Acta Pharmaceutica Sinica. B最新文献

英文中文

The homotherapy for heteropathy: GCGR/GLP1R pathway in fibrotic diseases

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2025.01.013

Yang Sun

引用次数: 0

Cocrystal pleomorphism-inspired drug nanoassembly for pulmonary-endothelium targeting and pulmonary hypertension treatment

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.11.008

Makhloufi Zoulikha , Jiahui Zou , Pei Yang , Jun Wu , Wei Wu , Kun Hao , Wei He

Endothelial dysfunction is one of the early triggers of vascular remodeling during pulmonary hypertension (PH) with complex predisposing mechanisms, mainly via an unbalanced generation of vasoactive factors, increased expression of growth factors, prothrombotic elements, and inflammatory markers. Conventional treatment regimens are restricted to a single therapeutic pathway, which usually leads to limited clinical outcomes. Combination therapies targeting multiple cells and several signaling pathways are increasingly adopted in PH treatment. Herein, inspired by the cocrystal pleomorphism theory, we prepared rod-shaped nanococrystals of the endothelin-1 (ET-1) receptor antagonist (bosentan, BST) and the anti-inflammatory drug (andrographolide, AG) for targeting the pulmonary endothelium and alleviating PH. The 525 nm-sized co-delivery system displayed a rod-like morphology, preferentially accumulated in the pulmonary endothelium and alleviated pulmonary artery (PA) remodeling. A three-week treatment with the preparation significantly alleviated the monocrotaline (MCT)- or Sugen 5416/hypoxia (SuHx)-induced PH by reducing the pulmonary artery pressure, increasing the survival rate, improving the hemodynamics, and inhibiting vascular remodeling. Mechanistically, the nanococrystals collaboratively repaired endothelial dysfunction by suppressing the pathways of ET-1/NF-κB/ICAM-1/TNF-α/IL-6. In conclusion, the cocrystal-based strategy offers a promising approach for constructing co-delivery systems. The developed rod-shaped nanococrystals effectively target the pulmonary endothelium and relieve experimental PH.

{"title":"Cocrystal pleomorphism-inspired drug nanoassembly for pulmonary-endothelium targeting and pulmonary hypertension treatment","authors":"Makhloufi Zoulikha , Jiahui Zou , Pei Yang , Jun Wu , Wei Wu , Kun Hao , Wei He","doi":"10.1016/j.apsb.2024.11.008","DOIUrl":"10.1016/j.apsb.2024.11.008","url":null,"abstract":"<div><div>Endothelial dysfunction is one of the early triggers of vascular remodeling during pulmonary hypertension (PH) with complex predisposing mechanisms, mainly <em>via</em> an unbalanced generation of vasoactive factors, increased expression of growth factors, prothrombotic elements, and inflammatory markers. Conventional treatment regimens are restricted to a single therapeutic pathway, which usually leads to limited clinical outcomes. Combination therapies targeting multiple cells and several signaling pathways are increasingly adopted in PH treatment. Herein, inspired by the cocrystal pleomorphism theory, we prepared rod-shaped nanococrystals of the endothelin-1 (ET-1) receptor antagonist (bosentan, BST) and the anti-inflammatory drug (andrographolide, AG) for targeting the pulmonary endothelium and alleviating PH. The 525 nm-sized co-delivery system displayed a rod-like morphology, preferentially accumulated in the pulmonary endothelium and alleviated pulmonary artery (PA) remodeling. A three-week treatment with the preparation significantly alleviated the monocrotaline (MCT)- or Sugen 5416/hypoxia (SuHx)-induced PH by reducing the pulmonary artery pressure, increasing the survival rate, improving the hemodynamics, and inhibiting vascular remodeling. Mechanistically, the nanococrystals collaboratively repaired endothelial dysfunction by suppressing the pathways of ET-1/NF-<em>κ</em>B/ICAM-1/TNF-<em>α</em>/IL-6. In conclusion, the cocrystal-based strategy offers a promising approach for constructing co-delivery systems. The developed rod-shaped nanococrystals effectively target the pulmonary endothelium and relieve experimental PH.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 557-570"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388379","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

