Acta Pharmaceutica Sinica. B最新文献_第9页

Artificial mesenchymal stem cell extracellular vesicles enhanced ischemic stroke treatment through targeted remodeling brain microvascular endothelial cells 人工间充质干细胞细胞外囊泡通过靶向重塑脑微血管内皮细胞增强缺血性卒中治疗

IF 14.6 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-08-01 DOI: 10.1016/j.apsb.2025.06.009

Shengnan Li , Wei Lv , Jiangna Xu , Jiaqing Yin , Yuqin Chen , Linfeng Liu , Xiang Cao , Wenjing Li , Zhen Li , Hua Chen , Hongliang Xin

{"title":"Artificial mesenchymal stem cell extracellular vesicles enhanced ischemic stroke treatment through targeted remodeling brain microvascular endothelial cells","authors":"Shengnan Li , Wei Lv , Jiangna Xu , Jiaqing Yin , Yuqin Chen , Linfeng Liu , Xiang Cao , Wenjing Li , Zhen Li , Hua Chen , Hongliang Xin","doi":"10.1016/j.apsb.2025.06.009","DOIUrl":"10.1016/j.apsb.2025.06.009","url":null,"abstract":"<div><div>Ischemic stroke is the leading cause of disability and mortality worldwide. The blood‒brain barrier (BBB) is the first line of defense after ischemic stroke. Disruption of the BBB induced by brain microvascular endothelial cells (BMECs) dysfunction is a key event that triggers secondary damage to the central nervous system, where blood-borne fluids and immune cells penetrate the brain parenchyma, causing cerebral edema and inflammatory response and further aggravating brain damage. Here, we develop a novel artificial mesenchymal stem cell (MSC) extracellular vesicles by integrating MSC membrane proteins into liposomal bilayers, which encapsulated miR-132-3p with protective effects on BMECs. The artificial extracellular vesicles (MSCo/miR-132-3p) had low immunogenicity to reduce non-specific clearance by the mononuclear phagocytosis system (MPS) and could target ischemia-injured BMECs. After internalization into the damaged BMECs, MSCo/miR-132-3p escaped the lysosomes <em>via</em> the H<sub>II</sub> phase transition of 1,2-dioleoyl<em>-sn-</em>glycero-3-phosphoethanolamine (DOPE) and decreased cellular reactive oxygen species (ROS) and apoptosis levels by regulating the RASA1/RAS/PI3K/AKT signaling pathway. In the transient middle cerebral artery occlusion (tMCAO) models, MSCo/miR-132-3p targeted impaired brain regions (approximately 9 times the accumulation of plain liposomes at 12 h), reduced cerebral vascular disruption, protected BBB integrity, and decreased infarct volume (from 44.95% to 6.99%).</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 8","pages":"Pages 4248-4264"},"PeriodicalIF":14.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144863169","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

HomoPROTACKeap1: A new strategy of chemical knockdown of Keap1 for allergic rhinitis 化学敲低Keap1治疗变应性鼻炎的新策略

IF 14.6 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-08-01 DOI: 10.1016/j.apsb.2025.07.032

Xiaofeng Qi

引用次数: 0

Cover Story 封面故事

IF 14.6 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-08-01 DOI: 10.1016/S2211-3835(25)00471-X

引用次数: 0

From S-nitrosation targets to drugs: A potential new paradigm in disease treatment 从s -亚硝化靶点到药物：疾病治疗的潜在新范式

IF 14.6 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-08-01 DOI: 10.1016/j.apsb.2025.05.035

Hui Ye , Jianbing Wu , Chen Zhang , Duorui Ji , Yihua Zhang , Zhangjian Huang

引用次数: 0

IMM-H007 promotes hepatic cholesterol and triglyceride metabolism by activating AMPKα to attenuate hypercholesterolemia IMM-H007通过激活AMPKα减轻高胆固醇血症，促进肝脏胆固醇和甘油三酯代谢

IF 14.6 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-08-01 DOI: 10.1016/j.apsb.2025.05.015

Jiaqi Li , Mingchao Wang , Kai Qu , Yuyao Sun , Zequn Yin , Na Dong , Xin Sun , Yitong Xu , Liang Chen , Shuang Zhang , Xunde Xian , Suowen Xu , Likun Ma , Yajun Duan , Haibo Zhu

