Acta Pharmaceutica Sinica. B最新文献

英文中文

Site-specific PEGylation of proteins: Insights into structural and functional changes 位点特异性聚乙二醇化的蛋白质：洞察结构和功能的变化

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 DOI: 10.1016/j.apsb.2025.10.014

Ming Ma , Jinwei Di , Chengcai Wang , Yanwei Xie , Fengqian Cui , Yanan Zhai , Shanwei Zhu , Jing Gao

Polyethylene glycol (PEG) is a polymer with different molecular weights formed by the polymerization of ethylene oxide monomers. Due to its ability to significantly reduce the immunogenicity of protein drugs and extend their half-life, as well as its high safety profile, it has been approved by the U.S. Food and Drug Administration (FDA) as the gold standard for delivering protein drugs. Although numerous PEGylated protein drugs have been marketed, the focus of research on PEGylated protein drugs has primarily been on reducing immunogenicity and extending in vivo circulation half-life. However, the understanding of how PEG modification affects the structure and function of proteins is still limited, with “activity” often being the sole criterion for evaluating changes in protein structure and function. A deeper exploration of the existence and interaction between PEG chains and proteins is of great significance for understanding the properties exhibited by PEGylated proteins. This review summarizes strategies for PEG site-specific modification of proteins, the interaction states between PEG and proteins, and the effects of PEG chains on protein spatial structure, solubility, activity, and thermal stability. It also summarizes the characterization techniques for PEG–protein interactions, aiming to predict or explain the functions of PEGylated protein drugs through the analysis of PEG–protein interactions.

聚乙二醇（PEG）是由环氧乙烷单体聚合而成的具有不同分子量的聚合物。由于它能够显著降低蛋白质药物的免疫原性和延长其半衰期，以及它的高安全性，它已被美国食品和药物管理局（FDA）批准为传递蛋白质药物的黄金标准。尽管许多聚乙二醇化蛋白药物已经上市，但聚乙二醇化蛋白药物的研究重点主要是降低免疫原性和延长体内循环半衰期。然而，对PEG修饰如何影响蛋白质结构和功能的理解仍然有限，“活性”往往是评估蛋白质结构和功能变化的唯一标准。深入探索聚乙二醇链与蛋白质之间的存在及其相互作用，对于理解聚乙二醇化蛋白所表现出的特性具有重要意义。本文综述了PEG位点特异性修饰蛋白质的策略，PEG与蛋白质的相互作用状态，以及PEG链对蛋白质空间结构、溶解度、活性和热稳定性的影响。总结了聚乙二醇蛋白相互作用的表征技术，旨在通过对聚乙二醇蛋白相互作用的分析来预测或解释聚乙二醇化蛋白药物的功能。

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引用次数: 0

Standardization of nasal airway structure model of Chinese Han nationality for characterization of nasal formulation spatial deposition atlases 中国汉族鼻气道结构模型标准化表征鼻腔配方空间沉积图谱

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 DOI: 10.1016/j.apsb.2025.09.018

Zeru Li , Huipeng Xu , Siwen Wang , Qin Nie , Bingqian Jia , Jiawen Su , Guanghong Xu , Rui Yang , Zhigang Wang , Jiwen Zhang , Li Wu

The deposition characteristics of nasal formulations directly determine the efficacy of the drugs, whilst the complexity of human nasal airway structure encumbers quantitative evaluation of nasal spatial deposition. Male and female standard nasal airway structure models were calculated from computed tomography data of 128 Chinese Han nationality using statistical shape model. The deposition evaluation devices were further designed, and an imaging method was then employed to obtain drug deposition information. Furthermore, drug spatial deposition atlases were proposed by UV unwrapping, a mathematical mapping procedure flattening three-dimensional (3D) information to two-dimension bidirectionally, to achieve quantification of drug deposition fractions in the regions of interest. Moreover, the feasibility and universality of this method were verified by correlating it with the chemical quantitative results and computational fluid dynamic simulation of drug deposition of mometasone furoate nasal spray and hydroxypropyl methylcellulose nasal powder, respectively. Finally, the unique drug spatial deposition atlases of these two formulations in the male and female evaluation devices were generated, respectively. In summary, the standard nasal airway structure models of the Chinese Han nationality and the drug spatial deposition atlases provide scientific tools for the formulation optimization and quality control of nasal formulations.

