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CRISPR/Cas technologies for cancer drug discovery and treatment. CRISPR/Cas技术用于癌症药物的发现和治疗。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-03-24 DOI: 10.1016/j.tips.2025.02.009
Kevin C Wang, Tiffany Zheng, Basil P Hubbard
{"title":"CRISPR/Cas technologies for cancer drug discovery and treatment.","authors":"Kevin C Wang, Tiffany Zheng, Basil P Hubbard","doi":"10.1016/j.tips.2025.02.009","DOIUrl":"https://doi.org/10.1016/j.tips.2025.02.009","url":null,"abstract":"<p><p>Clustered regularly interspaced short palindromic repeats (CRISPR) tools are revolutionizing the establishment of genotype-phenotype relationships and are transforming cell- and gene-based therapies. In the field of oncology, CRISPR/CRISPR-associated protein 9 (Cas9), Cas12, and Cas13 have advanced the generation of cancer models, the study of tumor evolution, the identification of target genes involved in cancer growth, and the discovery of genes involved in chemosensitivity and resistance. Moreover, preclinical therapeutic strategies employing CRISPR/Cas have emerged. These include the generation of chimeric antigen receptor T (CAR-T) cells and engineered immune cells, and the use of precision anticancer gene-editing agents to inactivate driver oncogenes, suppress tumor support genes, and cull cancer cells in response to genetic circuit output. This review summarizes the collective impact that CRISPR technology has had on basic and applied cancer research, and highlights the promises and challenges facing its clinical translation.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":13.9,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711371","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
Suzetrigine for moderate to severe acute pain. 舒三嗪用于中度至重度急性疼痛。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-03-24 DOI: 10.1016/j.tips.2025.02.008
Eun Bee Cho, Chenyao Jiang, Zihan Wang, Ying Yu, Jianxiong Jiang
{"title":"Suzetrigine for moderate to severe acute pain.","authors":"Eun Bee Cho, Chenyao Jiang, Zihan Wang, Ying Yu, Jianxiong Jiang","doi":"10.1016/j.tips.2025.02.008","DOIUrl":"10.1016/j.tips.2025.02.008","url":null,"abstract":"","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":13.9,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711376","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
The N terminus-only function of adhesion GPCRs: emerging concepts. 粘附gpcr的仅N端功能：新兴概念。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-03-01 Epub Date: 2025-02-15 DOI: 10.1016/j.tips.2025.01.004
Laura Lehmann, Victoria Elisabeth Groß, Rene Behlendorf, Simone Prömel
{"title":"The N terminus-only function of adhesion GPCRs: emerging concepts.","authors":"Laura Lehmann, Victoria Elisabeth Groß, Rene Behlendorf, Simone Prömel","doi":"10.1016/j.tips.2025.01.004","DOIUrl":"10.1016/j.tips.2025.01.004","url":null,"abstract":"<p><p>Adhesion G-protein-coupled receptors (aGPCRs) play key roles in health and disease. They are unique in that they not only activate G-protein pathways but also have distinct functions that rely solely on their N termini, making them complex drug targets. To date there have been only descriptive observations about these enigmatic N terminus-only functions. Emerging evidence from several aGPCRs now indicates that these are a defining characteristic of these receptors that allows them to operate bidirectionally across environments. Recent advances in characterizing aGPCR splice variants and receptor structure have revealed the G protein-independent mechanisms that underlie their N terminus-only functions. This review consolidates current findings, explores how the N termini integrate functions, and identifies common principles across aGPCRs. We consider the therapeutic implications and discuss how specifically targeting N terminus functions provides a novel perspective on the pharmacological potential of aGPCRs.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"231-248"},"PeriodicalIF":13.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426265","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
Poison exons: tuning RNA splicing for targeted gene regulation. 毒性外显子：调整RNA剪接以进行靶向基因调控。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-03-01 Epub Date: 2025-02-05 DOI: 10.1016/j.tips.2025.01.002
Christopher R Neil, Cassandra Schaening-Burgos, Maria S Alexis, Dominic J Reynolds, Peter G Smith, Michael W Seiler, Frédéric H Vaillancourt, Anant A Agrawal
{"title":"Poison exons: tuning RNA splicing for targeted gene regulation.","authors":"Christopher R Neil, Cassandra Schaening-Burgos, Maria S Alexis, Dominic J Reynolds, Peter G Smith, Michael W Seiler, Frédéric H Vaillancourt, Anant A Agrawal","doi":"10.1016/j.tips.2025.01.002","DOIUrl":"10.1016/j.tips.2025.01.002","url":null,"abstract":"<p><p>Poison exons (PEs) are a class of alternatively spliced exons whose inclusion targets mRNA transcripts for degradation via the nonsense-mediated decay (NMD) pathway. Although a role for NMD as an essential mRNA quality control pathway has long been appreciated, recent advances in RNA sequencing (RNA-seq) strategies and analyses have revealed that its coupling to RNA splicing is broadly used to regulate mRNA stability and abundance. Regulation of PE splicing affects patterns of targeted degradation across the transcriptome and influences gene expression in both healthy and disease states. Importantly, PEs represent a novel therapeutic opportunity to modulate the expression of disease-relevant genes with sequence-specific resolution. We review the emergence of PE splicing in endogenous gene regulation, its misregulation in disease, and the ways in which it can be leveraged for therapeutic benefit.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"264-278"},"PeriodicalIF":13.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143366002","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