{"title":"IMM-H007 promotes hepatic cholesterol and triglyceride metabolism by activating AMPKα to attenuate hypercholesterolemia","authors":"Jiaqi Li , Mingchao Wang , Kai Qu , Yuyao Sun , Zequn Yin , Na Dong , Xin Sun , Yitong Xu , Liang Chen , Shuang Zhang , Xunde Xian , Suowen Xu , Likun Ma , Yajun Duan , Haibo Zhu","doi":"10.1016/j.apsb.2025.05.015","DOIUrl":"10.1016/j.apsb.2025.05.015","url":null,"abstract":"<div><div>Hypercholesterolemia is a significant risk factor for the development of atherosclerosis. 2′,3′,5′-Tri-<em>O</em>-acetyl-<em>N</em><sup>6</sup>-(3-hydroxyphenyl) adenosine (IMM-H007), a novel AMPK agonist, has shown protective effects in metabolic diseases. However, its impact on cholesterol and triglyceride metabolism in hypercholesterolemia remains unclear. In this study, we aimed to elucidate the effects and specific mechanisms by which IMM-H007 regulates cholesterol and triglyceride metabolism. To achieve this goal, we used <em>Apoe</em><sup>−/−</sup> and <em>Ldlr</em><sup>−/−</sup> mice to establish a hypercholesterolemia/atherosclerosis model. Additionally, hepatocyte-specific <em>Ampka</em>1/2 knockout mice were subjected to a 5-week high-cholesterol diet to establish hypercholesterolemia, while atherosclerosis was induced <em>via</em> AAV-<em>PCSK9</em> injection combined with a 16-week high-cholesterol diet. Our results demonstrated that IMM-H007 improved cholesterol and triglyceride metabolism in mice with hypercholesterolemia. Mechanistically, IMM-H007 modulated the AMPK<em>α</em>1/2–LDLR signaling pathway, increasing cholesterol uptake in the liver. Furthermore, IMM-H007 activated the AMPK<em>α</em>1–FXR pathway, promoting the conversion of hepatic cholesterol to bile acids. Additionally, IMM-H007 prevented hepatic steatosis by activating the AMPK<em>α</em>1/2–ATGL pathway. In conclusion, our study suggests that IMM-H007 is a promising therapeutic agent for improving hypercholesterolemia and atherosclerosis through the activation of AMPK<em>α</em>.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 8","pages":"Pages 4047-4063"},"PeriodicalIF":14.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144863808","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

Bioisosterism-driven design of orally active, safe, and broad-spectrum biphenyl-DAPY derivatives as highly potent HIV-1 non-nucleoside reverse transcriptase inhibitors 口服活性、安全、广谱联苯- dapy衍生物作为高效HIV-1非核苷类逆转录酶抑制剂的生物等构驱动设计

IF 14.6 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-08-01 DOI: 10.1016/j.apsb.2025.06.016

Xiao-Mei Chen , Qing-Qing Hao , Christophe Pannecouque , Erik De Clercq , Shuai Wang , Fen-Er Chen

