Acta Pharmaceutica Sinica. B最新文献

{"title":"VenusMutHub: A systematic evaluation of protein mutation effect predictors on small-scale experimental data","authors":"Liang Zhang ,&nbsp;Hua Pang ,&nbsp;Chenghao Zhang ,&nbsp;Song Li ,&nbsp;Yang Tan ,&nbsp;Fan Jiang ,&nbsp;Mingchen Li ,&nbsp;Yuanxi Yu ,&nbsp;Ziyi Zhou ,&nbsp;Banghao Wu ,&nbsp;Bingxin Zhou ,&nbsp;Hao Liu ,&nbsp;Pan Tan ,&nbsp;Liang Hong","doi":"10.1016/j.apsb.2025.03.028","DOIUrl":"10.1016/j.apsb.2025.03.028","url":null,"abstract":"<div><div>In protein engineering, while computational models are increasingly used to predict mutation effects, their evaluations primarily rely on high-throughput deep mutational scanning (DMS) experiments that use surrogate readouts, which may not adequately capture the complex biochemical properties of interest. Many proteins and their functions cannot be assessed through high-throughput methods due to technical limitations or the nature of the desired properties, and this is particularly true for the real industrial application scenario. Therefore, the desired testing datasets, will be small-size (∼10–100) experimental data for each protein, and involve as many proteins as possible and as many properties as possible, which is, however, lacking. Here, we present VenusMutHub, a comprehensive benchmark study using 905 small-scale experimental datasets curated from published literature and public databases, spanning 527 proteins across diverse functional properties including stability, activity, binding affinity, and selectivity. These datasets feature direct biochemical measurements rather than surrogate readouts, providing a more rigorous assessment of model performance in predicting mutations that affect specific molecular functions. We evaluate 23 computational models across various methodological paradigms, such as sequence-based, structure-informed and evolutionary approaches. This benchmark provides practical guidance for selecting appropriate prediction methods in protein engineering applications where accurate prediction of specific functional properties is crucial.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 5","pages":"Pages 2454-2467"},"PeriodicalIF":14.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943566","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}

{"title":"Targeting the JAK2–STAT3–UCHL3–ENO1 axis suppresses glycolysis and enhances the sensitivity to 5-FU chemotherapy in TP53-mutant colorectal cancer","authors":"Haisong Xin ,&nbsp;Zitong Zhao ,&nbsp;Shichao Guo ,&nbsp;Ruoxi Tian ,&nbsp;Liying Ma ,&nbsp;Yang Yang ,&nbsp;Lianmei Zhao ,&nbsp;Guanglin Wang ,&nbsp;Baokun Li ,&nbsp;Xuhua Hu ,&nbsp;Yongmei Song ,&nbsp;Guiying Wang","doi":"10.1016/j.apsb.2025.03.041","DOIUrl":"10.1016/j.apsb.2025.03.041","url":null,"abstract":"<div><div>Approximately 60% of colorectal cancer (CRC) patients exhibit <em>TP53</em> mutations, which are strongly associated with tumor progression, chemotherapy resistance, and an unfavorable prognosis. However, targeting p53 has historically been challenging, and currently, there are no approved p53-based therapeutics for clinical use worldwide. In this study, we discovered that ubiquitin carboxyl terminal hydrolase L3 (UCHL3) plays a crucial role in high-level glycolysis, enhanced stem-like properties, and 5-fluorouracil (5-FU) chemoresistance in <em>TP53</em>-mutant CRC by exerting its deubiquitinating enzyme activity to stabilize <em>α</em>-enolase (ENO1) protein. Notably, we identified a newly Food and Drug Administration (FDA)-approved drug, pacritinib, that potently suppresses UCHL3 expression by blocking the janus kinase 2 (JAK2)–signal transducer and activator of transcription 3 (STAT3) pathway in <em>TP</em>53-mutant CRC. Furthermore, Pacritinib was demonstrated to effectively inhibit glycolysis and improve the sensitivity to 5-FU chemotherapy in <em>TP53</em>-mutant CRC. Our findings suggest that targeting the JAK2–STAT3–UCHL3–ENO1 axis is a promising strategy to suppress glycolysis and enhance the efficacy of 5-FU chemotherapy in <em>TP53</em>-mutant CRC. Pacritinib shows potential for clinical application in the treatment of <em>TP53</em>-mutant CRC.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 5","pages":"Pages 2529-2544"},"PeriodicalIF":14.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943571","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}

