Acta Pharmaceutica Sinica. B最新文献

英文中文

NO-releasing double-crosslinked responsive hydrogels accelerate the treatment and repair of ischemic stroke

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-02-01 DOI: 10.1016/j.apsb.2025.01.005

Wen Guo , Cheng Hu , Yue Wang , Wen Zhang , Shaomin Zhang , Jin Peng , Yunbing Wang , Jinhui Wu

Stroke is a global disease that seriously threatens human life. The pathological mechanisms of ischemic stroke include neuroinflammation, oxidative stress, and the destruction of blood vessels at the lesion site. Here, a biocompatible in situ hydrogel platform was designed to target multiple pathogenic mechanisms post-stroke, including anti-inflammation, anti-oxidant, and promotion of angiogenesis. Double-crosslinked responsive multifunctional hydrogels could quickly respond to the pathological microenvironment of the ischemic damage site and mediate the delivery of nitric oxide (NO) and ISO-1 (inhibitor of macrophage migration inhibitory factor, MIF). The hydrogel demonstrated good biocompatibility and could scavenge reactive oxygen species (ROS) and inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-10 (IL-10), and MIF. In a mouse stroke model, hydrogels, when situated within the microenvironment of cerebral infarction characterized by weak acidity and elevated ROS release, would release anti-inflammatory nanoparticles rapidly that exert an anti-inflammatory effect. Concurrently, NO was sustained release to facilitate angiogenesis and provide neuroprotective effects. Neurological function was significantly improved in treated mice as assessed by the modified neurological severity score, rotarod test, and open field test. These findings indicate that the designed hydrogel held promise for sustained delivery of NO and ISO-1 to alleviate cerebral ischemic injury by responding to the brain's pathological microenvironment.

{"title":"NO-releasing double-crosslinked responsive hydrogels accelerate the treatment and repair of ischemic stroke","authors":"Wen Guo , Cheng Hu , Yue Wang , Wen Zhang , Shaomin Zhang , Jin Peng , Yunbing Wang , Jinhui Wu","doi":"10.1016/j.apsb.2025.01.005","DOIUrl":"10.1016/j.apsb.2025.01.005","url":null,"abstract":"<div><div>Stroke is a global disease that seriously threatens human life. The pathological mechanisms of ischemic stroke include neuroinflammation, oxidative stress, and the destruction of blood vessels at the lesion site. Here, a biocompatible <em>in situ</em> hydrogel platform was designed to target multiple pathogenic mechanisms post-stroke, including anti-inflammation, anti-oxidant, and promotion of angiogenesis. Double-crosslinked responsive multifunctional hydrogels could quickly respond to the pathological microenvironment of the ischemic damage site and mediate the delivery of nitric oxide (NO) and ISO-1 (inhibitor of macrophage migration inhibitory factor, MIF). The hydrogel demonstrated good biocompatibility and could scavenge reactive oxygen species (ROS) and inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-10 (IL-10), and MIF. In a mouse stroke model, hydrogels, when situated within the microenvironment of cerebral infarction characterized by weak acidity and elevated ROS release, would release anti-inflammatory nanoparticles rapidly that exert an anti-inflammatory effect. Concurrently, NO was sustained release to facilitate angiogenesis and provide neuroprotective effects. Neurological function was significantly improved in treated mice as assessed by the modified neurological severity score, rotarod test, and open field test. These findings indicate that the designed hydrogel held promise for sustained delivery of NO and ISO-1 to alleviate cerebral ischemic injury by responding to the brain's pathological microenvironment.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 2","pages":"Pages 1112-1125"},"PeriodicalIF":14.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143591801","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

Engineering cellular dephosphorylation boosts (+)-borneol production in yeast

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-02-01 DOI: 10.1016/j.apsb.2024.12.039

Haiyan Zhang , Peng Cai , Juan Guo , Jiaoqi Gao , Linfeng Xie , Ping Su , Xiaoxin Zhai , Baolong Jin , Guanghong Cui , Yongjin J. Zhou , Luqi Huang

