Acta Pharmaceutica Sinica. B最新文献

{"title":"Emerging interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors or degraders as therapeutic agents for autoimmune diseases and cancer","authors":"Yifan Feng ,&nbsp;Chengjuan Chen ,&nbsp;Anqi Shao ,&nbsp;Lei Wu ,&nbsp;Haiyu Hu ,&nbsp;Tiantai Zhang","doi":"10.1016/j.apsb.2024.09.008","DOIUrl":"10.1016/j.apsb.2024.09.008","url":null,"abstract":"<div><div>Interleukin-1 receptor-related kinase (IRAK4) is a widely expressed serine/threonine kinase involved in the regulation of innate immunity. IRAK4 plays a pivotal role as a key kinase within the downstream signaling pathway cascades of interleukin-1 receptors (IL-1R) and Toll-like receptors (TLRs). The signaling pathways orchestrated by IRAK4 are integral to inflammatory responses, and its overexpression is implicated in the pathogenesis of inflammatory diseases, autoimmune disorders, and cancer. Consequently, targeting IRAK4-mediated signaling pathways has emerged as a promising therapeutic strategy. Small molecule inhibitors and degraders designed to modulate IRAK4 have shown efficacy in mitigating related diseases. In this paper, we will provide a detailed description of the structure and function of IRAK4, the role of IRAK4 in related diseases, as well as the currently reported small molecule inhibitors and degraders of IRAK4. It is expected to provide new directions for enriching the clinical treatment of inflammation and related diseases.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 12","pages":"Pages 5091-5105"},"PeriodicalIF":14.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11725142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977087","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":"New functions of oxylipins released by pyroptotic cells","authors":"Hui Xu ,&nbsp;Hong-Li Tan ,&nbsp;Hua-Jun Wang ,&nbsp;Xiao-Fei Zheng ,&nbsp;Yan-Ping Wu ,&nbsp;Rong-Rong He","doi":"10.1016/j.apsb.2024.10.007","DOIUrl":"10.1016/j.apsb.2024.10.007","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 12","pages":"Pages 5509-5511"},"PeriodicalIF":14.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11725132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977119","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":"AKR1C1 interacts with STAT3 to increase intracellular glutathione and confers resistance to oxaliplatin in colorectal cancer","authors":"Zhiwen Fu ,&nbsp;Tingting Wu ,&nbsp;Chen Gao ,&nbsp;Lulu Wang ,&nbsp;Yu Zhang ,&nbsp;Chen Shi","doi":"10.1016/j.apsb.2024.08.031","DOIUrl":"10.1016/j.apsb.2024.08.031","url":null,"abstract":"<div><div>Oxaliplatin (OXA), a platinum-based chemotherapeutic agent, remains a mainstay in first-line treatments for advanced colorectal cancer (CRC). However, the eventual development of OXA resistance represents a significant clinical challenge. In the present study, we demonstrate that the aldo-keto reductase 1C1 (AKR1C1) is overexpressed in CRC cells upon acquisition of OXA resistance, evident in OXA-resistant CRC cell lines. We employed genetic silencing and pharmacological inhibition strategies to establish that suppression of AKR1C1 restores OXA sensitivity. Mechanistically, AKR1C1 interacts with and activates the transcription factor STAT3, which upregulates the glutamate transporter EAAT3, thereby elevating intracellular glutathione levels and conferring OXA resistance. Alantolactone, a potent natural product inhibitor of AKR1C1, effectively reverses this chemoresistance, restricting the growth of OXA-resistant CRC cells both <em>in vitro</em> and <em>in vivo</em>. Our findings uncover a critical AKR1C1-dependent mechanism behind OXA resistance and propose a promising combinatorial therapeutic strategy to overcome this resistance in CRC.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 12","pages":"Pages 5305-5320"},"PeriodicalIF":14.