Acta Pharmaceutica Sinica. B最新文献

Modeling on in vivo disposition and cellular transportation of RNA lipid nanoparticles via quantum mechanics/physiologically-based pharmacokinetic approaches 通过量子力学/生理学药代动力学方法建立 RNA 脂质纳米粒子体内处置和细胞运输模型

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.06.011

Wei Wang , Shiwei Deng , Jinzhong Lin , Defang Ouyang

{"title":"Modeling on in vivo disposition and cellular transportation of RNA lipid nanoparticles via quantum mechanics/physiologically-based pharmacokinetic approaches","authors":"Wei Wang , Shiwei Deng , Jinzhong Lin , Defang Ouyang","doi":"10.1016/j.apsb.2024.06.011","DOIUrl":"10.1016/j.apsb.2024.06.011","url":null,"abstract":"<div><div>The lipid nanoparticle (LNP) has been so far proven as a strongly effective delivery system for mRNA and siRNA. However, the mechanisms of LNP's distribution, metabolism, and elimination are complicated, while the transportation and pharmacokinetics (PK) of LNP are just sparsely investigated and simply described. This study aimed to build a model for the transportation of RNA-LNP in Hela cells, rats, mice, and humans by physiologically based pharmacokinetic (PBPK) and quantum mechanics (QM) models with integrated multi-source data. LNPs with different ionizable lipids, particle sizes, and doses were modeled and compared by recognizing their critical parameters dominating PK. Some interesting results were found by the models. For example, the metabolism of ionizable lipids was first limited by the LNP disassembly rate instead of the hydrolyzation of ionizable lipids; the ability of RNA release from endosomes for three ionizable lipids was quantitively derived and can predict the probability of RNA release. Moreover, the biodegradability of three ionizable lipids was estimated by the QM method and the is generally consistent with the result of PBPK result. In summary, the transportation model of RNA LNP among various species for the first time was successfully constructed. Various <em>in vitro</em> and <em>in vivo</em> pieces of evidence were integrated through QM/PBPK multi-level modeling. The resulting new understandings are related to biodegradability, safety, and RNA release ability which are highly concerned issues of the formulation. This would benefit the design and research of RNA-LNP in the future.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4591-4607"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141775590","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

Engineering the microenvironment of P450s to enhance the production of diterpenoids in Saccharomyces cerevisiae 改造 P450s 的微环境以提高酿酒酵母中二萜类化合物的产量

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.05.019

引用次数: 0

Inhibition of liver cholesterol synthesis by a diet-induced gut hormone 饮食诱导的肠道激素抑制肝脏胆固醇合成

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.07.026

Xiabing Huang , Jianping Ye

引用次数: 0

ROS-degradable polythioketal urethane scaffold for porcine wound repair 用于猪伤口修复的 ROS 可降解聚硫酮聚氨酯支架

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.05.034

引用次数: 0

Ribonucleotide reductase small subunit M2 promotes the proliferation of esophageal squamous cell carcinoma cells via HuR-mediated mRNA stabilization 核糖核苷酸还原酶小亚基 M2 通过 HuR 介导的 mRNA 稳定促进食管鳞状细胞癌细胞增殖

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.07.022

Jing Zhang , Qiong Wu , Yifei Xie , Feng Li , Huifang Wei , Yanan Jiang , Yan Qiao , Yinhua Li , Yanan Sun , Han Huang , Mengmeng Ge , Dengyun Zhao , Zigang Dong , Kangdong Liu

{"title":"Ribonucleotide reductase small subunit M2 promotes the proliferation of esophageal squamous cell carcinoma cells via HuR-mediated mRNA stabilization","authors":"Jing Zhang , Qiong Wu , Yifei Xie , Feng Li , Huifang Wei , Yanan Jiang , Yan Qiao , Yinhua Li , Yanan Sun , Han Huang , Mengmeng Ge , Dengyun Zhao , Zigang Dong , Kangdong Liu","doi":"10.1016/j.apsb.2024.07.022","DOIUrl":"10.1016/j.apsb.2024.07.022","url":null,"abstract":"<div><div>Esophageal squamous cell carcinoma (ESCC), a malignancy of the digestive system, is highly prevalent and the primary cause of cancer-related deaths worldwide due to the lack of early diagnostic biomarkers and effective therapeutic targets. Dysregulated ribonucleotide reductase (RNR) expression has been confirmed to be causally linked to tumorigenesis. This study demonstrated that ribonucleotide reductase small subunit M2 (RRM2) is significantly upregulated in ESCC tissue and that its expression is negatively correlated with clinical outcomes. Mechanistically, HuR promotes <em>RRM2</em> mRNA stabilization by binding to the adenine/uridine (AU)-rich elements (AREs) within the 3′UTR, resulting in persistent overexpression of RRM2. Furthermore, bifonazole is identified as an inhibitor of HuR <em>via</em> computational screening and molecular docking analysis. Bifonazole disrupts HuR-ARE interactions by competitively binding to HuR at F65, R97, I103, and R153 residues, resulting in reduced RRM2 expression. Furthermore, bifonazole exhibited antitumor effects on ESCC patient-derived xenograft (PDX) models by decreasing RRM2 expression and the dNTP pool. In summary, this study reveals the interaction network among HuR, RRM2, and bifonazole and demonstrated that bifonazole is a potential therapeutic compound for ESCC through inhibition of the HuR/RRM2 axis.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4329-4344"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141945626","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