(+)-Borneol, the main component of "Natural Borneol" in the Chinese Pharmacopoeia, is a high-end spice and precious medicine. Plant extraction cannot meet the increasing demand for (+)-borneol, while microbial biosynthesis offers a sustainable supply route. However, its production was extremely low compared with other monoterpenes, even with extensively optimizing the mevalonate pathway. We found that the key challenge is the complex and unusual dephosphorylation reaction of bornyl diphosphate (BPP), which suffers the side-reaction and the competition from the cellular dephosphorylation process, especially lipid metabolism, thus limiting (+)-borneol synthesis. Here, we systematically optimized the dephosphorylation process by identifying, characterizing phosphatases, and balancing cellular dephosphorylation metabolism. For the first time, we identified two endogenous phosphatases and seven heterologous phosphatases, which significantly increased (+)-borneol production by up to 152%. By engineering BPP dephosphorylation and optimizing the MVA pathway, the production of (+)-borneol was increased by 33.8-fold, which enabled the production of 753 mg/L under fed-batch fermentation in shake flasks, so far the highest reported in the literature. This study showed that rewiring dephosphorylation metabolism was essential for high-level production of (+)-borneol in Saccharomyces cerevisiae, and balancing cellular dephosphorylation is also helpful for efficient biosynthesis of other terpenoids since all whose biosynthesis involves the dephosphorylation procedure.

{"title":"Engineering cellular dephosphorylation boosts (+)-borneol production in yeast","authors":"Haiyan Zhang , Peng Cai , Juan Guo , Jiaoqi Gao , Linfeng Xie , Ping Su , Xiaoxin Zhai , Baolong Jin , Guanghong Cui , Yongjin J. Zhou , Luqi Huang","doi":"10.1016/j.apsb.2024.12.039","DOIUrl":"10.1016/j.apsb.2024.12.039","url":null,"abstract":"<div><div>(+)-Borneol, the main component of \"Natural Borneol\" in the Chinese Pharmacopoeia, is a high-end spice and precious medicine. Plant extraction cannot meet the increasing demand for (+)-borneol, while microbial biosynthesis offers a sustainable supply route. However, its production was extremely low compared with other monoterpenes, even with extensively optimizing the mevalonate pathway. We found that the key challenge is the complex and unusual dephosphorylation reaction of bornyl diphosphate (BPP), which suffers the side-reaction and the competition from the cellular dephosphorylation process, especially lipid metabolism, thus limiting (+)-borneol synthesis. Here, we systematically optimized the dephosphorylation process by identifying, characterizing phosphatases, and balancing cellular dephosphorylation metabolism. For the first time, we identified two endogenous phosphatases and seven heterologous phosphatases, which significantly increased (+)-borneol production by up to 152%. By engineering BPP dephosphorylation and optimizing the MVA pathway, the production of (+)-borneol was increased by 33.8-fold, which enabled the production of 753 mg/L under fed-batch fermentation in shake flasks, so far the highest reported in the literature. This study showed that rewiring dephosphorylation metabolism was essential for high-level production of (+)-borneol in <em>Saccharomyces cerevisiae</em>, and balancing cellular dephosphorylation is also helpful for efficient biosynthesis of other terpenoids since all whose biosynthesis involves the dephosphorylation procedure.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 2","pages":"Pages 1171-1182"},"PeriodicalIF":14.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143591879","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

Intestinal stearoyl-coenzyme A desaturase-inhibition improves obesity-associated metabolic disorders

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-02-01 DOI: 10.1016/j.apsb.2024.11.022

Yangliu Xia , Yang Zhang , Zhipeng Zhang , Nana Yan , Vorthon Sawaswong , Lulu Sun , Wanwan Guo , Ping Wang , Kristopher W. Krausz , Oksana Gavrilova , James M. Ntambi , Haiping Hao , Tingting Yan , Frank J. Gonzalez

Stearoyl-coenzyme A desaturase 1 (SCD1) catalyzes the rate-limiting step of de novo lipogenesis and modulates lipid homeostasis. Although numerous SCD1 inhibitors were tested for treating metabolic disorders both in preclinical and clinic studies, the tissue-specific roles of SCD1 in modulating obesity-associated metabolic disorders and determining the pharmacological effect of chemical SCD1 inhibition remain unclear. Here a novel role for intestinal SCD1 in obesity-associated metabolic disorders was uncovered. Intestinal SCD1 was found to be induced during obesity progression both in humans and mice. Intestine-specific, but not liver-specific, SCD1 deficiency reduced obesity and hepatic steatosis. A939572, an SCD1-specific inhibitor, ameliorated obesity and hepatic steatosis dependent on intestinal, but not hepatic, SCD1. Mechanistically, intestinal SCD1 deficiency impeded obesity-induced oxidative stress through its novel function of inducing metallothionein 1 in intestinal epithelial cells. These results suggest that intestinal SCD1 could be a viable target that underlies the pharmacological effect of chemical SCD1 inhibition in the treatment of obesity-associated metabolic disorders.