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263630","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":"Spinal astrocyte-derived interleukin-17A promotes pain hypersensitivity in bone cancer mice","authors":"Huizhu Liu ,&nbsp;Xuejing Lv ,&nbsp;Xin Zhao ,&nbsp;Lanxing Yi ,&nbsp;Ning Lv ,&nbsp;Wendong Xu ,&nbsp;Yuqiu Zhang","doi":"10.1016/j.apsb.2024.09.016","DOIUrl":"10.1016/j.apsb.2024.09.016","url":null,"abstract":"<div><div>Spinal microglia and astrocytes are both involved in neuropathic and inflammatory pain, which may display sexual dimorphism. Here, we demonstrate that the sustained activation of spinal astrocytes and astrocyte-derived interleukin (IL)-17A promotes the progression of mouse bone cancer pain without sex differences. Chemogenetic or pharmacological inhibition of spinal astrocytes effectively ameliorates bone cancer-induced pain-like behaviors. In contrast, chemogenetic or optogenetic activation of spinal astrocytes triggers pain hypersensitivity, implying that bone cancer-induced astrocytic activation is involved in the development of bone cancer pain. IL-17A expression predominantly in spinal astrocytes, whereas its receptor IL-17 receptor A (IL-17RA) was mainly detected in neurons expressing VGLUT2 and PAX2, and a few in astrocytes expressing GFAP. Specific knockdown of IL-17A in spinal astrocytes blocked and delayed the development of bone cancer pain. IL-17A overexpression in spinal astrocytes directly induced thermal hyperalgesia and mechanical allodynia, which could be rescued by CaMKII<em>α</em> inhibitor. Moreover, selective knockdown IL-17RA in spinal <em>Vglut2</em>^<em>+</em> or <em>Vgat</em>⁺neurons, but not in astrocytes, significantly blocked the bone cancer-induced hyperalgesia. Together, our findings provide evidence for the crucial role of sex-independent astrocytic signaling in bone cancer pain. Targeting spinal astrocytes and IL-17A/IL-17RA-CaMKII<em>α</em> signaling may offer new gender-inclusive therapeutic strategies for managing bone cancer pain.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 12","pages":"Pages 5249-5266"},"PeriodicalIF":14.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11725171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977131","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 inhibition of Gus-expressing Enterococcus faecalis to promote intestinal stem cell and epithelial renovation contributes to the relief of irinotecan chemotoxicity by dehydrodiisoeugenol","authors":"Ruiyang Gao ,&nbsp;Bei Yue ,&nbsp;Cheng Lv ,&nbsp;Xiaolong Geng ,&nbsp;Zhilun Yu ,&nbsp;Hao Wang ,&nbsp;Beibei Zhang ,&nbsp;Fangbin Ai ,&nbsp;Ziyi Wang ,&nbsp;Donghui Liu ,&nbsp;Zhengtao Wang ,&nbsp;Kaixian Chen ,&nbsp;Wei Dou","doi":"10.1016/j.apsb.2024.09.018","DOIUrl":"10.1016/j.apsb.2024.09.018","url":null,"abstract":"<div><div>Irinotecan (CPT11) chemotherapy-induced diarrhea affects a substantial cancer population due to <em>β</em>-glucuronidase (Gus) converting 10-<em>O</em>-glucuronyl-7-ethyl-10-hydroxycamptothecin (SN38G) to toxic 7-ethyl-10-hydroxycamptothecin (SN38). Existing interventions primarily address inflammation and Gus enzyme inhibition, neglecting epithelial repair and Gus-expressing bacteria. Herein, we discovered that dehydrodiisoeugenol (DDIE), isolated from nutmeg, alleviates CPT11-induced intestinal mucositis alongside a synergistic antitumor effect with CPT11 by improving weight loss, colon shortening, epithelial barrier dysfunction, goblet cells and intestinal stem cells (ISCs) loss, and wound-healing. The anti-mucositis effect of DDIE is gut microbiota-dependent. Analysis of microbiome profiling data from clinical patients and CPT11-induced mucositis mice reveals a strong correlation between CPT11 chemotoxicity and Gus-expressing bacteria, particularly <em>Enterococcus faecalis</em> (<em>E. faecalis</em>). DDIE counters CPT11-induced augmentation of <em>E. faecalis</em>, leading to decreased intestinal Gus and SN38 levels. The Partial Least Squares Path Model (PLS-PM) algorithm initially links <em>E. faecalis</em> to dysregulated epithelial renovation. This is further validated in a 3D intestinal organoid model, in which both SN38 and <em>E. faecalis</em> hinder the formation and differentiation of organoids. Interestingly, colonization of <em>E. faecalis</em> exacerbates CPT11-induced mucositis and disturbs epithelial differentiation. Our study unveils a microbiota-driven, epithelial reconstruction-mediated action of DDIE against mucositis, proposing the ‘Gus bacteria–host–irinotecan axis’ as a promising target for mitigating CPT11 chemotoxicity.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 12","pages":"Pages 5286-5304"},"PeriodicalIF":14.