Acta Pharmaceutica Sinica. B最新文献_第9页

Establishment of interpretable cytotoxicity prediction models using machine learning analysis of transcriptome features 利用机器学习分析转录组特征建立可解释的细胞毒性预测模型

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-03-01 DOI: 10.1016/j.apsb.2025.02.009

You Wu , Ke Tang , Chunzheng Wang , Hao Song , Fanfan Zhou , Ying Guo

{"title":"Establishment of interpretable cytotoxicity prediction models using machine learning analysis of transcriptome features","authors":"You Wu , Ke Tang , Chunzheng Wang , Hao Song , Fanfan Zhou , Ying Guo","doi":"10.1016/j.apsb.2025.02.009","DOIUrl":"10.1016/j.apsb.2025.02.009","url":null,"abstract":"<div><div>Cytotoxicity, usually represented by cell viability, is a crucial parameter for evaluating drug safety <em>in vitro</em>. Accurate prediction of cell viability/cytotoxicity could accelerate drug development in the early stage. In this study, by integrating cellular transcriptome and cell viability data using four machine learning algorithms (support vector machine (SVM), random forest (RF), extreme gradient boosting (XGBoost), and light gradient boosting machine (LightGBM)) and two ensemble algorithms (voting and stacking), highly accurate prediction models of 50% and 80% cell viability were developed with area under the receiver operating characteristic curve (AUROC) of 0.90 and 0.84, respectively; these models also showed good performance when utilized for diverse cell lines. Concerning the characterization of the employed Feature Genes, the models were interpreted, and the mechanisms of bioactive compounds with a narrow therapeutic index (NTI) can also be analyzed. In summary, the models established in this research exhibit superior capacity to those of previous studies; these models enable accurate high-safety substance screening <em>via</em> cytotoxicity prediction across cell lines. Moreover, for the first time, Cytotoxicity Signature (CTS) genes were identified, which could provide additional clues for further study of mechanisms of action (MOA), especially for NTI compounds.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1344-1358"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776904","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

CDK5-triggered G6PD phosphorylation at threonine 91 facilitating redox homeostasis reveals a vulnerability in breast cancer cdk5触发的G6PD苏氨酸91磷酸化促进氧化还原稳态揭示了乳腺癌的脆弱性

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-03-01 DOI: 10.1016/j.apsb.2024.12.019

Yuncheng Bei , Sijie Wang , Rui Wang , Owais Ahmad , Meng Jia , Pengju Yao , Jianguo Ji , Pingping Shen

{"title":"CDK5-triggered G6PD phosphorylation at threonine 91 facilitating redox homeostasis reveals a vulnerability in breast cancer","authors":"Yuncheng Bei , Sijie Wang , Rui Wang , Owais Ahmad , Meng Jia , Pengju Yao , Jianguo Ji , Pingping Shen","doi":"10.1016/j.apsb.2024.12.019","DOIUrl":"10.1016/j.apsb.2024.12.019","url":null,"abstract":"<div><div>Glucose-6-phosphate dehydrogenase (G6PD), the first rate-limiting enzyme of the pentose phosphate pathway (PPP), is aberrantly activated in multiple types of human cancers, governing the progression of tumor cells as well as the efficacy of anticancer therapy. Here, we discovered that cyclin-dependent kinase 5 (CDK5) rewired glucose metabolism from glycolysis to PPP in breast cancer (BC) cells by activating G6PD to keep intracellular redox homeostasis under oxidative stress. Mechanistically, CDK5-phosphorylated G6PD at Thr-91 facilitated the assembly of inactive monomers of G6PD into active dimers. More importantly, CDK5-induced pho-G6PD was explicitly observed specifically in tumor tissues in human BC specimens. Pharmacological inhibition of CDK5 remarkably abrogated G6PD phosphorylation, attenuated tumor growth and metastasis, and synergistically sensitized BC cells to poly-ADP-ribose polymerase (PARP) inhibitor Olaparib, in xenograft mouse models. Collectively, our results establish the crucial role of CDK5-mediated phosphorylation of G6PD in BC growth and metastasis and provide a therapeutic regimen for BC treatment.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1608-1625"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776325","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

Long-chain acylcarnitine deficiency promotes hepatocarcinogenesis 长链酰基肉碱缺乏促进肝癌的发生

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-03-01 DOI: 10.1016/j.apsb.2025.01.017

