Acta Pharmaceutica Sinica. B最新文献_第5页

Nanotechnology-based tumor metabolic reprogramming: Insights into nutrient-delivery and metabolism reactivation therapy 基于纳米技术的肿瘤代谢重编程：营养输送和新陈代谢再激活疗法的启示

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.07.015

Xi Hu , Daishun Ling

引用次数: 0

Amylovis-201 is a new dual-target ligand, acting as an anti-amyloidogenic compound and a potent agonist of the σ1 chaperone protein Amylovis-201 是一种新型双目标配体，既是一种抗淀粉样蛋白生成化合物，又是σ1伴侣蛋白的强效激动剂

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.06.013

{"title":"Amylovis-201 is a new dual-target ligand, acting as an anti-amyloidogenic compound and a potent agonist of the σ1 chaperone protein","authors":"","doi":"10.1016/j.apsb.2024.06.013","DOIUrl":"10.1016/j.apsb.2024.06.013","url":null,"abstract":"<div><div>The aggregation of Amyloid-<em>β</em> (A<em>β</em>) peptides is associated with neurodegeneration in Alzheimer's disease (AD). We previously identified novel naphtalene derivatives, including the lead compound Amylovis-201, able to form thermodynamically stable complexes with A<em>β</em> species, peptides and fibrils. As the drug showed a chemical scaffold coherent for an effective interaction with the <em>σ</em><sub>1</sub> receptor chaperone and as <em>σ</em><sub>1</sub> agonists are currently developed as potent neuroprotectants in AD, we investigated the pharmacological action of Amylovis-201 on the <em>σ</em><sub>1</sub> receptor. We report that Amylovis-201 is a potent <em>σ</em><sub>1</sub> agonist by several <em>in silico</em>, <em>in vitro</em> and <em>in vivo</em> assays and that its anti-amnesic and neuroprotective effects involve a pharmacological action at <em>σ</em><sub>1</sub> receptors. Furthermore, we show for the first time that classical <em>σ</em><sub>1</sub> receptor agonist (PRE-084), and antagonist (NE-100) are able to interact and disaggregate A<em>β</em><sub>25–35</sub> fibrils. Interestingly, Amylovis-201 was the only compound inhibiting A<em>β</em><sub>25–35</sub> aggregates formation. Our results therefore highlight a dual action of Amylovis-201 as anti-aggregating agent and <em>σ</em><sub>1</sub> receptor agonist that could be highly effective in long-term treatment against neurodegeneration in AD.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4345-4359"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141528648","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

Spatial metabolomics highlights metabolic reprogramming in acute myeloid leukemia mice through creatine pathway 空间代谢组学凸显急性髓性白血病小鼠通过肌酸途径进行的代谢重编程

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.07.004

Yucheng Bao , Jing Qiao , Wenjie Gong , Ruihong Zhang , Yanting Zhou , Yinyin Xie , Yuan Xie , Jiuming He , Tong Yin

{"title":"Spatial metabolomics highlights metabolic reprogramming in acute myeloid leukemia mice through creatine pathway","authors":"Yucheng Bao , Jing Qiao , Wenjie Gong , Ruihong Zhang , Yanting Zhou , Yinyin Xie , Yuan Xie , Jiuming He , Tong Yin","doi":"10.1016/j.apsb.2024.07.004","DOIUrl":"10.1016/j.apsb.2024.07.004","url":null,"abstract":"<div><div>Acute myeloid leukemia (AML) is recognized as an aggressive cancer that is characterized by significant metabolic reprogramming. Here, we applied spatial metabolomics to achieve high-throughput, in situ identification of metabolites within the liver metastases of AML mice. Alterations at metabolite and protein levels were further mapped out and validated by integrating untargeted metabolomics and proteomics. This study showed a downregulation in arginine's contribution to polyamine biosynthesis and urea cycle, coupled with an upregulation of the creatine metabolism. The upregulation of creatine synthetases Gatm and Gamt, as well as the creatine transporter Slc6a8, resulted in a marked accumulation of creatine within tumor foci. This process further enhances oxidative phosphorylation and glycolysis of leukemia cells, thereby boosting ATP production to foster proliferation and infiltration. Importantly, we discovered that inhibiting Slc6a8 can counter these detrimental effects, offering a new strategy for treating AML by targeting metabolic pathways.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4461-4477"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141615087","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