硬脂酰辅酶 A 去饱和酶 1（SCD1）催化新脂肪生成的限速步骤，并调节脂质稳态。尽管在临床前和临床研究中测试了许多用于治疗代谢紊乱的 SCD1 抑制剂，但 SCD1 在调节肥胖相关代谢紊乱和决定化学 SCD1 抑制剂药理作用方面的组织特异性作用仍不清楚。本文揭示了肠道 SCD1 在肥胖相关代谢紊乱中的新作用。研究发现，肠道 SCD1 在人类和小鼠的肥胖过程中都会被诱导。肠特异性而非肝特异性的 SCD1 缺乏会减轻肥胖和肝脂肪变性。A939572是一种SCD1特异性抑制剂，它能改善肥胖和肝脂肪变性，但依赖于肠道而非肝脏的SCD1。从机理上讲，肠道 SCD1 缺乏会通过其在肠道上皮细胞中诱导金属硫蛋白 1 的新功能阻碍肥胖诱导的氧化应激。这些结果表明，肠道 SCD1 可能是一个可行的靶点，是化学抑制 SCD1 治疗肥胖相关代谢紊乱的药理作用的基础。

{"title":"Intestinal stearoyl-coenzyme A desaturase-inhibition improves obesity-associated metabolic disorders","authors":"Yangliu Xia , Yang Zhang , Zhipeng Zhang , Nana Yan , Vorthon Sawaswong , Lulu Sun , Wanwan Guo , Ping Wang , Kristopher W. Krausz , Oksana Gavrilova , James M. Ntambi , Haiping Hao , Tingting Yan , Frank J. Gonzalez","doi":"10.1016/j.apsb.2024.11.022","DOIUrl":"10.1016/j.apsb.2024.11.022","url":null,"abstract":"<div><div>Stearoyl-coenzyme A desaturase 1 (SCD1) catalyzes the rate-limiting step of <em>de novo</em> lipogenesis and modulates lipid homeostasis. Although numerous SCD1 inhibitors were tested for treating metabolic disorders both in preclinical and clinic studies, the tissue-specific roles of SCD1 in modulating obesity-associated metabolic disorders and determining the pharmacological effect of chemical SCD1 inhibition remain unclear. Here a novel role for intestinal SCD1 in obesity-associated metabolic disorders was uncovered. Intestinal SCD1 was found to be induced during obesity progression both in humans and mice. Intestine-specific, but not liver-specific, SCD1 deficiency reduced obesity and hepatic steatosis. A939572, an SCD1-specific inhibitor, ameliorated obesity and hepatic steatosis dependent on intestinal, but not hepatic, SCD1. Mechanistically, intestinal SCD1 deficiency impeded obesity-induced oxidative stress through its novel function of inducing metallothionein 1 in intestinal epithelial cells. These results suggest that intestinal SCD1 could be a viable target that underlies the pharmacological effect of chemical SCD1 inhibition in the treatment of obesity-associated metabolic disorders.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 2","pages":"Pages 892-908"},"PeriodicalIF":14.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143591916","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

Circadian clock regulates immune checkpoint inhibitor efficacy

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-02-01 DOI: 10.1016/j.apsb.2025.01.011

Yining Niu , Motao Zhu

引用次数: 0

Enhanced radiotheranostic targeting of integrin α5β1 with PEGylation-enabled peptide multidisplay platform (PEGibody): A strategy for prolonged tumor retention with fast blood clearance 利用 PEG 化的多肽复合体（PEGibody）增强整合素 α5β1 的放射治疗靶向性：延长肿瘤保留时间并快速清除血液的策略

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-02-01 DOI: 10.1016/j.apsb.2024.07.006

Siqi Zhang , Xiaohui Ma , Jiang Wu , Jieting Shen , Yuntao Shi , Xingkai Wang , Lin Xie , Xiaona Sun , Yuxuan Wu , Hao Tian , Xin Gao , Xueyao Chen , Hongyi Huang , Lu Chen , Xuekai Song , Qichen Hu , Hailong Zhang , Feng Wang , Zhao-Hui Jin , Ming-Rong Zhang , Kuan Hu

