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}
{"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}
{"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}
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}
{"title":"RMC-7977, a highly selective inhibitor of the active RAS-GTP to treat pancreatic cancer","authors":"Ying-Qi Song , Qingjun Li , Chunquan Sheng","doi":"10.1016/j.apsb.2024.07.014","DOIUrl":"10.1016/j.apsb.2024.07.014","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4622-4624"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141775570","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}
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}
{"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}
{"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}
{"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}