ACS Pharmacology and Translational Science最新文献

{"title":"Novel Soluble Epoxide Hydrolase Inhibitor: Toward Regulatory Preclinical Studies.","authors":"Júlia Jarne-Ferrer, Javier Sánchez, Sandra Codony, Marion Schneider, Christa E Müller, Coral Sanfeliu, Rafael Franco, Santiago Vazquez, Christian Griñán-Ferré, Mercè Pallàs","doi":"10.1021/acsptsci.4c00629","DOIUrl":"10.1021/acsptsci.4c00629","url":null,"abstract":"<p><p>Neuroinflammation is widely recognized as a key pathological hallmark of Alzheimer's disease (AD). Recently, inhibiting soluble epoxide hydrolase (sEH) has emerged as a promising therapeutic strategy for AD. sEH plays a pivotal role in neuroinflammation by hydrolyzing epoxyeicosatrienoic acids (EETs), which have anti-inflammatory and neuroprotective properties, into pro-inflammatory dihydroepoxyeicosatrienoic acids (DHETs). Furthermore, the overexpression of the enzyme in the brains of AD patients and animal models of the disease highlights its relevance as a therapeutic target. Our previous studies, using the inhibitor UB-SCG-51 demonstrated that sEH inhibition regulates neuroinflammation and other mechanisms, such as the unfolded protein response pathway, while reducing autophagy, apoptosis, and neuronal death, thereby promoting neuroprotection. Building on these findings, we evaluated the arginine salt of the compound, designated UB-SCG-74, which offers improved oral absorption compared to that of UB-SCG-51 while retaining high permeability, potency, and selectivity. In experiments using 5XFAD mice, UB-SCG-74 treatment significantly improved cognition and synaptic plasticity, outperforming donepezil, a standard AD drug, and ibuprofen, an anti-inflammatory drug. Remarkably, these benefits persisted for 4 weeks after administration cessation, suggesting lasting therapeutic effects. Safety pharmacology studies showed no toxicity, supporting the advancement of UB-SCG-74 into preclinical regulatory evaluation. Our findings further indicate that sEH inhibition engages multiple neuroprotective pathways, potentially modifying both AD symptoms and disease progression, thus reinforcing its therapeutic potential.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 2","pages":"533-542"},"PeriodicalIF":4.9,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11833725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143459972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synaptic Vesicle 2A (SV2A) Positron Emission Tomography (PET) Imaging as a Marker of Therapeutic Response in a Mouse Model of Depression.","authors":"Cassandre Corvo, Indira Mendez-David, Sébastien Goutal, Wadad Saba, Michel Bottlaender, Fabien Caillé, Rene Hen, Romain Colle, Emmanuelle Corruble, Nicolas Tournier, Claire Leroy, Denis J David","doi":"10.1021/acsptsci.4c00621","DOIUrl":"10.1021/acsptsci.4c00621","url":null,"abstract":"<p><p>In this preclinical pilot study, we used [¹¹C]UCB-J PET imaging to monitor the synaptic modulation in depression and after fluoxetine. PET imaging was performed in a validated mouse model of depression/anxiety (CORT model), and the effect of 5-week treatment with fluoxetine was tested. Depression/anxiety phenotype and antidepressant action of fluoxetine were confirmed using the novelty-suppressed feeding test, previously validated in the CORT model. PET data showed significant decreases of volume of distribution (<i>V</i> _T) of [¹¹C]UCB-J in most brain regions of CORT mice compared with controls. After 5 weeks of fluoxetine, a trend toward restoration of <i>V</i> _T values to control levels was observed, although it reached significance only in the olfactory bulb. These preliminary data support the use of [¹¹C]UCB-J PET imaging and the CORT model to study the synaptic modulation of antidepressants. It provides excellent translational opportunities to study the relationship between synaptic plasticity and the clinical efficacy of antidepressants.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 2","pages":"339-345"},"PeriodicalIF":4.9,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11833719/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143459206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Effective, but Safe? Physiologically Based Pharmacokinetic (PBPK)-Modeling-Based Dosing Study of Molnupiravir for Risk Assessment in Pediatric Subpopulations”","authors":"Sarang Mishra,&nbsp; and ,&nbsp;Katharina Rox*,&nbsp;","doi":"10.1021/acsptsci.5c0005310.1021/acsptsci.5c00053","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00053https://doi.org/10.1021/acsptsci.5c00053","url":null,"abstract":"","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 2","pages":"616 616"},"PeriodicalIF":4.9,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.5c00053","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to \"Effective, but Safe? Physiologically Based Pharmacokinetic (PBPK)-Modeling-Based Dosing Study of Molnupiravir for Risk Assessment in Pediatric Subpopulations\".","authors":"Sarang Mishra, Katharina Rox","doi":"10.1021/acsptsci.5c00053","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00053","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1021/acsptsci.4c00535.].