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Emerging mechanisms and therapeutics in inflammatory muscle diseases. 炎症性肌肉疾病的新机制和治疗方法。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-03-01 Epub Date: 2025-02-11 DOI: 10.1016/j.tips.2025.01.005
Sven Wischnewski, Hans-Werner Rausch, Chiseko Ikenaga, Jan Leipe, Thomas E Lloyd, Lucas Schirmer
{"title":"Emerging mechanisms and therapeutics in inflammatory muscle diseases.","authors":"Sven Wischnewski, Hans-Werner Rausch, Chiseko Ikenaga, Jan Leipe, Thomas E Lloyd, Lucas Schirmer","doi":"10.1016/j.tips.2025.01.005","DOIUrl":"10.1016/j.tips.2025.01.005","url":null,"abstract":"<p><p>Idiopathic inflammatory myopathies (IIMs), or myositis, are rare diseases marked by immune-driven muscle damage and complications like skin lesions and interstitial lung disease (ILD). Despite advances, challenges in diagnosis and treatment persist, particularly in inclusion body myositis (IBM), where no effective therapy exists. Recent breakthroughs, including transcriptomics and insights into antibody-mediated immunity and interferon (IFN) signaling, have clarified IIM pathophysiology and spurred the development of new therapies, such as chimeric antigen receptor (CAR) T cells and Janus kinase (JAK) inhibitors. We explore the latest findings on the mechanisms underlying adult-onset IIMs, emphasizing IBM pathobiology and its unique immune and degenerative pathways, such as a selective type 2 myofiber damage and severe cell stress. Finally, we highlight the recent advances in transcriptomics, single-cell analysis, and machine learning in transforming IIM research by improving diagnostic accuracy, uncovering therapeutic targets, and supporting the development of personalized treatment strategies.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"249-263"},"PeriodicalIF":13.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143410941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Leveraging non-enzymatic functions of LSD1 for novel therapeutics. 利用LSD1的非酶功能开发新疗法。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-03-01 Epub Date: 2025-02-17 DOI: 10.1016/j.tips.2025.01.006
Yihui Song, Bin Yu
{"title":"Leveraging non-enzymatic functions of LSD1 for novel therapeutics.","authors":"Yihui Song, Bin Yu","doi":"10.1016/j.tips.2025.01.006","DOIUrl":"10.1016/j.tips.2025.01.006","url":null,"abstract":"<p><p>Lysine-specific demethylase 1 (LSD1) is a key enzyme that removes the methylation marks from lysines in the histone tails of nucleosomes. Emerging evidence suggests that LSD1 exhibits both enzyme-dependent and independent functions across various diseases. However, most LSD1-targeted therapies in clinical trials focus on its classic demethylase activity. Only one allosteric inhibitor (SP-2577) and two nonproteolysis-targeting chimera (PROTAC) LSD1 degraders (BEA-17 and UM171), which target its enzyme-independent functions, have entered clinical assessment. Given the limited exploration of therapeutic strategies targeting the non-enzymatic functions of LSD1, in this opinion, we summarize current insights into its biological roles and structural characteristics. We also highlight potential therapeutic interventions targeting the non-enzymatic functions of LSD1, including allosteric inhibitors, protein-protein interaction (PPI) inhibitors, and small-molecule degraders, and discuss challenges and future directions in drug discovery targeting these functions.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"204-219"},"PeriodicalIF":13.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Exploring neutrophils as therapeutic targets in cardiometabolic diseases. 探索中性粒细胞作为心脏代谢疾病的治疗靶点。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-02-01 Epub Date: 2025-01-23 DOI: 10.1016/j.tips.2024.12.003
Mattia Albiero, Andrea Baragetti
{"title":"Exploring neutrophils as therapeutic targets in cardiometabolic diseases.","authors":"Mattia Albiero, Andrea Baragetti","doi":"10.1016/j.tips.2024.12.003","DOIUrl":"10.1016/j.tips.2024.12.003","url":null,"abstract":"<p><p>Current therapies for diabetes and atherosclerotic cardiovascular diseases (ACVDs) mainly target metabolic risk factors, but often fall short in addressing systemic inflammation, a key driver of disease onset and progression. Advances in our understanding of the biology of neutrophils, the cells that are principally involved in inflammatory situations, have highlighted their pivotal role in cardiometabolic diseases. Yet, neutrophils can reprogram their immune-metabolic functions based on the energetic substrates available, thus influencing both tissue homeostasis and the resolution of inflammation. In this review, we examine the effects of canonical therapies for cardiometabolic diseases on the key molecular pathways through which neutrophils respond to inflammatory stimuli. In addition, we explore potential synergies between these established therapeutic approaches and the anti-inflammatory therapies being evaluated for repurposing in the treatment of cardiometabolic diseases.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"102-116"},"PeriodicalIF":13.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143041964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Protein prenylation in mechanotransduction: implications for disease and therapy. 机械转导中的蛋白戊烯酰化：对疾病和治疗的影响。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-02-01 Epub Date: 2025-01-16 DOI: 10.1016/j.tips.2024.12.008
