Science Translational Medicine最新文献

{"title":"Modeling craniopharyngioma for drug screening reveals a neuronal mechanism for tumor growth","authors":"Si Li, Wei Li, Yuqi Miao, Meixi Gao, Yanfei Jia, Zhenhua Chen, Xi Chen, Taotao Pan, Shuangfeng Zhang, Zhifang Xing, Shuping Han, Xue-Lian Sun, Xiaochan Wei, Zhiming Liu, Wentao Zhou, Wentao Wu, Fangzheng Liu, Lei Han, Hongmei Zhu, Hongying Ye, Longqi Liu, Yinqing Li, Peng Zhang, Jian Gong, Yongji Tian, Youwei Ai, Peng Cao, Di Wu, Xiangbing Qi, Songbai Gui, Qing-Feng Wu","doi":"10.1126/scitranslmed.adn6763","DOIUrl":"https://doi.org/10.1126/scitranslmed.adn6763","url":null,"abstract":"Tumors occurring along the hypothalamus-pituitary axis receive axonal projection from neuroendocrine neurons, but it remains unclear whether neuroendocrine neuronal activity drives tumor expansion. Craniopharyngioma is a common suprasellar tumor with a propensity for invading the hypothalamus, leading to devastating endocrine and metabolic disorders. Here, we developed two autochthonous animal models that faithfully recapitulate the molecular pathology, clinical manifestations, and transcriptomic profiles of papillary craniopharyngioma. Using high-throughput drug screening, we identified 74 compounds with potent antitumor efficacy. The administration of ( <jats:italic>S</jats:italic> )-amlodipine besylate achieved tumor regression in vivo, potentially by abrogating calcium transients and neuron-to-tumor chemical transmission. Chemogenetic manipulation of neuroendocrine neuronal activity bidirectionally regulated tumor cell growth in our mouse model, suggesting that craniopharyngioma hijacks hypothalamic neurons to promote tumor progression. These findings deepen our understanding of suprasellar tumor biology and offer promising avenues for clinical exploration of effective chemotherapies.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"23 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841810","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}

{"title":"An influenza mRNA vaccine protects ferrets from lethal infection with highly pathogenic avian influenza A(H5N1) virus","authors":"Masato Hatta, Yasuko Hatta, Angela Choi, Jaber Hossain, Chenchen Feng, Matthew W. Keller, Jana M. Ritter, Ying Huang, Emma Fang, Elizabeth A. Pusch, Thomas Rowe, Juan A. De La Cruz, Monique C. Johnson, Jimma Liddell, Nannan Jiang, Daniel Stadlbauer, Li Liu, Arindam K. Bhattacharjee, Joseph R. Rouse, Michael Currier, Li Wang, Min Z. Levine, Marie K. Kirby, John Steel, Han Di, John R. Barnes, Carole Henry, C. Todd Davis, Raffael Nachbagauer, David E. Wentworth, Bin Zhou","doi":"10.1126/scitranslmed.ads1273","DOIUrl":"https://doi.org/10.1126/scitranslmed.ads1273","url":null,"abstract":"The global spread of the highly pathogenic avian influenza (HPAI) A(H5N1) virus poses a serious pandemic threat, necessitating the swift development of effective vaccines. The success of messenger RNA (mRNA) vaccine technology in the COVID-19 pandemic, marked by its rapid development and scalability, demonstrates its potential for addressing other infectious threats, such as HPAI A(H5N1). We therefore evaluated mRNA vaccine candidates targeting panzootic influenza A(H5) clade 2.3.4.4b viruses, which have been shown to infect a range of mammalian species, including most recently being detected in dairy cattle. Ferrets were immunized with mRNA vaccines encoding either hemagglutinin alone or hemagglutinin and neuraminidase, derived from a 2.3.4.4b prototype vaccine virus recommended by the World Health Organization. Kinetics of the immune responses, as well as protection against a lethal challenge dose of A(H5N1) virus, were assessed. Two doses of mRNA vaccination elicited robust neutralizing antibody titers against a 2022 avian isolate and a 2024 human isolate. Further, mRNA vaccination conferred protection from lethal challenge, whereas all unvaccinated ferrets succumbed to infection. It also reduced viral titers in the upper and lower respiratory tracts of infected ferrets. These results underscore the effectiveness of mRNA vaccines against HPAI A(H5N1), showcasing their potential as a vaccine platform for future influenza pandemics.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"82 6 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841782","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}

