Pages 2612-2624"},"PeriodicalIF":14.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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