Peptide-based radiopharmaceuticals targeting integrin α5β1 show promise for precise tumor diagnosis and treatment. However, current peptide-based radioligands that target α5β1 demonstrate inadequate in vivo performance owing to limited tumor retention. The use of PEGylation to enhance the tumor retention of radiopharmaceuticals by prolonging blood circulation time poses a risk of increased blood toxicity. Therefore, a PEGylation strategy that boosts tumor retention while minimizing blood circulation time is urgently needed. Here, we developed a PEGylation-enabled peptide multidisplay platform (PEGibody) for PR_b, an α5β1 targeting peptide. PEGibody generation involved PEGylation and self-assembly. [⁶⁴Cu]QM-2303 PEGibodies displayed spherical nanoparticles ranging from 100 to 200 nm in diameter. Compared with non-PEGylated radioligands, [⁶⁴Cu]QM-2303 demonstrated enhanced tumor retention time due to increased binding affinity and stability. Importantly, the biodistribution analysis confirmed rapid clearance of [⁶⁴Cu]QM-2303 from the bloodstream. Administration of a single dose of [¹⁷⁷Lu]QM-2303 led to robust antitumor efficacy. Furthermore, [⁶⁴Cu]/[¹⁷⁷Lu]QM-2303 exhibited low hematological and organ toxicity in both healthy and tumor-bearing mice. Therefore, this study presents a PEGibody-based radiotheranostic approach that enhances tumor retention time and provides long-lasting antitumor effects without prolonging blood circulation lifetime. The PEGibody-based radiopharmaceutical [⁶⁴Cu]/[¹⁷⁷Lu]QM-2303 shows great potential for positron emission tomography imaging-guided targeted radionuclide therapy for α5β1-overexpressing tumors.

以整合素 51 为靶点的肽基放射性药物有望用于肿瘤的精确诊断和治疗。然而，目前以 51 为靶点的多肽放射性配体由于肿瘤滞留能力有限而表现出不足。使用 PEG 化技术通过延长血液循环时间来提高放射性药物在肿瘤中的滞留时间，会带来增加血液毒性的风险。因此，迫切需要一种既能提高肿瘤保留率，又能尽量缩短血液循环时间的 PEG 化策略。在此，我们为 51 型靶向肽 PR_b 开发了一个支持 PEG 化的多肽多重显示平台（PEGibody）。PEGibody 的生成涉及 PEG 化和自组装。[Cu]QM-2303 PEGibody 显示出直径为 100 至 200 nm 的球形纳米颗粒。与非 PEG 化的放射性配体相比，[Cu]QM-2303 由于结合亲和力和稳定性的提高而显示出更强的肿瘤保留时间。重要的是，生物分布分析证实[Cu]QM-2303能迅速从血液中清除。单剂量给药[Lu]QM-2303具有强大的抗肿瘤疗效。此外，[Cu]/[Lu]QM-2303 对健康小鼠和肿瘤小鼠的血液和器官毒性都很低。因此，本研究提出了一种基于 PEGibody 的放射治疗方法，它能在不延长血液循环寿命的情况下延长肿瘤保留时间并提供持久的抗肿瘤效果。基于 PEGibody 的放射性药物[Cu]/[Lu]QM-2303 在正电子发射断层成像引导的 51 表达肿瘤放射性核素靶向治疗中显示出巨大的潜力。

