Acta Pharmaceutica Sinica. B最新文献

Emerging interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors or degraders as therapeutic agents for autoimmune diseases and cancer.

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-12-01 Epub Date: 2024-09-14 DOI: 10.1016/j.apsb.2024.09.008

Yifan Feng, Chengjuan Chen, Anqi Shao, Lei Wu, Haiyu Hu, Tiantai Zhang

{"title":"Emerging interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors or degraders as therapeutic agents for autoimmune diseases and cancer.","authors":"Yifan Feng, Chengjuan Chen, Anqi Shao, Lei Wu, Haiyu Hu, Tiantai Zhang","doi":"10.1016/j.apsb.2024.09.008","DOIUrl":"10.1016/j.apsb.2024.09.008","url":null,"abstract":"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.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 12","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}

引用次数: 0

New functions of oxylipins released by pyroptotic cells.

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-12-01 Epub Date: 2024-10-22 DOI: 10.1016/j.apsb.2024.10.007

Hui Xu, Hong-Li Tan, Hua-Jun Wang, Xiao-Fei Zheng, Yan-Ping Wu, Rong-Rong He

引用次数: 0

Spinal astrocyte-derived interleukin-17A promotes pain hypersensitivity in bone cancer mice.

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-12-01 Epub Date: 2024-09-21 DOI: 10.1016/j.apsb.2024.09.016

Huizhu Liu, Xuejing Lv, Xin Zhao, Lanxing Yi, Ning Lv, Wendong Xu, Yuqiu Zhang

{"title":"Spinal astrocyte-derived interleukin-17A promotes pain hypersensitivity in bone cancer mice.","authors":"Huizhu Liu, Xuejing Lv, Xin Zhao, Lanxing Yi, Ning Lv, Wendong Xu, Yuqiu Zhang","doi":"10.1016/j.apsb.2024.09.016","DOIUrl":"10.1016/j.apsb.2024.09.016","url":null,"abstract":"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 CaMKIIα inhibitor. Moreover, selective knockdown IL-17RA in spinal Vglut2 + or Vgat +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-CaMKIIα signaling may offer new gender-inclusive therapeutic strategies for managing bone cancer pain.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 12","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}

引用次数: 0

Targeted inhibition of Gus-expressing Enterococcus faecalis to promote intestinal stem cell and epithelial renovation contributes to the relief of irinotecan chemotoxicity by dehydrodiisoeugenol.

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-12-01 Epub Date: 2024-10-18 DOI: 10.1016/j.apsb.2024.09.018

Ruiyang Gao, Bei Yue, Cheng Lv, Xiaolong Geng, Zhilun Yu, Hao Wang, Beibei Zhang, Fangbin Ai, Ziyi Wang, Donghui Liu, Zhengtao Wang, Kaixian Chen, Wei Dou

{"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, Bei Yue, Cheng Lv, Xiaolong Geng, Zhilun Yu, Hao Wang, Beibei Zhang, Fangbin Ai, Ziyi Wang, Donghui Liu, Zhengtao Wang, Kaixian Chen, Wei Dou","doi":"10.1016/j.apsb.2024.09.018","DOIUrl":"10.1016/j.apsb.2024.09.018","url":null,"abstract":"Irinotecan (CPT11) chemotherapy-induced diarrhea affects a substantial cancer population due to β-glucuronidase (Gus) converting 10-O-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 Enterococcus faecalis (E. faecalis). DDIE counters CPT11-induced augmentation of E. faecalis, leading to decreased intestinal Gus and SN38 levels. The Partial Least Squares Path Model (PLS-PM) algorithm initially links E. faecalis to dysregulated epithelial renovation. This is further validated in a 3D intestinal organoid model, in which both SN38 and E. faecalis hinder the formation and differentiation of organoids. Interestingly, colonization of E. faecalis 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.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 12","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}

引用次数: 0

UBE2G2 inhibits vasculogenic mimicry and metastasis of uveal melanoma by promoting ubiquitination of LGALS3BP.

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-12-01 Epub Date: 2024-09-13 DOI: 10.1016/j.apsb.2024.09.005

Andi Zhao, Chenyu Zhou, Jinjing Li, Zijin Wang, Hui Zhu, Shiya Shen, Qing Shao, Qi Gong, Hu Liu, Xuejuan Chen

{"title":"UBE2G2 inhibits vasculogenic mimicry and metastasis of uveal melanoma by promoting ubiquitination of LGALS3BP.","authors":"Andi Zhao, Chenyu Zhou, Jinjing Li, Zijin Wang, Hui Zhu, Shiya Shen, Qing Shao, Qi Gong, Hu Liu, Xuejuan Chen","doi":"10.1016/j.apsb.2024.09.005","DOIUrl":"10.1016/j.apsb.2024.09.005","url":null,"abstract":"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.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 12","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}

引用次数: 0

Heterologous biosynthesis of saponin adjuvants from Quillaja saponaria: A symbolic achievement in metabolic engineering.

