Acta Pharmaceutica Sinica. B最新文献

英文中文

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 Q1 PHARMACOLOGY & PHARMACY

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

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 in vitro and in vivo 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.

迄今为止，脂质纳米粒子（LNP）已被证明是一种非常有效的 mRNA 和 siRNA 运送系统。然而，LNP 的分布、代谢和消除机制十分复杂，而对其运输和药代动力学（PK）的研究和描述却很少。本研究旨在通过基于生理学的药代动力学（PBPK）和量子力学（QM）模型，整合多源数据，建立RNA-LNP在Hela细胞、大鼠、小鼠和人体内的转运模型。通过识别主导 PK 的关键参数，对不同可电离脂质、粒度和剂量的 LNPs 进行了建模和比较。模型得出了一些有趣的结果。例如，可电离脂质的代谢首先受限于LNP的分解率，而不是可电离脂质的水解率；对三种可电离脂质从内体释放RNA的能力进行了定量推导，并可预测RNA释放的概率。此外，用QM方法估算了三种可电离脂质的生物降解能力，结果与PBPK结果基本一致。综上所述，该研究首次成功构建了 RNA LNP 在不同物种间的运输模型。通过 QM/PBPK 多层次建模，整合了各种证据。由此产生的新认识涉及生物降解性、安全性和 RNA 释放能力等制剂中备受关注的问题。这将有利于未来 RNA-LNP 的设计和研究。

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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 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.05.019

Cytochrome P450 enzymes play a crucial role as catalysts in the biosynthesis of numerous plant natural products (PNPs). Enhancing the catalytic activity of P450s in host microorganisms is essential for the efficient production of PNPs through synthetic biology. In this study, we engineered Saccharomyces cerevisiae to optimize the microenvironment for boosting the activities of P450s, including coexpression with the redox partner genes, enhancing NADPH supply, expanding the endoplasmic reticulum (ER), strengthening heme biosynthesis, and regulating iron uptake. This created a platform for the efficient production 11,20-dihydroxyferruginol, a key intermediate of the bioactive compound tanshinones. The yield was enhanced by 42.1-fold through 24 effective genetic edits. The optimized strain produced up to 67.69 ± 1.33 mg/L 11,20-dihydroxyferruginol in shake flasks. Our work represents a promising advancement toward constructing yeast cell factories containing P450s and paves the way for microbial biosynthesis of tanshinones in the future.

细胞色素 P450 酶作为催化剂在多种植物天然产物（PNPs）的生物合成过程中发挥着至关重要的作用。提高 P450s 在宿主微生物中的催化活性对于通过合成生物学方法高效生产 PNPs 至关重要。在这项研究中，我们改造了酿酒酵母，以优化提高 P450s 活性的微环境，包括与氧化还原伙伴基因共表达、增强 NADPH 供应、扩大内质网（ER）、加强血红素生物合成以及调节铁吸收。这为高效生产 11,20-二羟基铁杉醇（一种生物活性化合物丹参酮的关键中间体）创造了一个平台。通过 24 次有效的基因编辑，产量提高了 42.1 倍。优化后的菌株在摇瓶中可产生高达 67.69 ± 1.33 mg/L 的 11,20-二羟基铁杉醇。我们的工作代表了在构建含有 P450 的酵母细胞工厂方面取得的可喜进展，并为未来丹参酮的微生物生物合成铺平了道路。

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 Q1 PHARMACOLOGY & PHARMACY

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 Q1 PHARMACOLOGY & PHARMACY

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 Q1 PHARMACOLOGY & PHARMACY

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

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 RRM2 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 via 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.

食管鳞状细胞癌（ESCC）是一种消化系统恶性肿瘤，由于缺乏早期诊断生物标志物和有效的治疗靶点，其发病率很高，是全球癌症相关死亡的主要原因。核糖核苷酸还原酶（RNR）表达失调已被证实与肿瘤发生有因果关系。本研究表明，核糖核苷酸还原酶小亚基M2（RRM2）在ESCC组织中显著上调，其表达与临床预后呈负相关。从机理上讲，HuR通过与3′UTR内富含腺嘌呤/尿苷元素（AU）结合促进mRNA稳定，从而导致RRM2持续过表达。此外，通过计算筛选和分子对接分析，确定联苯苄唑是 HuR 的抑制剂。联苯苄唑通过在 F65、R97、I103 和 R153 残基与 HuR 竞争性结合，破坏了 HuR 与ARE 的相互作用，导致 RRM2 表达量减少。此外，联苯苄唑通过降低 RRM2 的表达和 dNTP 池，对 ESCC 患者衍生异种移植（PDX）模型产生抗肿瘤作用。总之，本研究揭示了 HuR、RRM2 和联苯苄唑之间的相互作用网络，并证明联苯苄唑是一种通过抑制 HuR/RRM2 轴治疗 ESCC 的潜在化合物。

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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 Q1 PHARMACOLOGY & PHARMACY

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

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 in vivo 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 c (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 in vivo 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.

