Pub Date : 2025-12-17DOI: 10.1016/j.phrs.2025.108071
Emanuela Bottani, Francesca Ciarpella, Benedetta Lucidi, Giulia Pedrotti, Chiara Santanatoglia, Eros Rossi, Enrica Cappellozza, Elisa De Tomi, Sissi Dolci, Giovanni Malerba, Giorgio Malpeli, Ilaria Decimo
Thyroid hormone (T3) deficiency during central nervous system development leads to severe and often incurable human pathologies, including intellectual disability and motor dysfunction. Using murine dorsal forebrain organoids, we showed that T3 is required to activate mitochondrial β-oxidation and OXPHOS biogenesis to sustain neuronal development, while its absence caused profound neurodevelopmental defects such as defective maturation, astrogliosis, and reduced spontaneous activity. Mechanistically, we identified the transcriptional coactivator PGC-1α as a central mediator of the T3 effect. Pharmacological inhibition of β-oxidation in T3-supplemented organoids recapitulated the T3-deficient phenotype, whereas Ppargc1a gene augmentation rescued neuronal development under T3-deprived conditions. Most importantly, pharmacological stimulation of the PGC-1α axis with Nicotinamide Riboside or Bezafibrate rescues mitochondrial bioenergetics and neuronal development, effectively correcting aberrant brain organoid maturation despite T3 deficiency. These findings reveal for the first time the role of T3 in supporting neurodevelopment via activation of mitochondrial β-oxidation and OXPHOS biogenesis, and identify the PGC-1α axis as a promising therapeutic avenue for otherwise intractable disorders linked to thyroid hormone deficiency.
{"title":"Targeting PGC-1α axis Rescues Aberrant Development from Thyroid Hormone Defect in Brain Organoids.","authors":"Emanuela Bottani, Francesca Ciarpella, Benedetta Lucidi, Giulia Pedrotti, Chiara Santanatoglia, Eros Rossi, Enrica Cappellozza, Elisa De Tomi, Sissi Dolci, Giovanni Malerba, Giorgio Malpeli, Ilaria Decimo","doi":"10.1016/j.phrs.2025.108071","DOIUrl":"https://doi.org/10.1016/j.phrs.2025.108071","url":null,"abstract":"<p><p>Thyroid hormone (T3) deficiency during central nervous system development leads to severe and often incurable human pathologies, including intellectual disability and motor dysfunction. Using murine dorsal forebrain organoids, we showed that T3 is required to activate mitochondrial β-oxidation and OXPHOS biogenesis to sustain neuronal development, while its absence caused profound neurodevelopmental defects such as defective maturation, astrogliosis, and reduced spontaneous activity. Mechanistically, we identified the transcriptional coactivator PGC-1α as a central mediator of the T3 effect. Pharmacological inhibition of β-oxidation in T3-supplemented organoids recapitulated the T3-deficient phenotype, whereas Ppargc1a gene augmentation rescued neuronal development under T3-deprived conditions. Most importantly, pharmacological stimulation of the PGC-1α axis with Nicotinamide Riboside or Bezafibrate rescues mitochondrial bioenergetics and neuronal development, effectively correcting aberrant brain organoid maturation despite T3 deficiency. These findings reveal for the first time the role of T3 in supporting neurodevelopment via activation of mitochondrial β-oxidation and OXPHOS biogenesis, and identify the PGC-1α axis as a promising therapeutic avenue for otherwise intractable disorders linked to thyroid hormone deficiency.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"108071"},"PeriodicalIF":10.5,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Calcific aortic valve disease (CAVD) is a progressive cardiovascular disorder pathologically defined by valvular sclerosis, fibrosis, and ectopic mineralization, which constitutes a substantial and growing public health burden. Currently, surgical intervention represents the sole effective treatment, underscoring a critical unmet need for novel pharmacological strategies that can halt disease progression or provide early therapeutic intervention. Extensive research has established that the pathogenesis of CAVD is driven by a complex interplay of multiple mechanisms including inflammatory responses, oxidative stress, and metabolic dysregulation which are intricately modulated by epigenetic regulation, post-transcriptional modifications, and protein post-translational modifications. In recent years, the field of epigenetics has garnered considerable attention, particularly for its pivotal role in the pathogenesis of oncological and cardiovascular diseases and the subsequent development of targeted therapeutic strategies. Consequently, numerous investigations have been dedicated to elucidating the involvement of epigenetic mechanisms in CAVD, encompassing DNA methylation, histone modifications (including methylation and acetylation), and RNA methylation, with a pronounced emphasis on the regulatory functions of non-coding RNAs. This review synthesizes recent advances in our understanding of epigenetic mechanisms underlying CAVD, with a specific focus on the role of RNA N6-methyladenosine (m6A) methylation, and highlights the pivotal significance of epigenetic modulation in critical biological processes and CAVD pathogenesis. Collectively, these findings offer valuable mechanistic insights and may illuminate novel paths toward the clinical translation of epigenetically targeted therapies for CAVD.