A rationally designed CD19 monoclonal antibody-triptolide conjugate for the treatment of systemic lupus erythematosus 用于治疗系统性红斑狼疮的合理设计的 CD19 单克隆抗体-曲托列肽共轭物

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.06.024

Lai Wang , Haoyuan Yin , Jiao Jiang , Qilin Li , Changxing Gao , Wenrui Li , Bo Zhang , Yue Xin , Hongyang Li , Ming Zhao , Qianjin Lu

{"title":"A rationally designed CD19 monoclonal antibody-triptolide conjugate for the treatment of systemic lupus erythematosus","authors":"Lai Wang , Haoyuan Yin , Jiao Jiang , Qilin Li , Changxing Gao , Wenrui Li , Bo Zhang , Yue Xin , Hongyang Li , Ming Zhao , Qianjin Lu","doi":"10.1016/j.apsb.2024.06.024","DOIUrl":"10.1016/j.apsb.2024.06.024","url":null,"abstract":"<div><div><em>Tripterygium wilfordii</em> Hook F (TWHF) is a traditional Chinese medicine widely used in the treatment of systemic lupus erythematosus (SLE), with triptolide (TP) as its main active ingredient. However, its side effects also induced by TP, especially hepatotoxicity and reproductive toxicity, largely limit its application in a subset of patients. Monoclonal antibodies (mAbs) developed for the treatment of SLE that deplete B cells by targeting B cell-expressing antigens, such as CD19, have failed in clinical trials, partly due to their poor efficacy in consuming B cells. Here, we report the development of a rationally designed antibody‒drug conjugate (ADC), CD19 mAb-TP conjugate, to alleviate the side effects of TWHF and simultaneously improve the therapeutic efficacy of CD19 mAb. The CD19 mAb-TP conjugate, which was named ADC-TP, selectively depleted B cell subsets both <em>in vitro</em> and <em>in vivo</em> and effectively alleviated disease symptoms in mouse lupus models with enhanced therapeutic efficacy than CD19 mAb and fewer side effects than TP. Our present study proposes a CD19 mAb‒TP conjugate strategy to mitigate the toxicity of TWHF while also enhancing the therapeutical efficacy of CD19 mAbs for the treatment of SLE, providing a feasible method for improving the current agents used for treating SLE.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4560-4576"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263628","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

A systematic, updated review of Xuezhikang, a domestically developed lipid-lowering drug, in the application of cardiovascular diseases 关于国产降脂药雪芝康在心血管疾病中应用的最新系统综述

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.05.011

{"title":"A systematic, updated review of Xuezhikang, a domestically developed lipid-lowering drug, in the application of cardiovascular diseases","authors":"","doi":"10.1016/j.apsb.2024.05.011","DOIUrl":"10.1016/j.apsb.2024.05.011","url":null,"abstract":"<div><div>Cardiovascular diseases (CVDs) are a major threat to public health globally. A large proportion of people with dyslipidaemia have poorly controlled lipid levels, emphasizing the need for alternative lipid-lowering treatments that are both effective and safe. Xuezhikang, a red yeast rice (RYR) extract, containing 13 kinds of monacolins and other bioactive components, emerges as one such promising option. Its discovery was built on a long history of RYR use as a functional food supplement and traditional Chinese medicine. Several randomized, controlled clinical trials have substantiated its lipid-lowering effects and its potential to protect against CVDs. Safety concerns with statins did not arise during decades of experience with Xuezhikang treatment in clinical practice. The approval of Xuezhikang in multiple regions of Asia marked a conceptual shift in CVD management, moving from single agents to polypills and from synthetic medicines to natural extracts. This review comprehensively addresses important topics related to this medicinal natural extract, including the ancient utilization of RYR, the development of Xuezhikang, its mechanisms of action, pleiotropic effects, clinical studies, challenges, and future perspectives to enhance our understanding regarding the role of Xuezhikang, a representative, domestic lipid-lowering drug of RYR, in prevention and treatment of CVD.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4228-4242"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141033795","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