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-12-01 Epub Date: 2024-09-19 DOI: 10.1016/j.apsb.2024.09.013

Weiqiang Chen, Zhichao Xu, Wei Sun

引用次数: 0

Recent advances in reactive oxygen species (ROS)-responsive drug delivery systems for photodynamic therapy of cancer.

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-12-01 Epub Date: 2024-11-02 DOI: 10.1016/j.apsb.2024.10.015

Danrong Hu, Yicong Li, Ran Li, Meng Wang, Kai Zhou, Chengqi He, Quan Wei, Zhiyong Qian

{"title":"Recent advances in reactive oxygen species (ROS)-responsive drug delivery systems for photodynamic therapy of cancer.","authors":"Danrong Hu, Yicong Li, Ran Li, Meng Wang, Kai Zhou, Chengqi He, Quan Wei, Zhiyong Qian","doi":"10.1016/j.apsb.2024.10.015","DOIUrl":"10.1016/j.apsb.2024.10.015","url":null,"abstract":"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.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 12","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}

引用次数: 0

Thio-ProTide strategy: A novel H₂S donor-drug conjugate (DDC) alleviates hepatic injury via innate lysosomal targeting.

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-12-01 Epub Date: 2024-11-09 DOI: 10.1016/j.apsb.2024.10.017

Haowen Jin, Jie Ma, Bixin Xu, Sitao Xu, Tianyu Hu, Xin Jin, Jiankun Wang, Guangji Wang, Le Zhen

{"title":"Thio-ProTide strategy: A novel H2S donor-drug conjugate (DDC) alleviates hepatic injury via innate lysosomal targeting.","authors":"Haowen Jin, Jie Ma, Bixin Xu, Sitao Xu, Tianyu Hu, Xin Jin, Jiankun Wang, Guangji Wang, Le Zhen","doi":"10.1016/j.apsb.2024.10.017","DOIUrl":"10.1016/j.apsb.2024.10.017","url":null,"abstract":"Hydrogen sulfide (H2S) is a gas signaling molecule with versatile bioactivities; however, its exploitation for disease treatment appears challenging. This study describes the design and characterization of a novel type of H2S donor-drug conjugate (DDC) based on the thio-ProTide scaffold, an evolution of the ProTide strategy successfully used in drug discovery. The new H2S DDCs achieved hepatic co-delivery of H2S and an anti-fibrotic drug candidate named hydronidone, which synergistically attenuated liver injury and resulted in more sufficient intracellular drug exposure. The potent hepatoprotective effects were also attributed to the H2S-mediated multipronged intervention in lipid peroxidation both at the whole cellular and lysosomal levels. Lysosomal H2S accumulation and H2S DDC activation were facilitated by the hydrolysis through the specific lysosomal hydrolase, representing a distinct mechanism for lysosomal targeting independent of the classical basic moieties. These findings provided a novel pattern for the design of optimally therapeutic H2S DDC and organelle-targeting functional molecules.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 12","pages":"5341-5356"},"PeriodicalIF":14.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11725097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977141","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

Microneedles as transdermal drug delivery system for enhancing skin disease treatment.

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-12-01 Epub Date: 2024-08-22 DOI: 10.1016/j.apsb.2024.08.013

Chaoxiong Wu, Qingyu Yu, Chenlu Huang, Fangzhou Li, Linhua Zhang, Dunwan Zhu

{"title":"Microneedles as transdermal drug delivery system for enhancing skin disease treatment.","authors":"Chaoxiong Wu, Qingyu Yu, Chenlu Huang, Fangzhou Li, Linhua Zhang, Dunwan Zhu","doi":"10.1016/j.apsb.2024.08.013","DOIUrl":"10.1016/j.apsb.2024.08.013","url":null,"abstract":"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.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 12","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}

引用次数: 0

A morphologically transformable hypoxia-induced radical anion for tumor-specific photothermal therapy.

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-12-01 Epub Date: 2024-09-21 DOI: 10.1016/j.apsb.2024.09.017

Hongyu Wang, Dengyuan Hao, Qihang Wu, Tingting Sun, Zhigang Xie

引用次数: 0