{"title":"Epigenetic Regulation in calcific aortic valve disease: Mechanisms and therapeutic potential","authors":"Hanshen Luo, Yuehang Yang, Chiyang Xie, Chuli Shi, Siyuan Liu, Jiawei Shi","doi":"10.1016/j.phrs.2025.108073","DOIUrl":"10.1016/j.phrs.2025.108073","url":null,"abstract":"<div><div>Calcific aortic valve disease (CAVD) is a progressive cardiovascular disorder pathologically defined by valvular sclerosis, fibrosis, and ectopic mineralization, which constitutes a substantial and growing public health burden. Currently, surgical intervention represents the sole effective treatment, underscoring a critical unmet need for novel pharmacological strategies that can halt disease progression or provide early therapeutic intervention. Extensive research has established that the pathogenesis of CAVD is driven by a complex interplay of multiple mechanisms including inflammatory responses, oxidative stress, and metabolic dysregulation which are intricately modulated by epigenetic regulation, post-transcriptional modifications, and protein post-translational modifications. In recent years, the field of epigenetics has garnered considerable attention, particularly for its pivotal role in the pathogenesis of oncological and cardiovascular diseases and the subsequent development of targeted therapeutic strategies. Consequently, numerous investigations have been dedicated to elucidating the involvement of epigenetic mechanisms in CAVD, encompassing DNA methylation, histone modifications (including methylation and acetylation), and RNA methylation, with a pronounced emphasis on the regulatory functions of non-coding RNAs. This review synthesizes recent advances in our understanding of epigenetic mechanisms underlying CAVD, with a specific focus on the role of RNA N6-methyladenosine (m6A) methylation, and highlights the pivotal significance of epigenetic modulation in critical biological processes and CAVD pathogenesis. Collectively, these findings offer valuable mechanistic insights and may illuminate novel paths toward the clinical translation of epigenetically targeted therapies for CAVD.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108073"},"PeriodicalIF":10.5,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Corrigendum to \"Tagitinin F has anti-inflammatory, anti-nociceptive and anti-matrix metalloproteinase properties: An in silico, in vitro and in vivo study\" [Pharmacol. Res. 164 (2021) 105303].","authors":"Laíla Pereira Silva, Eliziária Cardoso Santos, Bruno Arantes Borges, Marcia Paranho Veloso, Daniela Aparecida Chagas-Paula, Reggiani Vilela Gonçalves, Rômulo Dias Novaes","doi":"10.1016/j.phrs.2025.108070","DOIUrl":"https://doi.org/10.1016/j.phrs.2025.108070","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"108070"},"PeriodicalIF":10.5,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145782399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-14DOI: 10.1016/j.phrs.2025.108069
Hayriye Akel Bilgic, Marie Bek, Mirelle Kleuskens, Frank Redegeld
The gut mucosa serves as an essential interface between the internal and external environment, providing a continuous barrier against possible harmful luminal content. The regulation of this protective function is controlled by immune-mediated and non-immune mechanisms, wherein mast cells (MCs) play a key role. These versatile immune cells are strategically located in the lining of the gastrointestinal (GI) tract, where they help maintain the integrity of the intestinal barrier, regulate blood flow, control the entry of immune cells into tissues, and participate in various physiological processes, such as wound healing and intestinal peristalsis. However, excessive MC activation may disturb the gut balance, which could cause a "leaky gut", where increased permeability of the intestinal lining allows substances to pass into the bloodstream, causing various health problems. Studies have confirmed an increased presence of MCs in the intestinal lining of individuals with compromised barriers, as seen in conditions like gastrointestinal diseases (GIDs). Hence, precise regulation of MC activity is essential for maintaining intestinal health and limiting disease progression. In this review, we aim to offer a comprehensive and current overview of the role of MCs in GIDs by delving into their origins, functions, and interactions in the GI environment. We explore the "leaky gut" concept, examining how MCs influence the intestinal barrier and its association with GIDs. Additionally, we describe the latest advancements in MC research, including targeted therapies and potential future directions.