Cocrystal@protein-anchoring nanococktail for combinatorially treating multidrug-resistant cancer 用于组合治疗耐多药癌症的 Cocrystal@ 蛋白锚定纳米鸡尾酒

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.08.014

Jiahui Zou , Xuyang Xing , Chao Teng , Qingling Zhao , Wei He , Xuri Wu , Yuanzheng Xia

{"title":"Cocrystal@protein-anchoring nanococktail for combinatorially treating multidrug-resistant cancer","authors":"Jiahui Zou , Xuyang Xing , Chao Teng , Qingling Zhao , Wei He , Xuri Wu , Yuanzheng Xia","doi":"10.1016/j.apsb.2024.08.014","DOIUrl":"10.1016/j.apsb.2024.08.014","url":null,"abstract":"<div><div>Multidrug resistance (MDR), the major mechanism by which various cancers develop specific resistance to therapeutic agents, has set up enormous obstacles to many forms of tumor chemotherapy. Traditional cocktail therapy administration, based on the combination of multiple drugs for anti-MDR chemotherapy, often suffers from inconsistent <em>in vivo</em> pharmacokinetic behaviors that cannot act synchronously on the lesions, leading to limited pharmacodynamic outcomes. Despite the emergence of nanomedicines, which has improved chemotherapeutic drugs’ bioavailability and therapeutic effect on clinical application, these monotherapy-based nano-formulations still show poor progression in overcoming MDR. Herein, a “one stone and three birds” nanococktail integrated by a cocrystal@protein-anchoring strategy was purposed for triple-payload delivery, which paclitaxel-disulfiram cocrystal-like nanorods (NRs) were anchored with the basic protein drug Cytochrome <em>c</em> (Cyt C), followed by hyaluronic-acid modification. In particular, NRs were utilized as carrier-like particles to synchronously deliver biomacromolecule Cyt C into tumor cells and then promote cell apoptosis. Of note, on A549/Taxol drug-resistant tumor-bearing mice, the system with extraordinarily high encapsulation efficiency demonstrated prolonged <em>in vivo</em> circulation and increased tumor-targeting accumulation, significantly reversing tumor drug resistance and improving therapeutic efficacy. Our mechanistic study indicated that the system induced the apoptosis of Taxol-resistant tumor cells through the signal axis P-glycoprotein/Cyt C/caspase 3. Collectively, this nanococktail strategy offers a promising approach to improve the sensitivity of tumor cells to chemotherapeutic drugs and strengthen intractable drug-resistant oncotherapy.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4509-4525"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186908","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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Disease-derived circulating extracellular vesicle preconditioning: A promising strategy for precision mesenchymal stem cell therapy 疾病衍生循环细胞外囊泡预处理：间充质干细胞精准治疗的可行策略

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.06.027

{"title":"Disease-derived circulating extracellular vesicle preconditioning: A promising strategy for precision mesenchymal stem cell therapy","authors":"","doi":"10.1016/j.apsb.2024.06.027","DOIUrl":"10.1016/j.apsb.2024.06.027","url":null,"abstract":"<div><div>Mesenchymal stem cell (MSC)-based therapies have emerged as promising methods for regenerative medicine; however, how to precisely enhance their tissue repair effects is still a major question in the field. Circulating extracellular vesicles (EVs) from diseased states carry diverse pathological information and affect the functions of recipient cells. Based on this unique property, we report that disease-derived circulating EV (disease-EV) preconditioning is a potent strategy for precisely enhancing the tissue repair potency of MSCs in diverse disease models. Briefly, plasma EVs from lung or kidney tissue injuries were shown to contain distinctly enriched molecules and were shown to induce tissue injury-specific gene expression responses in cultured MSCs. Disease-EV preconditioning improved the performance (including proliferation, migration, and growth factor production) of MSCs through metabolic reprogramming (such as <em>via</em> enhanced oxidative phosphorylation and lipid metabolism) without inducing an adverse immune response. Consequently, compared with normal MSCs, disease-EV-preconditioned MSCs exhibited superior tissue repair effects (including anti-inflammatory and antiapoptotic effects) in diverse types of tissue injury (such as acute lung or kidney injury). Disease-derived EVs may serve as a type of “off-the-shelf” product due to multiple advantages, such as flexibility, stability, long-term storage, and ease of shipment and use. This study highlights the idea that disease-EV preconditioning is a robust strategy for precisely enhancing the regenerative capacity of MSC-based therapies.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4526-4543"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141549273","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