鼻腔剂型的沉积特性直接决定了药物的疗效，而人体鼻气道结构的复杂性阻碍了鼻腔空间沉积的定量评价。采用统计形状模型对128例汉族人群的ct数据进行计算，计算出男女标准鼻气道结构模型。进一步设计沉积评价装置，并采用成像方法获取药物沉积信息。此外，通过UV展开（一种将三维（3D）信息双向平坦化到二维的数学映射程序），提出了药物空间沉积图谱，以实现感兴趣区域药物沉积组分的量化。并分别与糠酸莫米松鼻喷雾剂和羟丙基甲基纤维素鼻粉药物沉积的化学定量结果和计算流体动力学模拟进行对比，验证了该方法的可行性和通用性。最后，分别生成这两种剂型在男性和女性评价装置中的独特药物空间沉积图谱。综上所述，中国汉族标准鼻气道结构模型和药物空间沉积图谱为鼻用制剂的处方优化和质量控制提供了科学的工具。

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引用次数: 0

Cover Story 封面故事

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 DOI: 10.1016/S2211-3835(25)00752-X

引用次数: 0

MYD88 regulates the intercellular crosstalk landscape in MASH liver against metaflammation and metabolic disorder MYD88调节MASH肝脏细胞间串扰景观对抗炎症和代谢紊乱

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 DOI: 10.1016/j.apsb.2025.09.041

Haonan Li , Daimin Luo , Chuangnan Qiu , Xianzhi Wei , Mengzhu Wu , Rui Wang , Xianyan Liu , Xianxing Jiang

Metabolic dysfunction-associated steatohepatitis (MASH) is the main cause of end-stage liver disease. We analyzed cell communication via ligand–receptor signaling at the single-cell level to elucidate cell-specific responses and spatial zonation in MASH. We screened and validated Myd88 hyperexpression in liver sinusoidal endothelial cells and liver capsular macrophages (LCM). We showed that Myd88 levels in the periportal endothelial cells of mice with MASH were higher than those in healthy controls, correlating significantly with dysregulation of capillarization markers in vivo. Moreover, Myd88⁺ LCM is a primary source of diverse signaling ligands involved in inflammatory cell recruitment during diet-induced MASH. CD24-Fc bound to the inhibitory receptor SIGLECG to significantly enhance SHP1 binding to MYD88, thereby inhibiting its activation and contributing to the restoration of immune-inflammatory homeostasis in the livers of diet-induced MASH mice. CD24-Fc improved amylin liver nonalcoholic steatohepatitis-induced MASH, which was partly abolished by AAV6-mediated Myd88 knockout in vivo. These findings underscore the central role of MYD88 in MASH etiology, and the specific targeting of MYD88 in liver sinusoidal endothelial cells and LCM may be a potential therapeutic approach to slow the progression of MASH.

代谢功能障碍相关脂肪性肝炎（MASH）是终末期肝病的主要原因。我们在单细胞水平上分析了通过配体受体信号传导的细胞通信，以阐明细胞特异性反应和MASH的空间分区。我们筛选并验证了Myd88在肝窦内皮细胞和肝包膜巨噬细胞（LCM）中的高表达。我们发现，患有MASH的小鼠门静脉周围内皮细胞中的Myd88水平高于健康对照组，这与体内毛细血管标记物的失调显著相关。此外，Myd88+ LCM是饮食诱导的MASH中参与炎症细胞募集的多种信号配体的主要来源。CD24-Fc与抑制受体SIGLECG结合，显著增强SHP1与MYD88的结合，从而抑制其激活，促进饮食诱导的MASH小鼠肝脏免疫炎症稳态的恢复。CD24-Fc改善了amylin肝非酒精性脂肪性肝炎诱导的MASH，这在体内被aav6介导的Myd88敲除部分消除。这些发现强调了MYD88在MASH病因学中的核心作用，并且MYD88特异性靶向肝窦内皮细胞和LCM可能是减缓MASH进展的潜在治疗方法。

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引用次数: 0

Hemoglobin nanocatalyst with tunable autoxidation activity for tumor apoptosis-ferroptosis combination therapy 具有可调自氧化活性的血红蛋白纳米催化剂用于肿瘤凋亡-铁凋亡联合治疗

