ACS Pharmacology and Translational Science最新文献

{"title":"Amino Acid Hepatotoxicity Biomarkers in Human Hepatic Organoids: Promising Standardization of Drug Toxicity Evaluation.","authors":"Haneul Noh, Seohyun Choi, Kyung Won Park, Shinji Lee, Dong Wook Seok, Young Eun Kim, Ha-Jeong Kwon, Hyemin Kim, Han-Jin Park, Tae-Young Kim, Dukjin Kang, Ji-Seon Jeong","doi":"10.1021/acsptsci.4c00612","DOIUrl":"10.1021/acsptsci.4c00612","url":null,"abstract":"<p><p>Human hepatic organoids (hHOs) are regarded as physiologically relevant in vitro platforms to evaluate hepatotoxicity, a critical step in drug development, but their applications are currently limited by the lack of qualified and standardized evaluation markers. In this study, by leveraging the established reference measurement system of amino acids (AAs), we propose 12 new biomarkers for drug-induced hepatotoxicity evaluation in human induced pluripotent stem cell-derived hHOs. Two orthogonal analytical methods for AAs were developed and validated based on isotope dilution mass spectrometry. Four AAs (aspartic acid, arginine, glutamine, and phenylalanine) and eight ratios of two designated AAs in the media of hHOs showed reliable alteration by drug treatment, which was confirmed by differentiating between hepatotoxic and nonhepatotoxic drugs. The superiorities of AA-based toxicity evaluation using the media of hHOs are as follows: (i) ability to use media only, without direct damage to or consumption of the organoids, (ii) ability to measure and compare quantities of AAs through a standardized reference measurement system rather than nonstandardized cell viability indicators, and (iii) no requirement for further data normalization in the case of the AA ratios. The AA analysis-based results demonstrate the reliability and potential of the proposed biomarkers as not only straightforward indicators of drug-induced hepatotoxicity but also absolutely comparable measures as a step toward standardization based on the AA reference measurement system.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 2","pages":"510-521"},"PeriodicalIF":4.9,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11833729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143459842","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":"Amino Acid Hepatotoxicity Biomarkers in Human Hepatic Organoids: Promising Standardization of Drug Toxicity Evaluation","authors":"Haneul Noh,&nbsp;Seohyun Choi,&nbsp;Kyung Won Park,&nbsp;Shinji Lee,&nbsp;Dong Wook Seok,&nbsp;Young Eun Kim,&nbsp;Ha-Jeong Kwon,&nbsp;Hyemin Kim,&nbsp;Han-Jin Park,&nbsp;Tae-Young Kim,&nbsp;Dukjin Kang and Ji-Seon Jeong*,&nbsp;","doi":"10.1021/acsptsci.4c0061210.1021/acsptsci.4c00612","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00612https://doi.org/10.1021/acsptsci.4c00612","url":null,"abstract":"<p >Human hepatic organoids (hHOs) are regarded as physiologically relevant in vitro platforms to evaluate hepatotoxicity, a critical step in drug development, but their applications are currently limited by the lack of qualified and standardized evaluation markers. In this study, by leveraging the established reference measurement system of amino acids (AAs), we propose 12 new biomarkers for drug-induced hepatotoxicity evaluation in human induced pluripotent stem cell–derived hHOs. Two orthogonal analytical methods for AAs were developed and validated based on isotope dilution mass spectrometry. Four AAs (aspartic acid, arginine, glutamine, and phenylalanine) and eight ratios of two designated AAs in the media of hHOs showed reliable alteration by drug treatment, which was confirmed by differentiating between hepatotoxic and nonhepatotoxic drugs. The superiorities of AA-based toxicity evaluation using the media of hHOs are as follows: (i) ability to use media only, without direct damage to or consumption of the organoids, (ii) ability to measure and compare quantities of AAs through a standardized reference measurement system rather than nonstandardized cell viability indicators, and (iii) no requirement for further data normalization in the case of the AA ratios. The AA analysis–based results demonstrate the reliability and potential of the proposed biomarkers as not only straightforward indicators of drug-induced hepatotoxicity but also absolutely comparable measures as a step toward standardization based on the AA reference measurement system.