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Promoting proteostasis by cAMP/PKA and cGMP/PKG. 通过 cAMP/PKA 和 cGMP/PKG 促进蛋白稳态。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-03-01 Epub Date: 2024-10-29 DOI: 10.1016/j.molmed.2024.10.006
Md Salim Ahammed, Xuejun Wang
{"title":"Promoting proteostasis by cAMP/PKA and cGMP/PKG.","authors":"Md Salim Ahammed, Xuejun Wang","doi":"10.1016/j.molmed.2024.10.006","DOIUrl":"10.1016/j.molmed.2024.10.006","url":null,"abstract":"<p><p>Proteasome functional insufficiency (PFI) is implicated in neurodegeneration and heart failure, where aberrant protein aggregation is common and impairs the ubiquitin (Ub)-proteasome system (UPS), exacerbating increased proteotoxic stress (IPTS) and creating a vicious circle. Breaking this circle represents a key to treating these diseases. Protein kinase (PK)-A and PKG can activate the proteasome and promote proteasomal degradation of misfolded proteins. PKA does so by phosphorylating Ser14-RPN6/PSMD11, but how PKG activates the proteasome remains unknown. Emerging evidence supports a strategy to treat diseases with IPTS by augmenting cAMP/PKA and cGMP/PKG. Conceivably, targeted activation of PKA and PKG at proteasome nanodomains would minimize the undesired effects from their actions on other targets. In this review, we discuss PKA and PKG regulation of proteostasis via the UPS.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":"224-239"},"PeriodicalIF":12.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547656","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
Bridging translational gaps in Mexico's new science era.
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-03-01 Epub Date: 2025-01-21 DOI: 10.1016/j.molmed.2025.01.003
Eduardo Perez-Campos, Victor Del Rio, Hector A Cabrera-Fuentes
{"title":"Bridging translational gaps in Mexico's new science era.","authors":"Eduardo Perez-Campos, Victor Del Rio, Hector A Cabrera-Fuentes","doi":"10.1016/j.molmed.2025.01.003","DOIUrl":"10.1016/j.molmed.2025.01.003","url":null,"abstract":"","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":"202-203"},"PeriodicalIF":12.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024871","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
Bone-brain crosstalk in osteoarthritis: pathophysiology and interventions. 骨关节炎中的骨脑串扰：病理生理学和干预措施。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-03-01 Epub Date: 2024-10-21 DOI: 10.1016/j.molmed.2024.09.006
Yilan Tang, Zhiyan Wang, Jin Cao, Yiheng Tu
{"title":"Bone-brain crosstalk in osteoarthritis: pathophysiology and interventions.","authors":"Yilan Tang, Zhiyan Wang, Jin Cao, Yiheng Tu","doi":"10.1016/j.molmed.2024.09.006","DOIUrl":"10.1016/j.molmed.2024.09.006","url":null,"abstract":"<p><p>Osteoarthritis (OA) is a prevalent articular disorder characterized by joint degeneration and persistent pain; it imposes a significant burden on both individuals and society. While OA has traditionally been viewed as a localized peripheral disorder, recent preclinical and clinical studies have revealed the crucial interconnections between the bone and the brain, highlighting the systemic nature of OA. The neuronal pathway, molecular signaling, circadian rhythms, and genetic underpinnings within the bone-brain axis play vital roles in the complex interplay that contributes to OA initiation and progression. This review explores emerging evidence of the crosstalk between the bone and brain in OA progression, and discusses the potential contributions of the bone-brain axis to the development of effective interventions for managing OA.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":"281-295"},"PeriodicalIF":12.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142508723","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
Immune-mediated colitis after immune checkpoint inhibitor therapy. 免疫检查点抑制剂治疗后的免疫介导结肠炎。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-03-01 Epub Date: 2024-10-29 DOI: 10.1016/j.molmed.2024.09.009
Sophie Giesler, Roxane Riemer, Theresa Lowinus, Robert Zeiser