GSFM: A genome-scale functional module transformation to represent drug efficacy for in silico drug discovery GSFM：用于表示药物疗效的基因组尺度功能模块转换，以促进硅学药物发现

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.08.017

Saisai Tian , Xuyang Liao , Wen Cao , Xinyi Wu , Zexi Chen , Jinyuan Lu , Qun Wang , Jinbo Zhang , Luonan Chen , Weidong Zhang

Pharmacotranscriptomic profiles, which capture drug-induced changes in gene expression, offer vast potential for computational drug discovery and are widely used in modern medicine. However, current computational approaches neglected the associations within gene‒gene functional networks and unrevealed the systematic relationship between drug efficacy and the reversal effect. Here, we developed a new genome-scale functional module (GSFM) transformation framework to quantitatively evaluate drug efficacy for in silico drug discovery. GSFM employs four biologically interpretable quantifiers: GSFM_Up, GSFM_Down, GSFM_ssGSEA, and GSFM_TF to comprehensively evaluate the multi-dimension activities of each functional module (FM) at gene-level, pathway-level, and transcriptional regulatory network-level. Through a data transformation strategy, GSFM effectively converts noisy and potentially unreliable gene expression data into a more dependable FM active matrix, significantly outperforming other methods in terms of both robustness and accuracy. Besides, we found a positive correlation between RS_GSFM and drug efficacy, suggesting that RS_GSFM could serve as representative measure of drug efficacy. Furthermore, we identified WYE-354, perhexiline, and NTNCB as candidate therapeutic agents for the treatment of breast-invasive carcinoma, lung adenocarcinoma, and castration-resistant prostate cancer, respectively. The results from in vitro and in vivo experiments have validated that all identified compounds exhibit potent anti-tumor effects, providing proof-of-concept for our computational approach.

药物转录组图谱捕捉了药物诱导的基因表达变化，为计算药物发现提供了巨大潜力，并在现代医学中得到广泛应用。然而，目前的计算方法忽视了基因-基因功能网络中的关联，也没有揭示药物疗效与逆转效应之间的系统关系。在此，我们开发了一种新的基因组尺度功能模块（GSFM）转换框架，用于定量评估药物疗效，以促进药物发现。GSFM 采用了四个可从生物学角度解释的量化指标：GSFM_Up、GSFM_Down、GSFM_ssGSEA 和 GSFM_TF，以全面评估每个功能模块（FM）在基因水平、通路水平和转录调控网络水平的多维度活动。通过数据转换策略，GSFM有效地将有噪声和潜在不可靠的基因表达数据转换成更可靠的功能模块活性矩阵，在鲁棒性和准确性方面都明显优于其他方法。此外，我们还发现 RS 与药物疗效之间存在正相关，这表明 RS 可以作为药物疗效的代表性指标。此外，我们还发现 WYE-354、perhexiline 和 NTNCB 分别是治疗乳腺浸润性癌、肺腺癌和阉割抵抗性前列腺癌的候选药物。实验结果验证了所有确定的化合物都具有强大的抗肿瘤作用，为我们的计算方法提供了概念证明。

{"title":"GSFM: A genome-scale functional module transformation to represent drug efficacy for in silico drug discovery","authors":"Saisai Tian , Xuyang Liao , Wen Cao , Xinyi Wu , Zexi Chen , Jinyuan Lu , Qun Wang , Jinbo Zhang , Luonan Chen , Weidong Zhang","doi":"10.1016/j.apsb.2024.08.017","DOIUrl":"10.1016/j.apsb.2024.08.017","url":null,"abstract":"<div><div>Pharmacotranscriptomic profiles, which capture drug-induced changes in gene expression, offer vast potential for computational drug discovery and are widely used in modern medicine. However, current computational approaches neglected the associations within gene‒gene functional networks and unrevealed the systematic relationship between drug efficacy and the reversal effect. Here, we developed a new genome-scale functional module (GSFM) transformation framework to quantitatively evaluate drug efficacy for <em>in silico</em> drug discovery. GSFM employs four biologically interpretable quantifiers: GSFM_Up, GSFM_Down, GSFM_ssGSEA, and GSFM_TF to comprehensively evaluate the multi-dimension activities of each functional module (FM) at gene-level, pathway-level, and transcriptional regulatory network-level. Through a data transformation strategy, GSFM effectively converts noisy and potentially unreliable gene expression data into a more dependable FM active matrix, significantly outperforming other methods in terms of both robustness and accuracy. Besides, we found a positive correlation between RS<sub>GSFM</sub> and drug efficacy, suggesting that RS<sub>GSFM</sub> could serve as representative measure of drug efficacy. Furthermore, we identified WYE-354, perhexiline, and NTNCB as candidate therapeutic agents for the treatment of breast-invasive carcinoma, lung adenocarcinoma, and castration-resistant prostate cancer, respectively. The results from <em>in vitro</em> and <em>in vivo</em> experiments have validated that all identified compounds exhibit potent anti-tumor effects, providing proof-of-concept for our computational approach.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 133-150"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186907","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