{"title":"Dextromethorphan inhibits collagen and collagen-like cargo secretion to ameliorate lung fibrosis","authors":"Muzamil M. Khan, George Galea, Juan Jung, Joanna Zukowska, David Lauer, Nadine Tuechler, Aliaksandr Halavatyi, Christian Tischer, Per Haberkant, Frank Stein, Ferris Jung, Jonathan J. M. Landry, Arif M. Khan, Viola Oorschot, Isabelle Becher, Beate Neumann, Thomas Muley, Hauke Winter, Julia Duerr, Marcus A Mall, Alessandro Grassi, Ernesto de la Cueva, Vladimir Benes, Janine Gote-Schniering, Mikhail Savitski, Rainer Pepperkok","doi":"10.1126/scitranslmed.adj3087","DOIUrl":"https://doi.org/10.1126/scitranslmed.adj3087","url":null,"abstract":"Excessive deposition of fibrillar collagen in the interstitial extracellular matrix (ECM) of human lung tissue causes fibrosis, which can ultimately lead to organ failure. Despite our understanding of the molecular mechanisms underlying the disease, no cure for pulmonary fibrosis has yet been found. We screened a drug library and found that dextromethorphan (DXM), a cough expectorant, reduced the amount of excess fibrillar collagen deposited in the ECM in cultured primary human lung fibroblasts, a bleomycin mouse model, and a cultured human precision-cut lung slice model of lung fibrosis. The reduced extracellular fibrillar collagen upon DXM treatment was due to reversible trafficking inhibition of collagen type I (COL1) in the endoplasmic reticulum (ER) in TANGO1- and HSP47-positive structures. Mass spectrometric analysis showed that DXM promoted hyperhydroxylation of proline and lysine residues on various collagens (COL1, COL3, COL4, COL5, COL7, and COL12) and latent transforming growth factor–β–binding protein (LTBP1 and LTBP2) peptides, coinciding with their secretion block. Additionally, proteome profiling of DXM-treated cells showed increased thermal stability of prolyl-hydroxylases P3H2, P3H3, P3H4, P4HA1, and P4HA2, suggesting a change in their activity. Transcriptome analysis of profibrotic stimulated primary human lung fibroblasts and human ex vivo lung slices after DXM treatment showed activation of an antifibrotic program through regulation of multiple pathways, including the MMP-ADAMTS axis, WNT signaling, and fibroblast-to-myofibroblast differentiation. Together, these data obtained from in vitro, in vivo, and ex vivo models of lung fibrogenesis show that DXM has the potential to limit fibrosis through inhibition of COL1 membrane trafficking in the ER.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841808","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}

{"title":"Striatal stimulation enhances cognitive control and evidence processing in rodents and humans","authors":"Adriano E. Reimer, Evan M. Dastin-van Rijn, Jaejoong Kim, Megan E. Mensinger, Elizabeth M. Sachse, Aaron Wald, Eric Hoskins, Kartikeya Singh, Abigail Alpers, Dawson Cooper, Meng-Chen Lo, Amanda Ribeiro de Oliveira, Gregory Simandl, Nathaniel Stephenson, Alik S. Widge","doi":"10.1126/scitranslmed.adp1723","DOIUrl":"https://doi.org/10.1126/scitranslmed.adp1723","url":null,"abstract":"Brain disorders, in particular mental disorders, might be effectively treated by direct electrical brain stimulation, but clinical progress requires understanding of therapeutic mechanisms. Animal models have not helped, because there are no direct animal models of mental illness. Here, we propose a potential path past this roadblock, by leveraging a common ingredient of most mental disorders: impaired cognitive control. We previously showed that deep brain stimulation (DBS) improves cognitive control in humans. We now reverse translate that result using a set-shifting task in rats. DBS-like stimulation of the midstriatum improved reaction times without affecting accuracy, mirroring our human