Heng Chen, Jian Yang, Qingzhen Yang, Yuanbo Jia, Xiaogang Guo
{"title":"Protein prenylation in mechanotransduction: implications for disease and therapy.","authors":"Heng Chen, Jian Yang, Qingzhen Yang, Yuanbo Jia, Xiaogang Guo","doi":"10.1016/j.tips.2024.12.008","DOIUrl":"10.1016/j.tips.2024.12.008","url":null,"abstract":"<p><p>The process by which cells translate external mechanical cues into intracellular biochemical signals involves intricate mechanisms that remain unclear. In recent years, research into post-translational modifications (PTMs) has offered valuable insights into this field, spotlighting protein prenylation as a crucial mechanism in cellular mechanotransduction and various human diseases. Protein prenylation, which involves the covalent attachment of isoprenoid groups to specific substrate proteins, profoundly affects the functions of key mechanotransduction proteins such as Rho, Ras, and lamins. This review provides the first comprehensive examination of the connections between prenylation and mechanotransduction, exploring both the mechanistic details and its impact on mechanosensitive cellular behaviors. We further highlight recent evidence linking protein prenylation to diseases associated with disrupted mechanical homeostasis, and outline emerging targeted therapeutic strategies.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"163-179"},"PeriodicalIF":13.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tension-induced organelle stress: an emerging target in fibrosis. 紧张诱导的细胞器应激：纤维化的新靶点。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-02-01 Epub Date: 2025-01-15 DOI: 10.1016/j.tips.2024.12.006
FuiBoon Kai, Andrew M Leidal, Valerie M Weaver
{"title":"Tension-induced organelle stress: an emerging target in fibrosis.","authors":"FuiBoon Kai, Andrew M Leidal, Valerie M Weaver","doi":"10.1016/j.tips.2024.12.006","DOIUrl":"10.1016/j.tips.2024.12.006","url":null,"abstract":"<p><p>Fibrosis accounts for approximately one-third of disease-related deaths globally. Current therapies fail to cure fibrosis, emphasizing the need to identify new antifibrotic approaches. Fibrosis is defined by the excessive accumulation of extracellular matrix (ECM) and resultant stiffening of tissue stroma. This stiffening appropriates actomyosin-mediated mechanical tension within cells to ultimately affect cell fate decisions and function. Recent studies demonstrate that subcellular organelles are physically connected to the actin cytoskeleton and sensitive to mechanoperturbations. These insights highlight mechanisms that may contribute to the chronic organelle stress in many fibrotic diseases, including those of the lung and liver. In this review, we discuss the hypothesis that a stiffened fibrotic ECM corrupts intracellular mechanical tension to compromise organelle homeostasis. We summarize potential therapeutics that could intervene in this mechanical dialog and that may have clinical benefit for resolving pathological organelle stress in fibrosis.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"117-131"},"PeriodicalIF":13.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11805623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012268","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 novel pharmacological entity toward integrated multimodal immunotherapy. 一种面向综合多模式免疫治疗的新型药理实体。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-02-01 Epub Date: 2024-12-24 DOI: 10.1016/j.tips.2024.12.001
Rafael Sirera, Manuel Beltrán-Visiedo, Lorenzo Galluzzi
{"title":"A novel pharmacological entity toward integrated multimodal immunotherapy.","authors":"Rafael Sirera, Manuel Beltrán-Visiedo, Lorenzo Galluzzi","doi":"10.1016/j.tips.2024.12.001","DOIUrl":"10.1016/j.tips.2024.12.001","url":null,"abstract":"<p><p>Most solid tumors are insensitive to single-agent immunotherapy, calling for the development of combinatorial treatment regimens. Recently, Lin and collaborators developed a pharmacological platform enabling the combination of different immunotherapies into a single chemical entity. This approach may effectively circumvent obstacles associated with the simultaneous delivery of multiple immunotherapeutic agents.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"95-97"},"PeriodicalIF":13.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142898417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Advances in the structural understanding of opioid allostery. 阿片变构的结构研究进展。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-02-01 Epub Date: 2025-01-17 DOI: 10.1016/j.tips.2024.12.007
Nokomis Ramos-Gonzalez, Balazs R Varga, Susruta Majumdar