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 2","pages":"510–521 510–521"},"PeriodicalIF":4.9,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402334","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":"Recommended Opioid Receptor Tool Compounds: Comparative <i>In Vitro</i> for Receptor Selectivity Profiles and <i>In Vivo</i> for Pharmacological Antinociceptive Profiles.","authors":"Linh T Tran, Katie T Freeman, Mary M Lunzer, Philip S Portoghese, Carrie Haskell-Luevano","doi":"10.1021/acsptsci.4c00604","DOIUrl":"10.1021/acsptsci.4c00604","url":null,"abstract":"<p><p>Opioid agonist ligands bind opioid receptors and stimulate downstream signaling cascades for various biological processes including pain and reward. Historically, before cloning the receptors, muscle contraction assays using isolated organ tissues were used followed by radiolabel ligand binding assays on native tissues. Upon cloning of the opioid G protein-coupled receptors (GPCRs), cell assays using transfected opioid receptor DNA plasmids became the standard practice including ³⁵S-GTPγS functional and cAMP based assays. A number of research laboratories have studied key \"tool\" reference opioid receptor ligands for decades and used them as control reference compounds. Some, but not all, of these commonly used tool compounds have been characterized and compared side by side in parallel assays for selectivity profiles at the different human opioid receptors isoforms. Herein, we performed the standard FLIPR calcium mobilization assay using HEK293 cells engineered to stably express the Gα_Δ6qi4myr in parallel, at human MOR, KOR, DOR, and NOP opioid receptors. The following tool compounds: morphine, fentanyl, oxycodone, DAMGO, DPDPE, U69593, deltorphin II, and nociceptin, were examined herein. These included the substance use disorder (SUD) compounds morphine, fentanyl, and oxycodone. Additionally, the antagonist tool compounds naloxone, NTI, norBNI, and β-FNA were assayed in parallel at the human MOR, KOR, DOR, and NOP opioid receptors. Furthermore, the agonist tool compounds were tested in the same <i>in vivo</i> tail-flick antinociception assays via intrathecal injection for ED₅₀ potencies. These data provide both <i>in vitro</i> comparative pharmacology as a reference for cellular activities and <i>in vivo</i> antinociception profiles for these tool compounds.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"225-244"},"PeriodicalIF":4.9,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143013418","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":"Molecular and Immunological Properties of a Chimeric Glycosyl Hydrolase 18 Based on Immunoinformatics Approaches: A Design of a New Anti-Leishmania Vaccine","authors":"José Ednésio daCruz Freire*,&nbsp;André Nogueira Cardeal dos Santos,&nbsp;Andrelina Noronha Coelho de Souza,&nbsp;Ariclécio Cunha de Oliveira,&nbsp;Roberto Nicolete,&nbsp;Bruno Lopes de Sousa,&nbsp;João Hermínio Martins da Silva,&nbsp;Yuri de Abreu Gomes Vasconcelos,&nbsp;Isaac Neto Goes da Silva,&nbsp;Paula Matias Soares,&nbsp;Maria Izabel Florindo Guedes and Vânia Marilande Ceccatto,&nbsp;","doi":"10.1021/acsptsci.4c0034110.1021/acsptsci.4c00341","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00341https://doi.org/10.1021/acsptsci.4c00341","url":null,"abstract":"<p >Leishmaniasis is a chronic inflammatory zoonotic illness caused by protozoan flagellates belonging to the <i>Leishmania</i> genus. Current data suggest that over 1 billion people worldwide are susceptible to infection, primarily in tropical and subtropical countries, where up to 2 million new cases are reported annually. Therefore, the development of a vaccine is crucial to combating this disease. This study employed immunoinformatics approaches to design a multiepitope anti-<i>Leishmania</i> vaccine, GH₁₈-cp<i>Leish</i>, based on a cluster of six glycosyl hydrolases 18. We identified six helper T lymphocyte (HTL) epitopes and twenty-six cytotoxic T lymphocyte (CTL) epitopes with IC₅₀ values &lt;50 nM, indicating high affinity. Additionally, we also identified 20 continuous and twenty-six discontinuous B-cell epitopes. Analysis for allergenicity and toxicity showed no potential to induce these phenomena. All data obtained from in silico tools suggest that physicochemical and biological studies indicate that the GH₁₈-cp<i>Leish</i> chimeric protein is a promising candidate for an anti-<i>Leishmania</i> vaccine. Docking analysis showed that the Pep₁-cp<i>Leish</i>::TLR₁, Pep₁-cp<i>Leish</i>::TLR₂, Pep₁-cp<i>Leish</i>::/TLR₃, and Pep₁-cp<i>Leish</i>::/TLR₄ complexes maintained a stable form. The best interaction cluster score was observed in the complex Pep₁-cp<i>Leish</i>::TLR₂ (center = −622.6 and lowest energy = −841.7 kcal.mol^–1) followed by the complexes Pep₁-cp<i>Leish</i>::TLR₄ (center = −590.3 and lowest energy = −590.3 kcal.mol^–1), Pep₁-cp<i>Leish</i>::TLR₃ (center = −589.1 and lowest energy = −657.0 kcal.mol^–1), and Pep₁-cp<i>Leish</i>::TLR₁ (center = −504.1 and lowest energy = −602.9 kcal.mol^–1), respectively. This study suggests that GH₁₈-cp<i>Leish</i> may be suitable for constructing second-generation anti-<i>Leishmania</i> and even third-generation vaccines, given that its gene sequence is optimized for this purpose.