Acta Pharmaceutica Sinica. B最新文献_第6页

Reprogramming tumor-associated macrophages and inhibiting tumor neovascularization by targeting MANF–HSF1–HSP70-1 pathway: An effective treatment for hepatocellular carcinoma 通过靶向 MANF-HSF1-HSP70-1 通路重编程肿瘤相关巨噬细胞并抑制肿瘤新生血管：肝细胞癌的有效治疗方法

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.05.001

{"title":"Reprogramming tumor-associated macrophages and inhibiting tumor neovascularization by targeting MANF–HSF1–HSP70-1 pathway: An effective treatment for hepatocellular carcinoma","authors":"","doi":"10.1016/j.apsb.2024.05.001","DOIUrl":"10.1016/j.apsb.2024.05.001","url":null,"abstract":"<div><div>In advanced hepatocellular carcinoma (HCC) tissues, M2-like tumor-associated macrophages (TAMs) are in the majority and promotes HCC progression. Contrary to the pro-tumor effect of M2-like TAMs, M1-like TAMs account for a small proportion and have anti-tumor effects. Since TAMs can switch from one type to another, reprogramming TAMs may be an important treatment for HCC therapy. However, the mechanisms of phenotypic switch and reprogramming TAMs are still obscure. In this study, we analyzed differential genes in normal macrophages and TAMs, and found that loss of MANF in TAMs accompanied by high levels of downstream genes negatively regulated by MANF. MANF reprogrammed TAMs into M1 phenotype. Meanwhile, loss of MANF promoted HCC progression in HCC patients and mice HCC model, especially tumor neovascularization. Additionally, macrophages with MANF supplement suppressed HCC progression in mice, suggesting MANF supplement in macrophage was an effective treatment for HCC. Mechanistically, MANF enhanced the HSF1–HSP70-1 interaction, restricted HSF1 in the cytoplasm of macrophages, and decreased both mRNA and protein levels of HSP70-1, which in turn led to reprogramming TAMs, and suppressing neovascularization of HCC. Our study contributes to the exploration the mechanism of TAMs reprogramming, which may provide insights for future therapeutic exploitation of HCC neovascularization.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4396-4412"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141036650","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

Targeted isolation of antiviral cinnamoylphloroglucinol-terpene adducts from Cleistocalyx operculatus by building blocks-based molecular networking approach 通过基于构件的分子网络方法，有针对性地从 Cleistocalyx operculatus 中分离出抗病毒的肉桂酰氯葡萄糖醇-萜烯加合物

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.04.031

{"title":"Targeted isolation of antiviral cinnamoylphloroglucinol-terpene adducts from Cleistocalyx operculatus by building blocks-based molecular networking approach","authors":"","doi":"10.1016/j.apsb.2024.04.031","DOIUrl":"10.1016/j.apsb.2024.04.031","url":null,"abstract":"<div><div>The building blocks-based molecular network (BBMN) strategy was applied to the phytochemical investigation of <em>Cleistocalyx operculatus</em>, leading to the targeted isolation of eighteen novel cinnamoylphloroglucinol-terpene adducts (CPTAs) with diverse skeleton types (cleistoperones A–R, <strong>1</strong>–<strong>18</strong>). Their structures including absolute configurations were determined by extensive spectroscopic methods, quantum chemical calculations, and single-crystal X-ray crystallographic experiments. Cleistoperone A (<strong>1</strong>), consisting of a cinnamoylphloroglucinol motif and two linear monoterpene moieties, represents an unprecedented macrocyclic CPTA, whose densely functionalized tricyclo[15.3.1.0<sup>3,8</sup>]heneicosane bridge ring skeleton contains an enolizable <em>β</em>,<em>β</em>′-triketone system and two different kinds of stereogenic elements (including five point and three planar chiralities). Cleistoperones B and C (<strong>2</strong> and <strong>3</strong>) are two new skeletal CPTAs with an unusual coupling pattern between the (nor)monoterpene moiety and the cinnamoyl chain of the cinnamoylphloroglucinol unit. Cleistoperone D (<strong>4</strong>) possesses an unprecedented cage-like 6/6/6/4/6-fused heteropentacyclic scaffold. The plausible biosynthetic pathways for <strong>1</strong>–<strong>18</strong> were also proposed. Notably, compounds <strong>1</strong>, <strong>4</strong>, <strong>7</strong>, <strong>8</strong>, and <strong>18</strong> exhibited significant antiviral activity against respiratory syncytial virus (RSV). The most potent one, cleistoperone A (<strong>1</strong>) with IC<sub>50</sub> value of 1.71 ± 0.61 μmol/L, could effectively inhibit virus replication <em>via</em> affecting the Akt/mTOR/p70S6K signaling pathway.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4443-4460"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140938696","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