{"title":"Enhanced radiotheranostic targeting of integrin α5β1 with PEGylation-enabled peptide multidisplay platform (PEGibody): A strategy for prolonged tumor retention with fast blood clearance","authors":"Siqi Zhang , Xiaohui Ma , Jiang Wu , Jieting Shen , Yuntao Shi , Xingkai Wang , Lin Xie , Xiaona Sun , Yuxuan Wu , Hao Tian , Xin Gao , Xueyao Chen , Hongyi Huang , Lu Chen , Xuekai Song , Qichen Hu , Hailong Zhang , Feng Wang , Zhao-Hui Jin , Ming-Rong Zhang , Kuan Hu","doi":"10.1016/j.apsb.2024.07.006","DOIUrl":"10.1016/j.apsb.2024.07.006","url":null,"abstract":"<div><div>Peptide-based radiopharmaceuticals targeting integrin <em>α</em>5<em>β</em>1 show promise for precise tumor diagnosis and treatment. However, current peptide-based radioligands that target <em>α</em>5<em>β</em>1 demonstrate inadequate <em>in vivo</em> performance owing to limited tumor retention. The use of PEGylation to enhance the tumor retention of radiopharmaceuticals by prolonging blood circulation time poses a risk of increased blood toxicity. Therefore, a PEGylation strategy that boosts tumor retention while minimizing blood circulation time is urgently needed. Here, we developed a PEGylation-enabled peptide multidisplay platform (PEGibody) for PR_b, an <em>α</em>5<em>β</em>1 targeting peptide. PEGibody generation involved PEGylation and self-assembly. [<sup>64</sup>Cu]QM-2303 PEGibodies displayed spherical nanoparticles ranging from 100 to 200 nm in diameter. Compared with non-PEGylated radioligands, [<sup>64</sup>Cu]QM-2303 demonstrated enhanced tumor retention time due to increased binding affinity and stability. Importantly, the biodistribution analysis confirmed rapid clearance of [<sup>64</sup>Cu]QM-2303 from the bloodstream. Administration of a single dose of [<sup>177</sup>Lu]QM-2303 led to robust antitumor efficacy. Furthermore, [<sup>64</sup>Cu]/[<sup>177</sup>Lu]QM-2303 exhibited low hematological and organ toxicity in both healthy and tumor-bearing mice. Therefore, this study presents a PEGibody-based radiotheranostic approach that enhances tumor retention time and provides long-lasting antitumor effects without prolonging blood circulation lifetime. The PEGibody-based radiopharmaceutical [<sup>64</sup>Cu]/[<sup>177</sup>Lu]QM-2303 shows great potential for positron emission tomography imaging-guided targeted radionuclide therapy for <em>α</em>5<em>β</em>1-overexpressing tumors.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 2","pages":"Pages 692-706"},"PeriodicalIF":14.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141612756","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

DELIVER: The core principles for the clinic translation of nanomedicines

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-02-01 DOI: 10.1016/j.apsb.2025.01.014

Chuan Hu , Xinling He , Huile Gao , Jinming Zhang

引用次数: 0

Integrated evidence chain-based effectiveness evaluation of traditional Chinese medicines (Eff-iEC): A demonstration study

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-02-01 DOI: 10.1016/j.apsb.2024.12.024

Ye Luo , Xu Zhao , Ruilin Wang , Xiaoyan Zhan , Tianyi Zhang , Tingting He , Jing Jing , Jianyu Li , Fengyi Li , Ping Zhang , Junling Cao , Jinfa Tang , Zhijie Ma , Tingming Shen , Shuanglin Qin , Ming Yang , Jun Zhao , Zhaofang Bai , Jiabo Wang , Aiguo Dai , Xiaohe Xiao

Addressing the enduring challenge of evaluating traditional Chinese medicines (TCMs), the integrated evidence chain-based effectiveness evaluation of TCMs (Eff-iEC) has emerged. This paper explored its capacity through a demonstration study that evaluated the effectiveness evidence of six commonly used anti-hepatic fibrosis Chinese patent medicines (CPMs), including Biejiajian Pill (BP), Dahuang Zhechong Pill (DZP), Biejia Ruangan Compound (BRC), Fuzheng Huayu Capsule (FHC), Anluo Huaxian Pill (AHP), and Heluo Shugan Capsule (HSC), using both Eff-iEC and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. The recognition of these CPMs within the TCM academic community was also assessed through their inclusion in relevant medical documents. Results showed that the evidence of BRC and FHC received higher assessments in both Eff-iEC and GRADE system, while the assessments for others varied. Analysis of community recognition revealed that Eff-iEC more accurately reflects the clinical value of these CPMs, exhibiting superior evaluative capabilities. By breaking through the conventional pattern of TCMs effectiveness evaluation, Eff-iEC offers a novel epistemology that better aligns with the clinical realities and reasoning of TCMs, providing a coherent methodology for clinical decision-making, new drug evaluations, and health policy formulation.