Kaifeng Wang , Zhixian Lan , Heqi Zhou , Rong Fan , Huiyi Chen , Hongyan Liang , Qiuhong You , Xieer Liang , Ge Zeng , Rui Deng , Yu Lan , Sheng Shen , Peng Chen , Jinlin Hou , Pengcheng Bu , Jian Sun

{"title":"Long-chain acylcarnitine deficiency promotes hepatocarcinogenesis","authors":"Kaifeng Wang , Zhixian Lan , Heqi Zhou , Rong Fan , Huiyi Chen , Hongyan Liang , Qiuhong You , Xieer Liang , Ge Zeng , Rui Deng , Yu Lan , Sheng Shen , Peng Chen , Jinlin Hou , Pengcheng Bu , Jian Sun","doi":"10.1016/j.apsb.2025.01.017","DOIUrl":"10.1016/j.apsb.2025.01.017","url":null,"abstract":"<div><div>Despite therapy with potent antiviral agents, chronic hepatitis B (CHB) patients remain at high risk of hepatocellular carcinoma (HCC). While metabolites have been rediscovered as active drivers of biological processes including carcinogenesis, the specific metabolites modulating HCC risk in CHB patients are largely unknown. Here, we demonstrate that baseline plasma from CHB patients who later developed HCC during follow-up exhibits growth-promoting properties in a case–control design nested within a large-scale, prospective cohort. Metabolomics analysis reveals a reduction in long-chain acylcarnitines (LCACs) in the baseline plasma of patients with HCC development. LCACs preferentially inhibit the proliferation of HCC cells <em>in vitro</em> at a physiological concentration and prevent the occurrence of HCC <em>in vivo</em> without hepatorenal toxicity. Uptake and metabolism of circulating LCACs increase the intracellular level of acetyl coenzyme A, which upregulates histone H3 Lys14 acetylation at the promoter region of <em>KLF6</em> gene and thereby activates KLF6/p21 pathway. Indeed, blocking LCAC metabolism attenuates the difference in <em>KLF6/p21</em> expression induced by baseline plasma of HCC/non-HCC patients. The deficiency of circulating LCACs represents a driver of HCC in CHB patients with viral control. These insights provide a promising direction for developing therapeutic strategies to reduce HCC risk further in the antiviral era.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1383-1396"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776844","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

USP25 ameliorates vascular remodeling by deubiquitinating FOXO3 and promoting autophagic degradation of FOXO3 USP25通过去泛素化FOXO3和促进FOXO3的自噬降解来改善血管重构

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-03-01 DOI: 10.1016/j.apsb.2024.12.033

Yanghao Chen , Bozhi Ye , Diyun Xu , Wante Lin , Zimin Fang , Xuefeng Qu , Xue Han , Wu Luo , Chen Chen , Weijian Huang , Hao Zhou , Gaojun Wu , Yi Wang , Guang Liang

{"title":"USP25 ameliorates vascular remodeling by deubiquitinating FOXO3 and promoting autophagic degradation of FOXO3","authors":"Yanghao Chen , Bozhi Ye , Diyun Xu , Wante Lin , Zimin Fang , Xuefeng Qu , Xue Han , Wu Luo , Chen Chen , Weijian Huang , Hao Zhou , Gaojun Wu , Yi Wang , Guang Liang","doi":"10.1016/j.apsb.2024.12.033","DOIUrl":"10.1016/j.apsb.2024.12.033","url":null,"abstract":"<div><div>Long-term hypertension causes excessive vascular remodeling and leads to adverse cardiovascular events. Balance of ubiquitination and deubiquitination has been linked to several chronic conditions, including pathological vascular remodeling. In this study, we discovered that the expression of ubiquitin-specific protease 25 (USP25) is significantly up-regulated in angiotensin II (Ang II)-challenged mouse aorta. Knockout of Usp25 augments Ang II-induced vascular injury such as fibrosis and endothelial to mesenchymal transition (EndMT). Mechanistically, we found that USP25 interacts directly with Forkhead box O3 (FOXO3) and removes the K63-linked ubiquitin chain on the K258 site of FOXO3. We also showed that this USP25-mediated deubiquitination of FOXO3 increases its binding to light chain 3 beta isoform and autophagosomic-lysosomal degradation of FOXO3. In addition, we further validated the biological function of USP25 by overexpressing USP25 in the mouse aorta with AAV9 vectors. Our studies identified FOXO3 as a new substrate of USP25 and showed that USP25 may be a potential therapeutic target for excessive vascular remodeling-associated diseases.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1643-1658"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776389","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