findings. Impulsivity, motivation, locomotor, and learning effects were ruled out through companion tasks and model-based analyses. To identify the specific cognitive processes affected, we applied reinforcement learning drift-diffusion modeling. This approach revealed that DBS-like stimulation enhanced evidence accumulation rates and lowered decision thresholds, improving domain-general cognitive control. Reanalysis of prior human data showed that the same mechanism applies in humans. This reverse/forward translational model could have near-term implications for clinical DBS practice and future trial design.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"23 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841784","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}

{"title":"IFN-γ–producing T H 1 cells and dysfunctional regulatory T cells contribute to the pathogenesis of Sjögren’s disease","authors":"Yin-Hu Wang, Wenyi Li, Maxwell McDermott, Ga-Yeon Son, George Maiti, Fang Zhou, Anthony Y. Tao, Dimitrius Raphael, Andre L. Moreira, Boheng Shen, Martin Vaeth, Bettina Nadorp, Shukti Chakravarti, Rodrigo S. Lacruz, Stefan Feske","doi":"10.1126/scitranslmed.ado4856","DOIUrl":"https://doi.org/10.1126/scitranslmed.ado4856","url":null,"abstract":"Sjögren’s disease (SjD) is an autoimmune disorder characterized by progressive salivary and lacrimal gland dysfunction, inflammation, and destruction, as well as extraglandular manifestations. SjD is associated with autoreactive B and T cells, but its pathophysiology remains incompletely understood. Abnormalities in regulatory T (T <jats:sub>reg</jats:sub> ) cells occur in several autoimmune diseases, but their role in SjD is ambiguous. We had previously shown that the function and development of T <jats:sub>reg</jats:sub> cells depend on store-operated Ca <jats:sup>2+</jats:sup> entry (SOCE), which is mediated by ORAI1 Ca <jats:sup>2+</jats:sup> channels and stromal interaction protein 1 (STIM1) and STIM2. Here, we show that mice with a Foxp3 <jats:sup>+</jats:sup> T <jats:sub>reg</jats:sub> cell–specific deletion of <jats:italic>Stim1</jats:italic> and <jats:italic>Stim2</jats:italic> develop a phenotype that fulfills all classification criteria of human SjD. Mutant mice have salivary and lacrimal gland inflammation characterized by strong lymphocyte infiltration and transcriptional signatures dominated by T helper 1 (T <jats:sub>H</jats:sub> 1) and interferon (IFN) signaling. CD4 <jats:sup>+</jats:sup> T cells from mutant mice are sufficient to induce SjD-like disease in an IFN-γ–dependent manner. Inhibition of IFN signaling with the JAK1/2 inhibitor baricitinib alleviated CD4 <jats:sup>+</jats:sup> T cell–induced SjD in mice. These findings are consistent with the transcriptional profiles of CD4 <jats:sup>+</jats:sup> T cells from patients with SjD, which indicate enhanced T <jats:sub>H</jats:sub> 1 but reduced memory T <jats:sub>reg</jats:sub> cell function. Together, our study provides evidence for a critical role of dysfunctional T <jats:sub>reg</jats:sub> cells and IFN-γ–producing T <jats:sub>H</jats:sub> 1 cells in the pathogenesis of SjD.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"86 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841783","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}

{"title":"The pharmacological basis for nonpeptide agonism of the GLP-1 receptor by orforglipron","authors":"Kyle W. Sloop, Amy L. Cox, David B. Wainscott, Alex White, Brian A. Droz, Cynthia Stutsman, Aaron D. Showalter, Todd M. Suter, James D. Dunbar, Brandy M. Snider, Libbey S. O’Farrell, Natalie Hewitt, J. Craig Ruble, Leah R. Padgett, Eric M. Woerly, Jeffrey A. Peterson, Tamer Coskun, Zhaomin Liu, David E. Coutant, Minrong Ai, Paul J. Emmerson, Panjamaporn Sangwung, Francis S. Willard","doi":"10.1126/scitranslmed.adp5765","DOIUrl":"https://doi.org/10.1126/scitranslmed.adp5765","url":null,"abstract":"Orally bioavailable, synthetic nonpeptide agonists (NPAs) of the glucagon-like peptide-1 receptor (GLP-1R) may offer an effective, scalable