YOD1 regulates microglial homeostasis by deubiquitinating MYH9 to promote the pathogenesis of Alzheimer's disease

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.11.020

Jinfeng Sun , Fan Chen , Lingyu She , Yuqing Zeng , Hao Tang , Bozhi Ye , Wenhua Zheng , Li Xiong , Liwei Li , Luyao Li , Qin Yu , Linjie Chen , Wei Wang , Guang Liang , Xia Zhao

Alzheimer's disease (AD) is the major form of dementia in the elderly and is closely related to the toxic effects of microglia sustained activation. In AD, sustained microglial activation triggers impaired synaptic pruning, neuroinflammation, neurotoxicity, and cognitive deficits. Accumulating evidence has demonstrated that aberrant expression of deubiquitinating enzymes is associated with regulating microglia function. Here, we use RNA sequencing to identify a deubiquitinase YOD1 as a regulator of microglial function and AD pathology. Further study showed that YOD1 knockout significantly improved the migration, phagocytosis, and inflammatory response of microglia, thereby improving the cognitive impairment of AD model mice. Through LC–MS/MS analysis combined with Co-IP, we found that Myosin heavy chain 9 (MYH9), a key regulator maintaining microglia homeostasis, is an interacting protein of YOD1. Mechanistically, YOD1 binds to MYH9 and maintains its stability by removing the K48 ubiquitin chain from MYH9, thereby mediating the microglia polarization signaling pathway to mediate microglia homeostasis. Taken together, our study reveals a specific role of microglial YOD1 in mediating microglia homeostasis and AD pathology, which provides a potential strategy for targeting microglia to treat AD.

{"title":"YOD1 regulates microglial homeostasis by deubiquitinating MYH9 to promote the pathogenesis of Alzheimer's disease","authors":"Jinfeng Sun , Fan Chen , Lingyu She , Yuqing Zeng , Hao Tang , Bozhi Ye , Wenhua Zheng , Li Xiong , Liwei Li , Luyao Li , Qin Yu , Linjie Chen , Wei Wang , Guang Liang , Xia Zhao","doi":"10.1016/j.apsb.2024.11.020","DOIUrl":"10.1016/j.apsb.2024.11.020","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is the major form of dementia in the elderly and is closely related to the toxic effects of microglia sustained activation. In AD, sustained microglial activation triggers impaired synaptic pruning, neuroinflammation, neurotoxicity, and cognitive deficits. Accumulating evidence has demonstrated that aberrant expression of deubiquitinating enzymes is associated with regulating microglia function. Here, we use RNA sequencing to identify a deubiquitinase YOD1 as a regulator of microglial function and AD pathology. Further study showed that YOD1 knockout significantly improved the migration, phagocytosis, and inflammatory response of microglia, thereby improving the cognitive impairment of AD model mice. Through LC–MS/MS analysis combined with Co-IP, we found that Myosin heavy chain 9 (MYH9), a key regulator maintaining microglia homeostasis, is an interacting protein of YOD1. Mechanistically, YOD1 binds to MYH9 and maintains its stability by removing the K48 ubiquitin chain from MYH9, thereby mediating the microglia polarization signaling pathway to mediate microglia homeostasis. Taken together, our study reveals a specific role of microglial YOD1 in mediating microglia homeostasis and AD pathology, which provides a potential strategy for targeting microglia to treat AD.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 331-348"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388191","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