Genome-wide pan-GPCR cell libraries accelerate drug discovery 全基因组泛 GPCR 细胞文库加速药物发现

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.06.023

{"title":"Genome-wide pan-GPCR cell libraries accelerate drug discovery","authors":"","doi":"10.1016/j.apsb.2024.06.023","DOIUrl":"10.1016/j.apsb.2024.06.023","url":null,"abstract":"<div><div>G protein-coupled receptors (GPCRs) are pivotal in mediating diverse physiological and pathological processes, rendering them promising targets for drug discovery. GPCRs account for about 40% of FDA-approved drugs, representing the most successful drug targets. However, only approximately 15% of the 800 human GPCRs are targeted by market drugs, leaving numerous opportunities for drug discovery among the remaining receptors. Cell expression systems play crucial roles in the GPCR drug discovery field, including novel target identification, structural and functional characterization, potential ligand screening, signal pathway elucidation, and drug safety evaluation. Here, we discuss the principles, applications, and limitations of widely used cell expression systems in GPCR-targeted drug discovery, GPCR function investigation, signal pathway characterization, and pharmacological property studies. We also propose three strategies for constructing genome-wide pan-GPCR cell libraries, which will provide a powerful platform for GPCR ligand screening, and facilitate the study of GPCR mechanisms and drug safety evaluation, ultimately accelerating the process of GPCR-targeted drug discovery.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4296-4311"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141549274","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

Pyroptosis: Induction and inhibition strategies for immunotherapy of diseases 热蛋白沉积：疾病免疫疗法的诱导和抑制策略

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.06.026

引用次数: 0

Target fishing and mechanistic insights of the natural anticancer drug candidate chlorogenic acid 天然抗癌候选药物绿原酸的靶点捕获和机理研究

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.07.005

Qinghua Wang , Tingting Du , Zhihui Zhang , Qingyang Zhang , Jie Zhang , Wenbin Li , Jian-Dong Jiang , Xiaoguang Chen , Hai-Yu Hu

{"title":"Target fishing and mechanistic insights of the natural anticancer drug candidate chlorogenic acid","authors":"Qinghua Wang , Tingting Du , Zhihui Zhang , Qingyang Zhang , Jie Zhang , Wenbin Li , Jian-Dong Jiang , Xiaoguang Chen , Hai-Yu Hu","doi":"10.1016/j.apsb.2024.07.005","DOIUrl":"10.1016/j.apsb.2024.07.005","url":null,"abstract":"<div><div>Chlorogenic acid (CGA) is a natural product that effectively inhibits tumor growth, demonstrated in many preclinical models, and phase II clinical trials for patients with glioma. However, its direct proteomic targets and anticancer molecular mechanisms remain unknown. Herein, we developed a novel bi-functional photo-affinity probe PAL/CGA and discovered mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) was one of the main target proteins of CGA by using affinity-based protein profiling (AfBPP) chemical proteomic approach. We performed in-depth studies on ACAT1/CGA interactions <em>via</em> multiple assays including SPR, ITC, and cryo-EM. Importantly, we demonstrated that CGA impaired cancer cell proliferation by inhibiting the phosphorylation of tetrameric ACAT1 on Y407 residue through a novel mode of action <em>in vitro</em> and <em>in vivo</em>. Our study highlights the use of AfBPP platforms in uncovering unique druggable modalities accessed by natural products. And identifying the molecular target of CGA sheds light on the future clinical application of CGA for cancer therapy.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4431-4442"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141612757","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

