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Crosstalk between androgen receptor and protein kinase G signaling in bone: implications for osteoporosis therapy.
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
Animal models of cocaine use: importance of social context and co-use.
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
Emerging mechanisms and therapeutics in inflammatory muscle diseases.
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.
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.
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":"","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":"","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
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