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11725075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977134","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":"UBE2G2 inhibits vasculogenic mimicry and metastasis of uveal melanoma by promoting ubiquitination of LGALS3BP","authors":"Andi Zhao ,&nbsp;Chenyu Zhou ,&nbsp;Jinjing Li ,&nbsp;Zijin Wang ,&nbsp;Hui Zhu ,&nbsp;Shiya Shen ,&nbsp;Qing Shao ,&nbsp;Qi Gong ,&nbsp;Hu Liu ,&nbsp;Xuejuan Chen","doi":"10.1016/j.apsb.2024.09.005","DOIUrl":"10.1016/j.apsb.2024.09.005","url":null,"abstract":"<div><div>Uveal melanoma (UM) poses a significant lethality, with approximately 50% of those developing metastases surviving less than one year. In the progression of UM, vasculogenic mimicry (VM) induced by hypoxia plays a pivotal role, which also partially explains the resistance of UM to anti-angiogenic therapies. Nevertheless, the crucial molecular mechanisms underlying VM in the progression of UM remain unclear. We identified ubiquitin conjugating enzyme E2 G2 (UBE2G2) as a critical suppressor through transcriptomic sequencing and metastasis correlation screening. In UM, hypoxia-induced VM and metastasis are markedly exacerbated by UBE2G2 knockdown and significantly alleviated by its overexpression. Mechanistically, UBE2G2 directly binds to galectin 3 binding protein (LGALS3BP) and forms a complex with the E3 ubiquitin ligase tripartite motif containing 38 (TRIM38), facilitating ubiquitination-mediated degradation of LGALS3BP at the K104 residue. Furthermore, UBE2G2 inhibits oncogenic phenotypes by inactivating intracellular PI3K/AKT signaling and reprogramming the tumor microenvironment. Therefore, targeting intercellular and intracellular molecular mechanisms of the hypoxia–UBE2G2–LGALS3BP axis may contribute to developing various therapeutic strategies for UM.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 12","pages":"Pages 5201-5218"},"PeriodicalIF":14.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11725101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142976765","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":"Heterologous biosynthesis of saponin adjuvants from Quillaja saponaria: A symbolic achievement in metabolic engineering","authors":"Weiqiang Chen ,&nbsp;Zhichao Xu ,&nbsp;Wei Sun","doi":"10.1016/j.apsb.2024.09.013","DOIUrl":"10.1016/j.apsb.2024.09.013","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 12","pages":"Pages 5518-5520"},"PeriodicalIF":14.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11725140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977100","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":"Comparison of Jinzhen oral liquid and ambroxol hydrochloride and clenbuterol hydrochloride oral solution in the treatment of acute bronchitis in children: A multicenter, non-inferiority, prospective, randomized controlled trial","authors":"Qinhua Fan ,&nbsp;Chongming Wu ,&nbsp;Yawei Du ,&nbsp;Boyang Wang ,&nbsp;Yanming Xie ,&nbsp;Zeling Zhang ,&nbsp;Wenquan Su ,&nbsp;Zizhuo Wang ,&nbsp;Changchang Xu ,&nbsp;Xueke Li ,&nbsp;Ying Ding ,&nbsp;Xinjiang An ,&nbsp;Jing Chen ,&nbsp;Yunying Xiao ,&nbsp;Rong Yu ,&nbsp;Nan Li ,&nbsp;Juan Wang ,&nbsp;Yiqun Teng ,&nbsp;Hongfen Lv ,&nbsp;Nian Yang ,&nbsp;Shengxian Wu","doi":"10.1016/j.apsb.2024.09.001","DOIUrl":"10.1016/j.apsb.2024.09.001","url":null,"abstract":"<div><div>The comparison between traditional Chinese medicine Jinzhen oral liquid (JZOL) and Western medicine in treating children with acute bronchitis (AB) showed encouraging outcomes. This trial evaluated the efficacy and safety of the JZOL for improving cough and expectoration in children with AB. 480 children were randomly assigned to take JZOL or ambroxol hydrochloride and clenbuterol hydrochloride oral solution for 7 days. The primary outcome was time-to-cough resolution. The median time-to-cough resolution in both groups was 5.0 days and the antitussive onset median time was only 1 day. This randomized controlled trial showed that JZOL was not inferior to cough suppressant and phlegm resolving western medicine in treating cough and sputum and could comprehensively treat respiratory and systemic discomfort symptoms. Combined with clinical trials, the mechanism of JZOL against AB was uncovered by network target analysis, it was found that the pathways in TRP channels like IL-1<em>β</em>/IL1R/TRPV1/TRPA1, NGF/TrkA/TRPV1/TRPA1, and PGE2/EP/PKA/TRPV1/TRPA1 might play important roles. Animal experiments further confirmed that inflammation and the immune regulatory effect of JZOL in the treatment of AB were of vital importance and TRP channels were the key mechanism of action.