Drofenine as a Kv2.1 inhibitor alleviated AD-like pathology in mice through Aβ/Kv2.1/microglial NLRP3/neuronal Tau axis

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.11.010

Jian Lu , Qian Zhou , Danyang Zhu , Hongkuan Song , Guojia Xie , Xuejian Zhao , Yujie Huang , Peng Cao , Jiaying Wang , Xu Shen

Alzheimer's disease (AD) is a neurodegenerative disease with clinical hallmarks of progressive cognitive impairment. Synergistic effects of the Aβ-Tau cascade reaction are tightly implicated in AD pathology, and microglial NLRP3 inflammasome activation drives neuronal tauopathy. However, the underlying mechanism of how Aβ mediates NLRP3 inflammasome remains unclear. Herein, we determined that oligomeric Aβ (o-Aβ) bound to microglial Kv2.1 and promoted Kv2.1-dependent potassium efflux to activate NLRP3 inflammasome resulting in neuronal tauopathy by using Kv2.1 inhibitor drofenine (Dfe) as a probe. The underlying mechanism has been intensively investigated by assays with Kv2.1 knockdown in vitro (si-Kv2.1) and in vivo (AAV-ePHP-si-Kv2.1). Dfe deprived o-Aβ of its capability to promote microglial NLRP3 inflammasome activation and neuronal Tau hyperphosphorylation by inhibiting the Kv2.1/JNK/NF-κB pathway while improving the cognitive impairment of 5×FAD-AD model mice. Our results have highly addressed that the Kv2.1 channel is required for o-Aβ-driven microglial NLRP3 inflammasome activation and neuronal tauopathy in AD model mice and highlighted that Dfe as a Kv2.1 inhibitor shows potential in the treatment of AD.

{"title":"Drofenine as a Kv2.1 inhibitor alleviated AD-like pathology in mice through Aβ/Kv2.1/microglial NLRP3/neuronal Tau axis","authors":"Jian Lu , Qian Zhou , Danyang Zhu , Hongkuan Song , Guojia Xie , Xuejian Zhao , Yujie Huang , Peng Cao , Jiaying Wang , Xu Shen","doi":"10.1016/j.apsb.2024.11.010","DOIUrl":"10.1016/j.apsb.2024.11.010","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a neurodegenerative disease with clinical hallmarks of progressive cognitive impairment. Synergistic effects of the A<em>β</em>-Tau cascade reaction are tightly implicated in AD pathology, and microglial NLRP3 inflammasome activation drives neuronal tauopathy. However, the underlying mechanism of how A<em>β</em> mediates NLRP3 inflammasome remains unclear. Herein, we determined that oligomeric A<em>β</em> (o-A<em>β</em>) bound to microglial Kv2.1 and promoted Kv2.1-dependent potassium efflux to activate NLRP3 inflammasome resulting in neuronal tauopathy by using Kv2.1 inhibitor drofenine (Dfe) as a probe. The underlying mechanism has been intensively investigated by assays with Kv2.1 knockdown <em>in vitro</em> (<em>si-Kv2.1</em>) and <em>in vivo</em> (AAV-ePHP-<em>si-Kv2.1</em>). Dfe deprived o-A<em>β</em> of its capability to promote microglial NLRP3 inflammasome activation and neuronal Tau hyperphosphorylation by inhibiting the Kv2.1/JNK/NF-<em>κ</em>B pathway while improving the cognitive impairment of 5×FAD-AD model mice. Our results have highly addressed that the Kv2.1 channel is required for o-A<em>β</em>-driven microglial NLRP3 inflammasome activation and neuronal tauopathy in AD model mice and highlighted that Dfe as a Kv2.1 inhibitor shows potential in the treatment of AD.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 371-391"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388193","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

Dimeric natural product panepocyclinol A inhibits STAT3 via di-covalent modification

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.10.001

Li Li , Yuezhou Wang , Yiqiu Wang , Xiaoyang Li , Qihong Deng , Fei Gao , Wenhua Lian , Yunzhan Li , Fu Gui , Yanling Wei , Su-Jie Zhu , Cai-Hong Yun , Lei Zhang , Zhiyu Hu , Qingyan Xu , Xiaobing Wu , Lanfen Chen , Dawang Zhou , Jianming Zhang , Fei Xia , Xianming Deng

Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

{"title":"Dimeric natural product panepocyclinol A inhibits STAT3 via di-covalent modification","authors":"Li Li , Yuezhou Wang , Yiqiu Wang , Xiaoyang Li , Qihong Deng , Fei Gao , Wenhua Lian , Yunzhan Li , Fu Gui , Yanling Wei , Su-Jie Zhu , Cai-Hong Yun , Lei Zhang , Zhiyu Hu , Qingyan Xu , Xiaobing Wu , Lanfen Chen , Dawang Zhou , Jianming Zhang , Fei Xia , Xianming Deng","doi":"10.1016/j.apsb.2024.10.001","DOIUrl":"10.1016/j.apsb.2024.10.001","url":null,"abstract":"<div><div>Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma <em>in vitro</em> and <em>in vivo,</em> especially those with constitutively activated STAT3 or STAT3<sup>Y640F</sup>. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 409-423"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388201","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

Discovery of a novel AhR–CYP1A1 axis activator for mitigating inflammatory diseases using an in situ functional imaging assay

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.09.014

Feng Zhang , Bei Zhao , Yufan Fan , Lanhui Qin , Jinhui Shi , Lin Chen , Leizhi Xu , Xudong Jin , Mengru Sun , Hongping Deng , Hairong Zeng , Zhangping Xiao , Xin Yang , Guangbo Ge

The aryl hydrocarbon receptor (AhR) plays a crucial role in regulating many physiological processes. Activating the AhR–CYP1A1 axis has emerged as a novel therapeutic strategy against various inflammatory diseases. Here, a practical in situ cell-based fluorometric assay was constructed to screen AhR-CYP1A1 axis modulators, via functional sensing of CYP1A1 activities in live cells. Firstly, a cell-permeable, isoform-specific enzyme-activable fluorogenic substrate for CYP1A1 was rationally constructed for in-situ visualizing the dynamic changes of CYP1A1 function in living systems, which was subsequently used for discovering the efficacious modulators of the AhR–CYP1A1 axis. Following screening of a compound library, LAC-7 was identified as an efficacious activator of the AhR–CYP1A1 axis, which dose-dependently up-regulated the expression levels of both CYP1A1 and AhR in multiple cell lines. LAC-7 also suppressed macrophage M1 polarization and reduced the levels of inflammatory factors in LPS-induced bone marrow-derived macrophages. Animal tests showed that LAC-7 could significantly mitigate DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice, and markedly reduced the levels of multiple inflammatory factors. Collectively, an optimized fluorometric cell-based assay was devised for in situ functional imaging of CYP1A1 activities in living systems, which strongly facilitated the discovery of efficacious modulators of the AhR–CYP1A1 axis as novel anti-inflammatory agents.

{"title":"Discovery of a novel AhR–CYP1A1 axis activator for mitigating inflammatory diseases using an in situ functional imaging assay","authors":"Feng Zhang , Bei Zhao , Yufan Fan , Lanhui Qin , Jinhui Shi , Lin Chen , Leizhi Xu , Xudong Jin , Mengru Sun , Hongping Deng , Hairong Zeng , Zhangping Xiao , Xin Yang , Guangbo Ge","doi":"10.1016/j.apsb.2024.09.014","DOIUrl":"10.1016/j.apsb.2024.09.014","url":null,"abstract":"<div><div>The aryl hydrocarbon receptor (AhR) plays a crucial role in regulating many physiological processes. Activating the AhR–CYP1A1 axis has emerged as a novel therapeutic strategy against various inflammatory diseases. Here, a practical <em>in situ</em> cell-based fluorometric assay was constructed to screen AhR-CYP1A1 axis modulators, <em>via</em> functional sensing of CYP1A1 activities in live cells. Firstly, a cell-permeable, isoform-specific enzyme-activable fluorogenic substrate for CYP1A1 was rationally constructed for <em>in-situ</em> visualizing the dynamic changes of CYP1A1 function in living systems, which was subsequently used for discovering the efficacious modulators of the AhR–CYP1A1 axis. Following screening of a compound library, <strong>LAC-7</strong> was identified as an efficacious activator of the AhR–CYP1A1 axis, which dose-dependently up-regulated the expression levels of both CYP1A1 and AhR in multiple cell lines. <strong>LAC-7</strong> also suppressed macrophage M1 polarization and reduced the levels of inflammatory factors in LPS-induced bone marrow-derived macrophages. Animal tests showed that <strong>LAC-7</strong> could significantly mitigate DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice, and markedly reduced the levels of multiple inflammatory factors. Collectively, an optimized fluorometric cell-based assay was devised for <em>in situ</em> functional imaging of CYP1A1 activities in living systems, which strongly facilitated the discovery of efficacious modulators of the AhR–CYP1A1 axis as novel anti-inflammatory agents.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 508-525"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388203","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