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"78–96 78–96"},"PeriodicalIF":4.9,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00341","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143087237","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":"Molecular and Immunological Properties of a Chimeric Glycosyl Hydrolase 18 Based on Immunoinformatics Approaches: A Design of a New Anti-<i>Leishmania</i> Vaccine.","authors":"José Ednésio da Cruz Freire, André Nogueira Cardeal Dos Santos, Andrelina Noronha Coelho de Souza, Ariclécio Cunha de Oliveira, Roberto Nicolete, Bruno Lopes de Sousa, João Hermínio Martins da Silva, Yuri de Abreu Gomes Vasconcelos, Isaac Neto Goes da Silva, Paula Matias Soares, Maria Izabel Florindo Guedes, Vânia Marilande Ceccatto","doi":"10.1021/acsptsci.4c00341","DOIUrl":"10.1021/acsptsci.4c00341","url":null,"abstract":"<p><p>Leishmaniasis is a chronic inflammatory zoonotic illness caused by protozoan flagellates belonging to the <i>Leishmania</i> genus. Current data suggest that over 1 billion people worldwide are susceptible to infection, primarily in tropical and subtropical countries, where up to 2 million new cases are reported annually. Therefore, the development of a vaccine is crucial to combating this disease. This study employed immunoinformatics approaches to design a multiepitope anti-<i>Leishmania</i> vaccine, GH₁₈-cp<i>Leish</i>, based on a cluster of six glycosyl hydrolases 18. We identified six helper T lymphocyte (HTL) epitopes and twenty-six cytotoxic T lymphocyte (CTL) epitopes with IC₅₀ values <50 nM, indicating high affinity. Additionally, we also identified 20 continuous and twenty-six discontinuous B-cell epitopes. Analysis for allergenicity and toxicity showed no potential to induce these phenomena. All data obtained from in silico tools suggest that physicochemical and biological studies indicate that the GH₁₈-cp<i>Leish</i> chimeric protein is a promising candidate for an anti-<i>Leishmania</i> vaccine. Docking analysis showed that the Pep₁-cp<i>Leish</i>::TLR₁, Pep₁-cp<i>Leish</i>::TLR₂, Pep₁-cp<i>Leish</i>::/TLR₃, and Pep₁-cp<i>Leish</i>::/TLR₄ complexes maintained a stable form. The best interaction cluster score was observed in the complex Pep₁-cp<i>Leish</i>::TLR₂ (center = -622.6 and lowest energy = -841.7 kcal.mol^-1) followed by the complexes Pep₁-cp<i>Leish</i>::TLR₄ (center = -590.3 and lowest energy = -590.3 kcal.mol^-1), Pep₁-cp<i>Leish</i>::TLR₃ (center = -589.1 and lowest energy = -657.0 kcal.mol^-1), and Pep₁-cp<i>Leish</i>::TLR₁ (center = -504.1 and lowest energy = -602.9 kcal.mol^-1), respectively. This study suggests that GH₁₈-cp<i>Leish</i> may be suitable for constructing second-generation anti-<i>Leishmania</i> and even third-generation vaccines, given that its gene sequence is optimized for this purpose.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"78-96"},"PeriodicalIF":4.9,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143013351","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":"Recommended Opioid Receptor Tool Compounds: Comparative In Vitro for Receptor Selectivity Profiles and In Vivo for Pharmacological Antinociceptive Profiles","authors":"Linh T. Tran,&nbsp;Katie T. Freeman,&nbsp;Mary M. Lunzer,&nbsp;Philip S. Portoghese and Carrie Haskell-Luevano*,&nbsp;","doi":"10.1021/acsptsci.4c0060410.1021/acsptsci.4c00604","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00604https://doi.org/10.1021/acsptsci.4c00604","url":null,"abstract":"<p >Opioid agonist ligands bind opioid receptors and stimulate downstream signaling cascades for various biological processes including pain and reward. Historically, before cloning the receptors, muscle contraction assays using isolated organ tissues were used followed by radiolabel ligand binding assays on native tissues. Upon cloning of the opioid G protein-coupled receptors (GPCRs), cell assays using transfected opioid receptor DNA plasmids became the standard practice including ³⁵S-GTPγS functional and cAMP based assays. A number of research laboratories