</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 2","pages":"616"},"PeriodicalIF":4.9,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11833713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143459873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synaptic Vesicle 2A (SV2A) Positron Emission Tomography (PET) Imaging as a Marker of Therapeutic Response in a Mouse Model of Depression","authors":"Cassandre Corvo,&nbsp;Indira Mendez-David,&nbsp;Sébastien Goutal,&nbsp;Wadad Saba,&nbsp;Michel Bottlaender,&nbsp;Fabien Caillé,&nbsp;Rene Hen,&nbsp;Romain Colle,&nbsp;Emmanuelle Corruble,&nbsp;Nicolas Tournier,&nbsp;Claire Leroy* and Denis J. David,&nbsp;","doi":"10.1021/acsptsci.4c0062110.1021/acsptsci.4c00621","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00621https://doi.org/10.1021/acsptsci.4c00621","url":null,"abstract":"<p >In this preclinical pilot study, we used [¹¹C]UCB-J PET imaging to monitor the synaptic modulation in depression and after fluoxetine. PET imaging was performed in a validated mouse model of depression/anxiety (CORT model), and the effect of 5-week treatment with fluoxetine was tested. Depression/anxiety phenotype and antidepressant action of fluoxetine were confirmed using the novelty-suppressed feeding test, previously validated in the CORT model. PET data showed significant decreases of volume of distribution (<i>V</i>_T) of [¹¹C]UCB-J in most brain regions of CORT mice compared with controls. After 5 weeks of fluoxetine, a trend toward restoration of <i>V</i>_T values to control levels was observed, although it reached significance only in the olfactory bulb. These preliminary data support the use of [¹¹C]UCB-J PET imaging and the CORT model to study the synaptic modulation of antidepressants. It provides excellent translational opportunities to study the relationship between synaptic plasticity and the clinical efficacy of antidepressants.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 2","pages":"339–345 339–345"},"PeriodicalIF":4.9,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Soluble Epoxide Hydrolase Inhibitor: Toward Regulatory Preclinical Studies","authors":"Júlia Jarne-Ferrer,&nbsp;Javier Sánchez,&nbsp;Sandra Codony,&nbsp;Marion Schneider,&nbsp;Christa E. Müller,&nbsp;Coral Sanfeliu,&nbsp;Rafael Franco,&nbsp;Santiago Vazquez,&nbsp;Christian Griñán-Ferré* and Mercè Pallàs*,&nbsp;","doi":"10.1021/acsptsci.4c0062910.1021/acsptsci.4c00629","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00629https://doi.org/10.1021/acsptsci.4c00629","url":null,"abstract":"<p >Neuroinflammation is widely recognized as a key pathological hallmark of Alzheimer’s disease (AD). Recently, inhibiting soluble epoxide hydrolase (sEH) has emerged as a promising therapeutic strategy for AD. sEH plays a pivotal role in neuroinflammation by hydrolyzing epoxyeicosatrienoic acids (EETs), which have anti-inflammatory and neuroprotective properties, into pro-inflammatory dihydroepoxyeicosatrienoic acids (DHETs). Furthermore, the overexpression of the enzyme in the brains of AD patients and animal models of the disease highlights its relevance as a therapeutic target. Our previous studies, using the inhibitor UB-SCG-51 demonstrated that sEH inhibition regulates neuroinflammation and other mechanisms, such as the unfolded protein response pathway, while reducing autophagy, apoptosis, and neuronal death, thereby promoting neuroprotection. Building on these findings, we evaluated the arginine salt of the compound, designated UB-SCG-74, which offers improved oral absorption compared to that of UB-SCG-51 while retaining high permeability, potency, and selectivity. In experiments using 5XFAD mice, UB-SCG-74 treatment significantly improved cognition and synaptic plasticity, outperforming donepezil, a standard AD drug, and ibuprofen, an anti-inflammatory drug. Remarkably, these benefits persisted for 4 weeks after administration cessation, suggesting lasting therapeutic effects. Safety pharmacology studies showed no toxicity, supporting the advancement of UB-SCG-74 into preclinical regulatory evaluation. Our findings further indicate that sEH inhibition engages multiple neuroprotective pathways, potentially modifying both AD symptoms and disease progression, thus reinforcing its therapeutic potential.