Characteristic roadmap of linker governs the rational design of PROTACs 链接器的特征路线图指导着 PROTAC 的合理设计

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.04.007

{"title":"Characteristic roadmap of linker governs the rational design of PROTACs","authors":"","doi":"10.1016/j.apsb.2024.04.007","DOIUrl":"10.1016/j.apsb.2024.04.007","url":null,"abstract":"<div><div>Proteolysis targeting chimera (PROTAC) technology represents a groundbreaking development in drug discovery, leveraging the ubiquitin‒proteasome system to specifically degrade proteins responsible for the disease. PROTAC is characterized by its unique heterobifunctional structure, which comprises two functional domains connected by a linker. The linker plays a pivotal role in determining PROTAC's biodegradative efficacy. Advanced and rationally designed functional linkers for PROTAC are under development. Nonetheless, the correlation between linker characteristics and PROTAC efficacy remains under-investigated. Consequently, this study will present a multidisciplinary analysis of PROTAC linkers and their impact on efficacy, thereby guiding the rational design of linkers. We will primarily discuss the structural types and characteristics of PROTAC linkers, and the optimization strategies used for their rational design. Furthermore, we will discuss how factors like linker length, group type, flexibility, and linkage site affect the biodegradation efficiency of PROTACs. We believe that this work will contribute towards the advancement of rational linker design in the PROTAC research area.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4266-4295"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140613731","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

Macrophage P2Y6R activation aggravates psoriatic inflammation through IL-27-mediated Th1 responses 巨噬细胞 P2Y6R 激活通过 IL-27 介导的 Th1 反应加剧银屑病炎症

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.06.008

{"title":"Macrophage P2Y6R activation aggravates psoriatic inflammation through IL-27-mediated Th1 responses","authors":"","doi":"10.1016/j.apsb.2024.06.008","DOIUrl":"10.1016/j.apsb.2024.06.008","url":null,"abstract":"<div><div>Purinergic signaling plays a causal role in the modulation of immune inflammatory response in the course of psoriasis, but its regulatory mechanism remains unclear. As a member of purinoceptors, P2Y<sub>6</sub>R mainly distributed in macrophages was significantly up-expressed in skin lesions from patients with psoriasis in the present study. Here, the severity of psoriasis was alleviated in imiquimod-treated mice with macrophages conditional knockout of P2Y<sub>6</sub>R, while the cell-chat algorithm showed there was a correlation between macrophage P2Y<sub>6</sub>R and Th1 cells mediated by IL-27. Mechanistically, P2Y<sub>6</sub>R enhanced PLC<sub><em>β</em></sub>/p-PKC/MAPK activation to induce IL-27 release dependently, which subsequently regulated the differentiation of Th1 cells, leading to erythematous and scaly plaques of psoriasis. Interestingly, we developed a novel P2Y<sub>6</sub>R inhibitor FS-6, which bonds with the ARG266 side chain of P2Y<sub>6</sub>R, exhibited remarkable anti-psoriasis effects targeting P2Y<sub>6</sub>R. Our study provides insights into the role of P2Y<sub>6</sub>R in the pathogenesis of psoriasis and suggests its potential as a target for the development of therapeutic interventions. A novel P2Y<sub>6</sub>R inhibitor FS-6 could be developed as an anti-psoriasis drug candidate for the clinic.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4360-4377"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141500635","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

Simultaneous enhancement of cellular and humoral immunity by the lymph node-targeted cholesterolized TLR7 agonist liposomes 淋巴结靶向胆固醇化 TLR7 激动剂脂质体可同时增强细胞和体液免疫力

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.06.006

Dandan Wan , Ziyi Bai , Yu Zhang , Li Chen , Haiying Que , Tianxia Lan , Weiqi Hong , Jiayu Huang , Cai He , Yuquan Wei , Qiang Pu , Xiawei Wei