{"title":"Mast cells in digestive diseases: New insights to keep them under control","authors":"Hayriye Akel Bilgic, Marie Bek, Mirelle Kleuskens, Frank Redegeld","doi":"10.1016/j.phrs.2025.108069","DOIUrl":"10.1016/j.phrs.2025.108069","url":null,"abstract":"<div><div>The gut mucosa serves as an essential interface between the internal and external environment, providing a continuous barrier against possible harmful luminal content. The regulation of this protective function is controlled by immune-mediated and non-immune mechanisms, wherein mast cells (MCs) play a key role. These versatile immune cells are strategically located in the lining of the gastrointestinal (GI) tract, where they help maintain the integrity of the intestinal barrier, regulate blood flow, control the entry of immune cells into tissues, and participate in various physiological processes, such as wound healing and intestinal peristalsis. However, excessive MC activation may disturb the gut balance, which could cause a \"leaky gut\", where increased permeability of the intestinal lining allows substances to pass into the bloodstream, causing various health problems. Studies have confirmed an increased presence of MCs in the intestinal lining of individuals with compromised barriers, as seen in conditions like gastrointestinal diseases (GIDs). Hence, precise regulation of MC activity is essential for maintaining intestinal health and limiting disease progression. In this review, we aim to offer a comprehensive and current overview of the role of MCs in GIDs by delving into their origins, functions, and interactions in the GI environment. We explore the \"leaky gut\" concept, examining how MCs influence the intestinal barrier and its association with GIDs. Additionally, we describe the latest advancements in MC research, including targeted therapies and potential future directions.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108069"},"PeriodicalIF":10.5,"publicationDate":"2025-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145768601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Understanding the in vivo behavior of nanomedicines is critical for optimizing their therapeutic efficacy and facilitating personalized treatment strategies. In the quest to develop positron emission tomography (PET) methodology for liposome biodistribution studies, we systematically compared three liposome radiolabeling strategies - remote loading of 64Cu into liposomes containing the hydrophilic chelator NOTA, membrane labeling using ATSM, and surface labeling with DSPE-NODAGA (phospholipid DSPE conjugated with chelator NODAGA) - to identify an effective method for liposome radiolabeling with 64Cu. Our results demonstrated that DSPE-NODAGA incorporated in PEGylated liposomes allows for achieving 100 % radiochemical yield of 64Cu at room temperature within just 5 min. Stability studies confirmed liposome integrity and minimal transchelation or dissociation in serum over 24 h, highlighting its suitability for in vivo applications. PET/MR imaging in healthy and tumor-bearing mice revealed prolonged circulation of 64Cu-labeled PEGylated liposomes (PL-NODAGA) and significant tumor accumulation, validating DSPE-NODAGA’s potential for real-time tracking of liposome delivery. These findings establish the incorporation of DSPE-NODAGA as a robust and adaptable platform for PET-based monitoring of lipidic nanomedicine.