{"title":"Integrated evidence chain-based effectiveness evaluation of traditional Chinese medicines (Eff-iEC): A demonstration study","authors":"Ye Luo , Xu Zhao , Ruilin Wang , Xiaoyan Zhan , Tianyi Zhang , Tingting He , Jing Jing , Jianyu Li , Fengyi Li , Ping Zhang , Junling Cao , Jinfa Tang , Zhijie Ma , Tingming Shen , Shuanglin Qin , Ming Yang , Jun Zhao , Zhaofang Bai , Jiabo Wang , Aiguo Dai , Xiaohe Xiao","doi":"10.1016/j.apsb.2024.12.024","DOIUrl":"10.1016/j.apsb.2024.12.024","url":null,"abstract":"<div><div>Addressing the enduring challenge of evaluating traditional Chinese medicines (TCMs), the integrated evidence chain-based effectiveness evaluation of TCMs (Eff-iEC) has emerged. This paper explored its capacity through a demonstration study that evaluated the effectiveness evidence of six commonly used anti-hepatic fibrosis Chinese patent medicines (CPMs), including Biejiajian Pill (BP), Dahuang Zhechong Pill (DZP), Biejia Ruangan Compound (BRC), Fuzheng Huayu Capsule (FHC), Anluo Huaxian Pill (AHP), and Heluo Shugan Capsule (HSC), using both Eff-iEC and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. The recognition of these CPMs within the TCM academic community was also assessed through their inclusion in relevant medical documents. Results showed that the evidence of BRC and FHC received higher assessments in both Eff-iEC and GRADE system, while the assessments for others varied. Analysis of community recognition revealed that Eff-iEC more accurately reflects the clinical value of these CPMs, exhibiting superior evaluative capabilities. By breaking through the conventional pattern of TCMs effectiveness evaluation, Eff-iEC offers a novel epistemology that better aligns with the clinical realities and reasoning of TCMs, providing a coherent methodology for clinical decision-making, new drug evaluations, and health policy formulation.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 2","pages":"Pages 909-918"},"PeriodicalIF":14.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143591917","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

Resistance to antibody–drug conjugates: A review

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-02-01 DOI: 10.1016/j.apsb.2024.12.036

Sijia Li , Xinyu Zhao , Kai Fu , Shuangli Zhu , Can Pan , Chuan Yang , Fang Wang , Kenneth K.W. To , Liwu Fu

Antibody–drug conjugates (ADCs) are antitumor drugs composed of monoclonal antibodies and cytotoxic payload covalently coupled by a linker. Currently, 15 ADCs have been clinically approved worldwide. More than 100 clinical trials at different phases are underway to investigate the newly developed ADCs. ADCs represent one of the fastest growing classes of targeted antitumor drugs in oncology drug development. It takes advantage of the specific targeting of tumor-specific antigen by antibodies to deliver cytotoxic chemotherapeutic drugs precisely to tumor cells, thereby producing promising antitumor efficacy and favorable adverse effect profiles. However, emergence of drug resistance has severely hindered the clinical efficacy of ADCs. In this review, we introduce the structure and mechanism of ADCs, describe the development of ADCs, summarized the latest research about the mechanisms of ADC resistance, discussed the strategies to overcome ADCs resistance, and predicted biomarkers for treatment response to ADC, aiming to contribute to the development of ADCs in the future.

{"title":"Resistance to antibody–drug conjugates: A review","authors":"Sijia Li , Xinyu Zhao , Kai Fu , Shuangli Zhu , Can Pan , Chuan Yang , Fang Wang , Kenneth K.W. To , Liwu Fu","doi":"10.1016/j.apsb.2024.12.036","DOIUrl":"10.1016/j.apsb.2024.12.036","url":null,"abstract":"<div><div>Antibody–drug conjugates (ADCs) are antitumor drugs composed of monoclonal antibodies and cytotoxic payload covalently coupled by a linker. Currently, 15 ADCs have been clinically approved worldwide. More than 100 clinical trials at different phases are underway to investigate the newly developed ADCs. ADCs represent one of the fastest growing classes of targeted antitumor drugs in oncology drug development. It takes advantage of the specific targeting of tumor-specific antigen by antibodies to deliver cytotoxic chemotherapeutic drugs precisely to tumor cells, thereby producing promising antitumor efficacy and favorable adverse effect profiles. However, emergence of drug resistance has severely hindered the clinical efficacy of ADCs. In this review, we introduce the structure and mechanism of ADCs, describe the development of ADCs, summarized the latest research about the mechanisms of ADC resistance, discussed the strategies to overcome ADCs resistance, and predicted biomarkers for treatment response to ADC, aiming to contribute to the development of ADCs in the future.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 2","pages":"Pages 737-756"},"PeriodicalIF":14.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143591791","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