Iron and siRNA co-encapsulated ferritin nanocages induce ferroptosis synergistically for cancer therapy

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.10.006

Danni Liu , Yaoqi Wang , Qi Sun , Dong Mei , Xiaoling Wang , Yan Su , Jie Zhang , Ran Huo , Yang Tian , Siyu Liu , Shuang Zhang , Chunying Cui

Ferroptosis has received great attention as an iron-dependent programmed cell death for efficient cancer therapy. However, with the accumulation of iron in tumor cells, the antioxidant system is activated by reducing glutathione (GSH) with glutathione peroxidase 4 (GPX4), which critically limits the ferroptosis therapeutic effect. Herein, an iron and GPX4 silencing siRNA (siGPX4) co-encapsulated ferritin nanocage (HFn@Fe/siGPX4) was developed to enhance ferroptosis by disruption of redox homeostasis and inhibition of antioxidant enzyme synergistically. The siGPX4 were loaded into the nanocages by pre-incubated with iron, which could significantly improve the loading efficiency of the gene drugs when compared with the reported gene drug loading strategy by ferritin nanocages. And more iron was overloaded into the ferritin through the diffusion method. When HFn@Fe/siGPX4 was taken up by human breast cancer cell MCF-7 in a TfR1-mediated pathway, the excess iron ions in the drug delivery system could for one thing induce ferroptosis by the production of reactive oxygen species (ROS), for another promote siGPX4 escaping from the lysosome to exert gene silencing effect more effectively. Both the in vitro and in vivo results demonstrated that HFn@Fe/siGPX4 could significantly inhibit tumor growth by synergistical ferroptosis. Thus, the developed HFn@Fe/siGPX4 afforded a combined ferroptosis strategy for ferroptosis-based antitumor as well as a novel and efficient gene drug delivery system.

{"title":"Iron and siRNA co-encapsulated ferritin nanocages induce ferroptosis synergistically for cancer therapy","authors":"Danni Liu , Yaoqi Wang , Qi Sun , Dong Mei , Xiaoling Wang , Yan Su , Jie Zhang , Ran Huo , Yang Tian , Siyu Liu , Shuang Zhang , Chunying Cui","doi":"10.1016/j.apsb.2024.10.006","DOIUrl":"10.1016/j.apsb.2024.10.006","url":null,"abstract":"<div><div>Ferroptosis has received great attention as an iron-dependent programmed cell death for efficient cancer therapy. However, with the accumulation of iron in tumor cells, the antioxidant system is activated by reducing glutathione (GSH) with glutathione peroxidase 4 (GPX4), which critically limits the ferroptosis therapeutic effect. Herein, an iron and GPX4 silencing siRNA (siGPX4) co-encapsulated ferritin nanocage (HFn@Fe/siGPX4) was developed to enhance ferroptosis by disruption of redox homeostasis and inhibition of antioxidant enzyme synergistically. The siGPX4 were loaded into the nanocages by pre-incubated with iron, which could significantly improve the loading efficiency of the gene drugs when compared with the reported gene drug loading strategy by ferritin nanocages. And more iron was overloaded into the ferritin through the diffusion method. When HFn@Fe/siGPX4 was taken up by human breast cancer cell MCF-7 in a TfR1-mediated pathway, the excess iron ions in the drug delivery system could for one thing induce ferroptosis by the production of reactive oxygen species (ROS), for another promote siGPX4 escaping from the lysosome to exert gene silencing effect more effectively. Both the <em>in vitro</em> and <em>in vivo</em> results demonstrated that HFn@Fe/siGPX4 could significantly inhibit tumor growth by synergistical ferroptosis. Thus, the developed HFn@Fe/siGPX4 afforded a combined ferroptosis strategy for ferroptosis-based antitumor as well as a novel and efficient gene drug delivery system.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 526-541"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388204","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