Intravenous delivery of STING agonists using acid-sensitive polycationic polymer-modified lipid nanoparticles for enhanced tumor immunotherapy 利用酸敏感聚阳离子聚合物修饰的脂质纳米粒子静脉注射 STING 激动剂，增强肿瘤免疫疗法的效果

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-03-01 DOI: 10.1016/j.apsb.2024.06.004

Ying He , Ke Zheng , Xifeng Qin , Siyu Wang , Xuejing Li , Huiwen Liu , Mingyang Liu , Ruizhe Xu , Shaojun Peng , Zhiqing Pang

{"title":"Intravenous delivery of STING agonists using acid-sensitive polycationic polymer-modified lipid nanoparticles for enhanced tumor immunotherapy","authors":"Ying He , Ke Zheng , Xifeng Qin , Siyu Wang , Xuejing Li , Huiwen Liu , Mingyang Liu , Ruizhe Xu , Shaojun Peng , Zhiqing Pang","doi":"10.1016/j.apsb.2024.06.004","DOIUrl":"10.1016/j.apsb.2024.06.004","url":null,"abstract":"<div><div>Although cancer immunotherapy has made great strides in the clinic, it is still hindered by the tumor immunosuppressive microenvironment (TIME). The stimulator of interferon genes (STING) pathway which can modulate TIME effectively has emerged as a promising therapeutic recently. However, the delivery of most STING agonists, specifically cyclic dinucleotides (CDNs), is performed intratumorally due to their insufficient pharmacological properties, such as weak permeability across cell membranes and vulnerability to nuclease degradation. To expand the clinical applicability of CDNs, a novel pH-sensitive polycationic polymer-modified lipid nanoparticle (LNP-B) system was developed for intravenous delivery of CDNs. LNP-B significantly extended the circulation of CDNs and enhanced the accumulation of CDNs within the tumor, spleen, and tumor-draining lymph nodes compared with free CDNs thereby triggering the STING pathway of dendritic cells and repolarizing pro-tumor macrophages. These events subsequently gave rise to potent anti-tumor immune reactions and substantial inhibition of tumors in CT26 colon cancer-bearing mouse models. In addition, due to the acid-sensitive property of the polycationic polymer, the delivery system of LNP-B was more biocompatible and safer compared with lipid nanoparticles formulated with an indissociable cationic DOTAP (LNP-D). These findings suggest that LNP-B has great potential in the intravenous delivery of CDNs for tumor immunotherapy.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1211-1229"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141392949","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

STK39 inhibits antiviral immune response by inhibiting DCAF1-mediated PP2A degradation STK39通过抑制dcaf1介导的PP2A降解抑制抗病毒免疫应答

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-03-01 DOI: 10.1016/j.apsb.2024.12.034

Chengfei Zhang , Ping Xu , Yongsheng Wang , Xin Chen , Yue Pan , Zhijie Ma , Cheng Wang , Haojun Xu , Guoren Zhou , Feng Zhu , Hongping Xia

{"title":"STK39 inhibits antiviral immune response by inhibiting DCAF1-mediated PP2A degradation","authors":"Chengfei Zhang , Ping Xu , Yongsheng Wang , Xin Chen , Yue Pan , Zhijie Ma , Cheng Wang , Haojun Xu , Guoren Zhou , Feng Zhu , Hongping Xia","doi":"10.1016/j.apsb.2024.12.034","DOIUrl":"10.1016/j.apsb.2024.12.034","url":null,"abstract":"<div><div>Evading host immunity killing is a critical step for virus survival. Inhibiting viral immune escape is crucial for the treatment of viral diseases. Serine/threonine kinase 39 (STK39) was reported to play an essential role in ion homeostasis. However, its potential role and mechanism in viral infection remain unknown. In this study, we found that viral infection promoted STK39 expression. Consequently, overexpressed STK39 inhibited the phosphorylation of interferon regulatory factor 3 (IRF3) and the production of type I interferon, which led to viral replication and immune escape. Genetic ablation or pharmacological inhibition of STK39 significantly protected mice from viral infection. Mechanistically, mass spectrometry and immunoprecipitation assays identified that STK39 interacted with PPP2R1A (a scaffold subunit of protein phosphatase 2A (PP2A)) in a kinase activity-dependent manner. This interaction inhibited DDB1 and CUL4 associated factor 1 (DCAF1)-mediated PPP2R1A degradation, maintained the stabilization and phosphatase activity of PP2A, which, in turn, suppressed the phosphorylation of IRF3, decreased the production of type I interferon, and then strengthened viral replication. Thus, our study provides a novel theoretical basis for viral immune escape, and STK39 may be a potential therapeutic target for viral infectious diseases.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1535-1551"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776317","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