have studied key “tool” reference opioid receptor ligands for decades and used them as control reference compounds. Some, but not all, of these commonly used tool compounds have been characterized and compared side by side in parallel assays for selectivity profiles at the different human opioid receptors isoforms. Herein, we performed the standard FLIPR calcium mobilization assay using HEK293 cells engineered to stably express the Gα_Δ6qi4myr in parallel, at human MOR, KOR, DOR, and NOP opioid receptors. The following tool compounds: morphine, fentanyl, oxycodone, DAMGO, DPDPE, U69593, deltorphin II, and nociceptin, were examined herein. These included the substance use disorder (SUD) compounds morphine, fentanyl, and oxycodone. Additionally, the antagonist tool compounds naloxone, NTI, norBNI, and β-FNA were assayed in parallel at the human MOR, KOR, DOR, and NOP opioid receptors. Furthermore, the agonist tool compounds were tested in the same <i>in vivo</i> tail-flick antinociception assays via intrathecal injection for ED₅₀ potencies. These data provide both <i>in vitro</i> comparative pharmacology as a reference for cellular activities and <i>in vivo</i> antinociception profiles for these tool compounds.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"225–244 225–244"},"PeriodicalIF":4.9,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143087064","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":"Sigma 1 Receptor and Its Pivotal Role in Neurological Disorders.","authors":"Mustafa M Shokr, Ghada A Badawi, Shimaa M Elshazly, Hala F Zaki, Ahmed F Mohamed","doi":"10.1021/acsptsci.4c00564","DOIUrl":"10.1021/acsptsci.4c00564","url":null,"abstract":"<p><p>Sigma 1 receptor (S1R) is a multifunctional, ligand-activated protein located in the membranes of the endoplasmic reticulum (ER). It mediates a variety of neurological disorders, including epilepsy, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease. The wide neuroprotective effects of S1R agonists are achieved by a variety of pro-survival and antiapoptotic S1R-mediated signaling functions. Nonetheless, relatively little is known about the specific molecular mechanisms underlying S1R activity. Many studies on S1R protein have highlighted the importance of maintaining normal cellular homeostasis through its control of calcium and lipid exchange between the ER and mitochondria, ER-stress response, and many other mechanisms. In this review, we will discuss S1R different cellular localization and explain S1R-associated biological activity, such as its localization in the ER-plasma membrane and Mitochondrion-Associated ER Membrane interfaces. While outlining the cellular mechanisms and important binding partners involved in these processes, we also explained how the dysregulation of these pathways contributes to neurodegenerative disorders.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"47-65"},"PeriodicalIF":4.9,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012643","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":"Sigma 1 Receptor and Its Pivotal Role in Neurological Disorders","authors":"Mustafa M. Shokr*,&nbsp;Ghada A. Badawi,&nbsp;Shimaa M. Elshazly,&nbsp;Hala F. Zaki and Ahmed F. Mohamed,&nbsp;","doi":"10.1021/acsptsci.4c0056410.1021/acsptsci.4c00564","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00564https://doi.org/10.1021/acsptsci.4c00564","url":null,"abstract":"<p >Sigma 1 receptor (S1R) is a multifunctional, ligand-activated protein located in the membranes of the endoplasmic reticulum (ER). It mediates a variety of neurological disorders, including epilepsy, amyotrophic lateral sclerosis, Alzheimer’s disease, Huntington’s disease. The wide neuroprotective effects of S1R agonists are achieved by a variety of pro-survival and antiapoptotic S1R-mediated signaling functions. Nonetheless, relatively little is known about the specific molecular mechanisms underlying S1R activity. Many studies on S1R protein have highlighted the importance of maintaining normal cellular homeostasis through its control of calcium and lipid exchange between the ER and mitochondria, ER-stress response, and many other mechanisms. In this review, we will discuss S1R different cellular localization and explain S1R-associated biological activity, such as its localization in the ER-plasma membrane and Mitochondrion-Associated ER Membrane interfaces. While outlining the cellular mechanisms and important binding partners involved in these processes, we also explained how the dysregulation of these pathways contributes to neurodegenerative disorders.