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 DOI: 10.1016/j.apsb.2025.09.031

Jing Li , Hongbo Wu , Hanyue Li , Yue Zhang , Hanjie Zhang , Ling Wang , Weilang Zhang , Tingxuan Li , Weiwei Zeng , Daquan Chen , Lin Mei

The clinical translation of catalytic therapy has been hindered in recent decades due to immunological risks, delayed degradation, and poorly understood metabolism associated with catalysts, despite promising results in antitumor therapy. Developing catalysts with nonmetallic active centers may provide an alternative to those with metallic active centers. In this study, a natural protein nanocatalyst, Hb@PtPP, is developed through the moderate polymerization of pyrrole and hemoglobin for tumor catalytic therapy. In comparison with BSA@PtPP prepared from bovine serum albumin, Hb@PtPP exhibits distinctive autoxidation activity in tumor cells in response to elevated hydrogen peroxide levels while maintaining relatively low activity in normal cells. This feature enables Hb@PtPP to effectively combat tumors by initiating a cascade of catalytic reactions, including the production of reactive oxygen species, the release of heme and iron ions, and the accumulation of lipid peroxidation, all of which contribute to apoptosis and ferroptosis in tumor cells. RNA-sequencing results further demonstrate that tumor cells undergo ferroptosis. Additionally, these catalytic processes are augmented by the photothermal effect, resulting in efficient tumor killing and growth inhibition both in vitro and in vivo. This study underscores the crucial role of hemoglobin in advancing catalytic therapy for tumors.

近几十年来，尽管在抗肿瘤治疗中有很好的结果，但由于免疫风险、延迟降解以及对催化剂相关代谢的了解不足，催化疗法的临床转化一直受到阻碍。开发具有非金属活性中心的催化剂可以为金属活性中心的催化剂提供一种替代方法。本研究通过吡咯和血红蛋白的适度聚合，开发了一种天然蛋白质纳米催化剂Hb@PtPP，用于肿瘤的催化治疗。与从牛血清白蛋白制备的BSA@PtPP相比，Hb@PtPP在肿瘤细胞中表现出独特的自氧化活性，以响应过氧化氢水平的升高，而在正常细胞中保持相对较低的活性。这一特性使Hb@PtPP能够通过启动一系列催化反应来有效地对抗肿瘤，包括活性氧的产生、血红素和铁离子的释放以及脂质过氧化的积累，所有这些都有助于肿瘤细胞的凋亡和铁凋亡。rna测序结果进一步证实肿瘤细胞发生铁下垂。此外，光热效应增强了这些催化过程，从而在体外和体内都能有效地杀死肿瘤和抑制生长。这项研究强调了血红蛋白在推进肿瘤催化治疗中的关键作用。

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引用次数: 0

Generation and applications of an expandable and mature hiPSC-derived liver organoid 可扩展和成熟的hipsc衍生的肝类器官的生成和应用

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 DOI: 10.1016/j.apsb.2025.09.029

Sen Liu , Ze Wang , Liuyang Zhu , Libo Wang , Tianyu Zhao , Pinsheng Han , Yongdeng Xu , Long Yang , Lei Hu , Fengying Yan , Xiaoliang Wang , Tao Cui , Chunli Li , Baofeng Yang

Organoids have emerged as a powerful tool for modeling liver diseases, drug screening, and personalized treatments. However, they have a limited capacity to generate functional hepatocytes in a reproducible and efficient manner. Here, we designed a novel method to efficiently and reproducibly establish a protocol for generating functionally mature SB-HEOs (SB431542/BMP4-hepatic endoderm organoids) from hiPSC-derived hepatic endoderm (HE) cells. The maturation of these organoids was confirmed through transcriptome analysis and functional expression detection. We extended this culture system to various biomedical applications. This system can be used to identify hepatotoxicity with DILI drugs, model disease using OA stress, metabolize drugs using liquid chromatography–tandem mass spectrometry, and repopulate FRG mice. These organoids have both expansion and maturation characteristics, high drug metabolism ability to prolong the survival of FRG mice, can accurately identify hepatotoxic and non-hepatotoxic drugs, and mimic metabolic dysfunction-associated steatotic liver disease. Thus, SB-HEO provide a new cellular system for toxicology testing, drug metabolism, modeling liver diseases, and regenerative medicine. Especially benefiting from the high expression of CYP450 activity, SB-HEO shows high potential in the fields of drug testing and regenerative medicine.