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 2","pages":"533–542 533–542"},"PeriodicalIF":4.9,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a Cannabinoid Receptor 2 Allosteric Site Using Computational Modeling and Pharmacological Analysis","authors":"Zara Farooq,&nbsp;Pietro Delre,&nbsp;Stylianos Iliadis,&nbsp;Giuseppe Felice Mangiatordi,&nbsp;Marialessandra Contino,&nbsp;Lesley A. Howell and Peter J. McCormick*,&nbsp;","doi":"10.1021/acsptsci.4c0054710.1021/acsptsci.4c00547","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00547https://doi.org/10.1021/acsptsci.4c00547","url":null,"abstract":"<p >Emerging evidence has demonstrated that cannabinoid receptor 2 (CB₂) is involved in a number of diseases, such as neurodegenerative disorders and various types of cancer, making it an attractive pharmacological target. Classically, a protein active site or an orthosteric binding site, where the endogenous ligand binds to, is used as a target for the design of most small-molecule drugs. This can present challenges when it comes to phylogenetically related proteins that have similar orthosteric binding sites, such as the cannabinoid receptors. An alternative approach is to target sites that are unique to these receptors yet still impact receptor function, known as allosteric binding sites. Using an inactive-state human cannabinoid receptor 2 crystal structure (PDB ID:5ZTY), we identified a putative CB₂ allosteric site using computational approaches. In vitro signaling assays using known allosteric modulators and CB₂ agonists have been used to verify the in silico results. This identification opens promising avenues for the development of selective and specific CB₂ ligands for therapeutic purposes.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 2","pages":"423–434 423–434"},"PeriodicalIF":4.9,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00547","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a Cannabinoid Receptor 2 Allosteric Site Using Computational Modeling and Pharmacological Analysis.","authors":"Zara Farooq, Pietro Delre, Stylianos Iliadis, Giuseppe Felice Mangiatordi, Marialessandra Contino, Lesley A Howell, Peter J McCormick","doi":"10.1021/acsptsci.4c00547","DOIUrl":"10.1021/acsptsci.4c00547","url":null,"abstract":"<p><p>Emerging evidence has demonstrated that cannabinoid receptor 2 (CB₂) is involved in a number of diseases, such as neurodegenerative disorders and various types of cancer, making it an attractive pharmacological target. Classically, a protein active site or an orthosteric binding site, where the endogenous ligand binds to, is used as a target for the design of most small-molecule drugs. This can present challenges when it comes to phylogenetically related proteins that have similar orthosteric binding sites, such as the cannabinoid receptors. An alternative approach is to target sites that are unique to these receptors yet still impact receptor function, known as allosteric binding sites. Using an inactive-state human cannabinoid receptor 2 crystal structure (PDB ID:5ZTY), we identified a putative CB₂ allosteric site using computational approaches. In vitro signaling assays using known allosteric modulators and CB₂ agonists have been used to verify the in silico results. This identification opens promising avenues for the development of selective and specific CB₂ ligands for therapeutic purposes.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 2","pages":"423-434"},"PeriodicalIF":4.9,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11833715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143459889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic DSS-Induced Colitis Exacerbates Parkinson's Disease Phenotype and Its Pathological Features Following Intragastric Rotenone Exposure.","authors":"Nishant Sharma, Monika Sharma, Disha Thakkar, Hemant Kumar, Sona Smetanova, Lucie Buresova, Petr Andrla, Amit Khairnar","doi":"10.1021/acsptsci.4c00286","DOIUrl":"10.1021/acsptsci.4c00286","url":null,"abstract":"<p><p><b>Background:</b> Parkinson's disease (PD) is intricately linked to gastrointestinal inflammation and the presence of neurotoxins in the gut, integrating α-syn pathologic alterations and subsequent neurodegeneration into the