Nanotechnology-based tumor metabolic reprogramming: Insights into nutrient-delivery and metabolism reactivation therapy 基于纳米技术的肿瘤代谢重编程：营养输送和新陈代谢再激活疗法的启示

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.07.015

Xi Hu , Daishun Ling

引用次数: 0

Amylovis-201 is a new dual-target ligand, acting as an anti-amyloidogenic compound and a potent agonist of the σ1 chaperone protein Amylovis-201 是一种新型双目标配体，既是一种抗淀粉样蛋白生成化合物，又是σ1伴侣蛋白的强效激动剂

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.06.013

{"title":"Amylovis-201 is a new dual-target ligand, acting as an anti-amyloidogenic compound and a potent agonist of the σ1 chaperone protein","authors":"","doi":"10.1016/j.apsb.2024.06.013","DOIUrl":"10.1016/j.apsb.2024.06.013","url":null,"abstract":"<div><div>The aggregation of Amyloid-<em>β</em> (A<em>β</em>) peptides is associated with neurodegeneration in Alzheimer's disease (AD). We previously identified novel naphtalene derivatives, including the lead compound Amylovis-201, able to form thermodynamically stable complexes with A<em>β</em> species, peptides and fibrils. As the drug showed a chemical scaffold coherent for an effective interaction with the <em>σ</em><sub>1</sub> receptor chaperone and as <em>σ</em><sub>1</sub> agonists are currently developed as potent neuroprotectants in AD, we investigated the pharmacological action of Amylovis-201 on the <em>σ</em><sub>1</sub> receptor. We report that Amylovis-201 is a potent <em>σ</em><sub>1</sub> agonist by several <em>in silico</em>, <em>in vitro</em> and <em>in vivo</em> assays and that its anti-amnesic and neuroprotective effects involve a pharmacological action at <em>σ</em><sub>1</sub> receptors. Furthermore, we show for the first time that classical <em>σ</em><sub>1</sub> receptor agonist (PRE-084), and antagonist (NE-100) are able to interact and disaggregate A<em>β</em><sub>25–35</sub> fibrils. Interestingly, Amylovis-201 was the only compound inhibiting A<em>β</em><sub>25–35</sub> aggregates formation. Our results therefore highlight a dual action of Amylovis-201 as anti-aggregating agent and <em>σ</em><sub>1</sub> receptor agonist that could be highly effective in long-term treatment against neurodegeneration in AD.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4345-4359"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141528648","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

Spatial metabolomics highlights metabolic reprogramming in acute myeloid leukemia mice through creatine pathway 空间代谢组学凸显急性髓性白血病小鼠通过肌酸途径进行的代谢重编程

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.07.004

Yucheng Bao , Jing Qiao , Wenjie Gong , Ruihong Zhang , Yanting Zhou , Yinyin Xie , Yuan Xie , Jiuming He , Tong Yin

{"title":"Spatial metabolomics highlights metabolic reprogramming in acute myeloid leukemia mice through creatine pathway","authors":"Yucheng Bao , Jing Qiao , Wenjie Gong , Ruihong Zhang , Yanting Zhou , Yinyin Xie , Yuan Xie , Jiuming He , Tong Yin","doi":"10.1016/j.apsb.2024.07.004","DOIUrl":"10.1016/j.apsb.2024.07.004","url":null,"abstract":"<div><div>Acute myeloid leukemia (AML) is recognized as an aggressive cancer that is characterized by significant metabolic reprogramming. Here, we applied spatial metabolomics to achieve high-throughput, in situ identification of metabolites within the liver metastases of AML mice. Alterations at metabolite and protein levels were further mapped out and validated by integrating untargeted metabolomics and proteomics. This study showed a downregulation in arginine's contribution to polyamine biosynthesis and urea cycle, coupled with an upregulation of the creatine metabolism. The upregulation of creatine synthetases Gatm and Gamt, as well as the creatine transporter Slc6a8, resulted in a marked accumulation of creatine within tumor foci. This process further enhances oxidative phosphorylation and glycolysis of leukemia cells, thereby boosting ATP production to foster proliferation and infiltration. Importantly, we discovered that inhibiting Slc6a8 can counter these detrimental effects, offering a new strategy for treating AML by targeting metabolic pathways.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4461-4477"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141615087","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