Acta Pharmaceutica Sinica. B最新文献_第7页

Icaritin inhibits the progression of urothelial cancer by suppressing PADI2-mediated neutrophil infiltration and neutrophil extracellular trap formation 淫羊藿苷通过抑制 PADI2 介导的中性粒细胞浸润和中性粒细胞胞外陷阱的形成来抑制尿道癌的进展

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-09-01 DOI: 10.1016/j.apsb.2024.06.029

{"title":"Icaritin inhibits the progression of urothelial cancer by suppressing PADI2-mediated neutrophil infiltration and neutrophil extracellular trap formation","authors":"","doi":"10.1016/j.apsb.2024.06.029","DOIUrl":"10.1016/j.apsb.2024.06.029","url":null,"abstract":"<div><p>Tumor relapse and metastasis are the major causes of mortality associated with urothelial cancer. In the tumor microenvironment, negative regulatory molecules and various immune cell subtypes suppress antitumor immunity. The inflammatory microenvironment, associated with neutrophils and neutrophil extracellular traps (NETs), promotes tumor metastasis. However, no drugs are currently available to specifically inhibit neutrophils and NETs. In this study, we first demonstrated that icaritin (ICT), a Chinese herbal remedy that is a first-line treatment for advanced and incurable hepatocellular carcinoma, reduces NETs caused by suicidal NETosis and prevents neutrophil infiltration in the tumor microenvironment. Mechanistically, ICT binds to and inhibits the expression of PADI2 in neutrophils, thereby suppressing PADI2-mediated histone citrullination. Moreover, ICT inhibits ROS generation, suppresses the MAPK signaling pathway, and inhibits NET-induced tumor metastasis. Simultaneously, ICT inhibits tumoral PADI2-mediated histone citrullination, which consequently suppresses the transcription of neutrophil-recruiting genes such as GM-CSF and IL-6. The downregulation of IL-6 expression, in turn, forms a regulatory feedback loop through the JAK2/STAT3/IL-6 axis. Through a retrospective study of clinical samples, we found a correlation between neutrophils, NETs, UCa prognosis, and immune evasion. Combining ICT with immune checkpoint inhibitors may have synergistic effects. In summary, our study demonstrated that ICT could be a novel inhibitor of NETs and a novel UCa treatment.</p></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 9","pages":"Pages 3916-3930"},"PeriodicalIF":14.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211383524002600/pdfft?md5=052d3d123fc6ac471b1e4968f1b74826&pid=1-s2.0-S2211383524002600-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141549271","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

Transferrin receptor-targeted immunostimulant for photodynamic immunotherapy against metastatic tumors through β-catenin/CREB interruption 转铁蛋白受体靶向免疫刺激剂通过β-catenin/CREB 干扰光动力免疫疗法治疗转移性肿瘤

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-09-01 DOI: 10.1016/j.apsb.2024.05.030

{"title":"Transferrin receptor-targeted immunostimulant for photodynamic immunotherapy against metastatic tumors through β-catenin/CREB interruption","authors":"","doi":"10.1016/j.apsb.2024.05.030","DOIUrl":"10.1016/j.apsb.2024.05.030","url":null,"abstract":"<div><p>The immunosuppressive phenotype of tumor cells extensively attenuates the immune activation effects of traditional treatments. In this work, a transferrin receptor (TfR) targeted immunostimulant (PTI) is fabricated for photodynamic immunotherapy against metastatic tumors by interrupting <em>β</em>-catenin signal pathway. To synthesize PTI, the photosensitizer conjugated TfR targeting peptide moiety (Palmitic-K(PpIX)-HAIYPRH) is unitized to encapsulate the transcription interrupter of ICG-001. On the one hand, the recognition of PTI and TfR can promote drug delivery into tumor cells to destruct primary tumors through photodynamic therapy and initiate an immunogenic cell death with the release of tumor-associated antigens. On the other hand, PTI will interrupt the binding between <em>β</em>-catenin and cAMP response element-binding protein (CREB), regulating the gene transcription to downregulate programmed death ligand 1 (PD-L1) while upregulating C–C motif chemokine ligand 4 (CCL4). Furthermore, the elevated CCL4 can recruit the dendritic cells to present tumor-specific antigens and promote T cells activation and infiltration, and the downregulated PD-L1 can avoid the immune evasion of tumor cells and activate systemic anti-tumor immunity to eradicate lung metastasis. This work may inspire the development of antibody antibody-free strategy to activate systemic immune response in consideration of immunosuppressive conditions.</p></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 9","pages":"Pages 4118-4133"},"PeriodicalIF":14.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211383524002260/pdfft?md5=bd3d0e528bea4dbf84a885e1aac3c35d&pid=1-s2.0-S2211383524002260-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141274200","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