pharmacotherapy to address the metabolic disease epidemic. One of the first molecules in the emerging class of GLP-1R NPAs is orforglipron, which is in clinical development for treating type 2 diabetes and obesity. Here, we characterized the pharmacological properties of orforglipron in comparison with peptide-based GLP-1R agonists and other NPAs. Competition binding experiments using either [ <jats:sup>125</jats:sup> I]GLP-1(7-36)NH <jats:sub>2</jats:sub> or [ <jats:sup>3</jats:sup> H]orforglipron indicated that orforglipron is a high-affinity [inhibition constant ( <jats:italic>K</jats:italic> <jats:sub>i</jats:sub> ) = 1 nM], selective ligand of the human GLP-1R. Signal transduction assays showed that orforglipron has low intrinsic efficacy for effector activation and negligible β-arrestin recruitment. To evaluate GLP-1R engagement in vivo, mice expressing the human GLP-1R were administered orforglipron and subjected to a glucose tolerance test. Predicted receptor occupancy was calculated using the receptor <jats:italic>K</jats:italic> <jats:sub>i</jats:sub> value of orforglipron and its unbound concentration in vivo that reduces hyperglycemia. These experiments revealed that low GLP-1R occupancy by orforglipron is sufficient to yield a full biological response. Moreover, in a model where CRISPR-Cas9 gene editing was used to sensitize the rat GLP-1R ( <jats:italic> Glp1r <jats:sup>S33W</jats:sup> </jats:italic> ) to GLP-1R NPAs, target engagement by orforglipron in the pancreas and brain was consistent with peptide-based GLP-1R agonists. Diet-induced obesity in <jats:italic> Glp1r <jats:sup>S33W</jats:sup> </jats:italic> rats enabled studies showing weight loss in animals orally administered orforglipron versus subcutaneous injection of GLP-1R agonist semaglutide. Furthermore, crossover studies indicated oral orforglipron can sustain efficacy initiated by parenteral semaglutide. The pharmacological properties of orforglipron may inform targeting of other peptide receptors with NPAs.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"19 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841786","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}

{"title":"Development of a fibrin-targeted theranostic for gastric cancer","authors":"Shadi A. Esfahani, Li Ma, Shriya Krishna, Hua Ma, Shvan J. Raheem, Sergey Shuvaev, Nicholas J. Rotile, Jonah Weigand-Whittier, Avery T. Boice, Nicholas Borges, Constantina A. Treaba, Caitlin Deffler, Himashinie Diyabalanage, Valerie Humblet, David E. Sosnovik, Umar Mahmood, Pedram Heidari, Angela Shih, Ciprian Catana, Matthew R. Strickland, Samuel J. Klempner, Peter Caravan","doi":"10.1126/scitranslmed.adn7218","DOIUrl":"https://doi.org/10.1126/scitranslmed.adn7218","url":null,"abstract":"Patients with advanced gastric cancer (GCa) have limited treatment options, and alternative treatment approaches are necessary to improve their clinical outcomes. Because fibrin is abundant in gastric tumors but not in healthy tissues, we hypothesized that fibrin could be used as a high-concentration depot for a high-energy beta-emitting cytotoxic radiopharmaceutical delivered to tumor cells. We showed that fibrin is present in 64 to 75% of primary gastric tumors and 50 to 100% of metastatic gastric adenocarcinoma cores. First-in-human <jats:sup>64</jats:sup> Cu-FBP8 fibrin–targeted positron emission tomography (PET) imaging in seven patients with gastric or gastroesophageal junction cancer showed high probe uptake in all target lesions with tumor-to-background (muscle) uptake ratios of 9.9 ± 6.6 in primary ( <jats:italic>n</jats:italic> = 7) and 11.2 ± 6.6 in metastatic ( <jats:italic>n</jats:italic> = 45) tumors. Using two mouse models of human GCa, one fibrin-high (SNU-16) and one fibrin-low (NCI-N87), we showed that PET imaging with a related fibrin-specific peptide, CM500, labeled with copper-64 ( <jats:sup>64</jats:sup> Cu-CM500) specifically bound to and precisely quantified tumor fibrin in both models. We then labeled the fibrin-specific peptide CM600 with yttrium-90 and showed that <jats:sup>90</jats:sup> Y-CM600 effectively decreased tumor growth in these mouse models. Mice carrying fibrin-high SNU-16 tumors experienced tumor growth inhibition and prolonged survival in response to either a single high dosage or fractionated lower dosage of <jats:sup>90</jats:sup> Y-CM600, whereas mice carrying fibrin-low NCI-N87 tumors experienced prolonged survival in response to a fractionated lower dosage of <jats:sup>90</jats:sup> Y-CM600. These results lay the foundation for a fibrin-targeted theranostic that may expand options for patients with advanced GCa.