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Emerging therapies in hereditary ataxias. 遗传性共济失调的新兴疗法。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-02-01 Epub Date: 2024-08-16 DOI: 10.1016/j.molmed.2024.07.008
Mallory L S Eisel, Matthew Burns, Tetsuo Ashizawa, Barry Byrne, Manuela Corti, Sub H Subramony
{"title":"Emerging therapies in hereditary ataxias.","authors":"Mallory L S Eisel, Matthew Burns, Tetsuo Ashizawa, Barry Byrne, Manuela Corti, Sub H Subramony","doi":"10.1016/j.molmed.2024.07.008","DOIUrl":"10.1016/j.molmed.2024.07.008","url":null,"abstract":"<p><p>Recent investigations have defined the pathophysiological basis of many hereditary ataxias (HAs), including loss-of-function as well as gain-of-function mechanisms at either the RNA or protein level. Preclinical studies have assessed gene editing, gene and protein replacement, gene enhancement, and gene knockdown strategies. Methodologies include viral vector delivery of genes, oligonucleotide therapies, cell-penetrating peptides, synthetic transcription factors, and technologies to deliver therapies to defined targets. In this review, we focus on Friedreich ataxia (FRDA) and the polyglutamine ataxias in which translational research is active. However, much remains to be done to identify safe and effective molecules, create ideal delivery methods, and perform innovative clinical trials to prove the safety and efficacy of treatments for these rare but devastating diseases.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":"181-194"},"PeriodicalIF":12.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996568","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
3-O-acylated bile acids: disrupters or harmonizers of metabolism? 3-O-acylated 胆汁酸：新陈代谢的破坏者还是协调者？
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-02-01 Epub Date: 2024-06-25 DOI: 10.1016/j.molmed.2024.06.003
Runzhi Chen, Xinhua Chen, Jiangtao Gao
{"title":"3-O-acylated bile acids: disrupters or harmonizers of metabolism?","authors":"Runzhi Chen, Xinhua Chen, Jiangtao Gao","doi":"10.1016/j.molmed.2024.06.003","DOIUrl":"10.1016/j.molmed.2024.06.003","url":null,"abstract":"<p><p>Unveiling a metabolic mystery, this article explores how 3-O-acylated bile acids, specifically 3-O-succinylated cholic acid (3-sucCA) and 3-acetylated cholic acid (3-acetyCA), modified by gut microbes Bacteroides uniformis and Christensenella minuta, respectively, may either disrupt or harmonize our metabolic processes, offering novel therapeutic avenues for conditions such as metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes mellitus (T2D).</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":"103-105"},"PeriodicalIF":12.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141459475","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 role of glucose-6-phosphatase activity in glucose homeostasis and its potential for diabetes therapy. 葡萄糖-6-磷酸酶活性在葡萄糖稳态中的作用及其在糖尿病治疗中的潜力。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-02-01 Epub Date: 2024-10-18 DOI: 10.1016/j.molmed.2024.09.005
Lay Shuen Tan, Hwee Hui Lau, Essam M Abdelalim, Chin Meng Khoo, Richard M O'Brien, E Shyong Tai, Adrian Kee Keong Teo
{"title":"The role of glucose-6-phosphatase activity in glucose homeostasis and its potential for diabetes therapy.","authors":"Lay Shuen Tan, Hwee Hui Lau, Essam M Abdelalim, Chin Meng Khoo, Richard M O'Brien, E Shyong Tai, Adrian Kee Keong Teo","doi":"10.1016/j.molmed.2024.09.005","DOIUrl":"10.1016/j.molmed.2024.09.005","url":null,"abstract":"<p><p>Glucose-6-phosphatase catalytic subunit (G6PC)1 and G6PC2 are crucial for glucose metabolism, regulating processes like glycolysis, gluconeogenesis, and glycogenolysis. Despite their structural and functional similarities, G6PC1 and G6PC2 exhibit distinct tissue-specific expression patterns, G6P hydrolysis kinetics, and physiological functions. This review provides a comprehensive overview of their enzymology and distinct roles in glucose homeostasis. We examine how inactivating mutations in G6PC1 lead to glycogen storage disease, and how elevated G6PC1 and G6PC2 expression can affect the incidence of diabetic complications, risk for type 2 diabetes mellitus (T2DM) and various cancers. We also discuss the potential of inhibiting G6PC1 and G6PC2 to protect against complications from elevated blood glucose levels, and highlight drug development efforts targeting G6PC1 and G6PC2, and the therapeutic potential of inhibitors for disease prevention.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":"152-164"},"PeriodicalIF":12.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142475607","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 inaccessible road to science for people with disabilities. 残疾人通往科学的无障碍之路。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-02-01 Epub Date: 2024-10-01 DOI: 10.1016/j.molmed.2024.08.006
Lisa M Meeks, Mytien Nguyen, Karina Pereira-Lima, Zoie C Sheets, Rylee Betchkal, Bonnielin K Swenor