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"47–65 47–65"},"PeriodicalIF":4.9,"publicationDate":"2024-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143087103","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":"Safe and Orally Bioavailable Inhibitor of Serine Palmitoyltransferase Improves Age-Related Sarcopenia.","authors":"Johanne Poisson, Ioanna Daskalaki, Vijay Potluri, Jean-David Morel, Sandra Rodriguez-Lopez, Alessia De Masi, Giorgia Benegiamo, Suresh Jain, Tanes Lima, Johan Auwerx","doi":"10.1021/acsptsci.4c00587","DOIUrl":"10.1021/acsptsci.4c00587","url":null,"abstract":"<p><p>The accumulation of ceramides and related metabolites has emerged as a pivotal mechanism contributing to the onset of age-related diseases. However, small molecule inhibitors targeting the ceramide <i>de novo</i> synthesis pathway for clinical use are currently unavailable. We synthesized a safe and orally bioavailable inhibitor, termed ALT-007, targeting the rate-limiting enzyme of ceramide <i>de novo</i> synthesis, serine palmitoyltransferase (SPT). In a mouse model of age-related sarcopenia, ALT-007, administered through the diet, effectively restored muscle mass and function compromised by aging. Mechanistic studies revealed that ALT-007 enhances protein homeostasis in <i>Caenorhabditis elegans</i> and mouse models of aging and age-related diseases, such as sarcopenia and inclusion body myositis (IBM); this effect is mediated by a specific reduction in very-long chain 1-deoxy-sphingolipid species, which accumulate in both muscle and brain tissues of aged mice and in muscle cells from IBM patients. These findings unveil a promising therapeutic avenue for developing safe ceramide inhibitors to address age-related neuromuscular diseases.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"203-215"},"PeriodicalIF":4.9,"publicationDate":"2024-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143013419","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":"A 3D Model of the Human Lung Airway for Evaluating Permeability of Inhaled Drugs.","authors":"Shekh M Rahman, Robert M Geiger, Md Shadiqur Rashid Roni, Isra Tariq, Omnia Ismaiel, Murali K Matta, Katherine Shea, Dylan Bruckner, Wenlei Jiang, Ross Walenga, Bryan Newman, Paula L Hyland, Alexandre J S Ribeiro, Jeffrey Florian, Ksenia Blinova, Kevin A Ford","doi":"10.1021/acsptsci.4c00607","DOIUrl":"10.1021/acsptsci.4c00607","url":null,"abstract":"<p><p>Current in vitro cell-based methods, relying on single cell types, have structural and functional limitations in determining lung drug permeability, which is a contributing factor affecting both local and systemic drug levels. To address this issue, we investigated a 3D human lung airway model generated using a cell culture insert, wherein primary human lung epithelial and endothelial cells were cocultured at an air-liquid interface (ALI). To ensure that the cell culture mimics the physiological and functional characteristics of airway tissue, the model was characterized by evaluating several parameters such as cellular confluency, ciliation, tight junctions, mucus-layer formation, transepithelial electrical resistance, and barrier function through assaying fluorescein isothiocyanate-dextran permeability. To understand how the characterized ALI quality attributes influenced the absorption of inhaled drugs through the epithelial-endothelial barrier, we measured the permeability and epithelial intracellular concentrations of albuterol sulfate (AL), formoterol fumarate (FO), and fluticasone furoate (FL). The presented characterization results overall demonstrate that this culture platform mimicked the airway-specific structure and barrier function. An apparent permeability (<i>P</i> _app) of 5.7 × 10^-6 cm/s and an intracellular concentration below 1% were quantified for AL over 3 h. The <i>P</i> _app of FO was 8.5 × 10^-6 cm/s, with an intracellular concentration of 3.8%. Due to its high lipophilicity, FL showed a higher intracellular concentration (17.4%) compared to AL and FO, but also a 73.1% loss of the compound over 3 h due to nonspecific binding, with a <i>P</i> _app as low as 1.3 × 10^-7 cm/s. While the model exhibited physiologically relevant properties, its utility in estimating the permeability of inhaled drugs may be drug-specific, warranting further optimization and study.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"245-255"},"PeriodicalIF":4.9,"publicationDate":"2024-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143013308","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}