brain. <b>Objectives:</b> This study aimed to explore the enduring impact of dextran sodium sulfate (DSS)-mediated colitis on the vulnerability of central dopaminergic neurons to subsequent rotenone exposure. <b>Methods:</b> To induce chronic colitis, 10-month-old C57BL/6 mice were pre-exposed to 3 cycles of 1 week of 1% (w/v) DSS administration in drinking water followed by 2 weeks of regular drinking water. After colitis induction, animals received a low dose of intragastric rotenone for the next 8 weeks, followed by testing for Parkinsonian behavior and GI phenotypes of inflammation. At the end of the 17th week, colon, brain stem, and midbrain tissue were isolated and analyzed for α-syn, inflammatory markers, and dopaminergic neuronal loss. Gut microbial composition was assessed by 16S rRNA sequencing analysis. <b>Results:</b> We found that chronic rotenone administration in the presence of preexisting colitis led to a further increase in colonic pro-inflammatory mediator expressions, α-syn expression, and reduced colonic tight junction protein expressions. We also found early impairment of GI functions and worsened grip strength in rotenone-exposed colitic mice. Furthermore, α-syn pathology specific to the colitic mice exposed to rotenone showed dopaminergic neurons degeneration and astroglial activation in substantia nigra and striatum, including regions of the brain stem, i.e., dorsal motor of the vagus and locus coeruleus. Finally, the result of 16S rRNA gene sequencing analysis indicated that colitic mice, after being exposed to rotenone, exhibited a discernible trend in their microbiota composition (<i>Catenibacterium, Turicibactor, and clostridium sensue stricto 1</i>), linking it to the development of PD. <b>Conclusions:</b> These findings indicate that prolonged low-dose rotenone exposure, combined with an early inflammatory intestinal milieu, provides a preconditioning effect on α-syn pathology and exerts neurodegeneration in the intragastric rotenone PD mouse model.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 2","pages":"346-367"},"PeriodicalIF":4.9,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11833723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143459870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanoparticle-Mediated mRNA Delivery to Triple-Negative Breast Cancer (TNBC) Patient-Derived Xenograft (PDX) Tumors","authors":"Sara El-Sahli,&nbsp;Shireesha Manturthi,&nbsp;Emma Durocher,&nbsp;Yuxia Bo,&nbsp;Alexandra Akman,&nbsp;Christina Sannan,&nbsp;Melanie Kirkby,&nbsp;Chiamaka Divine Iroakazi,&nbsp;Hannah Deyell,&nbsp;Shelby Kaczmarek,&nbsp;Seung-Hwan Lee,&nbsp;Umar Iqbal,&nbsp;Marceline Côté,&nbsp;Lisheng Wang* and Suresh Gadde*,&nbsp;","doi":"10.1021/acsptsci.4c0059710.1021/acsptsci.4c00597","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00597https://doi.org/10.1021/acsptsci.4c00597","url":null,"abstract":"<p >mRNA-based therapies can overcome several challenges faced by traditional therapies in treating a variety of diseases by selectively modulating genes and proteins without genomic integration. However, due to mRNA’s poor stability and inherent limitations, nanoparticle (NP) platforms have been developed to deliver functional mRNA into cells. In cancer treatment, mRNA technology has multiple applications, such as restoration of tumor suppressors and activating antitumor immunity. Most of these applications have been evaluated using simple cell-line-based tumor models, which failed to represent the complexity, heterogeneity, and 3D architecture of patient tumors. This discrepancy has led to inconsistencies and failures in clinical translation. Compared to cell line models, patient-derived xenograft (PDX) models more accurately represent patient tumors and are better suitable for modeling. Therefore, for the first time, this study employed two different TNBC PDX tumors to examine the effects of the mRNA-NPs. mRNA-NPs are developed using EGFP-mRNA as a model and studied in TNBC cell lines, ex vivo TNBC PDX organotypic slice cultures, and in vivo TNBC PDX tumors. Our findings show that NPs can effectively accumulate in tumors after intravenous administration, protecting and delivering mRNA to PDX tumors with different genetic and chemosensitivity backgrounds. These studies offer more clinically relevant modeling systems for mRNA nanotherapies in cancer applications.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 2","pages":"460–469 460–469"},"PeriodicalIF":4.9,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00597","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}