{"title":"Advances in the structural understanding of opioid allostery.","authors":"Nokomis Ramos-Gonzalez, Balazs R Varga, Susruta Majumdar","doi":"10.1016/j.tips.2024.12.007","DOIUrl":"10.1016/j.tips.2024.12.007","url":null,"abstract":"<p><p>Activation of the μ opioid receptor (MOR) can give analgesia, but also has dangerous side effects. Drugs that target MOR through an allosteric site, meaning they bind outside of the usual pocket, present a novel mode of receptor activation with different pharmacology relative to orthosteric drugs. Recent structural studies give valuable new information on how allosteric modulators interact with MOR.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"98-101"},"PeriodicalIF":13.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12001378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012265","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
Boosting CAR-T cell therapy through vaccine synergy. 通过疫苗协同促进CAR-T细胞治疗。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-02-01 Epub Date: 2025-01-03 DOI: 10.1016/j.tips.2024.12.004
Yan-Ruide Li, Zibai Lyu, Xinyuan Shen, Ying Fang, Lili Yang
{"title":"Boosting CAR-T cell therapy through vaccine synergy.","authors":"Yan-Ruide Li, Zibai Lyu, Xinyuan Shen, Ying Fang, Lili Yang","doi":"10.1016/j.tips.2024.12.004","DOIUrl":"10.1016/j.tips.2024.12.004","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment landscape for hematological cancers. However, achieving comparable success in solid tumors remains challenging. Factors contributing to these limitations include the scarcity of tumor-specific antigens (TSAs), insufficient CAR-T cell infiltration, and the immunosuppressive tumor microenvironment (TME). Vaccine-based strategies are emerging as potential approaches to address these challenges, enhancing CAR-T cell expansion, persistence, and antitumor efficacy. In this review, we explore diverse vaccine modalities, including mRNA, peptide, viral vector, and dendritic cell (DC)-based vaccines, and their roles in augmenting CAR-T cell responses. Special focus is given to recent clinical advancements combining mRNA-based vaccines with CAR-T therapy for the treatment of genitourinary cancers. In addition, we discuss crucial considerations for optimizing vaccine dosing, scheduling, and delivery to maximize CAR-T synergy, aiming to refine this combination strategy to improve treatment efficacy and safety.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"180-199"},"PeriodicalIF":13.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Data and AI-driven synthetic binding protein discovery. 数据和人工智能驱动的合成结合蛋白发现。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-02-01 Epub Date: 2025-01-03 DOI: 10.1016/j.tips.2024.12.002
Yanlin Li, Zixin Duan, Zhenwen Li, Weiwei Xue
{"title":"Data and AI-driven synthetic binding protein discovery.","authors":"Yanlin Li, Zixin Duan, Zhenwen Li, Weiwei Xue","doi":"10.1016/j.tips.2024.12.002","DOIUrl":"10.1016/j.tips.2024.12.002","url":null,"abstract":"<p><p>Synthetic binding proteins (SBPs) are a class of protein binders that are artificially created and do not exist naturally. Their broad applications in tackling challenges of research, diagnostics, and therapeutics have garnered significant interest. Traditional protein engineering is pivotal to the discovery of SBPs. Recently, this discovery has been significantly accelerated by computational approaches, such as molecular modeling and artificial intelligence (AI). Furthermore, while numerous bioinformatics databases offer a wealth of resources that fuel SBP discovery, the full potential of these data has not yet been fully exploited. In this review, we present a comprehensive overview of SBP data ecosystem and methodologies in SBP discovery, highlighting the critical role of high-quality data and AI technologies in accelerating the discovery of innovative SBPs with promising applications in pharmacological sciences.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"132-144"},"PeriodicalIF":13.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Therapeutic potential of cannabidiol polypharmacology in neuropsychiatric disorders. 大麻二酚多药理学在神经精神疾病中的治疗潜力。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-02-01 Epub Date: 2025-01-20 DOI: 10.1016/j.tips.2024.12.005
Olivier J Manzoni, Antonia Manduca, Viviana Trezza
{"title":"Therapeutic potential of cannabidiol polypharmacology in neuropsychiatric disorders.","authors":"Olivier J Manzoni, Antonia Manduca, Viviana Trezza","doi":"10.1016/j.tips.2024.12.005","DOIUrl":"10.1016/j.tips.2024.12.005","url":null,"abstract":"<p><p>Cannabidiol (CBD), the primary non-intoxicating compound in cannabis, is currently approved for treating rare, treatment-resistant seizures. Recent preclinical research suggests that CBD's multifaceted mechanisms of action in the brain, which involve multiple molecular targets, underlie its neuroprotective, anti-inflammatory, anxiolytic, and antipsychotic effects. Clinical trials are also exploring CBD's therapeutic potential beyond its current uses. This review focuses on CBD's polypharmacological profile and discusses the latest preclinical and clinical findings regarding its efficacy in neuropsychiatric disorders. Existing evidence suggests that CBD's ability to modulate multiple signaling pathways may benefit neuropsychiatric disorders, and we propose further research areas to clarify its mechanisms, address data gaps, and refine its therapeutic indications.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"145-162"},"PeriodicalIF":13.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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