{"title":"Immune-mediated colitis after immune checkpoint inhibitor therapy.","authors":"Sophie Giesler, Roxane Riemer, Theresa Lowinus, Robert Zeiser","doi":"10.1016/j.molmed.2024.09.009","DOIUrl":"10.1016/j.molmed.2024.09.009","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) have led to improved outcome in patients with various types of cancer. Due to inhibition of physiological anti-inflammatory mechanisms, patients treated with ICIs may develop autoimmune inflammation of the colon, associated with morbidity, decreased quality of life (QoL), and mortality. In this review, we summarize clinical and pathophysiological aspects of immune-mediated colitis (ImC), highlighting novel treatment options. In the colon, ICIs trigger resident and circulating T cell activation and infiltration of myeloid cells. In addition, the gut microbiota critically contribute to intestinal immune dysregulation and loss of barrier function, thereby propagating local and systemic inflammation. Currently available therapies for ImC include corticosteroids, antitumor necrosis factor-α (TNF-α)- and anti-integrin α<sub>4</sub>β<sub>7</sub> antibodies. Given that systemic immunosuppression might impair antitumor immune responses, novel therapeutic approaches are urgently needed.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":"265-280"},"PeriodicalIF":12.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547655","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
Clonal hematopoiesis of indeterminate potential: the root cause of, and fertile ground for, hematological malignancies. 具有不确定潜能的克隆造血：血液恶性肿瘤的根源和沃土。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-03-01 Epub Date: 2024-10-25 DOI: 10.1016/j.molmed.2024.10.005
Qiqi Zhuang, Shengjie Jin, Wei Wang, Yan Wang, Hongyan Tong, Zuyun Liu, Jie Sun
{"title":"Clonal hematopoiesis of indeterminate potential: the root cause of, and fertile ground for, hematological malignancies.","authors":"Qiqi Zhuang, Shengjie Jin, Wei Wang, Yan Wang, Hongyan Tong, Zuyun Liu, Jie Sun","doi":"10.1016/j.molmed.2024.10.005","DOIUrl":"10.1016/j.molmed.2024.10.005","url":null,"abstract":"<p><p>Clonal hematopoiesis (CH) of indeterminate potential (CHIP), characterized by propagation of blood cell clones carrying somatic mutations in specific driver genes, is increasingly recognized as a critical factor in the development of hematological malignancies. This phenomenon, which often emerges with age, underscores the complex interplay between genetic predisposition and environmental influences in cancer initiation and progression. Recent years have witnessed significant advances in our understanding of the link between CHIP and hematological diseases. In this review, we provide a comprehensive overview of the features of CHIP and explore its role in promoting tumorigenesis and influencing treatment outcomes for blood cancers. Finally, we summarize current available tools for risk stratification and discuss management strategies for patients with CHIP.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":"252-264"},"PeriodicalIF":12.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569163","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
Tackling 'lost in translation' issues: a response to Perez-Campos et al.
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-03-01 Epub Date: 2025-01-28 DOI: 10.1016/j.molmed.2025.01.007
Guillermo Aquino-Jarquin
{"title":"Tackling 'lost in translation' issues: a response to Perez-Campos et al.","authors":"Guillermo Aquino-Jarquin","doi":"10.1016/j.molmed.2025.01.007","DOIUrl":"10.1016/j.molmed.2025.01.007","url":null,"abstract":"","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":"204-205"},"PeriodicalIF":12.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143068081","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
Pi-ecing together brain calcification mechanisms for therapeutic advancement. 结合脑钙化机制促进治疗进展。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-03-01 Epub Date: 2025-01-04 DOI: 10.1016/j.molmed.2024.12.003
Åse K Bekkelund, Anette Siggervåg, Henriette Aksnes
{"title":"P<sub>i</sub>-ecing together brain calcification mechanisms for therapeutic advancement.","authors":"Åse K Bekkelund, Anette Siggervåg, Henriette Aksnes","doi":"10.1016/j.molmed.2024.12.003","DOIUrl":"10.1016/j.molmed.2024.12.003","url":null,"abstract":"<p><p>Seven primary familial brain calcification genes have been identified but their role in disease mechanisms has been less explored. Cheng et al. recently demonstrated that astrocyte-mediated regulation of brain phosphate (P<sub>i</sub>) involves direct and functional interactions among three of these proteins, paving the way for new strategies to combat brain calcification.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":"206-208"},"PeriodicalIF":12.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928462","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
Considerations for capsid-targeting antiretrovirals in pre-exposure prophylaxis.