类器官已经成为肝脏疾病建模、药物筛选和个性化治疗的有力工具。然而，它们以可重复和有效的方式产生功能性肝细胞的能力有限。在这里，我们设计了一种新的方法，以高效和可重复地建立从hipsc来源的肝内胚层（HE）细胞生成功能成熟的SB-HEOs （SB431542/ bmp4 -肝内胚层器官）的方案。通过转录组分析和功能表达检测证实了这些类器官的成熟。我们将这个培养系统扩展到各种生物医学应用中。该系统可用于DILI药物的肝毒性鉴定、OA应激的疾病模型、液相色谱-串联质谱法的药物代谢以及FRG小鼠的重建。这些类器官具有扩张和成熟的特点，具有较高的药物代谢能力，可以延长FRG小鼠的生存期，能够准确识别肝毒性和非肝毒性药物，模拟代谢功能障碍相关的脂肪变性肝病。因此，SB-HEO为毒理学测试、药物代谢、肝脏疾病建模和再生医学提供了一种新的细胞系统。特别是得益于CYP450活性的高表达，SB-HEO在药物检测和再生医学领域显示出巨大的潜力。

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引用次数: 0

How histone modifications influence cellular radiosensitivity: Pharmaceutically targeting epigenetic regulators as a promising avenue to overcome radioresistance 组蛋白修饰如何影响细胞放射敏感性：药物靶向表观遗传调节剂作为克服放射耐药的有希望的途径

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 DOI: 10.1016/j.apsb.2025.09.019

Jiawei Song , Lu Ye , Wei-Qun Ding , Huaijin Qiao , Junlong Dai , Hao Bai , Shuyu Zhang

Cancer remains the leading cause of mortality worldwide. Radiotherapy (RT), a cornerstone of oncological treatment for over a century, has achieved great success in various cancers. However, radioresistance remains the primary factor leading to the failure of radiotherapy. Histone modifications in cancer cells are known to play a pivotal role in regulating radiosensitivity by modulating chromatin structure, either by loosening or tightening it. Here, we provide a comprehensive summary of the link between aberrant histone modifications and radiation resistance across various cancer and normal tissue cells. Furthermore, we discuss the regulatory mechanisms of histone modifications and the enzymes on the recruitment of proteins that recognize histone modifications. Consequently, these processes substantially affect the radiosensitivity of tumors. In addition to cancer cells, we highlight the intricate interplay between histone modification and radiosensitivity, both within and beyond the cancer cells. Meanwhile, various drugs targeting histone modifications emerge as a promising therapeutic strategy to overcome radioresistance of tumors as well as radioprotection. The combination of histone modification inhibitors with radiotherapy presents a novel approach to enhance cancer treatment outcomes in clinical practice. Nevertheless, the underlying mechanisms through which histone modifications influence cancer radiosensitivity require further elucidation to identify novel targets for radiotherapeutic intervention.

癌症仍然是世界范围内导致死亡的主要原因。放射治疗（RT）是一个多世纪以来肿瘤治疗的基石，在各种癌症中取得了巨大的成功。然而，放射抵抗仍然是导致放疗失败的主要因素。已知癌细胞中的组蛋白修饰通过调节染色质结构（放松或收紧）在调节辐射敏感性方面发挥关键作用。在这里，我们提供了一个全面的总结在各种癌症和正常组织细胞的异常组蛋白修饰和辐射抗性之间的联系。此外，我们还讨论了组蛋白修饰的调控机制以及识别组蛋白修饰的蛋白质募集的酶。因此，这些过程实质上影响肿瘤的放射敏感性。除了癌细胞，我们还强调了组蛋白修饰和放射敏感性之间复杂的相互作用，包括癌细胞内部和外部。同时，针对组蛋白修饰的各种药物成为克服肿瘤放射耐药和放射保护的一种有前景的治疗策略。在临床实践中，组蛋白修饰抑制剂与放疗的结合为提高癌症治疗效果提供了一种新的途径。然而，组蛋白修饰影响癌症放射敏感性的潜在机制需要进一步阐明，以确定放射治疗干预的新靶点。