Novel carbazole attenuates vascular remodeling through STAT3/CIAPIN1 signaling in vascular smooth muscle cells 新型咔唑通过血管平滑肌细胞中STAT3/CIAPIN1信号通路减弱血管重构

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-03-01 DOI: 10.1016/j.apsb.2024.12.035

Joo-Hui Han , Jong-Beom Heo , Hyung-Won Lee , Min-Ho Park , Jangmi Choi , Eun Joo Yun , Seongpyo Lee , Gyu Yong Song , Chang-Seon Myung

{"title":"Novel carbazole attenuates vascular remodeling through STAT3/CIAPIN1 signaling in vascular smooth muscle cells","authors":"Joo-Hui Han , Jong-Beom Heo , Hyung-Won Lee , Min-Ho Park , Jangmi Choi , Eun Joo Yun , Seongpyo Lee , Gyu Yong Song , Chang-Seon Myung","doi":"10.1016/j.apsb.2024.12.035","DOIUrl":"10.1016/j.apsb.2024.12.035","url":null,"abstract":"<div><div>This study investigated the molecular mechanism of phenotypic switching of vascular smooth muscle cells (VSMCs), which play a crucial role in vascular remodeling using 9<em>H</em>-Carbazol-3-yl 4-aminobenzoate (CAB). CAB significantly attenuated platelet-derived growth factor (PDGF)-induced VSMC proliferation and migration. CAB suppressed PDGF-induced STAT3 activation by directly binding to the SH2 domain of STAT3. Downregulation of STAT3 phosphorylation by CAB attenuated CIAPIN1/JAK2/STAT3 axis through a decrease in CIAPIN1 transcription. Furthermore, abrogated CIAPIN1 decreased KLF4-mediated VSMC dedifferentiation and increased CDKN1B-induced cell cycle arrest and MMP9 suppression. CAB inhibited intimal hyperplasia in injury-induced neointima animal models by inhibition of the CIAPIN1/JAK2/STAT3 axis. However, CIAPIN1 overexpression attenuated CAB-mediated suppression of VSMC proliferation, migration, phenotypic switching, and intimal hyperplasia. Our study clarified the molecular mechanism underlying STAT3 inhibition of VSMC phenotypic switching and vascular remodeling and identified novel active CAB. These findings demonstrated that STAT3 can be a major regulator to control CIAPIN1/JAK2/STAT3 axis that may be a therapeutic target for treating vascular proliferative diseases.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1463-1479"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776318","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

The ubiquitin–proteasome system: A potential target for the MASLD 泛素-蛋白酶体系统：MASLD的潜在靶点

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-03-01 DOI: 10.1016/j.apsb.2025.01.010

Yue Liu , Meijia Qian , Yonghao Li , Xin Dong , Yulian Wu , Tao Yuan , Jian Ma , Bo Yang , Hong Zhu , Qiaojun He

{"title":"The ubiquitin–proteasome system: A potential target for the MASLD","authors":"Yue Liu , Meijia Qian , Yonghao Li , Xin Dong , Yulian Wu , Tao Yuan , Jian Ma , Bo Yang , Hong Zhu , Qiaojun He","doi":"10.1016/j.apsb.2025.01.010","DOIUrl":"10.1016/j.apsb.2025.01.010","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent chronic liver condition globally, lacks adequate and effective therapeutic remedies in clinical practice. Recent studies have increasingly highlighted the close connection between the ubiquitin–proteasome system (UPS) and the progression of MASLD. This relationship is crucial for understanding the disease's underlying mechanism. As a sophisticated process, the UPS govern protein stability and function, maintaining protein homeostasis, thus influencing a multitude of elements and biological events of eukaryotic cells. It comprises four enzyme families, namely, ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), ubiquitin-protein ligases (E3), and deubiquitinating enzymes (DUBs). This review aims to delve into the array of pathways and therapeutic targets implicated in the ubiquitination within the pathogenesis of MASLD. Therefore, this review unveils the role of ubiquitination in MASLD while spotlighting potential therapeutic targets within the context of this disease.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1268-1280"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776900","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

Remodeling tumor immunosuppressive microenvironment through dual activation of immunogenic panoptosis and ferroptosis by H2S-amplified nanoformulation to enhance cancer immunotherapy h2s扩增纳米制剂通过双激活免疫原性泛光和铁下垂重塑肿瘤免疫抑制微环境，增强肿瘤免疫治疗