多药耐药性（MDR）是各种癌症对治疗药物产生特异性耐药性的主要机制，它给多种形式的肿瘤化疗设置了巨大障碍。传统的鸡尾酒疗法是在多种药物联合作用的基础上进行抗 MDR 化疗，但往往存在药代动力学行为不一致的问题，无法同步作用于病灶，导致药效学效果有限。尽管纳米药物的出现提高了化疗药物在临床应用中的生物利用度和治疗效果，但这些基于单药治疗的纳米制剂在克服 MDR 方面仍然进展缓慢。本研究采用 "一石三鸟 "的纳米鸡尾酒法，将紫杉醇-双硫仑共晶纳米棒（NRs）与基础蛋白药物细胞色素（Cyt C）锚定，然后进行透明质酸修饰，从而实现三重载药。特别是，NRs 被用作类似载体的颗粒，将生物大分子 Cyt C 同步递送到肿瘤细胞中，然后促进细胞凋亡。值得注意的是，在 A549/Taxol 耐药肿瘤小鼠身上，这种具有超高封装效率的系统表现出了延长循环时间和增加肿瘤靶向积累的特性，显著逆转了肿瘤耐药性并提高了疗效。我们的机理研究表明，该系统通过 P-glycoprotein/Cyt C/caspase 3 信号轴诱导抗 Taxol 的肿瘤细胞凋亡。总之，这种纳米鸡尾酒策略为提高肿瘤细胞对化疗药物的敏感性和加强棘手的耐药性肿瘤治疗提供了一种前景广阔的方法。

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引用次数: 0

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 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.06.027

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 via 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.

基于间充质干细胞（MSC）的疗法已成为前景广阔的再生医学方法；然而，如何精确增强其组织修复效果仍是该领域的一个重大问题。来自疾病状态的循环细胞外囊泡（EVs）携带多种病理信息，并影响受体细胞的功能。基于这种独特的特性，我们报告说，疾病衍生循环EV（disease-EV）预处理是一种有效的策略，可精确增强间充质干细胞在不同疾病模型中的组织修复能力。简而言之，来自肺或肾组织损伤的血浆 EV 含有独特的富集分子，并能在培养的间充质干细胞中诱导组织损伤特异性基因表达反应。疾病-EV预处理通过代谢重编程（如增强氧化磷酸化和脂质代谢）改善了间充质干细胞的性能（包括增殖、迁移和生长因子的产生），而不会诱导不良的免疫反应。因此，与正常间充质干细胞相比，经疾病-EV 预处理的间充质干细胞在不同类型的组织损伤（如急性肺损伤或肾损伤）中表现出卓越的组织修复效果（包括抗炎和抗凋亡作用）。疾病衍生的EV具有多种优势，如灵活性、稳定性、长期储存以及易于运输和使用，因此可作为一种 "现成 "产品。这项研究强调了疾病-EV预处理是精确增强间充质干细胞疗法再生能力的有力策略这一观点。

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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 Q1 PHARMACOLOGY & PHARMACY

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 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.06.013

The aggregation of Amyloid-β (Aβ) 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 Aβ species, peptides and fibrils. As the drug showed a chemical scaffold coherent for an effective interaction with the σ₁ receptor chaperone and as σ₁ agonists are currently developed as potent neuroprotectants in AD, we investigated the pharmacological action of Amylovis-201 on the σ₁ receptor. We report that Amylovis-201 is a potent σ₁ agonist by several in silico, in vitro and in vivo assays and that its anti-amnesic and neuroprotective effects involve a pharmacological action at σ₁ receptors. Furthermore, we show for the first time that classical σ₁ receptor agonist (PRE-084), and antagonist (NE-100) are able to interact and disaggregate Aβ_25–35 fibrils. Interestingly, Amylovis-201 was the only compound inhibiting Aβ_25–35 aggregates formation. Our results therefore highlight a dual action of Amylovis-201 as anti-aggregating agent and σ₁ receptor agonist that could be highly effective in long-term treatment against neurodegeneration in AD.

淀粉样蛋白（A）肽的聚集与阿尔茨海默病（AD）的神经变性有关。我们之前发现了新型萘衍生物，包括先导化合物 Amylovis-201，它们能够与淀粉样蛋白、肽和纤维形成热力学稳定的复合物。由于该药物显示出与受体伴侣有效相互作用的化学支架，而且激动剂目前正被开发为治疗注意力缺失症的强效神经保护剂，因此我们研究了 Amylovis-201 对受体的药理作用。我们报告说，Amylovis-201 是一种强效受体激动剂，其抗失忆和神经保护作用涉及受体的药理作用。此外，我们首次发现经典受体激动剂（PRE-084）和拮抗剂（NE-100）能够相互作用并分解 A 纤维。有趣的是，Amylovis-201 是唯一抑制 A 聚集体形成的化合物。因此，我们的研究结果凸显了Amylovis-201作为抗聚集剂和受体激动剂的双重作用，它在长期治疗AD神经退行性病变方面可能非常有效。

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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 Q1 PHARMACOLOGY & PHARMACY

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

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.

急性髓性白血病（AML）被认为是一种侵袭性癌症，其特征是显著的代谢重编程。在这里，我们应用空间代谢组学实现了对急性髓性白血病小鼠肝转移灶内代谢物的高通量原位鉴定。通过整合非靶向代谢组学和蛋白质组学，进一步绘制并验证了代谢物和蛋白质水平的变化。这项研究显示，精氨酸对多胺生物合成和尿素循环的贡献下调，同时肌酸代谢上调。肌酸合成酶 Gatm 和 Gamt 以及肌酸转运体 Slc6a8 的上调导致肌酸在肿瘤病灶内明显积累。这一过程进一步增强了白血病细胞的氧化磷酸化和糖酵解，从而提高了 ATP 的产生，促进了细胞的增殖和浸润。重要的是，我们发现抑制 Slc6a8 可以抵消这些有害影响，从而为通过靶向代谢途径治疗急性髓细胞白血病提供了一种新策略。

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