{"title":"“Weibing” in traditional Chinese medicine—biological basis and mathematical representation of disease-susceptible state","authors":"Wanyang Sun ,&nbsp;Rong Wang ,&nbsp;Shuhua Ouyang ,&nbsp;Wanli Liang ,&nbsp;Junwei Duan ,&nbsp;Wenyong Gong ,&nbsp;Lianting Hu ,&nbsp;Xiujuan Chen ,&nbsp;Yifang Li ,&nbsp;Hiroshi Kurihara ,&nbsp;Xinsheng Yao ,&nbsp;Hao Gao ,&nbsp;Rongrong He","doi":"10.1016/j.apsb.2025.03.009","DOIUrl":"10.1016/j.apsb.2025.03.009","url":null,"abstract":"<div><div>“Weibing” is a fundamental concept in traditional Chinese medicine (TCM), representing a transitional state characterized by diminished self-regulatory abilities without overt physiological or social dysfunction. This perspective delves into the biological foundations and quantifiable markers of Weibing, aiming to establish a research framework for early disease intervention. Here, we propose the “Health Quadrant Classification” system, which divides the state of human body into health, sub-health, disease-susceptible state, and disease. We suggest the disease-susceptible stage emerges as a pivotal point for TCM interventions. To understand the intrinsic dynamics of this state, we propose laboratory and clinical studies utilizing time-series experiments and stress-induced disease susceptibility models. At the molecular level, bio-omics technologies and bioinformatics approaches are highlighted for uncovering intricate changes during disease progression. Furthermore, we discuss the application of mathematical models and artificial intelligence in developing early warning systems to anticipate and avert the transition from health to disease. This approach resonates with TCM’s preventive philosophy, emphasizing proactive health maintenance and disease prevention. Ultimately, our perspective underscores the significance of integrating modern scientific methodologies with TCM principles to propel Weibing research and early intervention strategies forward.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 5","pages":"Pages 2363-2371"},"PeriodicalIF":14.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143942935","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}

{"title":"Metabolic reprogramming nanomedicine potentiates colon cancer sonodynamic immunotherapy by inhibiting the CD39/CD73/ADO pathway","authors":"Yuanyuan Zhang ,&nbsp;Weiwei Jin ,&nbsp;Zhichao Deng ,&nbsp;Bowen Gao ,&nbsp;Yuanyuan Zhu ,&nbsp;Junlong Fu ,&nbsp;Chenxi Xu ,&nbsp;Wenlong Wang ,&nbsp;Ting Bai ,&nbsp;Lianying Jiao ,&nbsp;Hao Wu ,&nbsp;Mingxin Zhang ,&nbsp;Mingzhen Zhang","doi":"10.1016/j.apsb.2025.03.046","DOIUrl":"10.1016/j.apsb.2025.03.046","url":null,"abstract":"<div><div>Sonodynamic therapy (SDT) can potentially induce immunogenic cell death in tumor cells, leading to the release of ATP, and facilitating the initiation of an immune response. Nevertheless, the enzymes CD39 and CD73 can swiftly convert ATP into immunosuppressive adenosine (ADO), resulting in an immunosuppressive tumor microenvironment (TME). This study introduced a nanomedicine (QD/POM1@NP@M) engineered to reprogram TME by modulating the CD39/CD73/ADO pathway. The nanomedicine encapsulated sonosensitizers silver sulfide quantum dots, and the CD39 inhibitor POM1, while also incorporating homologous tumor cell membranes to enhance targeting capabilities. This integrated approach, on the one hand, stimulates the release of ATP <em>via</em> SDT, thereby initiating the immune response. In addition, it reduced the accumulation of ADO by inhibiting CD39 activity, which ameliorated the immunosuppressive TME. Upon administration, the nanomedicine demonstrated substantial anti-tumor efficacy by facilitating the infiltration of anti-tumor immune cells, while reducing the immunosuppressive cells. This modulation effectively transformed the TME from an immunologically “cold” state to a “hot” state. Furthermore, combined with the checkpoint inhibitor <em>α</em>-PDL1, the nanomedicine augmented systemic anti-tumor immunity and promoted the establishment of long-term immune memory. This study provides an innovative strategy for combining non-invasive SDT and ATP-driven immunotherapy, offering new ideas for future cancer treatment.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 5","pages":"Pages 2655-2672"},"PeriodicalIF":14.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943499","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}