Topical adhesive spatio-temporal nanosystem co-delivering chlorin e6 and HMGB1 inhibitor glycyrrhizic acid for in situ psoriasis chemo-phototherapy

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-02-01 DOI: 10.1016/j.apsb.2024.12.020

Lijun Su , Yixi Zhu , Xuebo Li , Di Wang , Xiangyu Chen , Zhen Liu , Jingjing Li , Chen Zhang , Jinming Zhang

Recently, photodynamic therapy (PDT) has gained considerable attention as a promising therapeutic approach for the treatment of psoriasis. Unfortunately, the activation of high mobility group box 1 protein (HMGB1) by PDT triggers innate and adaptive immune responses, which exacerbate skin inflammation. Herein, we combined glycyrrhizic acid (GA), a natural anti-inflammatory compound and immunomodulator derived from the herb Glycyrrhiza uralensis Fisch., with PDT actuated by the photosensitizer chlorin e6 (Ce6) by co-loading them in GA-based lipid nanoparticles coated with a catechol-modified quaternary chitosan salt (GC NPs/QCS-C). GC NPs/QCS-C exhibited high drug loading efficacy, uniform size distribution, an ideal topical adhesive property, enhanced skin retention and penetration in psoriasis-like lesions, and high intracellular uptake in epidermal cells compared with the counterparts. Subsequently, the transdermal administration of GC NPs/QCS-C followed by near-infrared laser radiation in an imiquimod-induced psoriasis-like mouse model significantly ameliorated psoriasis symptoms, promoted the apoptosis of hyperproliferative epidermal cells, and alleviated the inflammatory cascade. The significant therapeutic outcomes of GC NPs/QCS-C were attributed to the synergistic effects of GA and PDT on modulating immune cell recruitment and inhibiting dendritic cell maturation. Our results demonstrated that the topical bio-adhesive nanosystem that combines GA and Ce6 offers a synergistic chemo-phototherapeutic strategy for psoriasis treatment.

{"title":"Topical adhesive spatio-temporal nanosystem co-delivering chlorin e6 and HMGB1 inhibitor glycyrrhizic acid for in situ psoriasis chemo-phototherapy","authors":"Lijun Su , Yixi Zhu , Xuebo Li , Di Wang , Xiangyu Chen , Zhen Liu , Jingjing Li , Chen Zhang , Jinming Zhang","doi":"10.1016/j.apsb.2024.12.020","DOIUrl":"10.1016/j.apsb.2024.12.020","url":null,"abstract":"<div><div>Recently, photodynamic therapy (PDT) has gained considerable attention as a promising therapeutic approach for the treatment of psoriasis. Unfortunately, the activation of high mobility group box 1 protein (HMGB1) by PDT triggers innate and adaptive immune responses, which exacerbate skin inflammation. Herein, we combined glycyrrhizic acid (GA), a natural anti-inflammatory compound and immunomodulator derived from the herb <em>Glycyrrhiza uralensis</em> Fisch., with PDT actuated by the photosensitizer chlorin e6 (Ce6) by co-loading them in GA-based lipid nanoparticles coated with a catechol-modified quaternary chitosan salt (GC NPs/QCS-C). GC NPs/QCS-C exhibited high drug loading efficacy, uniform size distribution, an ideal topical adhesive property, enhanced skin retention and penetration in psoriasis-like lesions, and high intracellular uptake in epidermal cells compared with the counterparts. Subsequently, the transdermal administration of GC NPs/QCS-C followed by near-infrared laser radiation in an imiquimod-induced psoriasis-like mouse model significantly ameliorated psoriasis symptoms, promoted the apoptosis of hyperproliferative epidermal cells, and alleviated the inflammatory cascade. The significant therapeutic outcomes of GC NPs/QCS-C were attributed to the synergistic effects of GA and PDT on modulating immune cell recruitment and inhibiting dendritic cell maturation. Our results demonstrated that the topical bio-adhesive nanosystem that combines GA and Ce6 offers a synergistic chemo-phototherapeutic strategy for psoriasis treatment.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 2","pages":"Pages 1126-1142"},"PeriodicalIF":14.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143591800","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

Deubiquitinase JOSD2 alleviates colitis by inhibiting inflammation via deubiquitination of IMPDH2 in macrophages

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-02-01 DOI: 10.1016/j.apsb.2024.12.012