{"title":"Bioisosterism-driven design of orally active, safe, and broad-spectrum biphenyl-DAPY derivatives as highly potent HIV-1 non-nucleoside reverse transcriptase inhibitors","authors":"Xiao-Mei Chen , Qing-Qing Hao , Christophe Pannecouque , Erik De Clercq , Shuai Wang , Fen-Er Chen","doi":"10.1016/j.apsb.2025.06.016","DOIUrl":"10.1016/j.apsb.2025.06.016","url":null,"abstract":"<div><div>This study aimed to identify ideal pharmaceutical candidates featuring strong anti-HIV-1 activity and desirable drug-like characteristics. Our endeavor involved the implementation of a bioisosterism strategy, leading to the discovery of an assemblage of halogen-containing biphenyl-diarylpyrimidines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors. Notably, compound <strong>A12</strong> demonstrated exceptional efficacy against both WT HIV-1 (EC<sub>50</sub> = 1.9 nmol/L) and seven mutant strains (EC<sub>50</sub> = 1.7–157 nmol/L), surpassing that of the lead compound <strong>6</strong> and comparable to etravirine. Furthermore, this analog exhibited minimal adverse effects with significantly reduced cytotoxicity (CC<sub>50</sub> = 195 μmol/L) and a high selectivity index (SI = 102,608), superior to those of etravirine (CC<sub>50</sub> > 4.6 μmol/L, SI > 1436) and rilpivirine (CC<sub>50</sub> = 3.98 μmol/L, SI = 3989). It displayed low inhibition of CYP (IC<sub>50</sub> = 6.99–25 μmol/L) and hERG (IC<sub>50</sub> > 40 μmol/L), indicating a safer profile compared to etravirine and rilpivirine. No acute toxicity or organ pathological damage was observed at a single dose of 2 g/kg. Additionally, <strong>A12</strong> exhibited favorable oral bioavailability (<em>F</em> = 29.2%) and an extended elimination half-life (<em>T</em><sub>1/2</sub> = 13.56 h), enabling convenient oral administration at minimal doses. These findings indicated that <strong>A12</strong> could serve as a promising drug candidate for HIV treatment.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 8","pages":"Pages 4115-4136"},"PeriodicalIF":14.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144863243","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

FtsZ as a novel target for antibiotics development: Promises and challenges FtsZ作为抗生素开发的新靶点：前景与挑战

IF 14.6 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-08-01 DOI: 10.1016/j.apsb.2025.06.008

Ming-Wei Wang , Kaini Hang , Wei Han , Xin Li , Qingtong Zhou , Dehua Yang

{"title":"FtsZ as a novel target for antibiotics development: Promises and challenges","authors":"Ming-Wei Wang , Kaini Hang , Wei Han , Xin Li , Qingtong Zhou , Dehua Yang","doi":"10.1016/j.apsb.2025.06.008","DOIUrl":"10.1016/j.apsb.2025.06.008","url":null,"abstract":"<div><div>Filamenting temperature-sensitive mutant Z (FtsZ), a protein essential for bacterial cell division, is highly conserved across bacterial species but absent in humans, positioning it as a strategic target for the development of antibiotics. Significant efforts to identify FtsZ inhibitors—<em>via</em> biochemical assays (<em>e.g.</em>, GTPase activity) and cellular approaches (<em>e.g.</em>, immunofluorescence)—have yielded over 100 natural products and synthetic compounds, whose cheminformatics clustering underscores a limited chemical diversity among the current scaffolds. Structural studies, including X-ray crystallography and cryo-electron microscopy, have resolved 97 FtsZ structures revealing conserved polymerization mechanisms and conformational plasticity, as exemplified by extremophile adaptations (<em>e.g.</em>, <em>Shewanella benthica</em> from the high-pressure environment of the Mariana Trench's Challenger Deep). However, clinical translation is hindered by weak binding affinities, inhibitory inefficacy, dynamic conformational flexibility, and evolving drug resistance linked to FtsZ's functional plasticity. To address these challenges, future efforts should be directed to resolve transient assembly intermediates, leveraging machine learning with high-throughput screening, and integrating structural biology with pharmacokinetic optimization. Multidisciplinary strategies combining these approaches hold promise for translating FtsZ-focused research into clinically viable therapies, addressing the critical unmet need posed by antibiotics resistance.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 8","pages":"Pages 3978-3996"},"PeriodicalIF":14.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144863337","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

Augmentation of PRDX1–DOK3 interaction alleviates rheumatoid arthritis progression by suppressing plasma cell differentiation PRDX1-DOK3相互作用的增强通过抑制浆细胞分化来缓解类风湿关节炎的进展

IF 14.6 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-08-01 DOI: 10.1016/j.apsb.2025.06.006

Wenzhen Dang , Xiaomin Wang , Huaying Li , Yixuan Xu , Xinyu Li , Siqi Huang , Hongru Tao , Xiao Li , Yulin Yang , Lijiang Xuan , Weilie Xiao , Dean Guo , Hao Zhang , Qiong Wu , Jie Zheng , Xiaoyan Shen , Kaixian Chen , Heng Xu , Yuanyuan Zhang , Cheng Luo