Advancing cancer nanomedicine with machine learning 利用机器学习推动癌症纳米医学的发展

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-09-01 DOI: 10.1016/j.apsb.2024.06.018

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Jun12682, a potent SARS-CoV-2 papain-like protease inhibitor with exceptional antiviral efficacy in mice Jun12682 是一种强效的 SARS-CoV-2 木瓜蛋白酶样蛋白酶抑制剂，对小鼠具有卓越的抗病毒疗效

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-09-01 DOI: 10.1016/j.apsb.2024.07.001

Mianling Yang , Meehyein Kim , Peng Zhan

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Discovery and evaluation of a novel 18F-labeled vasopressin 1a receptor PET ligand with peripheral binding specificity 发现和评估具有外周结合特异性的新型 18F 标记加压素 1a 受体 PET 配体

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-09-01 DOI: 10.1016/j.apsb.2024.05.033

{"title":"Discovery and evaluation of a novel 18F-labeled vasopressin 1a receptor PET ligand with peripheral binding specificity","authors":"","doi":"10.1016/j.apsb.2024.05.033","DOIUrl":"10.1016/j.apsb.2024.05.033","url":null,"abstract":"<div><p>The arginine-vasopressin (AVP) hormone plays a pivotal role in regulating various physiological processes, such as hormone secretion, cardiovascular modulation, and social behavior. Recent studies have highlighted the V1a receptor as a promising therapeutic target. In-depth insights into V1a receptor-related pathologies, attained through <em>in vivo</em> imaging and quantification in both peripheral organs and the central nervous system (CNS), could significantly advance the development of effective V1a inhibitors. To address this need, we develop a novel V1a-targeted positron emission tomography (PET) ligand, [<sup>18</sup>F]V1A-2303 ([<sup>18</sup>F]<strong>8</strong>), which demonstrates favorable <em>in vitro</em> binding affinity and selectivity for the V1a receptor. Specific tracer binding in peripheral tissues was also confirmed through rigorous cell uptake studies, autoradiography, biodistribution assessments. Furthermore, [<sup>18</sup>F]<strong>8</strong> was employed in PET imaging and arterial blood sampling studies in healthy rhesus monkeys to assess its brain permeability and specificity, whole-body distribution, and kinetic properties. Our research indicated [<sup>18</sup>F]<strong>8</strong> as a valuable tool for noninvasively studying V1a receptors in peripheral organs, and as a foundational element for the development of next-generation, brain-penetrant ligands specifically designed for the CNS.</p></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 9","pages":"Pages 4014-4027"},"PeriodicalIF":14.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211383524002296/pdfft?md5=32b93366e822a62bc8cd622576bed926&pid=1-s2.0-S2211383524002296-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141280011","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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Allosteric regulation of Keap1 by 8β-hydroxy-α-cyclocostunolide for the treatment of acute lung injury 8β-hydroxy-α-cyclocostunolide 对 Keap1 的异位调节用于治疗急性肺损伤

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-09-01 DOI: 10.1016/j.apsb.2024.06.025

引用次数: 0

Cover Story 封面故事

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-09-01 DOI: 10.1016/S2211-3835(24)00298-3

引用次数: 0

Current status and trends in small nucleic acid drug development: Leading the future 小核酸药物开发的现状和趋势：引领未来

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-09-01 DOI: 10.1016/j.apsb.2024.05.008