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"27 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809859","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}

{"title":"ABCG1 orchestrates adipose tissue macrophage plasticity and insulin resistance in obesity by rewiring saturated fatty acid pools","authors":"Veronica D. Dahik, Pukar KC, Clément Materne, Canelle Reydellet, Marie Lhomme, Céline Cruciani-Guglielmacci, Jessica Denom, Eric Bun, Maharajah Ponnaiah, Florence Deknuydt, Eric Frisdal, Lise M. Hardy, Hervé Durand, Isabelle Guillas, Philippe Lesnik, Ivan Gudelj, Gordan Lauc, Maryse Guérin, Anatol Kontush, Antoine Soprani, Christophe Magnan, Marc Diedisheim, Olivier Bluteau, Nicolas Venteclef, Wilfried Le Goff","doi":"10.1126/scitranslmed.adi6682","DOIUrl":"https://doi.org/10.1126/scitranslmed.adi6682","url":null,"abstract":"The mechanisms governing adipose tissue macrophage (ATM) metabolic adaptation during diet-induced obesity (DIO) are poorly understood. In obese adipose tissue, ATMs are exposed to lipid fluxes, which can influence the activation of specific inflammatory and metabolic programs and contribute to the development of obesity-associated insulin resistance and other metabolic disorders. In the present study, we demonstrate that the membrane ATP-binding cassette g1 (Abcg1) transporter controls the ATM functional response to fatty acids (FAs) carried by triglyceride-rich lipoproteins, which are abundant in high-energy diets. Mice genetically lacking Abcg1 in the myeloid lineage presented an ameliorated inflammatory status in adipose tissue and reduced insulin resistance. Abcg1-deficient ATMs exhibited a less inflammatory phenotype accompanied by a low bioenergetic profile and modified FA metabolism. A closer look at the ATM lipidome revealed a shift in the handling of FA pools, including a redirection of saturated FAs from membrane phospholipids to lipid droplets, leading to a reduction in membrane rigidity and neutralization of proinflammatory FAs. ATMs from human individuals with obesity presented the same reciprocal relationship between <jats:italic>ABCG1</jats:italic> expression and this inflammatory and metabolic status. Abolition of this protective, anti-inflammatory phenotype in Abcg1-deficient ATMs was achieved through restoration of lipoprotein lipase (Lpl) activity, thus delineating the importance of the Abcg1/Lpl axis in controlling ATM metabolic inflammation. Overall, our study identifies the rewiring of FA pools by Abcg1 as a major pathway orchestrating ATM plasticity and insulin resistance in DIO.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"90 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809856","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}

{"title":"Repurposing an epithelial sodium channel inhibitor as a therapy for murine and human skin inflammation","authors":"Mårten C. G. Winge, Mazen Nasrallah, Leandra V. Jackrazi, Konnie Q. Guo, Jessica M. Fuhriman, Rebecca Szafran, Muthukumar Ramanathan, Irina Gurevich, Ngon T. Nguyen, Zurab Siprashvili, Mohammed Inayathullah, Jayakumar Rajadas, Douglas F. Porter, Paul A. Khavari, Atul J. Butte, M. Peter Marinkovich","doi":"10.1126/scitranslmed.ade5915","DOIUrl":"https://doi.org/10.1126/scitranslmed.ade5915","url":null,"abstract":"Inflammatory skin disease is characterized by a pathologic interplay between skin cells and immunocytes and can result in disfiguring cutaneous lesions and systemic inflammation. Immunosuppression is