{"title":"Simultaneous enhancement of cellular and humoral immunity by the lymph node-targeted cholesterolized TLR7 agonist liposomes","authors":"Dandan Wan , Ziyi Bai , Yu Zhang , Li Chen , Haiying Que , Tianxia Lan , Weiqi Hong , Jiayu Huang , Cai He , Yuquan Wei , Qiang Pu , Xiawei Wei","doi":"10.1016/j.apsb.2024.06.006","DOIUrl":"10.1016/j.apsb.2024.06.006","url":null,"abstract":"<div><div>Toll-like receptor (TLR) agonists, as promising adjuvants and immunotherapeutic agents, have the potential to enhance immune responses and modulate antigen-dependent T-cell immune memory through activation of distinct signaling pathways. However, their clinical application is hindered by uncontrolled systemic inflammatory reactions. Therefore, it is imperative to create a vaccine adjuvant for TLR receptors that ensures both safety and efficacy. In this study, we designed lymph node-targeted cholesterolized TLR7 agonist cationic liposomes (1V209-Cho-Lip<sup>+</sup>) to mitigate undesired side effects. Co-delivery of the model antigen OVA and cholesterolized TLR7 agonist facilitated DC maturation through TLR activation while ensuring optimal presentation of the antigen to CD8<sup>+</sup> T cells. The main aim of the present study is to evaluate the adjuvant effectiveness of 1V209-Cho-Lip<sup>+</sup> in tumor vaccines. Following immunization with 1V209-Cho-Lip<sup>+</sup>+OVA, we observed a pronounced \"depot effect\" and enhanced trafficking to secondary lymphoid organs. Prophylactic vaccination with 1V209-Cho-Lip<sup>+</sup>+OVA significantly delays tumor development, prolongs mouse survival, and establishes durable immunity against tumor recurrence. Additionally, 1V209-Cho-Lip<sup>+</sup>+OVA, while used therapeutic tumor vaccine, has demonstrated its efficacy in inhibiting tumor progression, and when combined with anti-PD-1, it further enhances antitumor effects. Therefore, the co-delivery of antigen and lymph node-targeted cholesterolized TLR7 agonist shows great promise as a cancer vaccine.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4577-4590"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263512","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

PGC-1α-mediated imbalance of mitochondria-lipid droplet homeostasis in neomycin-induced ototoxicity and nephrotoxicity PGC-1 在新霉素诱发的耳毒性和肾毒性中介导线粒体-脂滴平衡失调

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/j.apsb.2024.05.024

{"title":"PGC-1α-mediated imbalance of mitochondria-lipid droplet homeostasis in neomycin-induced ototoxicity and nephrotoxicity","authors":"","doi":"10.1016/j.apsb.2024.05.024","DOIUrl":"10.1016/j.apsb.2024.05.024","url":null,"abstract":"<div><div>Ototoxicity and nephrotoxicity are the most prevalent side effects of aminoglycoside antibiotics (gentamicin, amikacin, neomycin) and platinum anti-tumor drugs (cisplatin, carboplatin). The inner ear and kidney share similarities in drug deposition and toxicity, but the underlying pathophysiological mechanisms remain unclear. Investigating the shared mechanisms and metabolic alterations in these distinct organs will provide valuable insights for clinical therapy. A strong correlation has been identified between the spatiotemporal accumulation patterns of neomycin and the specific occurrence of lipid metabolism disorders in these two organs. The primary allocation of neomycin to mitochondria results in a notable escalation in the accumulation of lipid droplets (LDs) and more interactions between mitochondria and LDs, leading to a sequence of disturbances in lipid metabolism, such as increased lipid ROS and the blocked transfer of fatty acids from LDs to mitochondria. PGC-1<em>α</em> deficiency worsens the neomycin-induced disorders in lipid metabolism and intensifies the pathological interactions between mitochondria and LDs, as indicated by the exacerbated disturbance of dynamic LD turnover, increased level of oxidized lipids and decreased use of fatty acids. This investigation provides a fresh perspective on the lipid metabolic dysfunction related to mitochondria–LD interactions in drug-induced ototoxicity and nephrotoxicity, potentially providing novel avenues for intervention strategies.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4413-4430"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141277434","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

Cover Story 封面故事

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI: 10.1016/S2211-3835(24)00361-7

引用次数: 0