{"title":"Current status and trends in small nucleic acid drug development: Leading the future","authors":"","doi":"10.1016/j.apsb.2024.05.008","DOIUrl":"10.1016/j.apsb.2024.05.008","url":null,"abstract":"<div><p>Small nucleic acid drugs, composed of nucleotides, represent a novel class of pharmaceuticals that differ significantly from conventional small molecule and antibody-based therapeutics. These agents function by selectively targeting specific genes or their corresponding messenger RNAs (mRNAs), further modulating gene expression and regulating translation-related processes. Prominent examples within this category include antisense oligonucleotides (ASO), small interfering RNAs (siRNAs), microRNAs (miRNAs), and aptamers. The emergence of small nucleic acid drugs as a focal point in contemporary biopharmaceutical research is attributed to their remarkable specificity, facile design, abbreviated development cycles, expansive target spectrum, and prolonged activity. Overcoming challenges such as poor stability, immunogenicity, and permeability issues have been addressed through the integration of chemical modifications and the development of drug delivery systems. This review provides an overview of the current status and prospective trends in small nucleic acid drug development. Commencing with a historical context, we introduce the primary classifications and mechanisms of small nucleic acid drugs. Subsequently, we delve into the advantages of the U.S. Food and Drug Administration (FDA) approved drugs and mainly discuss the challenges encountered during their development. Apart from researching chemical modification and delivery system that efficiently deliver and enrich small nucleic acid drugs to target tissues, promoting endosomal escape is a critical scientific question and important research direction in siRNA drug development. Future directions in this field will prioritize addressing these challenges to facilitate the clinical transformation of small nucleic acid drugs.</p></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 9","pages":"Pages 3802-3817"},"PeriodicalIF":14.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211383524001850/pdfft?md5=447adc0ec646836acd3aa58994d7de39&pid=1-s2.0-S2211383524001850-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141028434","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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Unveiling ferroptosis as a promising therapeutic avenue for colorectal cancer and colitis treatment 揭示铁蛋白沉积是治疗结直肠癌和结肠炎的有效途径

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-09-01 DOI: 10.1016/j.apsb.2024.05.025

引用次数: 0

CRISPR-Cas9 gene editing strengthens cuproptosis/chemodynamic/ferroptosis synergistic cancer therapy CRISPR-Cas9 基因编辑技术加强了杯突症/化学动力学/铁突症的癌症协同疗法

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-09-01 DOI: 10.1016/j.apsb.2024.05.029

{"title":"CRISPR-Cas9 gene editing strengthens cuproptosis/chemodynamic/ferroptosis synergistic cancer therapy","authors":"","doi":"10.1016/j.apsb.2024.05.029","DOIUrl":"10.1016/j.apsb.2024.05.029","url":null,"abstract":"<div><p>Copper-based nanomaterials demonstrate promising potential in cancer therapy. Cu<sup>+</sup> efficiently triggers a Fenton-like reaction and further consumes the high level of glutathione, initiating chemical dynamic therapy (CDT) and ferroptosis. Cuproptosis, a newly identified cell death modality that represents a great prospect in cancer therapy, is activated. However, active homeostatic systems rigorously keep copper levels within cells exceptionally low, which hinders the application of cooper nanomaterials-based therapy. Herein, a novel strategy of CRISPR-Cas9 RNP nanocarrier to deliver cuprous ions and suppress the expression of copper transporter protein ATP7A for maintaining a high level of copper in cytoplasmic fluid is developed. The Cu<sub>2</sub>O and organosilica shell would degrade under the high level of glutathione and weak acidic environment, further releasing RNP and Cu<sup>+</sup>. The liberated Cu<sup>+</sup> triggered a Fenton-like reaction for CDT and partially transformed to Cu<sup>2+</sup>, consuming intracellular GSH and initiating cuproptosis and ferroptosis efficiently. Meanwhile, the release of RNP effectively reduced the expression of copper transporter ATP7A, subsequently increasing the accumulation of cooper and enhancing the efficacy of CDT, cuproptosis, and ferroptosis. Such tumor microenvironment responsive multimodal nanoplatform opens an ingenious avenue for colorectal cancer therapy based on gene editing enhanced synergistic cuproptosis/CDT/ferroptosis.</p></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 9","pages":"Pages 4059-4072"},"PeriodicalIF":14.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211383524002259/pdfft?md5=5ee9fb05f17131fb93692527bdc9ccea&pid=1-s2.0-S2211383524002259-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141391511","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