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引用次数: 0

Author correction to “Structurally defined tandem-responsive nanoassemblies composed of dipeptide-based photosensitive derivatives and hypoxia-activated camptothecin prodrugs against primary and metastatic breast tumors” [Acta Pharm Sin B 12 (2022) 952–966] 作者更正“结构上明确的串联响应纳米组件，由二肽基光敏衍生物和缺氧激活的喜树碱前体药物组成，用于原发性和转移性乳腺肿瘤”[Acta Pharm b12 (2022) 952-966]

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-11-01 DOI: 10.1016/j.apsb.2025.09.034

Mengchi Sun , Hailun Jiang , Tian Liu , Xiao Tan , Qikun Jiang , Bingjun Sun , Yulong Zheng , Gang Wang , Yang Wang , Maosheng Cheng , Zhonggui He , Jin Sun

引用次数: 0

Electrochemical biosensors with right-side-out-oriented cell membrane coating for the evaluation of AChE inhibitors as potential anti-Alzheimer's disease agents 右向外取向细胞膜涂层电化学生物传感器评价乙酰胆碱酯酶抑制剂作为潜在的抗阿尔茨海默病药物

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-11-01 DOI: 10.1016/j.apsb.2025.09.032

Ying Zhao , Xia Liu , Shuning Yang , Jiabo Wang , Dan Wu , Yusi Bu , Xiaoyu Xie

Biosensors based on acetylcholinesterase (AChE) are crucial for early diagnosis, less invasive treatment, and drug evaluation of Alzheimer's disease (AD). However, existing technologies often suffer from enzyme conformational changes, leading to altered activity and loss and reduced sensor efficacy. To address this challenge, we developed a novel right-side-out-oriented red blood cell membrane-coated electrochemical biosensors (ROCMCBs) to evaluate AChE inhibitors from traditional Chinese medicines (TCMs) as potential anti-AD agents. The developed right-side-out-oriented coating based on immunoaffinity not only fully exposed the binding sites of AChE on the cell membrane but also ensured its conformation and stability as a peripheral membrane-anchoring protein, which was conducive to maintaining its biological activity and producing optimal interaction with drugs. At the same time, the biosensors exhibited a satisfactory sensitivity (limit of detection = 0.41 pmol/L). Ultimately, six potentially active compounds against AD (baicalin, geniposide, gastrodin, berberine, rhynchophylline, and senkyunolide A) were rapidly identified and evaluated from TCMs. This project provides a promising strategy for developing cell membrane-coated electrochemical biosensors. The application of cell membrane-coated electrochemical biosensors with well-defined cell membrane orientation further expands new perspectives and methods for AChE-targeted anti-AD research.

基于乙酰胆碱酯酶（AChE）的生物传感器对阿尔茨海默病（AD）的早期诊断、微创治疗和药物评估至关重要。然而，现有技术经常受到酶构象变化的影响，导致活性改变和损失，降低传感器效率。为了解决这一挑战，我们开发了一种新型的右向外定向红细胞膜涂覆电化学生物传感器（rocmcb）来评估中药（tcm）中的AChE抑制剂作为潜在的抗ad药物。基于免疫亲和的右外取向包被不仅充分暴露了乙酰胆碱酯酶在细胞膜上的结合位点，而且保证了其作为外周膜锚定蛋白的构象和稳定性，有利于维持其生物活性并与药物产生最佳的相互作用。同时，该传感器具有良好的灵敏度（检出限为0.41 pmol/L）。最终，从中药材中快速鉴定出6种抗AD的潜在活性化合物（黄芩苷、京尼平苷、天麻素、小檗碱、蛇柳碱和仙球内酯A）。本课题为开发膜包覆电化学生物传感器提供了一条有前景的途径。具有明确细胞膜取向的膜包覆电化学生物传感器的应用，进一步为痛觉靶向抗ad研究拓展了新的视角和方法。

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引用次数: 0

From single-thread delivery to cascading therapy: The promise of nanoCRISPR in solid tumors 从单线程递送到级联治疗：纳米crispr在实体肿瘤中的前景

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-11-01 DOI: 10.1016/j.apsb.2025.10.015

Peng Mi , Horacio Cabral

引用次数: 0

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