Free fatty acid receptor-4 regulates T-cell-mediated allogeneic reaction through activating an aryl hydrocarbon receptor pathway

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.12.011

Maxwell Duah , Fei Zheng , Jingyi Shen , Yan Xu , Shuo Cao , Zhiling Yan , Qiu Lan , Ying Wang , Kailin Xu , Bin Pan

Targeting T-cell is a strategy to control allogeneic response disorders, such as acute graft-versus-host disease (GVHD) which is an important cause of therapy-failure after allogeneic hematopoietic cell transplants. Free fatty acid receptor-4 (FFAR4) is a regulator of obesity but its role in T-cell and allogeneic reactions is unknown. Here, we found knockout of Ffar4 in donor T-cells in a mouse allograft model increased acute GVHD whereas the natural FFAR4 ligands and the synthetic FFAR4 agonists decreased it. FFAR4 agonist-mediated anti-acute GVHD effects depended on FFAR4-expression in donor T-cells. The FFAR4 agonist CpdA suppressed donor T-cell-mediated alloreaction by activating an aryl hydrocarbon receptor (AhR) pathway. CpdA recruited β-Arrestin2 to FFAR4 which facilitated nuclear translocation of AhR and upregulation of IL-22. The CpdA-mediated anti-acute GVHD effect was absent in mice receiving Ahr-knockout or Il22-knockout T-cells. Recipient-expressing Ffar4 was also important for the anti-acute GVHD effect of CpdA which inhibited activation of antigen presenting cells. Importantly, CpdA decreased acute GVHD in obese mice, an effect also depended on Ffar4-expression in donor T-cells and recipients. Our study shows the immunoregulatory effect of FFAR4 in T-cell, and targeting FFAR4 might be a relative option for controlling allogeneic reactions in obese patients.

{"title":"Free fatty acid receptor-4 regulates T-cell-mediated allogeneic reaction through activating an aryl hydrocarbon receptor pathway","authors":"Maxwell Duah , Fei Zheng , Jingyi Shen , Yan Xu , Shuo Cao , Zhiling Yan , Qiu Lan , Ying Wang , Kailin Xu , Bin Pan","doi":"10.1016/j.apsb.2024.12.011","DOIUrl":"10.1016/j.apsb.2024.12.011","url":null,"abstract":"<div><div>Targeting T-cell is a strategy to control allogeneic response disorders, such as acute graft-versus-host disease (GVHD) which is an important cause of therapy-failure after allogeneic hematopoietic cell transplants. Free fatty acid receptor-4 (FFAR4) is a regulator of obesity but its role in T-cell and allogeneic reactions is unknown. Here, we found knockout of <em>Ffar4</em> in donor T-cells in a mouse allograft model increased acute GVHD whereas the natural FFAR4 ligands and the synthetic FFAR4 agonists decreased it. FFAR4 agonist-mediated anti-acute GVHD effects depended on FFAR4-expression in donor T-cells. The FFAR4 agonist CpdA suppressed donor T-cell-mediated alloreaction by activating an aryl hydrocarbon receptor (AhR) pathway. CpdA recruited <em>β</em>-Arrestin2 to FFAR4 which facilitated nuclear translocation of AhR and upregulation of IL-22. The CpdA-mediated anti-acute GVHD effect was absent in mice receiving <em>Ahr</em>-knockout or <em>Il22</em>-knockout T-cells. Recipient-expressing <em>Ffar4</em> was also important for the anti-acute GVHD effect of CpdA which inhibited activation of antigen presenting cells. Importantly, CpdA decreased acute GVHD in obese mice, an effect also depended on <em>Ffar4</em>-expression in donor T-cells and recipients. Our study shows the immunoregulatory effect of FFAR4 in T-cell, and targeting FFAR4 might be a relative option for controlling allogeneic reactions in obese patients.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 224-238"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388278","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