{"title":"Rapid 64Cu radiolabeling and in vivo evaluation of DSPE–NODAGA liposomes in a murine mammary tumor model","authors":"Elena Markova , Mathias Kranz , Morten Karlsen , Camilla Wolowczyk , Angel Moldes-Anaya , Nataša Škalko-Basnet , Rune Sundset , Alexandros Marios Sofias , Rodrigo Berzaghi , Montserrat Martin-Armas , Sjoerd Hak","doi":"10.1016/j.phrs.2025.108065","DOIUrl":"10.1016/j.phrs.2025.108065","url":null,"abstract":"<div><div>Understanding the <em>in vivo</em> behavior of nanomedicines is critical for optimizing their therapeutic efficacy and facilitating personalized treatment strategies. In the quest to develop positron emission tomography (PET) methodology for liposome biodistribution studies, we systematically compared three liposome radiolabeling strategies - remote loading of <sup>64</sup>Cu into liposomes containing the hydrophilic chelator NOTA, membrane labeling using ATSM, and surface labeling with DSPE-NODAGA (phospholipid DSPE conjugated with chelator NODAGA) - to identify an effective method for liposome radiolabeling with <sup>64</sup>Cu. Our results demonstrated that DSPE-NODAGA incorporated in PEGylated liposomes allows for achieving 100 % radiochemical yield of <sup>64</sup>Cu at room temperature within just 5 min. Stability studies confirmed liposome integrity and minimal transchelation or dissociation in serum over 24 h, highlighting its suitability for <em>in vivo</em> applications. PET/MR imaging in healthy and tumor-bearing mice revealed prolonged circulation of <sup>64</sup>Cu-labeled PEGylated liposomes (PL-NODAGA) and significant tumor accumulation, validating DSPE-NODAGA’s potential for real-time tracking of liposome delivery. These findings establish the incorporation of DSPE-NODAGA as a robust and adaptable platform for PET-based monitoring of lipidic nanomedicine.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108065"},"PeriodicalIF":10.5,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-12DOI: 10.1016/j.phrs.2025.108066
Shengqian Deng , Chengtao Sun , Dewen Liu , Yusha Zhang , Jizhou Zhang , Xiaojuan Li , Xu Jia , Guoyin Kai
Non-small cell lung cancer (NSCLC) accounts for 80–90 % of all lung cancer cases and is characterized by high incidence and mortality rates. The epidermal growth factor receptor (EGFR), one of the most frequently mutated genes in NSCLC, has become a key target for treatment through the development of EGFR-tyrosine kinase inhibitors (EGFR-TKIs). While EGFR-TKIs have shown significant therapeutic effects, clinical observations indicate that most patients eventually develop drug resistance. Antibody-drug conjugates (ADCs) represent a potent strategy to overcome EGFR-TKIs resistance by precisely delivering cytotoxic payloads to tumor cells via targets such as EGFR itself or other relevant molecules. In this review, we provide a comprehensive overview of EGFR-TKIs, including their structure, clinical applications, and mechanisms of resistance. We examine the role of ADCs in EGFR-mutated NSCLC, focusing on current targets such as MET, HER2, TROP2, and EGFR, as well as emerging targets under investigation. It is worth mentioning that the development of bispecific ADCs represents a novel frontier in overcoming resistance. We also discuss other novel therapeutic approaches to overcome EGFR-TKIs resistance, including protein degradation–targeting chimeras, poly (ADP-ribose) polymerase inhibitors, aurora kinase inhibitors, and metabolic reprogramming strategies. Finally, we summarize the main challenges associated with ADCs-based therapies and highlight future directions for optimizing treatment in EGFR-TKI-resistant NSCLC.