Crosstalk between androgen receptor and protein kinase G signaling in bone: implications for osteoporosis therapy. 骨中雄激素受体和蛋白激酶G信号之间的串扰：对骨质疏松症治疗的意义。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-03-01 Epub Date: 2025-02-25 DOI: 10.1016/j.tips.2025.01.007
Hema Kalyanaraman, Shyamsundar Pal China, Darren E Casteel, Renate B Pilz
{"title":"Crosstalk between androgen receptor and protein kinase G signaling in bone: implications for osteoporosis therapy.","authors":"Hema Kalyanaraman, Shyamsundar Pal China, Darren E Casteel, Renate B Pilz","doi":"10.1016/j.tips.2025.01.007","DOIUrl":"10.1016/j.tips.2025.01.007","url":null,"abstract":"<p><p>Testosterone, the primary androgen in males, is required for optimal bone mass and strength in men, but the benefits of testosterone therapy in elderly men with modestly reduced testosterone levels remain controversial. Androgens enhance bone formation by osteoblasts and inhibit resorption by osteoclasts. Recent data in osteoblasts indicate that rapid extranuclear androgen receptor (AR) signaling enhances nuclear AR-mediated transcription of the skeletal master regulator β-catenin, and boosts cell proliferation, differentiation, and survival. This novel signaling involves nitric oxide (NO), cGMP, and protein kinase G2 (PKG2). We discuss these recent developments and summarize bone-anabolic AR functions and AR/PKG2 interactions as revealed by the phenotypes of Ar and Pkg2 knockout and transgenic mice. We propose that tissue-selective AR modulators and PKG-activating agents may represent novel treatment options for osteoporosis.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"279-294"},"PeriodicalIF":13.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516911","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
IRAK4: potential therapeutic target for airway disease exacerbations. IRAK4：气道疾病恶化的潜在治疗靶点
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-03-01 Epub Date: 2025-01-16 DOI: 10.1016/j.tips.2025.01.001
Joseph A Jude, Reynold A Panettieri
{"title":"IRAK4: potential therapeutic target for airway disease exacerbations.","authors":"Joseph A Jude, Reynold A Panettieri","doi":"10.1016/j.tips.2025.01.001","DOIUrl":"10.1016/j.tips.2025.01.001","url":null,"abstract":"<p><p>Inflammatory lung diseases represent a significant healthcare burden. There is an unmet need for identifying therapeutic targets for inflammatory lung diseases, such as asthma, and chronic obstructive pulmonary disease (COPD). In a recent study, Sayers et al. validate the inhibition of interleukin (IL)-1 receptor-associated kinase (IRAK)-4 as a potential therapeutic strategy toward lung inflammation and inflammatory airway diseases more generally.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"201-203"},"PeriodicalIF":13.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012266","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
Animal models of cocaine use: importance of social context and co-use. 可卡因使用的动物模型：社会背景和共同使用的重要性。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-03-01 Epub Date: 2025-01-28 DOI: 10.1016/j.tips.2025.01.003
Mia I Allen, Michael A Nader
{"title":"Animal models of cocaine use: importance of social context and co-use.","authors":"Mia I Allen, Michael A Nader","doi":"10.1016/j.tips.2025.01.003","DOIUrl":"10.1016/j.tips.2025.01.003","url":null,"abstract":"<p><p>Cocaine-use disorders (CUDs) continue to be a major public health problem that requires effective treatments. Despite decades of preclinical research, there are no FDA-approved pharmacotherapies for cocaine use. While there are numerous potential reasons why no efficacious treatments have been identified or approved for cocaine use, we discuss two possible reasons in this review: the low number of studies incorporating social variables and the overlooking of the clinical reality of polysubstance use. These variables impact drug use across the substance-use cycle, including vulnerability, maintenance, and treatment. Recent preclinical and clinical data suggest that cocaine users who engage in polysubstance use should be viewed as a distinct and more prevalent population who require unique behavioral and pharmacological approaches to reduce cocaine use. Therefore, to understand the neurobiology and eventual treatments for CUDs, both variables should be included in animal models.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"220-230"},"PeriodicalIF":13.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11890930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143060557","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
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
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
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
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