{"title":"The inaccessible road to science for people with disabilities.","authors":"Lisa M Meeks, Mytien Nguyen, Karina Pereira-Lima, Zoie C Sheets, Rylee Betchkal, Bonnielin K Swenor","doi":"10.1016/j.molmed.2024.08.006","DOIUrl":"10.1016/j.molmed.2024.08.006","url":null,"abstract":"<p><p>This article examines the contributions of disabled scientists and the barriers they face, including systemic ableism and lack of inclusivity. It offers recommendations to foster an inclusive STEM environment, underscoring the importance of supporting disabled scientists to boost innovation and equity.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":"97-99"},"PeriodicalIF":12.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366582","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
Human organoids and organ-on-chips in coeliac disease research. 乳糜泻研究中的人体器官组织和器官芯片。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-02-01 Epub Date: 2024-10-23 DOI: 10.1016/j.molmed.2024.10.003
Hanna L Simpson, Eline Smits, Renée Moerkens, Cisca Wijmenga, Joram Mooiweer, Iris H Jonkers, Sebo Withoff
{"title":"Human organoids and organ-on-chips in coeliac disease research.","authors":"Hanna L Simpson, Eline Smits, Renée Moerkens, Cisca Wijmenga, Joram Mooiweer, Iris H Jonkers, Sebo Withoff","doi":"10.1016/j.molmed.2024.10.003","DOIUrl":"10.1016/j.molmed.2024.10.003","url":null,"abstract":"<p><p>Coeliac disease (CeD) is an immune-mediated disorder characterised by gluten-triggered inflammation and damage in the small intestine, with lifelong gluten-free diet (GFD) as the only treatment. It is a multifactorial disease, involving genetic and environmental susceptibility factors, and its complexity and lack of comprehensive human model systems have hindered understanding of its pathogenesis and development of new treatments. Therefore, it is crucial to establish systems that recapitulate patient genetic background and the interactions between the small intestinal epithelial barrier, immune cells, and environment that contribute to CeD. In this review, we discuss disease complexity, recent advances in stem cell biology, organoids, tissue co-cultures, and organ-on-chip (OoC) systems that facilitate the development of comprehensive human model systems, and model applications in preclinical studies of potential treatments.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":"117-137"},"PeriodicalIF":12.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142508725","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 roles of cyclin-dependent kinase 7 in health and diseases. 细胞周期蛋白依赖性激酶 7 在健康和疾病中的新作用。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-02-01 Epub Date: 2024-10-15 DOI: 10.1016/j.molmed.2024.09.004
Mahder Dawit Belew, Jingrui Chen, Zhaokang Cheng
{"title":"Emerging roles of cyclin-dependent kinase 7 in health and diseases.","authors":"Mahder Dawit Belew, Jingrui Chen, Zhaokang Cheng","doi":"10.1016/j.molmed.2024.09.004","DOIUrl":"10.1016/j.molmed.2024.09.004","url":null,"abstract":"<p><p>Cyclin-dependent kinase 7 (CDK7) regulates cell cycle and transcription, which are central for cancer progression. CDK7 inhibitors exhibit substantial anticancer activities in preclinical studies and are currently being evaluated in clinical trials. CDK7 is widely expressed in the body. However, the impact of CDK7 inhibition on normal tissues has received little attention. Here, we review the biological functions of CDK7, followed by its emerging roles in development, homeostasis and diseases. We discuss the regulatory mechanisms of CDK7 kinase activation and provide an overview of CDK7 substrates identified to date. Moreover, we highlight unanswered questions and propose key areas for future investigation. An advanced understanding of CDK7 will facilitate the pharmaceutical development of CDK7 inhibitors and help minimize undesirable adverse effects.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":"138-151"},"PeriodicalIF":12.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11825286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142475605","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
cGAS-STING DNA-sensing in inflammatory bowel diseases. 炎症性肠病中的 cGAS-STING DNA 传感。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-02-01 Epub Date: 2024-10-23 DOI: 10.1016/j.molmed.2024.10.002
Georges Dimitrov, Bernhard Ryffel, Dieudonnée Togbe, Valérie Quesniaux
{"title":"cGAS-STING DNA-sensing in inflammatory bowel diseases.","authors":"Georges Dimitrov, Bernhard Ryffel, Dieudonnée Togbe, Valérie Quesniaux","doi":"10.1016/j.molmed.2024.10.002","DOIUrl":"10.1016/j.molmed.2024.10.002","url":null,"abstract":"<p><p>Inflammatory bowel diseases (IBD) are chronic, incurable pathologies with unknown causes, affecting millions of people. Pediatric-onset IBD, starting before the age of 18 years, are increasing, with more aggressive and extensive features than adult-onset IBD. These differences remain largely unexplained. Intestinal mucosal damage, cell death, DNA release from nuclear, mitochondrial, or microbiota sources, and DNA-sensing activating the cGAS-STING pathway may contribute to disease evolution. Increased colonic cGAS and STING are increasingly reported in experimental and human IBD. However, limited knowledge of the mechanisms involved hinders the development of new therapeutic options. Here, we discuss recent advances and unresolved questions regarding DNA release, DNA sensor activation, and the role and therapeutic potential of the cGAS-STING pathway in inflammatory colitis.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":"165-180"},"PeriodicalIF":12.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142508724","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