{"title":"Antibody-drug conjugates: A new twist to overcome EGFR-TKIs resistance in non-small cell lung cancer","authors":"Shengqian Deng , Chengtao Sun , Dewen Liu , Yusha Zhang , Jizhou Zhang , Xiaojuan Li , Xu Jia , Guoyin Kai","doi":"10.1016/j.phrs.2025.108066","DOIUrl":"10.1016/j.phrs.2025.108066","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC) accounts for 80–90 % of all lung cancer cases and is characterized by high incidence and mortality rates. The epidermal growth factor receptor (EGFR), one of the most frequently mutated genes in NSCLC, has become a key target for treatment through the development of EGFR-tyrosine kinase inhibitors (EGFR-TKIs). While EGFR-TKIs have shown significant therapeutic effects, clinical observations indicate that most patients eventually develop drug resistance. Antibody-drug conjugates (ADCs) represent a potent strategy to overcome EGFR-TKIs resistance by precisely delivering cytotoxic payloads to tumor cells via targets such as EGFR itself or other relevant molecules. In this review, we provide a comprehensive overview of EGFR-TKIs, including their structure, clinical applications, and mechanisms of resistance. We examine the role of ADCs in EGFR-mutated NSCLC, focusing on current targets such as MET, HER2, TROP2, and EGFR, as well as emerging targets under investigation. It is worth mentioning that the development of bispecific ADCs represents a novel frontier in overcoming resistance. We also discuss other novel therapeutic approaches to overcome EGFR-TKIs resistance, including protein degradation–targeting chimeras, poly (ADP-ribose) polymerase inhibitors, aurora kinase inhibitors, and metabolic reprogramming strategies. Finally, we summarize the main challenges associated with ADCs-based therapies and highlight future directions for optimizing treatment in EGFR-TKI-resistant NSCLC.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108066"},"PeriodicalIF":10.5,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1016/j.phrs.2025.108064
Chunsik Lee , Myung-Jin Kim , Eunyoung Jung , Jianing Zhang , Vivek Hamse Kameshwar , Nayoung Oh , Anil Kumar , Han-Woong Lee , Xuri Li , Yonghwan Kim
Long overshadowed by VEGF-A, vascular endothelial growth factor B (VEGF-B) has emerged as a critical regulator of vascular, metabolic, and immune cross-talk. Unlike the potent angiogenic factor VEGF-A, VEGF-B does not induce vascular leakage but modulates tissue-specific functions, including fatty acid transport, neuronal survival, and immunometabolism, through its receptors VEGFR1 and NRP1. Its roles are often paradoxical, suppressing angiogenesis in some cancers while promoting metastasis and immune evasion in others, highlighting its profoundly context-dependent nature of action. Recent discoveries, such as the identification of FGFR1 as a key receptor and the essential role of VEGF-B in T cell survival, have revitalized interest in its therapeutic potential. However, clinical translation remains challenging, as exemplified by the recent failure of the anti-VEGF-B antibody CSL346 in diabetic kidney disease, underscoring our incomplete understanding of VEGF-B biology. This review integrates cutting-edge insights into the diverse functions of VEGF-B, proposes a mechanistic framework for its complex signaling networks, and outlines a roadmap for developing precision therapies for metabolic, cardiovascular, neurodegenerative, and oncological diseases. We address the critical translational challenges to maximize the therapeutic benefits while preserving the crucial homeostatic functions of VEGF-B.