Regulation of histidine metabolism by Lactobacillus Reuteri mediates the pathogenesis and treatment of ischemic stroke

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.10.003

Kangrui Hu , Zhihao Zhou , Haofeng Li , Jijun Xiao , Yun Shen , Ke Ding , Tingting Zhang , Guangji Wang , Haiping Hao , Yan Liang

Increasing evidence has underscored the significance of post-stroke alterations along gut–brain axis, while its role in pathogenesis and treatment of ischemic stroke (IS) remains largely unexplored. This study aimed to elucidate the therapeutic effects and action targets of Panax notoginseng saponins (PNS) on IS and explore a novel pathogenesis and treatment strategy of IS via profiling the microbial community and metabolic characteristics along gut–brain axis. Our findings revealed for the first time that the therapeutic effect of PNS on IS was microbiota-dependent. Ischemia/reperfusion (I/R) modeling significantly down-regulated Lactobacilli in rats, and PNS markedly recovered Lactobacilli, particularly Lactobacillus reuteri (L.Reu). Metabolomics showed a significant reduction in serum histidine (HIS) in clinical obsolete IS patients and rehabilitation period I/R rats. Meanwhile, the L.Reu colonization in I/R rats exhibited significant neuroprotective activity and greatly increased HIS in serum, gut microbiota, and brain. Moreover, exogenous HIS demonstrated indirect neuroprotective effects through metabolizing to histamine. Notably, vagus nerve severance in I/R rats was performed to investigate HIS's neuroprotective mechanism. The results innovatively revealed that PNS could promote HIS synthesis in gut by enhancing L.Reu proportion, thereby increasing intracerebral HIS through peripheral pathway. Consequently, our data provided novel insights into HIS metabolism mediated by L.Reu in the pathogenesis and treatment of IS.

{"title":"Regulation of histidine metabolism by Lactobacillus Reuteri mediates the pathogenesis and treatment of ischemic stroke","authors":"Kangrui Hu , Zhihao Zhou , Haofeng Li , Jijun Xiao , Yun Shen , Ke Ding , Tingting Zhang , Guangji Wang , Haiping Hao , Yan Liang","doi":"10.1016/j.apsb.2024.10.003","DOIUrl":"10.1016/j.apsb.2024.10.003","url":null,"abstract":"<div><div>Increasing evidence has underscored the significance of post-stroke alterations along gut–brain axis, while its role in pathogenesis and treatment of ischemic stroke (IS) remains largely unexplored. This study aimed to elucidate the therapeutic effects and action targets of <em>Panax notoginseng saponins</em> (PNS) on IS and explore a novel pathogenesis and treatment strategy of IS <em>via</em> profiling the microbial community and metabolic characteristics along gut–brain axis. Our findings revealed for the first time that the therapeutic effect of PNS on IS was microbiota-dependent. Ischemia/reperfusion (I/R) modeling significantly down-regulated <em>Lactobacilli</em> in rats, and PNS markedly recovered <em>Lactobacilli</em>, particularly <em>Lactobacillus reuteri</em> (<em>L.Reu</em>). Metabolomics showed a significant reduction in serum histidine (HIS) in clinical obsolete IS patients and rehabilitation period I/R rats. Meanwhile, the <em>L.Reu</em> colonization in I/R rats exhibited significant neuroprotective activity and greatly increased HIS in serum, gut microbiota, and brain. Moreover, exogenous HIS demonstrated indirect neuroprotective effects through metabolizing to histamine. Notably, vagus nerve severance in I/R rats was performed to investigate HIS's neuroprotective mechanism. The results innovatively revealed that PNS could promote HIS synthesis in gut by enhancing <em>L.Reu</em> proportion, thereby increasing intracerebral HIS through peripheral pathway. Consequently, our data provided novel insights into HIS metabolism mediated by <em>L.Reu</em> in the pathogenesis and treatment of IS.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 239-255"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388279","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

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