A researcher's guide to studying sex differences in immune aging. 研究人员研究免疫衰老性别差异的指南。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-01-29 DOI: 10.1016/j.molmed.2025.01.005
Clayton Baker, Minhoo Kim, Bérénice A Benayoun
{"title":"A researcher's guide to studying sex differences in immune aging.","authors":"Clayton Baker, Minhoo Kim, Bérénice A Benayoun","doi":"10.1016/j.molmed.2025.01.005","DOIUrl":"https://doi.org/10.1016/j.molmed.2025.01.005","url":null,"abstract":"<p><p>Sex differences in immune system aging significantly impact disease susceptibility and vaccine responses among older adults, but with notable disparities between men and women. This area has gained importance because vaccines can exhibit differential efficacy by sex in aging populations, underscoring the need for sex-specific strategies. As the global population ages, understanding these sex-based immune differences is crucial for developing targeted interventions for age-related diseases. Addressing these disparities requires robust preclinical models that mimic human immune aging to uncover mechanisms and inform personalized approaches. In this review we assess the translational potential of preclinical mouse models in studying sex differences in immune aging, and emphasize the urgency of sex-specific interventions to improve health outcomes in older adults.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143068079","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
Dysregulation of deubiquitinylases: a linchpin of gastrointestinal diseases. 去泛素酶失调：胃肠道疾病的关键。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-01-28 DOI: 10.1016/j.molmed.2025.01.001
Lorena Ferino, Michael Naumann
{"title":"Dysregulation of deubiquitinylases: a linchpin of gastrointestinal diseases.","authors":"Lorena Ferino, Michael Naumann","doi":"10.1016/j.molmed.2025.01.001","DOIUrl":"https://doi.org/10.1016/j.molmed.2025.01.001","url":null,"abstract":"<p><p>Ubiquitinylation of proteins regulates manifold processes and is reversed by deubiquitinylating enzymes (DUBs), which are therefore implicated in a plethora of cellular processes. DUBs are frequently upregulated in many diseases, while in a few cases downregulation of DUBs is associated with disease progression. This review focuses on the involvement of DUBs in the development and progression of gastrointestinal diseases with a particular emphasis on hepatic steatosis and hepatocellular, cholangio-, esophageal, gastric, colorectal, and pancreatic ductal carcinomas. In addition, pathogens that trigger the activity of several DUBs and thus suppress the immune response and cell survival are discussed. Finally, we highlight recent approaches made towards the therapeutic treatment of gastrointestinal diseases using DUB inhibitors.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143060675","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
Physical activity, cathepsin B, and cognitive health. 体育活动、组织蛋白酶B和认知健康。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-01-22 DOI: 10.1016/j.molmed.2024.12.010
Qian Yu, Zhihao Zhang, Fabian Herold, Sebastian Ludyga, Jin Kuang, Yanxia Chen, Zijun Liu, Kirk I Erickson, Bret H Goodpaster, Boris Cheval, Dominika M Pindus, Arthur F Kramer, Charles H Hillman, Teresa Liu-Ambrose, Keith W Kelley, Hyo Youl Moon, Aiguo Chen, Liye Zou
{"title":"Physical activity, cathepsin B, and cognitive health.","authors":"Qian Yu, Zhihao Zhang, Fabian Herold, Sebastian Ludyga, Jin Kuang, Yanxia Chen, Zijun Liu, Kirk I Erickson, Bret H Goodpaster, Boris Cheval, Dominika M Pindus, Arthur F Kramer, Charles H Hillman, Teresa Liu-Ambrose, Keith W Kelley, Hyo Youl Moon, Aiguo Chen, Liye Zou","doi":"10.1016/j.molmed.2024.12.010","DOIUrl":"https://doi.org/10.1016/j.molmed.2024.12.010","url":null,"abstract":"<p><p>Regular physical activity (PA) is beneficial for cognitive health, and cathepsin B (CTSB) - a protease released by skeletal muscle during PA - acts as a potential molecular mediator of this association. PA-induced metabolic and mechanical stress appears to increase plasma/serum CTSB levels. CTSB facilitates neurogenesis and synaptic plasticity in brain regions (e.g., hippocampus and prefrontal cortex) that support performance in specific cognitive domains including memory, learning, and executive function. However, the evidence regarding the role of PA-induced changes in CTSB as a mediator of PA-induced cognitive health in humans is mixed. To guide future research, this article identifies key factors that may explain the observed heterogeneity in the findings from human studies and proposes a PA-CTSB-cognition model.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029660","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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