{"title":"Targeting stiff stroma by neutralizing LOX-mediated matrix crosslinking in pancreatic cancer","authors":"Shan Zhang ,&nbsp;Zhiwei Cai ,&nbsp;Luju Jiang ,&nbsp;Shuqi Cai ,&nbsp;Zheqi Weng ,&nbsp;Shuheng Jiang","doi":"10.1016/j.apsb.2025.03.010","DOIUrl":"10.1016/j.apsb.2025.03.010","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 5","pages":"Pages 2783-2786"},"PeriodicalIF":14.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943500","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}

{"title":"RNA splicing: Novel star in pulmonary diseases with a treatment perspective","authors":"Zhihui Niu ,&nbsp;Bingqian Xu ,&nbsp;Wei Li ,&nbsp;Jian Sun ,&nbsp;Haihai Liang","doi":"10.1016/j.apsb.2025.03.023","DOIUrl":"10.1016/j.apsb.2025.03.023","url":null,"abstract":"<div><div>Alternative splicing (AS) serves as a fundamental regulatory mechanism in gene expression, contributing to proteomic diversity by generating an array of mRNA isoforms from precursor mRNA <em>via</em> distinct splice site combinations. In light of the limited therapeutic options currently available, the exploration of AS as a target for drug development is of paramount importance. This review offers an exhaustive analysis of the biological functions and underlying molecular mechanisms associated with various AS-induced splice variants, RNA-binding proteins, and <em>cis</em>-elements, highlighting their significance as clinical biomarkers. We place particular emphasis on the current therapeutic applications of AS in an array of lung diseases, including but not limited to lung cancer, cystic fibrosis, silicosis, acute respiratory distress syndrome, pneumonia, asthma, chronic obstructive pulmonary diseases, pulmonary arterial hypertension, and idiopathic pulmonary fibrosis. The review delves into the role of AS events in the diagnosis and treatment of lung diseases, focusing on the regulatory influence of splicing factors and RNA-binding proteins, while also enumerating the mutated components implicated in AS misregulation. Consequently, a comprehensive understanding of the intricate mechanisms governing these splicing events could potentially offer novel avenues for the development of splicing-targeted therapeutics and diagnostic tools for the prevention and treatment of lung diseases.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 5","pages":"Pages 2301-2322"},"PeriodicalIF":14.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943521","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}

{"title":"Skin as an autonomous immune organ: Antibody production and host protection","authors":"Wende Deng ,&nbsp;Ting Li","doi":"10.1016/j.apsb.2025.03.027","DOIUrl":"10.1016/j.apsb.2025.03.027","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 5","pages":"Pages 2795-2797"},"PeriodicalIF":14.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943540","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}

{"title":"TRIM21-based degradation strategy for multimeric proteins","authors":"Wei Wang,&nbsp;Chunquan Sheng","doi":"10.1016/j.apsb.2025.02.025","DOIUrl":"10.1016/j.apsb.2025.02.025","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 5","pages":"Pages 2798-2800"},"PeriodicalIF":14.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943541","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}