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 12","pages":"Pages 5186-5200"},"PeriodicalIF":14.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263513","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":"Microneedles as transdermal drug delivery system for enhancing skin disease treatment","authors":"Chaoxiong Wu,&nbsp;Qingyu Yu,&nbsp;Chenlu Huang,&nbsp;Fangzhou Li,&nbsp;Linhua Zhang,&nbsp;Dunwan Zhu","doi":"10.1016/j.apsb.2024.08.013","DOIUrl":"10.1016/j.apsb.2024.08.013","url":null,"abstract":"<div><div>Microneedles (MNs) serve as a revolutionary paradigm in transdermal drug delivery, heralding a viable resolution to the formidable barriers presented by the cutaneous interface. This review examines MNs as an advanced approach to enhancing dermatological pathology management. It explores the complex dermis structure and highlights the limitations of traditional transdermal methods, emphasizing MNs' advantage in bypassing the stratum corneum to deliver drugs directly to the subdermal matrix. The discourse outlines the diverse typologies of MNs, including solid, coated, hollow, hydrogel, and dissolvable versions. Each type is characterized by its unique applications and benefits. The treatise details the deployment of MNs in the alleviation of cutaneous cancers, the administration of inflammatory dermatoses such as psoriasis and atopic dermatitis, and their utility in wound management. Additionally, the paper contemplates the prospects of MNs within the realm of aesthetic dermatology and the burgeoning market traction of cosmetic MN formulations. The review summarizes the scientific and commercial challenges to the clinical adoption of MN therapeutics, including dosage calibration, pharmacodynamics, biocompatibility, patient compliance, sterilization, mass production, and regulatory oversight. It emphasizes the need for ongoing research, innovation, and regulatory harmonization to overcome these obstacles and fully realize MNs’ potential in treating skin diseases and improving patient welfare.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 12","pages":"Pages 5161-5180"},"PeriodicalIF":14.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11725105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977117","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":"Recent advances in reactive oxygen species (ROS)-responsive drug delivery systems for photodynamic therapy of cancer","authors":"Danrong Hu ,&nbsp;Yicong Li ,&nbsp;Ran Li ,&nbsp;Meng Wang ,&nbsp;Kai Zhou ,&nbsp;Chengqi He ,&nbsp;Quan Wei ,&nbsp;Zhiyong Qian","doi":"10.1016/j.apsb.2024.10.015","DOIUrl":"10.1016/j.apsb.2024.10.015","url":null,"abstract":"<div><div>Reactive oxygen species (ROS)-responsive drug delivery systems (DDSs) have garnered significant attention in cancer research because of their potential for precise spatiotemporal drug release tailored to high ROS levels within tumors. Despite the challenges posed by ROS distribution heterogeneity and endogenous supply constraints, this review highlights the strategic alliance of ROS-responsive DDSs with photodynamic therapy (PDT), enabling selective drug delivery and leveraging PDT-induced ROS for enhanced therapeutic efficacy. This review delves into the biological importance of ROS in cancer progression and treatment. We elucidate in detail the operational mechanisms of ROS-responsive linkers, including thioether, thioketal, selenide, diselencide, telluride and aryl boronic acids/esters, as well as the latest developments in ROS-responsive nanomedicines that integrate with PDT strategies. These insights are intended to inspire the design of innovative ROS-responsive nanocarriers for enhanced cancer PDT.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 12","pages":"Pages 5106-5131"},"PeriodicalIF":14.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11725102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977121","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}