commonly used to target the inflammatory component; however, these drugs are often expensive and associated with side effects. To identify previously unidentified targets, we carried out a nonbiased informatics screen to identify drug compounds with an inverse transcriptional signature to keratinocyte inflammatory signals. Using psoriasis, a prototypic inflammatory skin disease, as a model, we used pharmacologic, transcriptomic, and proteomic characterization to find that benzamil, the benzyl derivative of the US Food and Drug Administration–approved diuretic amiloride, effectively reversed keratinocyte-driven inflammatory signaling. Through three independent mouse models of skin inflammation (Rac1 <jats:sup>G12V</jats:sup> transgenic mice, topical imiquimod, and human skin xenografts from patients with psoriasis), we found that benzamil disrupted pathogenic interactions between the small GTPase Rac1 and its adaptor NCK1. This reduced STAT3 and NF-κB signaling and downstream cytokine production in keratinocytes. Genetic knockdown of sodium channels or pharmacological inhibition by benzamil prevented excess Rac1-NCK1 binding and limited proinflammatory signaling pathway activation in patient-derived keratinocytes without systemic immunosuppression. Both systemic and topical applications of benzamil were efficacious, suggesting that it may be a potential therapeutic avenue for treating skin inflammation.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"21 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809857","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}

{"title":"ATP citrate lyase drives vascular remodeling in systemic and pulmonary vascular diseases through metabolic and epigenetic changes","authors":"Yann Grobs, Charlotte Romanet, Sarah-Eve Lemay, Alice Bourgeois, Pierre Voisine, Charlie Theberge, Melanie Sauvaget, Sandra Breuils-Bonnet, Sandra Martineau, Reem El Kabbout, Chanil Valasarajan, Prakash Chelladurai, Andreanne Pelletier, Manon Mougin, Elizabeth Dumais, Jean Perron, Nicolas Flamand, François Potus, Steeve Provencher, Soni Savai Pullamsetti, Olivier Boucherat, Sebastien Bonnet","doi":"10.1126/scitranslmed.ado7824","DOIUrl":"https://doi.org/10.1126/scitranslmed.ado7824","url":null,"abstract":"ATP citrate lyase (ACLY), a crucial enzyme in de novo lipid synthesis and histone acetylation, plays a key role in regulating vascular smooth muscle cell (VSMC) proliferation and survival. We found that human coronary and pulmonary artery tissues had up-regulated ACLY expression during vascular remodeling in coronary artery disease and pulmonary arterial hypertension. Pharmacological and genetic inhibition of ACLY in human primary cultured VSMCs isolated from the coronary arteries of patients with coronary artery diseases and from the distal pulmonary arteries of patients with pulmonary arterial hypertension resulted in reduced cellular proliferation and migration and increased susceptibility to apoptosis. These cellular changes were linked to diminished glycolysis, reduced lipid synthesis, impairment in general control nonrepressed protein 5 (GCN5)–dependent histone acetylation and suppression of the transcription factor FOXM1. In vivo studies using a pharmacological inhibitor and VSMC-specific <jats:italic>Acly</jats:italic> knockout mice showed that ACLY inhibition alleviated vascular remodeling. ACLY inhibition alleviated remodeling in carotid injury and ligation models in rodents and attenuated pulmonary arterial hypertension in Sugen/hypoxia rat and mouse models. Moreover, ACLY inhibition showed improvements in vascular remodeling in human ex vivo models, which included cultured human coronary artery and saphenous vein rings as well as precision-cut lung slices. Our results propose ACLY as a novel therapeutic target for treating complex vascular diseases, offering promising avenues for future clinical intervention.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"23 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809860","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}