{"title":"Augmentation of PRDX1–DOK3 interaction alleviates rheumatoid arthritis progression by suppressing plasma cell differentiation","authors":"Wenzhen Dang , Xiaomin Wang , Huaying Li , Yixuan Xu , Xinyu Li , Siqi Huang , Hongru Tao , Xiao Li , Yulin Yang , Lijiang Xuan , Weilie Xiao , Dean Guo , Hao Zhang , Qiong Wu , Jie Zheng , Xiaoyan Shen , Kaixian Chen , Heng Xu , Yuanyuan Zhang , Cheng Luo","doi":"10.1016/j.apsb.2025.06.006","DOIUrl":"10.1016/j.apsb.2025.06.006","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation and joint damage, accompanied by the accumulation of plasma cells, which contributes to its pathogenesis. Understanding the genetic alterations occurring during plasma cell differentiation in RA can deepen our comprehension of its pathogenesis and guide the development of targeted therapeutic interventions. Here, our study elucidates the intricate molecular mechanisms underlying plasma cell differentiation by demonstrating that PRDX1 interacts with DOK3 and modulates its degradation by the autophagy–lysosome pathway. This interaction results in the inhibition of plasma cell differentiation, thereby alleviating the progression of collagen-induced arthritis. Additionally, our investigation identifies Salvianolic acid B (SAB) as a potent small molecular glue-like compound that enhances the interaction between PRDX1 and DOK3, consequently impeding the progression of collagen-induced arthritis by inhibiting plasma cell differentiation. Collectively, these findings underscore the therapeutic potential of developing chemical stabilizers for the PRDX1–DOK3 complex in suppressing plasma cell differentiation for RA treatment and establish a theoretical basis for targeting PRDX1-protein interactions as specific therapeutic targets in various diseases.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 8","pages":"Pages 3997-4013"},"PeriodicalIF":14.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144863338","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

Resistance mutations and the blood–brain barrier: Key challenges in targeted treatment of brain metastatic non-small cell lung cancer 耐药突变和血脑屏障：脑转移性非小细胞肺癌靶向治疗的关键挑战

IF 14.6 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-08-01 DOI: 10.1016/j.apsb.2025.06.002

Jamie Rijmers , Maria C. Lebre , Jos H. Beijnen , Alfred H. Schinkel

{"title":"Resistance mutations and the blood–brain barrier: Key challenges in targeted treatment of brain metastatic non-small cell lung cancer","authors":"Jamie Rijmers , Maria C. Lebre , Jos H. Beijnen , Alfred H. Schinkel","doi":"10.1016/j.apsb.2025.06.002","DOIUrl":"10.1016/j.apsb.2025.06.002","url":null,"abstract":"<div><div>Over the past two decades, marked progress has been made in treating non-small cell lung cancer (NSCLC) patients with EGFR-, ALK-, ROS1- and KRAS<sup>G12C</sup>-targeted inhibitors. NSCLC patients very often develop brain metastases. Despite the continuous development of newer and better inhibitors, the survival outcomes of NSCLC patients with brain metastases remain significantly worse than those of patients without. The main challenges in these pharmacotherapies are the development of resistance mutations, and, potentially, the presence of the blood–brain barrier (BBB). The outcomes of clinical studies show the improved efficacy of later-generation targeted inhibitors. The increase in progression free survival (PFS) in patients treated with these later-generation inhibitors is largely attributed to their efficacy against multiple resistance mutations, and possibly due to enhanced brain penetration. This review explores the different aspects hindering the targeted treatment of NSCLC and especially of brain metastases, focusing on recent clinical trials and emerging resistance mutations and the influence of the BBB on the efficacy of EGFR, ALK, ROS1 and KRAS<sup>G12C</sup> inhibitors. The role of the ABCB1 and ABCG2 drug transporters in differential efflux of the targeted drugs at the BBB is also discussed, since preclinical studies indicate that they may reduce the efficacy of transported inhibitors.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 8","pages":"Pages 3833-3851"},"PeriodicalIF":14.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144863332","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

A5—A dual-target antiviral compound that rewrites the rules of influenza therapy a5 -一种改写流感治疗规则的双靶点抗病毒化合物

IF 14.6 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-08-01 DOI: 10.1016/j.apsb.2025.07.033

Shibo Jiang

引用次数: 0