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-03-01 DOI: 10.1016/j.apsb.2024.12.014

Yingli Luo , Maoyuan Linghu , Xianyu Luo , Dongdong Li , Jilong Wang , Shaojun Peng , Yinchu Ma

{"title":"Remodeling tumor immunosuppressive microenvironment through dual activation of immunogenic panoptosis and ferroptosis by H2S-amplified nanoformulation to enhance cancer immunotherapy","authors":"Yingli Luo , Maoyuan Linghu , Xianyu Luo , Dongdong Li , Jilong Wang , Shaojun Peng , Yinchu Ma","doi":"10.1016/j.apsb.2024.12.014","DOIUrl":"10.1016/j.apsb.2024.12.014","url":null,"abstract":"<div><div>The deficiency in immunogenicity and the presence of immunosuppression within the tumor microenvironment significantly hindered the efficacy of immunotherapy. Consequently, a nanoformulation containing metal sulfide of FeS and GSDMD plasmid (NP<sub>FeS/GD</sub>) had been developed to effectively augment antitumor immune responses through dual activation of immunogenic PANoptosis and ferroptosis, as well as reprogramming immunosuppressive effects <em>via</em> H<sub>2</sub>S amplification. The bioactive NP<sub>FeS/GD</sub> exhibited controlled release of GSDMD plasmid, H<sub>2</sub>S, and Fe<sup>2+</sup> in response to the tumor microenvironment. Fe<sup>2+</sup>, H<sub>2</sub>S, and the expression of GSDMD protein could effectively elicit highly immunogenic PANoptosis and ferroptosis. Furthermore, releasing H<sub>2</sub>S could mitigate the overexpression of indoleamine 2,3-dioxygenase1 (IDO1) induced by immunogenic PANoptotic and ferroptotic cell death and disrupt the activity of IDO1. Consequently, NP<sub>FeS/GD</sub> effectively triggered the antitumor innate and adaptive immune responses through induction of PANoptotic and ferroptotic cell death and reshaped the tumor immunosuppressive microenvironment to enhance antitumor immunotherapy for metastasis inhibition. This study unveiled the significant potential of immunogenic PANoptosis and ferroptosis in H<sub>2</sub>S gas therapy for enhancing tumor immunotherapy, offering novel insights and ideas for the rational design of nanomedicine to enhance tumor immunogenicity while reprogramming the tumor immunosuppressive microenvironment.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1242-1254"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776316","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

Comprehensive investigation of multiple targets in the development of newer drugs for the Alzheimer's disease 在开发治疗阿尔茨海默病的新药过程中对多个靶点进行综合研究

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-03-01 DOI: 10.1016/j.apsb.2024.11.016

Patil Ashwini , Bodhankar Subhash , Muthal Amol , Dileep Kumar , Pawar Atmaram , Kulkarni Ravindra

{"title":"Comprehensive investigation of multiple targets in the development of newer drugs for the Alzheimer's disease","authors":"Patil Ashwini , Bodhankar Subhash , Muthal Amol , Dileep Kumar , Pawar Atmaram , Kulkarni Ravindra","doi":"10.1016/j.apsb.2024.11.016","DOIUrl":"10.1016/j.apsb.2024.11.016","url":null,"abstract":"<div><div>Alzheimer's disease, a significant contributor to dementia, is rapidly becoming a serious healthcare concern in the 21st century. The alarming number of patients with Alzheimer's disease is steadily increasing, which is contributed by the dearth of treatment options. The current treatment for Alzheimer's disease is heavily dependent on symptomatic treatment that has failed to cure the disease despite huge investments in the development of drugs. The clinical treatment of Alzheimer's disease with limited drugs is generally targeted towards the inhibition of <em>N</em>-methyl-<span>d</span>-aspartate receptor and acetylcholine esterase, which only elevate cognition levels for a limited period. Beyond the aforementioned molecular targets, <em>β</em>-amyloid was much explored with little success and thus created a feel and palpable growing emphasis on discovering new putative and novel targets for AD. This has inspired medicinal chemists to explore new targets, including microglia, triggering receptors expressed on myeloid cells 2 (Trem-2), and notum carboxylesterase, to discover new lead compounds. This review explores the functions, pathophysiological roles, and importance of all AD-related targets that address therapeutic and preventive approaches for the treatment and protection of Alzheimer's disease.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1281-1310"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776901","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