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-02-27 DOI: 10.1016/j.molmed.2025.01.013
William M McFadden, Mia Faerch, Karen A Kirby, Robert A Dick, Bruce E Torbett, Stefan G Sarafianos
{"title":"Considerations for capsid-targeting antiretrovirals in pre-exposure prophylaxis.","authors":"William M McFadden, Mia Faerch, Karen A Kirby, Robert A Dick, Bruce E Torbett, Stefan G Sarafianos","doi":"10.1016/j.molmed.2025.01.013","DOIUrl":"https://doi.org/10.1016/j.molmed.2025.01.013","url":null,"abstract":"<p><p>Antiretroviral therapy (ART) impairs viral replication in people living with HIV (PLWH) by suppressing infection or spread. However, not all treatment strategies apply to preventive applications like pre-exposure prophylaxis (PrEP) for uninfected individuals. To prevent the establishment of HIV infection, PrEP must block viral replication either before, or at the stage of integration into the host genome. A promising PrEP approach under investigation utilizes lenacapavir (LEN), which targets the HIV-1 capsid protein (CA) potently before integration. LEN, a first-in-class antiretroviral, has shown high protective efficacy in the ongoing PURPOSE trials thus far. Here, we discuss clinical investigations of LEN, theoretical suitability of preclinical CA-binding antivirals in PrEP, and other key considerations for preventing HIV-1 infection by targeting the capsid.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531891","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
Development of asparagine endopeptidase inhibitors for treating neurodegenerative diseases.
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-02-25 DOI: 10.1016/j.molmed.2025.01.009
Xin Meng, Bowei Li, Mengmeng Wang, Wenhua Zheng, Keqiang Ye
{"title":"Development of asparagine endopeptidase inhibitors for treating neurodegenerative diseases.","authors":"Xin Meng, Bowei Li, Mengmeng Wang, Wenhua Zheng, Keqiang Ye","doi":"10.1016/j.molmed.2025.01.009","DOIUrl":"https://doi.org/10.1016/j.molmed.2025.01.009","url":null,"abstract":"<p><p>Asparagine endopeptidase (AEP), or legumain, is a cysteine protease implicated in various disorders, including atherosclerosis, cancers, neurodegenerative diseases, and inflammation. The development of AEP inhibitors has emerged as a promising therapeutic strategy to modulate AEP activity and slow disease progression. Various AEP inhibitors have been explored, encompassing small molecules, peptide-based, antibody-based, and natural inhibitors. Substrate-mimetic and covalent inhibitors show significant potential for selectively targeting AEP's active site, whereas noncovalent inhibitors offer reversible modulation. Additionally, FDA-approved drugs have also garnered attention for their diverse structures and multitarget capabilities. In this review, we summarize advancements in AEP inhibitors, their mechanisms of action, therapeutic applications in neurodegenerative diseases, and the challenges in translating these findings into clinical practice.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143504332","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
Is there a place for engineered immune cell therapies in autoimmune diseases?
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-02-20 DOI: 10.1016/j.molmed.2025.01.011
Luca Perico, Federica Casiraghi, Ariela Benigni, Giuseppe Remuzzi
{"title":"Is there a place for engineered immune cell therapies in autoimmune diseases?","authors":"Luca Perico, Federica Casiraghi, Ariela Benigni, Giuseppe Remuzzi","doi":"10.1016/j.molmed.2025.01.011","DOIUrl":"https://doi.org/10.1016/j.molmed.2025.01.011","url":null,"abstract":"<p><p>The ability to engineer immune cells yielded a transformative era in oncology. Early clinical trials demonstrated the efficacy of chimeric antigen receptor (CAR) T cells in resetting the immune system, motivating the expansion of this treatment beyond cancer, including autoimmune conditions. In this review, we discuss the current state of CAR T cell research in autoimmune diseases, examining the main challenges that limit widespread adoption of this therapy, such as complex isolation protocols, stringent immunosuppression, risk of secondary malignancies, and variable efficacy. We also review the studies addressing these limitations by development of off-the-shelf allogeneic CAR T cells, tunable safety systems, and antigen-specific therapies, which hold the potential to improve safety and accessibility of this treatment in clinical practice.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143473004","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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