{"title":"VEGF-B: A multifaceted modulator with emerging therapeutic applications","authors":"Chunsik Lee , Myung-Jin Kim , Eunyoung Jung , Jianing Zhang , Vivek Hamse Kameshwar , Nayoung Oh , Anil Kumar , Han-Woong Lee , Xuri Li , Yonghwan Kim","doi":"10.1016/j.phrs.2025.108064","DOIUrl":"10.1016/j.phrs.2025.108064","url":null,"abstract":"<div><div>Long overshadowed by VEGF-A, vascular endothelial growth factor B (VEGF-B) has emerged as a critical regulator of vascular, metabolic, and immune cross-talk. Unlike the potent angiogenic factor VEGF-A, VEGF-B does not induce vascular leakage but modulates tissue-specific functions, including fatty acid transport, neuronal survival, and immunometabolism, through its receptors VEGFR1 and NRP1. Its roles are often paradoxical, suppressing angiogenesis in some cancers while promoting metastasis and immune evasion in others, highlighting its profoundly context-dependent nature of action. Recent discoveries, such as the identification of FGFR1 as a key receptor and the essential role of VEGF-B in T cell survival, have revitalized interest in its therapeutic potential. However, clinical translation remains challenging, as exemplified by the recent failure of the anti-VEGF-B antibody CSL346 in diabetic kidney disease, underscoring our incomplete understanding of VEGF-B biology. This review integrates cutting-edge insights into the diverse functions of VEGF-B, proposes a mechanistic framework for its complex signaling networks, and outlines a roadmap for developing precision therapies for metabolic, cardiovascular, neurodegenerative, and oncological diseases. We address the critical translational challenges to maximize the therapeutic benefits while preserving the crucial homeostatic functions of VEGF-B.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108064"},"PeriodicalIF":10.5,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145738628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-09DOI: 10.1016/j.phrs.2025.108063
Mirko G. Liturri, A. Bergna, A. Lai, C. Della Ventura, A. Gabrieli, I. Seravalli, S. Ciofi-Baffoni, E. Lenci, A. Trabocchi, S. Rusconi
{"title":"Evaluation of in vitro antiviral activity against different SARS-CoV-2 variants of a protease PROTAC degrader","authors":"Mirko G. Liturri, A. Bergna, A. Lai, C. Della Ventura, A. Gabrieli, I. Seravalli, S. Ciofi-Baffoni, E. Lenci, A. Trabocchi, S. Rusconi","doi":"10.1016/j.phrs.2025.108063","DOIUrl":"10.1016/j.phrs.2025.108063","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108063"},"PeriodicalIF":10.5,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145738627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-08DOI: 10.1016/j.phrs.2025.108062
Rigen Mo , Sarah Lucas , Xiao-Jiang Feng , Adrian Hackett , Ed Skucas , Kevin G. Liu , Ji-In Kim , Pegah Kolahi , Jack Gaffney , Jillian J. Spinney , Rachel S. Knipe , Jeegar P. Patel , M. Kathryn Steiner , Serra Elliott , William Marshall , James Hui , Shawn N. Grant , Masha V. Poyurovsky
Rho-associated coiled-coil kinases (ROCK1 and ROCK2) are important therapeutic targets in fibrosis. ROCK transduces profibrotic biomechanical (substrate stiffness) and biochemical (transforming growth factor-β, lysophosphatidic acid, connective tissue growth factor) stimuli from circulation and the extracellular matrix to cells. Herein, we present a novel selective inhibitor of ROCK1 and ROCK2 (pan-ROCK), ROC-101 (previously known as KD045), and demonstrate its activity as an antifibrotic agent. ROC-101 strongly inhibited ROCK in biochemical and cellular assays and exhibited optimal drug-like pharmacokinetics and physicochemical properties. ROC-101 was well tolerated following oral administration and had desirable selectivity against non-ROCK kinases and other high liability targets. ROC-101 treatment disrupted profibrotic gene expression in fibroblasts and reduced markers of vascular leakage in vivo. ROC-101 was efficacious in three different rodent models of pulmonary parenchymal, vascular, and airway diseases: 1) ROC-101 treatment reduced airway hypersensitivity to methacholine in an ovalbumin-induced asthma model and had blood pressure–lowering effects consistent with the role of ROCK in smooth muscle contractility and confirming in vivo target engagement; 2) ROC-101 showed efficacy in attenuating pulmonary arterial hypertension in the semaxanib/hypoxia-induced disease model; and 3) in the bleomycin-induced lung fibrosis model, ROC-101 demonstrated disease-modifying activity in the fibrotic lung, lowering collagen deposition, improving histology, reducing immune cell infiltration, and decreasing ROCK target phosphorylation. These in vivo and functional assessments support the development of ROC-101 as a potential therapeutic modality in pulmonary fibrosis and pulmonary hypertension.