Choroid plexus CCL2‒CCR2 signaling orchestrates macrophage recruitment and cerebrospinal fluid hypersecretion in hydrocephalus 脉络丛 CCL2-CCR2 信号协调脑积水中巨噬细胞的招募和脑脊液的高分泌

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.06.020

{"title":"Choroid plexus CCL2‒CCR2 signaling orchestrates macrophage recruitment and cerebrospinal fluid hypersecretion in hydrocephalus","authors":"","doi":"10.1016/j.apsb.2024.06.020","DOIUrl":"10.1016/j.apsb.2024.06.020","url":null,"abstract":"<div><div>The choroid plexus (ChP) serves as the principal origin of cerebrospinal fluid (CSF). CSF hypersecretion due to ChP inflammation has emerged as an important pathogenesis of hydrocephalus recently. Nevertheless, the precise mechanisms of ChP inflammation and the ensuing CSF hypersecretion in hydrocephalus remain ill-defined. In the present study, we elucidate the critical role of macrophages in the pathogenesis of ChP inflammation. Specifically, we identify the chemokine CCL2, released by ChP epithelial cells, recruits CCR2<sup>+</sup> monocytes to the ChP thereby inciting hydrocephalus pathogenesis. The accumulated ChP macrophages increase the inflammation in ChP epithelial cells through TNF-<em>α</em>/TNFR1/NF-<em>κ</em>B signaling cascade, thereby leading to CSF hypersecretion. Strikingly, augmentation of ChP‒CCL2 using an adeno-associated viral approach (AAV) exacerbates macrophage recruitment, activation, and ventriculomegaly in rat PHH models. Systemic application of Bindarit, a specific CCL2 inhibitor, significantly inhibits ChP macrophage infiltration and activation and reduces CSF secretion rate. Furthermore, the administration of CCR2 antagonist (INCB 3284) reduces ChP macrophage accumulation and ventriculomegaly. This study not only unveils the ChP CCL2‒CCR2 signaling in the pathophysiology of hydrocephalus but also unveils Bindarit as a promising therapeutic choice for the management of posthemorrhagic hydrocephalus.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4544-4559"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141549276","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

Zinc oxide nanoparticles with catalase-like nanozyme activity and near-infrared light response: A combination of effective photodynamic therapy, autophagy, ferroptosis, and antitumor immunity 具有类似催化酶的纳米活性和近红外光响应的氧化锌纳米颗粒：有效光动力疗法、自噬、铁变态和抗肿瘤免疫的结合

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.07.002

Jingru Wang , Man Liu , Jingwen Wang , Zhuoyue Li , Zhenhan Feng , Meiqi Xu , Hui Wang , Hui Li , Zhantao Li , Jianming Yu , Junwei Liu , Qingchao Wei , Shuang Zhang , Xuan Zhang

{"title":"Zinc oxide nanoparticles with catalase-like nanozyme activity and near-infrared light response: A combination of effective photodynamic therapy, autophagy, ferroptosis, and antitumor immunity","authors":"Jingru Wang , Man Liu , Jingwen Wang , Zhuoyue Li , Zhenhan Feng , Meiqi Xu , Hui Wang , Hui Li , Zhantao Li , Jianming Yu , Junwei Liu , Qingchao Wei , Shuang Zhang , Xuan Zhang","doi":"10.1016/j.apsb.2024.07.002","DOIUrl":"10.1016/j.apsb.2024.07.002","url":null,"abstract":"<div><div>We prepared biocompatible and environment-friendly zinc oxide nanoparticles (ZnO NPs) with upconversion properties and catalase-like nanozyme activity. Photodynamic therapy (PDT) application is severely limited by the poor penetration of UV–Visible light and a hypoxic tumor environment. Here, we used ZnO NPs as a carrier for the photosensitizer chlorin e6 (Ce6) to construct zinc oxide–chlorin e6 nanoparticles (ZnO-Ce6 NPs), simultaneously addressing both problems. In terms of penetration, ZnO NPs convert 808 nm near-infrared light into 401 nm visible light to excite Ce6, achieving deep-penetrating photodynamic therapy under long-wavelength light. Interestingly, the ability to emit short-wavelength light under long-wavelength light is usually observed in upconversion nanoparticles. As nanozymes, ZnO NPs can catalyze the decomposition of hydrogen peroxide in tumors, providing oxygen for photodynamic action and relieving hypoxia. The enhanced photodynamic action produces a large amount of reactive oxygen species, which overactivate autophagy and trigger immunogenic cell death (ICD), leading to antitumor immunotherapy. In addition, even in the absence of light, ZnO and ZnO-Ce6 NPs can induce ferroptosis of tumor cells and exert antitumor effects.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4493-4508"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141612761","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