Xin Liu , Yi Fang , Mincong Huang , Shiliang Tu , Boan Zheng , Hang Yuan , Peng Yu , Mengyao Lan , Wu Luo , Yongqiang Zhou , Guorong Chen , Zhe Shen , Yi Wang , Guang Liang

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, which increases the incidence of colorectal cancer (CRC). In the pathophysiology of IBD, ubiquitination/deubiquitination plays a critical regulatory function. Josephin domain containing 2 (JOSD2), a deubiquitinating enzyme, controls cell proliferation and carcinogenesis. However, its role in IBD remains unknown. Colitis mice model developed by dextran sodium sulfate (DSS) or colon tissues from individuals with ulcerative colitis and Crohn's disease showed a significant upregulation of JOSD2 expression in the macrophages. JOSD2 deficiency exacerbated the phenotypes of DSS-induced colitis by enhancing colon inflammation. DSS-challenged mice with myeloid-specific JOSD2 deletion developed severe colitis after bone marrow transplantation. Mechanistically, JOSD2 binds to the C-terminal of inosine-5′-monophosphate dehydrogenase 2 (IMPDH2) and preferentially cleaves K63-linked polyubiquitin chains at the K134 site, suppressing IMPDH2 activity and preventing activation of nuclear factor kappa B (NF-κB) and inflammation in macrophages. It was also shown that JOSD2 knockout significantly exacerbated increased azoxymethane (AOM)/DSS-induced CRC, and AAV6-mediated JOSD2 overexpression in macrophages prevented the development of colitis in mice. These outcomes reveal a novel role for JOSD2 in colitis through deubiquitinating IMPDH2, suggesting that targeting JOSD2 is a potential strategy for treating IBD.

{"title":"Deubiquitinase JOSD2 alleviates colitis by inhibiting inflammation via deubiquitination of IMPDH2 in macrophages","authors":"Xin Liu , Yi Fang , Mincong Huang , Shiliang Tu , Boan Zheng , Hang Yuan , Peng Yu , Mengyao Lan , Wu Luo , Yongqiang Zhou , Guorong Chen , Zhe Shen , Yi Wang , Guang Liang","doi":"10.1016/j.apsb.2024.12.012","DOIUrl":"10.1016/j.apsb.2024.12.012","url":null,"abstract":"<div><div>Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, which increases the incidence of colorectal cancer (CRC). In the pathophysiology of IBD, ubiquitination/deubiquitination plays a critical regulatory function. Josephin domain containing 2 (JOSD2), a deubiquitinating enzyme, controls cell proliferation and carcinogenesis. However, its role in IBD remains unknown. Colitis mice model developed by dextran sodium sulfate (DSS) or colon tissues from individuals with ulcerative colitis and Crohn's disease showed a significant upregulation of JOSD2 expression in the macrophages. JOSD2 deficiency exacerbated the phenotypes of DSS-induced colitis by enhancing colon inflammation. DSS-challenged mice with myeloid-specific JOSD2 deletion developed severe colitis after bone marrow transplantation. Mechanistically, JOSD2 binds to the C-terminal of inosine-5′-monophosphate dehydrogenase 2 (IMPDH2) and preferentially cleaves K63-linked polyubiquitin chains at the K134 site, suppressing IMPDH2 activity and preventing activation of nuclear factor kappa B (NF-<em>κ</em>B) and inflammation in macrophages. It was also shown that JOSD2 knockout significantly exacerbated increased azoxymethane (AOM)/DSS-induced CRC, and AAV6-mediated JOSD2 overexpression in macrophages prevented the development of colitis in mice. These outcomes reveal a novel role for JOSD2 in colitis through deubiquitinating IMPDH2, suggesting that targeting JOSD2 is a potential strategy for treating IBD.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 2","pages":"Pages 1039-1055"},"PeriodicalIF":14.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143591850","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

首页上一页

下一页尾页

类型

全部化学•材料生命科学医学物理工程技术环境•农林材料科学地球科学法学管理学化学环境科学与生态学计算机科学教育学经济学农林科学人文科学生物学数学物理与天体物理心理学综合性期刊其他工业工程理学历史学农学文学信息工程

数据库

全部 ACS Publications Elsevier ieeexplore Springer The Royal Society of Chemistry Wiley

期刊

Acta Pharmaceutica Sinica. B

全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.

﹀