{"title":"Modified probiotics and the related combinatorial therapeutics","authors":"Luo Zhao ,&nbsp;Mengya Niu ,&nbsp;Zilin Ma ,&nbsp;Fengyun He ,&nbsp;Xinxin Liu ,&nbsp;Xunwei Gong ,&nbsp;Zhanfei Chai ,&nbsp;Ziqing Wang ,&nbsp;Qianhua Feng ,&nbsp;Lei Wang","doi":"10.1016/j.apsb.2025.03.021","DOIUrl":"10.1016/j.apsb.2025.03.021","url":null,"abstract":"<div><div>Probiotics have shown excellent application prospects in preventing and treating many diseases. However, their sensitivity to the harsh environment <em>in vivo</em> always leads to a massive loss of viability and insufficient therapeutic effect. Fortunately, modified probiotics have emerged and provide multiple possibilities for their use in various diseases. Modification not only endows probiotics with extra capacity to resist severe environments but also gives them exogenous characteristics, such as prolonged retention time and improved therapeutic effects. Modified probiotics could combine with other therapies, which has opened up new avenues to enhance the efficacy of probiotic-based therapy. In this review, we have summarized the current physicochemical and biological modification strategies of probiotics. In addition, the progress of research on probiotic-based combination therapy has also been extensively reviewed, which contributes to the enhanced delivery of probiotics or other active constituents and provides new ideas for disease treatment, bioimaging, and diagnosis.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 5","pages":"Pages 2431-2453"},"PeriodicalIF":14.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943565","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}

{"title":"USP51/GRP78/ABCB1 axis confers chemoresistance through decreasing doxorubicin accumulation in triple-negative breast cancer cells","authors":"Yang Ou ,&nbsp;Kun Zhang ,&nbsp;Qiuying Shuai ,&nbsp;Chenyang Wang ,&nbsp;Huayu Hu ,&nbsp;Lixia Cao ,&nbsp;Chunchun Qi ,&nbsp;Min Guo ,&nbsp;Zhaoxian Li ,&nbsp;Jie Shi ,&nbsp;Yuxin Liu ,&nbsp;Siyu Zuo ,&nbsp;Xiao Chen ,&nbsp;Yanjing Wang ,&nbsp;Mengdan Feng ,&nbsp;Hang Wang ,&nbsp;Peiqing Sun ,&nbsp;Yi Shi ,&nbsp;Guang Yang ,&nbsp;Shuang Yang","doi":"10.1016/j.apsb.2025.03.004","DOIUrl":"10.1016/j.apsb.2025.03.004","url":null,"abstract":"<div><div>Recent studies have indicated that the expression of ubiquitin-specific protease 51 (USP51), a novel deubiquitinating enzyme (DUB) that mediates protein degradation as part of the ubiquitin‒proteasome system (UPS), is associated with tumor progression and therapeutic resistance in multiple malignancies. However, the underlying mechanisms and signaling networks involved in USP51-mediated regulation of malignant phenotypes remain largely unknown. The present study provides evidence of USP51's functions as the prominent DUB in chemoresistant triple-negative breast cancer (TNBC) cells. At the molecular level, ectopic expression of USP51 stabilized the 78 kDa Glucose-Regulated Protein (GRP78) protein through deubiquitination, thereby increasing its expression and localization on the cell surface. Furthermore, the upregulation of cell surface GRP78 increased the activity of ATP binding cassette subfamily B member 1 (ABCB1), the main efflux pump of doxorubicin (DOX), ultimately decreasing its accumulation in TNBC cells and promoting the development of drug resistance both <em>in vitro</em> and <em>in vivo</em>. Clinically, we found significant correlations among USP51, GRP78, and ABCB1 expression in TNBC patients with chemoresistance. Elevated USP51, GRP78, and ABCB1 levels were also strongly associated with a poor patient prognosis. Importantly, we revealed an alternative intervention for specific pharmacological targeting of USP51 for TNBC cell chemosensitization. In conclusion, these findings collectively indicate that the USP51/GRP78/ABCB1 network is a key contributor to the malignant progression and chemotherapeutic resistance of TNBC cells, underscoring the pivotal role of USP51 as a novel therapeutic target for cancer management.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 5","pages":"Pages 2593-2611"},"PeriodicalIF":14.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943575","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}