RMC-7977, a highly selective inhibitor of the active RAS-GTP to treat pancreatic cancer 用于治疗胰腺癌的活性 RAS-GTP 高选择性抑制剂 RMC-7977

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.07.014

Ying-Qi Song , Qingjun Li , Chunquan Sheng

引用次数: 0

Demethylzeylasteral induces PD-L1 ubiquitin–proteasome degradation and promotes antitumor immunity via targeting USP22 去甲斑蝥素诱导 PD-L1 泛素-蛋白酶体降解，并通过靶向 USP22 促进抗肿瘤免疫力

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.08.004

Yanyan Zhang , Yun Huang , Dianping Yu , Mengting Xu , Hongmei Hu , Qing Zhang , Minchen Cai , Xiangxin Geng , Hongwei Zhang , Jianhua Xia , Mengmeng Guo , Dong Lu , Hanchi Xu , Linyang Li , Xing Zhang , Qun Wang , Sanhong Liu , Weidong Zhang

{"title":"Demethylzeylasteral induces PD-L1 ubiquitin–proteasome degradation and promotes antitumor immunity via targeting USP22","authors":"Yanyan Zhang , Yun Huang , Dianping Yu , Mengting Xu , Hongmei Hu , Qing Zhang , Minchen Cai , Xiangxin Geng , Hongwei Zhang , Jianhua Xia , Mengmeng Guo , Dong Lu , Hanchi Xu , Linyang Li , Xing Zhang , Qun Wang , Sanhong Liu , Weidong Zhang","doi":"10.1016/j.apsb.2024.08.004","DOIUrl":"10.1016/j.apsb.2024.08.004","url":null,"abstract":"<div><div>Programmed cell death ligand-1 (PD-L1) is a T cell inhibitory immune checkpoint molecule that interacts with programmed cell death-1 (PD-1) to promote immune escape of tumor cells. Compared with antibody therapies, small molecule drugs show better prospects due to their advantages such as higher bioavailability, better tissue penetration, and reduced risk of immunogenicity. Here, we found that the small molecule demethylzeylasteral (Dem) can significantly downregulate the expression of PD-L1 in colorectal cancer cells and enhance the killing effect of T cells on tumor cells. Mechanistically, Dem binds to the deubiquitinating enzyme USP22 and promotes its degradation, resulting in increased ubiquitination and degradation of PD-L1 through the proteasome pathway. In addition, Dem increased the activity of cytotoxic T cells and reduced the number of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in tumor-infiltrating lymphocytes (TILs), thereby activating the tumor immune microenvironment and inhibiting the growth of subcutaneous MC38 tumors in C57BL/6 mice. Moreover, we also found that the combination of Dem and CTLA4 antibodies can further improve the efficacy of antitumor therapy. Our study reveals the mechanism by which Dem promotes PD-L1 degradation and suggests that the combination of Dem and CTLA4 antibodies may improve the efficacy of immunotherapy.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4312-4328"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186916","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

Activating autophagy improves paclitaxel-induced peripheral neuropathy in chemotherapy 激活自噬可改善化疗中紫杉醇诱导的周围神经病变

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.08.010

Jin Zhang , Yelan Huang , Xiaohan Sun , Xiya Chen , Xi Zhao , Chenqiu Ran , Bo Liu , Yue Hao

引用次数: 0