{"title":"Pharmacological profile and therapeutic evaluation of ROC-101, a potent and selective ROCK inhibitor, in arterial hypertension and pulmonary fibrosis","authors":"Rigen Mo , Sarah Lucas , Xiao-Jiang Feng , Adrian Hackett , Ed Skucas , Kevin G. Liu , Ji-In Kim , Pegah Kolahi , Jack Gaffney , Jillian J. Spinney , Rachel S. Knipe , Jeegar P. Patel , M. Kathryn Steiner , Serra Elliott , William Marshall , James Hui , Shawn N. Grant , Masha V. Poyurovsky","doi":"10.1016/j.phrs.2025.108062","DOIUrl":"10.1016/j.phrs.2025.108062","url":null,"abstract":"<div><div>Rho-associated coiled-coil kinases (ROCK1 and ROCK2) are important therapeutic targets in fibrosis. ROCK transduces profibrotic biomechanical (substrate stiffness) and biochemical (transforming growth factor-β, lysophosphatidic acid, connective tissue growth factor) stimuli from circulation and the extracellular matrix to cells. Herein, we present a novel selective inhibitor of ROCK1 and ROCK2 (pan-ROCK), ROC-101 (previously known as KD045), and demonstrate its activity as an antifibrotic agent. ROC-101 strongly inhibited ROCK in biochemical and cellular assays and exhibited optimal drug-like pharmacokinetics and physicochemical properties. ROC-101 was well tolerated following oral administration and had desirable selectivity against non-ROCK kinases and other high liability targets. ROC-101 treatment disrupted profibrotic gene expression in fibroblasts and reduced markers of vascular leakage <em>in vivo</em>. ROC-101 was efficacious in three different rodent models of pulmonary parenchymal, vascular, and airway diseases: 1) ROC-101 treatment reduced airway hypersensitivity to methacholine in an ovalbumin-induced asthma model and had blood pressure–lowering effects consistent with the role of ROCK in smooth muscle contractility and confirming <em>in vivo</em> target engagement; 2) ROC-101 showed efficacy in attenuating pulmonary arterial hypertension in the semaxanib/hypoxia-induced disease model; and 3) in the bleomycin-induced lung fibrosis model, ROC-101 demonstrated disease-modifying activity in the fibrotic lung, lowering collagen deposition, improving histology, reducing immune cell infiltration, and decreasing ROCK target phosphorylation. These <em>in vivo</em> and functional assessments support the development of ROC-101 as a potential therapeutic modality in pulmonary fibrosis and pulmonary hypertension.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108062"},"PeriodicalIF":10.5,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145725191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1016/j.phrs.2025.108053
Jing Wang , Chenyu Lin , Pengbo Zhang , Xixi Huang , Wei Zhou , Mufan Wu , Jiaming Wang , Fenyong Sun , Bingdi Chen
Platelets play a critical role in tumor progression and metastasis, yet the mechanisms by which they influence cancer cell behavior remain unclear. In this study, we investigated the interaction between platelets and colorectal cancer (CRC) cells and identified CAP-1 as a key mediator of platelet-induced tumor metastasis. Transcriptomic analyses showed that tumor-educated platelets induced significant gene expression changes in CRC cells, particularly involving pathways related to adhesion and migration. By intersecting upregulated genes in both tumor cells and patient-derived platelets, CAP-1 was identified and functionally validated as a critical gene using in vitro knockdown and in vivo metastasis models. CAP-1 depletion significantly impaired tumor cell migration, adhesion, cytoskeletal organization, and lung metastasis in mice without affecting cell proliferation or viability. A shape-based virtual screening strategy identified small-molecule CAP-1 inhibitors, among which compound CAPib-13 demonstrated strong binding affinity (KD = 2.57 µM), effectively inhibited tumor metastasis in vivo, and showed no significant toxicity. These findings uncover a novel role for CAP-1 in mediating platelet-cancer cell interactions and suggest that CAP-1 inhibition represents a promising therapeutic strategy for metastatic colorectal cancer.
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